Home » Articles posted by DR ANTHONY MELVIN CRASTO Ph.D (Page 169)

Author Archives: DR ANTHONY MELVIN CRASTO Ph.D

Which External GMP Audit Reports may be used?

March 3, 2016 5:19 am / Leave a comment

We are often asked about the acceptance of third GMP audits at API manufacturers. The background for this is that more and more organisations offer such audits. Now, the question is what do you have to pay attention to?

http://www.gmp-compliance.org/enews_05167_Which-External-GMP-Audit-Reports-may-be-used_15159,15099,15274,15179,Z-QAMPP_n.html

It is essential to clarify who gave the order: has the audit been initiated from another pharmaceutical company? From the auditor himself/ herself or the organisation behind? Or from the API manufacturer?

Audits (and their reports) which have been initiated by the API manufacturers or their traders have to be viewed in a critical light. Also audits performed by the auditor – i.e. the audit organisation requires closer examination and analysis. Especially possible conflicts of interest have to be clarified.

At best, a contract audit is requested by one or several medicinal product manufacturers who buy themselves a product from the API manufacturer. If the API manufacturer is the customer, then the independence of the auditor has to be clearly demonstrated. In such a case, it is absolutely necessary to obtain a confirmation from the auditor in writing.

Acceptance, Accreditation and “Conflict of Interest”: what should you keep in mind?

A medicinal product manufacturer can basically perform an audit himself or let it perform by a so-called Third Party. Commonly, the medicinal product manufacturer assigns a consultant who has experience in the performance of audits. Yet, – here again – a few elements should be considered because the external auditor will be acting for the pharmaceutical company as if he were an own employee. The important thing here is to choose an auditor who knows the processes which have to be audited. If for example a biopharmaceutical API i.e. the manufacturer has to be audited, the auditor should have relevant experiences in biopharmaceutical processes. The auditor should also confirm that he/ she hasn’t been acting as a consultant in the area to be audited for at least the last 2 years. This should help to avoid eventual conflicts of interest. For this, a documented confirmation is helpful but often forgotten. The qualification of the GMP auditor is an essential aspect. You should require a CV of the auditor (education, work experience, audit history and audit trainings) and qualify him/ her. The execution by an accredited body doesn’t play any role. Accreditation is of no significance in pharmaceutical law.

Purchasing audit reports later:

More and more audit reports are available for purchase. In principle there is no objection to the purchase of an audit report. However, the same rules apply as those concerning the initiation of an audit. In any case, the auditors must be independent. This must also be confirmed in writing. You should check whether the audited products are the products which are also relevant for your supplier qualification. The audit of another product is quite unhelpful. The audit report should contain concrete information about the product-specific processes and procedures. This is the only way for the customer to decide on the basis of the available information whether the supplier can be suitably qualified.

Important: an audit report is only a part of the supplier qualification!

Audit reports are the main focus of interest. However, it is often forgotten that audit reports are only a part of the supplier qualification but a central one. Audit reports contain a description of the GMP situation on the audit day(s). The real assessment of the results is done by the customer – for example by a quality unit or the Qualified Person. Beside the audit report, further data should be consulted like the experiences with the supplier and the assessment of the products delivered. How valuable is an audit report with a good GMP rating when repeated deviations from the specifications are observed in the course of withdrawal of samples? The assessment of further information like for example inspection reports of the FDA which are generally accessible through the Freedom of Information Act, or EDQM’s database with the list of CEPs of API manufacturers which have been withdrawn because of GMP deficiencies. All these data should flow into a risk analysis to be used to qualify (or not) a supplier.

///////External GMP, Audit Reports, API manufacturers

Indacaterol

March 2, 2016 7:42 am / Leave a comment

Indacaterol

QAB-149

CAS 753498-25-8 MALEATE
CAS 312753-06-3 (free base)

QAB-149 maleate
QAB-149-AFA

5-[2-(5,6-Diethylindan-2-ylamino)-1(R)-hydroxyethyl]-8-hydroxyquinolin-2(1H)-one maleate

R)-5-[2-[(5, 6-Diethyl-2, 3-dihydro-lH- inden-2-yl) amino]- 1 -hydroxy ethyl]-8-hydroxyquinolin-2(lH)-one, is an ultra long acting beta-adrenoceptor agonist developed by Novartis

Indacaterol (C ₂₄ H ₂₈ N ₂ O ₃ , M _r = 392.49 g / mol) is chiral and is in the drug as R enantiomer and indacaterol ago. It is a derivative of 8-hydroxyquinoline and 2-aminoindan and has a certain structural similarity with other beta2-agonists , for example salbutamol . Indacaterol is lipophilic, which is a prerequisite for its long duration of action.

Indacaterol (INN) is an ultra-long-acting beta-adrenoceptor agonist^[1] developed by Novartis. It was approved by the European Medicines Agency (EMA) under the trade name Onbrez Breezhaler on November 30, 2009,^[2] and by the United States Food and Drug Administration (FDA), under the trade name Arcapta Neohaler, on July 1, 2011.^[3] It needs to be taken only once a day,^[4]unlike the related drugs formoterol and salmeterol. It is licensed only for the treatment of chronic obstructive pulmonary disease(COPD) (long-term data in patients with asthma are thus far lacking). It is delivered as an aerosol formulation through a dry powder inhaler.

Indacaterol maleate (QAB-149) is a long-acting inhaled beta2-adrenoceptor agonist. In 2008, it was filed for approval in the U.S. and the E.U. by Novartis for the treatment of chronic obstructive pulmonary disease (COPD).

In 2009, approval was granted by the EMEA and a complete response letter was assigned by the FDA.

In 2010, Novartis resubmitted an NDA seeking approval for the long-term maintenance bronchodilator treatment of airflow obstruction in adult patients with COPD, including bronchitis and/or emphysema.

In 2011, the FDA approved this indication and in 2012 the product was launched in the U.S.

The product was approved and launched in Japan in 2011 for the treatment of COPD.

In 2010, indacaterol was first launched by Novartis in Denmark and Ireland.

Clinical trials

A Phase III trial published in March 2010 examined the efficacy and safety of indacaterol in COPD patients.^[5] This study, conducted in the U.S., New Zealand, and Belgium, compared indacaterol dry-powder inhaler to placebo in 416 COPD patients, mostly moderate to severe (mean FEV₁ of 1.5 L). Indacaterol produced statistically improved FEV₁ (both trough and AUC) and decreased use of rescue medication compared to placebo, but with safety and tolerability similar to those of placebo.

A year-long, placebo-controlled trial published in July 2010 suggests indacaterol may be significantly more effective than twice-daily formoterol in improving FEV₁. There were some reductions in the need for rescue medication, but these were not significantly different; nor was there any difference in the rate of exacerbation between the 2 active treatments.^[6]

A study published in October, 2011 in the European Respiratory Journal compared indacaterol with tiotropium over the study period of 12 weeks. The study found no statistical difference between the effects of the two drugs on FEV₁. Indacaterol yielded greater improvements in transition dyspnoea index (TDI) total score and St. George’s Respiratory Questionnaire (SGRQ) total score.^[7]

A recent Cochrane Library meta-analysis indicates that the clinical benefit in lung function from indacaterol is at least as good as that seen with twice-daily long-acting beta2-agonists. ^[8]

SYNTHESIS

Its synthesis is divided into two parts, a primary amine and a chiral epoxide.
Primary amine starting at 1,2 – diethyl benzene (JMC2010, 3676), two FC reaction into the ring post and then converted into oxime reduction, get four . Compound 5 obtained by Fries rearrangement 6 , phenolic hydroxyl group protected, chlorinated 7 , CBS asymmetric reduction to give the chiral secondary alcohols 8 , ring closure under alkaline conditions to obtain an epoxy compound 9 , a primary amine 4 on epoxy, to the benzyl protecting, salt to be Indacaterol Maleate.

PATENT

http://www.google.com/patents/WO2013132514A2?cl=en

Indacaterol chemically known as (R)-5-[2-[(5, 6-Diethyl-2, 3-dihydro-lH- inden-2-yl) amino]- 1 -hydroxy ethyl]-8-hydroxyquinolin-2(lH)-one, is an ultra long acting beta-adrenoceptor agonist developed by Novartis and has the following structural formula:

Indacaterol maleate is a long acting inhaled β2- agonist. Indacaterol maleate is marketed under the trade name Arcapta Neohaler in US and Onbrez in Europe.

Indacaterol maleate was disclosed in US6878721 by Novartis. The process for Indacaterol is depicted below.

Indacaterol Maleate

VII

In the above process for preparing Indacaterol maleate involves the step of reacting 8 substituted oxy-5-(R)-oxiranyl-(lH)-quinolin-2-one (III) with 2-amino- (5,6-diethyl)-indan (IV) to form a intermediate 5-[(R)-2-(5,6-diethyl-indan-2- ylamino)-l-hydroxy-ethyl]-8-substituted oxy-(lH)-quinolin-2-one (V). This epoxide ring opening is not region specific thereby along with 5-[(R)-2-(5,6- diethyl-indan-2-ylamino)- 1 -hydroxy-ethyl]-8-substituted oxy-( 1 H)-quinol intone, below mentioned products are being produced as impurities.

The above reaction mixture contains only about 60% of desired compound i.e. 5-[(R)-2-(5, 6-diethyl-indan-2-ylamino)-l-hydroxy-ethyl]-8-substituted oxy- (lH)-quinolin-2-one. The purification of this intermediate is done using silica gel chromatography which is tedious and requires large amounts of solvents, not suitable for industrial synthesis.

To overcome the above draw backs of the process for preparing Indacaterol, the patent US7534890 discloses a process that avoids the column purification by the formation of acid addition salts of intermediate (formula – IV).

Therefore, there exists a need to develop a novel process for the preparation of indacaterol maleate.

Examples

Example -1 Preparation of compound of IIIA, wherein R is Benzyl

The compound of formula IA (25 gm) was dissolved in DMSO (75 ml) and stirred for 15 min, then compound of formula IIA (0.09 mol) was added to the reaction mixture at 25 – 30°C. The triethylamine (0. 1 mol) was added to above contents slowly, following by added sodium iodide (0.03 mol) at same temperature and stirred the reaction mixture for 3 hours at same temperature. The purified water (250 ml) was added to the reaction mixture and stirred for 1.0 hour. The contents were filtered and washed with water. The wet material was dissolved in methanol (250 ml) and stirred for 30 minutes, and then water was added. The contents were stirred for lhour at 25 – 30°C and filtered to obtain the title compound. Yield: 76%

Example -2 Preparation of compound of IIIA, wherein R is Benzyl

The compound of formula IA (25 gm) was dissolved in DMSO (75 ml) and stirred for 15 min, then compound of formula IIA (0.09 mol) was added to the reaction mixture at 25 – 30°C. Potassium carbonate (0. 1 mol) was added to above contents slowly, following by added sodium iodide (0.03 mol) at same temperature and stirred the reaction mixture for 3 hours at same temperature. The purified water (250 ml) was added to the reaction mixture and stirred for 1.0 hour. The contents were filtered and washed with water. The wet material was dissolved in methanol (250 ml) and stirred for 30 minutes, and then water was added. The contents were stirred for lhour at 25 – 30 °C and filtered to obtain the title compound. Yield: 82%

Exam le -3 Preparation of compound of IIIA, wherein R is Benzyl

The compound of formula IA (25 gm) was dissolved in DMSO (75 ml) and stirred for 15 min, then compound of formula IIA (0.09 mol) was added to the reaction mixture at 25 – 30°C, then Sodium iodide (0.03 mol) was added to the reaction mixture at same temperature and stirred the reaction mixture for 3 hours at same temperature. The purified water (250 ml) was added to the reaction mixture and stirred for 1.0 hour. The contents were filtered and washed with water. The wet material was dissolved in methanol (250 ml) and stirred for 30 minutes, and then water was added. The contents were stirred for lho^‘ur at 25 – 30 °C and filtered to obtain the title compound. Yield: 84%

Exam le -4 Preparation of compound of IVA, wherein R is Benzyl

The Borane-dimethyl sulfide (0.11 mol) was added at 0-5^°C, followed by addition of R – (2)-Methyl CBS (0.01 mol) and stirred the contents for 10 minutes at same temperature. The compound of example-1 (20 gm) was dissolved in methylene chloride (200 ml) at same temperature and stirred the reaction mixture for 1.0 hour. The methanol was added to the reaction mixture followed by addition of 5% hydrogen peroxide (0.01 mol) at 0-5 ^°C and stirred the contents for 15 minutes at same temperature, gradually increased the temperature to 20- 30°C. The 6. ON sulfuric acid (10 ml) solution was added to the reaction mixture and stirred for 15 minutes.The layers were separated. The separated organic layer was washed with 2. ON sulfuric acid solution followed by washings with water, then distilled and dissolved in ethyl acetate. The contents were stirred for 1.0 hour, filtered and dried at 60^°C. Yield: 85%; E.e: > 95%.

Example -5 Preparation of compound of formula VA (Indacaterol)

The compound of example-4 (10 gm) was dissolved in methanol (100 ml), followed by addition of acetic acid (50 ml) to the reaction mixture. The 5% Pd/C was added to the reaction mixture and applied hydrogen pressure 3-4 Kg/cm³‘ and then the contents were stirred for 4.0 hours at 25-30°C, filtered and distilled. The residue was dissolved in ethyl acetate, stirred for 10 min and distilled to obtain the compound. Yield: 79%

Example -6 Preparation of Indacaterol Maleate

To a methanolic solution of Indacaterol, maleic acid (0.9 mol) in methanol was slowly added at 25 -30°C and stirred the isolated compound for 2.0 hours at same temperature. The reaction mass was cooled to 0 -10°C and maintained for 2.0 hrs at same temperature. The contents were filtered, washed with methanol and dried at 60 -65 °C. Yield: 93%; E.e: >99%.

Example -7 Preparation of compound of formula IXA, wherein R and Rl is benzyl

The (Bromo compound) of formula I (25 gm) was dissolved in DMF (150 ml) and stirred the contents for 15 min. The 5,6-Diethyl indane N-benzyl amine (0.9 mol) was added to the above mixture at 25 -30°C, followed by the slow addition of triethylamine, then the reaction mixture was stirred for 5.0 min. The sodium iodide (0.01 mol) was added to the reaction mixture at same temperature and stirred for 3 hours at same temperature. The purified water was added to the reaction mixture, and then the contents were filtered and washed with water. The wet compound was dissolved in methanol then water was added to the contents and stirred for lhour at 25 -30 °C. The contents were filtered and dried the compound at 60^°C. Yield: 70%.

Example -8 Preparation of compound of formula XA, wherein R and Rl is benzyl

A mixture of Borane-dimethyl sulfide (0.11 mol), R-(2)-Methyl CBS (0.01 mol) and methylene chloride was stirred for 10 minutes at 0-5 C. The compound of example-7 (20 gm) was dissolved in methylene chloride (200 ml) and was added to the reaction mixture at same temperature. The reaction mixture was stirred for 1.0 hour. The methanol was added to the reaction mixture followed by addition of 5% hydrogen peroxide (0.01 mol) at 0-5 C. Stirred the contents for 15 minutes at same temperature, gradually increased the temperature to 20-30°C. The 6. ON sulfuric acid (10 ml) solution was added to the reaction mixture and stirred for 5minutes.The layers were separated. The organic layer was washed with 2. ON sulfuric acid solution followed by washing with water. The organic layer was distilled and dissolved in ethyl acetate. Stirred the contents for 1.0 hour and filtered the compound. The compound was dried at 60^°C. Yield: 80%; Purity E.e: > 95%.

Example -9 Preparation of compound of formula VA (Indacaterol)

The compound of example-8 (10 gm) was dissolved in methanol (100 ml), followed by addition of acetic acid (50 ml) to the reaction mixture. Then 5% Pd/C was added to the reaction mixture and applied hydrogen pressure 3-4 Kg/cm³ The content was stirred for 4.0 hours at 25-30°C, filtered and the filtrate was distilled. The residue was dissolved in ethyl acetate (50 ml), stirred the contents for 10 min and distilled to obtain the compound. Yield: 80%

PATENT

http://www.google.com/patents/WO2014139485A1?cl=en

WO 0075114 Al is the first to describe preparation of indacaterol ((i?)-2) (Scheme 1).

Scheme 1 The synthesis is a follow-up of the previously published method for the preparation of 8- benzyloxy-5-(i?)-oxiranyl-(lH)-quinolin-2-one, published in WO 9525104 Al.This synthesis of indacaterol ((i?)-2) was further modified un WO 04076422 Al, WO 04087668 Al and WO 05123684 A2 to be better applicable for the industrial production. A weak point of the above mentioned synthesis is the use of the expensive benzyl trichloromethyl dichloroiodate as the chlorination agent in the first step. A considerable weak point of the above mentioned synthesis is the formation of undesired side products during the reaction of 8-benzyloxy-5-(R)- oxiranyl-(lH)-quinolin-2-one with 2-amino-5,6-diethylindane (Scheme 2).

Scheme 2

Crude 5-[(i?)-2-(5,6-diethyl-indan-2-ylamino)-l-hydroxyethyl]-8-benzyloxy-(lH)-quinolin-2- one ((i?)-l) can be purified from these undesired side products by conversion to the benzoate, which is then re-crystallized, reduced with hydrogen, converted to indacaterol maleinate, which is finally re-crystallized. According to WO 04076422 Al, WO 04087668 Al and WO 05123684 A2, the yield of 5-[(i?)-2-(5,6-diethyl-indan-2-ylamino)- 1 -hydroxyethyl]-8- benzyloxy-(lH)-quinolin-2-one ((i?)-l) benzoate from 8-benzyloxy-5-(i?)-oxiranyl-(lH)- quinolin-2-one is only 67%.

Scheme 3.

The starting 8-benzyloxy-5-(2,2-dihydroxyacetyl)-lH-quinolin-2-one and 2-amino-5,6- diethylindane were prepared according to US 2004167167 Al and F. Baur et al. J. Med.

Chem. 2010, 53, 3675-3684. Example 1. Preparation of 5-[2-(5,6-diethyI ndan-2-yIamino)-l-hydroxyethyl]-8- benzyloxy-(lH)-quinoIin-2-one (1)

A mixture of 8-benzyloxy-5-(2,2-dihydroxyacetyl)-lH-quinolin-2-one (1,15 g), 2-amino-5,6- diethylindane (0.83 g) and dimethyl sulfoxide (5 ml) was stirred at 20°C for 1 h. The resulting suspension was cooled down to 0°C and methanol (5 ml) was added at this temperature. Finely triturated NaB¾ (0.39 g) was added at 0°C and the resulting clear solution was stirred at 20°C for 16 hours. Water (20 ml) was added to the mixture and the mixture was stirred at 20°C for 6 h. The product was filtered off, washed with water and air-dried. The yield was 1.68 g (98%) of beige powder.

Example 2. Preparation of 5- [2-(5,6-diethyl-indan-2-yIamino)-l -hydrox ethyl] -8- benzyloxy-(lH)-quinolin-2-one (1) A mixture of 8-benzyloxy-5-(2,2-dihydroxyacetyl)-lH-quinolin-2-one (1.95 g), 2-amino-5,6- diethylindane (1.25 g), dimethyl sulfoxide (8 ml) and acetic acid (0.05 ml) was stirred at 20°C for 2 h. The resulting suspension was cooled down to 0°C and methanol (8 ml) was added at this temperature. Finely triturated NaBH (1.13 g) was added at 0°C and the produced clear solution was stirred at 20°C for 3 h. Water (32 ml) was added to the mixture and the mixture was stirred at 20°C for 16 h. The product was filtered off, washed with water and air-dried. The yield was 2.75 g (95%) of beige powder.

Example 3. Preparation of 5-[2-(5,6-diethyI-indan-2-ylamino)-l-hydroxyethyI]-8- benzyloxy-(lH)-quinolin-2-one (1)

A mixture of 8-benzyloxy-5-(2,2-dihydroxyacetyl)-lH-quinolin-2-one (115 mg), 2-amino-5,6- diethylindane (83 mg) and dimethyl acetamide (0.5 ml) was stirred at 20°C for 1 h. The resulting suspension was cooled down to 0°C and methanol (0.5 ml) was added at this temperature. Finely triturated NaBHU (39 mg) was added at 0°C and the obtained clear solution was stirred at 20°C for 16 h. Water (2 ml) was added to the mixture and the mixture was stirred at 20°C for 6 h. The product was filtered off, washed with water and air-dried. The yield was 160 mg (94%) of beige powder. Example 4. Preparation of 5-[2-(5,6-diethyI-indan-2-ylamino)-l-hydroxyethyI]-8- benzyloxy-(lH)-quinoLm-2-one (1)

A mixture of 8-benzyloxy-5-(2,2-dihydroxyacetyl)-lH-quinolin-2-one (115 mg), 2-amino-5,6- diethylindane (83 mg) and dichloromethane (2 ml) was stirred at 20°C for 2 h. Finely triturated NaBH(OAc)₃ (250 mg) was added at 20°C. The resulting mixture was stirred at 20°C for 16 h and then evaporated until dry. Water (2 ml) was added to the evaporation product and the mixture was stirred at 20°C for 6 h. The product was filtered off, washed with water and air-dried. The yield was 164 mg (96%) of beige powder.

Example 5. Preparation of 5-[2-(5,6-diethyl-indan-2-ylamino)-l-hydroxyethyl]-8- benzyloxy-(li?)-quinolin-2-one (1)

A mixture of 8-benzyloxy-5-(2,2-dihydroxyacetyl)-lH-quinolin-2-one (33 mg), 2-amino-5,6- diethylindane (21 mg) and tetrahydrofuran (1 ml) was stirred at 20°C for 1 h. The resulting suspension was cooled down to 0°C and 1 M BH₃ in tetrahydrofuran (0.5 ml) was added at this temperature. The produced clear solution was stirred at 20°C for 16 h and then evaporated until dry. Water (1 ml) was added to the evaporation product and the mixture was stirred at 20°C for 6 h. The product was filtered off, washed with water and air-dried. The yield was 48 mg (99%) of beige powder.

Example 6. Preparation of 5-[2-(5,6-diethyl-indan-2-ylamino)-l-hydroxyethyl]-8- hydroxy-(l/Z)-quinolin-2-one (2) A mixture of 5-[2-(5,6-diethyl-indan-2-ylamino)- 1 -hydroxyethyl]-8-benzyloxy-(lH)-quinolin- 2-one (1) (1.21 g), ethanol (100 ml) and 5 % Pd / C (80 mg) was stirred in a hydrogen atmosphere at 20°C at the pressure of 101 kPa for 2 h. A TLC analysis of the mixture showed the pure reactant, therefore the mixture was filtered and fresh 5% Pd / C (80 mg) was added to the filtrate. The mixture was stirred in a hydrogen atmosphere at 20°C at the pressure of 101 kPa for 2 h. A TLC analysis of the mixture showed the reactant accompanied by a small amount of the product, therefore the mixture was filtered and fresh 5 % Pd / C (80 mg) was again added to the filtrate. The mixture was stirred under a hydrogen atmosphere at 40°C at the pressure of 101 kPa for 4 h. A TLC analysis of the mixture showed the pure product, therefore the mixture was hot filtered and the residue on the filter was extensively washed with hot ethanol. The filtrate was evaporated in an evaporator at a reduced pressure. The yield was 0.97 g (99%) of yellow powder. Example 7. Preparation 5-[2-(5,6-diethyl-indan-2-ylamino)-l-hydroxyethyl]-8-hydroxy- (lfl)-quinoIin-2-one (2)

A mixture of 5-[2-(5,6-diemyl-indan-2-ylammo)-l-hydroxyethyl]-8-benzyloxy-(lH)-quinolin- 2-one (1) (1,21 g), ethanol (100 ml) and Raney nickel (1 g) was stirred at 20°C for 2 h. The mixture was filtered and 5% Pd / C (0.1 g) was added to the filtrate. The mixture was stirred under a hydrogen atmosphere at 40°C at the pressure of 101 kPa at 40°C. A TLC analysis of the mixture showed the pure product, therefore the mixture was hot filtered and the residue on the filter was extensively washed with hot ethanol. The filtrate was evaporated in an evaporator at a reduced pressure. The yield was 0.96 g (98%) of yellow powder.

Example 8. Preparation of indacaterol ((R)-2)

Indacaterol ((i?)-2) was resolved from Z 5-[2-(5,6-diethyl-indan-2-ylamino)-l-hydroxyethyl]- 8-hydroxy-(lH)-quinolin-2-one (2) (0.90 g) by means of preparative HPLC. Conditions of the resolution: UV detection at 260 nm, column length 500 mm, column internal diameter 50 mm, stationary phase Chiralcel OJ (20 μηι), temperature 25°C, flow rate 120 ml/min, mobile phase A: 500 ml of hexane + 1 ml triethylamine, mobile phase B: ethanol, isocratic elution 82% A + 18% B. The fractions containing indacaterol ((R)-2) were evaporated in an evaporator at a reduced pressure. The yield was 0.44 g (49%) of white powder. HPLC enantiomeric purity 99.0% ee.

Example 9. Preparation of 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-l-hydroxyethyl]-8- benzyloxy-(lH)-quinolin-2-one ((R)-l) 5-[(i?)-2-(5,6-diethyl-indan-2-ylamino)-l-hydroxyethyl]-8-benzyloxy-(lH)-quinolin-2-one ((R)-l) was resolved from 5-[2-(5,6-diethyl-indan-2-ylamino)-l-hydroxyethyl]-8-benzyloxy- (lH)-quinolin-2-one (1) (1.00 g) by means of preparative HPLC. Conditions of the resolution: UV detection at 260 nm, column length 500 mm, column internal diameter 50 mm, stationary phase Chiralcel AS-V (20 μηι), temperature 25°C, flow rate 120 ml/min, mobile phase A: phosphate buffer (1.15 g of NH₄H₂P0₄, dissolved in 1000 ml of water, adjusted to pH 6.0 with 25% aqueous NH₃), mobile phase B: acetonitrile, isocratic elution 20% A + 80% B. The fractions containing 5-[(i?)-2-(5,6-diethyl-indan-2-ylamino)-l -hydroxyethyl]-8-benzyloxy- (lH)-quinolin-2-one ((R)-l) were evaporated in an evaporator at a reduced pressure to the volume of about 50 ml. 25% aqueous NH₃ was added dropwise to the resulting suspension up to pH 8-9 and the product was extracted with ethyl acetate. The combined extracts were dried with Na₂S0₄ and evaporated in an evaporator at a reduced pressure. The yield was 0.48 g (48%) of white powder. HPLC enantiomeric purity 99.2% ee.

Example 10. Preparation of indacaterol ((R)-2)

A mixture of 5-[(i-)-2-(5,6-diethyl-indan-2-ylamino)-l-hydroxyethyl]-8-benzyloxy-(lH)- quinolin-2-one ((R)-l) (0.42 g, HPLC enantiomeric purity of 99.2% ee), ethanol (50 ml) and Raney nickel (0.5 g) was stirred at 20°C for 2 h. The mixture was filtered and 5% Pd / C (0.05 g) was added to the filtrate. The mixture was stirred under a hydrogen atmosphere at 40°C at the pressure of 101 kPa for 4 h. A TLC analysis of the mixture showed the pure product, therefore the mixture was hot filtered and the residue on the filter was extensively washed with hot ethanol. The filtrate was evaporated in an evaporator at a reduced pressure. The yield was 0.33 g (97%) of white powder. HPLC enantiomeric purity 99.0% ee.

PATENT

http://www.google.com/patents/WO2014044566A1?cl=en

The compound 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-l-hydroxyethyl]-8- hydroxy-(lH)-quinolin-2-one, which is known as Indacaterol (INN), and its corresponding salts are beta-selective adrenoceptor agonists with a potent bronchodilating activity. Indacaterol is especially useful for the treatment of asthma and chronic obstructive pulmonary disease (COPD) and is sold commercially as the maleate salt. WO 00/75114 and WO 2004/076422 describe the preparation of Indacaterol for the first time through the process:

regioisomer impurity

Puri

Dep

Overall

The condensation between the indanolamine and the quinolone epoxide leads to the desired product but always with the presence of a significant amount of impurities, the most significant being the dimer impurity, which is the

consequence of a second addition of the product initially obtained with another quinolone epoxide, as well as the formation of another isomer which is the result of the addition of the indanolamine to the secondary carbon of the epoxide.

In addition, the reaction conditions to achieve the opening of the epoxide require high energies (ex. 21 of WO 00/75114) with temperatures of 110 °C or more for several hours, which favours the appearance of impurities.

WO 2004/076422 discloses the purification of the reaction mixture by the initial formation of a salt with an acid, such as tartaric acid or benzoic acid,

hydrogenation and final formation of the maleate salt. However, the yield achieved by the end of the process is only 49% overall.

It has been found that impurities of tartrate and benzoate salts can exist in the final product as a result of displacing the tartrate or benzoate with maleate without prior neutralization to Indacaterol base. In addition, WO 2004/076422 discloses that proceeding via the free base of Indacaterol is not viable due to its instability in organic solvents. WO 00/75114 does disclose a method proceeding via the Indacaterol free base, but it is not isolated in solid form.

WO 2004/076422 furthermore discloses the method for obtaining the quinolone epoxide from the corresponding a-haloacetyl compound by reduction in the presence of a chiral catalyst, such as an oxazaborolidine compound, by proceeding via the a-halohydroxy compound.

Documents WO 2007/124898 and WO 2004/013578 disclose 8-(benzyloxy)-5- [(lR)-2-bromo-l-{[tert-butyl(dimethyl)silyl]oxy}ethyl]quinolin-2(lH)-one and 8- (benzyloxy)-5-[(lR)-2-bromo-l-{tetrahydro-2H-pyran-2-yl-oxy}ethyl]quinolin- 2(lH)-one, respectively. Said documents are however not concerned with the preparation of Indacaterol. There exists, therefore, the need to develop an improved process for obtaining Indacaterol and salts thereof, which overcomes some or all of the problems associated with known methods from the state of the art. More particularly, there exists the need for a process for obtaining Indacaterol and pharmaceutically acceptable salts thereof, which results in a higher yield and/or having fewer impurities in the form of the dimer and regioisomers impurities and/or salts other than the desired pharmaceutically acceptable salt.

Examples

Example 1 – protecting the ot-halohydroxy compound of formula VI

A flask is charged with 5 ml of tetrahydrofuran (THF) and 5 ml of toluene, p- toluene sulfonic acid (0,15 mmol) and molecular sieves are added with stirring for 30 minutes. 6 mmol of butyl-vinylether and 3 mmol of 8-(phenylmethoxy)-5-((R)- 2-bromo-l-hydroxy-ethyl)-(lH)-quinolin-2-one are added. The mixture is agitated at 20/25° C until completion of the reaction, followed by filtration and distillation of the filtrate to remove the solvent. The product is obtained in quantitative yield as an oil consisting of 50% of each of the diastereomers.

^-NMR (DMSO-c/6, δ), mixture 50/50 of diastereomers: 0.61 and 0.82 (3H, t, J=7.2 Hz, CHs-Pr-O), 1.12 and 1.22 (3H, d, J=5.6 Hz, acetalic CH₃), 0.90-1.40 (4H, m, CH₂ + CH₂), 3.20-3.80 (4H, m, CH₂-OAr + CH₂-Br), 4.51 and 4.82 (1H, q, J = 5.6 Hz, acetalic CH), 5.18 and 5.24 (1H, dd, J=4.0, 8.0 Hz, CH-O-acetal), 6.56 and 6.58 (1H, d, J = 10.0 Hz, H4), 7.00-7.57 (7H, m), 8.17 and 8.23 (1H, d, J = 10.0 Hz, H3), 10.71 (1H, s, NH)

¹³C-NMR (DMSO-c/6, δ), mixture 50/50 of diastereoisomers: 13.5 and 13.7 CH₃), 18.5 and 18.8 (CH₂), 19.9 and 20.0 (acetalic CH₃), 30.9 and 31.4 (CH₂), 36.8 and 37.3 (CH₂), 63.7 and 64.2 (CH₂-Br), 69.8 and 69.9 (CH₂-OAr), 73.8 and 75.1 (CH- O), 97.5 and 100.4 (acetalic CH), 111.8 (CH), 116.9 and 117.2 (C), 121.2 and 122.4 (CH), 122.3 and 122.6 (CH), 127.7 and 127.8 (C), 127.8 and 127.9 (CH), 128.2 and 128.3 (CH), 128.8 and 129.1 (C), 129.4 and 129.6 (C), 136.1 and 136.5 (CH), 136.5 and 136.6 (C), 144.0 and 144.2 (C), 160.7 and 160.8 (C=0). Example 2 – protecting the ot-halohydroxy compound of formula VI

Pivaloyl chloride (0.72 g) is added to a stirred mixture of 8-(phenylmethoxy)-5- 5 ((R)-2-chloro-l-hydroxy-ethyl)-(lH)-quinolin-2-one (0.74 g), dichloromethane (15 ml) and 4-dimethylaminopyridine (0.89 g) at 20/25° C, and the reaction is stirred until all the starting material disappeared . Water (22 ml) is added and the phases are separated.

10 The organic phase is washed with 1 M HCI (22 ml) and then with water (22 ml).

The solvent is removed and the residue is crystallized from acetone to obtain 0.82 g of the product.

^-NMR (DMSO-c/6, δ) : 1.13 (9H, s, CH₃), 3.92 (1H, dd, J= 4.0, 12.0 Hz, CH₂-Br), 15 4.00 (1H, dd, J= 8.4, 12.0 Hz, CH₂-CI), 5.28 (2H, s, Ph-CH₂-0), 6.25 (1H, dd, J = 4.0, 8.4 Hz, CH-OPiv), 6.59 (1H, d, J= 10.0 Hz, H4), 7.15 (1H, d, J= 8.4 Hz, H6), 7.20 (1H, d, J= 8.4 Hz, H7), 7.27-7.30 (1H, m, Ph), 7.33-7.37 (2H, m, Ph), 7.54- 7.56 (2H, m, Ph), 8.18 (1H, d, J= 10.0 Hz, H3), 10.77 (1H, s, NH).

20 ¹³C-NMR (DMSO-c/6, δ) : 26.7 (3 x CH₃), 38.3 (C), 46.4 (CH₂-CI), 69.8 (CH₂-Ph), 71.3 (CH-OPiv), 111.9 (CH), 116.8 (C), 120.5 (CH), 122.9(CH), 126.0 (C), 127.8 (2 x CH), 127.9 (CH), 128.3 (2 x CH), 129.5 (C), 136.0 (C), 136.5 (CH), 144.5 (C), 160.7 (CON), 176.2 (COO). Example 3 – preparation of the compound of formula IV

A flask is charged with 2.5 ml of THF and 2.5 ml of toluene, p-toluene sulfonic 5 acid (5 mg) and molecular sieves (0.2 g) are added with stirring for 30 minutes.

1.5 ml of butyl-vinylether and 2 g of 8-(phenylmethoxy)-5-((R)-2-bromo-l- hydroxy-ethyl)-(lH)-quinolin-2-one are added . The mixture is agitated at 20/25° C until completion of the reaction. 0.015 ml of diisopropylethyl amine is added, the mixture is filtered, and the solvent is distilled off.

The residue is dissolved in 6 ml of dimethylformamide (DMF), 1.9 ml of

diisoproypylethyl amine, 1.2 g sodium iodide, and 1.5 g of 2-amino-5,6- diethylindane are added and the mixture is heated to 100° C. After completion of the reaction the mixture is cooled to 20/25° C, 0.4 ml of concentrated hydrochloric 15 acid and 0.4 ml of water are added, and the mixture is stirred for 30 minutes.

HPLC analysis shows the expected product with a purity of 75% and being free from the dimer and regioisomer impurities.

20 20 ml of water, 20 ml of methylene chloride, and 3 ml of 6N NaOH are added with stirring. The organic phase is separated and washed with 20 ml of water. The organic phase is distilled and the solvent is changed to ethyl acetate with a final volume of 100 ml. The mixture is heated to 70° C, 0.8 g of L-tartaric acid is added, and stirring continues for 30 minutes at 70° C. The mixture is cooled

25 slowly to 20/25° C, filtered, and washed with 8 ml of ethyl acetate to obtain 8- (phenylmethoxy)-5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-l-hydroxy-ethyl]-(lH)- quinolin-2-one tartrate in 68% yield. The purity of the product is >95% by HPLC analysis. Example 4 – preparation of the compound of formula IV

A flask is charged with 19 ml of THF and 19 ml of toluene, p-toluene sulfonic acid (75 mg) and molecular sieves (1.5 g) are added and the mixture is stirred for 30 minutes. 11.2 ml of butyl-vinylether and 15 g of 8-(phenylmethoxy)-5-((R)-2- bromo-l-hydroxy-ethyl)-(lH)-quinolin-2-one are added. The mixture is agitated at 20/25° C until completion of the reaction. 0.1 ml of diisopropylethyl amine are added, the mixture is filtered, and the solvent is distilled off.

The residue is dissolved in 40 ml of butanone, 14.5 ml of diisoproypylethyl amine, 9 g sodium iodide, and 11.3 g of 2-amino-5,6-diethylindane are added and the mixture is heated to 90-100° C. After completion of the reaction the mixture is cooled to 20/25° C, 3 ml of concentrated hydrochloric acid and 3 ml of water are added, and the mixture is stirred for 30 minutes.

HPLC analysis shows the expected product with a purity of 84% and being free from the dimer and regioisomer impurities. 150 ml of water, 150 ml of methylene chloride, and 22.5 ml of 6N NaOH are added with stirring. The organic phase is separated and washed with 10 ml of water. The organic phase is distilled and the solvent is changed to isopropyl alcohol with a final volume of 300 ml. The mixture is heated to 70° C, 4.9 g of benzoic acid is added, and stirring continues for 30 minutes at 70° C. The mixture is cooled slowly to 20/25° C, filtered, and washed with 30 ml of isopropanol to obtain 8-(phenylmethoxy)-5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-l-hydroxy- ethyl]-(lH)-quinolin-2-one benzoate in 59 % yield. The purity of the product is > 99 % by HPLC analysis. Example 5 – preparation of the compound of formula IV

A flask is charged with 7.5 ml of THF and 7.5 ml of toluene, p-toluene sulfonic acid (30 mg) and molecular sieves (0.6 g) are added and the mixture is stirred for 30 minutes. 4.5 ml of butyl-vinylether and 6 g of 8-(phenylmethoxy)-5-((R)-2- bromo-l-hydroxy-ethyl)-(lH)-quinolin-2-one are added. The mixture is agitated at 20/25° C until completion of the reaction. 0.040 ml of diisopropylethyl amine are added, the mixture is filtered, and the solvent is distilled off.

The residue is dissolved in 18 ml of acetonitrile (ACN), 5,8 ml of diisoproypylethyl amine, 3.6 g sodium iodide, and 4.5 g of 2-amino-5,6-diethylindane are added and the mixture is heated to 80-90° C. After completion of the reaction the mixture is cooled to 20/25° C, 1.2 ml of concentrated hydrochloric acid and 1.2 ml of water are added, and the mixture is stirred for 30 minutes. HPLC analysis shows the expected product with a purity of 89% and being free from the dimer and regioisomer impurities.

60 ml of water, 60 ml of methylene chloride, and 9 ml of 6N NaOH are added with stirring. The organic phase is separated and washed with 60 ml of water. The organic phase is distilled and the solvent is changed to isopropyl alcohol with a final volume of 120 ml. The mixture is heated to 70° C, 1.9 g of succinic acid is added, and stirring continues for 30 minutes at 70° C. The mixture is cooled slowly to 20/25° C, filtered, and washed with 12 ml of isopropanol to obtain 8- (phenylmethoxy)-5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-l-hydroxy-ethyl]-(lH)- quinolin-2-one succinate in 56 % yield . The purity of the product is > 99 % by HPLC analysis. Example 6 : purification with EtOH/water

To 2.0 g of 8-(phenylmethoxy)-5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-l- hydroxy-ethyl]-(lH)-quinolin-2-one, a mixture of 35 ml/g of EtOH and 5 ml/g of water are added and heated to reflux. Once this temperature is reached, benzoic acid is added (1.2 eq.) as a solution in 5 ml/g of the mixture of EtOH/water. The temperature is maintained for 30 minutes. The mixture is then cooled slowly overnight to 20-25°C. The resulting suspension is filtered and a white solid is obtained and dried in vacuum. The white solid is analyzed by HPLC to determine the chromatographic purity and by chiral HPLC to determine the enantiomeric purity, obtaining a white solid product with a proportion of enantiomeric impurity below 0.05%. No other impurities are detected.

Example 7 : purification with Acetone/water

To 2.0 g of 8-(phenylmethoxy)-5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-l- hydroxy-ethyl]-(lH)-quinolin-2-one, a mixture of 35 ml/g of Acetone and 1 ml/g of water are added and heated to reflux. Once this temperature is reached, Dibenzoyl-L-tartaric monohydrate acid is added (1.2 eq.) as a solution in 5 ml/g of the mixture of Acetone /water. The temperature is maintained for 30 minutes. The mixture is then cooled slowly overnight to 20-25°C. The resulting suspension is filtered and a white solid is obtained and dried in vacuum. The white solid is analyzed by HPLC to determine the chromatographic purity and by chiral HPLC to determine the enantiomeric purity, obtaining a white solid product with a proportion of enantiomeric impurity below 0.05%. No other impurities are detected.

Example 8 : purification with EtOH/water

To 2.0 g of of 8-(phenylmethoxy)-5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-l- hydroxy-ethyl]-(lH)-quinolin-2-one, a mixture of 35 ml/g of EtOH and 5 ml/g of water are added and heated to reflux. Once this temperature is reached, L Tartaric acid is added (1.2 eq.) as a solution in 5 ml/g of the mixture of

EtOH/water. The temperature is maintained for 30 minutes. The mixture is then cooled slowly overnight to 20-25°C. The resulting suspension is filtered and a white solid is obtained and dried in vacuum. The white solid is analyzed by HPLC to determine the chromatographic purity and by chiral HPLC to determine the enantiomeric purity, obtaining a white solid product with a proportion of enantiomeric impurity below 0.06%. No other impurities are detected.

Example 9 : synthesis of protected benzyl Indacaterol

A solution of sodium carbonate (0.57 kg/kg, 2 equivalents) in water (13 l/kg) is prepared in another reactor. This carbonate solution is added to the product solution from example 1, diethyl indanolamine HCI (0.72 kg/kg, 1.2 equivalents) is added and the mixture is heated and distilled at atmospheric pressure until a volume of 13 l/kg . Water (3 l/kg) is added and the mixture is distilled at atmospheric pressure until a volume of 13 l/kg . The system is placed in reflux position and reflux is maintained for 20 hours. When the reaction is complete, the mixture is cooled to 20-25°C and methylene chloride (15 l/kg) is added. The mixture is agitated, decanted, and the aqueous phase is extracted with methylene chloride (5 l/kg). The organic phases are washed with water (5 l/kg).

Example 10 – preparation of Indacaterol maleate

28 g of 8-(phenylmethoxy)-5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-l-hydroxy- ethyl]-(lH)-quinolin-2-one tartrate is dissolved in a mixture of 560 ml of dichloromethane, 560 ml of water, and 30 ml of an aqueous solution of 6N sodium hydroxide under stirring . The phases are separated and the organic phase is washed with 280 ml of water. The organic phase is distilled to a final volume of 140 ml and 420 ml of methanol and 4.2 g of Pd/C (5% – 50% water) are added . The system is purged with nitrogen and subsequently with hydrogen at an overpressure of 0.3 bar and stirring until completion of the reaction. The catalyst is filtered off and the solvent is changed to isopropanol adjusting the final volume to 950 ml. The solution is heated to 70/80° C and a solution of 5.4 g maleic acid in 140 ml of isopropanol is added, maintaining the temperature between 70 and 80° C. The mixture is stirred at 70/80° C for 30 minutes and then slowly cooled to 20/25° C. The resulting suspension is filtered, the solid residue is washed with 90 ml of isopropanol and dried to obtain 18g of Indacaterol maleate (Yield : 79%). The product shows 99.6% purity by HPLC analysis.

Example 11 – Isolation of Indacaterol free base in solid form

lg of 8-(phenylmethoxy)-5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-l-hydroxy- ethyl]-(lH)-quinolin-2-one tartrate is dissolved in a mixture of 20 ml of dichloromethane,20 ml of water, andl ml of an aqueous solution of 6N sodium hydroxide under stirring. The phases are separated and the organic phase is washed with 10 ml of water.

The organic phase is distilled to a final volume of 5 ml and 15 ml of methanol and 0.15 g of Pd/C (5% – 50% water) are added . The system is purged with nitrogen and subsequently with hydrogen at an overpressure of 0.3 bar and stirring until completion of the reaction.

The catalyst is filtered off and the solvent is changed to isopropanol adjusting the final volume to 8 ml. The resulting suspension is cooled to 0-5°C, filtered and the solid residue is washed with isopropanol and dried to obtain 0.47 g of Indacaterol free base (77%) showing 99.6% purity by HPLC analysis.

A sample of Indacaterol free base stored at 20-25°C is analysed one month later without showing any loss of purity. Example 12 – obtaining the maleate salt from Indacaterol free base

0.47 g of solid Indacaterol are suspended in 20 ml of isopropanol, heated to 70/80° C, and a solution of 0.15 g of maleic acid in 5 ml of isopropanol are added, maintaining the temperature between 70 and 80° C. The mixture is cooled to 0/5°C and filtration of the resulting solid affords 0.52 g of Indacaterol maleate with a purity of 99.7%.

Comparative example 13 – direct conversion to Indacaterol maleate

8-(phenylmethoxy)-5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-l-hydroxy-ethyl]- (lH)-quinolin-2-one benzoate (4 g) is dissolved in acetic acid (40 ml). Pd/C (5 %, 50% wet, 0.6 g) is added and the product is hydrogenated under a hydrogen atmosphere. When the reaction is complete the catalyst is filtered off and the filtrate is vacuum distilled until a volume of 8 ml is reached.

Ethanol (40 ml) is added and the mixture is heated to 50° C. A solution of 1.2 g of maleic acid in 2.4 ml of ethanol is added and the mixture is seeded with

indacaterol maleate and then slowly cooled to 0/5° C. The solid is filtered and washed with 5 ml of ethanol and 3 ml of isopropanol to obtain 6.0 g of indacaterol maleate.

1H-NMR analysis of the solid shows the presence of acetic acid in 2-4 % by integration of the peak at δ 1.88 (400 MHz, DMSO-c/6) corresponding to acetic acid.

References

Cazzola M, Matera MG, Lötvall J (July 2005). “Ultra long-acting beta 2-agonists in development for asthma and chronic obstructive pulmonary disease”. Expert Opin Investig Drugs 14(7): 775–83. doi:10.1517/13543784.14.7.775.PMID 16022567.
European Public Assessment Report for Onbrez Breezhaler
“FDA approves Arcapta Neohaler to treat chronic obstructive pulmonary disease” (Press release). U.S. Food and Drug Administration. 2011-07-01. Retrieved 2011-07-02.[1]
Beeh KM, Derom E, Kanniess F, Cameron R, Higgins M, van As A (May 2007). “Indacaterol, a novel inhaled beta2-agonist, provides sustained 24-h bronchodilation in asthma”. Eur. Respir. J. 29 (5): 871–8. doi:10.1183/09031936.00060006.PMID 17251236.
Feldman, G; Siler, T; Prasad, N; Jack, D; Piggott, S; Owen, R; Higgins, M; Kramer, B; Study Group, I (2010). “Efficacy and safety of indacaterol 150 mcg once-daily in COPD: a double-blind, randomised, 12-week study”. BMC pulmonary medicine10: 11. doi:10.1186/1471-2466-10-11. PMC 2848004.PMID 20211002.
Dahl R; Chung KF; Buhl R; et al. (June 2010). “Efficacy of a new once-daily long-acting inhaled beta2-agonist indacaterol versus twice-daily formoterol in COPD”. Thorax 65 (6): 473–9.doi:10.1136/thx.2009.125435. PMID 20522841.
R. Buhl; L.J. Dunn; C. Disdier; et al. (October 2011). “Blinded 12-week comparison of once-daily indacaterol and tiotropium in COPD”. European Respiratory Journal 38 (4): 797–803.doi:10.1183/09031936.00191810. PMID 21622587.
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD010139.pub2/abstract;jsessionid=2E0FA3EB220BD4ADED29D7B5707FC667.f01t04

A. BORGHESE ET AL.: “Efficient Fast Screening Methodology for Optical Resolution Agents: Solvent Effects Are Used To Affect tge Efficiency of the Resolution Process“, ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 8, no. 3, 2004, pages 532-534, XP002725198,
2	*	D. BEATTIE ET AL.: “An investigation into the structure-activity relationships associated with the systematic modification of the beta2-adrenoreceptor agonist indacaterol“, BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 22, 2012, pages 6280-6285, XP002724553,
3		F. BAUR ET AL. J. MED. CHEM. vol. 53, 2010, pages 3675 – 3684
4	*	F. BAUR ET AL.: “The Identification of Indacaterol as an Ultralong-Acting Inhaled beta2-Adrenoceptor Agonist“, JOURNAL OF MEDICINAL CHEMISTRY, vol. 53, no. 9, 2010, pages 3675-3684, XP002724552,
5	*	KRAUSE M ET AL: “Optical resolution of flavanones by high-performance liquid chromatography on various chiral stationary phases“, JOURNAL OF CHROMATOGRAPHY, ELSEVIER SCIENCE PUBLISHERS B.V, NL, vol. 514, 1990, pages 147-159, XP026539395, ISSN: 0021-9673, DOI: 10.1016/S0021-9673(01)89386-9 [retrieved on 1990-01-01]
6	*	M. NISHIKATA ET AL.: “Method for Optical Resolution of Racemic Homochlorcyclizine and Comparison of Optical Isomers in Antihistamine Activity and Pharmacokinetics“, CHEMICAL AND PHARMACEUTICAL BULLETIN, vol. 40, no. 5, 1992, pages 1341-1342, XP002725199,

WO1995025104A1	Mar 3, 1995	Sep 21, 1995	Lee James Beeley	Novel heterocyclic ethanolamine derivatives with beta-adrenoreceptor agonistic activity
WO2000075114A1	Jun 2, 2000	Dec 14, 2000	Novartis Ag	Beta2-adrenoceptor agonists
WO2004074276A1 *	Feb 13, 2004	Sep 2, 2004	Theravance Inc	BIPHENYL DERIVATIVES HAVING β2 ADRENERGIC RECEPTOR AGONIST AND MUSCARINIC RECEPTOR ANTAGONIST ACTIVITY
WO2004076422A1	Feb 27, 2004	Sep 10, 2004	Olivier Lohse	Process for preparing 5-‘(r)-2-(5,6-diethyl-indian-2-ylamino)-1-hydroxy-ethyl!-8-hydroxy-(1h)-quinolin-2-one salt, useful as an adrenoceptor agonist
WO2004087668A1	Apr 1, 2004	Oct 14, 2004	Novartis Ag	A process for the preparation of 5-(haloacetyl)-8-(substituted oxy)-(1h)-quinolin-2-ones
WO2005123684A2	Jun 21, 2005	Dec 29, 2005	Stephan Abel	Enantioselektive preparation of quinoline derivative
WO2007124898A1 *	Apr 24, 2007	Nov 8, 2007	Almirall Lab	DERIVATIVES OF 4-(2-AMINO-1-HYDROXIETHYL)PHENOL AS AGONISTS OF THE β2 ADRENERGIC RECEPTOR
WO2008046598A1 *	Oct 17, 2007	Apr 24, 2008	Almirall Lab	DERIVATIVES OF 4-(2-AMINO-1-HYDROXYETHYL)PHENOL AS AGONISTS OF THE β2 ADRENERGIC RECEPTOR
WO2009106351A1 *	Feb 27, 2009	Sep 3, 2009	Almirall, S.A.	Derivatives of 4-(2-amino-1-hydroxyethyl) phenol as agonists of the b2 adrenergic receptor
EP0147719A2 *	Dec 11, 1984	Jul 10, 1985	Tanabe Seiyaku Co., Ltd.	Novel carbostyril derivative and process for preparing same
EP1405844A1 *	Jun 27, 2002	Apr 7, 2004	Nikken Chemicals Company, Limited	Cycloalkenone derivative
US20040167167	Feb 13, 2004	Aug 26, 2004	Mathai Mammen	Biphenyl derivatives

WO2000075114A1 *	Jun 2, 2000	Dec 14, 2000	Novartis Ag	Beta2-adrenoceptor agonists
WO2002045703A2 *	Dec 3, 2001	Jun 13, 2002	Bernard Cuenoud	Mixtures or organic compounds for the treatmentof airway diseases
WO2004076422A1 *	Feb 27, 2004	Sep 10, 2004	Olivier Lohse	Process for preparing 5-‘(r)-2-(5,6-diethyl-indian-2-ylamino)-1-hydroxy-ethyl!-8-hydroxy-(1h)-quinolin-2-one salt, useful as an adrenoceptor agonist
WO2004087668A1 *	Apr 1, 2004	Oct 14, 2004	Novartis Ag	A process for the preparation of 5-(haloacetyl)-8-(substituted oxy)-(1h)-quinolin-2-ones

Citing Patent	Filing date	Publication date	Applicant	Title
WO2014154841A1 *	Mar 27, 2014	Oct 2, 2014	Laboratorios Lesvi, S.L.	Process for the manufacture of (r)-5-[2-(5,6-diethylindan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-(1h)-quinolin-2-one

Indacaterol
Systematic (IUPAC) name


5-[2-[(5,6-Diethyl-2,3-dihydro-1H-inden-2-yl)amino]-1-hydroxyethyl]-8-hydroxyquinolin-2(1H)-one
Clinical data
Trade names	Onbrez, Arcapta
AHFS/Drugs.com	International Drug Names
Licence data	EU EMA: Onbrez US FDA: Indacaterol
Pregnancy category	US: C (Risk not ruled out)
Routes of administration	Inhalation
Legal status	UK: POM (Prescription only) US: ℞-only
Identifiers
CAS Number	312753-06-3
ATC code	R03AC18
PubChem	CID 6433117
IUPHAR/BPS	7455
ChemSpider	5293751
UNII	8OR09251MQ
KEGG	D09318
ChEBI	CHEBI:68575
ChEMBL	CHEMBL1095777
Chemical data
Formula	C₂₄H₂₈N₂O₃
Molar mass	392.490 g/mol

//////

O=C4/C=C\c1c(c(O)ccc1[C@@H](O)CNC3Cc2cc(c(cc2C3)CC)CC)N4

WO 2016027283, New patent, Indacaterol, Reddy-Cheminor Inc

March 2, 2016 6:58 am / Leave a comment

Beta 2 adrenoceptor agonist

Chronic obstructive pulmonary disease

WO 2016027283, New patent, Indacaterol, Reddy-Cheminor Inc

A process for preparing indacaterol and salts thereof

REDDY, G Pratap; (IN).
SUNKU, Venkataiah; (IN).
BABU, Sunkaraneni Suresh; (IN)

The present invention relates to a process for preparing indacaterol or salts thereof. The process comprises of forming compound of Formula 1 by reacting compound of Formula 2 and compound of Formula 3 in the presence of a solvent to Form compound of Formula 4, 5 which on removal of the protecting groups forms compound of Formula 1.

Indacaterol maleate is a beta-selective adrenoceptor agonist with potent bronchodilator activity. Indacaterol is chemically known as 5-[(R)-2-(5, 6-diethyl-indan-2- yl amino)-l-hydroxy-ethyl ]-8-hydroxy-(lH)-quinolin-2-one.

US7534890 claims a process to prepare 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)- 1 -hydroxy-ethyl] -8-hydroxy-(l H)-quinolin-2-one salt. One of the key steps in the process is reacting an epoxide, such as 8-substituted oxy-5-(R)- oxiranyl-(lH)-quinoline-2-one [Formula (I)] with an amine, such as 2-amino-(5,6-diethyl)-indan to form an intermediate 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-l -hydroxy-ethyl]-8- substituted oxy-(lH)-quinolin-2-one [Formula (Ha)].

The drawback of this process is opening of epoxide ring is not regioselective and thereby resulting, in formation of substantial quantities of impurities as by products, Formula (lib) and Formula (lie) resulting in overall lower yields. The quantity of 2- amino-(5,6-diethyl)-indan used in this step is also large excess than theoretical amounts. Subsequent improvements also did not address this problem effectively.

WO 2013/132514 discloses a process to prepare Indacaterol involving the steps of treating a compound of Formula (III), wherein L is a leaving group, with the amine, 2-amino-(5,6-diethyl)-indan or its acid addition salts to obtain a compound of Formula (IV) or its acid addition salts.

Though higher yields have been claimed, the process has not overcome completely all the problems mentioned earlier.

There is a need for developing a more efficient process for preparing Indacaterol or salts thereof especially for large scale production with higher yields.

The reaction scheme of synthesis of compound of Formula 3 is represented below.

Formula 3 Formula 13 Formula 12

xample 1

Process to prepare 5-[ (R)-2-(5, 6-diethyl-indan-2-ylamino)-l-hydroxy-ethyl]-8-hydroxy-( lH)-quinolin-2-one

2-Chloro-5,6-diethylindan (4.2g) was added to a solution of 5-[(R)-(2-amino-l-hydroxy-ethyl)-8-phenylmethoxy-(lH)-quinolin-2-one (6g) in dimethylformamide (20ml) followed by addition of N,N-diisopropyl-N-ethylamine (3.6 g) and sodium iodide (lg) at room temperature and stirred for 10 minutes. The reaction mixture was heated to 90° C and the temperature was maintained at 90 °C till the completion of reaction. The reaction mass was cooled to room temperature and diluted with dichloromethane (100ml) and water (100 ml) and stirred for 30 minutes. The organic phase was separated and the aqueous layer was extracted with dichloromethane. Combined organic layer was washed with water, dried and concentrated. The resulting residue was dissolved in isopropyl alcohol under reflux and cooled slowly to obtain 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-l-hydroxy-ethyl]-8-phenylmethoxy -(lH)-quinolin-2-one, which was isolated by filtration and dried under vacuum (7.4 g). Yield: 79.3 %. Purity of the product is >95 % (HPLC).

Example 2

Process to prepare 5-[(R)-2-(5, 6-diethyl-indan-2-ylamino)-l-hydroxy-ethyl]-8-hydroxy-( lH)-quinolin-2-one

Solution of 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-l-hydroxy-ethyl]-8-phenylmethoxy-(lH)-quinolin-2-one (lOg) in methanol (100ml) and acetic acid (20ml) was hydrogenated using palladium on charcoal 5% (1.5g) until completion of the reaction. The mixture was filtered over celite and the filtrate was concentrated at 55°C under vacuum. The residue obtained was dissolved in hot methanol to precipitate 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-! -hydroxy-ethyl]-8-hydroxy-(lH)-quinolin-2-one.

Example 3

Process to prepare 5-[(R)-2-(5, 6-diethyl-indan-2-ylamino)-l-hydroxy-ethyl]-8-hydroxy-(lH)-quinolin-2-one maleate

Crude 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-l -hydroxy-ethyl]-8-hydroxy-(lH)-quinolin-2-one prepared by the process of Example 2 was added to a solution of maleic acid (2.6g) in methanol and the resulting clear solution was slowly cooled to 5° C and stirred for 2 hours at the same temperature. The slurry was filtered, washed with cold methanol and dried to obtain 5-[(R)-2-(5, 6-diethyl-indan-2-ylamino)-l-hydroxy-ethyl]-8-hydroxy-(lH)-quinolin-2-one maleate (8.8g). Yield: 83.5 %. Purity of the product is >99%. E.e. >99 %.

Example 4

Process for preparing 5-[(R)-(2-phthalimido-l-hydroxy-ethyl)-8-phenylmethoxy-(lH)-quinolin-2-one

Diisopropylethylamine (6g) was added to a solution of phthalimide (6g) in dimethylformamide (30 ml) at room temperature. To this solution, 8-(phenylmethoxy)-5-[(R)-2-bromo-l-hydroxy-ethyl]-(lH)-quinoline-2-one (11 gm) was added slowly followed by sodium iodide (1 g). The resulting mass was heated to 90°C and stirred till the completion of reaction as monitored by TLC. The reaction mass was diluted with water (200 ml) and the crude product was isolated by filtration. The wet filter cake was suspended in water (60 ml), stirred for 1 hour, filtered, washed with water to obtain 5-[(R)-(2-phthalimido-l-hydroxy-ethyl)-8-phenylmethoxy-(lH)-quinolin-2-one (10.4 gm) after drying. Yield: 80.7 %.

Method A- Process for preparing 5-[(R)-(2-amino-l-hydroxy-ethyl)-8-phenylmethoxy-(lH)-quinolin-2-one

To a solution of 5-[(R)-(2-phthalimido-l-hydroxy-ethyl)-8-phenylmethoxy-(lH)-quinolin-2-one ( 13.2 g) in a mixture of isopropanol (86 ml) and water (14 ml) sodium borohydride (4.6 g) was added slowly at room temperature and stirred overnight. Thereafter, the pH of the reaction mass was lowered to 5.5 with acetic acid, and then the reaction mass was heated to reflux for two hours. Isopropanol was distilled out under reduced pressure. The residue was diluted with ethyl acetate (120 ml) and concentrated hydrochloric acid (8 ml) was added and stirred for 15 minutes for the salts to precipitate out. The reaction mass was filtered and the salt was washed with ethyl acetate. To the clear filtrate concentrated hydrochloric acid (10 ml) was added and stirred at 5° C for 30 minutes for 5-[(R)-(2-amino-l-hydroxy-ethyl)-8-phenylmethoxy-(lH)-quinolin-2-one to separate out as hydrochloride salt. The product was isolated by filtration and dried under vacuum (8.2 g). The hydrochloride salt was dissolved in minimum amount of water and basified with sodium hydroxide solution. The product was isolated as free amine by concentrating the solution under reduced pressure and extracting the residue with isopropyl alcohol and distilling out the solvent (7.45 g). Yield 80 %.

1H-NMR (CDC13) ppm: 2.56-2.70 (m, 2H), 3.35 (s, br, 2H, exchangeable), 4.89 (m, 1H), 5.29 (s, 2H), 5.76 (s, 1H, exchangeable), 6.53 (d, 1H), 7.11-7.19 (dd, 2H), 7.29-7.36 (dd, 1H), 7.39 (d, 2H), 7.57 (d, 2H), 8.21 (d, 1H), 10.7 (s, br, 1H, exchangeable).

Method B- Process for preparing 5-[(R)-(2-amino-l-hydroxy-ethyl)-8-phenylmethoxy-( lH)-quinolin-2-one

To a solution of 5-[(R)-(2-phthalimido-l-hydroxy-ethyl)-8-phenylmethoxy-(lH)-quinolin-2-one ( 10 g) in ethanol (60 ml) hydrazine hydrate (4.8 g) was added and refluxed the mixture for about 6 hours. The solvent was distilled out under reduced pressure. To the residue, concentrated hydrochloric acid (16 ml) was added and heated to about 80°C and maintained till the completion of the reaction. The reaction mass was cooled to room temperature and filtered. The clear filtrate was basified and concentrated under reduced pressure. The product was isolated as free amine (5.8 g) by extracting with isopropyl alcohol and distilling out the solvent. Yield: 83%.

Method C

Preparation of 5-(2-benzylamino-l-hydroxy-ethyl)-8-phenylmethoxy-( lH)-quinolin-2-one 5-Acetyl-8-phenylmethoxy-(lH)-quinolin-2-one (30 g) was refluxed with selenium dioxide

(11.5 g) in a mixture of dioxane (350 ml) and water (30 ml) for 16 hours. The reaction mixture was diluted with dioxane (150 ml) and precipitated inorganic salts were removed by filtration. Clear filtrate was concentrated to about 60 ml under vacuum and diluted with methanol (100 ml). The reaction mass was cooled to 15° C and benzylamine (7.5 g) was added slowly over a period of 45 minutes and stirred at the same temperature for two hours.

The reaction mass was further cooled to 0°C and sodium borohydride (2.8 g) was added slowly over a period of one hour. Thereafter, the reaction mass was stirred at room temperature for 12 hours. The reaction mixture was concentrated under vacuum and diluted with 300 ml water and stirred at 20° C for three hours. The precipitated product was collected by filtration, washed with water followed by isopropyl ether and then dried (28.2 g) to obtain 5-(2-benzylamino-l-hydroxy-ethyl)-8-phenylmethoxy-(lH)-quinolin-2-one.

Example 5

Preparation of 5-acetyl-8-phenylmethoxy-(lH)-quinolin-2-one

To a solution of 5-acetyl-8-hydroxy-(lH)-quinolin-2-one (35 g) in dimethylformamide (175 ml) potassium carbonate (35 g) was added at room temperature and stirred for 10 minutes. To the suspension, benzylbromide (32 g) was slowly added over a period of 30 minutes and stirred for 2 hours at the same temperature for completion of reaction (monitored by TLC). The reaction mass was diluted with water (800 ml) and stirred for 20 minutes for the product to precipitate out. The product was filtered, washed with water and dried under vacuum to get the title product (48 g).

Example 6

Preparation of 5-(2-bromoacetyl)-8-phenylmethoxy-( lH)-quinolin-2-one

Boron trifluoride-diethyletherate (29 ml) was slowly added to a solution of 5-acetyl-8-phenylmethoxy-(lH)-quinolin-2-one (50 g) in dichloromethane (500 ml) at 0° C and stirred for 10 minutes at the same temperature to get a thick precipitate. The reaction mass was heated to reflux temperature and bromine solution was added (29 g in 190 ml dichloromethane) slowly over a period of 2 hours under reflux (the HBr fumes coming from the condenser was scrubbed). Thereafter, the reaction mass was refluxed for further 45 minutes. The solvent was distilled out completely under vacuum and the mass was triturated with 10% aqueous sodium carbonate solution (100 ml). The suspension was filtered, washed with water and the crude product was taken for the next stage reaction.

Example 7

Preparation of 5-(2-phthalimido-l-oxo-ethyl)-8-phenylmethoxy-(lH)-quinolin-2-one

Potassium carbonate (33.4 g) was added to a solution of phthalimide (21.73 g) in dimethylformamide (80 ml) at room temperature and stirred for 10 minutes. To this suspension, crude 5-(2-bromoacetyl)-8-phenylmethoxy-(lH)-quinolin-2-one of example 6, dissolved in dimethylformamide (120 ml), was added slowly over a period of 20 minutes. The resulting suspension was stirred at 50° C for about 1 hour for the completion of reaction as monitored by TLC. The mixture was diluted with water (800 ml) and the crude product was isolated by filtration. The wet filter cake was suspended in water (600 ml), stirred for 1 hour, filtered, washed with water and dried under vacuum to get 5-(2- phthalimido-l-oxo-ethyl)-8-phenylmethoxy-(lH)-quinolin-2-one (67.4 g). Over all yield

(after two steps): 90%.

Example 8

Preparation of 5-[(R)-(2-phthalimido-l-hydroxy-ethyl)-8-phenylmethoxy-(lH)-q inolin-2-one

To a solution of (R)-2-methyl-CBS-oxazaborolidine (1M in toluene, 4.2 ml) in dry

tetrahydrofuran (THF, 50 ml) Borane-diethylaniline (19 ml) was added slowly at – 10° C

and the contents were stirred at the same temperature for 15 minutes. A solution of 5-(2-

Phthalimido-l-oxo-ethyl)-8-phenylmethoxy-(lH)-quinolin-2-one ( 8.3 g), of example 7, in

a mixture of dry THF (50 ml) and dichloromethane (50 ml), was added slowly to the

reaction mass at – 10° C. The reaction mass was further stirred for 2 hours and then

methanol was added and the temperature was slowly raised to room temperature. Dilute

sulfuric acid (6N, 10 ml) was added to the reaction mixture and stirred for 15 minutes. The

reaction mixture was concentrated under vacuum and the crude mass was extracted with

ethyl acetate. The organic phase was washed with dilute sulfuric acid and then water. The

solvent was distilled out completely under vacuum and triturated with hexane. The

compound was isolated by filtration and dried (7.6 g). Yield: 91.1%. e.e.. >97%.

Example 9

Process of preparing 2-chloroindan

2-hydroxy indan (lOOg) was dissolved in 1, 2-dichloroethane (400 ml) and added to thionyl

chloride (125 g) slowly over a period of an hour. Temperature was maintained at less than

10° C. Thereafter, the reaction mass was slowly heated and refluxed till the completion of the reaction. The reaction was monitored by TLC. The reaction mass was cooled to room temperature and poured in to ice water, stirred for 1 hour and organic layer was separated. The aqueous layer was extracted with dichloroethane. Organic layers were combined and washed with water, sodium bicarbonate solution and dried over anhydrous sodium sulphate. Solvent was distilled out completely and the crude product was distilled under vacuum to obtain 2-chloroindan as a colorless liquid (118 g).

Example 10

Process for preparing 5-acetyl-2-chloroindan

Aluminium chloride (146 g) was added in small lots to nitromethane (500 ml) and the solution was cooled to 5° C under inert atmosphere while stirring. Acetyl chloride (84 g) was slowly added keeping the temperature at 5° C. Solution of 2-chloroindan (118 g) was slowly added in acetyl chloride (84 g) keeping temperature at 5° C. After completion of reaction, monitored by TLC, the reaction mass was poured into cold IN HC1 (2000 ml) solution and stirred for 30 minutes. The product was extracted into di-isopropyl ether. The combined organic layer was washed with water, bicarbonate solution, brine and dried over anhydrous sodium sulphate. The solvent was completely distilled out to obtain 5-acetyl-2-chloroindan as yellow waxy solid (130 g).

Example 11

Process for preparing 2-chloro-5-ethylindan

1 Liter hydrogenation vessel was charged with 50 grams of 5-acetyl-2-chloroindan, 400 ml of methanol and 10 ml of acetic acid. Palladium on charcoal 5% (5 g) was added and the reaction mass was hydrogenated until complete conversion to 2-chloro-5-ethylindan. The mixture was filtered over a bed of celite. The filtrate was concentrated under reduced pressure to obtain 2-chloro-5-ethylindan as an oily mass (42 g).

Example 12

Process for preparing 5-acetyl-2-chloro-6-ethylindan

5-acetyl-2-chloro-6-ethylindan was prepared from 2-chloro-5-ethylindan (20 g) in accordance with the procedure followed in Example 10.

Example 13

Process for preparing 2-chloro-5, 6-diethylindan

Hydrogenation of 5-acetyl-2-chloro-6-ethylindan using Palladium on charcoal adopting the procedure as reported in Example 11, gave 2-chloro-5, 6-diethylindan as a liquid. The crude product was distilled under vacuum to get colorless liquid.

1H-NMR (CDC13) ppm: 1.19-1.29 (t, 6H), 2.61-2.66 (q, 4H), 3.13-3.18 (dd, 2H), 3.36-3.41 (dd, 2H), 4.66-4.72 (m, 1H), 7.05 (s, 2H).

////////////WO 2016027283, New patent, Indacaterol, Reddy-Cheminor Inc

SUVN-G3031, from Suven Life Sciences Ltd

March 2, 2016 4:13 am / Leave a comment

.2HCl

SUVN-G3031

N-[4-(1-cyclobutyl piperidin-4-yloxy)-phenyl]-2-(morpholin-4-yl) acet amide dihydrochloride

N-[4-(l-Cyclobutyl piperidin-4-yloxy) phenyl]-2-(morpholin-4-yl) acetamide dihydrochloride

4-Morpholineacetamide, N-[4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl]-, hydrochloride (1:2)

MF C₂₁ H₃₁ N₃ O₃ . 2 Cl H,

CAS 1394808-20-8

SUVN-G3031

Base

Cas 1394808-82-2

MF C₂₁ H₃₁ N₃ O_3, 373.49

4-Morpholineacetamide, N-[4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl]-

SUVN-G3031 (in phase I)

Suven Life Sciences Limited, IN 2011CH00520

Phase I Cognition disorders associated with Alzheimer disease patients.

https://clinicaltrials.gov/ct2/show/NCT02342041

Useful for treating cognitive disorders, dementia, attention deficit hyperactivity disorder, epilepsy, sleep disorders, obesity, schizophrenia, eating disorders and pain.

Histamine H3 receptor antagonists

Neuropsychotherapeutics; Nootropics

Suven Life Sciences is developing, Histamine H3 receptor antagonists, SUVN-G3031 (in phase I)

13 Jul 2015Suven Life Sciences has patent protection for SUVN G3031 in China and South Africa
16 Mar 2015SUVN G3031 is available for licensing as of 16 Mar 2015. http://www.suven.com/
16 Mar 2015Suven Life Sciences receives patents for SUVN G3031 in USA and New Zealand

H 3 receptors play a critical role as neuromodulators through their widespread distribution in the central nervous system. Blockade of this receptor augments the pre-synaptic release of both histamine and other neurotransmitters including acetylcholine from cholinergic neurons. Currently, several H 3 receptor antagonists/inverse agonists are in different stages of clinical trials for the potential treatment of narcolepsy, cognitive impairments associated with Alzheimer’s disease, Parkinson’s disease, schizophrenia and attention deficit hyperactivity disorder.

Histamine H₃ receptor is a G-protein coupled receptor (GPCR) and one out of the four receptors of Histamine family. Histamine H₃ receptor is identified in 1983 and its cloning and characterization were done in 1999. Histamine H₃ receptor is expressed to a larger extent in central nervous system and lesser extent in the peripheral nervous system.

Literature evidence suggests that Histamine H₃ receptor ligands can be used in treatment of cognitive disorders (British Journal of Pharmacology, 2008, 154(6), 1 166-1181), dementia (Drug News Perspective, 2010, 23(2), 99-103), attention deficit hyperactivity disorder, obesity (Indian Journal of Pharmacology, 2001, 33, 17-28), schizophrenia (Biochemical Pharmacology, 2007, 73(8), 1215-1224) and pain (Journal of Pharmacology and Experimental Therapeutics, 2011, 336(1), 30-37).

Patent publications WO 2007/137955, US 2009/0170869, US 2010/0029608, US 2010/0048580, WO 2009/100120, WO 2009/121812 and WO 2009/135842 disclosed series of compounds as ligands at Histamine H₃ receptors. While some Histamine H₃ receptor ligands have been disclosed, no compound till date is launched in market in this area of research, and there still exists a need and scope to discover new drugs with novel chemical structures for treatment of disorders affected by Histamine H₃ receptors.

Suven Life completes Phase 1 studies for SUVN- G3031 for Schizophrenia – Cognitive Impairment

Drugmaker Suven Life Science, which is mostly into researching for new molecules used for ailments of the central nervous system, has completed the single ascending dose (SAD) studies for SUVN- G3031, which is likely to be used for cognitive dysfunction associated with Alzheimer’s and schizophrenia.

The phase-1 study was said to be designed to evaluate safety, tolerability and pharmacokinetics of SUVN-G3031 in healthy volunteers. It was found that the tolerability of SUVN-G3031 up to the highest dose administered in SAD study was ‘excellent’ with ‘no serious adverse events’. The drug candidate was demonstrated for one-day dosing.

OLD CLIPS

SUVN-G3031 for Cognition in Alzheimer’s Disease commenced Phase 1 Clinical Trial in USA under US-IND 123179

HYDERABAD, INDIA (Nov 03, 2014) – Suven Life Sciences today informed that their NCE SUVN-3031 has commenced Phase 1 clinical trial in USA. SUVN-G3031 – A potent, selective, brain penetrant and orally active Histamine H3 antagonist for the treatment of cognitive dysfunction associated with Alzheimer’s Disease / Schizophrenia has completed all the pre-clinical, safety and early toxicological studies, GLP toxicological studies and was submitted forInvestigational New Drug Application {IND) to conduct Phase 1 clinical trial with the indication for Cognition in Alzheimer’s Disease under 505(1) of the Federal Food, Drug and Cosmetic Act (FDCA) which was assigned an IND number 123179.

Based on the IND “A Single Center, Double-blind, Placebo-controlled, Randomized, Phase 1 Study to Evaluate the safety, Tolerability, and Pharmacokinetics of SUVN-G3031 after Single Ascending Doses and Multiple Ascending Doses in Healthy Male Subjects” for Cognition in Alzheimer’s Disease is underway in USA

“We are very pleased that the second compound from our pipeline of molecules in CNS has moved into clinical trial that is being developed for cognitive disorders in Alzheimer’s and Schizophrenia with high unmet medical need which has huge market potential globally” says Venkat Jasti, CEO of Suven.

Suven Life Science is a biopharmaceutical company focused on discovering, developing and commercializing novel pharmaceutical products, which are first in class or best in class CNS therapies through the use of GPCR targets. The Company has eleven (11) internally-discovered therapeutic drug candidates currently in pre-clinical stage of development targeting conditions such as ADHD, dementia, major depressive disorder (MDD), Huntington’s disease, Parkinson’s disease and obesity in addition to this Phase 1 developmental candidate SUVN-G301 and Phase 2 a (PoC) ready SUVN-502 for Alzheimer’s disease and Schizophrenia.

SYNTHESIS

PATENT

WO2012114348

OR SEE

https://www.google.com/patents/US20140135304?cl=en22

PATENT

WO2014030170

Scheme I as shown below.

PATENT

WO-2016027275

process for large scale production of N-[4-(l-Cyclobutyl piperidin-4-yloxy) phenyl]-2-(morpholin-4-yl) acetamide dihydrochloride of formula (I).

N-[4-(l-Cyclobutyl piperidin-4-yloxy) phenyl]-2-(moφholin-4-yl) acetamide dihydrochloride, is a promising pharmaceutical agent, which is potent and selective Histamine ¾ receptor ligand intended for the symptomatic treatment of cognitive disorders, dementia, attention deficit hyperactivity disorder, epilepsy, sleep disorders, sleep apnea, obesity, schizophrenia, eating disorders and pain. N-[4-(l-Cyclobutyl piperidin-4-yloxy) phehyl]-2-(morpholin-4-yl) acetamide dihydrochloride and its synthesis is disclosed by Ramakrishna et al. in WO20121 14348.

Currently N-[4-(l-Cyclobutyl piperidin-4-yloxy) phenyl] -2-(morpholin-4-yl) acetamide dihydrochloride has completed preclinical studies and is ready to enter human clinical trials. The demand for N-[4-(l-Cyclobutyl piperidin-4-yloxy) phenyl]-2-(morpholin-4-yl) acetamide dihydrochloride as a drug substance has increased substantially with the advent of its clinical testing. The future need for much larger amounts is projected due to the intended commercialization of N-[4-( 1 -Cyclobutyl piperidin-4-yloxy) phenyl]-2-(morpholin-4-yl) acetamide dihydrochloride.

For the person skilled in art, it is a well known fact that various parameters will change during the manufacture of a compound on a large scale when compared to the synthetic procedures followed in laboratory. Therefore, there is a need to establish and optimize large scale manufacturing process. The process for the preparation of N-[4-(l-Cyclobutyl piperidin-4-yloxy) phenyl]-2-(morpholin-4-yl) acetamide dihydrochloride disclosed in WO20121 14348 was proved to be unsatisfactory for adaptation to the large scale manufacturing. Hence it is highly desirable to establish optimized manufacturing process of N-[4-(l-Cyclobutyl piperidin-4-yloxy) phenyl] -2 -(morpholin-4-yl) acetamide dihydrochloride of formula (I), which is amenable to the large scale manufacturing of the compound.

Example 1: Preparation of N-[4-(l-Cyclobutyl piperidin-4-yloxy) phenyl]-2-(raorpholin-4-yl) acetamide dihydrochloride

Step (i): Preparation of l-cycIobutylpiperidin-4-ol

Ethylene dichloride (235 L) was charged into the reactor at 20-25 °C followed by 4-hydroxy piperidine (9.5 Kg, 93.92 M). The mass was stirred for ~ 15 minutes to obtain a clear, solution. Then cyclobutanone (7.9 Kg, 1 12.71 M) was charged into the reactor at 20-25 °C and stirred the mass for 90 minutes at the same temperature. The mass was cooled to 15-20 °C and started lot wise addition of sodium triacetoxy borohydride (39.9 Kg, 188.26 M) maintaining the mass temperature below 25 °C in ~ 110 minutes. After completion of addition, the mass was stirred for 30 minutes at ~ 20 °C. The mass temperature was raised to 25-30 °C and maintained at the same temperature for ~ 13.1 hours, while monitoring the progress of the reaction by Thin Layer Chromatography (TLC). After completion of the reaction, water (1 12 L) was charged into the reactor at 25-30 °C. The mass was then cooled to 15-20 °C and pH of the reaction mass was adjusted to 13.0-13.5 with a solution of aqueous sodium hydroxide (24.6 Kg of sodium hydroxide dissolved in 106 L of demineralised water (DM water) maintaining the mass

temperature below 20 °C in about 1 hour 20 minutes. In the meanwhile, nutsche filter with hyflow bed (using 4.75 Kg hyflow and 47.5 L DM water) was made ready for filtration of dirt and sodium acetate salt, for the purpose of clean layer separations during extraction of the product. The reaction mass was filtered through nutsche and the nutsche was washed with 23.75 L of ethylene dichloride. The filtrate containing the product was collected into clean and dedicated containers. The combined filtrate and washings were transferred to a reactor, stirred 15 minutes and settled for 15 minutes at 25-30 °C. The bottom organic layer (containing the product) was collected in dedicated containers and the mass was dried over anhydrous sodium sulfate (9.5 Kg). The supernatant, clean, dry organic layer was taken in a reactor and solvent was removed by distillation under vacuum maintaining mass temperature below 50 °C. The residual crude mass was cooled to 25-30 °C.

2^nd extraction of the aqueous layer: The aqueous layer separated as above was taken in a reactor and charged dichloromethane (DCM) (56 L) at 25-30 °C. The mass was stirred 15 minutes and settled for 15 minutes. The bottom organic layer (containing product) was separated into dedicated containers. The aqueous layer was collected and taken for 3 ^rd extraction.

3 ^rd extraction of the aqueous layer: The aqueous layer separated as above was takenin a reactor and charged DCM (56 L) at 25-30 °C. The mass was stirred 15 minutes and settled for 15 minutes. The bottom organic layer (containing product) was separated into dedicated containers. The aqueous layer was collected and taken for 4^th extraction.

4^th extraction of the aqueous layer: The aqueous layer separated as above was taken in a reactor and charged DCM (56 L) at 25-30 °C. The mass was stirred 15 minutes and settled for 15 minutes. The bottom organic layer (containing product) was separated into dedicated containers. The aqueous layer was collected and taken for 5^th extraction.

5^th extraction of the aqueous layer: The aqueous layer separated as above was taken in a reactor and charged dichloromethane (56 L) at 25-30 °C. The mass was stirred 15 minutes and settled for 15 minutes. The bottom organic layer

(containing product) was separated into dedicated containers. The aqueous layer was collected in dedicated containers and kept aside.

The organic layer obtained from second extraction to fifth extraction was combined and dried over anhydrous sodium sulfate (13.5 Kg). The supernatant, clean, dry organic layer was taken in the reactor, containing the crude product obtained from first extraction, and solvent was removed by distillation under reduced pressure (>500 mm Hg) maintaining mass temperature below 50 °C. The residual mass was cooled to 25-30 °C and collected the technical product (14.36 Kg).

Yield: 98.49 %;

Ή-NMR (δ ppm, CDC1₃): 1.55 – 1.69 (5H, m), 1.83 – 2.02 (8H, m), 2.65 – 2.69 (3H, m), 3.66 – 3.70 (1H, m);

Mass (m/z): 156.2 (M+H)⁺.

Step (ii): Preparation of 4-(l-cyclobutylpiperidin-4-yIoxy)-l-nitrobenzene

Tetrahydrofuran (THF) (43.2 L) was charged into a Stainless steel reactor (SS reactor) at 25-30 °C under nitrogen atmosphere followed by addition of sodium hydride (5.22 Kg) maintaining mass temperature at 25-30 °C under nitrogen atmosphere. The contents were stirred for 15 minutes at 25-30 °C. The temperature of the reaction mass was raised to 35-40 °C.

THF (56.7 L) was charged into another SS reactor at 25-30 °C under nitrogen atmosphere by the addition of above obtained step (i) material (13.5 Kg, 86.96 M). The mass was stirred for 15 minutes at 25-30 °C to obtain a clear solution. The resulting solution was added to the above reactor containing sodium hydride in THF, maintaining the mass temperature of the main reactor at 35-40 °C over a period of ~ 45 minutes under nitrogen atmosphere. The resulting mass was further stirred for 90 minutes at 35-40 °C.

In the meanwhile THF (35.8 L) was charged into another SS reactor at 25-30 °C under nitrogen atmosphere, followed by the addition of 4-fluoro-l-nitrobenzene (14.72 Kg, 104.32 M). The contents of the reactor were stirred for 15 minutes at 25-30 °C to obtain a clear solution. The clear solution, thus obtained, was slowly transferred to the main reactor in ~ 45 minutes maintaining the mass temperature of the main reactor at 35-40 °C. The temperature of the reaction mass was further maintained at 35-40 °C for 5 hours under stirring and under nitrogen atmosphere, while monitoring the progress of the reaction by TLC. After completion of the reaction, the reaction mass was cooled to 15-20 °C.

. Charged water (675 L) into another SS reactor under nitrogen atmosphere. The contents of the reactor were cooled to 5-10 °C. Then the reaction mass from the main reactor was transferred carefully to this reactor containing water, maintaining the mass temperature below 20 °C in ~ 45 minutes. The resulting mass was further stirred for 30 minutes maintaining the temperature at 15-20 °C. The solid mass was centrifuged and the mother liquors were collected in dedicated containers. The cake on the centrifuge was washed with water (2 x 135 L) and spin dried to obtain technical product (19.80 Kg).

Purity: 99.5 %.

Purification: Dissolved the technical product obtained as above (19.80 Kg) in ~ 200 L of 10 % aqueous acetic acid solution (~ 20.59 Kg acetic acid diluted with 180 L with water) at 25-30 °C.

1^st toluene extraction: Stirred 15 minutes and then charged toluene (33 L) at 25-30 °C. Stirred 15 minutes and settled for 15 minutes and layers separated, The top organic layer containing the impurities was kept aside in a dedicated container.

2^nd toluene extraction: The lower aqueous product layer was taken into the reactor again and charged toluene (33 L) at 25-30 °C. Stirred 15 minutes and settled for 15 minutes and layers separated. The top organic layer containing the impurities was kept aside in the dedicated container.

3^rd toluene extraction: The lower aqueous product layer was taken again into the reactor and charged toluene (25 L) at 25-30 °C. Stirred 15 minutes and settled for 15 minutes and layers separated. The top organic layer containing the impurities was kept aside in the dedicated container.

The aqueous product layer was charged into the reactor at 25-30 °C. The mass was cooled to 10 – 15 °C. pH of the reaction mass was adjusted to 1 1.5 -12.0; with 20 % w/v aqueous sodium hydroxide solution (prepared by dissolving 15.44 Kg sodium hydroxide flakes in 69.3 L of DM water) while maintaining mass temperature at 10-15 °C for 1.45 hours. The resulting mass was stirred for 15 minutes at 25-30 °C at pH 11.55. The solids that separated were centrifuged. The cake was washed with (40 L x 2) DM water and the product was spin dried (19.9 Kg), Yield: 53.56 %

Purity: 99.52 %.

Ή-NMR (δ ppm, CDC1₃): 1.58 – 1.73 (2H, m), 1.84 – 1.93 (4H, m), 2.02 – 2.06 (4H, m), 2.19 (2H, s), 2.62 (2H, s), 2.71 – 2.76 (1H, m), 4.45 (1H, s), 6.93 – 6.95 (2H, d, J = 9.07 Hz), 8.18 – 8.20 (2H, d, J = 9.02 Hz);

Mass (m/z): 277.2 (M+H)⁺.

The aqueous layer (obtained after eentrifuging and washing the product) was collected in dedicated containers for isolation of the second crop.

Step (iii): Preparation of 4-(l-cyclobutylpiperidin-4-yloxy) aniline

The reaction was done in a SS reactor under nitrogen blanket. DM Water

(33.59 L) was charged into a SS reactor at 25-30 °C followed by iron powder (10.43 Kg, 186.75 M, 1 :4 ratio) under stirring. Then ammonium chloride (11.5 Kg, 215 M) was charged at 25-30 °C and stirred the contents for 15 minutes at 25-30 °C. The mass temperature was raised slowly to 95- 100 °C and maintained at that temperature (95-100 °C).for.^.90 minutes. The mass was cooled to 75-80 °C.

In the meanwhile, ethyl alcohol (128.7 L) was charged into another reactor at 25-30 °C, followed by addition above obtained compound (19.9 Kg). The contents were stirred for 15 minutes and then raised the mass temperature to 50-55 °C, where by a clear solution was obtained. The mass was slowly transferred to the main reactor, containing the activated iron powder at 78-80 °C over a period of ~ 70 minutes. The mass was further stirred for 3 hours, while maintaining the mass temperature at 75-80 °C. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was cooled to 25-30 °C and filtered through nutsche, containing hyflow bed. The filtrate was collected into dedicated containers. The bed was washed with 3 x 32.18 L of ethyl alcohol and collected the washings into dedicated containers. The combined filtrate was charged into a clean SS reactor at 25-30 °C. All the volatiles are distilled off under reduced pressure (> 500 mm Hg) maintaining the mass temperature below 55 °C. The residual mass was cooled to 25-30 °C and charged DM water (32.18 L). The pH of the reaction mass was adjusted to 9.0 – 10.0 with 91 L of sodium carbonate solution (prepared by dissolving 21.5 Kg of sodium carbonate in 80 L of DM water), while maintaining the mass temperature at 25-30 °C. Final pH is 9.14. The solid mass, separated in the reactor, was cehtrifuged and collected the filtrate in dedicated containers. The product was spin dried (20.34 Kg).

Ethylacetate (EtOAc) (80 L) was charged into a clean SS reactor at 25-30 °C followed by the wet cake (20.34 Kg) obtained above. The mass was stirred for 15 minutes at 25-30 °C. Then added DM water (32 L) and further stirred the mass for 15 minutes and settled for 15 minutes. The aqueous layer was separated and collected in dedicated containers.

The organic layer containing the product was filtered through nutsche filter through hyflow bed (formed with 5.15 Kg hyflow and 26 L water) and filtrate was collected in dedicated containers. The bed was washed with EtOAc (13 L). The combined organic layer and EtOAc washings were charged into a clean SS reactor. Charged 20 L DM water, stirred for 15 minutes and settled for 15 minutes at 25-30 °C. The aqueous layer is separated and the organic layer was dried over anhydrous sodium sulfate (20 Kg).

The clean, dried organic layer was charged into a reactor at 25-30 °C. Solvent was distilled off under reduced pressure (> 500 mm Hg) below 50 °C (Solvent recovered: 70 L). The residual product was cooled to 25-30 °C and unloaded into dedicated containers (12.30 Kg) and sent for complete analysis. Weight of the product: 12.3 Kg (wet with solvent EtOAc: 9.1 %),

Yield (on dry basis): 9.7.5 %;

Purity: 97.79 %;

IR (cm-‘): 3424, 3345, 2943, 1627, 1509, 1229, 1 168, 1044, 821 ;

1H-NMR (5 ppm, DMSO): 1.49 – 1.61 (4H, m), 1.71 – 1.83 (4H, m), 1.92 – 1.97 (5H, m), 2.52 – 2.53 (2H, m), 3.99 – 4.04 (1 H, m), 4.59 (2H, bs), 6.46 – 6.48 (2H, d, J = 8.60 Hz), 6.61 – 6.63 (2H, d, J = 8.66 Hz);

Mass (m/z): 247.4 (M+H)⁺.

Step (iv): Preparation of 2-chloro-N-[4-(l-cycIobutyI piperidin-4-yloxy).

phenyl] acetamide

The reaction was done in a SS reactor under nitrogen blanket. THF (89.6

L) was charged into a Glass reactor (GLR) at 25-30 °C followed by addition of above obtained material (1 1.2 Kg on dry basis, 45.46 M). The contents were stirred 15 minutes. Then charged anhydrous potassium carbonate (K₂C0₃) powder (12.54 Kg, 90.73 M) into the reactor and stirred the mass for 15 minutes at 25-30 °C. The reaction mass was cooled to -10 to -5 °C by circulating brine in the jacket. Then a solution of chloroacetylchloride (6.72 Kg, 59.5 M) dissolved in THF (44.8 L) was slowly introduced into the reactor through a holding tank, under nitrogen atmosphere, in ~ 2.5 hours maintaining the mass temperature at -10 to -5 °C. The reaction mass was further maintained under stirring at -10 to -5 °C for another 2 hours while monitoring the progress of the reaction by TLC.

After completion of the reaction, slow addition of chilled DM water (186 L) through the addition funnel started at -10 to -5 °C. Towards the end of addition of DM water (addition time 45 minutes), it was so adjusted that the mass temperature reached 10-15 °C. After completion of addition of DM water the mass temperature was raised to 25-30 °C.

1^st extraction: Ethyl acetate (1 12 L) charged into the reactor at 25-30 °C. The mass was stirred 30 minutes and settled for 30 minutes. Layers separated and the organic product layer was collected in dedicated containers.

2^nd extraction: The aqueous layer obtained as above was charged into the reactor followed by EtOAc (1 12 L) at 25-30 °C. The mass was stirred 30 minutes and settled for 30 minutes. Layers separated and the organic product layer and the aqueous layer were collected in dedicated containers.

The combined organic layer, obtained from the above extractions, was charged into a clean GLR followed by the addition of 116 L of brine solution (prepared by dissolving 33.6 Kg sodium chloride in 1 12 L DM water) at 25-30 °C. The mass was stirred for 30 minutes and settled for 30 minutes at 25-30 °C. The aqueous layer was separated and collected in dedicated containers. The organic product layer was dried over anhydrous sodium sulfate (22.4 Kg). The volume of the organic layer was 360 L. The organic layer obtained as above was charged into a clean GLR at 25-30 °C. Solvent was distilled off under reduced pressure (> 500 mm Hg) maintaining mass temperature below 55 °C (volume of recovered solvent; 178 L). The mass was cooled to 25-30 °C. Solid mass separated in the reactor.

Recrystallization

Isopropanol (72.8 L) was charged into the reactor containing the solids (~ 13.5 Kg) at 25-30 °C, followed by methanol (~ 58.2 L) at 25-30 °C. Stirred the reaction mass at 25-30 °C for 30 minutes. The mass temperature was raised slowly to reflux temperature and maintained at reflux till a clear solution is obtained (~ 30 minutes). Then the mass was cooled to 25-30 °C and stirred the mass for 60 minutes. The mass was further cooled to -12 -15 °C, stirred for 30 minutes and centrifuged the material. The cake on the centrifuge was washed with 2 x 7 L isopropanol (25-30 °C) and spin dried thoroughly.

The wet cake (1 1.2 Kg) was dried in a vacuum tray drier (VTD) for ~ 4 hours at 40-50 °C to obtain crystallized product (9.7 Kg).

Yield: 66.12 %;

Purity (by HPLC): 99.56 %; – IR (cm-¹): 3307, 3278, 2951, 1670.43, 1612, 1554.69, 1508.4/1240.28, 1 171.81 , 1047.39, 953.84, 832.32;

1H-NMR (δ ppm, DMSO): 1.53 – 1.61 (4H, m), 1.72 – 1.74 (2H, m), 1.87 – 1.99 (6H, m), 2.49 – 2.53 (2H, m), 2.64 – 2.68 (1H, m), 4.19 (2H, s), 4.24 – 4.29 (1H, m), 6.88 – 6.90 (2H, d, J = 8.96 Hz), 7.44 – 7.46 (2H, d, J = 8.96 Hz), 10.12 (1H, s); …. . . .. ^■÷. ^“

Mass (m/z): 323.3, 325.2 (M+H)⁺.

Mother liquor obtained, after recrystallization and centrifuging the product, was processed for isolating second crop.

Step (v): Preparation of N-[4-(l-cycIoburyl piperidin-4-yIoxy) phenyI]-2-(morphoIin-4-yl) acetamide

Acetonitrile (1.41 L) was charged into the GLR at 25-30 °C under nitrogen atmosphere, followed by addition of the above obtained material (9.4 Kg, 29.11 M). Then, charged anhydrous K₂C0₃ granules (6.0 Kg, 43.41 M) into the reactor at 25-30 °C. Stirred the reaction mass in the reactor for 10 minutes and charged morpholine (3.3 Kg, 37.88 M). The contents of the reactor were stirred for 15 minutes at 25-30 °C. The temperature of the reaction mass was raised slowly to reflux (80-82 °C) and maintained at reflux for 4 hours while monitoring the progress of the reaction every two hours by HPLC.

Analysis of the sample by HPLC after 4 hours reflux: 89.61 % product and 8.83 % starting material (SM).

Charged morpholine (253 grams) and K₂C0₃ (400 grams) and further refiuxed. Analysis by of the sample at 7.5 hours: 92.8 % product and 5.63 % SM. So charged morpholine (506 grams), K₂C0₃ (810 grams) and acetonitrile (30 L) and heated the mass at reflux for another five hours. Analysis of the sample at 12.5 hours: 96.78 % product and 2.06 % SM. Again charged K₂C0₃ (820 grams), morpholine (255 gm) and acetonitrile (40 L) and maintained the mass under reflux. Analysis of the sample at 19.5 hours: 97.52 % product and 0.9 % SM. The reaction mass was cooled to 30-35 °C and filtered solids through nutsche at 30-35 °C. The cake on the nutsche was washed with 15 L acetonitrile; Mother liquors (~ 210 L filtrate) were taken back into the main reactor (GLR) and kept under stirring at 30 – 35 °C, while workup of the solid cake (22.4 Kg), containing the product along with salts, was going on in another reactor.

Wet weight of cake: 22.4 Kg (contained ~ 23 % product).

Charged 30 L water into another reactor followed by the wet cake obtained after nutsche filtration (22.4 Kg). Stirred the mass for 30 minutes and charged EtOAc (47 L). The mass was stirred 15 minutes and settled for 15 minutes. The organic layer containing the product was collected in dedicated containers. pH of the aqueous mother liquors was found to be 10.05 on pH meter.

2^nd extraction: Charged the above obtained aqueous layer into the reactor followed by EtOAc (47 L). The mass was stirred 15 minutes and settled for 15 minutes and layers separated. The organic layer containing the product was collected in dedicated containers.

3^nd extraction: Charged the above obtained aqueous layer into the reactor followed by EtOAc (40 L). The mass was stirred 15 minutes and settled for 15 minutes and layers separated. The organic layer containing the product was collected in dedicated containers.

The combined organic layer was dried over sodium sulfate (9.4 Kg) and the clean organic layer was taken for distillation under reduced pressure (> 500 mm Hg) at 50-55 °C. The mass was cooled to 25-30 °C. Added 23.5 L of acetonitrile and stirred well.

Part of the reaction mass (65 L of acetonitrile solution) from GLR was unloaded and charged into the above reaction mass at 25-30 °C and stirred 30 minutes, whereby a clear solution was obtained. The mass was transferred to the main reactor. Washing was given to this reactor with 20 L fresh acetonitrile at 40-45 °C and again transferred to the main reactor and stirred 15 minutes before sampling.

The final, uniformly mixed reaction mass was sampled from the main GLR and analyzed. HPLC: 99.09 % product and 0.31 % SM. So charged morpholine (510 grams) and K₂C0₃ (825 grams) and the mass was heated to reflux and further maintained the mass at reflux temperature for 2 hours. A sample was analyzed after 2 hours reflux. Starting material was absent (product purity: 99.24 %).

The reflux was further continued for another 2 hours and then cooled the mass temperature to 30-35 °C. Solvent was distilled off under reduced pressure (> 500 mm Hg), maintaining mass temperature below 55 °C.

1^st Extraction: Charged DM water (23.5 L) to the residual mass at 25-30 °C. Stirred the mass for 15 minutes and charged ethyl acetate (80 L). A clear solution was obtained. Stirred the mass for 15 minutes and settled the mass for 15 minutes. Layers separated and the product organic layer collected in dedicated containers. 2^ndExtraction: The aqueous layer obtained as above (pH was found to be 9.9 on meter) was charged into the reactor followed by ethyl acetate (40 L). Stirred the mass for 15 minutes and settled the mass for 15 minutes. Layers separated and the product organic layer collected in dedicated containers.

3^nd Extraction: The aqueous layer obtained as above was once again charged into the reactor followed by ethyl acetate (40 L). Stirred the mass for 15 minutes and settled the mass for 15 minutes. Layers separated and the product organic layer collected in dedicated containers.

Brine washing: The combined organic layer was taken in the reactor and charged

~ 35 L brine solution (prepared by dissolving 9.4 Kg sodium chloride in 28.2 L DM water). The mass was stirred for 15 minutes and settled for 30 minutes.

Layers separated and collected aqueous layer in dedicated containers.

The organic product layer was dried over anhydrous sodium sulfate (18.8

Kg). Total volume of the organic layer was 185 L. The solvent was distilled off under reduced pressure (> 500 mm Hg) maintaining mass temperature below 55 °C. Solid mass (Step-5 material) separated in reactor.

Yield: Quantitative; ⁵

Purity: 99.51 %;

1H-NMR (CDC1₃, δ ppm): 1.65 – 2.04 (12H, m), 2.61 – 2.63 (6H, m), 2.69 – 2.77 (1H, m), 3.12 (2H, s), 3.76 – 3.78 (4H, m), 4.26 – 4.27 (1H, m), 6.87 – 6.89 (2H, d, J = 8.82 Hz), 7.43 – 7.45 (2H, d, J – 8.80 Hz), 8.91 (1H, s);

Mass (m/z): 374.4 (M+H)⁺.

Step (vi): Preparation of N-[4-(l-CyclobutyI piperidin-4 yloxy) phenyl]-2-(morphoIin-4-yl) acetamide dihydrochloride

Charged isopropyl alcohol (75 L) into the reactor containing step (v) product. The reaction mass temperature was raised to 50-55 °C and stirred for 30 minutes to obtain a clear solution. The mass was cooled to 25 °C before starting the addition of isopropanolic hydrochloride (Isopropanolic HC1).

Isopropanolic HC1 (16.2 L, 16.1 % w/v) was diluted with isopropanol (8 L) and charged into a holding tank. Isopropanolic HC1 in the holding tank was transferred slowly into the reactor in 90 minutes, maintaining mass temperature ~ 22 – 28 °C (now and then giving jerks with brine in the reactor jacket). The resulting mass was further stirred under maintenance at 25-30 °C for 6 hours. The mass was centrifuged; the cake on the centrifuge was washed with fresh isopropanol, 16 L (for slurry wash) + 5.5 L (for spray wash) and spin dried to obtain 20.26 Kg of wet product. Purity: 99.37 %. The material was unloaded into trays and dried in a VTD at 50 – 60 °C for 16 hours.

Final weight: 12.62 Kg;

Yield: 97 %;

Ή-NMR (δ ppm, DMSO): 1.65 – 2.0 (4H, m), 2.13 – 2.19 (4H, m), 2.33 – 2.48 (2H, m), 2.8 – 3.42 (6H, m), 3.67 – 3.92 (6H, m), 4.16 (2H, s), 4.49 – 4.70 (2H, m), 6.97 – 7.03 (2H, m), 7.51 – 7.54 (2H, m), 10.54 (1H, bs), 10.73 (1H, bs), 1 1.01 (lH, bs);

Mass (m/z): 374.4 (M+H)⁺.

Step (vii): Recrystallization of N-[4-(l-CycIobutyl piperidin-4-yloxy) phenyl]-2-(morphoIin-4-yl) acetamide dihydrochloride

The reaction was done in a GLR reactor under nitrogen blanket. Methanol (24.8 L) was charged into a GLR followed by addition of above obtained technical material (6.2 Kg, 13.89 M) at 25-30 °C. The mass was stirred for 30 minutes to obtain a clear solution. Filtered the mass through nutsche and washed the nutsche with methanol (6.2 L). The filtrate and washing were charged into a clean GLR at 25-30 °C.

The contents of the reactor were heated to 62-63 °C, where a gentle reflux of methanol started. Addition of isopropanol (31 L) through the addition tank started at this temperature of ~ 62 °C. Addition of isopropanol was completed in one hour, while maintaining mass temperature at 62-63 °C. The mass was allowed to cool on its own to room temperature by applying air in the jacket. Solids were separated in the reactor at 48 °C in 3 hours. The mass was allowed to cool to ~ 35 °C on its own. The mass was further cooled to ~ 15 – 20 °C in 2 hours (brine jerks given to the reactor jacket) and the temperature was maintained at ~ 15 – 20 °C for 15 minutes.

The mass was centrifuged. The wet cake on the filter was washed with isopropanol (slurry wash) using 9 L isopropanol at 25-30 °C. The mass was spin dried in the centrifuge for 1 hour, unloaded (wet weight: 5.0 Kg) taken to vacuum tray drier and dried at 50-60 °C for 12 hours.

Weight of the product: 4.20 Kg;

Yield: 67.7 %;

HPLC purity (gradient): 99.71 %;

Any other impurity: < 0.1 %;

Salt content (di HC1): 16.16 %;

Melting Range: 247.0 – 249.5 °C;

DSC (2 °C / min, onset): 246.41 °C

TGA (5 °C / min): 0.45 %

Chemical Assay (% w/w): 101.53 %;

IR (cm^“1): 3280, 3085, 2935, 2498, 1689, 1604, 1552, 1505, 1235, 1 120 and 830. Ή-NMR (δ ppm, DMSO): 1.62 – 2.0 (4H, m), 2.12 – 2.16 (4H, m), 2.37 – 2.42

(2H, m), 2.78 – 2.91 (2H, m), 3.16 – 3.60 (6H, m), 3.66 – 3.91 (5H, m), 4.17 (2H, s), 4.47 – 4.70 (1 H, m), 6.96 – 7.03 (2H, m), 7.52 – 7.56 (2H, m), 10.69 (1H, bs),

10.86 – 10.89 (1H, bd), 1 1.36 – 1 1.37 (1 H, bd);

Mass (m/z): 374.4 (M+H)⁺.

¹³C-NMR (DMSO, δ ppm): 13.48, 13.61, 24.94, 25.10, 25.98, 27.89, 43.85, 47.06,

52.00, 57.08, 58.16, 63.38, 67.29, 71.20, 1 16.33, 1 17.07, 121.36, 132.02, 132.24,

153.03, 153.37, 162.43.

SCHEME 1

Step (i): coupling of 4-hydroxy piperidine of formula (1) with cyclobutanone of formula (2) in presence of sodium triacetoxy borohydride in a suitable solvent to obtain l-cyclobutylpiperidin-4-ol of formula (3). The solvent used in the reaction can be selected from halohydrocarbons, preferably ethylene dichloride. This reaction is carried out at a temperature of 20 °C to 30 °C, preferably 25 °C to 30 °C. The duration of the reaction may range from 12 hours to 14 hours, preferably from a period of 13 hours to 13.5 hours.

Step (ii): coupling of 1 -cyclobutylpiperidin-4-ol of formula (3) with 4-fluoro-l-nitrobenzene of formula (4) in a suitable solvent and base to obtain 4-(l-cyclobutylpiperidin-4-yloxy)-l -nitrobenzene of formula (5). The solvent used in the reaction can be selected from ethers, preferably tetrahydrofuran. The base used in the reaction can be selected from alkali metal hydrides, preferably sodium hydride. This reaction is carried out at temperature of 30 °C to 45 °C, preferably 35 °C to 40 °C. The duration of the reaction may range from 5 hours to 6 hours, preferably from a period of 5.5 hours to 6 hours.

Step (iii): reduction of 4-(l-cyclobutylpiperidin-4-yloxy)-l -nitrobenzene of formula (5) using ammonium chloride and iron powder, in a suitable solvent to obtain 4-(l-cyclobutylpiperidin-4-yloxy) aniline of formula (6). The solvent used in the reaction can be selected from aqueous alcohols, preferably aqueous ethyl alcohol. This reaction is carried out at temperature of 70 °C to 85 °C, preferably 75 °C to 80 °C. The duration of the reaction may range from 3 hours to 5 hours, preferably for a period of 4 hours.

Step (iv): reaction of 4-(l-cyclobutylpiperidin-4-yloxy) aniline of formula (6) with chloroacetylchloride of formula (7) in a suitable solvent and base to obtain 2-chloro-N-[4-(l-cyclobutyl piperidin-4-yloxy)phenyl]acetamide of formula (8). The solvent used in reaction can be selected from ethers, preferably tetrahydrofuran. The base used in reaction can be selected from alkali metal carbonates, preferably potassium carbonate. This reaction is carried out at a temperature of -10 °C to 0 °C, preferably -10 °C to -5 °C. The duration of the reaction may range from 4.5 to 5.5 hours, preferably for a period of 5 hours.

Step (v): reaction of 2-chloro-N-[4-(l -cyclobutyl piperidin-4-yloxy)phenyl]acetamide of formula (8) with morpholine of formula (9) in a suitable solvent and base to obtain N-[4-(l-cyclobutyl piperidin^-yloxy) phenyl]-2-(morpholin-4-yl) acetamide of formula (10). The solvent used in the reaction can be selected from nitrile solvents, preferably acetonitrile. The base used in the reaction can be selected from alkalimetal carbonates, preferably potassium carbonate. This reaction is carried out at temperature of 75 °C to 85 °C, preferably 80 °C to 82 °C. The duration of the reaction may range from 20 hours to 30 hours, preferably for a period of 24 hours to 26 hours.

Step (vi): converting N-[4-(l-Cyclobutyl piperidin-4-yloxy) phenyl]-2-(morpholin-4-yl) acetamide of formula (10) in presence of isopropanolic hydrochloride and isopropanol to N-[4-(l-cyclobutyl piperidin-4-yloxy) phenyl]-2-(morpholin-4-yl) acetamide dihydrochloride of formula (11). This reaction is carried out at a temperature of 20 °C to 30 °C, preferably 25 °C to 30 °C. The duration of the reaction may range from 7 hours to 8.5 hours, preferably from a period of 7.5 hours to 8 hours.

Step (vii): recrystallization of N-[4-(l-Cyclobutyl piperidin-4-yloxy) phenyl]-2-(morpholin-4-yl) acetamide dihydrochloride of formula (11) in presence of isopropanol and methanol to obtain N-[4-(l-Cyclobutyl piperidin-4-yloxy) phenyl] -2-(morpholin-4-yl) acetamide dihydrochloride of formula (I). This reaction is carried out at a temperature of 58 °C to 63 °C, preferably 62 °C to 63 °C. The duration of the reaction may range from 4 hours to 5 hours, preferably for a period of 4.5 hours.

SUVEN Life Sciences Ltd

REFERENCES

https://www.nia.nih.gov/alzheimers/clinical-trials/suvn-g3031-safety-tolerability-and-pharmacokinetics

http://www.alzheimersanddementia.com/article/S1552-5260(14)01286-2/abstract

http://suven.com/news_Apr2015_13.htm

///////SUVN-G3031, HISTAMINE H3 RECEPTOR ANTAGONIST, TREATMENT OF COGNITIVE DEFICITS, SUVN G3031, PHASE 1, SUVEN

O=C(CN1CCOCC1)Nc4ccc(OC2CCN(CC2)C3CCC3)cc4

KHK 7580, MT 4580 structure cracked correctly in Mar 2015……It is Evocalcet

March 1, 2016 2:24 pm / 1 Comment on KHK 7580, MT 4580 structure cracked correctly in Mar 2015……It is Evocalcet

2D chemical structure of 870964-67-3

Evocalcet [INN]
RN: 870964-67-3
UNII: E58MLH082P

Benzeneacetic acid, 4-((3S)-3-(((1R)-1-(1-naphthalenyl)ethyl)amino)-1-pyrrolidinyl)-

KHK 7580, MT 4580 structure cracked correctly in Mar 2015……It is Evocalcet

http://chem.sis.nlm.nih.gov/chemidplus/rn/870964-67-3

read my original post

https://newdrugapprovals.org/2015/03/16/khk-7580/

Tags: Evocalcet, KHK-7580, Kyowa Hakko Kirin Co Lt, Mitsubishi Tanabe Pharma, MT 4580, phase 2

By DR ANTHONY MELVIN CRASTO Ph.D in Phase2 drugs on March 16, 2015

//////////

C[C@H](c1cccc2c1cccc2)N[C@H]3CCN(C3)c4ccc(cc4)CC(=O)O

SUVN-502, From Suven Life Sciences Ltd

March 1, 2016 9:17 am / 1 Comment on SUVN-502, From Suven Life Sciences Ltd

STR1

SUVN-502

CAS OF MONOHYDRATE MESYLATE 1791396-45-6

CAS MESYLATE 1791396-46-7

1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole dimesylate monohydrate

l-{(2-BROMOPHE YL) SULFONYLJ-5-METHOXY-3- [(4-METHYL-l-PIPERAZINYL) METHYLJ-1H-INDOLE DIMESYLATE MONOHYDRATE

l-[(2- bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-l-piperazinyl)methyl]-lH-indoIe dimesylate monohydrate

MF OF DIMESYLATE – C₂₁ H₂₄ Br N₃ O₃ S . 2 C H₄ O₃ S

Serotonin 6 receptor antagonists

STR1

……………..BASE form of SUVN-502

1 -[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-l -piperazinyl)methyl]-lH-indole

CAS OF BASE 701205-60-9, 478.40, C₂₁ H₂₄ Br N₃ O₃ S

1H-Indole, 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-, methanesulfonate (1:2)

5-HT 6 receptor antagonist

SUVN-502 (in phase II)

https://www.clinicaltrials.gov/ct2/show/NCT02580305

Suven Life Sciences Ltd

IN 2013CH05537

Used as 5-HT 6 receptor antagonist for treating Alzheimer’s disease, attention deficit hyperactivity disorder, Parkinson’s disease and schizophrenia.

SUVN-502

SUVN-502 is a pure 5-HT₆ receptor antagonist with >1200-fold selectivity over 5-HT_2A receptor with a superior profile that differentiates from competitor 5-HT₆ antagonists. SUVN-502 has an excellent human pharmacokinetics for once a day treatment.

The Phase 2A trial is designed to evaluate the safety, tolerability, pharmacokinetics and efficacy of SUVN-502 for the treatment of moderate Alzheimer’s Disease (AD).This trial is expected to enrol 537 patients and the primary objective of the study is to evaluate the efficacy of a serotonin receptor subtype 6 (5-HT₆) antagonist, SUVN-502, at daily doses of 50 mg or 100 mg compared to placebo, as adjunct treatment in subjects with moderate Alzheimer’s disease (Mini-Mental State Examination [MMSE] score of 12 to 20) currently treated with the acetylcholinesterase inhibitor, Donepezil Hydrochloride (HCl) and the N-methyl-D-aspartic acid (NMDA) antagonist, MemantineHCl. Efficacy will be assessed by the 11-item Alzheimer’s Disease Assessment Scale for Cognitive Behaviour (ADAScog-11) after 26 weeks of treatment. The trial is likely to complete by end of second quarter 2017, subject to the achievement of estimated 12 months’ enrolment goal in USA.

Secondary objectives of this POC study are to further evaluate the efficacy of these treatments usingClinical Dementia Rating (CDR) Scale, Sum of Boxes (CDR-SB), MMSE, Alzheimer’s Disease Co-operative Study Activity of Daily Living (ADCS-ADL), Neuropsychiatric Inventory (NPI) 12 item and Cornell Scale for Depression and Dementia (C-SDD).

This study is being coordinated by Dr. Jeffrey Cummings, MD, Director, Cleveland Clinic Lou RuvoCenter for Brain Health, Las Vegas, NV, USA.

Prior to the initiation of Phase 2A study, SUVN-502 has successfully undergone two phase 1 studies in Switzerland and USA on 122 healthy young and elderly male populations with no major adverse events and no serious adverse events.

5-HT₆ receptor is one of the potential therapeutic target for the development of cognitive enhancers for the treatment of Alzheimer’s disease (AD) and schizophrenia. 5-HT₆ receptor is localized exclusively in central nervous system, in areas important for learning and memory. In recent years several studies (Brain Research, 1997, 746, 207-219; Journal of

Neuroscience, 1998, 18(15), 5901-5907; International Review of Neurobiology Volume 96, 201 1 , 27-47 & Annual Reviews in Pharmacology and Toxicology, 2000, 40, 319-334a) have reported that 5-HT₆ receptor antagonists show beneficial effect on cognition in animal models.

PATENT

WO2015083179

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015083179

l-[(2- bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-l-piperazinyl)methyl]-lH-indoIe dimesylate monohydrate of formula (I) of the present invention is illustrated by the Sc eme-1 as given below:

Mannich Adduct

Scheme-1

Example 1: Preparation of l-[(2-bromophenyI)suIfonyl]-5-methoxy-3-[(4-methyl-l-piperazinyI)methyl]-lH-indole dimesylate monohydrate

Step (i) & (u): Preparation of 5-methoxy-3-[(4-methyl-l-piperazinyI)methyl]-lH-indole

Step (i):

1-Methylpiperazine (15 Kg, 0.15 Kg Mole) was charged into a reactor. The mass was cooled to 5 °C – 10 °C. Demineralised water (12 Kg) was added to the above mass slowly, maintaining the mass temperature 10 °C – 20 °C, over a period of 30 minutes. Then added acetic acid (6.16 Kg, 0.103 Kg Mole) to the above mass in 30 minutes, maintaining the mass temperature at 10 °C – 20 °C. The mass was further stirred for another 15 – 20 minutes at 10 °C – 20 °C and aqueous formaldehyde solution (15.67 Kg, 30 % w/v, 0.1567 Kg Mole) was added in 60 minutes maintaining the mass temperature at 15 °C – 20 °C. The resultant thick, red colored reaction mass was stirred for another 2 hours at 20 °C – 30 °C to obtain the mannich adduct.

Step (ii):

Simultaneously in a separate reactor 125 Kg of methanol was charged at 25 °C – 35 °C. 5-methoxyindole (20 Kg, 0.1359 Kg Mole) was added and the mass was stirred to obtain a clear solution. The mass was cooled to 8 °C – 10 °C in 1.5 hours by circulating brine in the reactor jacket. The Mannich adduct, prepared as above, was charged into the reactor containing cooled methanolic solution of 5-methoxyindole from an addition tank over a period of 50 – 60 minutes, while maintaining the temperature of the reaction mass at 8 °C – 16 °C. After completion of addition, the mass temperature was allowed to rise to 20 °C – 35 °C. Then the reaction mass was further stirred for 3 hours at 20 °C – 35 °C. After completion of the reaction (thin layer chromtography), the reaction mass was discharged into clean and dry containers.

Another reactor was charged with 400 L of demineralised water followed by the addition of 20 Kg of lye solution at 20 °C – 35 °C. The content was cooled to 10 °C – 15 °C under stirring. The above reaction mass in the containers was added to the reactor, maintaining the mass temperature at 10 °C – 15 °C in 30 – 40 minutes. The final pH of the solution was adjusted to 9 – 12, if necessary by adding some more lye solution. Then the product was extracted with ethyl acetate (1 x 260 L & 4 x 160 L) maintaining the mass temperature at 10 °C – 15 °C during the entire operations. The pH of aqueous layer was adjusted to 9 – 12 before each extraction.

The combined organic layer was washed with (2 x 170 Kg) of brine solution (the brine solution was prepared by adding 95 Kg of vacuum salt to 245 Kg of demineralised water) at 20 °C – 35 °C. The total organic extracts, obtained after the brine washing, were dried over 35 Kg of anhydrous sodium sulfate under stirring for 30 minutes at 20 °C – 35 °C.

The organic layer was filtered and charged into another clean reactor. The solvent was removed totally under 500 – 600 mm of Hg vacuum, at 20 °C – 45 °C.

The residual mass, thus obtained, was cooled to room temperature and charged 60 L toluene and stirred the contents at 20 °C – 45 °C for 15 minutes. The solvent was distilled off under reduced pressure (500 – 700 mm of Hg vacuum) at 45 °C – 65 °C. The operation was repeated again by the addition of 60 L toluene and stirring the contents at 20 °C – 45 °C for 15 min. The solvent was distilled off under reduced pressure (500 – 700 mm of Hg vacuum) at 45 °C – 65 °C again to ensure total removal of ethylacetate to avoid losses during recrystallization step. The residual technical product, 5-methoxy-3-[(4-methyl-l- piperazinyl)methyl]-lH-indole, thus obtained, was recrystallized twice, as per the details given below, to obtain the product of desired purity.

Step (Hi): Crystallization of 5-methoxy-3-[(4-methyI-l-piperazinyl)methyl]-lH-indoIe

Charged 61 Kg of toluene into the above reactor which contains the technical product, 5-methoxy-3-[(4-methyl-l-piperazinyl)methyl]-lH-indole. The contents were heated to 85 °C – 95 °C and maintained for an hour at 85 °C – 95 °C. The clear solution, thus obtained, was allowed to cool to 30 °C – 40 °C by circulating room temperature water in the reactor jacket. The mass was further cooled to 10 °C – 15 °C and maintained for 3 hours at the same temperature. The crystalline solid mass was filtered through nutsche and the solid on the nutsche was washed with 18 L of chilled (10 °C – 15 °C) toluene and sucked well. The material was further washed with 20 L of n-hexane and sucked dry to obtain 22.7 Kg of crystalline material.

Step (iv): Recrystallization of 5-methoxy-3-[(4-methyI-l-piperazinyI)methyl]-lH-indole

Charged 40 Kg of toluene into a reactor followed by the addition of the 5-methoxy- 3-[(4-methyl-l-piperazinyl)methyl]-l H-indole (22.7 Kg) obtained in the first crystallization step under stirring. The contents were heated to 95 °C – 105 °C and maintained for 2 hours to obtain a clear solution. The mass was allowed to cool to 35 °C -40 °C by circulating room temperature water in the jacket. It was further cooled to 10 °C -15 °C and maintained for 3 hours at 10 °C – 15 °C. The crystalline solid mass was filtered through nutsche and the solid on the nutsche was washed with 8 L of chilled (10 °C – 15 °C) toluene and sucked well. The material was further washed with 15 L of n-hexane and sucked dry. The material was further dried in tray driers at 20 °C – 25 °C to obtain the title product, as off white crystalline powder.

Weight of the crystallized material: 19.95 Kg;

Yield (based on 5-methoxyindole charged): 56.6 %;

HPLC purity: 99.74 %;

Total impurities: 0.26 %;

Assay: 100.6 %;

Moisture content: 0.24 %;

Melting range (°C): 139 – 140.6;

IR spectra (cm^“1): 3125, 2951, 1875, 1622, 1585, 1492, 1351, 1288, 1215, 1059, 930, 654; Ή – NMR (CDCI3, δ ppm): 2.30 (3H, s), 2.5 (8H, bs), 3.71 (2H, s), 3.86 (3H, s), 6.83 -6.86 (1H, dd, J = 8.81, 2.7 Hz), 7.01 (1H, d, J = 2.06 Hz), 7.18 – 7.20 (2H, m), 8.91 (1H, s); ¹³C – NMR (CDCI3, δ ppm): 45.89, 52.79, 53.39, 55.1 1, 55.83, 101.3, 1 1 1.39, 11 1.75, 1 11.81, 124.88, 128.45, 131.48, 153.77;

Mass [M+H]⁺: 260.3.

Step (v): Preparation of l-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-l-piperazinyl)methyI]-lH-indoIe

Tetrahydrofuran (85.78 Kg) was charged into a reactor at 20 °C – 35 °C. Then charged the crystallized 5-methoxy-3-[(4-methyl-l-piperazinyl)methyl]-lH-indole (21.5 Kg, 0.0829 Kg Mole) into the reactor at 20 – 35 °C and stirred the mass well. The mass was cooled to 10 °C – 20 °C with chilled water in the jacket. Charged powdered potassium hydroxide (16.1 1 Kg) to the above suspension at 10 °C – 20 °C in 10 minutes under stirring. Slight exotherm was observed. Mass temperature rose from 15.1 °C to 16.3 °C. The mass was further stirred for 60 minutes at 10 °C – 20 °C. A solution of 2-bromobenzenesulfonyl chloride (27.71 Kg, 0.1084 Kg Mole) in 41.72 Kg tetrahydrofuran was added through addition tank at a constant rate in 60 minutes at 10 °C – 30 °C. The reaction was exothermic and the mass temperature went up from 16 °C to 30 °C. Then removed the chilled water from the jacket and stirred the mass for 3 hours at 25 °C – 35 °C. As the reaction was progressing the mass thickened due to formation of potassium chloride. The progress of the reaction was monitored by thin layer chromatography (Eiuent system: Chloroform and Methanol in 8:2 ratio and the product is relatively non-polar). Since thin layer chromatography shows the presence of starting material (5-methoxy-3-[(4-methyl-l-piperazinyl)methyl]-lH-indole), another lot of 2-bromo benzenesulfonyl chloride (4.5 Kg, 0.0176 Kg Mole) dissolved in 13.71 Kg tetrahydrofuran was added to the reaction mass at 30 °C in 25 minutes. No exotherm observed. The reaction mass was further stirred for 60 minutes at 30 °C – 35 °C. Since the starting material was absent as per thin layer chromatography, it was taken for further workup.

In the mean while charged 360 L demineralised water into another reactor and cooled the contents to 10 °C – 15 °C. The above reaction mass was quenched into chilled water in 60 minutes (mass temperature was 12.1 °C). The pH of the reaction mass was adjusted to ~ 9.5 with an aqueous solution of potassium hydroxide. The product was extracted with (4 x 155 L) ethyl acetate maintaining the mass temperature at 10 °C – 15 °C. The pH of aqueous layer was adjusted to ~ 9.5 before each extraction. The combined organic layer was taken for extraction of the product into aqueous acetic acid. _…. j

Acetic acid (8.69 Kg, 0.1448 Kg mole) was dissolved in 137 L of demineralised water and cooled the mass to 10 °C – 15 °C. Charged the above organic extracts into it and stirred for 30 minutes at 10 °C – 15 °C. The mass was allowed to settle for 20 minutes and separated the bottom aqueous acetic acid extract containing the product into a fresh clean reactor.

Further, the extraction and separation process with fresh aqueous acetic acid solution was repeated thrice using 3 x 145 Kg of aqueous acetic acid solution (prepared by dissolving 25.74 Kg, 0.429 Kg Mole of acetic acid in 412 L of demineralised water) following the similar procedure mentioned above, maintaining mass temperature at 10 °C -15 °C. The combined aqueous acetic acid extracts (containing the product) were taken into the reactor. It was washed with 44 L of ethyl acetate by stirring the mass at 10 °C – 15 °C for 15 minutes, followed by 15 minutes settling. The aqueous product layer was separated. The pH of the aqueous solution was found to be 4.5. The mass was cooled to 10 °C – 15 °C and the pH of the solution was adjusted to ~ 9.5 with chilled caustic lye solution (31 Kg). The product was extracted with (4 x 155 L) of ethyl acetate, maintaining the mass temperature at 10 °C – 15 °C. The pH of aqueous layer was adjusted to ~ 9.5 before each extraction.

The organic layer was washed with (2 x 1 12 Kg) brine solution (prepared from 51.6 Kg vacuum salt and 175 L water) at 10 °C – 15 °C. The organic layer was dried over 32 Kg of anhydrous sodium sulfate at 20 °C – 35 °C and filtered into another clean reactor.

Solvent was removed under 500 – 600 mm Hg by circulating 50 °C – 55 °C water in the jacket of the reactor.

To the residual mass in the reactor after solvent removal, charged 36 L of methanol followed by 72 L of isopropanol. The reaction mass was heated to reflux temperature (65 °C – 75 °C). At mass temperature ~ 70 °C a clear solution was obtained. The mass was allowed to cool to 35 – 45 °C with room temperature water circulation in the reactor jacket. Further, it was cooled to 15 °C – 20 °C by circulating brine in the jacket and maintained under stirring for 2 hours at 15 °C – 20 °C. The solids were filtered through nutsche and sucked well under vacuum. The cake was washed with 36 L of isopropanol (15 °C – 20 °C) and sucked well. The wet solid material (37.76 Kg) was taken in tray drier and air dried at 25 °C – 35 °C for 60 minutes. Further, it was dried at 40 °C – 45 °C for 6 hours to obtain 32.64 Kg of the title product.

Overall Yield: 82.3 % (based on Mannich base charged);

HPLC purity: 99.36 %;

Single major impurity: 0.29 %;

Total impurities: 0.64 %;

Assay: 100.5 %;

Loss on drying at 105 °C: 0.21 %;

Melting range (°C): 128.1 – 129.2;

IR spectra (cm^‘1): 2931, 2786, 1607, 1474, 1369, 1222, 1 178, 1032, 737, 597;

Ή – NMR (CDC1₃, δ ppm): 2.29 (3H, s), 2.32 – 2.50 (8H, bs), 3.62 (2H, s), 3.83 (3H, s),

6.83 – 6.86 (1H, dd, J = 8.98, 2.46 Hz), 7.19 – 7.20 (1H, d, J = 2.42 Hz), 7.36 – 7.40 (1 H, dt,

J.= 7.68, 1.56 Hz), 7.45 – 7.47 (1H, t, J = 7.50 Hz), 7.53 – 7.55 (1H, d, J = 9.00, Hz), 7.64 – 7.66 (2H, m), 8.03 – 8.05 (1H, dd, J = 7.89, 1.54 Hz);

¹³C – NMR (CDCI3, δ ppm): 45.94, 53.07, 53.33, 55.17, 55.60, 103.28, 1 13.20, 1 13.69,

117.83, 120.42, 127.05, 127.69, 129.57, 131.16, 131.57, 134.48, 135.90, 138.09, 156.12;

Mass [M+Hf: 478.1, 480.1.

Step (vi): Preparation of l-[(2-bromophenyl)sulfonyI]-5-methoxy-3-[(4-methyI-l-piperazinyl)methyI]-lH-indoIe dimesylate

Charged 182.5 Kg of absolute ethanol into a reactor at 20 °C – 35 °C. Then charged l-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-l-piperazinyl)methyl]-lH-indole -(obtained in the above step, 32.02 Kg, 0.067 Kg Mole) under stirring in a single lot at 20 °C – 35 °C (mass temperature), added methanesulfonic acid (13.9 Kg, 0.1446 Kg Mole) slowly to the above reaction mass from a holding tank in 60 minutes, maintaining mass temperature at 20 °C – 35 °C. No clear solution was obtained at any stage. The mass became thick, but stirrable. The reaction mass was stirred for 24 hours maintaining mass temperature between 25 °C – 30 °C. The mass was filtered through nutsche under nitrogen atmosphere and it was sucked well. The cake, thus obtained, was washed thoroughly with 48 L of ethyl alcohol (slurry wash), sucked well and the cake was again washed with 18 L of ethyl alcohol (spray wash) followed by washing with n-hexane (27 L). It was sucked dry to obtain 70.23 Kg wet cake. The wet cake was taken in a tray drier and dried at 20 °C – 35 °C for 10 hours to obtain 49.43 Kg product (LOD: ~ 9.57 %).

Weight of product on dry basis: 44.65 Kg

Yield of salt: Quantitative (based on l -[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methy 1- 1 -piperaziny l)methy 1]- 1 H- indo le charged) ;

HPLC purity: 99.69 %;

Total impurities: 0.31 %;

Salt content: 27.39 %.

Step (vii): Preparation of l-[(2-bromop enyl)sulfonyI]-5-methoxyr3-[(4-methyI-l-piperazinyl)methyl]-lH-indole dimesylate monohydrate

Charged 415 Kg of aqueous ethanol (95 % ethanol & 5 % water) into a reactor, followed by the addition of l-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-l-piperazinyl)methyl]-lH-indole dimesylate (44.65 Kg, 0.0666 Kg Mole, obtained from the above step) at 20 °C – 35 °C. In the meanwhile carbon slurry was prepared separately by adding 6.7 Kg of carbon powder into 18 Kg of aqueous ethanol (95 % ethanol & 5 % water). Then the carbon slurry was transferred to the reactor and the reaction mass was heated at 75 °C – 80 °C by circulating 80 °C – 90 °C hot water in the reactor jacket for 45 minutes. The mass was filtered hot into another clean reactor, washed the carbon bed with 54.25 Kg of aqueous ethanol (95% ethanol & 5% water) at 75 °C – 80 °C. The contents of the reactor were heated at reflux temperature (76 ^PC – 78 °C) for 30 minutes to obtain a clear solution. The mass was allowed to cool on its own to 45 °C in 10 hours by applying compressed air in the reactor jacket. It was further cooled to 10 °C – 15 °C with chilled water circulated in the jacket and maintained under stirring for 3 hours. Filtered the crystalline material through a centrifuge and the material on the centrifuge was washed with 18.6 Kg of aqueous ethanol (95 % ethanol & 5 % water) (10 °C – 15 °C) and spin dried. The whole material was air dried in a tray drier for 14 hours at 20 °C – 35 °C. The material was milled, sieved and collected in poly bag to obtain 37.7 Kg of the title product. The uniform material was sampled for analysis.

Weight of dry product: 37.7 Kg;

Yield of salt: 82.2 %;

HPLC purity: 99.7 %;

Single impurity: 0.3 %;

Assay: 99.9 %;

Moisture content: 2.61 %;

Salt content (Dimesylate) 27.56 %;

Melting range (°C): 218.0 – 220.0;

IR spectra (cm^“1): 3148, 3012, 161 1, 1590, 1471, 1446, 1439, 1382, 1220, 1 194, 1 180, 1045, 775, 596;

Ή – NMR (D20, δ ppm): 2.65 (6H, s), 2.89 (3H, s), 3.52 (8H, bs), 3.70 (3H, s), 4.46 (2H, s), 6.75 – 6.78 (1H, dd, J = 9.07, 2.02 Hz), 7.10 – 7.1 1 (1H, d, J = 1.9 Hz), 7.32 – 7.38 (2H, m), 7.44 – 7.47 (1H, t, J = 7.6 Hz), 7.54 – 7.56 (1H, dd, J = 7.79 Hz), 8.04 (1H, s), 8.14 -8.16 (lH, d, J = 7.94 Hz);

^, C – NMR (δ ppm): 38.42, 42.79, 48.19, 50.35, 55.80, 102.57, 108.20, 113.72, 114.07, 1 19.62, 128.25, 128.56, 130.17, 131.80, 132.15, 135.28, 135.95, 156.21 ;

Mass [M+H]⁺: 478, 480.

PATENT………on metabolite and not the drug

caution……….drug has a methyl

WO-2016027276

Suven Life Sciences Ltd is developing l-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl- l -piperazinyl)methyl]-lH-indole dimesylate monohydrate, which is a selective 5-HT₆ receptor antagonists intended for the symptomatic treatment of AD and other disorders of memory and cognition like attention deficient hyperactivity, parkinson’s and schizophrenia. 1 -[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-l -piperazinyl)methyl]-lH-indole, and its pharmaceutically acceptable salts were disclosed by Ramakrishna et al. in WO 2004/048330. l -[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-l-piperazinyl)methyl]-lH-indole dimesylate;monohydrate has already completed Phase 1 clinical trials. Based on phase I clinical trials results, we confirmed l -[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(l -piperazinyl)methyl]-lH-indole of formula (I) as an active metabolite of l -[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl- 1 -piperazinyl)methyl]- 1 H-indoIe dimesylate monohydrate in human volunteers.

The development and understanding of the metabolism of l-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-l -piperazinyl)methyl]-lH-indole dimesylate monohydrate is desirable for progression of science and necessary step in the commercialization of this compound. Therefore, there is a need to understand regarding metabolism and metabolites of l-t(2-bromophenyl)sulfonyI]-5-methoxy-3-[(4-methyl-l -piperazinyl)methyl]-lH-indole dimesylate monohydrate.

In order to improve pharmaceutical properties and efficacy of active metabolite, we performed salt selection program for l -[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[( l -piperazinyl)methyl]-lH-indole. Based on the results obtained, dimesylate dihydrate salt of 1-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(l-piperazinyl)methyl]-lH-indole of formula (Π) is selected for further development along with the compound of formula (I).

l -[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[( l -piperazinyl)methyl]-lH-indole. NOTE THE DRUG IS WITH A METHYL

SCHEME 1

SCHEME2

Example 1: Preparation of l-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(l-piperazinyl)methyl]-lH-indo

Step (i) & (ii): Preparation of 3-[(l-t-Butyloxycarbonyl piperazin-4-yl)methyI]-5-methoxy-lH-indole

Step (i):

Demineralized water (DM water) (660 mL) and N-Boc piperazine ( 150.0 grams, 0.8034 moles) were charged into a 2 Litres three necked round bottomed flask provided with a mechanical stirrer and a thermometer pocket. The mass was stirred for 10 minutes at 25 °C, to obtain a clear solution. Then acetic acid (32.5 mL, 0.5416 moles) was added to the above mass while maintaining the mass temperature at ~ 25 °C in 10 minutes. After completion of addition, the clear solution was stirred at 25 °C for 30 minutes.

To the above stirred mass at 25 °C, aqueous formaldehyde solution (81 mL, 30 % w/v, 0.81 moles) was added slowly through an addition funnel over a period of 30 minutes maintaining the mass temperature below 25 °C. During the addition, white slurry mass was formed. The resultant white slurry mass was stirred for another 1 hour at 25 – 30 °C. Methanol (MeOH) (300 mL) was added to the above mass to obtain a clear solution. The solution was further stirred for 30 minutes at 25 °C to obtain Mannich adduct.

Step (ii):

5-Methoxyindole (106.4 grams, 0.7238 moles) and methanol (550 mL) were charged into a 4 necked round bottom flask. The mass was stirred for 10 minutes at 25 °C to obtain a clear solution and then cooled the mass to 18 – 20 °C. The mannich adduct (prepared in above step) was added to the flask through an addition funnel maintaining mass temperature below 20 °C, over a period of 1 hour. The mass was further stirred for a period of 1 hour at 25 – 30 °C, while monitoring the progress of the reaction by thin layer chromatography (TLC).

After completion of the reaction (1 hour), DM water (2.2 Litres) and ethyl acetate (1

Litre) were added to the reaction mass and pH adjusted to 10.5 (on pH paper) with lye solution (80 mL) maintaining the mass temperature at 20 – 24 °C. The organic (product) layer was separated and the aqueous layer was further extracted with ethyl acetate (2 x 500 mL). The combined organic layer was washed with saturated brine solution (300 mL) and dried over anhydrous sodium sulfate. The organic layer was filtered free of sodium sulfate and concentrated under reduced pressure. n-Hexane (300 mL) was added to the residual mass and further concentrated under vacuum for removal of traces of ethyl acetate to obtain 272.2 grams of technical product.

Purity: 96.16 %;

Ή – NMR (CDC1₃, δ ppm): 1.45 (9H, s), 2.44 (4H, bm), 3.41 – 3.43 (4H, bm), 3.69 (2H, s), 3.87 (3H, s), 6.85 – 6.88 (1H, dd, J = 8.75, 2.23 Hz), 7.10 ( 1 H, d, J = 0.96 Hz), 7.19 (1 H, d, J = 2.24 Hz), 7.24 – 7.26 (1H, d), 8.04 (1H, bs);

Mass [M+H]⁺: 346.2.

Step (iii): Purification of 3-[(l-t-Butyloxycarbonyl piperazin-4-yl)methyI]-5-methoxy-lH-indole

n-Hexane (1.25 Litres) was taken in 2 Litres four necked round bottom flask equipped with thermometer pocket and mechanical stirrer and charged the above obtained technical compound (270.9 grams). The mass was stirred for 1 hour at 25 °C. The product was filtered through Buckner funnel under vacuum. The compound was washed with n-hexane (2 x 125 mL), sucked well and air dried at 25 °C for 20 hours to obtain 240.0 grams of above title compound. Yield: 96 %;

Purity: 97.09 %;

Ή – NMR (CDCI3, δ ppm): 1.45 (9H, s), 2.45 (4H, s), 3.43 (4H, s), 3.69 (2H, s), 3.86 (3H, s), 6.85 – 6.88 (1H, dd, J = 8.7, 2.2 Hz), 7.08 – 7.09 (1H, d, J = 1 .57 Hz), 7.19 ( 1 H, d, J = 2.2 Hz), 7.23 – 7.25 (l H, d, J = 8.77 Hz), 8.25 (lH, bs); –

Mass [M+H]⁺: 346.2.

Step (iv): Preparation of l-[(2-BromophenyI)sulfonyl]-5-methoxy-3-[(l-t-butyloxycarbonyl piperazin-4-yl)methyI]-lH-indole

Tetrahydrofuran (THF) (4.6 Litres) was charged into a reactor at 25 °C, followed by the addition of powdered potassium hydroxide (860.6 grams, 85 %, 13.06 moles) at 25 °C under stirring. THF (3 Litres) was charged into a 5 Litres, three necked round bottom flask, provided with a mechanical stirrer and thermometer pocket. 3-[(l -t-Butyloxycarbonyl piperazin-4-yl) methyl]-5-methoxy-lH-indole (obtained in above step) (1287.7 grams, 3.7324 moles) was charged into the flask at 25 °C and stirred the mass well for complete dissolution. Then the clear 3-[(l-t-Butyloxycarbonyl piperazin-4-yl) methyl]-5-methoxy-l H-indole solution, prepared as above, was slowly transferred to the reactor containing potassium hydroxide under stirring, maintaining the mass temperature below 25 °C. After completion of the addition, the reaction mass was stirred at 25 °C for 2 hours. A solution of 2-bromophenylsulfonyl chloride (1293.04 grams, 5.062 moles) dissolved in THF (2.0 Litres) was added to the reaction mass through an addition funnel at a constant rate in 30 minutes, maintaining the mass temperature at 20 – 32 °C. The reaction was exothermic in nature. The mass was further stirred for 1 hour at 25 – 30 °C.

As the reaction was progressing the mass thickened due to formation of potassium chloride. The progress of the reaction was monitored by TLC (Eluent system: Ethyl acetate) and the product is relatively non-polar. The starting material was absent as per TLC. A second lot of 2-bromophenylsuIfonyl chloride (52.5 grams, dissolved in 100 mL of THF) was added to the reaction mass at 28 °C and further stirred the mass at 28 °C for another hour to ensure completion of the reaction, The reaction mass was unloaded into neat carboys.

Ice-water (40 Litres) was charged into a clean reactor and the reaction mass unloaded in the carboys was quenched into the reactor under stirring and the pH of the resulting solution was found to be 1 1.5 (pH paper). The product was extracted with (15 Litres + 7.5 Litres + 7.5 Litres) ethyl acetate. The combined organic layer was washed with saturated brine solution (2 x 5 L) and dried over anhydrous sodium sulfate. Total volume of the organic layer was 30 Litres. A small portion of the organic layer was concentrated in laboratory and the solid obtained was analyzed to check the quality of the technical product.

Purity: 91.46 %;

Ή – NMR (CDC1₃, 5 ppm): 1.45 (9H, s), 2.42 – 2.43 (4H, bs), 3.42 (4H, bs), 3.62 (2H, s), 3.81 (3H, s), 6.83 – 6.86 (1H, m), 7.18 – 7.19 (1H, m), 7.38 – 7.45 (2H, m), 7.52 – 7.55 (1H, m), 7.64

– 7.66 (2H, m), 8.06 – 8.08 (1H, d, J = 7.76 Hz);

Mass [M+Hf : 564.3, 566.4.

The organic layer.was taken for further workup and the technical product was purified without isolation.

Step (v): Purification of l-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(l-t-butyloxycarbonyl piperazin-4-yI)methyI]-lH-indole

The above organic layer was filtered (30 Litres) and charged into a reactor. Solvent was distilled off under vacuum at 40 – 45 °C to obtain solids. Isopropanol (14 Litres) and methanol (7 Litres) were charged into the reactor containing the solid product. The reaction mass was heated to reflux temperature (70.5 °C) under stirring and further stirred the mass at reflux for two hours to ensure formation of clear solution.

Reaction mass was then slowly cooled to room temperature (30 minutes) with room temperature water circulation in the jacket. It was further cooled to 18 °C and stirred for 1 hour. The product was centrifuged and the cake on the centrifuge was washed with isopropanol / methanol mixture (1.6 Litres + 0.8 Litres). It was sucked well and air dried at 40 – 45 °C for 4 hours in tray driers.

Weight of compound: 1554.8 grams, Cream colored crystalline powder, Yield: 77.7 %

Purity: 99.42 %;

Ή – NMR (CDCI₃, δ ppm): 1.45 (9H, s), 2.42 (4H, bs), 3.42 (4H, bs), 3.63 (2H, s), 3.82 (3H, s), 6.83 – 6.86 (lH, dd, J = 8.34, 2.09 Hz), 7.19 (1 H, d, J = 2.0 Hz), 7.36 – 7.40 (1 H, t, J = 7.14 Hz), 7.43 – 7.47 (1H, t, J = 7.56 Hz), 7.52 – 7.55 (1 H, d, J = 8.95 Hz), 7.64 – 7.66 (2H, m), 8.06

– 8.08 ( 1H, d, J = 7.87 Hz); Mass: [M+H]⁺: 564.3, 566.3.

Step (vi): Preparation of l-((2-bromophenyl)snlfonyI]-5-methoxy-3-[(l-piperazinyl)methyl]-lH-indole dihydrochloride

l-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(4-t-butyloxycarbonyl-l -piperazinyl)methyl]-lH-indole (20.2 grams, 0.03578 M, obtained in the above step) was suspended in 250 mL of absoliite ethanol at 25 °C and then added 20 mL of 30 % (w/w) aqueous hydrochloric acid drop wise under stirring over a period of 30 minutes, whereby a clear solution was obtained. The reaction was exothermic and temperature went upto 38 °C. The mass was further heated at reflux for 4 hours. During this period solids separated. The mass was stirred for another 2 hours at reflux. The progress of the reaction was monitored by thin layer chromtography. After completion of the reaction, the mass was cooled to 25 °C and filtered the solids under suction. The solid on the filter was washed with 30 mL of absolute ethanol and the mass was dried under rotavacuum at 40 – 45 °C for 1 hour to obtain l-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[( 1 -piperazinyl)methyl]- 1 H-indole dihydrochloride (19.28 grams).

Purity: 99.8 %,

Mass: [M+H]⁺: 464.2, 466.2.

Step (vii): Preparation of l-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(l-piperazinyl)methyl]-lH-indole

The above obtained compound (19.09 grams) was suspended in demineralised water (300 mL) and cooled to 15 – 20 °C. The mass was basified to pH 10.5 to 1 1.0 by adding 40 % (w/w) lye solution, maintaining mass temperature below 20 °C under nitrogen atmosphere. The product was extracted with (2 x 150 mL) ethylacetate. The combined organic layer was washed with (100 mL) saturated brine solution, dried over anhydrous sodium sulfate and

solvent removed under rotavacuum at 40 – 45 °C to obtain the title compound (15.91 grams).

Yield: 96. 4 %

Purity: 99.89 %,

DSC (5 °C / minutes): 99.6 °C;

TGA (5 °C / minutes): 0.76 %;

Ή – NMR (CDCI₃, δ ppm): 1.85 (1H, s), 2.44 (4H, bs), 2.86 – 2.88 (4H, t), 3.59 (2H, s), 3.76 (3H, s), 6.82 – 6.84 (lH, dd, J = 9.0, 2.45 Hz), 7.20 – 7.21 (1H, d, J = 2.28 Hz), 7.33 – 7.37 (1H, dt, J = 7.48 Hz), 7.41 – 7.44 (1 H, t), 7.52 – 7.54 (1H, d, J = 7.65 Hz), 7.62 – 7.64 (2H, m), 8.01 – 8.03 (1H, dd, J = 7.98, 1.15 Hz);

Mass: [M+H]⁺: 464.2, 466.2.

Example 2: Preparation of l-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(l-piperazinyl)methyl]-lH-in

Step (i) & (ii): Preparation of 3-[(l-t-Butyloxycarbonyl piperazin-4-yl)methyl]-5-methoxy-lH-indoIe

Step (i):

Step (ii):

5-Methoxy indole (106.4 grams, 0.7238 moles) and methanol (550 mL) were charged into a 4 necked round bottom flask. The mass was stirred for 10 minutes at 25 °C to obtain a clear solution and then cooled the mass to 18 – 20 °C. The mannich adduct (prepared in above step) was added to the flask through an addition funnel maintaining mass temperature below 20 °C, over a period of 1 hour. The mass was further stirred for a period of 1 hour at 25 – 30 °C, while monitoring the progress of the reaction by thin layer chromatography (TLC).

After completion of the reaction (1 hour), DM water (2.2 Litres) and ethyl acetate (1 Litre) were added to the reaction mass and pH adjusted to 10.5 (on pH paper) with lye solution (80 mL) maintaining the mass temperature at 20 – 24 °C. The organic (product) layer was separated and the aqueous layer was further extracted with ethyl acetate (2 x 500 mL). The combined organic layer was washed with saturated brine solution (300 mL) and dried over anhydrous sodium sulfate. The organic layer was filtered free of sodium sulfate and concentrated under reduced pressure. n-Hexane (300 mL) was added to the residual mass and further concentrated under vacuum for removal of traces of ethyl acetate to obtain 272.2 grams of technical product.

Purity: 96.16 %;

Ή – NMR (CDC1₃, δ ppm): 1.45 (9H, s), 2.44 (4H, bm), 3.41 – 3.43 (4H, bm), 3.69 (2H, s), 3.87 (3H, s), 6.85 – 6.88 (1H, dd, J = 8.75, 2.23 Hz), 7.10 (1Ή, d, J = 0.96 Hz), 7.19 (1H, d, J = 2.24 Hz), 7.24 – 7.26 (1 H, d), 8.04 (1H, bs);

Mass [M+H]⁺: 346.2.

Step (iii): Purification of 3-[(l-t-ButyloxycarbonyI piperazin-4-yl)methyl]-5-methoxy-lH-indole

Purity: 97.09 %;

Ή – N R (CDC1₃, δ ppm): 1.45 (9H, s), 2.45 (4H, s), 3.43 (4H, s), 3.69 (2H, s), 3.86 (3H, s), 6.85 – 6.88 (lH,jdd, J = 8.7, 2.2 Hz), 7.08 – 7.09 (1 H, d, J = 1.57 Hz), 7.19 ( 1H, d, J = 2.2 Hz),

7.23 – 7.25 (1H, d, J = 8.77 Hz), 8.25 (1H, bs);

Mass [M+H]⁺: 346.2.

Step (iv): Preparation of l-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(l-t-butyloxycarbonyl pipera

the addition, the reaction mass was stirred at 25 °C for 2 hours. A solution of 2- bromophenylsulfonyl chloride (1293.04 grams, 5.062 moles) dissolved in THF (2.0 Litres) was added to the reaction mass through an addition funnel at a constant rate in 30 minutes, maintaining the mass temperature at 20 – 32 °C. The reaction was exothermic in nature. The mass was further stirred for 1 hour at 25 – 30 °C.

As the reaction was progressing the mass thickened due to formation of potassium chloride. The progress of the reaction was monitored by TLC (Eluent system: Ethyl acetate) and the product is relatively non-polar, The starting material was absent as per TLC. A second lot of 2-bromophenylsulfony] chloride (52.5 grams, dissolved in 100 mL of THF) was added to the reaction mass at 28 °C and further stirred the mass at 28 °C for another hour to ensure completion of the reaction. The reaction mass was unloaded into neat carboys.

Ice-water (40 Litres) was charged into a clean reactor and the reaction mass unloaded in the carboys was quenched into the reactor under stirring and the pH of the resulting solution was 11.5 (pH paper). The product was extracted with (15 Litres + 7.5 Litres + 7.5 Litres) ethyl acetate. The combined organic layer was washed with saturated brine solution (2 x 5 L) and dried over anhydrous sodium sulfate. Total volume of the organic layer was 30 Litres. A small portion of the organic layer was concentrated in laboratory and the solid obtained was analyzed to check the quality of the technical product.

Purity: 91.46 %;

Ή – NMR (CDC , δ ppm): 1.45 (9H, s), 2.42 – 2.43 (4H, bs), 3.42 (4H, bs), 3.62 (2H, s), 3.81 (3H, s), 6.83 – 6.86 (1 H, m), 7.18 – 7.19 (1H, m), 7.38 – 7.45 (2H, m), 7.52 – 7.55 (1 H, m), 7.64 – 7.66 (2H, m), 8.06 – 8.08 (1 H, d, J = 7.76 Hz);

, Mass [M+H : 564.3, 566.4.

The organic layer was taken for further workup and the technical product was purified without isolation.

Step (v): Purification of l-[(2-BromophenyI)suIfonyl]-5-methoxy-3-[(l-t- butyloxycarbonyl piperazin-4-yl)methyl]-lH-indole

The above organic layer was filtered (30 Litres) and charged into a reactor. Solvent was distilled off under vacuum at 40 – 45 °C to obtain solids. Isopropanol (14 Litres) and

methanol (7 Litres) were charged into the reactor containing the solid product. The reaction mass was heated to reflux temperature (70.5 °C) under stirring and further stirred the mass at reflux for two hours to ensure formation of clear solution.

Reaction mass was then slowly cooled to room temperature (30 minutes) with room temperature water circulation in the jacket. It was further cooled to 18 °C and stirred for 1 hour. The product was centrifuged and the cake on the centrifuge was washed with isopropanol / methanol mixture (1 .6 Litres + 0.8 Litres). It was sucked well and air dried at 40

– 45 °C for 4 hours in tray driers.

Weight of compound: 1554.8 grams, Gream colored crystalline powder, Yield: 77.7 %

Purity: 99.42 %;

Ή – NMR (CDQlj, δ ppm): 1.45 (9H, s), 2.42 (4H, bs), 3.42 (4H, bs), 3.63 (2H, s), 3.82 (3H, s), 6.83 – 6.86 (1H, dd, J =.8.34^* 2.09 Hz), 7.19 (1H, d, J = 2.0 Hz), 7.36 – 7.40 (1H, t, J = 7.14 Hz), 7.43 – 7.47 (1H, t, J = 7÷56 Hz), 7.52 – 7.55 (lH, d, J = 8.95 Hz), 7.64 – 7.66 (2H, m), 8.06

– 8.08 (1 H, d, J = 7.87 Hz); Mass: [M+H]⁺: 564.3, 566.3.

Step (vi): Preparation of l-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(l-piperazinyl)methyl)-l

l-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(l -t-butyIoxycarbonyl piperazin-4-yl)methyl]-lH-indole (obtained in the above step, 1540 grams, 2.73 mole) was dissolved in acetone (30.8 Litres) and charged into a glass lined reactor. The temperature of the reaction mass was raised to reflux temperature (56 °C). Methanesulfonic acid (920 grams, 9.57 moles) diluted with acetone (6 Litres) was added to the above mass at reflux temperature, slowly over a period of 30 minutes, through an addition funnel. During addition vigorous reflux was observed. The reaction mass was a clear solution before and after the addition of methanesulfonic acid solution. After stirring for ~ 90 minutes at reflux, thick mass of solids separated out. The progress of the reaction was monitored by TLC. The reaction was completed in 4 hours. Then the mass was cooled to 25 °C and further stirred for two hours at 25 °C. The product was filtered through nutsche filter under vacuum. The product on the nutsche filter was washed with acetone (8 Litres). The material was unloaded into trays and air dried at 30-35 °C for 4 hours in a tray drier. Weight of the product: 1.61 Kg (off white with pinkish tinge).

Yield: 90 %;

Salt content (dimesylate): 32.1 % w/w;

Purity: 99.97 %;

Ή – NMR (D₂0, 5 ppm): 2.64 (6H, s), 3.48 (4H, bs), 3.53 (4H, bs), 3.70 (3H, s), 4.50 (2H, s), 6.75 – 6.78 (1H, dd, J = 8.97, 1.92 Hz), 7.11 (1H, d, J = 1.78 Hz), 7.32 – 7.34 ( 1H, t, J = 9.28 Hz), 7.34 – 7.38 (lH, t, J = 7.63 Hz), 7.44 – 7.48 ( 1H, d, 3 = 7.76 Hz), 7.54 – 7.56 (2H, d, J = 7.85 Hz), 8.06 (1H, s), 8.15 – 8.17 (2H, d, J = 7.87 Hz);

Mass: [M+H]⁺: 464.2, 466.2.

Step (vii): Preparation of l-{(2-Bromophenyl)suIfonyl]-5-methoxy-3-[(l-piperazinyl)methyl]-l

Acetone (24.15 L) was taken in a Glass Lined Reactor at 25-30 °C, followed by l-[(2-Bromo phenyl)sulfonyl]-5-methoxy-3-[(l-piperazinyl)methyl]-lH-indole dimesylate (obtained in the above step) (1.61 Kg) and the resulting mass was stirred To obtain slurry. DM water (4.0 L) was added to the reactor and then the mass temperature was raised to reflux temperature (56.0-57.5 °C). A clear solution was obtained at reflux. It was maintained for 15 minutes. The mass was cooled to 45-50 °C and added activated carbon (161 grams) to the mass and stirred the mass for 45 minutes at reflux temperature: It was filtered hot into another reactor, which was maintained at 50 °C. The clear filtrate was allowed to cool on its own, under nitrogen

blanket. Solids separated when the mass temperature was ~ 44 °C. The mass was allowed to cool to room temperature (30-35 °C) and then it was further cooled at 10-12 °C for 2 hours. The product was centrifuged, washed with acetone (5 L) and sucked well. The wet product (weight: 1.5 Kg) was spread into trays and dried in a tray drier at 40-45 °C for 7.5 hours, till organic volatile impurities are below the allowable limits. Weight of the dry product obtained: 1.3 Kg. Yield: – 76.5 %

Purity: 99.98 %;

Melting range (°C): 203.8 – 205.3;

Salt content (Dimesylate): 28.26 %;

Moisture Content: 5.2 %;

TGA: 4.9 %; ,

Ή – NMR (D₂0, δ ppm): 2.65 (6H, s), 3.48 (8H, bm), 3.71 (3H, s), 4.48 (2H, s), 6.77 – 6.80 (1H, dd, J = 9.18, 2.24 Hz), 7.12 – 7.13 (1 H, d, J = 2.12 Hz), 7.35 – 7.37 (1H, d, J = 9.06 Hz), 7.37 – 7.41 (1 H, t, J = 7.98 Hz), 7.46 – 7.50 (1 H, t, J = 7.66 Hz), 7.57 – 7.58 (1 H, d, J = 7.86 Hz), 8.06 ( 1H, s), 8.17 – 8.20 (1H, dd, J = 7.95, 0.87 Hz),

Mass [M+H]⁺: 464.2, 466.1 ;

PATENT

WO 2004/048330

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2004048330

REFERENCES

http://www.avarx.com/search/showOpportunityDetails?asset_id=2424
Phase II
Alzheimer’s disease; Schizophrenia
Phase I
Attention-deficit hyperactivity disorder; Cognition disorders; Parkinson’s disease

05 Jan 2016
Suven Life Sciences has patent protection for chemical entities targeting serotonin receptors for the treatment of neurodegenerative disorders in Canada, Africa and South Korea
11 Dec 2015
Suven Life Sciences receives patent allowance for chemical entities targeting serotonin receptors in Eurasia, Europe, Israel and Macau
01 Oct 2015
Phase-II clinical trials in Schizophrenia in USA (PO)

////////

Brc1ccccc1S(=O)(=O)n4cc(CN2CCN(C)CC2)c3cc(ccc34)OC

SUVN-D4010 from Suven Life Sciences Ltd

March 1, 2016 7:55 am / Leave a comment

str1

1H-Indazole, 3-[5-[1-(3-methoxypropyl)-4-piperidinyl]-1,3,4-oxadiazol-2-yl]-1-(1-methylethyl)-

CAS BASE 1428862-32-1, C₂₁ H₂₉ N₅ O_2, 383.49

str1

SUVN-D4010

C₂₁ H₂₉ N₅ O₂ . C₂ H₂ O₄

1H-Indazole, 3-[5-[1-(3-methoxypropyl)-4-piperidinyl]-1,3,4-oxadiazol-2-yl]-1-(1-methylethyl)-, ethanedioate (1:1)

1-isopropyl-3-{5-[1-(3-methoxypropyl)-piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate

l-isopropyl-3-{5-[l-(3-methoxy propyl) piperidin-4-yl]- [l,3_>4]oxadiazol-2-yl}-lH-indazole oxalate salt

SUVN-1004028; SUVN-D-1208045; SUVN-D1003019; SUVN-D1104010; SUVN-D1108121;

l-ISOPROPYL-3-{5-[l-(3-METHOXYPROPYL) PIPERIDIN-4-YL]-[l,3,4]OXADIAZOL-2-YL}-1H-INDAZOLE OXALATE

OXALATE CAS 1428862-33-2

IN 2011CH03203, WO2013042135, WO 2015092804,

In phase I, for treating cognitive dysfunction associated with Alzheimer’s disease, schizophrenia and neurological diseases.

Suven Life Sciences Limited, Phase I Alzheimer’s disease; Schizophrenia

https://www.clinicaltrials.gov/ct2/show/NCT02575482

Class Antidementias
Mechanism of Action Serotonin 4 receptor agonists

Used as 5-HT4 receptor agonist for treating Alzheimer’s disease, cognitive disorders, Attention deficit hyperactivity disorder, Parkinson’s and schizophrenia

05 Jan 2016Suven Life Sciences has patent protection for chemical entities targeting serotonin receptors for the treatment of neurodegenerative disorders in Canada, Africa and South Korea
11 Dec 2015Suven Life Sciences receives patent allowance for chemical entities targeting serotonin receptors in Eurasia, Europe, Israel and Macau
02 Nov 2015SUVN D4010 is available for licensing as of 02 Nov 2015. http://www.suven.com

SUVN-D4010 for Cognition in Alzheimer’s disease commenced Phase 1 Clinical Trial in USA under US-IND 126099

HYDERABAD, INDIA (Sept 02, 2015) – Suven Life Sciences today informed that their NCE SUVN-D4010 has commenced Phase 1 clinical trial in USA. SUVN-D4010 is a potent, selective, brain penetrant and orally active 5-HT4 receptor partial agonist for the treatment of cognitive dysfunction associated with Alzheimer’s disease and other dementias. Suven submitted Investigational New Drug Application (IND) to US FDA to conduct Phase-1 clinical trial for Cognition in Alzheimer’s Disease, under 505(1) of the Federal Food, Drug and Cosmetic Act (FDCA) which was assigned an IND number 126099.

Based on the IND# 126099, “A Single Center, Double-blind, Placebo-controlled, Randomized, Phase 1 Study to Evaluate the safety, Tolerability, and Pharmacokinetics of SUVN-D4010 after Single Ascending Doses and Multiple Ascending Doses in Healthy Male Subjects” for Cognition in Alzheimer’s Disease is underway in USA

“We are very pleased that the third compound from our pipeline of molecules in CNS has moved into clinical trial that is being developed for cognitive disorders in Alzheimer’s and Schizophrenia, a high unmet medical need which has huge market potential globally” says Venkat Jasti, CEO of Suven.

Suven Life Science is a biopharmaceutical company focused on discovering, developing and commercializing novel pharmaceutical products, which are first in class or best in class CNS therapies through the use of GPCR targets.Suven has 3 clinical stage compounds, a Phase 2 initiated candidate SUVN-502, Phase 1 completed candidate SUVN-G3031 and Phase 1 initiated candidate SUVN-D4010 for Alzheimer’s disease and Schizophrenia. In addition to that the Company has ten (10) internally-discovered therapeutic drug candidates currently in pre-clinical stage of development targeting conditions such as ADHD, dementia, depression, Huntington’s disease, Parkinson’s disease and pain

SUVEN Life Sciences Ltd

Alzheimer’s disease (AD) is a neurodegenerative disorder of advanced age characterized by loss of memory, accumulation of amyloid beta protein (Αβ) deposits and decreased levels of the neurotransmitter acetylcholine. Approximately forty percent of AD patients suffer from significant depression. 5-HT4 receptor partial agonists may be of benefit for both the symptomatic and disease-modifying treatment for AD and may offer improved clinical efficacy and/or tolerability relative to acetylcholine esterase inhibitors. 5-HT4 receptor agonists also have antidepressant like properties (Expert Review of Neurotherapeutics, 2007, 7, 1357-1374; Experimental Neurology, 2007, 203(1), 274- 278; Neuroscience & Medicine, 201 1 , 2, 87 – 92; Schizophrenia Bulletin, 2007, 33 (5), 1 100 – 1 1 19).

1 -Isopropyl-3 – { 5 – [ 1 -(3 -methoxypropyl) piperidin-4-yl] – [ 1 ,3 ,4]oxadiazol-2-y 1 } -1 H-indazole oxalate of formula (I) is a promising pharmaceutical agent, which is a potent, selective and orally bioavailable 5-HT₄ receptor partial agonist intended for both disease modifying and symptomatic treatment of Alzheimer’s disease and other disorders of memory and cognition like Attention deficient hyperactivity,

Parkinson’s and Schizophrenia. . In addition to the pro-cognitive effects, the compound also demonstrated dose dependent antidepressant like effects in the mouse forced swim test. l-Isopropyl-3-{5-[l-(3-methoxypropyl) piperidin-4-yl]-[l,3,4]oxadiazol-2-yl}-lH-indazole oxalate and its synthesis is disclosed by Ramakrishna et al. in WO2013042135.

At present, l-Isopropyl-3-{5-[l-(3-methoxypropyl) piperidin-4-yl]-[l,3,4] oxadiazol-2-yl}-l H-indazole oxalate of formula (I) has completed preclinical studies and is ready to enter human clinical trials. The demand for l-Isopropyl-3-{ 5- [ 1 -(3 -methoxypropyl) piperidin-4-yl]- [ 1 ,3 ,4]oxadiazol-2-yl } – 1 H-indazole oxalate of formula (I) as a drug substance would be increased substantially with the advent of its human clinical trials. The future need for much larger amounts is projected due to the intended commercialization of l-Isopropyl-3-{5-[l-(3-methoxypropyl) piperidin-4-yl]-[l ,3,4]oxadiazol-2-yl}-lH-indazole oxalate of formula (I).

For the person skilled in art, it is a well known fact that various parameters will change during the manufacturing of a compound on a large scale when compared to the synthetic procedures followed in laboratory. Therefore, there is a need to establish and optimize large scale manufacturing process. The process for the preparation of l -Isopropyl-3-{5-[l-(3-methoxypropyl) piperidin-4-yl]-[l ,3,4] oxadiazol-2-yl}-l H-indazole oxalate of formula (I) which was disclosed in WO2013042135 had been proved to be unsatisfactory for the large scale synthesis. Eventually, it is highly desirable to establish optimized manufacturing process for l-Isopropyl-3-{5-[l-(3-methoxypropyl) piperidin-4-yl]-[l ,3,4] oxadiazol-2-yl}-l H-indazole oxalate of formula (I) which is amenable to the large scale preparation.

PATENT

WO2013042135

http://www.google.com/patents/WO2013042135A1?cl=en

Example 3: Preparation of l-isopropyl-3-{5-[l-(3-methoxy propyl) piperidin-4-yl]- [l,3_>4]oxadiazol-2-yl}-lH-indazole oxalate salt

Step (i): Preparation of l-isopropyI-3-{5-[l-(3-methoxy propyl) piperidin-4-yI]- [l,3,4]oxadiazol-2-yl}-lH-indazo!e

To the mixture of l-isopropyl-lH-indazole-3-carboxylic acid hydrazide (15.0 grams, 68.8 mmol) and l-(3-Methoxy propyl)-piperidine-4-carboxylic acid hydrochloride (20.9 grams, 88.2 mmol, obtained in preparation 7) cooled at 0 °C was added phosphoryl chloride (130 mL). The reaction temperature was gradually raised to 100 °C and stirred was 2 hours. Upon completion of the reaction, it was cooled to 0 °C and triturated with hexanes (3 x 250 mL). The crude product was basified with aqueous sodium hydroxide solution and extracted with 5% methanol in dichloromethane. The combined organic layer was dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography to obtain l-isopropyl-3-{5-[l-(3-methoxy propyl) piperidin-4-yl]- [l,3,4]oxadiazol-2-yl}-lH-indazole (15.78 grams)

Yield: 59 %.

Ή – NMR (CDCb): δ 8.35 (d, J = 8.1 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.47 (t, J *= 7.0 Hz, 1H), 7.33 (t, J = 7.4 Hz, 1H), 5.05-4.90 (m, 1H), 3.44 (t, J = 6.4 Hz, 2H), 3.35 (s, 3H), 3.15-2.97 (m, 3H), 2.48 (t, J = 7.3 Hz, 2H), 2.26-2.02 (m, 6H), 1.88-1.75 (m, 2H), 1.67 (d, J = 6.7 Hz, 6H);

Mass (m/z): 384.5 (M+H)⁺.

Step (ii): Preparation of l-Isopropyl-3-{5-[l-(3-methoxy-propyl)-piperidin-4-yl]- [l,3,4]oxadiazoI-2-yl}-lH-indazole oxalate salt

To a stirred solution of l-isopropyl-3-{5-[l-(3-methoxy propyl) piperidin-4-yl]- [l,3,4]oxadiazol-2-yl}-lH-indazole (12.55 grams, 32.7 mmol, obtained in the above step) in 2-propanol (200 mL), oxalic acid (4.12 grams, 32.7 mmol) was added. After stirring at room temperature for 1 hour the reaction was further diluted with 2-propanol and refluxed for 2 hours. The crystalline product which was precipitated after cooling the reaction mixture to room temperature was filtered, dried under vacuum to obtain 1- isopropyl-3-{5-[l-(3-methoxy propyl) piperidin-4-yl]-[l,3,4]oxadiazol-2-yl}-lH- indazole oxalate salt (16.4 grams)

Yield: 88 %

Ή – NMR (DMSO-d₆): δ 8.18 (d, J = 8.1 Hz, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7.54 (t, J = 7.4 Hz, 1H), 7.38 (t, J = 7.7 Hz, 1H), 5.23 – 5.10 (m, 1H), 3.50 – 3.40 (m, 3H), 3.37 (t, J = 5.9 Hz, 2H), 3.23 (s, 3H), 3.10 -2.96 (m, 4H), 2.35 – 2.25 (m, 2H), 2.18-2.02 (m, 2H), 1.94 – 1.85 (m, 2H), 1.53 (d, J = 6.6 Hz, 6H);

Mass (m/z): 384.3 (M+H)⁺.

Patent

WO2016027277

The large scale manufacturing process for preparation of l-Isopropyl-3-{5-[l-(3-methoxypropyl) piperidin-4-yl]-[l ,3,4]oxadiazol-2-yl}-lH-indazole oxalate of

Scheme-1

Preparation 1: Preparation of l-Isopropyl-lH-indazoIe-3-carboxylic acid

To a stirred solution of dimethylformamide (DMF) (50 L) at 25 °C to 30 °C under nitrogen atmosphere, sodium tert-butoxide (6.0 Kg, 62.43 mols) was added over a period of 15 minutes. The reaction mixture was stirred for 10 minutes after which it was cooled to 0 °C to 5 °C. A solution of indazole-3-carboxylic acid (4.0 Kg, 24.67 mols) in DMF (50 L) was added slowly into the reactor over a period of 45 minutes, maintaining the reaction mass temperature at 0 °C to 5 °C. The cooling was removed and the reaction temperature was gradually raised to 25 °C to 30 °C over a period of 30 minutes. After stirring at this temperature for 1 hour the reaction mixture was cooled to 0 °C and isopropyl iodide (6.32 Kg, 37.18 mo!s) was added over a period of 30 minutes. The cooling was removed and the reaction temperature was allowed to rise to 25 °C to 30 °C. After 17 hours of stirring, the HPLC analysis of the reaction mixture revealed <10 % of indazole-7-carboxylic acid remaining. The reaction mass was diluted cautiously with water (200 L) and washed with ethylacetate (2 x 100 L). The resultant aqueous layer was acidified to 4.0 – 4.5 pH with aqueous hydrochloride solution (6.0 N, 21.5 L) and extracted with ethylacetate (2 x 144 L). The combined organic layer was washed with water (2 x 100 L), brine solution (200 L) and dried over anhydrous sodium sulfate (4.0 Kg). The filtered organic layer was subjected to solvent removal under reduced pressure (> 500 mm of Mercury) at 50 °C to 60 °C to obtain a crude mass. The obtained crude mass was diluted with dichloromethane (DCM) (28.0 L) and was stirred for 15 minutes. The solids precipitated (un-reacted indazole-7-carboxylic acid) were filtered through nutsche filter and the filter bed was washed once with DCM (8.0 L). The combined filtrate was distilled under reduced pressure (> 500 mm of Mercury) at 45 °C to 55 °C to obtain a crude mass which was stirred with ether (7.0 L) for 30 minutes and filtered through nutsche filter to obtain the wet solid which was dried further in vacuum oven under reduced pressure (> 500 mm of Mercury) at 45 °C to 55 °C to obtain above titled compound (3.0 Kg) as an off-white crystalline powder.

Yield: 59.5 %;

Purity: 99.86 %;

IR (cm-‘): 2980, 1729, 1682, 1487, 1287, 1203, 1 170, 1 127, 1085, 754;

Ή-NMR (δ ppm, CDC1₃): 8.27 (d, J= 8.1 Hz, 1H), 7.55 (d, J= 8.4 Hz, 1H), .7.46 (t, J = 7.6 Hz, 1H), 7.34 (t, J = 7.4 Hz, 1H), 5.01 – 4.95 (m, 1H), 1 .68 (d, J = 6.65 Hz, 6H);

Mass (m/z): 205.1 (M+H)⁺.

Preparation 2: Preparation of l-(3-Methoxypropyl) piperidine-4-carboxyIic acid hydrazide

Step (i): Preparation of Ethyl 1 -(3-methoxj propyl) piperidine-4-carboxylate

To a stirred solution of acetonitrile (97.5 L) under nitrogen atmosphere at 25 °C to 30 °C, ethyl isonipecotate (6.5 Kg, 41.35 mols) was added. The contents were stirred for 10 minutes after which potassium carbonate powder (7.35 Kg, 53.2 mols) and l-Bromo-3-methoxy propane (6.89 Kg, 45.0 mols) were sequentially added. The reaction mixture was gradually heated to reflux (82 °C – 85 °C) over a period of 30 minutes and was maintained at this temperature for 7 hours. At this time, the TLC revealed complete consumption of ethylisonipecotate. The volatiles were distilled off under reduced pressure (> 500 mm of Mercury) at 50 °C to 60 °C. The crude mass was cooled to 25 °C to 30 °C and was diluted with water (71.5 L) and DCM (136.5 L). After stirring the contents the two layers were separated. The organic layer was washed with water (71.5 L), dried over anhydrous sodium sulfate (6.5 Kg) and the volatiles were removed under reduced pressure (> 500 mm of Mercury) at 50 °C to 55 °C to obtain the desired product (9.3 Kg) as pale yellow colored liquid.

Yield: 98 %;

Purity: 98.8 %;

IR (cm^“‘): 2949, 1732, 1449, 1376, 1 179, 11 19, 1048;

Ή-NMR (6 ppm, CDC13): 4.06 (q, J = 7.1 Hz, 2H), 3.37 – 3.34 (t, J – 6.4 Hz, 2H), 3.27 (s, 3H), 2.83 – 2.80 (m, 2H), 2.34 (t, J = 7.5 Hz, 2H), 2.22 – 2.18 (m, 1H), 1.96 – 1.94 (m, 2H), 1.85 – 1.82 (m, 2H), 1.74 -1.68 (m, 4H), 1.19 (t, J= 7.04 Hz, 3H);

Mass (m/z): 230.4 (M+H)⁺.

Step (ii): Preparation of l-(3-Methoxypropyl) piperidine-4-carboxylic acid hydrazide

To a stirred solution of methanol (38 L) under nitrogen atmosphere at 25 °C to 30 °C, ethyl l-(3-methoxypropyl) piperidine-4-carboxylate (5.0 Kg, 21.8 mols, obtained in above step) was added. After stirring the reaction mixture for 15 minutes, hydrazine hydrate (80 % w/v, 4.1 Kg, 65.4 mols) was added over a period of 15 minutes. The reaction mixture was gradually heated to reflux (70 °C) over 30 minutes and continued stirring for 4 hours. Additional amount of hydrazine hydrate (80 % w/v, 4.1 Kg, 65.4 mols) was added and the stirring continued for another 4 hours. Another installment of hydrazine hydrate (80 % w/v, 4.1 Kg, 65.4 mols) was added and the stirring was continued for 16 hours at 70 °C, upon which the Thin Layer Chromatography (TLC) reveals < 5 % of ester. The volatiles were distilled off under reduced pressure (> 500 mm of Mercury) at 60 °C until syrupy mass appeared. After cooling syrypy mass to room temperature (25 °C – 30 °C), it was diluted with DCM (38.0 L) and was stirred for 15 minutes. The observed two layers were then separated. The organic layer was dried over anhydrous sodium sulfate (5.0 Kg) and the solvent was evaporated under reduced pressure (> 500 mm of Mercury) at 55 °C until dryness. The solid product which was separated was cooled to 25 °C to 30 °C, diluted with hexanes (15.0 L) and the resultant slurry was filtered at nutsche filter. The filter bed was washed once with hexanes (15.0 L) and ethylacetate (2 x 10.0 L). The product cake was vacuum dried and the solid material thus separated was further dried in vacuum oven under reduced pressure (> 500 mm of Mercury) at 50 °C for 6 hours to obtain the above titled compound (4.1 Kg) as an off-white crystalline powder.

Yield: 87 %;

Purity: 99.79 %;

IR (cm-‘): 3290, 3212, 2948, 2930, 1637, 1530, 1378, 1 124, 1 1 13, 986, 948, 789, 693;

Ή-NMR (δ ppm, CDC1₃): 6.83 (s, 1H), 3.86 (bs, 2H), 3.41 (t, J = 6.4 Hz, 2H), 3.32 (s, 3H), 2.99 – 2.96 (m, 2H), 2.42 (t, J= 7.44 Hz, 2H), 2.1 1 – 1.96 (m, 3H), 1.82 – 1.73 (m, 6H);

Mass (m/z): 216.3 (M+H)⁺.

Example 1: Preparation of l-Isopropyl-3-{5-[l-(3-methoxypropyl) piperidin-4-yI]-[l,3,4]oxadiazol-2-yl}-lH-indazole oxalate

Step (i): Preparation of N-[l-(3-Methoxypropyl) piperidine-4-carbonyI] ‘-(l-isopropyI-lH-indazole-3-carbonyl) hydrazine

To a stirred solution of 1 ,2-dichloroethane (19.8 L) under nitrogen atmosphere at 25 °C to 30 °C, l -isopropyl-lH-indazole-3-carboxylic acid (3.0 Kg, 14.69 moles, obtained in preparation 1 ) was added and the reaction mixture was stirred for 15 minutes for complete dissolution. Thionyl chloride (3.6 Kg, 30.25 mols) was then added to the reaction mixture by maintaining its temperature below 30 °C over a period of 15 minutes. The reaction temperature was then gradually raised to 75 °C over a period of 30 minutes and was stirred for 2 hours at that temperature. The TLC revealed complete conversion of acid to acid chloride. The solvent 1,2-dichloroethane and excess thionyl chloride was removed under reduced pressure (> 500 mm of Mercury) below 60 °C temperature. The obtained residual mass was cooled to 25 °C to 30 °C, and diluted with DCM (15.6 L). The contents were further cooled to 0 °C to 5 °C. A solution of l-(3-Methoxypropyl) piperidine-4-carboxylic acid hydrazide (3.0 Kg, 1 3.94 mols, obtained in the preparation 2) in DCM (18.0 L) was added to the reaction mass over a period of 30 minutes. The reaction temperature was then gradually raised to 25 °C to 30 °C and the reaction mixture was stirred for 2 hours. The progress of the reaction was monitored by TLC which showed absence of hydrazide (< 1.0 %). The reaction mixture was then diluted with water (30.0 L), stirred for 15 minutes and the two layers were separated. The aqueous layer was washed with DCM (1 x 30.0 L), cooled to 0 °C to 5 °C and cautiously basified to pH 7.6 with aqueous sodium bicarbonate solution (10 % w/v, 46.5 L). The basified aqueous layer was then extracted with DCM (2 x 30.0 L). The combined organic layer was dried over anhydrous sodium sulfate (6.0 Kg) and the solvent was removed under reduced pressure (> 500 mm of Mercury) below 55 °C. The residue was then cooled to 25 °C – 30 °C and diluted with solvent hexane (9.0 L). The slurry, thus obtained, was centrifuged at room temperature under nitrogen atmosphere and the wet product cake was washed with hexanes (6.0 L). The wet product was then dried in oven at 55 °C -60 °C until loss on drying was < 1.0 % to obtain the above titled compound (4.4 Kg) as an off white crystalline powder.

Yield: 74.5 %;

Purity: 98.75 %;

IR (cm-¹): 3506, 3233, 2943, 1703, 1637, 1523, 1487, 1 195, 1 1 16, 750;

Ή-NMR (δ ppm, CDC1₃): 9.35 (bs, 1H), 8.70 (bs, 1H), 8.30 (d, J = 8.1 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.42 (t, J = 8.2 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 4.90 -4.85 (m, 1H), 3.40 (t, J = 6.4 Hz, 2H), 3.33 (s, 3H), 2.94 – 2.85 (m, 2H), 2.39 -2.31 (m, 3H), 1.92 – 1.88 (m, 4H), 1.76 – 1.65 (m, 4H), 1.59 (d, J = 6.6 Hz, 6H); Mass (m/z): 402.2 (M+H)⁺.

Step (ii): Preparation of l-Isopropyl-3-{5-[l-(3-methoxypropyl) piperidin-4-yl]-[l,3_»4]oxadiazol-2-yl}-lH-indazole

To a stirred solution of 1 ,2-dichloroethane (60 L) under nitrogen atmosphere at 25 °C to 30 °C, N-[l-(3-methoxypropyl) piperidine-4-carbonyl] N’-(l -isopropyl-1 H-indazole-3-carbonyl) hydrazine (3.0 Kg, 7.47 mols, obtainted in above step) was added and the contents were stirred for 15 minutes afterwhich, thionyl chloride (1.77 Kg, 15.0 mols) was added over 15 minutes time. The reaction mixture temperature was then gradually raised to 79 °C – 83 °C over a period of 30 minutes at which the reaction mixture starts refluxing. Upon completion of 9 hours, the reaction mass showed complete consumption of starting material when checked by TLC. The excess thionyl chloride and solvent 1,2-dichloroethane were distilled off under reduced pressure (> 500 mm of Mercury) below 60 °C. The reaction mass was cooled to 25 °C – 30 °C, diluted with water (39.0 L) and solvent ether (19.5 L). The resulting mass was stirred for 15 minutes and the two layers were separated. The pH of the aqueous layer was adjusted to 9 – 10 by adding an aqueous solution of sodium hydroxide (2.5N, 3.0 L). The basified aqueous layer was then extracted with DCM (2 x 54.0 L). The combined organic layer was washed with cold (5 °C – 10 °C) aqueous sodium hydroxide solution (0.6 N, 54.0 L), dried over anhydrous sodium sulfate (6.0 Kg) and the solvent was removed under reduced pressure (> 500 mm of Mercury) below 55 °C, which yielded above titled compound (2.6 Kg) as brown colored syrupy mass.

Yield: 90.5 %;

Purity: 99.3 %;

IR (cm^“1): 3054, 2946, 2808, 1599, 1563, 1462, 1389, 121 1, 1 120, 1069, 999, 749; Ή-NMR (6 ppm, CDC1₃): 8.34 (d, J = 8.12 Hz, 1H), 7.53 (d, J – 8.44 Hz, 1H), 7.45 (t, J = 7.58 Hz, 1H), 7.32 (t, J = 7.44 Hz, 1H), 4.98 – 4.93 (m, 1H), 3.44 (t, J = 6.44 Hz, 2H), 3.03 – 3.00 (m, 3H), 3.34 (s, 3H), 2.46 (t, J = 7.54 Hz, 2H), 2.20 -2.02 (m, 6H), 1.80 (t, J= 7.27 Hz, 2H), 1.66 (d, J= 6.72 Hz, 6H);

Mass (m/z): 384.3 (M+H)⁺.

Step (iii): Purification of l-Isopropyl-3-{5-[l-(3-methoxypropyI) piperidin-4-yl]-[l,3.4]oxadiazoI-2-yl}-lH-indazole

The above obtained crude step (ii) product was dissolved in a stirring aqueous acetic acid solution (10 % w/v, 26.0 L) and washed with ethylacetate (2 x 26.0 L). The resultant aqueous layer pH was adjusted to 9.0 – 10.0 by adding an aqueous sodium hydroxide solution (0.5N, 52.0 L). The basified aqueous layer was extracted with solvent ether (2 x 26.0 L) and the combined organic layer was dried over anhydrous sodium sulfate (3.0 Kg). The volatiles were removed under reduced pressure (> 500 mm of Mercury) below 55 °C to obtain a brown colored syrupy mass (2.19 Kg).

Yield: 84 %;

Purity: 99.72 %;

IR (cm^“1): 3054, 2978, 2946, 2808, 2772, 1599, 1563, 1462, 1389, 1 194, 1 177, 1 120, 1069, 999, 749;

Ή-NMR (δ ppm, CDC1₃): 8.34 (d, J = 8.12 Hz, 1H), 7.53 (d, J = 8.44 Hz, 1H), 7.45 (t, J = 7.58 Hz, 1H), 7.32 (t, J = 7.44 Hz, l H), 4.98 – 4.93 (m, 1H), 3.44 (t, J = 6.44 Hz, 2H), 3.03 – 3.00 (m, 3H), 3.34 (s, 3H), 2.46 (t, J = 7.54 Hz, 2H), 2.20 -2.02 (m, 6H), 1.80 (t, J= 7.27 Hz, 2H), 1.66 (d, J = 6.72 Hz, 6H);

Mass (m/z): 384.4 (M+H)⁺.

Step (iv): Preparation of l-Isopropyl-3-{5-[l-(3-methoxypropyl) piperidin-4-yI]-[l,3,4]oxadiazol-2-yi}-lH-indazole oxalate

To a stirred solution of isopropanol (60.8 L) under nitrogen atmosphere at 25 °C -30 °C, l-isopropyl-3-{5-[l -(3-methoxypropyl) piperidin-4-yl]-[l,3,4]oxadiazol-2-yl}-lH-indazole (6.08 Kg, 15.86 mols, obtained in step (iii) was added, followed by oxalic acid (1.46 Kg, 16.2 mols) addition. The reaction mixture was stirred for 2 hours and solid product that is precipitated was filtered through nutsche filter under nitrogen atmosphere. The wet product bed was washed with isopropanol (10.0 L) and solvent ether (60.8 L) to obtain a technical grade product.

IR (cm^“1): 3437, 2975, 2932, 2890, 1703, 1604, 1564, 1458, 1391, 1281, 1217, 1 192, 1 1 14, 992, 750;

Ή-NMR (δ ppm, DMSO-d₆): 10.72, (bs, 2H), 8.16 (d, J = 8.1 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.51 (t, J = 7.4 Hz, 1 H), 7.35 (t, J = 7.7 Hz, 1H), 5.20 – 5.07 (m, 1H), 3.55 – 3.43 (m, 3H), 3.36 (t, J = 5.9 Hz, 2H), 3.21 (s, 3H), 3.1 8 – 2.98 (m, 4H), 2.40 – 2.30 (m, 2H), 2.26-2.12 (m, 2H), 1.96 – 1.85 (m, 2H), 1.53 (d, J = 6.6 Hz, 6H);

Mass (m/z): 384.4 (M+H)⁺.

Step (v): Recrystallization of l-Isopropyl-3-{5-[l-(3-methoxypropyI) piperidin-4-yl]-[l,3,4]oxadiazol-2-yl}-lH-indazole oxalate

The above obtained product was suspended in a mixture of isopropanol (35.26 L) and water (7.3 L) and refluxed (76 °C) for 4 hours until complete dissolution. The homogenous solution thus obtained was gradually cooled to 25 °C – 30 °C and maintained at this temperature under slow stirring for 16 hours. The precipitated oxalate salt was centrifuged under nitrogen atmosphere. The product cake was washed with isopropanol (15.0 L) and ether (60.8 L). The suction dried product was then dried in vacuum oven at 25 °C – 30 °C for 2 hours and at 65 °C for 1 hour to obtain above titled compound (4.24 Kg) as light cream colored crystalline material.

Yield: 60 %;

Purity: 99.92 %;

Salt content (oxalate salt): 20.37 %;

Heavy metals: < 20 ppm;

IR (cm-¹): 3437, 2975, 2932, 2890, 1703, 1604, 1564, 1458, 1391, 1281, 1217, 1 192, 1 1 14, 992, 750;

1H-NMR (δ ppm, DMSO-d₆): 10.72, (bs, 2H), 8.16 (d, J- 8.1 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.51 (t, J = 7.4 Hz, 1H), 7.35 (t, J = 7.7 Hz, 1H), 5.20 – 5.07 (m, 1H), 3.55 – 3.43 (m, 3H), 3.36 (t, J = 5.9 Hz, 2H), 3.21 (s, 3H), 3.18 – 2.98 (m, 4H), 2.40 – 2.30 (m, 2H), 2.26-2.12 (m, 2H), 1.96 – 1.85 (m, 2H), 1.53 (d, J= 6.6 Hz, 6H);

Mass (m/z): 384.4 (M+H)⁺.

REFERENCES

http://www.sciencedirect.com/science/article/pii/S1552526014012874

http://www.suven.com/news_Sep2015_02.htm

SUVN-D4010: Novel 5-HT4 receptor partial agonist for the treatment of Alzheimer’s disease
45th Annu Meet Soc Neurosci (October 17-21, Chicago) 2015, Abst 54.08

SEE BELOW

Characterization of SUVN-D1104010: A potent, selective and orallyactive 5-HT4 receptor partial agonist
Alzheimer’s Assoc Int Conf (AAIC) (July 14-19, Vancouver) 2012, Abst P2-392

SUVN-D1104010 displayed IC50 values > 45 and > 10 mcM for cytochrome P450 3A4 and 2D6, respectively. In dog, rat and human liver microsome preparations, it showed respective stabilities of 64, 26 and 26%. It displayed rat brain, rat plasma and human plasma protein binding values of 94, 89 and 93%, respectively. For parmacokinetic studies, the agent was administered to male Wistar rats (1 mg/kg i.v.; 3 mg/kg p.o.) and male Beagle dogs (1 mg/kg i.v. and p.o.). Following intravenous administration, the rats showed AUC(0-24 h), t1/2, MRT Last, Cl and Vdss values of 245 ng·h/mL, 1.1 hours, 1.1 hours, 67 mL/min/kg and 5.3 L/kg, respectively. Following intravenous administration to dogs, these respective values were 951 ng·h/mL, 6 hours, 3.9 hours, 18 mL/min/kg and 5.1 L/kg. Following oral administration to rats, the respective values were 136 ng·h/mL, 0.42 hours, 222 hours, 1.4 mL/min/kg and 1.4 L/kg. For dogs, these respective values were 179 ng·h/mL, 0.58 hours, 711 hours, 4.6 mL/min/kg and 4.0 L/kg. Oral bioavailabilty values in rats and dogs were 30 and 72%, respectively. The brain penetration profile was studied 1 hour after the administration of 1, 3 and 10 mg/kg p.o. in rats. Plasma, cerebrospinal fluid (CSF), whole brain samples were collected and drug concentrations were analyzed by liquid chromatography – mass spectrometry. Dosing at 1, 3 and 10 mg/kg p.o. was associated with respective plasma concentrations of 42, 136 and 537 nM; respective brain concentrations of 120, 352 and 1674 nM; respective CSF concentrations of 7, 18 and 90 nM; ratios of CSF concentrations over Ki values of 0.3, 0.8 and 3.8; ratios of brain concentrations over Ki values of 5, 5 and 70; and ratios of brain over plasma concentrations of 2.8, 2.5 and 3. Further studies included in vivo receptor occupancy (brain 5-HT4 receptor) analysis. The drug showed dose-dependent occupancy in the rat striatum and gained ready access to the brain. An ED50 of 2.75 mg/kg p.o. was noted. Brain cortical soluble amyloid precursor protein alpha (sAPPalpha) levels were assessed in male C57BL6 mice injected with 1-10 mg/kg s.c. and sacrificed 30/60 minutes later. Results were compared to vehicle-treated mice. At 3 and 10 mg/kg doses, significant increases in sAPPalpha levels were noted (P values < 0.05 and < 0.01, respectively) using ELISA. To study changes in CSF beta-amyloid levels, Wistar rats were administered the drug orally at 0.03-3 mg/kg and 2 hours later, CSF was collected and analyzed for beta-amyloid protein 42 (Abeta42) and 40 (Abeta40) by ELISA. The drug induced a decrease of 19-35% in Abeta42 levels and a decrease of 20-38% in Abeta40 levels in rat CSF at a dose of 0.1 mg/kg (P < 0.01). Toxicity studies are currently under way.

March 16, 2015

Drug firm Suven Life Sciences has been granted a patent each by the US and New Zealand for a drug used in the treatment of neuro-degenerative diseases.

The patents are valid until 2030 and 2031, respectively, Suven Life Sciences said in a filing to the BSE.

Commenting on the development, Suven Life CEO Venkat Jasti said: “We are very pleased by the grant of these patents to Suven for our pipeline of molecules in CNS arena that are being developed for cognitive disorders with high unmet medical need with huge market potential globally.”

SUVEN, Chief executive and chairman Venkat Jasti

The company has “secured patents in USA and New Zealand to one of their new chemical entity (NCE) for CNS therapy through new mechanism of action – H3 Inverse agonist…,” Suven Life Sciences said.

With these new patents, Suven has a total of 20 granted patents from US and 23 granted patents from New Zealand.

“These granted patents are exclusive intellectual property of Suven and are achieved through the internal discovery research efforts.

“Products out of these inventions may be out-licensed at various phases of clinical development like at Phase-I or Phase-II,” Suven said.

Pdf Link: Suven Life Sciences secures 2 (two) Product Patents for their NCE’s through New mechanism of action – H3 Inverse Agonist in USA & New Zealand

http://www.bseindia.com/xml-data/corpfiling/AttachLive/suven_life_sciences_ltd_160315.pdf

Suven Life Sciences secures 2 (two) Product Patents for their NCE’s through New mechanism of action – H3 Inverse Agonist in USA & New Zealand HYDERABAD, INDIA (March 16, 2015) – Suven Life Sciences Ltd (Suven) announced today that they secured patents in USA (us 8912179) and New Zealand (614567) to one of their New Chemical Entity (NCE) for CNS therapy through new mechanism of action – H3 Inverse agonist and these patents are valid until 2030 and 2031 respectively. The granted claims of the patent include the class of selective H3 ligands discovered by Suven and are being developed as therapeutic agents and are useful in the treatment of cognitive impairment associated with neurodegenerative disorders

Suven Life Sciences Ltd.
6th Floor, SDE Serene Chambers,
Avenue – 7, Road No. 5, Banjara Hills,
Hyderabad-500 034, Telangana, INDIA

Phone : +91-40-2354-1142, 2354-3311
Fax : +91~40~2354-1152
Email id: info@suven.com

INDIAN PATENT

Nirogi, Ramakrishna; Shinde, Anil Karbhari; Kambhampati, Ramasastri; Namala, Rambabu; Dwarampudi, Adi Reddy; Kota, Laxman; Gampa, Murlimohan; Kodru, Padmavathi; Tiriveedhi, Taraka Naga Vinaykumar; Kandikere, Vishwottam Nagaraj; et al
From Indian Pat. Appl. (2012), IN 2010CH02551

PATENT

http://www.google.com/patents/US8912179

The present invention relates to heterocyclyl compounds of formula (I) and their pharmaceutically acceptable salts, its process of preparation and compositions containing them, for the treatment of various disorders that are related to Histamine H₃ receptors.

ONE EXAMPLE

EXAMPLE 1

Example 1

Preparation of 1-[2-(1-Cyclobutyl-piperidin-4-yloxy)-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl]-propan-1-one tartrate

Step (i): Preparation of 2-(1-Cyclobutyl-piperidin-4-yloxy)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butyl ester

1-Cyclobutyl-piperidin-4-ol (1.6 grams, 10 mmol) in tetrahydrofuran (20 mL) was treated with cooled and stirred suspension of sodium hydride (0.9 grams, 18 mmol) in tetrahydrofuran (20 mL) slowly over a period of 30 minutes; the reaction mixture was stirred for 1 hour. A solution of 2-Bromo-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butyl ester (3 grams, 9 mmol, obtained in preparation 1) in tetrahydrofuran (30 mL) was added drop wise over a period of 15 minutes and refluxed the reaction for 6 hours. Reaction mass was quenched with ice cold water and the product was extracted with ethyl acetate (3×50 mL). Combined organics were washed with water followed by brine and dried over anhydrous sodium sulphate. Organic volatiles were evaporated under vacuum. The residue was purified by flash chromatography (ethylacetate/n-hexane, 1/1) to obtain the title compound (2.0 grams).

¹H-NMR (δ ppm): 1.48 (9H, s), 1.65-1.72 (2H, m), 1.85-1.92 (4H, m), 2.01-2.07 (4H, m), 2.18-2.19 (2H, m), 2.57 (2H, m), 2.62-2.66 (2H, m), 2.71-2.75 (1H, m), 3.70 (2H, m), 4.43 (2H, m), 4.93 (1H, m);

Mass (m/z): 394.2 (M+H)⁺.

Step (ii): Preparation of 2-(1-Cyclobutyl-piperidin-4-yloxy)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridineA solution of 2-(1-Cyclobutyl-piperidin-4-yloxy)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butyl ester (2.0 grams, 5 mmol, obtained in above step) in dichloromethane (30 mL) was treated with trifluroacetic acid (5.0 mL, 50 mmol) at 0° C. Reaction mass was stirred for 4 hours. After completion of reaction, the reaction mass was quenched into ice cold water and adjust pH to 10, by using 40% aqueous sodium hydroxide solution. The product was extracted with dichloromethane (3×50 mL), combined organics were washed with water followed by brine and dried over anhydrous sodium sulphate. Organic volatiles were evaporated under vacuum to obtain the title compound (1.3 grams).

¹H-NMR (δ ppm): 1.68-1.74 (2H, m), 1.85-1.93 (4H, m), 2.06 (4H, m), 2.19 (2H, m), 2.60-2.61 (4H, m), 2.73-2.80 (1H, m), 2.90-3.10 (1H, m), 3.13-3.16 (2H, m), 3.85 (2H, s), 4.90-4.93 (1H, m);

Mass (m/z): 294.2 (M+H)⁺.

Step (iii): Preparation of 1-[2-(1-Cyclobutyl-piperidin-4-yloxy)-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl]-propan-1-oneA solution of 2-(1-Cyclobutyl-piperidin-4-yloxy)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine (1.3 grams, 4 mmol, obtained in above step) and triethylamine (1.9 mL, 13 mmol) in dichloromethane (30 mL) was cooled to 0° C. Propionylchloride (0.4 mL, 5 mmol) in dichloromethane (5 mL) was added drop wise over a period of 15 minutes and stirred the reaction for 30 minutes. Reaction mass was poured onto ice cold water and the product was extracted with ethyl acetate (3×50 mL). Combined organics were washed with water followed by brine and dried over anhydrous sodium sulphate. Organic volatiles were evaporated under vacuum. The residue was purified by flash chromatography (methanol/chloroform, 2/98) to obtain the title compound (1.0 gram).

¹H-NMR (δ ppm): 1.17-1.21 (3H, m), 1.65-1.72 (5H, m), 1.87-1.91 (4H, m), 2.01-2.07 (4H, m), 2.22 (1H, m), 2.38-2.45 (2H, m), 2.45 (1H, m), 2.68-2.76 (3H, m), 3.72-3.74 (1H, m), 4.47-4.62 (2H, m), 4.92-4.94 (1H, m).

Mass (m/z): 350.4 (M+H)⁺.

Step (iv): Preparation of 1-[2-(1-Cyclobutyl-piperidin-4-yloxy)-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl]-propan-1-one tartrateA solution of 1-[2-(1-Cyclobutyl-piperidin-4-yloxy)-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl]-propan-1-one (0.8 grams, 2.3 mmol, obtained in above step) in methanol (10 mL) was treated with L(+)-Tartaric acid (0.34 grams, 2.3 mmol) at 0° C. Stirred the reaction mass for about 1 hour and the solvent was evaporated under vacuum to dryness. The solids were washed with diethyl ether and dried under vacuum to obtain the title compound (1.1 grams).

¹H-NMR (δ ppm): 1.12-1.20 (3H, m), 1.82-1.87 (2H, m), 2.16-2.32 (7H, m), 2.45-2.55 (2H, m), 2.63-2.66 (3H, m), 2.72 (1H, m), 3.20 (2H, m), 3.47-3.50 (1H, m), 3.66-3.70 (1H, m), 3.81-3.88 (2H, m), 4.45 (2H, s), 4.60 (2H, s), 5.18 (5H, m);

Mass (m/z): 350.4 (M+H)⁺.

Publication number	US8912179 B2
Publication type	Grant
Application number	US 13/818,152
PCT number	PCT/IN2010/000740
Publication date	Dec 16, 2014
Filing date	Nov 15, 2010
Priority date	Sep 2, 2010
Also published as	CA2812970A1, 4 More »
Inventors	Ramakrishna Nirogi, Anil Karbhari Shinde,Ramasastri Kambhampati, Rambabu Namala,Adi Reddy Dwarampudi, Laxman Kota,Murlimohan Gampa, Padmavathi Kodru,Taraka Naga Vinaykumar Tiriveedhi,Vishwottam Nagaraj Kandikere, Nageshwara Rao Muddana, Ramanatha Shrikantha Saralaya, Pradeep Jayarajan, Dhanalakshmi Shanmuganathan, Ishtiyaque Ahmad,Venkateswarlu Jasti, Less «
Original Assignee	Suven Life Sciences Limited
Export Citation	BiBTeX, EndNote, RefMan
Patent Citations (12), Non-Patent Citations (10), Classifications (16),Legal Events (1)

External Links: USPTO, USPTO Assignment, Espacenet

……………….

Banjara Hills,Hyderabad

Banjara Hills, Hyderabad, Telangana

TAJ KRISHNA

SUBWAY RESTAURANT

//////

CC(C)n4nc(c1nnc(o1)C2CCN(CCCOC)CC2)c3ccccc34

WO 2016027077, Cipla Ltd, New patent, Dabigatran

March 1, 2016 6:48 am / 3 Comments on WO 2016027077, Cipla Ltd, New patent, Dabigatran

(WO2016027077) PROCESSES FOR THE PREPARATION OF DABIGATRAN ETEXILATE AND INTERMEDIATES THEREOF

WO 2016027077, Cipla Ltd, New patent, Dabigatran

CIPLA LIMITED [IN/IN]; Cipla House Peninsula Business Park Ganpatrao Kadam Marg Lower Parel Mumbai 400 013 (IN).

RAO, Dharmaraj Ramachandra; (IN).
MALHOTRA, Geena; (IN).
PULLELA, Venkata Srinivas; (IN).
ACHARYA, Vinod Parameshwaran; (IN).
SINARE, Sudam Nanabhau; (IN)

Dabigatran etexilate (a compound of Formula I) is the international commonly accepted nonproprietary name for ethyl 3-{[(2-{[(4-{(hexyloxy)carbonyl]carbamimidoyl}phenyl)amino]methyl}-1 -methyl-1 H- benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate,

(I)

Dabigatran etexilate is the pro-drug of the active substance, dabigatran. The mesylate salt (1 : 1 ) of dabigatran etexilate is known to be therapeutically useful as an oral anticoagulant from the class of the direct thrombin inhibitors and is commercially marketed as oral hard capsules as Pradaxa™ in Australia, Europe and in the United States; as Pradax™ in Canada and as Prazaxa™ in Japan. Additionally, it is also marketed in Europe under the same trade mark for the primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery.

Dabigatran etexilate was first described in U.S. Patent No. 6,087,380, according to which the synthesis of dabigatran etexilate was carried out in three synthetic steps as depicted in Scheme 1.

Scheme 1

1. HCL , EtOH

2. (NH4)2C03, EtOH

Dabigatran etexilate

II. HCI

The process involves the condensation between ethyl 3-{[3-amino-4-(methylamino)benzoyl] (pyridin-2-yl)amino}propanoate (compound VI) and N-(4-cyanophenyl)glycine (compound VIII) in the presence of Ν,Ν’-carbonyldiimidazole (CDI) in tetrahydrofuran (THF) to give the hydrochloride salt of ethyl 3-{[(2-{[(4-cyanophenyl)amino]methyl}-1-methyl-1 H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino} propanoate (compound IV), which is subsequently reacted with ethanolic hydrochloric acid, ethanol and ammonium carbonate to give the hydrochloride salt of ethyl 3-{[(2-[{(4-carbamimidoylphenyl)amino]methyl}-1-methyl-1 H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino} propanoate (compound II). Finally, the reaction between compound II and n-hexyl chloroformate (compound IX), in the presence of potassium carbonate, in a mixture of THF and water, affords dabigatran etexilate of Formula (I) after work- up and chromatographic purification. However, no information is given about the purity of the isolated dabigatran etexilate (I) product. Further, the process is not viable industrially as it requires chromatographic purification in several of its steps, thus making it very difficult and costly to implement on an industrial scale.

In order to simplify the process for obtaining dabigatran etexilate described in U.S. Patent No. 6,087,380, several alternative processes have been developed and reported in the art.

EP2118090B discloses a process for the preparation of the intermediate compound of Formula (II) by crystallization from a salt with p-toluenesulfonic acid. The amidine salt (ll-pTsOH) is obtained from a compound of formula (IV), which is also isolated in the form of a hydrobromide salt, (IV-HBr).

EP2262771A discloses a process for the preparation of the intermediate compound of Formula (IV), which is obtained in the form of a salt with oxalic acid. This document indicates that the oxalate intermediate of the compound (IV) crystallizes easily and is a good synthesis intermediate to obtain the amidine hydrochloride salt (ll-HCI) with high purity on an industrial scale. The compound (IV) in oxalate salt form is transformed in dabigatran following the process disclosed in WO 98/37075.

WO 2006/000353 describes an alternative process for the synthesis of dabigatran etexilate as depicted in Scheme 2.

Dabigatran etexilate

The process involves condensation between ethyl 3-{[3-amino-4-(methylamino)benzoyl](pyridin-2-yl)amino}propanoate (compound VI) and 2-[4-(1 ,2,4-oxadiazol-5-on-3-yl)phenylamino]acetic acid (compound Villa) in the presence of a coupling agent such as CDI, propanephosphonic anhydride (PPA), or pivaloyl chloride, to give ethyl 3-{[(2-{[(4-{1 ,2,4-oxadiazol-5-on-3-yl}phenyl)amino]methyl}-1 -methyl-1 H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate (compound IVa), which is subsequently hydrogenated in the presence of a palladium catalyst to give ethyl 3-{[(2-{[(4-carbamimidoylphenyl)amino]methyl}-1-methyl-1 H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino} propanoate (compound II). The compound II is acylated with n-hexyl chloroformate (compound I) to give dabigatran etexilate. Finally, dabigatran etexilate is converted into its mesylate salt. Although the patent describes the HPLC purities of intermediate compounds II, IVa, Villa and VI, no information is given concerning the purity of the isolated dabigatran etexilate or the mesylate salt thereof.

WO 2010/045900 discloses a process to prepare the intermediate amidine hydrochloride compound (ll-HCI) from the oxalate salt of the compound (IV) by reacting with hydrogen chloride in ethanol, followed by reaction with ammonium carbonate to avoid chromatography which is not feasible on an industrial scale.

WO 2014/012880 discloses a process to prepare an intermediate of dabigatran etexilate (compound IV) by reacting carboxylic acid (compound VIII) with diamaine (compound VI) in the presence of the coupling agent CDI, followed by reaction with 6 equivalents of acetic acid at 130°C to obtain compound IV in acetate salt form, having a purity of 94%. The isolated solid is further recrystallized from ethanol to obtain a purity of 99%. The purified (compound IV. acetate) is reacted with hydrogen chloride in the presence of an alcohol, and then with ammonia in an aqueous medium to form the amidine hydrochloride salt (compound ll-HCI) in the presence of water.

The synthesis of intermediate compound II has been reported in the patent literature and known methods require either chromatographic purification or a lengthy purification procedure, such as converting the compound into the HCI salt followed by recrystallization, to obtain 97% pure intermediate compound II. In previously reported methods, the product yield is undesirably less than 50 %.

Similarly, the intermediate compound IV prepared by CDI mediated coupling with glycine derivatives followed by acetic acid mediated cyclization according to known methods results in the formation of highly impure products, which require purification by either column chromatography or by converting the crude reaction mixture to suitable salts. Previously reported methods afford low product yields and purity, which mean that such processes are not suitable for the commercial scale production of dabigatran.

In view of the foregoing, it is of great interest to continue investigating and develop other alternative simplified processes for the large scale industrial production of the active pharmaceutical ingredient dabigatran etexilate or salts thereof, which avoid complicated and costly purification steps in the synthesis of intermediates, while maintaining a high quality of synthesis intermediates and improving the yields of each step of reaction.

SCHEME 3

SCHEME4

Examples:

Example 1. Preparation of DAB Glycin-CDI complex of Formula (VII)

71.02 g (0.438 mol) of CDI was dissolved in 700 ml dichloromethane under nitrogen atmosphere. Added 66.89 g (0.379 mol) of 2-(4-cyanophenylamino)acetic acid of Formula (VIII), under stirring at 20-25°C and stirred for 90-100 minutes. Solid was isolated by filtration under nitrogen atmosphere and washed with 100 ml dichloromethane to yield DAB Glycin-CDI complex.

Example 2. Preparation of ethyl 3-(2-((4-cyanophenylamino)methyl)- l-methyl-N- (pyridin-2-yl)-IH-benzo[d]- imidazole-5-carboxamido) propanoate of Formula (IV)

DAB Glycin-CDI Complex obtained in Example 1 was stirred in 650 ml toluene. Added 100 g (0.292 mol) of ethyl 3-(3-amino-4-(methyl amino)-N-(pyridin-2-yl)benzamido)propanoate of Formula (VI) to the reaction mass and stirred for 3 hours at -45-50°C. The reaction mass was further refluxed for 3 hours. The reaction mass was cooled to 75-80°C, added 50 ml ethanol, further cooled to 20-25°C and stirred for 6 hours. The solid was isolated by filtration and washed with 100 ml toluene.

The wet cake was stirred in 500 ml water at 20-25°C for about 1 hour. The solid was isolated by filtration, washed with 100 ml water and dried in vacuum below 60 °C.

Yield: 120 g

Efficiency: 85%

Example 3. Preparation of ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-IH-benzo[d]imidazole-5-carboxamido) propanoate of Formula (II)

100 g (0.207 mol) of ethyl 3-(2-((4-cyanophenylamino)methyl)- l-methyl-N- (pyridin-2-yl)-IH-benzo[d]- imidazole-5-carboxamido) propanoate of Formula (IV) was added to 1000 ml EtOH.HCI (32-35%w/w) at 5-10°C under nitrogen atmosphere and stirred for 24 hours at 15-20°C. The solvent was distilled off in vacuum below 40°C. Added 500 ml ethanol and cooled to 0-5°C. The pH of the reaction mass was adjusted to 9.5-10.0 by addition of 400 ml EtOH.NH₃ (10-13%w/w). The temperature of the reaction mass was raised to 20-25°C and stirred for 12 hours. The reaction mass was filtered and the clear filtrate was partially distilled to the half volume below 40°C. The temperature of the reaction mass was raised to 55-60°C. Added 600 ml ethyl acetate at reflux. The reaction mass was cooled to 20-25°C and stirred further for 5 hours. The solid was isolated by filtration and washed with 100 ml-ethyl acetate. The solid was dried in vacuum below 45 °C.

Yield: 72.5 g

Efficiency: 70%

Example 4. Preparation of DAB etexilate of Formula (I)

120 ml acetone, 60 ml water, 16.6 g (0.120 mol) potassium carbonate and 20g (0.040 mol) of ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-IH-benzo[d]imidazole-5-carboxamido) propanoate of Formula (II) were stirred at 20-25°C. A solution of 9.88 g (0.060 mol) of hexyl chloroformate of Formula (IX) in 50 ml acetone was added to the reaction mass at 15-20°C in 1 .5 hours. The reaction mass was further stirred for 2 hours at 15-20°C. The precipitated solid was filtered and washed with 40 ml water.

The wet cake was dissolved in 160 ml acetone at 20-25°C. The insoluble were removed by filtration. Added 160 ml water to the clear filtrate at 20-25°C in 2 hours and the reaction mass was further stirred for 2 hours. The solid was isolated by filtration, washed with mixture of acetone : water (1 : 1), and dried under vacuum below 45°C to obtain dabigatran etexilate.

Yield: 18.85 g

Efficiency: 75%

Purification:

18 g of Dabigatran etaxilate was stirred in mixture of acetone: ethanol: ethyl acetate (1.5:0.5:6 volumes) at 50-55°C and stirred for 20 minutes. The reaction mass was cooled to 20-25°C and further chilled to 15-20 °C for 3 hours. The solid was isolated by filtration, washed with ethyl acetate and dried under vacuum below 45°C to obtain dabigatran etexilate.

Yield: 13.5 g

Efficiency: 75%

Example 5. Preparation of DAB etexilate mesylate

10 g (0.02 mol) of dabigatran etexilate was dissolved in 200 ml acetone under nitrogen atmosphere. The temperature of the reaction mass was raised to 50-55°C and treated with a solution of 1.86 g (0.0193 mol) of methane sulfonic acid in 50 ml acetone. The reaction mixture was stirred for 45 minutes, then cooled to 20-25 °C and further stirred for 45 minutes. The solid was isolated by filtration, washed with acetone and dried under vacuum below 45°C to obtain dabigatran etexilate mesylate.

Yield: 10 g

Efficiency: 86%

Example 6. Preparation of ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-IH-benzo[d]imidazole-5-carboxamido) propanoate of Formula (ll)using N-acetyl cysteine

10 g (0.020 mol) of ethyl 3-(2-((4-cyanophenylamino)methyl)- l-methyl-N- (pyridin-2-yl)-IH-benzo[d]- imidazole-5-carboxamido) propanoate of Formula (IV) was dissolved in 600 ml EtOH.NH₃ (15-18%w/w) and stirred at 25°C. Added 3.38 g (0.020 mol) of N-acetyl cysteine to the reaction mass and stirred for 24 hours at 70-75°C under 2.0-2.3 kg of pressure. The ethanol was distilled under vacuum and residue was purified by column.

Yield: 5.5 g

Efficiency: 53%

Example 7. Preparation of DAB Amidine of Formula (II) using N-acetyl cysteine

10 g (0.020 mol) of ethyl 3-(2-((4-cyanophenylamino)methyl)- l-methyl-N- (pyridin-2-yl)-IH-benzo[d]- imidazole-5-carboxamido) propanoate of Formula (IV) with 3.5 g (0.021 mol) of N-acetyl-(S)cysteine were initially charged in 10 ml of ethanol. The reaction mixture was heated to 60-65°C, and saturated with ammonia. After 4 hours, ethanol was distilled under vacuum to obtain titled compound as a solid.

Yield: 7.0 g

Efficiency: 67%

Example 8. Preparation of 2-pyridyl impurity B

Part I: 12.0g (0.016 mol) of dabigatran etexilate was added to the solution of 2.8 g (0.07 mol) sodium hydroxide (in 300 ml water and 150 ml ethanol. The reaction mass was stirred for 5 hours. The solution was concentrated under vacuum and neutralized with aq. solution of citric acid (10%v/v). The solid was separated by filtration and washed with cold water and dried under vacuum to afford the acid as a white crystal.

Yield: 8.50 g

Part 11:10 g ( 0.0166 mol) of DAB-Acid obtained in part I was stirred with 25 ml thionyl chloride under nitrogen The temperature of the reaction mass was raised to 40-45°C and maintained for 1 hour. Thionyl chloride was distilled under vacuum completely The residue was stirred in solution of 100 ml toluene and 10 ml triethyl amine at 5-10°C. Added 3.1 g (0.0329 mol) 2-amino pyridine to the reaction mass at 5-10°C under nitrogen atmosphere. Temperature of the reaction mass was raised to 50-55°C and stirred. Toluene was distilled under vacuum and the residue was dissolved in 150 ml DCM. The organic layer was washed with water, dried on sodium sulfate. The organic layer was distilled under vacuum to obtain t crude 2-Pyridyl impurity which was purified by column chromatography.

Yield: 4.0 g

Example 9. Preparation of ethyl 3-(2-((4-cyanophenylamino)methyl)- l-methyl-N- (pyridin-2-yl)-IH-benzo[d]- imidazole-5-carboxamido) propanoate of Formula (IV)

To a solution of N, N-Carbonyldiimidazole (1.17kg, 7.21 mol) and dichloromethane (1 1.25 L), added 2-(4-cyanophenylamino)acetic acid of Formula (VIII), (1.15Kg,6.52 mol) at 30°C under nitrogen atmosphere. The reaction mixture was stirred for 90-100 min and the resulting solid was filtered under nitrogen atmosphere to obtain form Dab glycine CDI complex of Formula (VII).

Dab glycine CDI complex of Formula (VII) was stirred in toluene (9.0L). Added ethyl 3-(3-amino-4-(methyl amino)-N-(pyridin-2-yl)benzamido)propanoate of Formula (VI) (1.5Kg, 4.38 mol) and maintained the reaction at 45-55°C for 3.0 hrs to form DAB coupling intermediate of Formula (V), which further heated to 90-100°C for 3.0 hrs. The reaction mixture was cooled to 25-30°C and the solid precipitated out was isolated by filtration. The wet cake was stirred in water (9.0L), filtered and dried in vacuum below 60 °C to obtain titled compound.

Yield: 1.80kg

Efficiency: 85 %

Example 10. Preparation of ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-IH-benzo[d]imidazole-5-carboxamido) propanoate of Formula (II)

A mixture of ethyl 3-(2-((4-cyanophenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-IH-benzo[d]-imidazole-5-carboxamido) propanoate of Formula (IV) (1.73 kg,3.58mol) was stirred in ethanol denatured with toluene HCI (32-35 % w/w) (20.76 L) at 15- 20°C for 24 hrs. Reaction mass was distilled out completely and the residue was treated with ethanol denatured with toluene. NH₃ (at 10-15% w/w) was added to get the pH 9.0-9.5. The reaction mixture was stirred further for 12.0 hrs. The inorganic was separated by filtration and the filtrate was distilled out and the residue was stirred in ethyl acetate (10 L) . The solid was isolated by filtration and washed with ethyl acetate. The solid was dried in vacuum below 45°C to obtain titled compound.

Yield: 1.70kg

Efficiency: 95 %

Example 11. Preparation of DAB etexilate of Formula (I)

To a solution of ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-IH-benzo[d]imidazole-5-carboxamido) propanoate of Formula (II) (1.61 kg, 3.22mol ), acetone (19.32 L), water( 9.66 L) and potassium carbonate (1.34Kg, 9.69moles ) was added hexyl chloroformate (0.795 kg, 83 moles) slowly at 20-25°C in 2-3 hrs. The reaction mixture was stirred further for 90 min. The solid was filtered and stirred in 7.5 volumes of acetone at 35-40°C. To the clear solution was added dropwise, 7.5 volumes of purified water. The reaction mixture was stirred further for 2 hours at 20-25°C, solid was isolated by filtration and dried at 45°C. The solid was stirred in a mixture of ethanol: ethyl acetate (1 : 10 volume) at 35-40°C to get clear solution, then gradually cooled to 10-15°C and further stirred for 6.0 hours. The solid was isolated by filtration, washed with ethyl acetate and dried under vacuum below 45°C to obtain dabigatran etexilate.

Yield: 1.10 kg

Efficiency: 65%

Example 12. Preparation of DAB etexilate mesylate

Dabigatran etexilate (1.0Kg, 1.59mol) was dissolved in acetone (20.0L) at 50-55°C under nitrogen atmosphere and treated with a solution of methane sulfonic acid (0.15Kg, 1 .56mol) in acetone (1 .5L). The reaction mixture was stirred for 45 minutes, then cooled to 20-25 °C and further stirred for 45 minutes. The solid was isolated by filtration, washed with acetone and dried under vacuum below 45°C to obtain dabigatran etexilate mesylate.

Yield: 1.10kg Efficiency: 95 %

//////////WO-2016027077, WO 2016027077, Cipla Ltd, New patent, Dabigatran

Trelagliptin

February 25, 2016 2:29 pm / Leave a comment

Trelagliptin

865759-25-7; UNII-Q836OWG55H

Molecular Formula:	C₁₈H₂₀FN₅O₂
Molecular Weight:	357.382103 g/mol

2-[[6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxopyrimidin-1-yl]methyl]-4-fluorobenzonitrile

(R) -2 – ((6 (3-amino-piperidin-1-yl) -3-methyl-2,4-dioxo-3,4-dihydropyrimidine -1 (2H) – yl) methyl) synthesis of 4-fluoro-benzonitrile

(R)-2-((6-(3-amino-3-methylpiperidin-l-yl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)methyl)-4-fluorobenzonitrile

A dipeptidyl peptidase-4 (DPP-4) inhibitor used to treat type 2 diabetes.

Research Code SYR-472
CAS No. 865759-25-7 (Trelagliptin)

1029877-94-8 (Trelagliptin Succinate)

APPROVED, JAPAN MARCH 26 2015

Dipeptidyl Peptidase IV (IUBMB Enzyme Nomenclature EC.3.4.14.5) is a type π membrane protein that has been referred to in the literature by a wide a variety of names including DPP4, DP4, DAP-IV, FAPβ, adenosine deaminase complexing protein 2, adenosine deaminase binding protein (AD Abp), dipeptidyl aminopeptidase IV; Xaa-Pro-dipeptidyl-aminopeptidase; Gly-Pro naphthylamidase; postproline dipeptidyl aminopeptidase IV; lymphocyte antigen CD26; glycoprotein GPI lO; dipeptidyl peptidase IV; glycylproline aminopeptidase; glycylproline aminopeptidase; X-prolyl dipeptidyl aminopeptidase; pep X; leukocyte antigen CD26; glycylprolyl dipeptidylaminopeptidase; dipeptidyl-peptide hydrolase; glycylprolyl aminopeptidase; dipeptidyl-aminopeptidase IV; DPP ΓV/CD26; amino acyl-prolyl dipeptidyl aminopeptidase; T cell triggering molecule TρlO3; X-PDAP. Dipeptidyl Peptidase IV is referred to herein as “DPP-IV.” [0003] DPP-W is a non-classical serine aminodipeptidase that removes Xaa-Pro dipeptides from the amino terminus (N-terminus) of polypeptides and proteins. DPP-IV dependent slow release of dipeptides of the type X-GIy or X-Ser has also been reported for some naturally occurring peptides.
DPP-IV is constitutively expressed on epithelial and endothelial cells of a variety of different tissues (intestine, liver, lung, kidney and placenta), and is also found in body fluids. DPP-IV is also expressed on circulating T-lymphocytes and has been shown to be synonymous with the cell-surface antigen, CD-26. DPP-IV has been implicated in a number of disease states, some of which are discussed below.
[0005] DPP-IV is responsible for the metabolic cleavage of certain endogenous peptides (GLP-I (7-36), glucagon) in vivo and has demonstrated proteolytic activity against a variety of other peptides (GHRH, NPY, GLP-2, VIP) in vitro.

GLP-I (7-36) is a 29 amino-acid peptide derived by post-translational processing of proglucagon in the small intestine. GLP-I (7-36) has multiple actions in vivo including the stimulation of insulin secretion, inhibition of glucagon secretion, the promotion of satiety, and the slowing of gastric emptying. Based on its physiological profile, the actions of GLP-I (7-36) are believed to be beneficial in the prevention and treatment of type II diabetes and potentially obesity. For example, exogenous administration of GLP-I (7-36) (continuous infusion) in diabetic patients has been found to be efficacious in this patient population. Unfortunately, GLP-I (7-36) is degraded rapidly in vivo and has been shown to have a short half -life in vivo (t_1/2=1.5 minutes).
Based on a study of genetically bred DPP-IV knock out mice and on in vivo I in vitro studies with selective DPP-IV inhibitors, DPP-IV has been shown to be the primary degrading enzyme of GLP-I (7-36) in vivo. GLP-I (7-36) is degraded by DPP-IV efficiently to GLP-I (9-36), which has been speculated to act as a physiological antagonist to GLP-I (7-36). Inhibiting DPP-TV in vivo is therefore believed to be useful for potentiating endogenous levels of GLP-I (7-36) and attenuating the formation of its antagonist GLP-I (9-36). Thus, DPP-IV inhibitors are believed to be useful agents for the prevention, delay of progression, and/or treatment of conditions mediated by DPP-IV, in particular diabetes and more particularly, type 2 diabetes mellitus, diabetic dislipidemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose (WG), metabolic acidosis, ketosis, appetite regulation and obesity.

DPP-IV expression is increased in T-cells upon mitogenic or antigenic stimulation (Mattem, T., et al., Scand. J. Immunol, 1991, 33, 737). It has been reported that inhibitors of DPP-IV and antibodies to DPP-IV suppress the proliferation of mitogen-stimulated and antigen-stimulated T-cells in a dose-dependant manner (Schon, E., et al., Biol. Chem., 1991, 372, 305). Various other functions of T-lymphocytes such as cytokine production, IL-2 mediated cell proliferation and B-cell helper activity have been shown to be dependent on DPP-IV activity (Schon, E., et al., Scand. J. Immunol, 1989, 29, 127). DPP-IV inhibitors, based on boroProline, (Flentke, G. R., et al., Proc. Nat. Acad. Set USA, 1991, 88, 1556) although unstable, were effective at inhibiting antigen-induced lymphocyte proliferation and IL-2 production in murine CD4+ T-helper cells. Such boronic acid inhibitors have been shown to have an effect in vivo in mice causing suppression of antibody production induced by immune challenge (Kubota, T. et al, Clin. Exp. Immun., 1992, 89, 192). The role of DPP-IV in regulating T lymphocyte activation may also be attributed, in part, to its cell-surface association with the transmembrane phosphatase, CD45. DPP-IV inhibitors or non-active site ligands may possibly disrupt the CD45-DPP-TV association. CD45 is known to be an integral component of the T-cell signaling apparatus. It has been reported that DPP-IV is essential for the penetration and infectivity of HTV-I and HTV-2 viruses in CD4+ T-cells (Wakselman, M., Nguyen, C, Mazaleyrat, J.-P., Callebaut, C, Krust, B., Hovanessian, A. G., Inhibition of HIV-I infection of CD 26+ but not CD 26-cells by a potent cyclopeptidic inhibitor of the DPP-IV activity of CD 26. Abstract P.44 of the 24.sup.th European Peptide Symposium 1996). Additionally, DPP-IV has been shown to associate with the enzyme adenosine deaminase (ADA) on the surface of T-cells (Kameoka, J., et al., Science, 193, 26 466). ADA deficiency causes severe combined immunodeficiency disease (SCID) in humans. This ADA-CD26 interaction may provide clues to the pathophysiology of SCID. It follows that inhibitors of DPP-TV may be useful immunosuppressants (or cytokine release suppressant drugs) for the treatment of among other things: organ transplant rejection; autoimmune diseases such as inflammatory bowel disease, multiple sclerosis and rheumatoid arthritis; and the treatment of AIDS.
It has been shown that lung endothelial cell DPP-IV is an adhesion molecule for lung-metastatic rat breast and prostate carcinoma cells (Johnson, R. C, et al., J. Cell. Biol, 1993, 121, 1423). DPP-IV is known to bind to fibronectin and some metastatic tumor cells are known to carry large amounts of fibronectin on their surface. Potent DPP-IV inhibitors may be useful as drugs to prevent metastases of, for example, breast and prostrate tumors to the lungs.
High levels of DPP-PV expression have also been found in human skin fibroblast cells from patients with psoriasis, rheumatoid arthritis (RA) and lichen planus (Raynaud, F., et al., J. Cell. Physiol, 1992, 151, 378). Therefore, DPP-TV inhibitors may be useful as agents to treat dermatological diseases such as psoriasis and lichen planus. [0011] High DPP-TV activity has been found in tissue homogenates from patients with benign prostate hypertrophy and in prostatosomes. These are prostate derived organelles important for the enhancement of sperm forward motility (Vanhoof, G., et al., EMr. /.

Clin. Chem. Clin. Biochem., 1992, 30, 333). DPP-IV inhibitors may also act to suppress sperm motility and therefore act as a male contraceptive agent. Conversely, DPP-IV inhibitors have been implicated as novel for treatment of infertility, and particularly human female infertility due to Polycystic ovary syndrome (PCOS, Stein-Leventhal syndrome) which is a condition characterized by thickening of the ovarian capsule and . formation of multiple follicular cysts. It results in infertility and amenorrhea.
DPP-IV is thought to play a role in the cleavage of various cytokines
(stimulating hematopoietic cells), growth factors and neuropeptides.
[0013] Stimulated hematopoietic cells are useful for the treatment of disorders that are characterized by a reduced number of hematopoietic cells or their precursors in vivo. Such conditions occur frequently in patients who are immunosuppressed, for example, as a consequence of chemotherapy and/or radiation therapy for cancer. It was discovered that inhibitors of dipeptidyl peptidase type PV are useful for stimulating the growth and differentiation of hematopoietic cells in the absence of exogenously added cytokines or other growth factors or stromal cells. This discovery contradicts the dogma in the field of hematopoietic cell stimulation, which provides that the addition of cytokines or cells that produce cytokines (stromal cells) is an essential element for maintaining and stimulating the growth and differentiation of hematopoietic cells in culture. (See, e.g., PCT Intl. Application No. PCT/US93/017173 published as WO 94/03055).
[0014] DPP-IV in human plasma has been shown to cleave N-terminal Tyr-Ala from growth hormone-releasing factor and cause inactivation of this hormone. Therefore, inhibitors of DPP-IV may be useful in the treatment of short stature due to growth hormone deficiency (Dwarfism) and for promoting GH-dependent tissue growth or re-growth.
DPP-IV can also cleave neuropeptides and has been shown to modulate the activity of neuroactive peptides substance P, neuropeptide Y and CLIP (Mentlein, R., Dahms, P., Grandt, D., Kruger, R., Proteolytic processing of neuropeptide Y and peptide YY by dipeptidyl peptidase IV, Regul. Pept., 49, 133, 1993; Wetzel, W., Wagner, T., Vogel, D., Demuth, H.-U., Balschun, D., Effects of the CLIP fragment ACTH 20-24 on the duration of REM sleep episodes, Neuropeptides, 31, 41, 1997). Thus DPP-IV inhibitors may also be useful agents for the regulation or normalization of neurological disorders.
Several compounds have been shown to inhibit DPP-IV. Nonetheless, a need still exists for new DPP-IV inhibitors that have advantageous potency, stability, selectivity, toxicity and/or pharmacodynamics properties. In this regard, synthetic methods are provided that can be used to make a novel class of DPP-IV inhibitors.

Trelagliptin (Zafatek) is a pharmaceutical drug used for the treatment of type 2 diabetes (diabetes mellitus).^[1]

Indications for Medical Use

It is a highly selective dipeptidyl peptidase (DPP-4) inhibitor that is typically used as an add on treatment when the first line treatment of metformin is not achieving the expected glycemic goals; though it has been approved for use as a first line treatment when metformin cannot be used.^[1]

Biochemistry

DPP-4 inhibitors activate T-cells and are more commonly known as T-cell activation antigens (specifically CD26).^[1]^[2] Chemically, it is a fluorinated derivative of alogliptin.

Development

Formulated as the salt trelagliptin succinate, it was approved for use in Japan in March 2015.^[3] Takeda, the company that developed trelagliptin, chose to not get approval for the drug in the USA and EU.^[1] The licensing rights that Takeda purchased from Furiex Pharmaceuticals for DPP-4 inhibitors included a clause specific to development of this drug in the USA and EU.^[1] The clause required that all services done for phase II and phase III clinical studies in the USA and EU be purchased through Furiex.^[1] Takeda chose to cease development of this drug in the USA and EU because of the high costs quoted by Furiex for these services.^[1] Gliptins have been on the market since 2006 and there are 8 gliptins currently registered as drugs (worldwide).^[4] Gliptins are an emerging market and are thus being developed at an increasing rate; there are currently two gliptins in advanced stages of development that are expected to be on the market in the coming year.^[4]

Gliptins are thought to have cardiovascular protective abilities though the extent of these effects is still being studied.^[4] They are also being studied for the ability that this class of drugs has at promoting B-cell survival.^[4]

Administration and Dosing

Similar drugs in the same class as trelagliptin are administered once daily while trelagliptin is administered once weekly.^[1]^[5] Alogliptin (Nesina) is the other major DPP-4 inhibitor on the market. It is also owned by Takeda and is administered once daily. A dosing of once per week is advantageous as a reduction in the frequency of required dosing is known to increase patient compliance.^[1]^[2]

Zafatek is administered in the form trelagliptin succinate in a 1:1 mixture of trelagliptin and succinic acid.^[6] The drug is marketed with the IUPAC name Succinic acid – 2-({6-[(3R)-3-amino-1-piperidinyl]-3-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl}methyl)-4-fluorobenzonitrile (1:1), has a molecular mass of 475.470143 grams/mol, and has the molecular formula | C=22 | H=26 | F=1 | N=5 | O=6 .^[6]^[7]

SYNTHESIS …………….

PAPER

J. Med .Chem.,2011, 54, 510-524

Synthesis started with selective alkylation of chlorouracil 80, followed by methylation provided compound153via152.

The displacement of chloride with 3-(R)-aminopiperidine83afforded trelagliptin154..

DOI: 10.1021/jm101016w

http://pubs.acs.org/doi/abs/10.1021/jm101016w

The discovery of two classes of heterocyclic dipeptidyl peptidase IV (DPP-4) inhibitors, pyrimidinones and pyrimidinediones, is described. After a single oral dose, these potent, selective, and noncovalent inhibitors provide sustained reduction of plasma DPP-4 activity and lowering of blood glucose in animal models of diabetes. Compounds 13a, 27b, and 27j were selected for development.

2-[6-(3-Aminopiperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluorobenzonitrile, TFA salt (27j)

A mixture of 3-methyl-6-chlorouracil (0.6 g, 3.8 mmol), 2-bromomethyl-4-fluorobenzonitrile (0.86 g, 4 mmol), and K₂CO₃ (0.5 g, 4 mmol) in DMSO (10 mL) was stirred at 60 °C for 2 h. The mixture was diluted with water and extracted with EtOAc. The organics were dried over MgSO₄, and the solvent was removed. The residue was purified by column chromatography to give 0.66 g of 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluorobenzonitrile (60%). ¹H NMR (400 MHz, CDCl₃): δ 7.73 (dd, J = 7.2, 8.4 Hz, 1H), 7.26 (d, J = 4.0 Hz, 1H), 7.11−7.17 (m, 1H), 6.94 (dd, J = 2.0, 9.0 Hz, 1H), 6.034 (s, 2H), 3.39 (s, 3H). MS (ES) [M + H] calcd for C₁₃H₉ClFN₃O₂, 293; found 293.

2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluorobenzonitrile (300 mg, 1.0 mmol), 3-(R)-aminopiperidine dihydrochloride (266 mg, 1.5 mmol), and sodium bicarbonate (500 mg, 5.4 mmol) were stirred in a sealed tube in EtOH (3 mL) at 100 °C for 2 h. The final compound (367 mg, 81% yield) was obtained as a TFA salt after HPLC purification. ¹H NMR (400 MHz, CD₃OD): δ 7.77−7.84 (m, 1H), 7.16−7.27 (m, 2H), 5.46 (s, 1H), 5.17−5.34 (ABq, 2H, J = 35.2, 15.6 Hz), 3.33−3.47 (m, 2H), 3.22 (s, 3H), 2.98−3.08 (m, 1H), 2.67−2.92 (m, 2H), 2.07−2.17 (m, 1H), 1.82−1.92 (m, 1H), 1.51−1.79 (m, 2H). MS (ES) [M + H] calcd for C₁₈H₂₀FN₅O₂, 357; found, 357.

PATENT

WO 2007035629

http://www.google.com/patents/WO2007035629A3?cl=en

(R)-2-((6-(3-amino-3-methylpiperidin-l-yl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)methyl)-4-fluorobenzonitrile (30). 2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-ylmethyl)-4-fluoro-benzonitrile (300 mg, 1.0 mmol), (R)-3-amino-3-methyl-piperidine dihydrochloride (266 mg, 1.4 mmol) and sodium bicarbonate (500 mg, 5.4 mmol) were stirred in a sealed tube in EtOH (3 mL) at 100⁰C for 2 hrs. The final compound was obtained as TFA salt after HPLC purification. ¹H-NMR (400 MHz, CD3OD): δ. 7.78-7.83 (m, IH), 7.14-7.26 (m, 2H), 5.47 (s, IH), 5.12-5.36 (ABq, 2H, J = 105.2, 15.6 Hz), 3.21 (s, IH), 2.72-3.15 (m, 4H), 1.75-1.95 (m, 4H), 1.39 (s, 3H). MS (ES) [m+H] calc’d for C19H22FN5O2, 372.41; found, 372.41.
Compound 34

4-Fluoro-2-methylbenzonitrile (31). A mixture of 2-bromo-5-fluorotoluene (3.5 g, 18.5 mmol) and CuCN (2 g, 22 mmol) in DMF (100 mL) was refluxed for 24 hours. The reaction was diluted with water and extracted with hexane. The organics were dried over MgSO₄ and the solvent removed to give product 31 (yield 60%). ¹H-NMR (400 MHz, CDCl₃): δ 7.60 (dd, J=5.6, 8.8 Hz, IH), 6.93-7.06 (m, 2H), 2.55 (s, 3H).
2-Bromomethyl-4-fluorobenzonitrile (32). A mixture of 4-fluoro-2-methylbenzonitrile (2 g, 14.8 mmol), NBS (2.64 g, 15 mmol) and AIBN (100 mg) in CCl₄ was refluxed under nitrogen for 2 hours. The reaction was cooled to room temperature. The solid was removed by filtration. The organic solution was concentrated to give crude product as an oil, which was used in the next step without further purification. ¹H-NMR (400 MHz, CDCl₃): δ 7.68 (dd, J= 5.2, 8.4 Hz, IH), 7.28 (dd, J= 2.4, 8.8 Hz, IH), 7.12 (m, IH), 4.6 (s, 2H).
Alternatively, 32 was made as follows. 4-Fluoro-2-methylbenzonitrile (1 kg) in DCE (2 L) was treated with AJJBN (122 g) and heated to 75⁰C. A suspension of DBH (353 g) in DCE (500 mL) was added at 75⁰C portionwise over 20 minutes. This operation was repeated 5 more times over 2.5 hours. The mixture was then stirred for one additional hour and optionally monitored for completion by, for example, measuring the amount of residual benzonitrile using HPLC. Additional AJ-BN (e.g., 12.5 g) was optionally added to move the reaction toward completion. Heating was stopped and the mixture was allowed to cool overnight. N,N-diisopropylethylamine (1.3 L) was added (at <10°C over 1.5 hours) and then diethyl phosphite (1.9 L) was added (at <20°C over 30 min). The mixture was then stirred for 30 minutes or until completion. The mixture was then washed with 1% sodium metabisulfite solution (5 L) and purified with water (5 L). The organic phase was concentrated under vacuum to afford 32 as a dark brown oil (3328 g), which was used without further purification (purity was 97% (AUC)).
2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-ylmethyl)-4-fluoro-benzonitrile (33). A mixture of crude 3-methyl-6-chlorouracil (0.6 g, 3.8 mmol), 2-bromomethyl-4-fluorobenzonitrile (0.86 g, 4 mmol) and K₂CO₃ (0.5 g, 4 mmol) in DMSO (10 mL) was stirred at 6O⁰C for 2 hours. The reaction was diluted with water and extracted with EtOAc. The organics were dried over MgSO₄ and the solvent removed. The residue was purified by column chromatography. 0.66 g of the product was obtained (yield: 60%). ¹H-NMR (400 MHz, CDCl₃): δ 7.73 (dd, 1=1.2, 8.4Hz, IH), 7.26 (d, J-4.0Hz, IH), 7.11-7.17 (m, IH), 6.94 (dd, J=2.0, 9.0 Hz, IH), 6.034 (s, 2H), 3.39 (s, 3H). MS (ES) [m+H] calc’d for C₁₃H₉ClFN₃O₂, 293.68; found 293.68.
Alternatively, 33 was made as follows. To a solution of 6-chloro-3-methyluracil (750 g) and W,iV-diisopropylethylarnine (998 mL) in NMP (3 L) was added (at <30°C over 25 min) a solution of 32 (2963 g crude material containing 1300 g of 32 in 3 L of toluene). The mixture was then heated at 6O⁰C for 2 hours or until completion (as determined, for example, by HPLC). Heating was then stopped and the mixture was allowed to cool overnight. Purified water (3.8 L) was added, and the resultant slurry was stirred at ambient temperature for 1 hour and at <5°C for one hour. The mixture was then filtered under vacuum and the wet cake was washed with IPA (2 X 2.25 L). The material was then dried in a vacuum oven at 40±5°C for 16 or more hours to afford 33 as a tan solid (>85% yield; purity was >99% (AUC)).
2-[6-(3-Amino-piperidin-l-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-ylmethyl]-4-fluoro-benzonitrile (34). 2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-ylmethyl)-4-fluoro-benzonitrile (300 mg, 1.0 mmol), (R)-3-amino-piperidine dihydrochloride (266 mg, 1.5 mmol) and sodium bicarbonate (500 mg, 5.4 mmol) were stirred in a sealed tube in EtOH (3 mL) at 100⁰C for 2 hrs. The final compound was obtained as TFA salt after HPLC purification. ¹H-NMR (400 MHz, CD₃OD): δ. 7.77-7.84 (m, IH), 7.16-7.27 (m, 2H), 5.46 (s, IH), 5.17-5.34 (ABq, 2H, J = 35.2, 15.6 Hz), 3.33-3.47 (m, 2H), 3.22 (s, 3H), 2.98-3.08 (m, IH), 2.67-2.92 (m, 2H), 2.07-2.17 (m, IH), 1.82-1.92 (m, IH), 1.51-1.79 (m, 2H). MS (ES) [m+H] calc’d for C₁₈H₂₀FN₅O₂, 357.38; found, 357.38.
Alternatively, the free base of 34 was prepared as follows. A mixture of 33 (1212 g), IPA (10.8 L), (R)-3-amino-piperidine dihydrochloride (785 g), purified water (78 mL) and potassium carbonate (2.5 kg, powder, 325 mesh) was heated at 6O⁰C until completion (e.g., for >20 hours) as determined, for example, by HPLC. Acetonitrile (3.6 L) was then added at 6O⁰C and the mixture was allowed to cool to <25°C. The resultant slurry was filtered under vacuum and the filter cake was washed with acetonitrile (2 X 3.6 L). The filtrate was concentrated at 45⁰C under vacuum (for >3 hours) to afford 2.6 kg of the free base of 34.
The HCl salt of 34 was prepared from the TFA salt as follows. The TFA salt (34) was suspended in DCM, and then washed with saturated Na₂CO₃. The organic layer was dried and removed in vacuo. The residue was dissolved in acetonitrile and HCl in dioxane (1.5 eq.) was added at 0⁰C. The HCl salt was obtained after removing the solvent. ¹H-NMR (400 MHz, CD₃OD): δ. 7.77-7.84 (m, IH), 7.12-7.26 (m, 2H), 5.47 (s, IH), 5.21-5.32 (ABq, 2H, J = 32.0, 16.0 Hz), 3.35-3.5 (m, 2H), 3.22 (s, 3H), 3.01-3.1 (m, IH), 2.69-2.93 (m, 2H), 2.07-2.17 (m, IH), 1.83-1.93 (m, IH), 1.55-1.80 (m, 2H). MS (ES) [m+H] calc’d for C₁₈H₂₀FN₅O₂, 357.38; found, 357.38.
Alternatively, the HCl salt was prepared from the free base as follows. To a solution of free base in CH₂Cl₂ (12 L) was added (at <35°C over 18 minutes) 2 M hydrochloric acid (3.1 L). The slurry was stirred for 1 hour and then filtered. The wet cake was washed with CH₂Cl₂ (3.6 L) and then THF (4.8 L). The wet cake was then slurried in THF (4.8 L) for one hour and then filtered. The filter cake was again washed with THF (4.8 L). The material was then dried in a vacuum oven at 5O⁰C (with a nitrogen bleed) until a constant weight (e.g., >26 hours) to afford 34 as the HCl salt as a white solid (1423 g, >85% yield).
The succinate salt of 34 was prepared from the HCl salt as follows. To a mixture of the HCl salt of 34 (1414 g), CH₂Cl₂ (7 L) and purifed water (14 L) was added 50% NaOH solution (212 mL) until the pH of the mixture was >12. The biphasic mixture was stirred for 30 min and the organic layer was separated. The aqueous layer was extracted with CH₂Cl₂ (5.7 L) and the combined organic layers were washed with purified water (6 L). The organic layer was then passed through an in-line filter and concentrated under vacuum at 3O⁰C over three hours to afford the free base as an off-white solid. The free base was slurried in prefiltered THF (15 L) and prefiltered IPA (5.5 L). The mixture was then heated at 6O⁰C until complete dissolution of the free base was observed. A prefiltered solution of succinic acid (446 g) in THF (7 L) was added (over 23 min) while maintaining the mixture temperature at >57°C. After stirring at 6O⁰C for 15 min, the heat was turned off, the material was allowed to cool, and the slurry was stirred for 12 hours at 25±5°C. The material was filtered under vacuum and the wet cake was washed with prefiltered IPA (2 X 4.2 L). The material was then dried in a vacuum oven at 70±5°C (with a nitrogen bleed) for >80 hours to afford the succinate salt of 34 as a white solid (1546 g, >90% yield).
The product was also converted to a variety of corresponding acid addition salts. Specifically, the benzonitrile product (approximately 10 mg) in a solution of MeOH (1 mL) was treated with various acids (1.05 equivalents). The solutions were allowed to stand for three days open to the air. If a precipitate formed, the mixture was filtered and the salt dried. If no solid formed, the mixture was concentrated in vacuo and the residue isolated. In this way, salts of 34 were prepared from the following acids: benzoic, p-toluenesulfonic, succinic, R-(-)-Mandelic and benzenesulfonic. The succinate was found to be crystalline as determined by x-ray powder diffraction analysis.
In addition, the methanesulfonate salt was prepared as follows. A 10.5 g aliquot of the benzonitrile product was mixed with 400 mL of isopropylacetate. The slurry was heated to 75°C and filtered through #3 Whatman filter paper. The solution was heated back to 75⁰C and a IM solution of methanesulfonic acid (30.84 mL) was added slowly over 10 minutes while stirring. The suspension was cooled to room temperature at a rate of about 20°C/hr. After 1 hr at room temperature, the solid was filtered and dried in an oven overnight to obtain the methanesulfonate salt.

PATENT

US 2008227798

http://www.google.com/patents/US20080227798

EXAMPLES

Compound I may be prepared by the follow synthetic route (Scheme 1)

A. Preparation of 4-fluoro-2-methylbenzonitrile (Compound B)

Compound B was prepared by refluxing a mixture of 2-bromo-5-fluoro-toluene (Compound A) (3.5 g, 18.5 mmol) and CuCN (2 g, 22 mmol) in DMF (100 mL) for 24 hours. The reaction was diluted with water and extracted with hexane. The organics were dried over MgSO₄and the solvent removed to give product B (yield 60%). ¹H-NMR (400 MHz, CDCl₃): δ 7.60 (dd, J=5.6, 8.8 Hz, 1H), 6.93-7.06 (m, 2H), 2.55 (s, 3H).

B. Preparation of 2-bromomethyl-4-fluorobenzonitrile (Compound C)

Compound C was prepared by refluxing a mixture of 4-fluoro-2-methylbenzonitrile (Compound B) (2 g, 14.8 mmol), N-bromosuccinimide (NBS) (2.64 g, 15 mmol) and azo-bis-isobutyronitrile (AIBN) (100 mg) in CCl₄under nitrogen for 2 hours. The reaction was cooled to room temperature. The solid was removed by filtration. The organic solution was concentrated to give the crude product the form of an oil, which was used in the next step without further purification. ¹H-NMR (400 MHz, CDCl₃): δ 7.68 (dd, J=5.2, 8.4 Hz, 1H), 7.28 (dd, J=2.4, 8.8 Hz, 1H), 7.12 (m, 1H), 4.6 (s, 2H).

C. Preparation of 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile (Compound D)

Compound E was prepared by stirring a mixture of crude 3-methyl-6-chlorouracil D (0.6 g, 3.8 mmol), 2-bromomethyl-4-fluorobenzonitrile (0.86 g, 4 mmol) and K₂CO₃(0.5 g, 4 mmol) in DMSO (10 mL) at 60° C. for 2 hours. The reaction was diluted with water and extracted with EtOAc. The organics were dried over MgSO₄and the solvent removed. The residue was purified by column chromatography. 0.66 g of the product was obtained (yield: 60%). ¹H-NMR (400 MHz, CDCl₃): δ 7.73 (dd, J=7.2, 8.4 Hz, 1H), 7.26 (d, J=4.0 Hz, 1H), 7.11-7.17 (m, 1H), 6.94 (dd, J=2.0, 9.0 Hz, 1H), 6.034 (s, 2H), 3.39 (s, 3H). MS (ES) [m+H] calc’d for C₁₃H₉ClFN₃O₂, 293.68; found 293.68.

D. Preparation of 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile (Compound F)

Compound F was prepared by mixing and stirring 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile (Compound E) (300 mg, 1.0 mmol), (R)-3-amino-piperidine dihydrochloride (266 mg, 1.5 mmol) and sodium bicarbonate (500 mg, 5.4 mmol) in a sealed tube in EtOH (3 mL) at 100° C. for 2 hrs. The final compound was obtained as trifluoroacetate (TFA) salt after HPLC purification. ¹H-NMR (400 MHz, CD₃OD): δ. 7.77-7.84 (m, 1H), 7.16-7.27 (m, 2H), 5.46 (s, 1H), 5.17-5.34 (ABq, 2H, J=35.2, 15.6 Hz), 3.33-3.47 (m, 2H), 3.22 (s, 3H), 2.98-3.08 (m, 1H), 2.67-2.92 (m, 2H), 2.07-2.17 (m, 1H), 1.82-1.92 (m, 1H), 1.51-1.79 (m, 2H). MS (ES) [m+H] calc’d for C₁₈H₂₀FN₅O₂, 357.38; found, 357.38.

E. Preparation of Compound I: the succinic acid salt of 2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile

The TFA salt prepared in the above step (Example 1, Step D) was suspended in DCM, and then washed with saturated Na₂CO₃. The organic layer was dried and removed in vacuo. The benzonitrile product (approximately 10 mg) was dissolved in MeOH (1 mL) and to which succinic acid in THF (1.05 equivalents) was added. The solutions were allowed to stand for three days open to the air. If a precipitate formed, the solid was collected by filtration. If no solid formed, the mixture was concentrated in vacuo, and the succinate salt was obtained after removing the solvent. ¹H-NMR (400 MHz, CD₃OD): δ. 7.77-7.84 (m, 1H), 7.12-7.26 (m, 2H), 5.47 (s, 1H), 5.21-5.32 (ABq, 2H, J=32.0, 16.0 Hz), 3.35-3.5 (m, 2H), 3.22 (s, 3H), 3.01-3.1 (m, 1H), 2.69-2.93 (m, 2H), 2.07-2.17 (m, 1H), 1.83-1.93 (m, 1H), 1.55-1.80 (m, 2H). MS (ES) [m+H] calc’d for C₁₈H₂₀FN₅O₂, 357.38; found, 357.38.
Compound I such prepared was found to be crystalline as determined by x-ray powder diffraction analysis (FIG. 1). The crystal material was designated Form A.

TABLE A

Approximate Solubilities of Compound I
		Solubility
	Solvent	(mg/mL)^a

	Acetone	2
	Acetonitrile (ACN)	<1
	Dichloromethane (DCM)	<1
	Dimethyl Formamide (DMF)	68
	1,4-Dioxane	<1
	Ethanol (EtOH)	2
	Ethyl Acetate (EtOAc)	<1
	di-Ethyl ether	<1
	Hexanes	<1
	2-Propanol (IPA)	<1
	Methanol (MeOH)	20
	Tetrahydrofuran (THF)	<1
	Toluene	<1
	Trifluoroethanol (TFE)	>200
	Water (H₂O)	51
	ACN:H₂O (85:15)	101
	EtOH:H₂O (95:5)	5
	IPA:H₂O (88:12)	11

	^aApproximate solubilities are calculated based on the total solvent used to give a solution; actual solubilities may be greater because of the volume of the solvent portions utilized or a slow rate of dissolution. Solubilities are reported to the nearest mg/mL.

PATENT

WO2012118180

Reference Example 2
in the following formula 2, 2 – ((6 – ((3R) -3- amino-piperidin-1-yl) -3-methyl-2,4-dioxo-3,4-dihydropyrimidine -1 (2H ) – yl) shown in the following example of a production process of a methyl) -4-fluoro-benzonitrile succinate (4b).

[Formula 2]

str1

[In the formula 2, 2 – ((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidine -1 (2H) – yl) methyl) -4-fluorobenzonitrile (2b) manufacturing process]
ethyl acetate (3.5 vol), 2- (bromomethyl) -4-fluorobenzonitrile (1b) (1 equiv, 1wt.), 6- chloro-3-methyl uracil (1.05 eq, 0.79wt), N- methylpyrrolidone (NMP;.. 3.5 times the amount), diisopropylethylamine (Hunig’s base, 2.1 eq, 1.27wt) was heated to an internal temperature of 60 ~ 70 ℃ a.
The mixture was stirred until 2-4 hours or the completion of the reaction at 60 ~ 70 ℃.
Then cooling the solution to 40 ~ 50 ℃, after stirring at least 30 minutes, 40 ~ 50 ℃ isopropanol (1.5 times) while maintaining, water (3.5 times the amount) was added, then at least one hour stirring did. The solution was cooled to 20 ~ 30 ℃, was then stirred for at least 1 hour. The solution was cooled to 0 ~ 10 ℃, was then stirred for at least 1 hour. The resulting slurry was filtered, washed with 0 ~ 10 ℃ in cold isopropanol (4.0 vol), and vacuum dried at 45 ~ 55 ℃, to give the above compound (2b).

[In the formula 2, 2 – ((6 – ((3R) -3- amino-piperidin-1-yl) -3-methyl-2,4-dioxo-3,4-dihydropyrimidine -1 (2H) – yl) methyl) -4-manufacturing process of the fluorobenzonitrile (3b)]
the above compound (2b) (1 eq, 1wt.), (R) -3- aminopiperidine dihydrochloride (1.1 eq, 0.65wt .), potassium carbonate (2.5 equivalents, 1.18wt.), isopropanol (5.0 vol), water (1.5 times) until the completion of the reaction with 65 ~ 75 ℃ (eg, 3 to 7 hours ) was allowed to react. Potassium carbonate in 65 ~ 75 ℃ (7.05 eq, 3.32wt.), Water (5.5 vol) was added, and after stirring for about 30 minutes, the phases were separated at 50 ℃ ~ 70 ℃. The organic solvent was concentrated under reduced pressure to approximately 5 times. And water (5 vol) was added to the solution and concentrated under reduced pressure to approximately 5 times. The solution was stirred for about 40 minutes at 55 ℃ ~ 75 ℃. The solution was cooled to 20 ℃ ~ 30 ℃, was then stirred for at least 1 hour. The solution was cooled to 0 ~ 10 ℃, subsequently stirred for at least 1 hour, the resulting slurry was filtered, washed with 0 ~ 10 ℃ in cold water (2.0 times the amount), 45 ~ 55 ℃ was vacuum dried to give the above compound (3b).

[In the above formula 2, the compound production step of succinate (4b) of (3b)]
Compound (3b), tetrahydrofuran (6.0 vol), isopropanol (3.0 vol), water (0. a 6-fold amount) was heated to 55 ~ 65 ℃. Tetrahydrofuran solution of succinic acid (20 ℃ ~ 30 ℃) was added and the solution was stirred for about 15 minutes and maintained at 55 ~ 65 ℃.
The solution was cooled to 20 ~ 30 ℃, the mixture was stirred for at least 1 hour. The solution was cooled to 0 ~ 10 ℃, was then stirred for at least 1 hour. After the resulting slurry filtered and washed with isopropanol (6.0 vol). The resulting wet crystals were dried at 65 ~ 75 ℃, was obtained succinate of the compound (3b) and (4b) as a white crystalline solid.

PATENT

http://www.google.com/patents/CN103030631A?cl=en

2 – ({6 -! [(3R) -3- amino-piperidin-1-yl] -3-methyl-dihydro-pyrimidin _3,4_ _2,4_ dioxo-1 (2 1) – yl} methyl) benzonitrile is an effective DPP-1V inhibitors class of drugs in recent years in Japan, the structural formula

As shown below.

Chinese Patent Application CN1926128 discloses a process for preparing 2_ ({6_ [(3R) -3- amino-piperidin-1-yl] -3-methyl-2,4-dioxo-3,4- dihydropyrimidine-1 (2 1!) – yl} methyl) benzonitrile method, as shown in Scheme I:

Scheme I

In the above reaction scheme, 6-chloro-uracil and 2-bromomethyl-benzene cyanide in a mixed solvent of DMF-DMSO, in the presence of NaH and LiBr alkylation reaction to give compound 2 in a yield of 54%. Compound 2 is further alkylation reaction of compound yield 3 is 72%. The total yield of the compound 4 prepared in 20% yield is low, and the preparation of compound 4 obtained purity is not high, but also the need for further purification, such as recrystallization, column chromatography and other means in order to obtain high-purity suitable Pharmaceutically acceptable 2 – ({6 – [(3R) -3- amino-piperidin-1-yl] -3-methyl-2,4-dioxo-3,4-dihydro-pyrimidin _1 (2! 1) – yl} methyl) benzonitrile compound. Preparation still find more suitable for industrial production, a higher yield of the 2- ({6- [(3R) -3- amino-piperidin-1-yl] -3-methyl-2,4-dioxo -3, (2Η) 4- dihydropyrimidine-1 – yl} methyl) benzonitrile or a salt or the like.

PATENT

WO 2015137496

Example 15
(R) -2 – ((6 (3-amino-piperidin-1-yl) -3-methyl-2,4-dioxo-3,4-dihydropyrimidine -1 (2H) – yl) methyl) synthesis of 4-fluoro-benzonitrile

100mL four-necked flask of water and isopropanol 1/1 (v / v) mixture 60mL was added, pyridine 21.4μL [d = 0.98, mw.79.10, 0.26mmol], (R) -1- (3- (2 – cyano-5-fluoro-benzyl) -1-methyl-2,6-dioxo-1,2,3,6-tetra-hydro-4-yl) piperidin-3-carboxamide 2.00g [mw.385.39, 5.19mmol] of It was added to the order. Then, iodobenzene diacetate 1.84g [mw.322.10, 5.71mmol] was added, and the mixture was stirred for 3 h at 20 ℃. After volatile components were distilled off under reduced pressure by an evaporator, and the aqueous solution was washed twice with ethyl acetate 20mL. After cooling to near 0 ℃, potassium carbonate 16g added stepwise at 15 ℃ or less, was extracted by the addition of toluene 6mL and isopropanol 6mL. After separation, the organic layer was washed with saturated brine 10mL, adding toluene 6mL after concentration under reduced pressure by an evaporator, and further subjected to vacuum concentration. It was suspended by the addition of toluene 6mL to concentrate, by the addition of n-heptane 6mL, after 1 hour and aged at 0 ℃, reduced pressure filtration, to obtain the desired compound after drying under reduced pressure at 50 ℃. White crystalline powder, 1.6g, 86% yield.

1 H-NMR (500 MHz, CDCl 3 ) delta (ppm) 1.23 (D, J = 11.03 Hz, 1H) 1.30 (BRS, 2H) 1.56-1.67 (M, 1H) 1.72-1.83 (M, 1H) 1.95 (dd , J = 12.77 Hz, 3.94 Hz, 1H) 2.41 (m, 1H) 2.61 (m, 1H) 2.87-2.98 (m, 2H) 2.99-3.05 (m, 1H) 3.32 (s, 3H) 5.23-5.32 (m , 2H) 5.39 (s, 1H) 6.86 (dd, J = 8.99 Hz, 2.36 Hz, 1H) 7.09 (td, J = 8.04 Hz, 2.52 Hz, 1H) 7.69 (dd, J = 8.51 Hz, 5.36 Hz, 1H ).

13 C NMR (126 MHz, CDCl 3 ) ppm 28.0, 33.4, 46.1, 51.9, 59.7, 90.8, 114.6,114.7, 115.6, 115.8, 116.4, 135.4, 135.5, 144.6, 152.7, 159.5, 162.9.
Reference Example 4
(R) -2 – ((6 (3-amino-piperidin-1-yl) -3-methyl-2,4-dioxo-3,4-dihydropyrimidine -1 (2H) – yl) methyl) synthesis of 4-fluoro-benzonitrile succinate

50mL eggplant-shaped flask (R) -2 – ((6- (3- amino-1-yl) -3-methyl-2,4-dioxo-3,4-dihydro-pyrimidine -1 (2H) – yl) methyl) -4-fluorobenzonitrile 1.0g [mw.357.38, 2.8mmol], it was added tetrahydrofuran 4.5mL and water 2 drops. After heated and dissolved at 65 ℃, was dropped to the solution was dissolved at the same temperature 0.331g succinic acid [mw.118.09, 2.8mmol] with tetrahydrofuran 4mL and isopropanol 2.5mL. Aged for 16 hours at room temperature after stirring for 30 min at 65 ℃, and stirred for a further 2 hours at 0 ℃. The crystallization product was collected by terrorism to vacuum filtration. To obtain the desired compound after drying under reduced pressure at 45 ℃. White crystalline powder, 1.2g, 93% yield.

1 H-NMR (500 MHz, DMSO) delta (ppm) 1.35 (D, J = 8.83 Hz, 1H) 1.42-1.57 (M, 1H) 1.66-1.97 (M, 2H) 2.54-2.77 (M, 2H) 2.91 ( d, J = 11.35 Hz, 1H) 3.00-3.07 (m, 1H) 3.08 (m, 1H) 3.09 (s, 3H) 3.14 (m, 1H) 5.12 (d, J = 16.08 Hz, 1H) 5.20 (d, J = 16.39 Hz, 1H) 5.38 (s, 1H) 7.17 (dd, J = 9.62 Hz, 2.36 Hz, 1H) 7.35 (td, J = 8.51 Hz, 2.52 Hz, 1H) 7.95 (dd, J = 8.67 Hz, 5.52 Hz, 1H).

13 C NMR (126 MHz, DMSO) delta ppm 27.9, 31.6, 46.3, 47.0, 51.7, 55.8, 90.3, 106.9, 115.7, 117.1, 136.45, 136.53, 145.8, 152.3, 159.7, 162.7, 164.1 , 166.1, 175.2.

PATENT

http://www.google.com/patents/CN102964196A?cl=en

PATENT

WO 2016024224,

New Patent, Trelagliptin, SUN PHARMA

SUN PHARMACEUTICAL INDUSTRIES LIMITED [IN/IN]; Sun House, Plot No. 201 B/1 Western Express Highway Goregaon (E) Mumbai, Maharashtra 400 063 (IN)

BARMAN, Dhiren, Chandra; (IN).
NATH, Asok; (IN).
PRASAD, Mohan; (IN)

The present invention provides a process for the preparation of 4-fluoro-2- methylbenzonitrile of Formula (II), and its use for the preparation of trelagliptin or its salts. The present invention provides an efficient, simple, and commercially friendly process for the preparation of 4-fluoro-2-methylbenzonitrile, which is used as an intermediate for the preparation of trelagliptin or its salts. The present invention avoids the use of toxic and hazardous reagents, high boiling solvents, and bromo intermediates such as 2-bromo-5-fluorotoluene, which is lachrymatory in nature and thus difficult to handle at a commercial scale.

Trelagliptin is a dipeptidyl peptidase IV (DPP-IV) inhibitor, chemically designated as 2- [[6-[(3i?)-3 -aminopiperidin- 1 -yl] -3 -methyl -2,4-dioxopyrimidin- 1 -yljmethyl] -4-fluorobenzonitrile, represented by Formula I.

Formula I

Trelagliptin is administered as a succinate salt of Formula la, chemically designated as 2-[[6-[(3i?)-3-aminopiperidin-l-yl]-3-methyl-2,4-dioxopyrimidin-l-yl]methyl]-4-fluorobenzonitrile butanedioic acid (1 : 1).

Formula la

U.S. Patent Nos. 7,795,428, 8,288,539, and 8,222,411 provide a process for the preparation of 4-fluoro-2-methylbenzonitrile by reacting 2-bromo-5-fluorotoluene with copper (I) cyanide in N,N-dimethylformamide.

Chinese Patent No. CN 102964196 provides a process for the preparation of 4-fluoro-2-methylbenzonitrile by reacting 4-fluoro-2-methylbenzyl alcohol with cuprous iodide in the presence of 2,2′-bipyridine and 2,2,6,6-tetramethylpiperidine oxide (TEMPO) in an anhydrous ethanol.

Copper (I) cyanide is toxic to humans, and therefore its use in the manufacture of a drug substance is not advisable. In addition, 2-bromo-5-fluorotoluene is converted to 4-fluoro-2-methylbenzonitrile by refluxing in N,N-dimethylformamide at 152°C to 155°C for 24 hours. This leads to some charring, resulting in a tedious work-up process and low yield. Furthermore, the use of reagents like cuprous iodide, 2,2′-bipyridine, and 2,2,6,6-tetramethylpiperidine oxide (TEMPO) is hazardous and/or environmentally-unfriendly, and therefore their use in the manufacture of a drug substance is not desirable.

The present invention provides an efficient, simple, and commercially friendly process for the preparation of 4-fluoro-2-methylbenzonitrile, which is used as an intermediate for the preparation of trelagliptin or its salts. The present invention avoids the use of toxic and hazardous reagents, high boiling solvents, and bromo intermediates such as 2-bromo-5-fluorotoluene, which is lachrymatory in nature and thus difficult to handle at a commercial scale.

EXAMPLES

Example 1 : Preparation of 4-fluoro-2-methylbenzaldoxime

4-Fluoro-2-methylbenzaldehyde (1.38 g) was added to ethanol (10 mL) to obtain a solution. To this solution, hydroxylamine hydrochloride (2.76 g) and pyridine (1 mL) were added, and then the mixture was stirred at 20°C to 25 °C for 3 hours. The solvent was recovered up to maximum extent from the reaction mixture under reduced pressure to afford the title compound. Yield: 3.1 g

Example 2: Preparation of 4-fluoro-2-methylbenzaldoxime

4-Fluoro-2-methylbenzaldehyde (5 g) was added to ethanol (37 mL) to obtain a solution. To this solution, hydroxylamine hydrochloride (10 g) and N,N-diisopropylethylamine (3.6 mL) were added, and then the mixture was stirred at 20°C to 25 °C for 2 hours. The solvent was recovered up to maximum extent from the reaction mixture under reduced pressure to afford the title compound. Yield: 3.1 g

Example 3 : Preparation of 4-fluoro-2-methylbenzaldoxime

4-Fluoro-2-methylbenzaldehyde (10 g) was added to ethanol (40 mL) to obtain a solution. To this solution, hydroxylamine hydrochloride (20 g) and N,N-diisopropylethylamine (7.5 mL) were added, and then the mixture was stirred at 20°C to 25 °C for 4 hours. The solvent was recovered from the reaction mixture under reduced pressure to afford the title compound. Yield: 11.0 g

Example 4: Preparation of 4-fluoro-2-methylbenzaldoxime

4-Fluoro-2-methylbenzaldehyde (50 g) was added to ethanol (500 mL) to obtain a solution. To this solution, hydroxylamine hydrochloride (70 g) and N,N-diisopropylethylamine (36 mL) were added, and then the mixture was stirred at 20°C to 25 °C for 6 hours. The solvent was recovered from the reaction mixture under reduced pressure to afford the title compound. Yield: 51.0 g

Example 5 : Preparation of 4-fluoro-2-methylbenzaldoxime

4-Fluoro-2-methylbenzaldehyde (20 g) was added to ethanol (200 mL) to obtain a solution. To this solution, hydroxylamine hydrochloride (20 g) and N,N-diisopropylethylamine (18 mL) were added, and then the mixture was stirred at 20°C to 25 °C for 4 hours. The solvent was recovered from the reaction mixture under reduced pressure to obtain a residue. Deionized water (60 mL) was charged into the residue, and then the slurry was stirred at 0°C to 5°C for 1 hour. The solid obtained was filtered, then washed with deionized water (2 x 20 mL). The wet solid was dried in an air oven at 40°C to 45 °C for 4 hours to 5 hours. The crude product obtained was recrystallized in ethanol (50 mL) to afford the pure title compound. Yield: 21.0 g

Example 6: Preparation of 4-fluoro-2-methylbenzaldoxime

4-Fluoro-2-methyl benzaldehyde (50 g) was added to ethanol (500 mL) to obtain a solution. To this solution, hydroxylamine hydrochloride (50 g) and N,N-diisopropylethylamine (46.4 mL) were added, and then the mixture was stirred at 20°C to 25 °C for 4 hours. The solvent was recovered from the reaction mixture under reduced pressure to obtain a residue. Deionized water (150 mL) was charged to the residue, and then the slurry was stirred at 0°C to 5°C for 1 hour. The solid obtained was filtered, then washed with deionized water (2 x 50 mL). The wet solid was dried in an air oven at 40°C to 45 °C for 4 hours to 5 hours. The crude product obtained was recrystallized in ethanol (200 mL) to afford the pure title compound. Yield: 53.5 g

Example 7: Preparation of 4-fluoro-2-methylbenzonitrile

4-Fluoro-2-methylbenzaldoxime (3.1 g) and phosphorous pentoxide (1 g) were added to toluene (30 mL) to obtain a reaction mixture. The reaction mixture was refluxed at 110°C to 115°C for 24 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 25°C to 30°C. Deionized water (30 mL) was added to the mixture and then the layers were separated. The organic layer was concentrated under reduced pressure to afford the title compound. Yield: 1.1 g

Example 8: Preparation of 4-fluoro-2-methylbenzonitrile

4-Fluoro-2-methylbenzaldoxime (3 g) and phosphorous pentoxide (2 g) were added to toluene (30 mL) to obtain a reaction mixture. The reaction mixture was refluxed at 110°C to 115°C for 24 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 25°C to 30°C. Deionized water (30 mL) was added to the mixture and then the layers were separated. The organic layer was concentrated under reduced pressure to afford the title compound. Yield: 1.0 g

Example 9: Preparation of 4-fluoro-2-methylbenzonitrile

4-Fluoro-2-methylbenzaldoxime (5 g) and concentrated sulphuric acid (2 mL) were added to toluene (100 mL) to obtain a reaction mixture. The reaction mixture was refluxed at 110°C to 115°C for 5 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 25°C to 30°C. Deionized water (50 mL) was added to the mixture and then the layers were separated. The organic layer was concentrated under reduced pressure to afford the title compound. Yield: 3.24 g

Example 10: Preparation of 4-fluoro-2-methylbenzonitrile

4-Fluoro-2-methylbenzaldoxime (25 g) and concentrated sulphuric acid (35 g) were added to toluene (500 mL) to obtain a reaction mixture. The reaction mixture was refluxed at 110°C to 115°C for 6 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 25°C to 30°C. Deionized water (250 mL) was added to the mixture and then the layers were separated. The organic layer was concentrated under reduced pressure to afford the title compound. Yield: 20.5 g

Example 11 : Preparation of 4-fluoro-2-methylbenzonitrile

4-Fluoro-2-methyl benzaldoxime (5 g) and sodium bisulphate monohydrate (3.1 g) were added to toluene (50 mL) to obtain a reaction mixture. The reaction mixture was refluxed at 110°C to 115°C for 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 25°C to 30°C, then filtered, and then washed with toluene (10 mL). The filtrate was concentrated under reduced pressure to afford the title compound. Yield: 3.0 g

Example 12: Preparation of 4-fluoro-2-methylbenzonitrile

4-Fluoro-2-methyl benzaldoxime (50 g) and sodium bisulphate monohydrate (31.6 g) were added to toluene (500 mL) to obtain a reaction mixture. The reaction mixture was refluxed at 110°C to 115°C using a Dean-Stark apparatus for 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 25 °C to 30°C, then filtered, and then washed with toluene (100 mL). The filtrate was concentrated under reduced pressure to afford a crude product. The crude product obtained was recrystallized in a mixture of toluene (200 mL) and hexane (500 mL) to afford the title compound.

Yield: 38.0 g

Sun Pharma managing director Dilip Shanghvi.

References

1 McKeage, Kate (2015-06-27). “Trelagliptin: First Global Approval”. Drugs 75 (10): 1161–1164. doi:10.1007/s40265-015-0431-9. ISSN 0012-6667.
2 Inagaki, Nobuya; Onouchi, Hitoshi; Sano, Hiroki; Funao, Nobuo; Kuroda, Shingo; Kaku, Kohei. “SYR-472, a novel once-weekly dipeptidyl peptidase-4 (DPP-4) inhibitor, in type 2 diabetes mellitus: a phase 2, randomised, double-blind, placebo-controlled trial”. The Lancet Diabetes & Endocrinology 2 (2): 125–132. doi:10.1016/s2213-8587(13)70149-9.
3″New Drug Application Approval of Zafatek® Tablets for the treatment of Type 2 Diabetes in Japan | Takeda Pharmaceutical Company Limited”. http://www.takeda.com. Retrieved 2015-11-13.
4 Cahn, Avivit; Raz, Itamar (2013-06-01). “Emerging gliptins for type 2 diabetes”. Expert Opinion on Emerging Drugs 18 (2): 245–258. doi:10.1517/14728214.2013.807796. ISSN 1472-8214. PMID 23725569.
5Inagaki, Nobuya; Onouchi, Hitoshi; Maezawa, Hideaki; Kuroda, Shingo; Kaku, Kohei. “Once-weekly trelagliptin versus daily alogliptin in Japanese patients with type 2 diabetes: a randomised, double-blind, phase 3, non-inferiority study”. The Lancet Diabetes & Endocrinology 3 (3): 191–197. doi:10.1016/s2213-8587(14)70251-7.
6″TRELAGLIPTIN SUCCINATE | C22H26FN5O6 – PubChem”. pubchem.ncbi.nlm.nih.gov. Retrieved 2015-11-13.
7″Trelagliptin succinate | C22H26FN5O6 | ChemSpider”. http://www.chemspider.com. Retrieved 2015-11-13.

http://www.cbijournal.com/paper-archive/may-june-2014-vol-3/Review-Paper-1.pdf

Patent	Submitted	Granted
TABLET [US2012129878]	2010-07-27	2012-05-24
AROMATIC RING COMPOUND [US2015045378]	2013-02-12	2015-02-12

Patent	Submitted	Granted
Combination therapy for the treatment of diabetes and related conditions [US2011263617]	2011-10-27
Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral or non-oral antidiabetic drug [US2011275561]	2011-11-10
Treatment for diabetes in patients with inadequate glycemic control despite metformin therapy comprising a DPP-IV inhibitor [US2011301182]	2011-12-08
COATED PREPARATION [US2010166853]	2008-07-10	2010-07-01
Solid preparation comprising 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-4-fluorobenzonitrile [US7994183]	2008-03-12	2011-08-09
Diabetes therapy [US2012165251]	2011-06-23	2012-06-28
MEDICAL USE OF A DPP-4 INHIBITOR [US2014371243]	2014-06-13	2014-12-18
TREATMENT OF GENOTYPED DIABETIC PATIENTS WITH DPP-IV INHIBITORS SUCH AS LINAGLIPTIN [US2013196898]	2010-11-26	2013-08-01
ANTIDIABETIC MEDICATIONS COMPRISING A DPP-4 INHIBITOR (LINAGLIPTIN) OPTIONALLY IN COMBINATION WITH OTHER ANTIDIABETICS [US2012094894]	2010-02-12	2012-04-19
DPP-IV INHIBITORS FOR TREATMENT OF DIABETES IN PEDIATRIC PATIENTS [US2012122776]	2010-01-29	2012-05-17

Patent	Submitted	Granted
LAMINATED TABLET AND MANUFACTURING METHOD THEREFOR [US2014023708]	2012-03-02	2014-01-23
Combination therapy for the treatment of diabetes and related conditions [US2013310398]	2013-07-24	2013-11-21
USE OF KERATINOCYTES AS A BIOLOGICALLY ACTIVE SUBSTANCE IN THE TREATMENT OF WOUNDS, SUCH AS DIABETIC WOUNDS, OPTIONALLY IN COMBINATION WITH A DPP-4 INHIBITOR [US2013315975]	2013-05-23	2013-11-28
USE OF A DPP-4 INHIBITOR IN AUTOIMMUNE DIABETES, PARTICULARLY LADA [US2013317046]	2013-05-21	2013-11-28
USE OF A DPP-4 INHIBITOR FOR MODIFYING FOOD INTAKE AND REGULATING FOOD PREFERENCE [US2013324463]	2013-05-21	2013-12-05
COMBINATION THERAPY [US2013281373]	2011-05-05	2013-10-24
USE OF A DPP-4 INHIBITOR IN PODOCYTES RELATED DISORDERS AND/OR NEPHROTIC SYNDROME [US2013303462]	2013-05-13	2013-11-14
USE OF A DPP-4 INHIBITOR IN SIRS AND/OR SEPSIS [US2013303554]	2013-05-13	2013-11-14
Combination of a GPR119 Agonist and the DPP-IV Inhibitor Linagliptin for Use in the Treatment of Diabetes and Related Conditions [US2013109703]	2011-03-18	2013-05-02
Treatment for diabetes in patients inappropriate for metformin therapy [US2011263493]	2011-10-27

Patent	Submitted	Granted
DIPEPTIDYL PEPTIDASE INHIBITORS [US7781584]	2008-07-03	2010-08-24
POLYMORPHS OF SUCCINATE SALT OF 2-[6-(3-AMINO-PIPERIDIN-1-YL)-3-METHYL-2,4-DIOXO-3,4-DIHYDRO-2H-PYRIMIDIN-1-YLMETHY]-4-FLUOR-BENZONITRILE AND METHODS OF USE THEREFOR [US2008227798]	2008-09-18
GPR119 receptor agonists in methods of increasing bone mass and of treating osteoporosis and other conditions characterized by low bone mass, and combination therapy relating thereto [US7816364]	2009-10-29	2010-10-19
DIPEPTIDYL PEPTIDASE INHIBITORS [US8222411]	2009-11-05	2012-07-17
ADMINISTRATION OF DIPEPTIDYL PEPTIDASE INHIBITORS [US2008287476]	2008-11-20
POLYMORPHS OF SUCCINATE SALT OF 2-[6-(3-AMINO-PIPERIDIN-1-YL)-3-METHYL-2,4-DIOXO-3,4-DIHYDRO-2H-PYRIMIDIN-1-YLMETHY]-4-FLUOR-BENZONITRILE AND METHODS OF USE THEREFOR [US8084605]	2008-11-13	2011-12-27
WEEKLY ADMINISTRATION OF DIPEPTIDYL PEPTIDASE INHIBITORS [US8093236]	2008-11-06	2012-01-10
Therapeutic Agent for Diabetes [US2009042863]	2009-02-12
ADMINISTRATION OF DIPEPTIDYL PEPTIDASE INHIBITORS [US2007060530]	2007-03-15
DIPEPTIDYL PEPTIDASE INHIBITORS [US7795428]	2008-01-03	2010-09-14

Patent	Submitted	Granted
Dipeptidyl peptidase inhibitors [US7807689]	2005-11-24	2010-10-05
DIPEPTIDYL PEPTIDASE INHIBITORS [US2008108807]	2008-05-08
DIPEPTIDYL PEPTIDASE INHIBITORS [US2008108808]	2008-05-08
FUSED CYCLIC COMPOUNDS [US7732626]	2010-01-07	2010-06-08
DIPEPTIDYL PEPTIDASE INHIBITORS [US7906523]	2008-08-07	2011-03-15
DIPEPTIDYL PEPTIDASE INHIBITORS [US8188275]	2008-07-24	2012-05-29
DIPEPTIDYL PEPTIDASE INHIBITORS [US8173663]	2009-01-08	2012-05-08
ADMINISTRATION OF DIPEPTIDYL PEPTIDASE INHIBITORS [US2011077402]	2011-03-31
DPP-IV INHIBITORS FOR USE IN THE TREATMENT OF NAFLD [US2011092510]	2011-04-21
PURIN DERIVATIVES FOR USE IN THE TREATMENT OF FAB-RELATED DISEASES [US2011190322]	2011-08-04

Patent	Submitted	Granted
Administration of Dipeptidyl Peptidase Inhibitors [US2011192748]	2011-08-11
PHARMACEUTICAL COMPOSITION COMPRISING A GLUCOPYRANOSYL-SUBSTITUTED BENZENE DERIVATE [US2011195917]	2011-08-11
DPP-IV INHIBITOR COMBINED WITH A FURTHER ANTIDIABETIC AGENT, TABLETS COMPRISING SUCH FORMULATIONS, THEIR USE AND PROCESS FOR THEIR PREPARATION [US2011206766]	2011-08-25
COMBINATION OF A CERTAIN DPP-4 INHIBITOR AND VOGLIBOSE [US2014343014]	2014-05-16	2014-11-20
CARDIO- AND RENOPROTECTIVE ANTIDIABETIC THERAPY [US2014274889]	2014-03-14	2014-09-18
TREATMENT FOR DIABETES IN PATIENTS INAPPROPRIATE FOR METFORMIN THERAPY [US2014274890]	2014-06-03	2014-09-18
Fused ring compound and use thereof [US2010190747]	2010-07-29
FUSED RING COMPOUND AND USE THEREOF [US2010197683]	2010-08-05
Fused cyclic compounds [US8088821]	2010-08-05	2012-01-03
GPR119 Receptor Agonists in Methods of Increasing Bone Mass and of Treating Osteoporosis and Other Conditions Characterized by Low Bone Mass, and Combination Therapy Relating Thereto [US8101626]	2010-07-29	2012-01-24

Trelagliptin
Systematic (IUPAC) name

Succinic acid – 2-({6-[(3R)-3-amino-1-piperidinyl]-3-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl}methyl)-4-fluorobenzonitrile (1:1)
Clinical data
Trade names	Zafatek
Chemical data
Formula	C₂₂H₂₆FN₅O₆
Molar mass	475.470143 g/mol

/////////Trelagliptin, PMDA, JAPAN 2015

Cn1c(=O)cc(n(c1=O)Cc2cc(ccc2C#N)F)N3CCC[C@H](C3)N

CN1C(=O)C=C(N(C1=O)CC2=C(C=CC(=C2)F)C#N)N3CCCC(C3)N

WO 2016025720, New Patent, by Assia Chemicals and Teva on Ibrutinib

February 25, 2016 7:02 am / Leave a comment

WO 2016025720, New Patent, by Assia Chemicals and Teva on Ibrutinib

ASSIA CHEMICAL INDUSTRIES LTD. [IL/IL]; 2 Denmark Street 49517 Petach Tikva (IL)
TEVA PHARMACEUTICALS USA, INC. [US/US]; 1090 Horsham Road P.O. Box 1090 North Wales, PA 19454 (US)

COHEN, Meital; (IL).
COHEN, Yuval; (IL).
MITTELMAN, Ariel; (IL).
MOHA-LERMAN, Elana, Ben; (IL).
TZANANI, Idit; (IL).
LEVENFELD, Leonid; (IL)

The present invention encompasses solid state forms of Ibrutinib, including forms G, J and K, and pharmaceutical compositions thereof.

Ibrutinib, l-{(3R)-3- [4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo [3,4-d] pyrimidin-l-yl] piperidin-l-yl] prop-2-en-l-one, having the following formula,

is a kinase inhibitor indicated for the treatment of patients with B-cell lymphoma.

Ibrutinib is described in US 7,514,444 and in US 8,008,309. Solid state forms, including forms A-F and amorphous form of Ibrutinib, are described in WO 2013/184572.

Polymorphism, the occurrence of different crystalline forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g. measured by thermogravimetric analysis – “TGA”, or differential scanning calorimetry – “DSC”), X-ray diffraction pattern, infrared absorption fingerprint, and solid state (¹³C-) NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.

Different salts and solid state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms and solvates may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, changing the dissolution profile in a favorable direction, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different salts and solid state forms may also offer improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts and solid state forms and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to assess variations in the properties and characteristics of a solid active pharmaceutical ingredient.

Discovering new solid state forms and solvates of a pharmaceutical product may yield materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification, or may serve as desirable intermediate crystal forms that facilitate purification or conversion to other polymorphic forms. New solid state forms of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., a different crystal habit, higher crystallinity or polymorphic stability which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life (chemical/physical stability). For at least these reasons, there is a need for additional solid state forms (including solvated forms) of ibrutinib.

Example 1: Preparation of Crystalline Form G of Ibrutinib

[0057] Ibrutinib (0.3 gr, amorphous form) was dissolved in acetic acid (1.2 ml) and the obtained solution was stirred at room temperature overnight followed by the addition of water (2.4 ml). A gum was obtained which was turned into cloudy solution upon stirring. The obtained cloudy solution was stirred for 9 days at room temperature and the obtained precipitate was collected by suction filtration. The obtained solid was dried in an oven at 40°C under vacuum for 16h to obtain form G of Ibrutinib (0.12g), as confirmed by XRPD.

Example 2: Preparation of Crystalline Form J of Ibrutinib

Ibrutinib (5.2 g) was dissolved in Anisole (15 ml), the solution was stirred at room temperature until precipitation was occurred. The slurry was stirred over night at room temperature and the precipitate was collected by suction filtration. The cake was dried in a vacuum oven at 50°C overnight. The obtained product was analyzed by XRPD and found to be form J.

Example 3: Preparation of Crystalline Form J of Ibrutinib

Ibrutinib (10.5 g) was dissolved in Anisole (21 ml) and MTBE (32 ml), the solution was stirred at room temperature until precipitation was occurred . The slurry was heated to reflux and was gradually cooled to room temperature. After 3 hours the precipitate was collected by suction filtration. The obtained product was analyzed by XRPD and found to be form J.

Example 4: Preparation of Crystalline Form G of Ibrutinib

A I L reactor was charged with Ibrutinib (100 g), acetonitrile (417.5 ml_), water (417.5 ml_) and acetic acid (27.15 g). The mixture was heated to 90°C until dissolution; the solution was gradually cooled to 0°C, then heated to 25°C and stirred over 48 hours at 25°C. The obtained slurry was filtered and washed with water (100 ml_). The product was dried overnight in a vacuum oven at 40°C to obtain Ibrutinib form G (72.9 g), as confirmed by XRPD.

Example 5: Preparation of Crystalline Form G of Ibrutinib

A 250 mL round flask was charged with isopropanol (10 ml_) and water (120 ml_), and a solution of Ibrutinib (10 g) in Acetic acid (40 mL) was added dropwise. The mixture was stirred at 25°C for 48 hours. The obtained slurry was filtered and the wet product was slurried in water (50 mL) for 5 min and filtered again. The obtained product was dried under vacuum at room temp in the presence of a N₂ atmosphere and found to be form G, as confirmed by XRPD.

Example 6: Preparation of Crystalline Form K of Ibrutinib

Ibrutinib (10 g) was dissolved in toluene (50 mL) and dimethylformamide (DMA) (30 mL) at room temperature, the solution was heated to 50 °C and water (30 mL) was added. The phases were separated and methyl tert-butyl ether (MTBE) (30 mL) was added to the organic phase. The solution was cooled in an ice bath and seeded with amorphous Ibrutinib. After further stirring at the same temperature the obtained slurry was filtered under vacuum. The obtained solid was analyzed by XRPD and found to be Form K (Figure 5).

assia chemical industries - teva tech site in ramat hovav

//////////////WO 2016025720, WO-2016025720, New Patent, Assia Chemicals, Teva, Ibrutinib

	shivkr2 on SPSR Excellence Award 2025 – S…
	Bonkasaurus on Infigratinib phosphate
	PALOVAROTENE \| ORGAN… on Palovarotene
	Pfizer just purchase… on Temanogrel
	Pfizer To Cash In On… on Temanogrel

Author Archives: DR ANTHONY MELVIN CRASTO Ph.D

SEARCH THIS BLOG

Blog Stats

Flag and hits

Follow Blog via Email

Pages

Archives

Categories

Recent Posts

ORGANIC SPECTROSCOPY

SUBSCRIBE

Follow Blog via Email

Verified Services

Pages

Archives

Categories

Recent Comments

SEARCH THIS BLOG

Share this:

Clinical trials

PATENT

References

Share this:

Share this:

Suven Life completes Phase 1 studies for SUVN- G3031 for Schizophrenia – Cognitive Impairment

OLD CLIPS

SUVN-G3031 for Cognition in Alzheimer’s Disease commenced Phase 1 Clinical Trial in USA under US-IND 123179

Share this:

Evocalcet [INN] RN: 870964-67-3 UNII: E58MLH082P

Benzeneacetic acid, 4-((3S)-3-(((1R)-1-(1-naphthalenyl)ethyl)amino)-1-pyrrolidinyl)-

Share this:

PATENT

Share this:

SUVN-D4010 for Cognition in Alzheimer’s disease commenced Phase 1 Clinical Trial in USA under US-IND 126099

Share this:

Share this:

Trelagliptin

Indications for Medical Use

Biochemistry

Development

Administration and Dosing

SYNTHESIS …………….

PAPER

PATENT

PATENT

PATENT

PATENT

PATENT

PATENT

PATENT

References

Share this:

Share this:

Post navigation

SEARCH THIS BLOG

FLAGS AND HITS

Follow Blog via Email

Evocalcet [INN]
RN: 870964-67-3
UNII: E58MLH082P