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Filgotinib

August 18, 2015 5:51 am / Leave a comment

Filgotinib

EU APPROVED 2020/9/24, JYSELECA

JAPAN APPROVED2020/9/25

C₂₁H₂₃N₅O₃S
MW425.504
Elemental Analysis: C, 59.28; H, 5.45; N, 16.46; O, 11.28; S, 7.54

1206161-97-8

Cyclopropanecarboxamide, N-[5-[4-[(1,1-dioxido-4-thiomorpholinyl)methyl]phenyl][1,2,4]triazolo[1,5-a]pyridin-2-yl]-

G146034

GLPG0634

N-(5-(4-((1,1-dioxidothiomorpholino)methyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

Galapagos Nv INNOVATOR

PHASE 3, Crohn’s disease, Rheumatoid arthritis, Ulcerative colitis

Filgotinib is an orally available inhibitor of JAK1/JAK2 and TYK2 in phase III clinical development at Galapagos and Gilead for the treatment of rheumatoid arthritis, moderate or severe Crohn’s disease and ulcerative colitis

IL-6 antagonist; Jak1 tyrosine kinase inhibitor; Tyk2 tyrosine kinase inhibitor; Jak3 tyrosine kinase inhibitor; Jak2 tyrosine kinase inhibitor

Autoimmune disease; Cancer; Colitis; Crohns disease; Inflammatory disease; Neoplasm; Rheumatoid arthritis; Transplant rejection

In 2017, orphan drug designation was assigned to the compound in the U.S. for the treatment of pediatric Crohn’s disease and pediatric ulcerative colitis.

GlaxoSmithKline had been developing filgotinib preclinically for the treatment of rheumatoid arthritis pursuant to a license; however, in 2010, the compound was re-acquired by Galapagos. In 2012, the product was licensed to Abbott for development and marketing. In January 2013, Abbott spun-off its research-based pharmaceutical business into a newly-formed company AbbVie. The license agreement between Galapagos and Abbott was terminated in September 2015, Galapagos regaining all rights to the product. The same year, Galapagos and Gilead entered into a global partnership and Gilead obtained the global rights of codevelopment and commercialization for the treatment of inflammatory diseases

Filgotinib (GLPG0634), by the Belgian biotech company Galápagos NV, is a drug which is currently under investigation for the treatment of rheumatoid arthritis and Crohn’s disease.

Filgotinib (GLPG0634) is an orally-available, selective inhibitor of JAK1 (Janus kinase 1) for the treatment of rheumatoid arthritis and potentially other inflammatory diseases. Filgotinib (GLPG0634) dose-dependently inhibited Th1 and Th2 differentiation and to a lesser extent the differentiation of Th17 cells in vitro. GLPG0634 was well exposed in rodents upon oral dosing, and exposure levels correlated with repression of Mx2 expression in leukocytes. The JAK1 selective inhibitor GLPG0634 (Filgotinib) is a promising novel therapeutic with potential for oral treatment of rheumatoid arthritis and possibly other immune-inflammatory diseases. Filgotinib (GLPG0634) is currently in a Phase 2 study in Crohn’s disease.

Mechanism of action

Filgotinib is a Janus kinase inhibitor with selectivity for subtype JAK1 of this enzyme. It is considered a promising agent as it inhibits JAK1 selectively. Less selective JAK inhibitors (e.g. tofacitinib) are already being marketed. They show long-term efficacy in the treatment of various inflammatory diseases. However, their lack of selectivity leads to dose-limiting side effects.^[1] It is thought that inhibition of all JAK isoenzymes is beneficial in rheumatoid arthritis. However, pan-JAK inhibition might also lead to unwanted side effects that might not outweigh its benefits. This is the rationale for the development of newer and more selective inhibitors like filgotinib.

The signal transmission of large numbers of proinflammatory cytokines is dependent on JAK1. Inhibition of JAK2 may also contribute to the efficacy against RA. Nonetheless it is thought that JAK2 inhibition might lead to anemia and thrombopenia by interference witherythropoietin and thrombopoietin and granulocyte-macrophage colony-stimulating factor. Therefore one might prefer to choose a more selective JAK1 inhibitor as a primary therapeutic option. Filgotinib exerts a 30-fold selectivity for JAK1 compared to JAK2.^[2] It is however still to be seen to what extent JAK2 inhibition should be avoided.

Novel crystalline forms of filgotinib salts, particularly hydrochloride salt, useful for treating JAK-mediated diseases eg inflammatory diseases, autoimmune diseases, proliferative diseases, allergy and transplant rejection. Galapagos and licensee AbbVie are developing filgotinib, a selective JAK-1 inhibitor, for treating rheumatoid arthritis (RA) and Crohn’s disease (CD). In August 2015, the drug was reported to be in phase 2 clinical development for treating RA and CD. The drug is also being investigated for the treatment of colitis and was discovered as part of the company’s arthritis alliance with GSK; however in August 2010 Galapagos reacquired the full rights. See WO2013189771, claiming use of filgotinib analog for treating inflammatory diseases. Also see WO2010010190 (co-assigned with GSK and Abbott) and WO2010149769 (assigned to Galapagos) claiming filgotinib, generically and specifically, respectively.

Clinical trials and approval

The efficacy of filgotinib is currently studied in a phase2b program (DARWIN trial 1, 2) with involvement of 886 rheumatoid arthritis patients and 180 Crohn’s disease patients.

Phase 1 study

It was shown in phase 1 studies that the pharmacokinetics of filgotinib metabolism is independent of hepatic CYP450 enzymatic degradation. The drug metabolism is however mediated by carboxylesterases. There is no interference reported with the metabolism of methotrexate nor with any of the investigated transport proteins.^[3]

Phase 2 study: Proof of concept (2011)

In november 2011 Galápagos released the results of their phase 2 study (identification: NCT01384422, Eudract: 2010-022953-40) in which 36 patients were treated who showed a suboptimal clinical response to methotrexate treatment. Three groups of twelve patients were treated either with 200 mg filgotinib in a single dose, 200 mg divided in two doses or placebo. The primary end-point was the ACR20 score, which monitors improvements in the symptomatology of the patient. After the scheduled 4 weeks of treatment, 83% of the respondents showed an improved ACR20-score. Half of the treated patients showed a complete (or near complete) remission of the disease. There were no reports ofanemia nor changes in lipidemia. The company stated in their press release that filgotinib is the first selective JAK1 inhibitor that shows clinical efficacy. As a result of this study, the company stated that “GLPG0634 shows one of the highest initial response rates ever reported for rheumatoid arthritis treatments”.^[4]

DARWIN 1 trial

The DARWIN 1 trial is a 24 week double blind placebo-controlled trial with 599 rheumatoid arthritis patients enrolled. All participants have moderate to severe RA and showed an insufficient response to standard methotrexate treatment. The trial compares three dosages of filgotinib as a once or twice per day regimen. During the trial all participants remain on their methotrexate treatment. According to the company, the results of this trial are expected in July 2015.^[5]

DARWIN 2 trial

The DARWIN 2 trial is a double blind placebo-controlled trial with 280 rheumatoid arthritis patients enrolled who show an insufficient response to standard methotrexate treatment. This trial, in contrast to the previous DARWIN 1 trial, methotrexate is discontinued. Therefore, this trial investigates filgotinib as a monotherapy.^[6] The recruitment of DARWIN trial 2b ended in november 2014.^[7] Preliminary results are expected in the second quarter of 2015 and a full completion of the study is expected in the third quarter of 2015.

DARWIN 3 trial

Patients who complete DARWIN 1 and 2 will be eligible for DARWIN 3.

COSY PREDICT

Time line

june 2011: results of first phase 2 trial
november 2014: initiation of DARWIN 1 and 2 trials
april 2015: expected date of DARWIN 1 trial results
june 2015: expected date of DARWIN 2 trial results

NMR FROM NET….ABMOLE, DMSOD6

NMR MEDKOO DMSOD6

CHEMIETEK

GLPG-0634, Current Lot, Certificate of Analysis

GLPG-0634, Current Lot, NMR

GLPG-0634, Current Lot, HPLC-MS

1H NMR PREDICT

13C NMR PREDICT

……………………

MORE PREDICTS

1H NMR PREDICT

13C NMR PREDICT

PRODUCT PATENT

http://www.google.com/patents/WO2010149769A1?cl=en

Applicants:	GALAPAGOS NV [BE/BE]; Generaal De Wittelaan L11/A3 B-2800 Mechelen (BE) (For All Designated States Except US). MENET, Christel Jeanne Marie [FR/BE]; (BE) (For US Only). SMITS, Koen Kurt [BE/BE]; (BE) (For US Only)
Inventors:	MENET, Christel Jeanne Marie; (BE). SMITS, Koen Kurt; (BE)

WO2010149769

International Filing Date:

25.06.2010

ESTIMATED EXP 2030

Condensation of 2-amino-6-bromopyridine (I) with ethoxycarbonyl isothiocyanate (II) in CH2Cl2 gives 1-(6-bromopyridin-2-yl)-3-carboethoxythiourea (III), which upon cyclization with hydroxylamine hydrochloride (IV) in the presence of DIEA in EtOH/MeOH yields 2-amino-5-bromo[1,2,4]triazolo[1,5-a]pyridine (V). N-Acylation of amine (V) with cyclopropanecarbonyl chloride (VI) using Et3N in acetonitrile, and subsequent treatment with methanolic ammonia furnishes the carboxamide (VII) (1-3), which upon Suzuki coupling with 4-(hydroxymethyl)phenylboronic acid (VIII) in the presence of PdCl2(dppf) and K2CO3 in dioxane/H2O at 90 °C, followed by bromination with PBr3 in CHCl3 affords intermediate (IX). Condensation of benzyl bromide derivative (IX) with thiomorpholine-1,1-dioxide (X) using DIEA in CH2Cl2/MeOH yields filgotinib (1,2). Alternatively, condensation of (4-bromomethylphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (XI) with thiomorpholine 1,1-dioxide (X) in the presence of DIEA in CH2Cl2/MeOH gives intermediate (XII), which undergoes Suzuki coupling with aryl bromide (VII) in the presence of PdCl2(dppf) and K2CO3 in dioxane/H2O at 90 °C to afford the target filgotinib

The present invention is based on the discovery that the compound of the invention is able to act as an inhibitor of JAK and that it is useful for the treatment of inflammatory conditions, autoimmune diseases, proliferative diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IL6. In a specific aspect the compound is an inhibitor of JAKl and JAK2. The present invention also provides methods for the production of this compound, a pharmaceutical composition comprising this compound and methods for treating inflammatory conditions, autoimmune diseases, proliferative diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IL6 by administering the compound of the invention.

Accordingly, in a first aspect of the invention, a compound of the invention is provided having a formula (I):

[0017] The compound of the invention is a novel inhibitor of JAK that appears to exhibit a dramatically improved in vivo potency as compared to structurally similar compounds. In a particular embodiment the compound of the invention is an inhibitor of JAKl and JAK2. In particular it appears to exhibit this increase in potency at lower in vivo exposure levels compared to structurally similar compounds. The use of a compound with these improvements is expected to result in a lower dosage requirement (and therefore an improved dosing schedule).

General Synthetic Method Scheme 1

1. RCOCI, Et₃N 2. NH₃ / MeOH CH₃CN, 20 ⁰C 2O ⁰C

wherein Ar represents phenyl-Ll-heterocycloalkyl, where Ll is a bond, -CH₂– or -CO- and the heterocycloalkyl group is optionally substituted.

General

1.1.1 l-(6-Bromo-pyridin-2-yl)-3-carboethoxy-thiourea (2)

(2)

[00117] To a solution of 2-amino-6-bromopyridine (1) (253.8 g, 1.467 mol) in DCM (2.5 L) cooled to 5 ⁰C is added ethoxycarbonyl isothiocyanate (173.0 mL, 1.467 mol) dropwise over 15 min. The reaction mixture is then allowed to warm to room temp. (20 ⁰C) and stirred for 16 h. Evaporation in vacuo gives a solid which may be collected by filtration, thoroughly washed with petrol (3×600 mL) and air-dried to afford (2). The thiourea may be used as such for the next step without any purification. ¹H (400 MHz, CDCl₃) δ 12.03 (IH, br s, NH), 8.81 (IH, d, J 7.8 Hz, H-3), 8.15 (IH, br s, NH), 7.60 (IH, t, J 8.0 Hz, H-4), 7.32 (IH, dd, J 7.7 and 0.6 Hz, H-5), 4.31 (2H, q, J 7.1 Hz, CH₂), 1.35 (3H, t, J 7.1 Hz, CH₃).

7.7.2 5-Bromo-[l, 2, 4]triazolo[l, 5-a]pyridin-2-ylamine (3)

[00118] To a suspension of hydroxylamine hydrochloride (101.8 g, 1.465 mol) in EtOH/MeOH

(1 :1, 900 mL) is added N,N-diisopropylethylamine (145.3 mL, 0.879 mol) and the mixture is stirred at room temp. (20 ⁰C) for 1 h. l-(6-Bromo-pyridin-2-yl)-3-carboethoxy-thiourea (2) (89.0 g, 0.293 mol) is then added and the mixture slowly heated to reflux (Note: bleach scrubber is required to quench H₂S evolved). After 3 h at reflux, the mixture is allowed to cool and filtered to collect the precipitated solid. Further product is collected by evaporation in vacuo of the filtrate, addition Of H₂O (250 mL) and filtration. The combined solids are washed successively with H₂O (250 mL), EtOH/MeOH (1 : 1, 250 mL) and Et₂O (250 mL) then dried in vacuo to afford the triazolopyridine derivative (3) as a solid. The compound may be used as such for the next step without any purification. ¹H (400 MHz, DMSO-t/β) δ 7.43-7.34 (2H, m, 2 x aromatic-H), 7.24 (IH, dd, J 6.8 and 1.8 Hz, aromatic-H), 6.30 (2H, br, NH₂); m/z 213/215 (1 :1, M+H⁺, 100%).

7.7.3 General procedure for mono-acylation to afford intermediate (4):

[00119] To a solution of the 2-amino-triazolopyridine (3) (7.10 g, 33.3 mmol) in dry CH₃CN

(150 mL) at 5 ⁰C is added Et₃N (11.6 mL, 83.3 mmol) followed by cyclopropanecarbonyl chloride (83.3 mmol). The reaction mixture is then allowed to warm to ambient temperature and stirred until all starting material (3) is consumed. If required, further Et₃N (4.64 mL, 33.3 mmol) and cyclopropanecarbonyl chloride (33.3 mmol) is added to ensure complete reaction. Following solvent evaporation in vacuo the resultant residue is treated with 7 N methanolic ammonia solution (50 mL) and stirred at ambient temp, (for 1-16 h) to hydro lyse any bis-acylated product. Product isolation is made by removal of volatiles in vacuo followed by trituration with Et₂O (50 mL). The solids are collected by filtration, washed with H₂O (2x50mL), acetone (50 mL) and Et₂O (50 mL), then dried in vacuo to give the required bromo intermediate (4).

Method A

Preparation of compounds of the invention via Suzuki coupling (5):

[00120] An appropriate boronic acid (2eq.) is added to a solution of bromo intermediate (4) in

1 ,4-dioxane/water (5:1). K₂CO3 (2 eq.) and PdCl₂dppf (5%) are added to the solution. The resulting mixture is then heated in a microwave at 140 ⁰C for 30 min (this reaction can also be carried out by traditional heating in an oil bath at 90⁰C for 16h under N₂). Water is added and the solution is extracted with ethyl acetate. The organic layers are dried over anhyd. MgSθ₄ and evaporated in vacuo. The final compound is obtained after purification by flash chromatography or preparative HPLC. HPLC: Waters

XBridge Prep Cl 8 5μm ODB 19mm ID x 100mm L (Part No.186002978). All the methods are using

MeCN/H₂O gradients. H₂O contains either 0.1% TFA or 0.1% NH₃.

Method B

Bl. 4 4-[2-(Cyclopropanecarbonyl-amino)-[ 1 , 2, 4]triazolo[l, 5-a] pyridin-5-yl] -benzoyl chloride

[00121] 2 Drops of DMF are added to a solution of 4-[2-(cyclopropanecarbonyl-amino)- [l,2,4]triazolo[l,5-a]pyridin-5-yl]-benzoic acid (1 eq) obtained by Method A using 4-carboxyphenylboronic acid in DCM under N₂ atmosphere. Then oxalyl chloride (2 eq) is added dropwise to this resulting solution (gas release). The mixture is stirred at room temperature for 2 hours. After completion of the reaction by LCMS, the solvent is removed. The crude acid chloride is used without further purification in next step.

B2. Amide formation (General Method)

[00122] An appropriate amine (1.1 eq) and Et₃N (5 eq) are dissolved in DCM under N₂ atmosphere and cooled at 0⁰C. The acid chloride (Bl, 1 eq) dissolved in DCM is added dropwise to this solution. The reaction is stirred at room temperature for 16 h. After this time, reaction is complete. The compound is extracted with EtOAc and water, washed with brine and dried over anhyd. MgSO₄. Organic layers are filtered and evaporated. The final compound is isolated by preparative HPLC. Preparative HPLC: Waters XBridge Prep C18 5μm ODB 19mm ID x 100mm L (Part No.186002978). All the methods are using MeCN/H₂O gradients. H₂O contains either 0.1% TFA or 0.1% NH₃.

Method C

Wherein R^3a or R^3b together with the nitrogen atom to which they are attached, may form a heterocycloalkyl.

Reductive alkylation (general method)

[00123] An appropriate amine (2 eq.), cyclopropanecarboxylic acid (for example cyclopropanecarboxylic acid [5-(4-formyl-phenyl)-[l,2,4]triazolo[l,5-a]pyridine-2-yl]-amide) prepared by method A (1 eq.) and Ti(OPr)₄ are mixed and stirred at room temperature for 3 hrs. The mixture is diluted in ethanol and Na(CN)BH₃ (leq.) is added. The resulting solution is stirred at room temperature for 16 hrs. The mixture is diluted in water and filtered. The filtrate is washed with ethanol. The combined solvent phases are evaporated under vacuum. The final compound is isolated by preparative HPLC.

Method D
wherein R¹ and R² together with the Nitrogen atom to which they are attached, may form a heterocycloalkyl.

Reaction ofalkylation

[00124] 2-(4-Bromomethyl-phenyl)-4,4,5,5-tetramethyl-[l,3,2]dioxaborolane (leq) and Et₃N (2 eq) (or AgCO₃) are dissolved in DCM/MeOH (4:1 v:v) under N₂ and an amine (2 eq) is added dropwise. The resulting solution is stirred at room temperature for 16h. After this time, the reaction is complete. The solvent is evaporated. The compound is extracted with EtOAc and water, washed with brine and dried over anhyd. MgSθ₄. Organic layers are filtered and evaporated. The final compound is isolated by flash chromatography.

Suzuki coupling

[00125] The obtained boronic acid (2eq.) is added to a solution of cyclopropanecarboxylic acid

(5-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-yl)-amide (4) in 1 ,4-dioxane/water (5:1). K₂CO₃ (2 eq.) and PdCl₂dppf (5%) are added to the solution. The resulting mixture is then heated in a microwave at 140 ⁰C for 30 min (This reaction can also be carried out by traditional heating in an oil bath at 90⁰C for 16h under N₂). Water is added and the solution is extracted with ethyl acetate. The organic layers are dried over anhyd. MgSθ₄ and evaporated in vacuo. The final compound is obtained after purification by flash chromatography or preparative HPLC. HPLC: Waters XBridge Prep C18 5μm ODB 19mm ID x 100mm L (Part No.186002978). All the methods are using MeCN/H₂O gradients. H₂O contains either 0.1% TFA or 0.1% NH₃.

Synthesis of the compound of the invention and comparative examples

Compound l(the compound of the invention)

Step 1:

[00126] 2-(4-Bromomethyl-phenyl)-4,4,5,5-tetramethyl-[l,3,2]dioxaborolane (leq) and DIPEA

(2 eq) were dissolved in DCM/MeOH (5:1 v:v) under N₂ and thiomorpholine 1,1 -dioxide (2 eq) was added portionwise. The resulting solution was stirred at room temperature for 16h. After this time, the reaction was complete. The solvent was evaporated. The compound was extracted with EtOAc and water, washed with brine and dried over anhyd. MgS O₄. Organic layers were filtered and evaporated. The final compound was isolated without further purification.

Step 2: Suzuki coupling

[00127] 4-[4-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzyl]-thiomorpholine-l,l-dioxide

(l.leq.) was added to a solution of cyclopropanecarboxylic acid (5-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-yl)-amide in 1 ,4-dioxane/water (4:1). K₂CO₃ (2 eq.) and PdCl₂dppf (0.03 eq.) were added to the solution. The resulting mixture was then heated in an oil bath at 90⁰C for 16h under N₂. Water was added and the solution was extracted with ethyl acetate. The organic layers were dried over anhyd. MgSθ₄ and evaporated in vacuo. The final compound was obtained after purification by flash chromatography.

[00128] Alternatively, after completion of the reaction, a palladium scavenger such as 1,2-bis(diphenylphosphino)ethane, is added, the reaction mixture is allowed to cooled down and a filtration is performed. The filter cake is reslurried in a suitable solvent (e.g. acetone), the solid is separated by filtration, washed with more acetone, and dried. The resulting solid is resuspended in water, aqueous HCl is added, and after stirring at RT, the resulting solution is filtered on celite (Celpure P300). Aqueous NaOH is then added to the filtrate, and the resulting suspension is stirred at RT, the solid is separated by filtration, washed with water and dried by suction. Finally the cake is re-solubilised in a mixture of THF/H₂O, treated with a palladium scavenger (e.g. SMOPEX 234) at 50⁰C, the suspension is filtered, the organic solvents are removed by evaporation, and the resulting slurry is washed with water and methanol, dried and sieved, to obtain the title compound as a free base.

Alternative route to Compound l(the compound of the invention):

Step 1:

[00129] 4-(Hydroxymethyl)phenylboronic acid (l.leq.) was added to a s o luti o n o f cyclopropanecarboxylic acid (5-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-yl)-amide in 1 ,4-dioxane/water (4:1). K₂CO₃ (2 eq.) and PdCl₂dppf (0.03 eq.) were added to the solution. The resulting mixture was then heated in an oil bath at 90⁰C for 16h under N₂. Water was added and the solution was extracted with ethyl acetate. The organic layers were dried over anhyd. MgSθ₄ and evaporated in vacuo. The resulting mixture was used without further purification.

Step 2:

[00130] To a solution of cyclopropanecarboxylic acid [5-(4-hydroxymethyl-phenyl)- [l,2,4]triazolo[l,5-a]pyridin-2-yl]-amide (1.0 eq) in chloroform was slowly added phosphorus tribromide (1.0 equiv.). The reaction mixture was stirred at room temperature for 20 hours, quenched with ice and water (20 mL) and extracted with dichloromethane. The organic layer was dried over anhyd. MgSθ₄, filtered and concentrated to dryness. The resulting white residue was triturated in dichloromethane/diethyl ether 2:1 to afford the expected product as a white solid.

Step 3:

[00131] Cyclopropanecarboxylic acid [5-(4-bromomethyl-phenyl)-[l,2,4]triazolo[l,5-a]pyridin- 2-yl]-amide (leq) and DIPEA (2 eq) were dissolved in DCM/MeOH (5:1 v:v) under N₂ and thiomorpholine 1,1 -dioxide (1.1 eq) was added dropwise. The resulting solution was stirred at room temperature for 16h. After this time, the reaction was complete. The solvent was evaporated. The compound was dissolved in DCM, washed with water and dried over anhyd. MgSO^ Organic layers were filtered and evaporated. The final compound was isolated by column chromatography using EtOAc to afford the desired product.

PATENT

WO 2010010190

WO 2013173506

WO 2013189771

WO 2015117980

WO 2015117981

POLYMORPH

CN 105061420

CN105061420

https://encrypted.google.com/patents/CN105061420A?cl=en

JAK inhibitor N-(5-(4-(1,1-dioxothiomorpholinyl)methyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide, and methods for preparing the four crystal forms, wherein the four crystal forms respectively are a crystal form H1, a crystal form H2, a crystal form H3 and a crystal form H4,

POLYMORPH

E CRYSTAL

CN 105111206

D CRYSTAL

CN 105111207

H CRYSYAL

CN 105198876

CN 105198877

F CN 105198878

C CN 105198880

POLYMORPH

WO 2016105453

POLYMORPH

Preparation of solid forms of filgotinib free base

WO 2017012773

The present invention relates to cryst. filgotinib free base (I), a method of its prepn. and a pharmaceutical compn. comprising the same. Thus, reacting the compd. II with thiomorpholine dioxide afforded 92% I (purity of 98.6%) which was then converted into its hydrochloride salt. Pharmaceutical compn. comprising compd. I was disclosed.

POLYMORPH

CN 105669669

The present invention provides a crystal form A, B, D, G and M of N-[5-[4-[(1,1-dioxido-4-thiomorpholinyl)methyl]phenyl][1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide hydrochloride.

PAPER

Future Medicinal Chemistry (2015), 7(2), 203-235. | Language: English, Database: CAPLUSA review. The discovery of the JAK-STAT pathway was a landmark in cell biol. The identification of these pathways has changed the landscape of treatment of rheumatoid arthritis and other autoimmune diseases. The two first (unselective) JAK inhibitors have recently been approved by the US FDA for the treatment of myelofibrosis and rheumatoid arthritis and many other JAK inhibitors are currently in clin. development or at the discovery stage. Research groups have demonstrated the different roles of JAK member and the therapeutic potential of targeting them selectively. ………..

https://www.future-science.com/doi/10.4155/fmc.14.149

PAPER

Journal of Pharmaceutical Sciences (Philadelphia, PA, United States) (2018), 107(6), 1624-1632.

PATENT

US2010/331319 A1, ; Page/Page column 13-14

http://www.google.com/patents/US20100331319

Synthetic Preparation of the Compound of the Invention and Comparative Examples

The compound of the invention and the comparative examples can be produced according to the following scheme.

wherein Ar represents phenyl-L1-heterocycloalkyl, where L1 is a bond, —CH₂— or —CO— and the heterocycloalkyl group is optionally substituted.

General 1.1.1 1-(6-Bromo-pyridin-2-yl)-3-carboethoxy-thiourea (2)

To a solution of 2-amino-6-bromopyridine (1) (253.8 g, 1.467 mol) in DCM (2.5 L) cooled to 5° C. is added ethoxycarbonyl isothiocyanate (173.0 mL, 1.467 mol) dropwise over 15 min. The reaction mixture is then allowed to warm to room temp. (20° C.) and stirred for 16 h. Evaporation in vacuo gives a solid which may be collected by filtration, thoroughly washed with petrol (3×600 mL) and air-dried to afford (2). The thiourea may be used as such for the next step without any purification. ¹H (400 MHz, CDCl₃) δ 12.03 (1H, br s, NH), 8.81 (1H, d, J=7.8 Hz, H-3), 8.15 (1H, br s, NH), 7.60 (1H, t, J=8.0 Hz, H-4), 7.32 (1H, dd, J 7.7 and 0.6 Hz, H-5), 4.31 (2H, q, J 7.1 Hz, CH₂), 1.35 (3H, t, J 7.1 Hz, CH₃).

1.1.2 5-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (3)

To a suspension of hydroxylamine hydrochloride (101.8 g, 1.465 mol) in EtOH/MeOH (1:1, 900 mL) is added N,N-diisopropylethylamine (145.3 mL, 0.879 mol) and the mixture is stirred at room temp. (20° C.) for 1 h. 1-(6-Bromo-pyridin-2-yl)-3-carboethoxy-thiourea (2) (89.0 g, 0.293 mol) is then added and the mixture slowly heated to reflux (Note: bleach scrubber is required to quench H₂S evolved). After 3 h at reflux, the mixture is allowed to cool and filtered to collect the precipitated solid. Further product is collected by evaporation in vacuo of the filtrate, addition of H₂O (250 mL) and filtration. The combined solids are washed successively with H₂O (250 mL), EtOH/MeOH (1:1, 250 mL) and Et₂O (250 mL) then dried in vacuo to afford the triazolopyridine derivative (3) as a solid. The compound may be used as such for the next step without any purification. ¹H (400 MHz, DMSO-d₆) δ 7.43-7.34 (2H, m, 2×aromatic-H), 7.24 (1H, dd, J 6.8 and 1.8 Hz, aromatic-H), 6.30 (2H, br, NH₂); m/z 213/215 (1:1, M+H⁺, 100%).

1.1.3 General Procedure for Mono-Acylation to Afford Intermediate (4)

To a solution of the 2-amino-triazolopyridine (3) (7.10 g, 33.3 mmol) in dry CH₃CN (150 mL) at 5° C. is added Et₃N (11.6 mL, 83.3 mmol) followed by cyclopropanecarbonyl chloride (83.3 mmol). The reaction mixture is then allowed to warm to ambient temperature and stirred until all starting material (3) is consumed. If required, further Et₃N (4.64 mL, 33.3 mmol) and cyclopropanecarbonyl chloride (33.3 mmol) is added to ensure complete reaction. Following solvent evaporation in vacuo the resultant residue is treated with 7 N methanolic ammonia solution (50 mL) and stirred at ambient temp. (for 1-16 h) to hydrolyse any bis-acylated product. Product isolation is made by removal of volatiles in vacuo followed by trituration with Et₂O (50 mL). The solids are collected by filtration, washed with H₂O (2×50 mL), acetone (50 mL) and Et₂O (50 mL), then dried in vacuo to give the required bromo intermediate (4).

Method A Preparation of Compounds of the Invention Via Suzuki Coupling (5):

An appropriate boronic acid (2 eq.) is added to a solution of bromo intermediate (4) in 1,4-dioxane/water (5:1). K₂CO₃(2 eq.) and PdCl₂dppf (5%) are added to the solution. The resulting mixture is then heated in a microwave at 140° C. for 30 min (this reaction can also be carried out by traditional heating in an oil bath at 90° C. for 16 h under N₂). Water is added and the solution is extracted with ethyl acetate. The organic layers are dried over anhyd. MgSO₄and evaporated in vacuo. The final compound is obtained after purification by flash chromatography or preparative HPLC. HPLC: Waters XBridge Prep C18 5 μm ODB 19 mm ID×100 mm L (Part No. 186002978). All the methods are using MeCN/H₂O gradients. H₂O contains either 0.1% TFA or 0.1% NH₃.

Method B

B1. 4 4-[2-(Cyclopropanecarbonyl-amino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl]-benzoyl chloride

2 Drops of DMF are added to a solution of 4-[2-(cyclopropanecarbonyl-amino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl]-benzoic acid (1 eq) obtained by Method A using 4-carboxyphenylboronic acid in DCM under N₂atmosphere. Then oxalyl chloride (2 eq) is added dropwise to this resulting solution (gas release). The mixture is stirred at room temperature for 2 hours. After completion of the reaction by LCMS, the solvent is removed. The crude acid chloride is used without further purification in next step.

B2. Amide Formation (General Method)

An appropriate amine (1.1 eq) and Et₃N (5 eq) are dissolved in DCM under N₂atmosphere and cooled at 0° C. The acid chloride (B1, 1 eq) dissolved in DCM is added dropwise to this solution. The reaction is stirred at room temperature for 16 h. After this time, reaction is complete. The compound is extracted with EtOAc and water, washed with brine and dried over anhyd. MgSO₄. Organic layers are filtered and evaporated. The final compound is isolated by preparative HPLC. Preparative HPLC: Waters XBridge Prep C18 5 μm ODB 19 mm ID×100 mm L (Part No. 186002978). All the methods are using MeCN/H₂O gradients. H₂O contains either 0.1% TFA or 0.1% NH₃.

…

Synthesis of the Compound of the Invention and Comparative Examples Compound 1 (the Compound of the Invention) Step 1:

2-(4-Bromomethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1 eq) and DIPEA (2 eq) were dissolved in DCM/MeOH (5:1 v:v) under N₂and thiomorpholine 1,1-dioxide (2 eq) was added portionwise. The resulting solution was stirred at room temperature for 16 h. After this time, the reaction was complete. The solvent was evaporated. The compound was extracted with EtOAc and water, washed with brine and dried over anhyd. MgSO₄. Organic layers were filtered and evaporated. The final compound was isolated without further purification.

STEP 2: Suzuki coupling

4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-thiomorpholine-1,1-dioxide (1.1 eq.) was added to a solution of cyclopropanecarboxylic acid (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amide in 1,4-dioxane/water (4:1). K₂CO₃(2 eq.) and PdCl₂dppf (0.03 eq.) were added to the solution. The resulting mixture was then heated in an oil bath at 90° C. for 16 h under N₂. Water was added and the solution was extracted with ethyl acetate. The organic layers were dried over anhyd. MgSO₄and evaporated in vacuo. The final compound was obtained after purification by flash chromatography.

Alternatively, after completion of the reaction, a palladium scavenger such as 1,2-bis(diphenylphosphino)ethane, is added, the reaction mixture is allowed to cooled down and a filtration is performed. The filter cake is reslurried in a suitable solvent (e.g. acetone), the solid is separated by filtration, washed with more acetone, and dried. The resulting solid is resuspended in water, aqueous HCl is added, and after stirring at RT, the resulting solution is filtered on celite (Celpure P300). Aqueous NaOH is then added to the filtrate, and the resulting suspension is stirred at RT, the solid is separated by filtration, washed with water and dried by suction. Finally the cake is re-solubilised in a mixture of THF/H₂O, treated with a palladium scavenger (e.g. SMOPEX 234) at 50° C., the suspension is filtered, the organic solvents are removed by evaporation, and the resulting slurry is washed with water and methanol, dried and sieved, to obtain the title compound as a free base.

Alternative Route to Compound 1 (the Compound of the Invention): Step 1:

4-(Hydroxymethyl)phenylboronic acid (1.1 eq.) was added to a solution of cyclopropanecarboxylic acid (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amide in 1,4-dioxane/water (4:1). K₂CO₃(2 eq.) and PdCl₂dppf (0.03 eq.) were added to the solution. The resulting mixture was then heated in an oil bath at 90° C. for 16 h under N₂. Water was added and the solution was extracted with ethyl acetate. The organic layers were dried over anhyd. MgSO₄and evaporated in vacuo. The resulting mixture was used without further purification.

Step 2:

To a solution of cyclopropanecarboxylic acid [5-(4-hydroxymethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amide (1.0 eq) in chloroform was slowly added phosphorus tribromide (1.0 equiv.). The reaction mixture was stirred at room temperature for 20 hours, quenched with ice and water (20 mL) and extracted with dichloromethane. The organic layer was dried over anhyd. MgSO₄, filtered and concentrated to dryness. The resulting white residue was triturated in dichloromethane/diethyl ether 2:1 to afford the expected product as a white solid.

Step 3:

Cyclopropanecarboxylic acid [5-(4-bromomethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amide (1 eq) and DIPEA (2 eq) were dissolved in DCM/MeOH (5:1 v:v) under N₂and thiomorpholine 1,1-dioxide (1.1 eq) was added dropwise. The resulting solution was stirred at room temperature for 16 h. After this time, the reaction was complete. The solvent was evaporated. The compound was dissolved in DCM, washed with water and dried over anhyd. MgSO₄. Organic layers were filtered and evaporated. The final compound was isolated by column chromatography using EtOAc to afford the desired product.

…………………….

PATENT

WO 2015117981

Novel salts and pharmaceutical compositions thereof for the treatment of inflammatory disorders

Also claims a method for preparing filgotinib hydrochloride trihydrate. The present filing forms a pair with this week’s filing, WO2015117980, claiming a tablet composition comprising filgotinib hydrochloride.

The compound cyclopropanecarboxylic acid {5-[4-(l,l-dioxo-thiomorpholin-4-ylmethyl)-phenyl]-[l,2,4]triazolo[l,5-a]pyridin-2-yl -amide (Compound 1), which has the chemical structure:

is disclosed in our earlier application WO 2010/149769 (Menet C. J., 2010) as being an inhibitor of JAK and as being useful in the treatment of inflammatory conditions, autoimmune diseases, proliferative diseases, allergy, transplant rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IL6 or interferons. Hereafter this compound is named Compound 1. The data presented in WO 2010/149769 demonstrate that despite similar in vitro activities, Compound 1 has unexpectedly high in vivo potency compared with structurally similar compounds.

Example 1. Preparation of Compound 1

1.1. Route 1

1.1.1. 4-[4-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzyl]-thiomorpholine-l,l-dioxide

[00205] 2-(4-Bromomethyl-phenyl)-4,4,5,5-tetramethyl-[l,3,2]dioxaborolane (1 eq) and DIPEA (2 eq) are dissolved in DCM/MeOH (5:1 v:v) under N₂ and thiomorpholine 1,1 -dioxide (2 eq) is added portionwise. The resulting solution is stirred at room temperature for 16h. After this time, the reaction is complete. The solvent is evaporated. The compound is extracted with EtOAc and water, washed with brine and dried over anhydrous MgSO i. Organic layers are filtered and evaporated. The final compound is isolated without further purification.

1.1.2. Cyclopropanecarboxylic acid (5-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-yl)-amide

1.1.2.1. Step i): l-(6-Bromo-pyridin-2-yl)-3-carboethoxy-thiourea

[00206] To a solution of 2-amino-6-bromopyridine (1) (253.8 g, 1.467 mol) in DCM (2.5 L) cooled to 5°C is added ethoxycarbonyl isothiocyanate (173.0 mL, 1.467 mol) dropwise over 15 min. The reaction

mixture is then allowed to warm to room temp. (20 °C) and stirred for 16 h. Evaporation in vacuo gives a solid which may be collected by filtration, thoroughly washed with petrol (3 x 600 niL) and air-dried to afford the desired product. The thiourea may be used as such for the next step without any purification. ^lH (400 MHz, CDC1₃) δ 12.03 (1H, br s), 8.81 (1H, d), 8.15 (1H, br s), 7.60 (1H, t), 7.32 (1H, dd), 4.31 (2H, q), 1.35 (3H, t).

1.1.2.2. Step ii): 5-Bromo-[l,2,4]triazolo[l,5-a]pyridin-2-ylamine

[00207] To a suspension of hydroxylamine hydrochloride (101.8 g, 1.465 mol) in EtOH/MeOH (1 : 1, 900 mL) is added NN-diisopropylethylamine (145.3 mL, 0.879 mol) and the mixture is stirred at room temp. (20 °C) for 1 h. l-(6-Bromo-pyridin-2-yl)-3-carboethoxy-thiourea (2) (89.0 g, 0.293 mol) is then added and the mixture slowly heated to reflux (Note: bleach scrubber is required to quench H₂S evolved). After 3h at reflux, the mixture is allowed to cool and filtered to collect the precipitated solid. Further product is collected by evaporation in vacuo of the filtrate, addition of H₂0 (250 mL) and filtration. The combined solids are washed successively with H₂0 (250 mL), EtOH/MeOH (1 : 1, 250 mL) and Et₂0 (250 mL) then dried in vacuo to afford the triazolopyridine derivative (3) as a solid. The compound may be used as such for the next step without any purification. ^lH (400 MHz, DMSO-i¼) δ 7.43-7.34 (2H, m, 2 x aromatic-H), 7.24 (1H, dd, J 6.8 and 1.8 Hz, aromatic-H), 6.30 (2H, br, NH₂); m/z 213/215 (1 : 1, M+H⁺, 100%).

1.1.2.3. Step Hi): Cyclopropanecarboxylic acid (5-bromo-[l ,2,4]triazolo[l ,5-a]pyridin-2-yl)-amide

[00208] To a solution of the 2-amino-triazolopyridine obtained in the previous step (7.10 g, 33.3 mmol) in dry MeCN (150 mL) at 5°C is added Et₃N (11.6 mL, 83.3 mmol) followed by cyclopropanecarbonyl chloride (83.3 mmol). The reaction mixture is then allowed to warm to ambient temperature and stirred until all starting material is consumed. If required, further Et₃N (4.64 mL, 33.3 mmol) and cyclopropanecarbonyl chloride (33.3 mmol) is added to ensure complete reaction. Following solvent evaporation in vacuo the resultant residue is treated with 7 N methanolic ammonia solution (50 mL) and stirred at ambient temp, (for 1-16 h) to hydro lyse any bis-acylated product. Product isolation is made by removal of volatiles in vacuo followed by trituration with Et₂0 (50 mL). The solids are collected by filtration, washed with H₂0 (2x50mL), acetone (50 mL) and Et₂0 (50 mL), then dried in vacuo to give the desired compound.

1.1.3. Compound 1

[00209] 4-[4-(4,4,5,5-Tetramethyl-[l ,3,2]dioxaborolan-2-yl)-benzyl] hiomoφholine , l -dioxide (l . l eq.) is added to a solution of cyclopropanecarboxylic acid (5-bromo-[l ,2,4]triazolo[l ,5-a]pyridin-2-yl)-amide in 1 ,4-dioxane/water (4: 1). K₂CO₃ (2 eq.) and PdC^dppf (0.03 eq.) are added to the solution. The resulting mixture is then heated in an oil bath at 90°C for 16h under N₂. Water is added and the solution is extracted with ethyl acetate. The organic layers are dried over anhydrous MgS0₄ and evaporated in vacuo.

[00210] The final compound is obtained after purification by flash chromatography.

[00211] Alternatively, after completion of the reaction, a palladium scavenger such as 1 ,2-bis(diphenylphosphino)ethane, is added, the reaction mixture is allowed to cool down and a filtration is performed. The filter cake is reslurried in a suitable solvent (e.g. acetone), the solid is separated by filtration, washed with more acetone, and dried. The resulting solid is resuspended in water, aqueous HC1 is added, and after stirring at room temperature, the resulting solution is filtered on celite (Celpure P300). Aqueous NaOH is then added to the filtrate, and the resulting suspension is stirred at room temperature, the solid is separated by filtration, washed with water and dried by suction. Finally the cake is re-solubilised in a mixture of THF/H₂0, treated with a palladium scavenger (e.g. SMOPEX 234) at 50°C, the suspension is filtered, the organic solvents are removed by evaporation, and the resulting slurry is washed with water and methanol, dried and sieved, to obtain the desired compound as a free base.

1.2. Route 2

1.2.1. Step 1: cyclopropanecarboxylic acid [5-(4-hydroxymethyl-phenyl)-[l,2, 4]triazolo[l, 5- a] pyridin-2-yl] -amide

[00212] 4-(Hydroxymethyl)phenylboronic acid (l . l eq.) is added to a solution of cyclopropanecarboxylic acid (5-bromo-[l ,2,4]triazolo[l ,5-a]pyridin-2-yl)-amide in 1 ,4-dioxane/water

(4:1). K2CO3 (2 eq.) and PdC^dppf (0.03 eq.) are added to the solution. The resulting mixture is then heated in an oil bath at 90°C for 16h under N₂. Water is added and the solution is extracted with ethyl acetate. The organic layers are dried over anhydrous MgS0₄ and evaporated in vacuo. The resulting mixture is used without further purification.

1.2.2. Step 2: Cyclopropanecarboxylic acid [5-(4-bromomethyl-phenyl)-[l,2,4]triazolo[l,5- a Jpyridin-2-ylJ -amide

[00213] To a solution of cyclopropanecarboxylic acid [5-(4-hydroxymethyl-phenyl)-[l,2,4]triazolo[l,5-a]pyridin-2-yl] -amide (1.0 eq) in chloroform is slowly added phosphorus tribromide (1.0 eq.). The reaction mixture is stirred at room temperature for 20 h, quenched with ice and water (20 mL) and extracted with dichloromethane. The organic layer is dried over anhydrous MgSO i, filtered and concentrated to dryness. The resulting white residue is triturated in dichloromethane/diethyl ether 2:1 to afford the desired product.

1.2.3. Step 3:

[00214] Cyclopropanecarboxylic acid [5-(4-bromomethyl-phenyl)-[l,2,4]triazolo[l,5-a]pyridin-2-yl]-amide (l eq) and DIPEA (2 eq) are dissolved in DCM/MeOH (5: 1 v:v) under N₂ and thiomorpho line 1,1-dioxide (1.1 eq) is added dropwise. The resulting solution is stirred at room temperature for 16h. After this time, the reaction is complete. The solvent is evaporated. The compound is dissolved in DCM, washed with water and dried over anhydrous MgSO i. Organic layers are filtered and evaporated. The final compound is isolated by column chromatography using EtOAc to afford the desired product.

…………………

PATENT

http://www.google.co.in/patents/WO2013189771A1?cl=en

Example 1. Synthesis of the compounds

1.1. Route 1

1.1.1. Synthesis of 5-Bromo-[l,2,4]triazolo[l,5-a]pyridin-2-ylamine (Intermediate 3)

led to 5 °C was added ethoxycarbonyl isothiocyanate (173.0 mL, 1.467 mol) dropwise over 15 min. The reaction mixture was then allowed to warm to room temp. (20 °C) and stirred for 16 h. Evaporation in vacuo gave a solid which was collected by filtration, thoroughly washed with petrol (3×600 mL) and air-dried to afford (2). The thiourea was used as such in the next step without any purification.

[00157] ^lH (400 MHz, CDC1₃) δ 12.03 (IH, br s, NH), 8.81 (IH, d, J 7.8 Hz, H-3), 8.15 (IH, br s, NH), 7.60 (IH, t, J 8.0 Hz, H-4), 7.32 (IH, dd, J 7.7 and 0.6 Hz, H-5), 4.31 (2H, q, J 7.1 Hz, CH₂), 1.35 (3H, t, J 7.1 Hz, CH₃).

1.1.1.2. 5-Bromo-f 1,2, 4]triazolo[ 1 ,5-a] pyridin-2-ylamine (3)

[00158] To a suspension of hydroxylamine hydrochloride (101.8 g, 1.465 mol) in EtOH/MeOH (1 : 1, 900 mL) was added NN-diisopropylethylamine (145.3 mL, 0.879 mol) and the mixture was stirred at room temp. (20 °C) for 1 h. l-(6-Bromo-pyridin-2-yl)-3-carboethoxy-thiourea (2) (89.0 g, 0.293 mol) was then added and the mixture slowly heated to reflux (Note: bleach scrubber was required to quench H₂S evolved). After 3 h at reflux, the mixture was allowed to cool and filtered to collect the precipitated solid. Further product was collected by evaporation in vacuo of the filtrate, addition of H₂0 (250 mL) and filtration. The combined solids were washed successively with H₂0 (250 mL), EtOH/MeOH (1 : 1, 250 mL) and Et₂0 (250 mL) then dried in vacuo to afford the triazolopyridine derivative (3) as a solid. The compound was used as such in the next step without any purification.

[00159] ^lH (400 MHz, DMSO-i¼) δ 7.43-7.34 (2H, m, 2 x aromatic-H), 7.24 (1H, dd, J 6.8 and 1.8 Hz, aromatic-H), 6.30 (2H, br, NH₂); m/z 213/215 (1 : 1, M+H⁺, 100%).

1.1.2. Synthesis of 4-[ 4-(4, 4, 5, 5-Tetramethyl-f 1, 3,2] ‘ dioxaborolan-2-yl) -benzyl] ‘- thiomor holine- 1, 1 -dioxide (Intermediate 4)

[00160] 2-(4-Bromomethyl-phenyl)-4,4,5,5-tetramethyl-[l,3,2]dioxaborolane (1 eq) and DIPEA (2 eq) were dissolved in DCM/MeOH (5:1 v:v) under N₂ and thiomorpholine 1,1 -dioxide (2 eq) was added portion wise. The resulting solution was stirred at room temperature for 16h. After this time, the reaction was complete. The solvent was evaporated. The compound was extracted with EtOAc and water, washed with brine and dried over anhydrous MgSO i. Organic layers were filtered and evaporated. The final compound was isolated without further purification.

1.1.3. Synthesis of 5-[4-(l, l-Dioxothiomorpholin-4-ylmethyl)-phenyl]-[l,2,4]triazolo[l,5- a ridin-2-ylamine (Formula I)

[00161] 4-[4-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzyl]-thiomorpholine-l,l-dioxide (l .leq.) was added to a solution of 5-bromo-[l,2,4]triazolo[l,5-a]pyrid in-2-ylamine (4: 1). K₂CO₃ (2 eq.) and PdC^dppf (0.03 eq.) were added to the solution. The resulting mixture was then heated in an oil bath at 90°C for 16h under N₂. Water was added and the solution was extracted with ethyl acetate. The organic layers were dried over anhydrous MgSC>4 and evaporated in vacuo. The final compound was obtained after purification by flash chromatography.

[00162] ^lH (400 MHz, CDC1₃) δ 7.94-7.92 (d, 2H), 7.52-7.48 (m, 3H), 7.37-7.34 (m, 1H), 7.02-7.00 (m, 1H), 6.00 (d, 2H), 3.76 (d, 2H), 3.15-3.13 (m, 4H), 2.93-2.91 (m, 4H).

[00163] m/z 358.2 (M+H⁺, 100%). 1.2. Route 2

1.2.1. Cyclopropanecarboxylic acid {5-[4-(l, l-dioxo-thiomorpholin-4-ylmethyl)-phenylJ- [l,2,4]triazolo[l,5-a]pyridin-2-yl}-amide (Formula II)

[00164] The compound according to Formula II may be synthesized according to the procedure described in WO 2010/149769.

1.2.2. Synthesis of 5-[4-(l, l-Dioxothiomorpholin-4-ylmethyl)-phenyl]-[l,2,4]triazolo[l,5- aJpyridin-2-ylamine (Formula I)

[00165] The compound according to Formula I can also be produced by hydrolysis of the compound accor ing to Formula II:

[00166] Hydrochloric acid 30% aq (12.06 kg; 3.9 rel. volumes) was added to a slurry of the compound according to Formula II (3.45 kg; 1.0 equiv.) in demineralized water (10.0 kg; 3.0 rel. volumes). Subsequently, a line rinse was performed with demineralized water (3.4 kg; 1.0 rel. volumes). The reaction mixture was heated to 80±5°C for 14.5 h. After completion of the reaction (conversion > 99%>), the reaction mixture was cooled to 20±5°C. The reaction mixture was diluted with demineralized water (6.8 kg; 2.0 rel. volumes) and sodium hydroxide 33%> aq (9.52 kg; 3.7 rel volumes) was dosed at such a rate that the temperature of the reactor contents remained below 35°C. An additional amount of sodium hydroxide 33%> aq (2.55 kg; 1.0 rel. volumes) was needed to get the pH > 10. The product was filtered off, washed twice with demineralized water (1.5 rel. volumes) and dried under vacuum for 1 h, thus yielding the crude compound according to Formula I.

[00167] The crude compound according to Formula I (5.70 kg) was re-slurried in demineralized water (23.0 kg; 8.5 rel. volumes). Hydrochloric acid 30%> aq (1.65 kg; 0.7 rel. volumes) and demineralized water (4.3 kg; 1.6 rel. volumes) were added and the reaction mixture was stirred at 20±5°C for 45 min. As the compound according to Formula I was not dissolved completely, the reaction mixture was stirred at 45±5°C for 1 h. The reaction mixture was filtered and the residue was washed with demineralized water (2.0 kg 0.75 rel. volumes). Sodium hydroxide 33%> aq (1.12 kg; 0.6 rel volumes) was added to the filtrate. An additional amount of sodium hydroxide 33%> aq (1.01 kg) was needed to get the pH > 10. The resulting reaction mixture was stirred at 20±5°C for about 3 h. The product was filtered off, washed twice with demineralized water (4.1 kg; 1.5 rel. volumes), and twice with methyl tert-butyl ether (MTBE; 3.0 kg; 1.5 rel. volumes) and dried under vacuum for 15.5 h on the filter. The product was further dried in a vacuum oven at 40±5°C for 202 h, thus affording the desired compound according to Formula I.

Update

WO-2016179207

Scheme 1: General S nthesis of Compounds of Formula I or A

Formula A

Scheme 7.

(16) (17) (18)

(18a): R^3a=R^3b=R^2a=R (18b): R^3a=R^3b=D; R^2a 18c): R^3a=R^3b=H; R^2a

References

Namour, Florence; Diderichsen, Paul Matthias; Cox, Eugène; Vayssière, Béatrice; Van der Aa, Annegret; Tasset, Chantal; Van’t Klooster, Gerben (2015-02-14). “Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Modeling of Filgotinib (GLPG0634), a Selective JAK1 Inhibitor, in Support of Phase IIB Dose Selection”. Clin Pharmacokinet. Epub ahead of print.doi:10.1007/s40262-015-0240-z.
Van Rompaey, L; Galien, R; Van der Aar, E; Clement-Lacroix, P; Van der Aar, E; Nelles, L; Smets, B; Lepescheux, L; Cristophe, T; Conrath, K; Vandeghinste, N; Vayssiere, B; De Vos, S; Fletcher, S; Brys, R; Van’t Klooster, G; Feyen, J; Menet, C (2013-10-01). “Preclinical characterization of GLPG0634, a selective inhibitor of JAK1 for the treatment of inflammatory diseases”. J Immunol. 191(7). doi:10.4049/jimmunol.1201348.
http://acrabstracts.org/abstracts/phase-1-and-phase-2-data-confirm-that-glpg0634-a-selective-jak1-inhibitor-has-a-low-potential-for-drug-drug-interactions/
“Galapagos’ GLPG0634 shows excellent efficacy and safety in rheumatoid arthritis Phase II study” (PDF) (Press release). Retrieved 2015-02-26.
“Galapagos reports that the last patient in DARWIN 1 has completed 12 weeks of treatment” (PDF) (Press release). Retrieved 2015-02-26.
“Galapagos completes recruitment for Darwin 1 study with GLPG0634 (filgotinib) in RA”. EuroInvestor. Retrieved 2015-02-26.
NASDAQ OMX Corporate Solutions. “Galapagos completes recruitment for Darwin 2 monotherapy study with GLPG0634 (filgotinib) in RA”. Yahoo Finance. Retrieved 2015-02-26.

US8551980	Nov 17, 2010	Oct 8, 2013	Bayer Intellectual Property Gmbh	Substituted triazolopyridines
US8796457	Jun 25, 2010	Aug 5, 2014	Galapagos Nv	Compound useful for the treatment of degenerative and inflammatory diseases

Filgotinib
Systematic (IUPAC) name

N-[5-[4-[(1,1-dioxo-1,4-thiazinan-4-yl)methyl]phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide
Clinical data
Routes of administration	Oral
Pharmacokinetic data
Biological half-life	6 hours^[1]
Identifiers
CAS Registry Number	1206161-97-8
ATC code	L01XE18
IUPHAR/BPS	7913
ChemSpider	28189566
UNII	3XVL385Q0M
ChEMBL	CHEMBL3301607
Chemical data
Formula	C₂₁H₂₃N₅O₃S
Molecular mass	425.50402 g/mol

Patent	Submitted	Granted
Compound useful for the treatment of degenerative and inflammatory diseases [US8088764]	2010-12-30	2012-01-03
NOVEL COMPOUNDS USEFUL FOR THE TREATMENT OF DEGENERATIVE AND INFLAMMATORY DISEASES [US2011190260]	2011-08-04

सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये। औकात बस इतनी देना, कि औरों का भला हो जाये।

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09b37-misc2b027 LIONEL MY SON

He was only in first standard in school when I was hit by a deadly one in a million spine stroke called acute transverse mylitis, it made me 90% paralysed and bound to a wheel chair, Now I keep him as my source of inspiration and helping millions, thanks to millions of my readers who keep me going and help me to keep my son happy

सुकून उतना ही देना प्रभू, जितने से

जिंदगी चल जाये।

औकात बस इतनी देना,

कि औरों का भला हो जाये।

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL

/////////Galapagos, GLPG0634, Filgotinib, PHASE 2, orphan drug designation, PHASE 3, Crohn’s disease, Rheumatoid arthritis, Ulceraticolitis

ve SMILES code: O=C(C1CC1)NC2=NN3C(C4=CC=C(CN5CCS(CC5)(=O)=O)C=C4)=CC=CC3=N2

Orilotimod

August 18, 2015 4:34 am / Leave a comment

ChemSpider 2D Image | Orilotimod | C16H19N3O5

Orilotimod

(2R)-2-amino-5-{[(1R)-1-carboxy-2-(1H-indol-3-yl)ethyl]amino}-5-oxopentanoic acid

186087-26-3

Apo805,UNII-Q66Z43C5XM; Thymodepressin; Orilotimod [USAN]; AC1OIBUF;

C₁₆H₁₉N₃O₅
MW 333.339

Apotex Technologies Inc. INNOVATOR

2D chemical structure of 960155-19-5

Orilotimod potassium,

APO805K1

D-Tryptophan, D-gamma-glutamyl-, potassium salt (1:1), CAS 960155-19-5

The drug, orilotimod, was originally developed and launched by Immunotech Developments; however, ApoPharma (a subsidiary of Apotex) is developing orilotimod, presumably a topical formulation, for the treatment of psoriasis. In August 2015, the ApoPharma’s drug was reported to be in phase 2 clinical development.

Thymodepressin is the free diacid having Chemical Abstracts Service (CAS) Registry Number@ of 186087-26-3. U.S. Pat. No. 5,736,519 discloses H-D-iGlu-D-Trp-OH and a process for its preparation wherein it is purified by ion exchange chromatography. It is an immunosuppressant and selectively inhibits proliferation of hemopoietic precursor cells and stimulates granulocyte and lymphocyte apoptosis (Sapuntsova, S. G., et al. (May 2002), Bulletin of Experimental Biology and Medicine, 133(5), 488-490).

Thymodepressin is currently being sold in Russia as the disodium salt of D-isoglutamyl-D-tryptophan in liquid formulation for injection and intranasal administration for the treatment of psoriasis and atopic dermatitis. The solid form of the disodium salt of D-isoglutamyl-D-tryptophan is an amorphous powder which is hygroscopic and very difficult to handle. The disodium salt of D-isoglutamyl-D-tryptophan has the molecular formula C16H17N3Na2O5 and is reported in Kashirin, D. M., et al. (2000), Pharmaceutical Chemistry Journal, 34(11), 619-622.

PAPENT

BEAWARE EXAMPLE WITH AN ESTER GP

http://www.google.im/patents/WO2012129671A1?cl=en

Preparation of H-D-Glu( -Trp-OH)-0-Et hydrochloride salt (Apo836.HCI)

A. Preparation of Boc-D-Glu(D-Trp-0-Bzl)-0-Et

Proceeding in a similar manner as described under Example 3A, Boc-D- Glu(D-Trp-0-Bzl)-0-Et was prepared in 87% yield.¹H NMR ( DMSO-D_6l 400 MHz) δ ppm: 10.87, (s, 1 H), 8.35 (d, J = 7.2 Hz, 1 H), 7.48 (d, J = 7.8 Hz, 1 H), 7.35 (d, J = 7.9 Hz, 1 H), 7.29-7.33 (m, 3H), 7.23 (d, J = 7.7 Hz, 1H), 7.09-7.22 (m, 3H), 7.08 (t, J = 7.6 Hz, 1H), 6.98 (t, J = 7,7 Hz, 1 H), 4.98 – 5.06 (m, 2H), 4.55 (apparent q, J = 7.3 Hz, 1 H), 4.04 – 4.11 (m, 2H), 3.90 – 3.95 (m, 1 H), 3.04 – 3.19 (m, 2H), 2.18 – 2.23 (m, 2H), 1.84 – 1.89 (m, 1 H), 1.70 – 1.77 (m, 1 H), 1.38 (s, 9H), 1.16 (t, J = 7.1 Hz, 3H); MS-ESI (m/z): 552 [ +1]⁺.

B. Preparation of Boc-D-Glu(D-Trp-OH)-0-Et

Proceeding in a similar manner as described under Example 3B, Boc-D-

Glu(D-Trp-OH)-0-Et was prepared in quantitative yield. ¹H NMR ( DMSO-D₆, 400 MHz) δ ppm: 12.62 (br. 1H), 10.82, (s, 1 H), 8.10 (d, J = 7.7 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 7.5 Hz, 1 H), 7.12 (s, 1 H), 7.06 (t, J = 7.3 Hz, 1 H), 6.98 (t, J = 7.5 Hz, 1 H)„ 4.45 (apparent q, J = 7.7 Hz, 1 H), 4.03 – 4.11 (m, 2H), 3.87 – 3.92 (m, 1 H), 3.13 – 3.18 (m, 1H), 2.96 – 3.03 (m,

1 H), 2.13 – 2.20 (m, 2H), 1.82 – 1.88 (m, 1H), 1.69-1.75 (m, 1 H), 1.38 (s, 9H>, 1.17 (t, J = 7.1 Hz, 3H); MS-ESI (m/z): 462 [M+1]⁺.

C. Preparation of H-D-Glu(D-Trp-OH)-0-Et.HCI (Apo836 HCI)

To an ice-cooled solution of Boc-D-Glu(D-Trp-OH)-0-Et (4.55 g, 9.8 mmol) obtained in Section B above in dichloromethane (100 mL) was bubbled HCI gas for 15 min. The reaction mixture was concentrated under vacuum by rotary evaporation to give H-D-Glu(D-Trp-OH)-0-Et hydrochloride (Apo836.HCI, 4.0 g) as a foamy solid. ¹ H NMR ( DMSO-D₆, 400 MHz) δ ppm: 12.68 (br. s, 1 H), 10.90, (s, 1H), 8.66 (br, s, 3H), 8.33 (d, J = 7.8 Hz, 1 H), 7.52 (d, J = 7.8 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 7.12 (d, J = 1.5 Hz, 1H), 7.06 (t, J = 7.2 Hz, 1 H), 6.98 (t, J = 7.2 Hz, 1 H), 4.47 (apparent q, J = 4.8 Hz, 1 H), 4.13 – 4.19 (m, 2H), 3.90 (br, 1 H), 3.16 – 3.20 (m, 1H), 2.98 – 3.04 (m, 1 H), 2.29 – 2.33 (m, 2H), 1.94 – 1.98

(m, 2H), 1.20 (t, J = 7.1 Hz, 3H); MS-ESI (m/z): 362 [M+1]⁺ (free base).

……………………..

US 20150225341

file:///H:/ORILOTIMODUS20150225341A1.pdf

Novel crystalline and amorphous salts of thymodepressin (orilotimod), particularly potassium salt, useful for treating psoriasis and atopic dermatitis. Also claims salt exchange method for preparing thymodepressin salts.

hymodepressin is the free diacid having Chemical Abstracts Service (CAS) Registry Number@ of 186087-26-3. U.S. Pat. No. 5,736,519 discloses H-D-iGlu-D-Trp-OH and a process for its preparation wherein it is purified by ion exchange chromatography. It is an immunosuppressant and selectively inhibits proliferation of hemopoietic precursor cells and stimulates granulocyte and lymphocyte apoptosis (Sapuntsova, S. G., et al. (May 2002), Bulletin of Experimental Biology and Medicine, 133(5), 488-490).

Thymodepressin is currently being sold in Russia as the disodium salt of D-isoglutamyl-D-tryptophan in liquid formulation for injection and intranasal administration for the treatment of psoriasis and atopic dermatitis. The solid form of the disodium salt of D-isoglutamyl-D-tryptophan is an amorphous powder which is hygroscopic and very difficult to handle. The disodium salt of D-isoglutamyl-D-tryptophan has the molecular formula C16H17N3Na2O5 and which is reported in Kashirin, D. M., et al. (2000), Pharmaceutical Chemistry Journal, 34(11), 619-622.

Through investigations in our laboratory, we have determined that the freeze-dried disodium salt of D-isoglutamyl-D-tryptophan is extremely hygroscopic turning into a gel in a matter of minutes in air and cannot easily be handled.

A powdery or amorphous form of a compound, intended for pharmaceutical use may give rise to manufacturing problems due to bulk density issues, hygroscopicity and variable water content that cannot be corrected by vacuum drying. D-isoglutamyl-D-tryptophan is a dipeptide and the drying of an amorphous form at elevated temperature, for example, 80-100° C. under vacuum is not recommended. Thus, there are serious difficulties experienced during the purification of the disodium salt of D-isoglutamyl-D-tryptophan and obtaining the pure disodium salt on a manufacturing scale. Further, there is no published procedure for its preparation.

The monosodium salt of D-isoglutamyl-D-tryptophan is identified by the CAS Registry System and is listed in the CAS REGISTRYSM File with a CAS Registry Number@ of 863988-88-9. However, there are no references citing the substance and thus no publication of its identity, its physical and/or chemical properties, its characterization or a procedure for its preparation. Freeze-dried powders of mono sodium and disodium salts of peptide drugs may not have controllable powder bulk density ranges for formulation. They may require significant investment in freeze-dried dispersion technology.

EXAMPLES

Example 1

Preparation of potassium salt of D-isoglutamyl-D-tryptophan (1:1) from D-isoglutamyl-D-tryptophan and potassium hydroxide

In a 100-mL round bottom flask equipped with a magnetic stir bar was placed 5 mL of potassium hydroxide solution (0.5 N). The solution was cooled to 0° C. in an ice-water bath, and solid H-D-iGlu-D-Trp-OH (1.00 g, 3 mmol) was added. The mixture was stirred while the pH of the solution was adjusted to ca. 6.0 by adding a few drops of potassium hydroxide solution (0.5 N). The solution was filtered to remove any solid particulates. The filtrate was evaporated to dryness at a bath temperature of about 30° C. to afford a solid. After drying under vacuum at room temperature for overnight, the salt was obtained in quantitative yield, with a HPLC purity (peak area percent) of 98.3%. HPLC method; Column: XTerra MS C18; 5 μm, 4.6×250 mm; Mobile phase: A=the aqueous phase: 4 mM Tris, 2 mM EDTA, pH 7.4; B=the organic phase: CH3CN; gradient: B %: 0 min. 5%, 15 min. 55%, 30 min. 55%, 32 min. 5%, 35 min. 5%; Flow rate: 1 mL/min; injection volume: 5 μL; λ: 222, 254, 282, 450 nm; retention time of the product: 6.41 min. The XRPD pattern of this crystalline material is shown in FIG. 1A; the water content by Karl-Fischer test is 0.7%; UV (water, c=23.8 ρM, λmax nm): 221 (ε 33270), 280 (ε 5417); MS (m/z): 372.0 [M]+, 334.2 [C16H20N3O5]+, 187.9 (100%). The FT-IR (KBr) spectrum is shown in FIG. 1B.

Example 2

A. Preparation of mono potassium salt of D-isoglutamyl-D-tryptophan (1:1) from the mono ammonium salt of D-isoglutamyl-D-tryptophan (1:1)

A solution of H-D-iGlu-D-Trp-OH, mono ammonium salt (1:1), (1.66 g, 4.05 mmol) and potassium hydroxide (253 mg, 4.50 mmol) in water (20 mL) was stirred at room temperature for 15 min. The pH of the solution was about 9. The reaction mixture was evaporated under reduced pressure to a volume of about 1 mL. After cooling to room temperature, isopropanol was added until a solid precipitated out. The resulting suspension was stirred at room temperature for 15 min, then filtered. The solid was washed with isopropanol (2×20 mL) and ethyl acetate (20 mL), then dried under vacuum in an oven at 42° C. overnight. An off white solid was obtained (1.49 g, 99% yield). The water content by Karl-Fischer test is 2.5%. Analytical data (XRPD pattern, FT-IR and MS spectra) are similar to those described in Example 1.

B. Preparation of amorphous form of potassium salt of D-isoglutamyl-D-tryptophan (1:1) from the mono ammonium salt of D-isoglutamyl-D-tryptophan (1:1)

A solution of H-D-iGlu-D-Trp-OH, mono ammonium salt (1:1), (517 mg, 1.40 mmol) and potassium hydroxide (82 mg, 1.46 mmol) in water (10 mL) was stirred at room temperature for 30 minutes. The resulting mixture was freeze-dried overnight. An off white solid was obtained in quantitative yield. The XRPD pattern spectrum confirmed that this material is amorphous.

1H NMR (D2O) δ: 7.69 (d, J=7.9 Hz, 1H), 7.48 (d, J=8.2 Hz, 1H), 7.23 (t, J=7.6 Hz, 1H), 7.22 (s, 1H), 7.16 (t, J=7.4 Hz, 1H), 4.59 (dd, J=8.7, 4.8 Hz, 1H), 3.51 (dd, J=6.8, 5.8 Hz, 1H), 3.38 (dd, J=14.8, 4.8 Hz, 1H), 3.11 (dd, J=14.8, 8.8 Hz, 1H), 2.20-2.49 (m, 2H) and 1.85-1.94 (m, 2H);

13C NMR (D2O) δ: 181.4, 177.0, 176.6, 138.8, 129.9, 126.9, 124.5, 121.9, 121.4, 114.5, 113.2, 58.6, 57.0, 34.6 (CH2), 30.2 (CH2) and 29.3 (CH2);

the water content by Karl-Fischer test is 5.4%;

the FT-IR (KBr) spectrum is shown in FIG. 1C;

MS (m/z): 371.7 [M]+, 334.2 [C16H20N3O5]+, 187.9 (100%);

HPLC purity (peak area percent): 99.8%, Retention time: 5.04 min; HPLC conditions: Column Waters Symmetry C18, 3.9×150 mm, 5 μm; Mobile phase: 0.035% HClO4, pH 2/CH3CN, 85/15, isocratic, Flow rate: 1 mL/min; λ: 220, 254, 280 nm.

Patent	Submitted	Granted
GAMMA-GLUTAMYL AND BETA-ASPARTYL CONTAINING IMMUNOMODULATOR COMPOUNDS AND METHODS THEREWITH [EP1042286]	2000-10-11	2010-08-25
CRYSTALLINE D-ISOGLUTAMYL-D-TRYPTOPHAN AND THE MONO AMMONIUM SALT OF D-ISOGLUTAMYL-D-TRYPTOPHAN [US8119606]	2010-01-21	2012-02-21
Pharmaceutically Acceptable Salts of Thymodepressin and Processes for their Manufacture [US8138221]	2010-03-04	2012-03-20
CRYSTALLINE FORMS OF THE MONO-SODIUM SALT OF D-ISOGLUTAMYL-D-TRYPTOPHAN [US8207217]	2010-02-04	2012-06-26

////////Orilotimod, PHASE 2, thymodepressin, APO 805K1

C1=CC=C2C(=C1)C(=CN2)CC(C(=O)O)NC(=O)CCC(C(=O)O)N

SD-809, Deutetrabenazine

August 15, 2015 6:25 am / 1 Comment on SD-809, Deutetrabenazine

SD-809, Deutetrabenazine

Tetrabenazine-d₆

(3RS,11Brs)-9,10-di((2H3)methoxy)-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydro-2H-benzo(a)quinolizin-2-one

2H-Benzo[a]quinolizin-2-one, 1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d₃)-3-(2-methylpropyl)-, (3R,11bR)-rel–

2H-Benzo(a)quinolizin-2-one, 1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d3)-3-(2-methylpropyl)-, (3R,11bR)-rel-

(RR,SS)-1,3,4,6,7,11b-Hexahydro-9,10-di(methoxy-d₃)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one

(3RS,11Brs)-9,10-di((2H3)methoxy)-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydro-2H-benzo(a)quinolizin-2-one
Treatment of Chorea Associated with Huntington Disease

MF C19-H21-D6-N-O3

C19-H27-N-O3

Molecular Weight, 323.4629

CAS 1392826-25-3

UNII P341G6W9NB

Chemistry Review(s) (PDF) fda approved 2017

Deutetrabenazine

TEVA

Image result for deutetrabenazine

LINK……………https://newdrugapprovals.org/2015/08/15/sd-809-deutetrabenazine-nda-submitted-by-teva/

Austedo		FDA 4/3/2017	For the treatment of chorea associated with Huntington’s disease Drug Trials Snapshot Chemistry Review(s) (PDF)

SD-809 was granted Orphan Drug Designation for the treatment of HD by the FDA in November 2014 and became part of Teva’s CNS portfolio with the acquisition of Auspex Pharmaceuticals in May 2015.

Teva announced that the New Drug Application (NDA) for SD-809 (deutetrabenazine) has been accepted by the U.S. Food and Drug Administration (FDA) for the treatment of chorea associated with Huntington disease (HD), a rare and fatal neurodegenerative disorder caused by the progressive breakdown of nerve cells in the brain that affects about five to seven people per 100,000 in western countries, according to the World Health Organization.

(3RS,11Brs)-9,10-di((2H3)methoxy)-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydro-2H-benzo(a)quinolizin-2-one.png

…………………….

Patent for preparing tetrabenazine

http://www.google.com/patents/WO2012081031A1?cl=en

Chemically tetrabenazine is cis rac -1, 3, 4, 6, 7, 1 lb-hexahydro-9, 10-dimethoxy-3-(2- methylpropyl)-2Hbenzo[a]quinolizin-2-one and it is represented by compound of structural formula I.

Formula 1

The proprietary name of tetrabenazine is Xenazine and is marketed by Biovail Americas. Xenazine is indicated for the treatment of chorea associated with Huntington’s disease. U.S. patent no. 2,830,993 discloses a process for the preparation of tetrabenazine compound of structural formula I wherein 1 -carbethoxymethyl-6, 7-dimethoxy-l , 2, 3, 4- tetrahydroisoquinoline compound of structural formula IV is being reacted with mono- isobutylmalonic acid dimethyl ester compound of structural formula V and paraformaldehyde in methanol solvent to get l-carbethoxymethyl-2 (2, 2-dicarbomethoxy-4-methyl-n-pentyl)-6, 7- dimethoxy-1, 2, 3, 4-tetrahydroisoquinoline compound of structural formula VI. The 1- carbethoxymethyl-2(2,2-dicarbomethoxy-4-methyl-n-pentyl)-6,7-dimethoxy-l ,2,3,4- tetrahydroisoquinoline compound of structural formula VI is subjected to Dieckmann cyclization , hydrolysis and decarboxylation to get tetrabenazine compound of structural formula I, which is recrystallized from di-isopropyl ether solvent.

Formula I

Scheme I

U. S. patent no. 4,678,792 discloses a process for the preparation of 6, 7-dimethoxy-3, 4- dihydroisoquinoline compound of structural formula VII wherein 2-(3, 4-dimethoxyphenyl)- ethylamine compound of structural formula II is being reacted with chloral hydrate at 120°C to get N-formyl-2-(3, 4-dimethoxyphenyl)-ethylamine compound of structural formula III. The N- formyl-2-(3, 4-dimethoxyphenyl)-ethylamine compound of structural formula III is further reacted with polyphosphoric acid to get 6, 7-dimethoxy-3, 4-dihydroisoquinoline compound of structural formula VII. The 6, 7-dimethoxy-3, 4-dihydroisoquinoline compound of structural formula VII is being used as an intermediate for the preparation of tetrabenazine compound of structural formula I.

Formula III

Formula II

Polyphosphoric acid

Formula VII

Scheme II

Bull. Korean Chem. Soc. 2002 Volume (23). No. l , page no. 149 discloses N-formylation of various amines and alcohols with formic acid in toluene.

U.S. patent publication no. 2010/0130480 discloses a process for the preparation of 6, 7- dimethoxy-3, 4-dihydroisoquinoline compound of structural formula VII by reacting 2-(3, 4- dimethoxyphenyl)-ethylamine compound of structural formula II with hexamethylenetetramine in presence of acetic acid or trifluoroacetic acid.

Hexamethylenetetramine

Formula II Formula VII

U.S. patent publication no. 2008/0167337 discloses a process for the preparation of tetrabenazine compound of structural formula I wherein 6, 7-dimethoxy-3, 4-dihydroisoquinoline compound of structural formula VII is reacted with 3-dimethylaminomethyl-5-methyl-hexan-2-one methiodide compound of structural formula VIII to get crude tetrabenazine compound. The crude tetrabenazine compound was purified by employing flash column chromatography technique and

Formula VIII Formula I

The prior-art processes for preparing N-formyl-2-(3, 4-dimethoxyphenyl)-ethylamine compound of structural formula III produces below mentioned compound of structural formula XVII, XVIII, XIX, XX, XXI and XXII as a by-product of the reaction due to the demethylation and formylation of resulting hydroxy compounds.

Formula XX Formula XXI Formula XXII

The compounds of structural formula XVII, XVIII, XIX, XX, XXI and XXII are being carry- forwarded into the further steps of reactions of preparing tetrabenazine compound of structural formula I and therefore there is a need in the art to develop an improved process of preparing 6, 7-dimethoxy-3, 4-dihydroisoquinoline compound of structural formula VII, which obviates the prior-art problems. Accordingly there is provided a process of preparing tetrabenazine compound of structural formula I wherein 6, 7-dimethoxy-3, 4-dihydroisoquinoline compound of structural formula VII is being formed without the formation of above mentioned compounds of structural formula XVII, XVIII, XIX, XX, XXI and XXII.

EXAMPLE: PROCESS FOR THE PREPARATION OF SUBSTANTIAL PURE CRYSTALLINE FORM A OF TETRABENAZINE

Stage A: Process for the preparation of 6, 7-dimethoxy-3, 4-dihydroisoquinoIine

Step 1 : Process for the preparation of N-formyl-2-(3, 4-dimethoxyphenyl)-ethylamine

A solution of 2-(3, 4-dimethoxyphenyl)-ethylamine (500gm) in toluene (2000ml) was added formic acid (150gm) at 25°C, the resulting reaction mixture was diluted with toluene (500ml) and heated up to 45°C. The reaction mixture was maintained at 40-45°C for 5 hours and then the resulting reaction mixture was concentrated under reduced pressure at 50°C to get the title compound

Yield: 570gm

Purity: 99.98% (By HPLC)

Step 2: Process for the preparation of 6, 7-dimethoxy-3, 4-dihydroisoquinoline

A solution of N-formyl-2-(3, 4-dimethoxyphenyl)-ethylamine (250gm) obtained from step 1 in toluene (500ml) and polyphosphoric acid (50gm) was heated at 110°C for 5 hours. The resulting reaction mixture was cooled to 50°C, quenched with water (500ml) and pH of the resulting solution was adjusted to about 8.3 with aqueous solution of sodium hydroxide [sodium hydroxide (690gm) + water (690ml)]. The resulting reaction mass was extracted by ethyl acetate (2 1250ml), dried over anhydrous sodium sulfate (50gm) and concentrated under reduced pressure to get 6, 7-dimethoxy-3, 4-dihydroisoquinoline (190gm).

Yield: 215gm

Purity: 99.67% (By HPLC)

Stage B: Process for the preparation of 3-((dimethylamino) methyi)-5-methylhexan-2-one methiodide

Step 1 : Process for the preparation of 3-((dimethylamino) methyl)-5-methylhexan-2-one Dimethylamine hydrochloride (180gm) and paraformaldehyde (lOOgm) were added to a solution of 5-methylhexan-2-one (900ml) in methanol (1600ml). The resulting reaction mass was heated at reflux for 12 hours, and then the pH was adjusted to about 8.75 with aqueous solution of sodium hydroxide [sodium hydroxide(90gm) + water (900ml)] at 25 °C. The resulting reaction solution was extracted by toluene (2x1234ml). The organic layer was dried over anhydrous sodium sulfate (50gm) and concentrated under reduced pressure to get title compound.

Yield: 900gm

Purity: 99.80% (By HPLC)

Step 2: Process for the preparation of 3-((dimethylamino) methyl)-5-methylhexan-2-one methiodide

Methyl iodide (323gm) was added dropwise to a solution of 3-((dimethylamino) methyl)-5- methylhexan-2-one (195gm) obtained from step 1 , in ethyl acetate (1650ml) at 25-30°C in 30 minutes. The resulting reaction mixture was stirred at 25 °C for 12 hours and then the resulting solids were filtered, washed with water (200ml) and suck-dried to get wet compound (400gm). The wet compound was slurried with water (1000ml) at 25°C for 1 hour and then it was again filtered, washed with water (200ml) and dried at 45-50°C to get title compound

Yield: 300gm

Purity: 99.86% (By HPLC)

Stage C: Preparation of substantial pure crystalline form A of Tetrabenazine

3-((Dimethylamino) methyl)-5-methylhexan-2-one methiodide (80gm) was added to the solution of 6, 7-dimethoxy-3, 4-dihydroisoquinoline (40gm) in isopropanol (288ml) at 25°C and the resulting reaction mass was heated at 40-45°C for 15 hours. The resulting insoluble material was filtered, washed with isopropanol (80ml) and filtrate was concentrated under reduced pressure up to the 150ml reaction volume. The reaction solution was diluted with methylene dichloride (1200ml) and water (1000ml) and pH was adjusted to 8.5 with sodium hydroxide solution [10%, 100ml]. The organic layer was separated, washed with water (3 x 1000ml) and concentrated under reduced pressure to obtain residue. The residue was dissolved in methanol (300ml) at 50°C, and resulting solution was treated with an activated carbon (20gm) at 50-60°C for 30minutes and then it was filtered and filtrate was further stirred at 20-25°C for 2 hours. The resulting solids were filtered, washed with methanol (150ml), dried at 50-55°C for 8 hours. The resulting solids were milled, sifted through 40 mesh sieve and micronized.

Yield: 65gm

Purity: 99.96% (By HPLC)

………………………

PAPER

Org. Lett., 2011, 13 (24), pp 6500–6503

DOI: 10.1021/ol202792q

http://pubs.acs.org/doi/abs/10.1021/ol202792q

A concise synthesis of tetrabenazine and dihydrotetrabenazine is described. The key feature of this synthesis is the intramolecular aza-Prins-type cyclization of an amino allylsilane via oxidative C–H activation.

http://www.hgxb.com.cn/EN/abstract/abstract12047.shtml

……………
PAPER

J Labelled Comp Radiopharm. 2011 Jun 15; 54(7): 367–370.

doi: 10.1002/jlcr.1881

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3126153/

An external file that holds a picture, illustration, etc. Object name is nihms279693f2.jpg

The TBZ (4) for these reactions was prepared by reacting 3,4-dihydro-6,7-dimethoxyisoquinoline (3) and the Mannich base (2) as shown in Scheme 1.¹⁴ The α,β-unsaturated TBZ (5), which was the original substrate, was obtained by further treatment with chloranil in refluxing benzene.

Tetrabenazine (4a)

To a solution of 3,4-dihydro-6,7-dimethoxyisoquinoline hydrochloride (3, 3.5 g, 15.4 mmol) in cold H₂O (20 mL) in an ice water bath, was added 3-(dimethylaminomethyl)-5-methyl-2-hexanone (2, 3.15 g, 18.3 mmol) as the free base with stirring. Precipitate formed within 3 h, and stirring was continued until the solid-gummy precipitate prevented stirring. The mixture was allowed to stand at RT (room temperature) for 3 days. The solid–gum mixture was filtered, and the yellow solid–gum mixture was dissolved in hot MeOH. The solution was chilled at −10°C for 18 h. The pale yellow solid was filtered to give 2.1 g (43%) of TBZ (4a).

TLC: R_f = 0.62; silica gel; 4% MeOH/96% CH₂Cl₂.

MS: (DCl-NH₃) m/z 318 (M+H).

UV: (EtOH) λ_max 282.0 nm (ε4431).

¹H NMR: (300 MHz, CDCl₃) δ 6.61 (s, 1H), 6.55 (s, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.51 (br dd, 1H), 3.29 (dd, 1H), 3.13 (m, 2H), 2.90 (dd, 1H), 2.75 (m, 2H), 2.57 (m, 2H), 2.35 (t, 1H), 1.81 (ddd, 1H), 1.65 (m, 1H), 1.04 (ddd, 1H), 0.92 (d, 3H), 0.89 (d, 3H) ppm.

¹³C NMR: (75 MHz, CDCl₃) δ 210.00, 147.86, 147.54, 128.60, 126.11, 111.53, 107.94, 62.48, 61.52, 56.01, 55.92, 50.58, 47.62, 47.57, 36.09, 29.38, 25.44, 23.21, 22.11 ppm.

EA: Anal. Calc for C₁₉H₁₇NO₃: C, 71.89; H, 8.57; N, 4.41. Found C, 72.15; H, 8.69; N, 4.47.

HPLC: Brownlee 25 cm × 4.6 mm silica gel column; 30% isopropanol/70% hexane; 1 mL/min; ret. time 5.94 min; purity >99.5%.

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http://www.google.ga/patents/WO2008154243A1?cl=en

Example 10 Removal The Boc Protecting Group From First Intermediate 12 And Amino Cyclization Provide (+)-Tetrabenazine XVII

[0063] First intermediate 12 (1.0 eq) was dissolved in 10% Me₂S- dichloromethane to provide an 82 mM solution. The solution was cooled to 0 ⁰C and triisopropylsilane (1.1 eq.) followed by TFA (precooled to 0 ⁰C) was added to the reaction mixture to provide a final concentration of 41 mM. The reaction mixture was permitted to stir at 0 ⁰C for 1 h. Following the allotted time the reaction mixture was quenched at 0 ⁰C by the addition of saturated aqueous potassium carbonate solution and concentrated under reduced pressure to remove the majority of the dimethylsulfide. The mixture was extracted with five portions of dichloromethane, and the combined organic extracts were washed with brine, dried (MgSO₄), filtered and concentrated under reduced pressure to provide the crude product as a yellow solid. The crude product was recrystallized from 3.5% dimethoxyethane in hexanes. The resulting colorless crystals were washed with hexanes to provide pure (+)- tetrabenazine (XVII) 46%: mp 126.0 ⁰C (3.5% DME-hexanes) (a crystal polymorph was observed at 116 ⁰C); [α]²⁶ _D +37.2 (c 0.41, CH₂Cl₂); ¹H NMR (CD₂Cl₂) δ 0.89 (apparent t, J = 7.2 Hz, 6H), 0.98 (ddd, J = 12, 6.0, 4.0 Hz, IH), 1.59-1.68 (m, IH), 1.74 (ddd, J = 12, 5.9, 5.7 Hz, IH), 2.32 (apparent t, J = 11.7 Hz, IH), 2.46 (apparent t, J = 12.3 Hz, IH), 2.55 (ddd, J = 12, 10.0, 3.8 Hz, IH), 2.65-2.73 (m, 2H), 2.83 (dd, J = 5.5, 2.8Hz, IH), 2.97-3.07 (m, IH), 3.07-3.14 (m, IH), 3.25 (dd, J =9.7, 6.3 Hz, IH), 3.47 (apparent d, J = 12Hz, IH), 3.75 (s, 3H), 3.77 (s, 3H), 6.55 (s, IH), 6.60 (s, IH) ¹³C NMR (CD₂Cl₂) δ 21.98, 23.02, 25.51, 29.46, 35.16, 47.47, 47.63, 50.47, 55.87, 56.01, 61.47, 62.46, 108.46, 111.72, 126.37, 128.96, 147.65, 147.98, 209.72; HRMS-(ESI+) calcd for (C₁₉H₂₇NO₃ + H) ([M+H]⁺ 318.2069, found 318.2082.

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US 20150152099

………….

WO 2015077520

NBI-98854 (CAS # 1025504-59-9), (S)-(2R,3R,l lbR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,1 lb-hexahydro-lH-pyrido[2,l-a]isoquinolin-2-yl 2-amino-3-methylbutanoate, is a VMAT2 inhibitor. NBI-98854 is currently under investigation for the treatment of movement disorders including tardive dyskinesia. WO 2008058261; WO 2011153157; and US 8,039,627. NBI-98854, a valine ester of (+)-a-dihydrotetrabenazine, in humans is slowly hydrolyzed to (+)-a-dihydrotetrabenazine which is an active metabolite of tetrabenazine.

NBI-98854

EXAMPLE 1

D6-(±)-3-Isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-lH-pyrido[2,l-a]isoquinolin-2(l lbH)-one ((±)-Tetrabenazine-<d6)

Step 1

[0193] Jgrt-butyl 3,4-dihydroxyphenethylcarbamate : A solution of dopamine

hydrochloride (209 g, 1.11 mol, 1.00 equiv), sodium carbonate (231 g, 2.75 mol, 2.50 equiv) and di-tert-butyl dicarbonate (263 g, 1.21 mol, 1.10) in 2.4 L tetrahydrofuran / water (5: 1) was stirred at 20°C for 2.5 h. After the starting material was consumed completedly, the reaction was diluted with ethyl acetate (2 L) and washed with water (2×600 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure until two volumes of solvent was left. The precipitated solid was isolated by filtration and dried under vacuum to give 254 g (91%) of ieri-butyl 3,4-dihydroxyphenethylcarbamate as white solid. Ή-ΝΜΪ (300 MHz, CDC1₃) 8.72 (s, 1H), 8.62 (s, 1H), 6.79 (m, 1H), 6.62 (m, 1H), 6.51 (m, 1H), 6.40 (m, 1H), 3.03 (m, 2H), 2.50 (m, 2H), 1.37 (s, 1H). LC-MS: m /z = 254 (MH) ⁺.

Step 2

[0194] D6-fert-butyl 3,4-dimethoxyphenethylcarbamate: A solution of ieri-butyl 3,4-dihydroxyphenethylcarbamate (127 g, 397 mmol, 1.00 equiv), potassium carbonate (359.3 g, 2.604 mmol, 3.00 equiv) and 18-crown-6 (1,4,7,10,13,16-hexaoxacyclooctadecane ) (68.64 g, 0.26 mmol, 0.03 equiv) in acetone (800 mL) was stirred at 38°C. After 30 min., CD₃I (362 g, 2.604 mmol, 3.00 equiv) was added to the reaction, and the mixture was stirred at 38°C for 12 h. Then an additional CD3I (120 g, 0.868 mmol, 1.00 equiv) was added to the solution and the solution was stirred for 5 h. Then the mixture was cooled to room temperature and the solid was filtered. The filtrate was concentrated under vacuum. The resultant solid was dissolved in H2O (300 mL) and extracted with EA (3×300 mL), the organic layers was combined and concentrated under vacuum to give 114 g (79%) of de-tert-butyl 3,4-dimethoxyphenethylcarbamate as white

solid. ^-NMR (300 MHz, CDC1₃) <Π.39 (m, 5H), 6.82 (m, 1H), 6.73 (m, 2H), 5.12 (s, 1H), 3.45 (m, 2H), 2.77 (m, 2H). LC-MS: m /z = 288 (MH) ⁺.

Step 3

[0195] D6-2-(3,4-dimethoxyphenyl)ethanamine: A solution of de-tert-butyl 3,4-dimethoxyphenethylcarbamate (128 g, 455.26 mmol, 1.00 equiv) in ethyl acetate (1.5 L) was stirred at room temperature. Then HC1 gas was introduced into the reaction mixture for 2h. The precipitated solid was isolated by filtration. The solid was dissolved in 300 mL of water. The pH value of the solution was adjusted to 12 with sodium hydroxide (solid). The resulting solution was stirred for 1 h at 5-10°C. The resulting solution was extracted with 6×800 mL of ethyl acetate and the organic layers combined, dried over sodium sulfate, and concentrated under vacuum to give 64 g (78%) of d6-2-(3,4-dimethoxyphenyl)ethanamine as yellow oil.

^-NMR (300 MHz, CDC ) 6.77 (m, 3H), 3.89 (s, 3H), 3.87 (s, 3H), 2.96 (m, 2H), 2.71 (m, 2H), 1.29 (s, 2H). LC-MS: m /z = 182 (MH) ⁺.

Step 4

[0196] D6-N-r2-(3,4-dimethoxy-phenyl)ethyllformamide: A solution of d₆-2-(3,4-dimethoxyphenyl)ethanamine (69 g, 368 mmol, 1.00 equiv) in ethyl formate(250 mL) was heated under reflux overnight. The solution was concentrated under vacuum to give 71 g (91%) of d6-N-[2-(3,4-dimethoxy-phenyl)ethyl]formamide as yellow solid. The crude solid was used in next step without purification. ^-NMR (300 MHz, CDCb) £8.17 (s, 1H), 6.81 (m, 3H), 5.53 (br, 1H).3.59 (m, 2H), 2.81 (t, 2H, / = 6.9 Hz). LC-MS: m /z = 216 (MH) ⁺.

Step 5

[0197] D6-6,7-dimethoxy-3,4-dihvdroisoguinoline: A solution of d6-N-[2-(3,4-dimethoxy-phenyl)ethyl]formamide (71 g, 329 mmol, 1.00 equiv) in phosphorus oxychloride (100 mL) was stirred at 105°C for 1 h. Then the solution was concentrated under vacuum to remove

phosphorus oxychloride. The residual oil was dissolved in ice / water. The solution was made basic with potassium carbonate with cooling. The basic aqueous solution was extracted with dichloromethane. The collected organic phase was dried using sodium sulfate and then filtered. The dichloromethane was removed by concentration under vacuum to give an orange oil.

Purification by silica gel (ethyl acetate:petroleum ether = 1: 1 ~ ethyl acetate) to give 43 g (66%) of d6-6,7-dimethoxy-3,4-dihydroisoquinoline as orange solid (yield 66%). Ή-ΝΜΡ (300 MHz, CDC1₃) 8.24 (s, 1H), 6.82 (s, 1H), 6.68 (s, 1H), 3.74 (m, 2H), 2.69 (t, 2H, J = 12 Hz). LC-MS: m /z = 198 (MH) ⁺.

Step 6

[0198] Trimethyl(5-methylhex-2-en-2-yloxy)silane: To a cold (-78°C), stirred solution of j-PrMgBr (500 mL of 2 M solution in tetrahydrofuran, 1 mol, 1.00 equiv) in anhydrous tetrahydrofuran (1 L) was added Cul (19.02 g, 0.1 mol, 0.10 equiv) and the resultant mixture was stirred for 15 min at -78°C. Anhydrous hexamethylphosphorous triamide (358.4 g, 2 mmol, 2 equiv) was added and after 20 min, a solution of methyl vinyl ketone (70 g, 0.1 mol, 1.00 equiv), trimethylsilyl chloride (217 g, 0.2 mol, 2.00 equiv), in tetrahydrofuran (200 mL) was added dropwise over 30 min. After the reaction mixture was stirred at -78 °C for lh, triethylamine (20.2g, 200 mmol, 2.00 equiv) was added and the resulting mixture stirred for 10 min at 0 °C. To this was added ie/ -butyl methyl ether (2 L), and the solution was washed with 5% ammonia solution (6×300 mL). Then the organic phase was dried over sodium sulfate and concentrated under vacuum at 25°C to give 155 g crude product as yellow liquid. The liquid was purified by distilling (64-68°C/40 mmHg) to provide 118 g (63.3%) of trimethyl(5-methylhex-2-en-2-

yloxy)silane (E:Z = 56 : 44) as a colorless oil. ^XH-NMR (300 MHz, J₆-DMSO) 4.58 (m, 0.56H), 4.43 (m, 0.44H), 1.73 (s, 1.69H), 1.66 (s, 1.32H), 1.53 (m, 1H), 0.84 (m, 6 H), 0.15(m, 9H).

Step 7

[0199] 3-r(Dimethylamino)methyl1-5-methylhexan-2-one: To a stirred solution of trimethyl(5-methylhex-2-en-2-yloxy)silane (118 g, 633 mmol, 1.00 equiv) in anhydrous acetonitrile (800 mL) was added N-methyl-N-methylenemethanaminium iodide (128.8 g, 696.3 mmol, 1.10 equiv) in several batches and the resultant mixture was stirred at 20°C overnight. Then the solution was concentrated under vacuum to remove the solvent. The residue was dissolved in 400 mL 1 N HC1 (aq.) and extracted with ieri-butyl methyl ether. Then the water phase was basiced with 2 N aq. NaOH and extracted with ie/ -butyl methyl ether. The organic phase was dried and concentrated under vacuum. The liquid was purified by distilling (80°C/0.5 mmHg) to provide 50 g (46%) of 3-[(dimethylamino)methyl]-5-methylhexan-2-one as a colorless oil. ^XH-NMR (300 MHz, J₆-DMSO) £0.92 (d, 3H), 0.98 (d, 3H), 1.11-1.23 (m, 1H), 1.23-1.38 (m, 1H), 1.54-1.70 (m, 1H), 2.30 (s, 3H), 3.01 (s, 9H), 3.10-3.32 (m, 2H), 3.81-3.88 (m, 1H).

Step 8

[0200] 2-Acetyl-N,N V,4-tetramethylpentan-l-aminium iodide: A solution of 3-[(dimethylamino)methyl]-5-methylhexan-2-one (50 g, 15.00 mmol, 1.00 equiv) and methyl iodide (4.26 g, 30.00 mmol, 2.00 equiv) in 50 mL diethyl ether was stirred overnight at room temperature. The precipitated solid was isolated by filtration and dried under vacuum to give 79 g (86%) of 2-acetyl-N,N,N,4-tetramethylpentan-l-aminium iodide as white solid. ^XH-NMR (300 MHz, Je-DMSO) 0.89-0.98 (m, 6H), 1.11-1.20 (m, 1H), 1.40 (m, 1H), 1.66 (m, 1H), 2.30 (s, 3H), 3.01(s, 9H), 3.21 (m, 2H), 3.85 (m, 1H).

Step 9

[0201] Ρό- (±) -tetrabenazine : A solution of d6-6,7-dimethoxy-3,4-dihydroisoquinoline (33.4 g, 169 mmol, 1.10 equiv) and 2-acetyl-N,N,N,4-tetramethylpentan-l-aminium iodide (48 g, 153 mmol, 1.00 equiv) in 300ml of methanol was heated under reflux for 48 h. Then 150 mL water was added. The solution was cooled to room temperature. The precipitated solid was isolated by filtration and dried under vacuum to give 38 g of crude d6-tetrabenazine as yellow solid. The crude tetrabenazine was dissolved in ieri-butyl methyl ether (15 volumes), the mixture was heated until the solid was almost dissolved. The yellow solid which was unsolvable was filtered. The filtrate was concentrated under vacuum until 2 volumes ieri-butyl methyl ether was left. The solid was filtered and collected. The above solid was dissolved in ethanol (4 volumes), then the mixture was heated until the solid was dissolved. The solution was stirred and cooled to room temperature at the rate of 20°C/h. Then the mixture was stirred at 0°C for lh. The precipitated solid was isolated by filtration and dried under vacuum to give 25 g (50.4%) of tetrabenazine-<d6 as white solid.

^-NMR (300 MHz, CD₂C1₂) £6.61 (s, 1H), 6.55 (s, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 3.50 (d, 1H, / = 12 Hz), 3.27 (dd, 1H, / = 11.4Hz, / = 6.3 Hz), 3.11 (m, 2H), 2.84 (dd, 1H, / = 10.5 Hz, / = 3 Hz), 2.74 (m, 2H), 2.56 (m, 2H), 2.31 (t, 1H, J = 12 Hz), 1.76 (m, 1H), 1.63 (m, 1H), 0.98 (m, 1H), 0.89 (m, 6H).

LC-MS: m /z = 324 (MH) ⁺.

………………

NMR PREDICT

Watch out will be updated……………….

Rob Koremans, MD, President and CEO of Global Specialty Medicines at Teva.

Michael Hayden, M.D., Ph.D., President of Global R&D and Chief Scientific Officer at Teva

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update on 2018

Novel Process for Preparation of Tetrabenazine and Deutetrabenazine

Purna Chandra Ray *

, Yogesh Dadaji Pawar

, Dnyaneshwar Tukaram Singare, Tushar Nandkumar Deshpande, and Girij Pal Singh

Lupin Research Park, Lupin Limited, 46 & 47A, Village Nande, Taluka Mulshi, Pune-412115, Maharashtra, India

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.8b00011

*E-mail: purnaray@lupin.com.

Abstract

A novel process for the synthesis of tetrabenazine (1) and deutetrabenazine (2), two well-known drugs used for the treatment of chorea associated with Huntington’s disease, has been developed. All of the reaction parameters were optimized through a series of reactions and by using Design of Experiment techniques. The newly developed methods are industrially scalable and employ cheap, commercially available raw materials and hence are highly efficient. The added advantage is that the developed processes evade the use of genotoxic alkylating agents and therefore could be considered as safe and viable alternatives to the existing methods.

Tetrabenazine (1) was invented by Hoffmann-La-Roche (Nutley, NJ, USA). It was also known as Ro 1-9569, Nitoman, and Xenazine. It is a benzoquinolizine derivative with the chemical name 1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[α]quinolizin-2-one . Initially it was developed as an antipsychotic agent.Despite 50 years of medicinal background, the U.S. Food and Drug Administration (FDA) approved 1 on August 15, 2008, for the treatment of chorea associated with Huntington’s disease.

Chemical structures of 1 and 2.

Deutetrabenazine (2) (trade name Austedo) is a stable, nonradioactive deuterium analogue of the approved drug tetrabenazine in which the six hydrogen atoms of the 9- and 10-methoxy (−OCH₃) substituents have been replaced by deuterium atoms . Deutetrabenazine was found to be more effective for the treatment of chorea associated with Huntington’s disease because of improved pharmacokinetic properties compared with the nondeuterated drug tetrabenazine. Deutetrabenazine was originally developed by Auspex Pharmaceuticals (La Jolla, CA, USA). In 2015, Teva acquired Auspex Pharmaceuticals and submitted a new drug application (NDA) in the United States for the treatment of Huntington’s disease. On April 3, 2017, Teva Pharmaceutical received approval from the FDA to market deutetrabenazine as the first deuterated drug for the treatment of chorea associated with Huntington’s disease.(4) Both 1 and 2 are racemic mixtures .

(a) Brossi, A.; Lindlar, H.; Walter, M.; Schnider, O. Helv. Chim. Acta 1958, 41, 119– 139, DOI: 10.1002/hlca.660410117

.

(b) Brossi, A.; Schnider, O.; Walter, M. Quinolizine derivatives.U.S. Patent 2,830,993, 1958.
Pletscher, A.; Brossi, A.; Gey, K. F. Int. Rev. Neurobiol. 1962, 4, 275– 306, DOI: 10.1016/S0074-7742(08)60024-0
Mestre, T.; Ferreira, J.; Coelho, M. M.; Rosa, M.; Sampaio, C. Cochrane Database Syst. Rev. 2009, 3,CD006456, DOI: 10.1002/14651858.CD006456.pub2
U.S. Food and Drug Administration. Novel Drug Approvals for 2017.https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/ucm537040 (accessed Jan 15, 2018).

SYNTHESIS
Brossi, A. Preparation of substituted 2-oxobenzoquinolizines. U.S. Patent 3,045,021, 1962.
Gant, T. G.; Shahbaz, M. M. Benzoquinoline inhibitors of vesicular monoamine transporter-2. U.S. Patent 8,524,733, 2013.

Large-Scale Preparation of Tetrabenazine (1)

1 (262.3 g, 96%). FTIR (in KBr): 2942, 2919, 1701, 1516, 1465, 1370, 1263, 1159, 1010, 860, 749 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ 6.63 (s, 1H), 6.57 (s, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 3.52 (d, 1H, J = 11.2 Hz), 3.32 (dd, 1H, J = 11.6, 6.4 Hz), 3.13–3.10 (m, 2H), 2.93–2.90 (m, 1H), 2.77–2.73 (m, 2H), 2.64–2.53 (m, 2H), 2.37 (t, 1H, J = 11.6 Hz), 1.83–1.80 (m, 1H), 1.69–1.66 (m, 1H), 1.08–1.04 (m, 1H), 0.94–0.91 (m, 6H). ESI-MS: m/z 318.3 [M + H]⁺.

Purification of 1

1 (9.6 g, 96%). HPLC purity: 99.75%.

FTIR (in KBr): 2942, 2919, 1701, 1516, 1465, 1370, 1263, 1159, 1010, 860, 749 cm^–1.

¹H NMR (500 MHz, DMSO-d6): δ 6.70 (s, 1H), 6.69 (s, 1H), 3.72 (s, 6H), 3.46 (d, 1H, J = 10.0 Hz), 3.24 (dd, 1H, J = 11.5, 6.0 Hz), 3.15–3.11 (m, 1H), 2.95–2.89 (m, 1H), 2.85 (dd, 1H, J = 13.0, 3.0 Hz), 2.69–2.65 (m, 2H), 2.52–2.46 (m, 2H), 2.28 (t, 1H, J= 12.0 Hz), 1.66–1.63 (m, 2H), 0.94–0.85 (m, 7H).

ESI-MS: m/z 318.3 [M + H]⁺.

Large-Scale Preparation of Deutetrabenazine (2)FTIR (in KBr): 2942, 2920, 2246, 2067, 1700, 1513, 1269, 1113, 990, 747 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ 6.63 (s, 1H), 6.56 (s, 1H), 3.53 (d, 1H, J = 10.5 Hz), 3.32–3.30 (m, 1H), 3.17–3.13 (m, 2H), 2.92 (dd, 1H, J = 13.5,3.0 Hz), 2.77–2.73 (m, 2H), 2.64–2.53 (m, 2H), 2.37 (t, 1H, J = 11.5 Hz), 1.84–1.79 (m, 1H), 1.69–1.67 (m, 1H), 1.08–1.04 (m, 1H), 0.94–0.91 (m, 6H). ESI-MS: m/z 324.4 [M + H]⁺

Large-Scale Purification of 2

Mp: 128.75–129.42 °C.

FTIR (in KBr): 2942, 2920, 2246, 2067, 1700, 1513, 1269, 1113, 990, 747 cm^–1.

¹H NMR (500 MHz, DMSO-d₆): δ 6.69 (s, 2H), 3.46 (d, 1H, J = 10.0 Hz), 3.25 (dd, 1H, J = 11.5, 6.0 Hz), 3.15–3.11 (m, 1H), 2.95–2.89 (m, 1H), 2.85 (dd, 1H, J = 13.5, 3.0 Hz), 2.70–2.64 (m, 2H), 2.52–2.44 (m, 2H), 2.28 (t, 1H, J = 11.5 Hz), 1.66–1.63 (m, 2H), 0.93–0.85 (m, 7H).

ESI-MS: m/z 324.4 [M + H]⁺.

[α]_D −0.3 [c 0.3, DCM at 25 °C].

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Sacubitril

August 13, 2015 7:00 am / Leave a comment

Sacubitril, AHU 377

NEPRILYSIN INHIBITOR

FOR HEART FAILURE

CAS 149709-62-6

CAS SODIUM SALT 149690-05-1

(2R,4S)-5-(biphenyl-4-yl)-4-((3-carboxypropionyl)amino)-2-methylpentanoic acid ethyl ester

5-(Biphenyl-4-yl)-4(S)-(3-carboxypropionamido)-2(R)-methylbutyric acid ethyl ester

N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methyl butanoic acid ethyl ester

[1,1′-Biphenyl]-4-pentanoic acid, γ-[(3-carboxy-1-oxopropyl)amino]-α-methyl-, α-ethyl ester, (αR,γS)-

[1,1′-Biphenyl]-4-pentanoic acid, γ-[(3-carboxy-1-oxopropyl)amino]-α-methyl-, ethyl ester, [S-(R*,S*)]-
(2R,4S)-4-[(3-Carboxy-1-oxopropyl)amino]-4-[(p-phenylphenyl)methyl]-2-methylbutanoic acid ethyl ester
(2R,4S)-5-(Biphenyl-4-yl)-4-[(3-carboxypropionyl)amino]-2-methylpentanoic acid ethyl ester
Formula C₂₄H₂₉N O₅

MW 411.49 g/mol

Formula	C₂₄H₂₉N O₅
MW	411.49 g/mol

AHU377; AHU-377; Sacubitril; 149709-62-6; UNII-17ERJ0MKGI; Alpha-ethyl (alphaR,gammaS)-gamma-<(3-carboxy-1-oxopropyl)amino>-alpha-methyl<1,1′-biphenyl>-4-pentanoate

Sacubitril sodium
149690-05-1

2D chemical structure of 149690-05-1

Sacubitril is an antihypertensive drug used in combination with valsartan. The combination drug, valsartan/sacubitril, known during trials as LCZ696 and marketed under the brand name, Entresto, is a treatment for heart failure.^[1] It was approved under the FDA’spriority review process for use in heart failure on July 7, 2015.

Mechanism of action

Sacubitril is a prodrug that is activated to LBQ657 by de-ethylation via esterases.^[2] LBQ657 inhibits the enzyme neprilysin,^[3] which is responsible for the degradation of atrial and brain natriuretic peptide, two blood pressure lowering peptides that work mainly by reducing blood volume.^[4]

SYNTHESIS

CLICK ON IMAGE FOR CLEAR VIEW

SYNTHESIS

WO-2008031567

http://www.google.com/patents/WO2008031567A1?cl=en

the following steps:

and optionally the following additional steps:

Example 1 :

(E)-(R)-5-biphenyl-4-yl-4-fert-butoxycarbonylamino-2-methylpent-2-enoic acid

(E)-(R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpent-2-enoic acid ethyl ester (CAS# 149709-59-1) is hydrolysed using lithium hydroxide in ethanol to yield (£)-(f?)-5-biphenyl-4-yl-4-te/t-butoxycarbonylamino-2-methylpent-2-enoic acid as a white solid. δ_H (400 MHz; DMSO) 1.31 (9H₁ s, (CH₃J₃), 1.59 (3H, s, 1- CH₃), 2.68 (1H, dd, J 6.8, 13.2, 5-H_A), 2.86 (1H, m, 5-H_B), 4.44 (1H, m, 4-H), 6.51 (1H₁ d, J 9.2, 3-H), 7.16 (1H, d, J 8.0, NH), 7.26 (2H, d, J 8.0, Ar-ortho- H(Ph)), 7.31 (1H, t, J 7.6, Ar-(Ph)-para-H), 7.40 (2H, t, J 8.0, Ar-(Ph)-metø-H), 7.54 (2H, d, J 8.0, Ar-mefa-H(Ph), 7.60 (2H, d, J 7.6, Ar-(Ph)-ort/vo-H), 12.26 (1H, s, CO₂H); m/z (+ESI) 404 ([MNa]⁺, 17%), 382 ([MHf, 2), 326 (10), 264 (100), 167 (13).

Example 2:

(2/?,4S)-5-biphenyl-4-yl-4-fert-butoxycarbonylamino-2-methylpentanoic acid in crystalline form [2(i-a)]

2(i-a) To a suspension of (E)-(f?)-5-biphenyl-4-yl-4-te/t-butoxycarbonylamino-2- methylpent-2-enoic acid [2(ii-a)] (200 g, 524.3 mmol) in degassed ethanol (900 ml) at 40 °C a solution of diiodo(p-cymene)ruthenium(ll) dimer (0.052 g, 0.0524 mmol) and (αf?,αf?)-2,2^>-bis(α-Λ/,Λ/-dimethylaminophenylmethyl)-(S,S)- 1 ,1′-bis[di(3,5-dimethyl-4-methoxyphenyl)phosphine]ferrocene (= Mandyphos SL-M004-1) (0.116 g, 0.110 mmol) is added in degassed ethanol (100 ml). The solution is degassed using vacuum and a pressure of 20 bar hydrogen applied. The mixture is stirred at 40 ⁰C for 6 h. Vessel is then purged with nitrogen. Ethanol (700 ml) is removed by distillation, lsopropyl acetate (600 ml) is added. Solvent (600 ml) is removed by distillation, lsopropyl acetate (600 ml) is added. Solvent (600 ml) is removed by distillation, lsopropyl acetate (300 ml) is added and the solution is heated to reflux. Heptane fraction (1200 ml) is added and the mixture is cooled to room temperature. The solid is collected by filtration and washed with heptane fraction-isopropyl acetate 2 : 1 mixture (360 ml). The solid is dried overnight at 50 ⁰C under 1-50 mbar vacuum to afford the title compound as a white/off-white solid [Ratio 2(i-a) : 2(i-b) 99 : 1, as determined by HPLC analysis]. Mpt 146-147 ⁰C; δ_H (500 MHz; DMSO) 1.07 (3H₁ d, J 7.0, 1-CH₃), 1.34 (9H, s, (CH₃)₃), 1-38 (1H, m, 3-H_A), 1.77 (1H, m, 3-H_B), 2.43 (1H, m, 2-H), 2.70 (2H, d, J 7.0, 5-H)₁ 3.69 (1 H, m, 4-H), 6.74 (1 H, d, J 9.0, NH)₁ 7.27 (2H, d, J 8.0, Ar-ortA;o-H(Ph)), 7.36 (1H, t, J 7.0, Ar-(Ph)-para-H), 7.46 (2H, t, J 7.5, Ar-(Ph)- meta-H), 7.57 (2H, d, J 8.0, Ar-mefa-H(Ph), 7.64 (2H, d, J 7.5, Ar-(Ph)-orfΛo-H), 12.01 (1H, s, CO₂H); δ_c (500 MHz, DMSO) 18.1 (1-CH₃), 28.3 [(CH₃)₃], 35.9 (2- C), 37.9 (3-C), 40.7 (5-C), 50.0 (4-C), 77.4 [(C(CH₃)₃], 126.3, 126.5, 127.2, 128.9, 129.8 (Ar-CH), 137.7 (Ar-/pso-C(Ph)), 138.3 (Ar-para-C(Ph)), 140.1 (Ar- (Ph)-/pso-C), 155.2 (NCO), 177.2 (CO₂H); mlz (+ESI) 406 ([MNa]⁺, 6%), 384 ([MH]⁺, 31 ), 328 (100), 284 (19); Found: [MH]⁺, 384.21691. C₂₃H₃₀NO₄ requires MH 384.21693

PATENT

http://www.google.com/patents/EP0555175A1

Example 1….THE SODIUM SALT

To a solution of N-(3-carbo(t)butoxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoic acid ethyl ester (0.80 g) in 15 ml of CH₂CI₂ at room temperature are added 3 ml of trifluoroacetic acid. The mixture is stirred overnight and concentrated. The residue is dissolved in tetrahydrofuran (THF), and 6.5 ml of 1 N NaOH is added. The mixture is concentrated and triturated with ether. The solid can be recrystallized from methylene chloride-hexane to give sodium N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methyl butanoic acid ethyl ester melting at 159-160°C; [a]D20 = – 11.4° (methanol).

SODIUM SALT

The starting material is prepared as follows:

A solution of a-t-BOC-(R)-tyrosine methyl ester (5.9 g, 20 mmol) and pyridine (8 mL, 100 mmol) in methylene chloride (30 mL) is cooled to 0-5°C. Trifluoromethanesulfonic anhydride (4 mL, 23 mmol) is added at 0-5°C, and the resulting mixture is held for another 30 minutes. The reaction mixture is diluted with water (60 mL) and methylene chloride (100 mL), and washed sequentially with 0.5 N sodium hydroxide solution (1 x 50 mL), water (1 x 60 mL), 10% citric acid solution (2 x 75 mL) and water (1 x 60 mL). The organic phase is dried over MgS0₄ and concentrated to an oil. The oil is purified by column chromatography (silica gel, hexane/ethyl acetate, 2:1 to give methyl(R)-2-(t-butoxycarbonylamino)-3-[4-(trifluoromethylsulfonyloxy)phenyl]-propionate which crystallizes on standing; m.p. 46-48°C; [a]²⁰ _D-36.01⁰ (c=1, CHCI₃).

Nitrogen is passed through a suspension of (R)-2-(t-butoxycarbonylamino)-3-[4-(trifluoromethylsulfonyloxy)-phenyl]-propionate (1.75mmol), phenylboronic acid (3.5 mmol), anhydrous potassium carbonate (2.63 mmol) and toluene (17 mL) for 15 minutes. Tetrakis(triphenyiphosphine)paiiadium(0) is added, and the mixture is heated at 85-90° for 3 hours. The reaction mixture is cooled to 25°C, diluted with ethyl acetate (17 mL) and washed sequentially with saturated sodium bicarbonate (1 x 20 mL), water (1 x 20 mL), 10% citric acid (1 x 20 mL), water (1 x 20 mL) and saturated sodium chloride solution (1 x 20 mL). The organic phase is concentrated, and the residue is purified by column chromatography (silica gel, hexane/ethyl acetate 2:1) to yield methyl (R)-2-(t-butoxycarbonylamino)-3-(p-phenylphenyl)-propionate which can also be called N-(R)-t-butoxycarbonyl-(p-phenylphenyl)-alanine methyl ester.

To a solution of N-(R)-t-butoxycarbonyl-(p-phenylphenyl)-alanine methyl ester (6.8 g) in 60 ml of THF and 20 ml of methanol are added 20 ml of aqueous 1 N sodium hydroxide solution. The mixture is stirred for 1 h at room temperature and then acidified with 21 ml of 1 N hydrochloric acid. The aqueous solution is extracted 3x with ethyl acetate. The combined organic extracts are dried (MgS0₄), filtered and concentrated to give N-(R)-t-butoxycarbonyl-(p-phenylphenyl)-alanine, m.p. 98-99°C; [a]²°_D -18.59° (c=1, methanol).

To a solution of N-(R)-t-butoxycarbonyl-(p-phenylphenyl)-alanine (4.8 g) in 70 ml of methylene chloride (CH₂CI₂) at 0°C with 1.65 g of N,O-dimethylhydroxylamine HCI, 1.7 g of triethylamine and 2.85 g of hydroxybenzotriazole are added 5.37 g of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride. The mixture is stirred 17 h at room temperature. The mixture is concentrated taken up in ethyl acetate (EtOAc) and washed with saturated sodium bicarbonate, 1N HCI and brine, then dried (MgS0₄), filtered and concentrated to give N-(R)-t-butoxycarbonyl-(p-phenylphenyl)-alanine N,O-dimethyl hydroxylamine amide.

To a 0°C solution of N-(R)-t-butoxycarbonyl-(p-phenylphenyl)-alanine N,O-dimethyl hydroxylamine amide (5.2 g) in 250 ml of diethyl ether are added 0.64 g of lithium aluminum hydride. The reaction is stirred for 30 min. and quenched with aqueous potassium hydrogen sulfate. The mixture is stirred for additional 5 min., poured onto 1N HCI, extracted (3x) with EtOAc, dried (MgS0₄), filtered, and concentrated to give N-(R)-4-t-butoxycarbonyl-(p-phenylphenyl)-alanine carboxaldehyde as a colorless oil.

To a 0°C solution of N-(R)-t-butoxycarbonyl-(p-phenylphenyl)-alanine carboxaldehyde (4.4 g) in 200 ml of CH₂CI₂are added 10 g of carboethoxyethylidene phenyl phosphorane. The mixture is warmed to room temperature, stirred for 1 h, washed with brine, dried (MgS0₄), filtered and concentrated. The residue is chromatographed on silica gel eluting with (1:2) ether:hexane to give N-t-butoxycarbonyl-(4R)-(p-phenylphenylme- thyl)-4-amino-2-methyl-2-butenoic acid ethyl ester.

A solution of N-t-butoxycarbonyl-(4R)-(p-phenylphenylmethyl)-4-amino-2-methyl-2-butenoic acid ethyl ester (4.2 g) in 400 ml of ethanol is suspended with 2.0 g of 5% palladium on charcoal and then is hydrogenated at 50 psi for 6h. The catalyst is removed by filtration and the filtrate is concentrated to give N-t-butoxycarbonyl(4S)-(p-phenylphenylmethyl)-4-amino-2-methylbutanoic acid ethyl ester as a 80:20 mixture of diastereomers.

To the N-t-butoxycarbonyl(4S)-(p-phenylphenylmethyl)-4-amino-2-methylbutanoic acid ethyl ester (4.2 g) in 40 ml of CH₂CI₂ at 0°C is bubbled dry hydrogen chloride gas for 15 min. The mixture is stirred 2 h and concentrated to give (4S)-(p-phenylphenylmethyl)-4-amino-2-methylbutanoic acid ethyl ester hydrochloride as a 80:20 mixture of diastereomers.

To a room temperature solution of the above amine salt (3.12 g) in 15 ml of CH₂CI₂ and 15 ml of pyridine are added 13.5 g of succinic anhydride. The mixture is stirred for 17 h, concentrated, dissolved in ethyl acetate, washed with 1N HCI and brine, and dried (MgS0₄) to give N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenyl- methyl)-4-amino-2-methylbutanoic acid ethyl ester as a 80:20 mixture of diastereomers.

The above N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2-methylbutanoic acid ethyl ester diastereomeric mixture (3.9 g) and N,N-dimethylformamide-di-t-butyl acetal (8.8 ml) are heated at 80°C in 40 ml of toluene for 2 h. The mixture is poured onto ice- 1N HCI, extracted with ether, chromatographed on silica gel eluting with (2:1) toluene:ethyl acetate to give N-(3-carbo(t)butoxy-1-oxopropyl)-(4S)-(p-phenylphe- nylmethyl)-4-amino-2R-methylbutanoic acid ethyl ester as the more polar material and the corresponding (S,S) diastereomer as the less polar material.

Example 2………THE ACID

To a solution of N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester (0.33 g) in 20 ml of (1:1) ethanol:tetrahydrofuran (THF) at room temperature are added 5 ml of 1 N sodium hydroxide solution (NaOH) and stirred for 17 h. The mixture is concentrated, dissolved in water and washed with ether. The aqueous layer is acidified with 1 N hydrochloric acid (HCI), extracted 3x with ethyl acetate (EtOAc), dried over magnesium sulfate (MgS0₄), filtered and concentrated. The residue is triturated with ether to yield N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid melting at 158-164°C, [α]_D ²⁰= -23.5° (methanol).

PATENT

CN 104557600

http://www.google.com/patents/CN104557600A?cl=zh

United States Patent US5217996 and international patent W02008031567, W02010136474 and W02012025501 reported a synthetic route follows to the chiral amino alcohols as raw materials, oxidized to the aldehyde, Victoria ladder tin reaction, chiral hydrogenation and amidation condensation reaction to obtain the objective product.

In addition, the international patent TO2008083967, TO2011088797, TO2012025502 and TO2014198195 reported that another type of preparation. The route through the 2-oxo-proline as raw material, carboxyl activating biphenyl substituted carbonyl reduction, chiral methylation, ring-opening reaction and amide condensation reaction to obtain the objective product.

Example Eight:

in the reaction flask was added (2R, 4S) -2- methyl-4-amino -5- (l, P- biphenyl-4-yl) – pentanoic acid ethyl ester (VII) (1.55g, 5mmol ), Jie of pyridine (1.2g, 15mmol) and dichloromethane burning 25mL, stirring to dissolve, butyric anhydride (1.0g, 10mmol), was heated to 4〇-45 ° C, the reaction was stirred for 6 hours. Fill Gaudin anhydride (0. 5g, 5mmol), the reaction was continued for 4 hours and the end of the reaction by TLC. Concentrated under reduced pressure, the residue was recrystallized from ethyl acetate and n-hexane to give an off-white solid sand sacubitril Kubica song (I) L 6g, a yield of 77.9%;

1H NMR (CDCl3) S 7.51 (d, 2H), 7.46 ( d, 2H), 7.36 (m, 2H), 7. 27 (m, 1H), 7. 17 (d, 2H), 5. 72 (d, 1H), 4. 19 (brs, 1H), 4. 06 (q, 2H), 2. 87-2. 72 (m, 2H), 2. 62-2. 54 (m, 2H), 2. 49 (brs, 1H), 2. 43-2. 33 ( m, 2H), I 88 (m 1H), I 54-1 43 (m, 1H), I. 18 (t, 3H), l 10 (d, 3H);…..

FAB-MSm / z : 412 [M + H] +.

PATENT

http://www.google.com/patents/WO2014198195A1?cl=en

Example 7

(2 Standby

Acetyl chloride (1 mL) 0 ° C was added ethanol (10 mL), and at room temperature for 0.5 hours, the compound (3R, 5S) -5- biphenyl-4-methyl-1- (2,2- methyl-propionyl) -3-methyl pyrrolidone (520 mg, 1.49 mmol), the reaction was refluxed for 3 days. After cooling to room temperature, and concentrated. The reaction mixture was dissolved in 8 mL of dichloromethane and pyridine 1: 1 mixed solution, and then butyryl anhydride (223 mg, 2.23 mmol). 30 ° C overnight. LC-MS detection, a small amount of starting material remaining, fill Gading anhydride (75 mg, 0.74 mmol), continue to reflect four hours. Concentrated and reverse phase column chromatography to give a white foam solid (2R, 4S) -5- biphenyl-4-yl-4- (3-carboxy – propionylamino) -2-methyl – acetic acid ester a (355 mg, 58%) and white solid (2R, 4S) -5- biphenyl-4-yl-4- (3-carboxy – propionylamino) -2-methyl – pentanoic acid b ( 13 mg, 2.3%).

a: 1H MR (400 MHz, CDCl ₃ ) [delta] 7.51 (d, = 7.8 Hz, 2H), 7.46 (d, = 7.8 Hz, 2H), 7.36 (t, J = 7.6 Hz, 2H), 7.27 (t, J = 7.2 Hz, IH), 7.17 (d, J = 7.9 Hz, 2H), 5.72 (d, J = 8.1 Hz, IH), 4.19 (brs, IH), 4.06 (q, J = 7.0 Hz, 2H) , 2.87-2.72 (m, 2H), 2.62-2.54 (m, 2H), 2.49 (brs, IH), 2.43-2.33 (m, 2H), 1.88 (ddd, = 13.2, 9.5, 3.9 Hz, IH), 1.54-1.43 (m, IH), 1.18 (t, = 7.0 Hz, 3H), 1.10 (d, = 7.2 Hz, 3H).

LC-MS: t _R = 3.43 min; [M + H] +: 412.0.

……………………

Paper

JOURNAL OF MEDICINAL CHEMISTRY, vol. 38, no. 10, 1995, pages 1689-1700,

http://pubs.acs.org/doi/pdf/10.1021/jm00010a014

NOTE———–DIACID

(aR,yS)-y-[ (3-Carbo-1-oxopropyl)aminol-a-methyl- [l,l’-biphenyllpentanoic Acid (21a).

To the sodium salt of 19a (0.73 g, 1.68 mM) in 20 mL of THF:EtOH was added 1 N NaOH (5.0 mL, 5.0 “01). The reaction mixture was stirred overnight and then washed with ether. The aqueous layer was acidified with 1 N HCI, re-extracted with EtOAc (3 x 10 mL), dried (MgSO& and evaporated to dryness. The solid was recrystallized from ethanol to yield 435 mg of 21a DIACID OF SACUBITRIL

melting at 165-167 “C:

[a] D25~ -28.73 (c = 10.1 in MeOH);

‘H NMR, DMSOD6

PPM 12.0, (s, 2H), 7.75 (d, 1H), 7.62 (d, 2H), 7.55 (d, 2H), 7.45 (t, 2H), 7.32 (t, lH), 7.25 (d, 2H), 4.92 (m, lH), 2.70 (d, 2H), 2.35 (t, 3H), 2.25 (m, 2H), 1.75 (m, lH), 1.32 (m, lH), 1.03 (d, 3H).

Anal. (C22H25N05) C,H,N

Note diacid is sacubitrilat (LBQ657)

NMR PREDICT

1H NMR PREDICT

13C NMR PREDICT

COSY PREDICT

…………….

Formula Image

NMR…..http://www.chemietek.com/Files/Line3/CHEMIETEK,%20AHU-377%20,%20Lot%2001,%20NMR-MeOD,%201.1.pdf


Mol. Formula:C₂₄H₂₉NO₅ ∙ C₄H₁₁NO₃

MW:532.6
HPLC………http://www.chemietek.com/Files/Line2/CHEMIETEK,%20AHU-377%20,%20Lot%2001,%20HPLC.pdf

update………

PATENT

WO2016180275

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016180275&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=FullText

Heart failure is a very high mortality syndrome, for patients with heart failure, so far no drug can significantly improve mortality and morbidity, and thus a new type of therapy is necessary. AHU-377 (CAS No. 149709-62-6) is an enkephalinase inhibitor, which is a prodrug ester groups can be lost through hydrolysis, converted to pharmaceutically active LBQ657, inhibit endorphin enzyme (NEP) the role of the main biological effects of NEP is to natriuretic peptides, bradykinin and other vasoactive peptide degradation failure. AHU-377 and angiotensin valsartan composition according to the molar ratio of 1 LCZ696. LCZ696 is an angiotensin receptor enkephalinase inhibitors, which can lower blood pressure, treat heart failure may become a new drug. Clinical data show, LCZ696 is more effective for the treatment of hypertension than valsartan alone.

Patents US 5,217,996 and US 5,354,892 reported the first synthesis of AHU-377, the synthetic route is as follows:

Reaction with unnatural D-tyrosine derivative as a substrate, more expensive, while the second step in the synthesis is necessary to use Pd-catalyzed Suzuki coupling reaction, whereby preparative route costs than the AHU-377 high.

Patent US 8,115,016 above routes also reported the departure from the pyroglutamate, through multi-step process for preparing a reaction AHU-377, which is more difficult methylation reaction, and the yield is not high. Patent US 8,580,974 also reported a carbonyl group of the a- introducing N, N- dimethyl enamine is converted to methyl, however, there are some problems in the route for constructing methyl chiral centers, are not suitable for scale-up synthesis route as follows:

About the latest AHU377 synthesis intermediates, Patent WO2014032627A1 reported using a Grignard reagent to react with epichlorohydrin, a quicker been important intermediates, synthetic route Compound AHU377 synthesized as follows:

However, the second step of the synthetic route use succinimide nitrogen atoms introduced by Mitsunobu reaction with hydrochloric acid hydrolysis to remove, then converted to Boc protected at the end of the synthesis process AHU377 Boc will have to take off protection, then any connection with succinic anhydride reaction product introduced into the structure of succinic acid portion, so that this method of atom economy and the economy of the steps are low.

Example 1

Synthesis of Compound 2

In inert atmosphere, a solution of three 500mL flask was added compound 1 (10g, 1eq), dissolved after 90mL THF, was added CuI (4.814g, 0.1eq), the system moves to the low temperature in the cooling bath to -20 ℃ when, biphenyl magnesium bromide dropwise addition, the internal temperature was controlled not higher than -10 ℃. Bi closed refrigeration drop, return to room temperature overnight. Completion of the reaction, the reaction solution was poured into saturated the NH ₄ of Cl (10vol, 100 mL) was stirred at room temperature for 0.5h. Suction filtered, the filter cake was rinsed with a small amount of EA, and the filtrate was transferred to a separatory funnel carved, and the aqueous phase was extracted with EA (10vol × 2,100mL × 2) and the combined organic phases with saturated NaHC [theta] ₃ , the NH ₄ of Cl, each Brine 150mL (15vol) washed once, dried over anhydrous over MgSO ₄ dried, suction filtered, and concentrated to give a white solid. Product obtained was purified by column 15.2g, yield 78%.

NMR data for the product are as follows:

¹ the H NMR (400MHz, CDCl ₃ ) [delta] 7.57 (D, J = 7.6Hz, 2H), 7.52 (D, J = 8.1Hz, 2H), 7.42 (T, J = 7.6Hz, 2H), 7.38-7.25 (m, 8H), 4.62-4.47 ( m, 2H), 4.09 (dd, J = 6.7,3.5Hz, 1H), 3.54 (dd, J = 9.5,3.5Hz, 1H), 3.43 (dd, J = 9.4 , 6.9Hz, 1H), 2.84 ( d, J = 6.6Hz, 2H), 2.38 (s, 1H).

Example 2

Synthesis of Compound 3

In an inert gas, at room temperature was added to the flask 500mL three Ph3P (18.54g, 2eq), 240mL DCM dissolution, butyryl diimide (of 6.44 g), compound 2 (15g), an ice-water bath cooling to 0 ℃ or so, was added dropwise DIAD (14mL) was complete, the reaction go to room temperature.Starting material the reaction was complete, the system was added to water (100 mL) quenched the reaction was stirred for 10min; liquid separation, the aqueous phase was extracted with DCM (100mL × 2), the combined organic phases with saturated Brine 100mL × 2), dried over anhydrous over MgSO ₄ dried , filtration, spin dry to give a white solid; product was purified by column 15.4g, yield 82%.

NMR data for the product are as follows:

¹ the H NMR (400MHz, CDCl ₃ ) [delta] 7.56 (D, J = 7.4Hz, 2H), 7.49 (D, J = 8.0Hz, 2H), 7.42 (T, J = 7.6Hz, 2H), 7.37-7.30 (m, 3H), 7.27 ( d, J = 6.7Hz, 3H), 7.22 (d, J = 8.0Hz, 2H), 4.75 (s, 1H), 4.56 (d, J = 12.0Hz, 1H), 4.45 (d, J = 12.0Hz, 1H ), 4.06 (t, J = 9.6Hz, 1H), 3.70 (dd, J = 10.0,5.2Hz, 1H), 3.23 (dd, J = 13.8,10.3Hz, 1H) , 3.14-3.00 (m, 1H), 2.48 (d, J = 4.0Hz.4H).

Example 3

Synthesis of Compound 4

Protection of inert gas, at room temperature was added to the flask 1L three compound 3 (18.81g), 470mL EtOH was dissolved, was added Pd / C, replaced the H ₂ three times, move heated on an oil bath at 60 ℃ reaction. Raw reaction was complete, the system was removed from the oil bath, the reaction solution was suction filtered through Celite and concentrated to give the crude product. It was purified by column pure 11.8g, a yield of 81.2%.

NMR data for the product are as follows:

₁ the H NMR (400MHz, CDCl ₃ ) [delta] 7.57 (D, J = 7.8Hz, 2H), 7.51 (D, J = 7.8Hz, 2H), 7.42 (T, J = 7.5Hz, 2H), 7.33 (T , J = 7.2Hz, 1H), 7.26 (d, J = 7.2Hz, 2H), 4.55 (d, J = 5.2Hz, 1H), 4.06-3.97 (m, 1H), 3.86 (dd, J = 12.0, 3.1Hz, 1H), 3.16 (dd , J = 8.1,2.9Hz, 2H), 2.58 (t, J = 7.0Hz, 4H), 1.26 (s, 2H).

Example 4

Synthesis of Compound 7

Protection of inert gas, at room temperature to a 25mL flask was added three Dess-Martin oxidant (767.7mg), 10mL DCM was dissolved, the system was cooled down to -10 deg.] C, was added 4 (500mg). Starting material the reaction was complete, to the system was added saturated NaHCO3 and Na2S2O3 each 5mL, quench the reaction stirred for 10min; aqueous phase was extracted with DCM (10mL × 3) and the combined organic phases with saturated NaHCO3, Brine 30mL each wash, dried over anhydrous MgSO4, filtration, spin dried to give the crude product used directly in the next reaction cast.

Example 5

Synthesis of Compound 8

Inert gas, at room temperature for three to 500mL flask 7 (497.5mg), 10mL DCM to dissolve an ice water bath to cool, added phosphorus ylide reagent (880.6mg), the system was removed from the ice water bath at room temperature. The reaction material completely stop the reaction, the system was added to water (5mL) to quench the reaction. Liquid separation, the aqueous phase was extracted with DCM (10mL × 2), organic phases were combined, washed with saturated Brine 20mL × 2, dried over anhydrous MgSO4, filtration, spin crude done. Product obtained was purified by column 563mg, 90% yield.

NMR data for the product are as follows:

¹ the H NMR (400MHz, CDCl ₃ ) δ7.60-7.53 (m, 2H), 7.51 (D, J = 8.1Hz, 2H), 7.42 (T, J = 7.6Hz, 2H), 7.33 (D, J = 7.3Hz, 1H), 7.23 (d , J = 8.1Hz, 2H), 7.13 (dd, J = 9.2,1.5Hz, 1H), 5.26 (td, J = 9.5,6.9Hz, 1H), 4.25-4.05 ( m, 2H), 3.40 (dd , J = 13.7,9.7Hz, 1H), 3.13 (dd, J = 13.8,6.7Hz, 1H), 2.53 (d, J = 2.2Hz, 4H), 1.85 (d, J = 1.4Hz, 3H), 1.30 ( t, J = 7.1Hz, 3H).

Example 6

Synthesis of Compound 9

Protection of inert gas, at room temperature to a 50mL flask was added three 8 (365mg, 1eq), 9mL of ethanol and stirred to dissolve, the system was replaced with hydrogen three times, was added Pd / C (25% w / w) at room temperature. The reaction material completely stop the reaction, the system was added to water (5mL) to quench the reaction. The reaction mixture was suction filtered through Celite and concentrated to give the crude product. Product was purified by column, yield 80.2%, purity 97.2%.

Example 7

Synthesis of Compound 10

Equipped with Compound 9 (100mg) acetic acid A reaction flask (9mL), hydrochloric acid (1mL). The reaction was heated oil bath at 80 deg.] C. The reaction material completely stop the reaction, the system was added to water (5mL) to quench the reaction. After saturated NaHCO3 and extracted with EA and concentrated to give crude product. Product obtained was purified by column 90mg, yield 84%.

NMR data for the product are as follows:

¹ the H NMR (400MHz, CDCl ₃ ) δ7.61-7.54 (m, 2H), 7.53-7.48 (m, 2H), 7.41 (dd, J = 10.5,4.9Hz, 2H), 7.31 (dd, J = 8.3 , 6.4Hz, 1H), 7.22 ( d, J = 8.2Hz, 2H), 5.93 (t, J = 9.7Hz, 1H), 4.34-4.00 (m, 3H), 2.91-2.71 (m, 2H), 2.68 -2.57 (m, 2H), 2.55 (ddd, J = 9.4,7.0,4.3Hz, 1H), 2.42 (dt, J = 13.3,6.8Hz, 2H), 1.97-1.74 (m, 1H), 1.64-1.46 (m, 1H), 1.23 ( td, J = 7.1,3.3Hz, 3H), 1.14 (dd, J = 7.1,3.9Hz, 3H)

Example 8

Synthesis of Compound 5

Example 8-1: The reaction flask was added compound 4 (1eq) was added water (2VOL), concentrated hydrochloric acid (2VOL), 110 ℃ reaction was heated in an oil bath overnight, complete conversion of starting material, the HPLC peak area 97%. 10% NaOH solution was added to adjust the pH to about 10, filtration products. Yield 85%.

Example 8-2: The reaction flask was added compound 4 (1eq) was added ethanol (5 vol), water (5 vol), potassium hydroxide (8 eq), was heated in an oil bath overnight at 110 ℃ reaction, complete conversion of the starting material, the HPLC peak area 99%. Water was added (5Vol), filtered to obtain the product. Yield 95%. Product was dissolved in toluene, was added ethanolic hydrochloric acid, the precipitated hydrochloride Compound 5.

NMR data for the product are as follows:

¹ the H NMR (400MHz, of DMSO) [delta] 8.31 (S, 3H), 7.70-7.61 (m, 4H), 7.47 (T, J = 7.6Hz, 2H), 7.42-7.31 (m, 3H), 4.09 (the dq- , J = 42.6,7.1Hz, 1H), 3.62-3.51 (m, 1H), 3.50-3.41 (m, 1H), 3.11-3.00 (m, 1H), 2.95-2.84 (m, 1H), 1.30-1.10 (m, 1H).

EXAMPLE 9

Synthesis of Compound 6

To the reactor was added compound 5, was added absolute ethanol (3vol). Temperature of the outer set 30 ℃ heating, stirring was continued after the temperature reached 25 ℃ 20min. Was added 30% NaOH aqueous solution (1.1eq). External temperature 65 ℃ heating provided, after the internal temperature reached 60 deg.] C was slowly added (of Boc) ₂ O (1.1 eq). Stirring 0.5h, reaction monitoring. After completion of the reaction, water was added slowly dropwise (8vol), turn off the heating and natural cooling. The system temperature was lowered to 25 deg.] C and continue stirring for 2h. Filter cake at 50 ℃ blast oven drying to obtain the product.

NMR data of the product are as follows:

¹ the H NMR (400MHz, CDCl ₃ ) δ7.61-7.50 (m, 4H), 7.61-7.50 (m, 4H), 7.46-7.39 (m, 2H), 7.48-7.38 (m, 2H), 7.38-7.23 (m, 3H), 7.37-7.26 ( m, 3H), 4.82 (d, J = 7.9Hz, 1H), 4.82 (d, J = 7.9Hz, 1H), 3.91 (s, 1H), 3.70 (d, J = 11.0Hz, 1H), 3.77-3.54 (m, 2H), 3.65-3.47 (m, 1H), 2.88 (d, J = 7.0Hz, 2H), 2.88 (d, J = 7.0Hz, 2H), 2.51 (s, 1H), 2.51 (s, 1H), 1.42 (s, 9H), 1.42 (s, 9H).

Synthesis of Intermediate Compound 6 to Compound 10, i.e., the AHU-377, a synthetic route in the background of the present invention, the cited patent application WO2014032627A1 loaded in detail, not in this repeat.

Example 10

Synthesis of Compound 2

Benzyl glycidyl ether preparation (50g) in THF (200mL) was added. Under inert gas protection, the biphenyl magnesium bromide (365mmol) was added to THF (1020mL) was added the reaction flask is placed in a low temperature bath -40 ℃ cooling. Cuprous iodide (O.leq) when the internal temperature dropped to -9 ℃. Continued to decrease the temperature of -23 ℃ dropwise addition of benzyl glycidyl ether in THF was added dropwise to control the internal temperature process of not higher than -15 deg.] C, 47 min when used, the addition was completed the cooling off the reaction was stirred overnight. The cooling system to -20 ℃ quenched with 1N HCl aqueous solution, <10 ℃ Go stirred 30min at room temperature. Liquid separation, the aqueous phase was extracted with THF, the combined THF phases. Respectively saturated ammonium chloride (250mL), saturated brine (250mL) washed. Rotary evaporation to remove THF, and water (200 mL) Continue rotary evaporation 1h, cool to precipitate a solid. Suction crude. Crude n-heptane was added 2Vol beating, suction filtration to obtain the product in a yield of 90 ~ 95%, HPLC peak area 94%. In another column purification was pure, columned yield 88.6%, HPLC 99.1%.

Example 11

Synthesis of Compound 3

Preparation Example 9, said compound taking the embodiment 2 (5g) added to the reaction flask, the reaction flask was added toluene (80mL), phthalimide (2.55 g of) and triphenylphosphine (5.35g of), the nitrogen was replaced protection. An ice-salt bath cooling to -5 deg.] C, was added dropwise DIAD (4.12g), dropwise addition was exothermic, the temperature was raised to 5 ℃. The reaction was continued 1h sampling HPLC test material substantially complete reaction. Join 12g silica spin column done to collect the product (including DIEA derivative).

Example 12

Synthesis of Compound 11

Compound 3 (3g) was added to the reaction flask embodiment taken in Preparation Example 10, was added ethanol (30 mL), with stirring. Was added hydrazine hydrate (2g) was heated in an oil bath reflux 1h, when supplemented with 20mL ethanol was stirred difficulties, the reaction was continued to 2.5h, HPLC showed the starting material the reaction was complete. Add EA / H2O 100mL each liquid separation, the EA phase was washed with water (100mL) and the combined organic phases were washed with water (100mL) and saturated brine (100mL) washed. Anhydrous magnesium sulfate and filtered spin column was done product 1.88g, yield 88%, HPLC 94%.

NMR data of the product are as follows:

¹ the H NMR (400MHz, of DMSO) [delta] 7.64 (D, J = 7.2Hz, 2H), 7.57 (D, J = 8.1Hz, 2H), 7.45 (T, J = 7.6Hz, 2H), 7.39-7.32 ( m, 5H), 7.29 (d , J = 8.1Hz, 3H), 4.55-4.43 (m, 2H), 3.38-3.23 (m, 3H), 3.18-3.10 (m, 1H), 2.82-2.74 (m, 1H), 2.61-2.52 (m, 1H ).

Example 13

Synthesis of Compound 11

To the toluene solution of the compound 2 was added phthalimide (1.1 eq), triphenylphosphine (1.3 eq) with stirring. External bath set -10 ℃, to cool the system, the internal temperature dropped to 0 ~ 5 ℃, start dropping DIAD (1.3eq), control the internal temperature -5 ~ 5 ℃. Completion of the dropwise addition, the cooling bath was turned off outside the reaction was stirred at room temperature. The reaction was stirred for 1 to 4 hours. The reaction solution to give compound 3, administered directly in the next reaction. To the above reaction mixture was added hydrazine hydrate (6 eq), heated to 70 ~ 80 ℃, to complete the reaction, filtered hot, the filtrate. Aqueous sodium hydroxide solution (20vol 10%) was stirred for 0.5h, allowed to stand for liquid separation from toluene phase. Water was added (20vol) was stirred for 0.5h, allowed to stand for liquid separation from toluene phase. The toluene phase was added hydrochloric acid (20vol, 3N), stirred for 0.5h, to form a solid precipitate. Filtration and drying to obtain a product, i.e. compound 11, the hydrochloride salt, yield 60% in two steps.

NMR data of the product are as follows:

¹ the H NMR (400MHz, of DMSO) [delta] 8.46 (S, 3H), 7.63 (dd, J = 16.4,7.7Hz, 4H), 7.47 (T, J = 7.6Hz, 2H), 7.42-7.22 (m, 8H ), 4.56 (d, J = 12.1Hz, 1H), 4.48 (d, J = 12.1Hz, 1H), 3.58 (d, J = 7.9Hz, 2H), 3.47 (dd, J = 10.9,6.3Hz, 1H ), 3.11 (dd, J = 13.5,4.9Hz, 1H), 2.92 (dd, J = 13.4,9.1Hz, 1H).

Example 14

Synthesis of Compound 12

Weigh Compound 11 (1.38g) was added to the reaction flask. To the reaction flask plus DCM (14ml) and Et3N (462mg, 0.73ml). Weighed (of Boc) ₂O (1.23 g of) was added to DCM (5ml) was dissolved. Room temperature (8 ℃), a solution (of Boc) ₂ DCM solution O was added dropwise to the reaction, (2ml) rinsed with DCM. The reaction mixture was stirred at room temperature, detected by HPLC, the reaction ends 4h. Reaction mixture was washed (15ml) 3 times with Brine (15ml) The reaction solution was washed 1 times. Inorganic sulfate, concentrated and purified by column PE:EA = 15:1 give product 560mg, yield 30.8%, HPLC 99.92%.

NMR data of the product are as follows:

¹ the H NMR (400MHz, CDCl ₃ ) [delta] 7.57 (D, J = 7.6Hz, 2H), 7.49 (D, J = 7.4Hz, 2H), 7.43 (T, J = 7.3Hz, 2H), 7.39-7.28 (m, 5H), 7.24 ( d, J = 9.0Hz, 3H), 5.00-4.80 (br, 1H), 4.51 (q, J = 11.8Hz, 2H), 4.08-3.85 (br, 1H), 3.43 ( d, J = 2.9Hz, 2H) , 3.02-2.77 (m, 2H), 1.42 (s, 9H).

Example 15

Synthesis of Compound 6

Weigh Compound 12 (250mg) and methanol (9ml) was added to the reaction flask. Added Pd / C (138mg, 1 / 4w / w, water content 55%). The H ₂replaced 3 times, 50 ℃ stirred and heated. HPLC detection reaction, the reaction end 30h. Filtered off Pd / C, 40 ℃ concentrated under reduced pressure to remove methanol. PE:EA = 3:1 florisil column to give the product 196mg, 100% yield, 99.34% purity.

NMR data of the product are as follows:

Method for preparing the AHU-377, characterized by comprising the steps of: (a) Compound (1) S- benzyl glycidyl ether and biphenyl Grignard reagent produced by the reaction of the compound (2) in an organic solvent; ( b) compound (2) with a succinimide or phthalimide Mitsunobu reaction occurs in an organic solvent to form a compound (3); (C) compound (3) in an organic solvent in the role of a catalyst under removal debenzylation protected form compound (4); (D) compound (4) with an oxidizing agent oxidation reaction occurs in an organic solvent to form a compound (7); (E) compound (7) with a phosphorus ylide reagent in an organic solvent to give the compound (8); (F.) compound (8) in an organic solvent in the selective catalytic hydrogenation of the compound (9); and (g) of the compound (9) in an organic solvent in the hydrolysis reaction of the amide compound occurs in the presence of an acid ( 10), i.e., AHU-377;

References

John J.V. McMurray, Milton Packer, Akshay S. Desai, et al. for the PARADIGM-HF Investigators and Committees (August 30, 2014).“Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure”. N Eng J Med 371. doi:10.1056/NEJMoa1409077.
Solomon, SD. “HFpEF in the Future: New Diagnostic Techniques and Treatments in the Pipeline”. Boston. p. 48. Retrieved 2012-01-26.
Gu, J.; Noe, A.; Chandra, P.; Al-Fayoumi, S.; Ligueros-Saylan, M.; Sarangapani, R.; Maahs, S.; Ksander, G.; Rigel, D. F.; Jeng, A. Y.; Lin, T. H.; Zheng, W.; Dole, W. P. (2009). “Pharmacokinetics and Pharmacodynamics of LCZ696, a Novel Dual-Acting Angiotensin Receptor-Neprilysin Inhibitor (ARNi)”. The Journal of Clinical Pharmacology 50 (4): 401–414. doi:10.1177/0091270009343932.PMID 19934029. edit
Schubert-Zsilavecz, M; Wurglics, M. “Neue Arzneimittel 2010/2011.” (in German)

WO2004085378A1 *	Mar 15, 2004	Oct 7, 2004	Joseph D Armstrong Iii	Process for the preparation of chiral beta amino acid derivatives by asymmetric hydrogenation
WO2006057904A1 *	Nov 18, 2005	Jun 1, 2006	Merck & Co Inc	Stereoselective preparation of 4-aryl piperidine amides by asymmetric hydrogenation of a prochiral enamide and intermediates of this process
WO2006069617A1 *	Dec 5, 2005	Jul 6, 2006	Dsm Fine Chem Austria Gmbh	Process for transition metal-catalyzed asymmetric hydrogenation of acrylic acid derivatives, and a novel catalyst system for asymmetric transition metal catalysis
US5217996 *	Jan 22, 1992	Jun 8, 1993	Ciba-Geigy Corporation	Biaryl substituted 4-amino-butyric acid amides

NON-PATENT CITATIONS

Reference
1	*	KSANDER, GARY M. ET AL: “Dicarboxylic Acid Dipeptide Neutral Endopeptidase Inhibitors” JOURNAL OF MEDICINAL CHEMISTRY, vol. 38, no. 10, 1995, pages 1689-1700, XP002340280 cited in the application

Patent	Submitted	Granted
ORGANIC COMPOUNDS [US2009156585]	2009-06-18
METHODS OF TREATMENT AND PHARMACEUTICAL COMPOSITION [US8101659]	2008-10-23	2012-01-24
Substituted Aminobutyric Derivatives as Neprilysin Inhibitors [US2010305145]	2010-12-02
PROCESS FOR PREPARING BIARYL SUBSTITUTED 4-AMINO-BUTYRIC ACID OR DERIVATIVES THEREOF AND THEIR USE IN THE PRODUCTION OF NEP INHIBITORS [US2009326066]	2009-12-31
Process for preparing 5-biphenyl-4-amino-2-methyl pentanoic acid [US8115016]	2010-05-06	2012-02-14
Methods of treatment and pharmaceutical composition [US7468390]	2003-07-31	2008-12-23
Process for Preparing 5-biphenyl-4-amino-2-methyl Pentanoic Acid [US2014249320]	2014-03-25	2014-09-04
Substituted Aminobutyric Derivatives as Neprilysin Inhibitors [US2012252830]	2012-06-07	2012-10-04
Process for preparing 5-biphenyl-4-amino-2-methyl pentanoic acid [US8716495]	2011-12-21	2014-05-06

Sacubitril
Systematic (IUPAC) name

4-{[(2S,4R)-1-(4-Biphenylyl)-5-ethoxy-4-methyl-5-oxo-2-pentanyl]amino}-4-oxobutanoic acid
Clinical data
Legal status	Investigational
Identifiers
CAS Registry Number	149709-62-6
ATC code	None
PubChem	CID: 9811834
ChemSpider	7987587
Synonyms	AHU-377; AHU377
Chemical data
Formula	C₂₄H₂₉N O₅
Molecular mass	411.49 g/mol

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Sacubitril
Systematic (IUPAC) name

4-{[(2S,4R)-1-(4-Biphenylyl)-5-ethoxy-4-methyl-5-oxo-2-pentanyl]amino}-4-oxobutanoic acid
Identifiers
CAS Number	149709-62-6
ATC code	None
PubChem	CID: 9811834
ChemSpider	7987587
Synonyms	AHU-377; AHU377
Chemical data
Formula	C₂₄H₂₉NO₅
Molecular mass	411.49 g/mol
SMILES [hide] CCOC(=O)[C@H](C)C[C@@H](CC1=CC=C(C=C1)C2=CC=CC=C2)NC(=O)CCC(=O)O

Message

Comwinchem <comwinchem@foxmail.com>
Date: 1 September 2016 at 15:16
Subject: LCZ696 (SACUBITRIL+VALSARTAN)/ Changzhou Comwin Fine Chemicals Co,. Ltd
To: amcrasto <amcrasto@gmail.com>
Dear SirHow do you do! Sincerely hope my email will bring you more LCZ696 (SACUBITRIL+VALSARTAN) possibilities.I am Wang Zhuo of ComWin from China, and in charge of LCZ696 (SACUBITRIL+VALSARTAN) global marketing.

LCZ696 (sacubitril/Valsartan) is a combination drug for use in heart failure developed by Novartis. It consists of valsartan and sacubitril, in a 1:1 mixture by molecule count. It was approved by US FDA in July 2015.

Sacubitril (Hemicalcium) is a neprilysin inhibitor, We have developed this project since 2nd half of 2014. At present, some intermediates are in commercial scale, and some are in pilot production.

We will put our most focus on this project from 2nd half of this year. Certainly we will file DMF for Sacubitril and make submission to regulartory market. We have sold Sacbutitril to some EU customers for evaluation purpose, such as Teva, Chemo. Also, we are doing the development of LCZ696 (the final API). It’s co-crystallized valsartan and sacubitril, in a one-to one molar ratio. One LCZ696 complex consists of six valsartan anions, six sacubitril anions, 18 sodium cations, and 15 molecules of water. Now we have the sample of LCZ696 in kilogram grade.

Best Regards
Wang Zhuo
Sales Executive
Changzhou ComWin Fine Chemicals Co.,Ltd.
24th Floor, Jiaye International Commercial Plaza
99 Yanling West Road, Changzhou
Jiangsu 213003 China
Tel: 0086 519 8663 2882

Fax: 0086 519 8661 3190

email: wang.zhuo@comwin-china.com
www.comwin-china.com

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सुकून उतना ही देना प्रभू, जितने से
जिंदगी चल जाये।
औकात बस इतनी देना,
कि औरों का भला हो जाये।

////// antihypertensive drug, Heart Failure, Sacubitril, AHU 377

CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(cc1)c2ccccc2)NC(=O)CCC(=O)O

CCOC(=O)[C@H](C)C[C@@H](CC1=CC=C(C=C1)C2=CC=CC=C2)NC(=O)CCC(=O)O

Updating of the HMPC-Guideline on the use of the CTD Format in the Registration of Traditional Herbal Medicinal Products

August 13, 2015 5:18 am / Leave a comment

DRUG REGULATORY AFFAIRS INTERNATIONAL

Updating of the HMPC-Guideline on the use of the CTD Format in the Registration of Traditional Herbal Medicinal Products

Compared to herbal medicinal products (HMPs) there is a simplified registration procedure for traditional herbal medicinal products (THMP).

EMA’s HMPC (Committee on Herbal Medicinal Products) published the draft of revision 2 on the use of the CTD format in the preparation of a registration application for traditional herbal medicinal products on 10 March 2015.

This guideline contains instructions on how to prepare a CTD for a registration application of traditional herbal medicinal products.

Now, there is a new annex 2 with a mock-up which shows by means of a concrete example where and to what extent information should be given on traditional herbal medicinal products in the dossier.

Appendix 1 is a best practice guide for module 3 on quality.

For further information please see the complete draft revision 2 of the…

View original post 33 more words

Indian and Chinese API Manufacturers in the Focus of European Authorities

August 13, 2015 4:51 am / Leave a comment

DRUG REGULATORY AFFAIRS INTERNATIONAL

Indian and Chinese API Manufacturers in the Focus of European Authorities

The EudraGMP database was originally launched in April 2007 and is used to exchange information on compliance with the Good Manufacturing Practices (GMP) between the relevant regulatory authorities of the EU Member States – including Iceland, Liechtenstein and Norway. Since January 2011 the data of all national authorities can be accessed. Further, since April 2013 the database also contains information about GDP, why it is referred to as Eudra GMDP database now.

The database comprising the reports about deficiencies found in inspections by the European authorities – the “non-compliance reports” or, officially, “statement of non-compliance with GMP” – was extended by three reports last week: two of these reports related to Chinese firms, one report to a company in India. The inspections were conducted by inspectors of the Italian authority.

The inspection of the Indian site (antibiotic…

View original post 224 more words

MIRABEGRON

August 12, 2015 9:34 am / 1 Comment on MIRABEGRON

MIRABEGRON

Betanis
Myrbetriq
UNII-MVR3JL3B2V
YM 178
YM178

Мирабегрон ميرابيغرون 米拉贝隆

2-(2-Amino-1,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide

MF: C₂₁H₂₄N₄O₂S =396.5

Mirabegron (YM-178, Astellas Pharma), is an orally active, first-in-class selective β₃-adrenoceptor agonist for the symptomatic treatment of overactive bladder (OAB), and has been approved for urinary frequency and urinary incontinence associated with OAB

Mirabegron (YM-178) is the first β3-adrenoceptor agonist that is clinically effective for overactive bladder. Mirabegron (0.3 and 1 mg/kg) inhibits mechanosensitive single-unit afferent activities (SAAs) of Aδ fibers in response to bladder filling. Mirabegron activates the β3 adrenergic receptor in the detrusor muscle in the bladder, which leads to muscle relaxation and an increase in bladder capacity. Mirabegron (YM-178) acts partly as an irreversible or quasi-irreversible metabolism-dependent inhibitor of CYP2D6. Mirabegron at a dose of 3 mg/kg i.v. decreased the frequency of rhythmic bladder contraction induced by intravesical filling with saline without suppressing its amplitude in anesthetized rats. Mirabegron decreases primary bladder afferent activity and bladder microcontractions in rats. Mirabegron (YM-178) also reduced non-micturition bladder contractions in an awake rat model of bladder outlet obstruction.

Mirabegron is a white crystalline powder, not hygroscopic and freely soluble in dimethyl sulfoxide, soluble in methanol and soluble in water between neutral to acidic pH. The chemical name is 2-(2- Amino-1,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2- phenylethyl]amino}ethyl)phenyl]acetamide., Mirabegron exhibits stereoisomerism due to the presence of one chiral centre. The R enantiomer has been used in the manufacture of the finished product. The enantiomeric purity is controlled routinely by chiral HPLC-UV. Polymorphism has been observed for the active substance. The polymorphic form α is routinely and consistently produced by the synthetic process and it is used in the manufacture of the finished product…….http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002388/WC500137308.pdf

Mirabegron (formerly YM-178, trade name Myrbetriq, Betmiga in Spain) is a drug for the treatment of overactive bladder.^[2] It was developed by Astellas Pharma and was approved in the United States in July 2012.^[3]

Mirabegron activates the β3 adrenergic receptor in the detrusor muscle in the bladder, which leads to muscle relaxation and an increase in bladder capacity.^[4]\

NMR PREDICT

PAPER

http://jocpr.com/vol7-iss4-2015/JCPR-2015-7-4-1473-1478.pdf

Journal of Chemical and Pharmaceutical Research, 2015, 7(4):1473-1478

In the first approach, the introduction of the chiral hydroxyl group was planned at the later stage (Scheme 1). Accordingly, 2-(4-nitrophenyl)ethyl amine 4 was protected as the Boc-derivative 5, followed by the reduction of the nitro group using stannous chloride to furnish corresponding aniline 6. Alternate reducing conditions such as hydrogenation in the presence of 10% Pd-C were also provided the desired 6 in good yield. Amide coupling of the aniline 6 with 2-(2-aminothiazol-4-yl) acetic acid 7 in the presence of EDC, HOBt/DIPEA furnished the desired amide 8. Interestingly, lower reactivity of 2-aminothiazole precluded any self-coupling of 7.

Removal of Boc-group in 8, set the stage for the critical step of introducing the chiral hydroxyl by means of stereocontrolled ring opening of the chiral (R)-styrene epoxide 10. Epoxide opening reaction of 10 was initially attempted with amine 9 in the presence of Et3N in MeOH as the solvent. Alternatively, epoxy opening was also performed under simple isopropanol reflux condition to get the desired 1. The desired product 1 was isolated in 27% yield after purification by column chromatography. This is due to the formation of N-alkylated derivatives of 1 by undesired reaction of 10 with amino functionalities of 1. However, the inefficiency of the epoxide opening reaction precluded a high purity of final product, Mirabegron 1. Since it is not practical to embark on repeated purifications at the last stage (which leads to poor yields), this route was not pursued for further optimization.

13C NMR PREDICT

1H NMR PREDICT

………………

1H NMR PREDICT

13C NMR PREDICT

COSY PREDICT
COSY NMR prediction (24)

CN 103896872
http://www.google.com/patents/CN103896872A?cl=en

Third, Mira Veron synthesis:
reaction:

in 500mL three-necked flask, 2- (2-aminothiazol-4-yl) acetic acid 17.42g (0.086mol), N, N- dimethylformamide 180mL, then added H0BT15.12g (0.104 mol), was added (R) _2 _ ((4- aminophenyl) amino) phenyl-ethan-l-ol -1_ 20g (0.078mol), was added triethylamine 13.04g (0.13mol), was added portionwise EDCI21. 46g (0.104mol), under magnetic stirring, room temperature for 5h, TLC until the reaction was complete tracking.
After treatment: After the completion of the reaction, the reaction solution was poured into 900mL saturated saline water, and then extracted with 400mL of dichloromethane each time, and extracted three times, each time the organic phase is then washed with 200mL of saturated aqueous sodium carbonate solution, washed three times, each time with distilled water and then 200mL of water, washed three times, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a white solid in methylene chloride was distilled off Mira Veron crude, the crude product was recrystallized from methanol solution, wherein the methanol solution of methanol and water, the volume ratio of 10: 4, and recrystallized to give 25.08g, yield 81.0%.
The present embodiment Mira Veron synthesized for testing and structural identification:
mp138 ~ 140 ° C (137 ~ 139 ° C)
[α] 20-18. ~ -22. (CH3OH)
chemical purity HPLC: 99.96%
Optical purity: 97.55ee%
HRMS (ES1-MS, m / z) calcd: for C21H25N4O2S [M + H] + 397.16.Found:. 397.16
1H Mffi (400MHz, DMS0) Sl0.00 (s, lH), 7.50 ( d, J = 8.5Hz, 2H), 7.30 (dd, J = 9.5,5.1Hz, 4H), 7.23 (dd, J = 6.0, 2.7Hz, 1H), 7.12 (d, J = 8.5Hz, 2H), 6.90 (s, 2H), 6.30 (s, 1H), 5.24 (s, 1H), 4.60 (s, 1H), 3.45 (s, 2H), 2.74 (dd, J = 9.8, 3.5Hz, 2H), 2.64 (m, 4H).
13C NMR (101MHz, DMSO) δ 168.69 (s), 168.26 (s), 146.35 (s), 145.03 (s), 137.66 (s), 135.51 (s), 129.24 (s ), 128.38 (s), 127.22 (s), 126.33 (s), 119.46 (s), 103.03 (s), 71.88 (s), 57.94 (s), 51.20 (s), 40.40 (s), 40.20 (s ), 39.99 (s), 39.78 (s), 39.57 (s), 35.77 (s)

1H NMR FIG2…SEE…….http://orgspectroscopyint.blogspot.in/2015/08/mirabegron.html

13C NMR FIG3

………….

CN 103193730
http://www.google.com/patents/CN103193730A?cl=en

By and O ° C under nitrogen protection temperature conditions, 7.3g (R) -2- amino _1_ benzeneethanol added 250mL three-necked flask, the stirring was dissolved in 50mL of dichloromethane Mira Veron Intermediate C was added dropwise to the reaction solution to form three-necked flask. Stirred for I hour under nitrogen, with stirring 4.12g of sodium borohydride was added to the reaction mixture. The reaction mixture was stirred (under TC 3 hours to TLC the reaction was complete. The reaction is complete the reaction mixture was added dropwise a saturated aqueous ammonium chloride solution IOmL quenched reaction was washed twice with 40mL of water, the organic phase was separated. The The organic phase at the conditions at 0 ° C was added concentrated sulfuric acid was stirred IOmL until TLC after 0.5 hours the reaction was complete, then was added 20mL of 20% aqueous sodium hydroxide solution to complete the reaction of the organic phase was adjusted to pH 10 and stirred for 15 minutes minutes solution. The organic phase first with 50mL saturated brine I times with IOg anhydrous sodium sulfate and concentrated to give crude product was recrystallized from methanol and water to give 18.7g of the final product Mira Veron purity of 99.33%, chiral purity of 99.01%, a yield of 88.12%.
Mira Veron use randomly selected samples prepared by the synthesis method of the present invention is detected by liquid chromatography.
Test conditions: Instrument: Agilent 1100 HPLC;
Column: Luna C18, 4.6mmX 250mm, 5 μ m;
Column temperature: 25 ° C;
flow rate: 1.0mL / min;
The detection wavelength: 2IOnm;
Injection volume: 5ul;
Mobile phase A: acetonitrile;
Mobile phase B: 0.1% phosphoric acid aqueous solution;
Running time: 40min.
FIG liquid chromatography after detection of the sample shown in Figure 1; results are shown in Table I.
Table 1: The Mira Veron chromatographic analysis sample preparation method of the present invention

……….

http://www.google.co.in/patents/EP1440969A1?cl=en

Example 4 (Production of the α-form crystal from wet cake of the β-form crystal) :

The same procedures as in Example 2 were followed to obtain 23.42 kg of a wet cake of the β-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide from 6.66 kg of (R)-2-[[2-(4-aminophenyl)ethyl]amino]-1-phenylethanol monohydrochloride. This cake was added with and dissolved in 92 L of water and 76 L of ethanol by heating at about 80°C, and the solution was cooled at a rate of about 10°C per hour, to which was then added 8.4 g of the α-form crystal at 55°C. Thereafter, the mixture was cooled to 20°C. A crystal was filtered and dried to obtain 6.56 kg of the α-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide.
Powder X-ray diffraction diagram and thermal analysis diagram of the α-form crystal are shown in Fig. 4 and Fig. 5, respectively.
¹H-NMR (DMSO-d ₆, 500 MHz) δ (ppm) = 1.60 (1H, s), 2.59 to 2.66 (4H, m), 2.68 to 2.80 (2H, m), 3.45 (2H, s), 4.59 (1H, br), 5.21 (1H, br), 6.30 (1H, s), 6.89 (2H, s), 7.11 (2H, d, J = 8.5 Hz), 7.19 to 7.23 (1H, m), 7.27 to 7.33 (4H, m), 7.49 (2H, d, J = 8.5 Hz), 9.99 (1H,s). FAB-MS m/z: 397 (M+H)⁺.

References

“mirabegron (Rx) – Myrbetriq”. Medscape Reference. WebMD. Retrieved 17 November 2013.
Gras, J (2012). “Mirabegron for the treatment of overactive bladder”. Drugs of today (Barcelona, Spain : 1998) 48 (1): 25–32. doi:10.1358/dot.2012.48.1.1738056. PMID 22384458.
Sacco, E; Bientinesi, R et al. (Apr 2014). “Discovery history and clinical development of mirabegron for the treatment of overactive bladder and urinary incontinence”. Expert Opin Drug Discov9 (4): 433–48. doi:10.1517/17460441.2014.892923. PMID 2455903.
“New Drug Approvals 2012 – Pt. XIV – Mirabegron (MyrbetriqTM)”. ChEMBL. 5 July 2012. Retrieved 28 September 2012.
“MYRBETRIQ (mirabegron) tablet, film coated, extended release [Astellas Pharma US, Inc.]“. DailyMed. Astellas Pharma US, Inc. September 2012. Retrieved 17 November 2013.
“Betmiga 25mg & 50mg prolonged-release tablets”. electronic Medicines Compendium. Astellas Pharma Ltd. 22 February 2013. Retrieved 17 November 2013.
Cypess, Aaron; Weiner, Lauren; Roberts-Toler, Carla; Elía, Elisa; Kessler, Skyler; Kahn, Peter; English, Jeffrey; Chatman, Kelly; Trauger, Sunia; Doria, Alessandro; Kolodny, Gerald (6 January 2015). “Activation of Human Brown Adipose Tissue by a β3-Adrenergic Receptor Agonist”. Cell Metabolism 21 (1): 33–38. doi:10.1016/j.cmet.2014.12.009. PMID 25565203. Retrieved 26 January 2015.

External links

Sacco, E.; Bientinesi, R. (2012). “Mirabegron: A review of recent data and its prospects in the management of overactive bladder”. Therapeutic Advances in Urology 4 (6): 315–24. doi:10.1177/1756287212457114. PMC 3491758. PMID 23205058.

Mirabegron
Systematic (IUPAC) name

2-(2-Amino-1,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide
Clinical data
Trade names	Myrbetriq (US), Betanis (Japan), Betmiga (EU)
Licence data	EMA:Link, US FDA:link
Pregnancy category	US: C (Risk not ruled out)
Legal status	UK: Prescription-only (POM) US: ℞-only
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	29-35%^[1]
Protein binding	71%^[1]
Metabolism	Hepatic via (direct) glucuronidation, amide hydrolysis, and minimal oxidative metabolism in vivo byCYP2D6 and CYP3A4. Some involvement of butylcholinesterase^[1]
Biological half-life	50 hours^[1]
Excretion	Urine (55%), faeces (34%)^[1]
Identifiers
CAS Registry Number	223673-61-8
ATC code	G04 BD12
PubChem	CID: 9865528
ChemSpider	8041219
Synonyms	YM-178
Chemical data
Formula	C₂₁H₂₄N₄O₂S
Molecular mass	396.506 g/mol

Patent	Submitted	Granted
Alpha-form or beta-form crystal of acetanilide derivative [US7342117]	2005-01-06	2008-03-11
Pharmaceutical composition for treating stress incontinence and/or mixed incontinence [US2006004105]	2006-01-05
Pharmaceutical composition comprising a beta-3-adrenoceptor agonist and a serotonin and/or norepinephrine reuptake inhibitor Pharmaceutical composition comprising a beta-3-adrenoceptor agonist and a serotonin and/or norepinephrine reuptake inhibitor [US2009012161]	2005-11-24
Pharmaceutical composition consisting of a beta-3-adrenoceptor agonist and alpha-agonist [US2005154041]	2005-07-14
Pharmaceutical composition consisting of a beta-3-adrenoceptor agonist and an active substance which influences prostaglandin metabolism [US2005119239]	2005-06-02
Pharmaceutical Composition For Treating Stress Incontinence And/Or Mixed Incontinence [US2007129435]	2007-06-07
Remedy for overactive bladder comprising acetic acid anilide derivative as the active ingredient [US7750029]	2006-06-01	2010-07-06
[alpha]-form or [beta]-form crystal of acetanilide derivative [US7982049]	2008-09-04	2011-07-19
BETA ADRENERGIC RECEPTOR AGONISTS FOR THE TREATMENT OF B-CELL PROLIFERATIVE DISORDERS [US2010009934]	2010-01-14
PHARMACEUTICAL COMPOSITION FOR IMPROVING LOWER URINARY TRACT SYMPTOMS [US2010261770]	2010-10-14

11 to 16 of 16
Patent	Submitted	Granted
PHARMACEUTICAL COMPOSITION FOR MODIFIED RELEASE [US2010144807]	2010-06-10
BENZYLAMINE DERIVATIVE OR PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALT THEREOF, AND USE THEREOF FOR MEDICAL PURPOSES [US8148427]	2010-04-22	2012-04-03
Pharmaceutical composition containing a beta-3-adrenoceptor agonist and an alpha antagonist and/or a 5-alpha reductase inhibitor [US2005101607]	2005-05-12
REMEDY FOR OVERACTIVE BLADDER COMPRISING ACETIC ACID ANILIDE DERIVATIVE AS THE ACTIVE INGREDIENT [US2009093529]	2009-04-09
PHARMACEUTICAL COMPOSITION FOR TREATING OVERACTIVE BLADDER [US2010240697]	2010-09-23
Pharmaceutical composition comprising beta-3-adrenoceptor-agonists and antimuscarinic agents [US2005261328]	2005-11-24

US Patent No	Patent Expiry	patent use
6346532	Oct 15, 2018
6562375	Aug 1, 2020
6699503	Sep 10, 2013
7342117	Nov 4, 2023
7750029	Dec 18, 2023	U-913
7982049	Nov 4, 2023

Exclusivity Code	Exclusivity Date
NCE	Jun 28, 2017

U-913……….TREATMENT OF OVERACTIVE BLADDER WITH SYMPTOMS OF URGE URINARY INCONTINENCE, URGENCY, AND FREQUENCY

//////Mirabegron, Overactive bladder, FDA 2012, ASTELLAS PHARMA, YM-178, Myrbetriq, Betmiga

Updates…….

Overactive bladder (OAB) is characterized by symptoms of urinary urgency, with or without urgency incontinence, usually with increased daytime frequency and nocturia.(1-3) Current guidelines recommend oral antimuscarinics drugs as the first-line pharmacologic therapy in the management of OAB despite the companion adverse effects.(4, 5) Mirabegron is an orally active β3 adrenoceptor agonist approved by the FDA for treatment of OAB in 2012, which is an important step toward the better treatment options for the management of OAB.(6)

(R)-Styrene oxide 1 and 4-nitrophenethylamine 2 were exploited as starting materials in the first synthesis of mirabegron (Scheme 1). Heating 1 and 2 in i-propanol afforded amino alcohol 3, and then the amino group was protected by di-tert-butyl dicarbonate (Boc2O), followed by a condensation with 2-aminothiazol-4-acetic acid. Deprotection of the condensation product 7 finally afforded mirabegron.(7-10) Although reactions in the whole process were all conventional reactions, optically pure 1 was not industrially available, which restricted its application in industry.

(R)-Mandelic 8 and 4-nitrophenethylamine hydrochloride 9 were exploited as starting materials in an alternate route (Scheme 2). Condensation of 8 and 9 in the presence of 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBt), and triethylamine in N,N-dimethylformamide (DMF) furnished the corresponding amide 10, which was further reduced in the presence of borane-tetrahydrofuran complex in a mixed solution of 1,3-dimethyl-2-imidazolidinone (DMI) and tetrahydrofuran (THF), affording amine 11. The nitro group of 11 was then reduced by hydrogenation affording aniline 12 which was further amidated by an aqueous EDCI coupling affording mirabegron. This route was rather concise with only four steps, in which the sole stereogenic center was introduced via a bulk starting material 8.(11-13) However, usage of the costly EDCI twice, especially in the first step, led to a high cost and more impurities.

mail: chm_zhenggx@ujn.edu.cn, chm_zhenggx@ujn.edu.cn

1 Abrams, P.; Cardozo, L.; Fall, M.; Griffiths, D.; Rosier, P.; Ulmsten, U.; Van Kerrebroeck, P.; Victor, A.; Wein,A. UROLOGY 2003, 61, 37, DOI: 10.1016/S0090-4295(02)02243-4
2.Abrams, P.; Chapple, C.; Khoury, S.; Roehrborn, C.; de la Rosette, J. J. Urol. 2009, 181, 1779, DOI: 10.1016/j.juro.2008.11.127
3.Jaiprakash, H.; Benglorkar, G. M. RJPBCS 2014, 5 ( 3) 213
4.Lucas, M. G.; Ruud, J. L.; Bosch, R. J. L.; Burkhard, F. C.; Cruz, F.; Madden, T. B.; Nambiar, A. K.; Neisius,A.; de Ridder, D. J. M. K.; Tubaro, A.; Turner, W.; Pickard, R. Eur. Urol. 2012, 62, 1130, DOI: 10.1016/j.eururo.2012.08.047
5.Gormley, E. A.; Lightner, D. J.; Burgio, K. L.; Chai, T. C.; Clemens, J. Q.; Culkin, D. J.; Das, A. K.; Foster, H. E.; Scarpero, H. M.; Tessier, C. D.; Vasavada, S. P. J. Urol. 2012, 188, 2455, DOI: 10.1016/j.juro.2012.09.079
6.Sacco, E.; Bientinesi, R. World J. Obstet Gynecol 2013, 2 ( 4) 65, DOI: 10.5317/wjog.v2.i4.65
7.Maruyama, T.; Suzuki, T.; Onda, K.; Hayakawa, M.; Moritomo, H.; Kimizuka, T.; Matsui, T. US6346532,2002.
8.Kawazoe, S.; Sakamoto, K.; Awamura, Y.; Maruyama, T.; Suzuki, T.; Onda, K.; Takasu, T. EP144096A1,2004.
9.Takasu, T.; Sato, S.; Ukai, M.; Maruyama, T. EP1559427A1, 2005.
10Zhang, H.; Li, Y.; Chen, S.; Shen, M.; Wang, X. CN103896872A, 2014

//////////

MORINIDAZOLE 吗啉硝唑

August 11, 2015 10:05 am / 1 Comment on MORINIDAZOLE 吗啉硝唑

Stockhausen's Mai 1.1 of the innovative spirit of antimicrobial agents (morpholine metronidazole) chemical structure

MORINIDAZOLE

吗啉硝唑

(迈灵达^®

1- [3- (4-morpholinyl) -2-hydroxypropyl] -2-methyl-5- nitro -1H- imidazole

CAS 92478-27-8

Jiangsu Hansoh Pharmaceutical Co., Ltd.

Morinidazole was approved by China Food and Drug Administration (CFDA) on February 24, 2014. It was developed and marketed as a step Lingda ® by Hansoh Pharmaceutical.

A nitroimidazoles antibiotic used to treat bacterial infections including appendicitis and pelvic inflammatory disease.

Morinidazole is a nitroimidazoles antibiotic indicated for the treatment of bacterial infections including appendicitis and pelvic inflammatory disease (PID) caused by anaerobic bacteria.

str1

PATENT

WO2006058457A1.

http://www.google.com/patents/WO2006058457A1?cl=en

……………………….

PATENT
CN1981764A.

https://www.google.com/patents/CN1981764A?cl=en

1- (2,3-epoxypropoxy yl) -2-methyl-5-nitro-imidazole (10g), morpholino (10g), 100ml of acetonitrile under reflux for 2 hours, vacuum recovery of acetonitrile, water was added 100ml, heating to the whole solution, filtered hot, let cool, filtering, washing and drying to obtain an off-white solid (11g).

Proton nuclear magnetic resonance data: 1HNMR (CD3Cl) δ2.39 ~ 2.73 (6H, m) δ2.61 (3H, s) δ3.71 ~ 3.81 (4H, m) δ4.10 ~ 4.17 (2H, m) δ4 .63 ~ 4.66 (1H, m) δ8.00 (1H, s)

CN 102199147

http://www.google.com/patents/CN102199147A?cl=en

CN 1605586

https://www.google.com/patents/CN1605586A?cl=en

Example 7 Preparation of α- (morpholino-1-yl) methyl-2-methyl-5-nitroimidazole-1-ethanol according to Example 4 the same manner as in Preparation α- (morpholino-1-yl) methyl-2-methyl-5-nitroimidazole-1-ethanol, except for using morpholine instead of 4-hydroxypiperidine, prepared by the present invention Compound 7. Proton nuclear magnetic resonance data: 1HNMR (CD3Cl) δ2.39 ~ 2.73 (6H, m) δ2.61 (3H, s) δ3.71 ~ 3.81 (4H, m) δ4.10 ~ 4.17 (2H, m) δ4

Jiangsu Hansoh Pharmaceutical Co., Ltd.

NMR PREDICT

1H NMR PREDICT

13C NMR PREDICT

COSY

CN1810815B	Mar 8, 2006	Mar 16, 2011	陕西合成药业有限公司	Nitroimidazole derivative for treatment
CN1903846B	Aug 15, 2006	Jul 13, 2011	杨成	Ornidazole derivative used for therapy, its preparation method and use
CN100387233C	Jun 9, 2006	May 14, 2008	南京圣和药业有限公司	Use of levo morpholine nidazole for preparing medicine for antiparasitic infection
CN100427094C	Dec 13, 2005	Oct 22, 2008	江苏豪森药业股份有限公司	Usage of alpha-(Morpholin-1-base) methyl-2-methyl-5-azathio-1-alcohol in preparation of anti-trichomoniasis and anti-ameba medicines
CN100540549C	Dec 15, 2005	Sep 16, 2009	南京圣和药业有限公司	Alpha-substituted-2-methyl-5-nitro-diazole-1-alcohol derivative with optical activity
WO2007079653A1 *	Dec 25, 2006	Jul 19, 2007	Junda Cen	OPTICALLY PURE α-SUBSTITUTED 2-METHYL-5-NITROIMIDAZOLE-1-ETHANOL DERIVATIVES

ENZALUTAMIDE

August 5, 2015 7:11 am / 4 Comments on ENZALUTAMIDE

Enzalutamide, MDV-3100

MDV3100 is an orally bioavailable, organic, non-steroidal small molecule targeting the androgen receptor (AR) with potential antineoplastic activity. MDV3100 (Enzalutamide) blocks androgens from binding to the androgen receptor and prevents nuclear translocation and co-activator recruitment of the ligand-receptor complex. It also induces tumour cell apoptosis, and has no agonist activity. Early preclinical studies also suggest that MDV3100 inhibits breast cancer cell growth.

1H NMR FROM THE NET

1H NMR PREDICT AND 13 C NMR PREDICT BELOW

COSY PREDICT

Synthesis pics

……………………..

PATENT
http://www.google.com/patents/WO2015063720A1?cl=en

Enzalutamide is chemically described as 4-{3-[4-cyano-3-(trifluoromethyl)phenyl] -5 ,5 -dimethyl-4-oxo-2-sulfanylideneimidazolidin- 1 -yl } -2-fluoro-N-methylbenzamide of Formula I.

FORMULA I

Processes for the preparation of enzalutamide are described in U.S. Publication Nos. 2007/0004753 and 2007/0254933 and PCT Publication Nos. WO 2007/127010, WO 2006/124118, and WO 2011/106570.

PCT Publication No. WO 2011/106570 discloses that the processes described in U.S. Publication Nos. 2007/0004753 and 2007/0254933 result in a 25% yield of enzalutamide in the final step, which accounts for a 15% overall yield. PCT Publication No. WO 2011/106570 further discloses that the known processes for preparing enzalutamide involve the use of extremely toxic reagents, for example, acetone cyanohydrin.

Acetone cyanohydrin is toxic and therefore its use as a reagent should be avoided for industrial production of a pharmaceutical ingredient. Thus, there is a need in the art to develop a process for the preparation of enzalutamide that avoids the use of acetone cyanohydrin as a reagent

Example 6: Process for the preparation of Enzalutamide (Formula I)

Ethyl N-[3-fluoro-4-(methylcarbamoyl)-phenyl]-2-methylalaninate (Formula IV; 0.2 g) and 4-isothiocyanato 2-(triflouromethyl)-benzonitrile (Formula V; 0.33 g) were added to dimethyl sulfoxide (0.2 mL) and isopropyl acetate (0.4 mL) and heated to 90°C to 95°C. The reaction mixture was cooled to 70°C followed by the addition of methanol (0.4 mL). The reaction mixture was stirred for 2 hours. Isopropyl acetate (4 mL) was added to the reaction mixture followed by washing with water (4 mL). The organic layer was concentrated at 35°C under vacuum to obtain an oily residue which was further purified using silica gel column to obtain the title compound.

Yield: 0.2 g

…………………………

PAPER

J Med Chem 2010, 53(7): 2779

http://pubs.acs.org/doi/full/10.1021/jm901488g
A structure−activity relationship study was carried out on a series of thiohydantoins and their analogues 14 which led to the discovery of 92 (MDV3100) as the clinical candidate for the treatment of hormone refractory prostate cancer.

N-Methyl-4-[3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl]-2-fluorobenzamide, 92

………………………..and concentrated and the residue was purified with SiO2 column chromatography (dichloromethane/acetone, 95:5) to give92 (30 mg, 51%) as colorless crystals.

1H NMR (CDCl3, 400 MHz) δ 1.61 (s, 6H), 3.07 (d, 3H, J= 4.1 Hz), 6.71 (m, 1 H), 7.15 (dd, 1H, J = 11.7, 2.0 Hz), 7.24 (dd, 1H, J = 8.4, 2.0 Hz), 7.83 (dd, 1H, J = 8.2, 2.1 Hz), 7.95 (d, 1H, J = 2.1 Hz), 7.99 (d, 1H, J = 8.2 Hz), 8.28 (dd, 1H, J = 8.4, 8.4 Hz).

13C NMR (CDCl3, 125 MHz) δ 23.8, 26.9, 66.5, 110.3, 114.6, 117.7, 117.9, 121.7 (q, J = 272.3 Hz), 126.1, 126.9 (q, J = 4.6 Hz), 132.0, 133.3, 133.6 (q, J = 33.4 Hz), 135.2, 136.7, 138.9 (d, J = 10.8 Hz), 160.3 (d, J = 248.6 Hz), 162.6 (d, J = 3.3 Hz), 174.3, 179.6.

19F NMR (CDCl3, 100 MHz) δ −111.13, −62.58.

HRMS: found 465.1023 [M + H]+, calculated for [C21H16F4N4O2S + H]+ 465.1003.

COMPARISON OF 1H NMR KNOWN VALUES WITH PREDICTED —-KNOWN IN RED

REF

MEDIVATION PROSTATE THERAPEUTICS, INC.; JAIN, Rajendra, Parasmal; ANGELAUD, Remy; THOMPSON, Andrew; LAMBERSON, Carol; GREENFIELD, Scott Patent: WO2011/106570 A1, 2011 ; Location in patent: Page/Page column 46

Regents of the University of California Patent: US2007/254933 A1, 2007 ; Location in patent: Page/Page column 7 ;

WO2011/106570 A1,

J Med Chem 2010, 53(7): 2779

WO2013067151A1 *	Nov 1, 2012	May 10, 2013	Medivation Prostate Therapeutics, Inc.	Treatment methods using diarylthiohydantoin derivatives
WO2014041487A2 *	Sep 11, 2013	Mar 20, 2014	Dr. Reddy’s Laboratories Limited	Enzalutamide polymorphic forms and its preparation
WO2014066799A2 *	Oct 25, 2013	May 1, 2014	Memorial Sloan-Kettering Cancer Center	Modulators of resistant androgen receptor
WO2014167428A3 *	Mar 5, 2014	Feb 19, 2015	Shilpa Medicare Limited	Amorphous 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-n-methylbenzamide
EP2536708A2 *	Feb 16, 2011	Dec 26, 2012	Aragon Pharmaceuticals, Inc.	Androgen receptor modulators and uses thereof

Fine

From 2-fluoro-4-bromo – benzoic acid s-1, firstly the carboxylic acid is converted to acid chloride with SOCl2 s-2, and then methylamine to give the enamine compound s-3, and s-3 bromide aminoisobutyric acid Ullmann (Goldberg) in CuCl catalyzed reaction to give the compound s-4, followed by reaction of the carboxylic acid and methyl iodide to give the corresponding methyl ester compound s-5.
Aniline compound s-6 in the sulfur phosgene primary amine is converted to the isothiocyanate s-7.
Finally, the nitrogen atom of the compound s-5 attack isothiocyanate s-7, followed by transesterification ring closure to give the final Xtandi (Enzalutamide, uh miscellaneous Lu amine). Scheme: WO2011106570A1

//////////

Indian Generics 2016

August 4, 2015 7:18 am / Leave a comment

The generic APIs market is expected to continue to rise faster than the branded/innovative APIs, by 7.7%/year to reach $30.3 billion in 2016. Asia-Pacific is expected to show the fastest growth rates (10.8%/year). The 24 fastest growing markets will include 11 in Asia-Pacific, seven in Eastern Europe and CIS, four in Africa-Middle East and two in Latin America (Figure ).

Figure – Top growth markets for generic APIs to 2016

By 2016, China will account for 27.7% of the global generic API merchant market, while the US will have fallen to 23.8%; the mature markets as a whole will see their share fall from 41.8% in 2012 to 36.9%. India will be the third largest, with a 7.2% share.

सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये।औकात बस इतनी देना,कि औरों का भला हो जाये।………..P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

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WO 2017012773

References

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Orilotimod potassium,

D-Tryptophan, D-gamma-glutamyl-, potassium salt (1:1), CAS 960155-19-5

EXAMPLES

Example 1

Preparation of potassium salt of D-isoglutamyl-D-tryptophan (1:1) from D-isoglutamyl-D-tryptophan and potassium hydroxide

Example 2

A. Preparation of mono potassium salt of D-isoglutamyl-D-tryptophan (1:1) from the mono ammonium salt of D-isoglutamyl-D-tryptophan (1:1)

B. Preparation of amorphous form of potassium salt of D-isoglutamyl-D-tryptophan (1:1) from the mono ammonium salt of D-isoglutamyl-D-tryptophan (1:1)

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(3RS,11Brs)-9,10-di((2H3)methoxy)-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydro-2H-benzo(a)quinolizin-2-one

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Watch out will be updated……………….

Novel Process for Preparation of Tetrabenazine and Deutetrabenazine

Abstract

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Sacubitril, AHU 377

(2R,4S)-5-(biphenyl-4-yl)-4-((3-carboxypropionyl)amino)-2-methylpentanoic acid ethyl ester

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PATENT

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COSY PREDICT

…………….

NMR…..http://www.chemietek.com/Files/Line3/CHEMIETEK,%20AHU-377%20,%20Lot%2001,%20NMR-MeOD,%201.1.pdf

update………

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(RR,SS)-1,3,4,6,7,11b-Hexahydro-9,10-di(methoxy-d₃)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one