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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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Imidafenacin, イミダフェナシン


Imidafenacin.png

Imidafenacin

イミダフェナシン

Cas 170105-16-5

C20H21N3O, 319.408

APPROVED JAPAN 2015-07-29

4-(2-methyl-1H-imidazol-1-yl)-2,2-diphenylbutanamide
4-(2-methylimidazol-1-yl)-2,2-di(phenyl)butyramide
D06273
KRP-197
KRP-197;ONO-8025
ONO-8025
UNII:XJR8Y07LJO
Company:Kyorin (Originator), Ono (Originator)
Image result for Ono Pharmaceutical Co., Ltd
Image result for KYORIN
 4-(2-methyl-1-imidazolyl)- 2,2-diphenylbutyramide as a colorless needle: mp 189.0±190.0 C (from ethyl acetate:ethanol);
High MS (EI+) m/z calcd for C20H21N3O 319.1685, found 319.1671;
1 H NMR (400 MHz, CDCl3) d 2.23 (3H, s), 2.69±2.74 (2H, m), 3.77±3.82 (2H, m), 5.33 (1H, s), 5.49 (1H, s), 6.73 (1H, s), 6.85 (1H, s), 7.31±7.42 (10H, m).
イミダフェナシン
Imidafenacin

C20H21N3O : 319.4
[170105-16-5]

Imidafenacin (INN) is a urinary antispasmodic of the anticholinergic class. It’s molecular weight is 319.40 g/mol

Imidafenacin (INN) is a urinary antispasmodic of the anticholinergic class.

Kyorin and Ono have developed and launched imidafenacin, an oral M1 and M3 muscarinic receptor antagonist. Family members of the product case, WO9515951, expire in the US in 2019

Imidafenacin was approved by Pharmaceuticals Medical Devices Agency of Japan (PMDA) on Apr 18, 2007. It was marketed as Uritos® by Kyorin, and marketed as Staybla® by Ono.

Imidafenacin is a potent M1 and M3-subtype antagonist indicated for the treatment of urinary urgency, frequent urination and urgency urinary incontinence due to overactive bladder.

Uritos® is available as tablet for oral use, containing 0.1 mg of free Imidafenacin. The recommended dose is 0.1 mg twice daily, and it can be increased to 0.2 mg twice daily, if the efficacy was not enough.

Uritos® / Staybla®

Image result for Uritos®

Image result for Staybla®

MOA:Muscarinic acetylcholine receptor antagonist

Indication:Urinary incontinence; Urinary urgency and frequency

ChemSpider 2D Image | Imidafenacin | C20H21N3O

Image result for KYORIN

PAPER

WO-2016142173

Imidafenacin, the compound of formula (I), is an antimuscarinic agent marketed in Japan under the brand name Uritos® used to treat overactive bladder, a disease defined by the presence of urinary urgency, usually accompanied by frequency and nocturia, with or without urge incontinence. Overactive bladder dysfunction has a considerable impact on patient quality of life, although it does not affect survival.

(I)

Synthesis of 4-(2-methyl-1 -imidazolyl)-2,2-diphenylbutanamide is first disclosed in Japanese patent JP3294961 B2 as shown in Scheme 1 . 4-bromo-2,2-diphenylbutanenitrile (II) is reacted with three equivalents of 2-methylimidazol, in dimethylformamide and in the presence of triethylamine as a base, to afford 4-(2-methyl-1 H-imidazol-1 -yl)-2,2-diphenylbutanenitrile, compound of formula (III), which is purified by column chromatography and, further, converted into its hydrochloride salt and recrystallized. Then, compound (III) is hydrolyzed with an excess of 70% sulfuric acid at 140-150 °C, followed by basification and recrystallization to provide imidafenacin (I), in an overall yield of only 25% (as calculated by data provided in docume

(III) (I)

Scheme 1

This route of document JP3294961 B2 implies several drawbacks. Firstly, purification of intermediate (III) is carried out by means of chromatographic methods, which are generally expensive, environmentally unfriendly and time consuming. Secondly, the hydrolysis of the nitrile group is carried out under strong acidic conditions and high temperature not convenient for industrial application.

Japanese document JP2003-201281 discloses a process for preparing imidafenacin as shown in Scheme 2. 4-bromo-2,2-diphenylbutanenitrile (II) is reacted, with five equivalents of 2-methylimidazol, which acts also as a base, in dimethylsufoxide to provide intermediate (III), which after an isolation step is further reacted with phosphoric acid in ethanol to provide the phosphate salt of 4-(2-methyl-1 H-imidazol-1-yl)-2,2-diphenylbutanenitrile. Hydrolysis with potassium hydroxide, followed by purification with a synthetic adsorbent provides imidafenacin (I) in a moderate overall yield

(II) (I)

Scheme 2

The use of a synthetic adsorbent is associated with problems with operativities and purification efficiencies from the viewpoint of industrial production, therefore, the process disclosed in document JP2003-201281 is not suitable for industrial application.

EP1845091 A1 discloses a process for preparing imidafenacin, according to previous document JP2003-201281 , however the purification step is carried out by either preparing the hydrochloride or the phosphate salt of imidafenacin followed by neutralization as shown in Scheme 3. Purified imidafenacin is provided in low yield, overall yield of about 31 % (as calculated by data provided in document EP1845091 A1 ). This process has several disadvantages. Firstly, EP1845091 A1 states that the penultimate intermediate, the 4-(2-methyl-1 H-imidazol-1 -yl)-2,2-diphenylbutanenitrile phosphate is hygroscopic, which implies handling problems. Secondly, the additional steps carried out for purification increases the cost of the final imidafenacin process and the pharmaceutical compositions containing it, which already resulted in expensive medications.

(II) (I)

HCI or

H3PO4

purified (I) HCI or Ή3ΡΟ4

Scheme 3

The intermediate phosphate salt of 4-(2-methyl-1 H-imidazol-1 -yl)-2,2-diphenylbutanenitrile obtained and used in prior art processes is a solid form having needle-shaped crystals, which are difficult to filtrate. Moreover, said needle-shaped crystals are very hygroscopic and unstable and transform over time to other solid forms. In addition, the water absorbed by this solid form described in the prior art may react with the intermediate to generate further impurities.

Therefore, there is still a need to develop an improved industrially feasible process for the manufacture of imidafenacin in good purity and good yield, involving the use of stable intermediates having also improved handling characteristics.

Example 1 :

Preparation of 4-(2-methyl-1 H-imidazol-1 -yl)-2,2-diphenylbutanenitrile phosphate in solid Form I

4-bromo-2,2-diphenylbutanenitrile (II, 1.000 Kg, 3.33 mol) and 2-methylimidazol (1 .368 Kg, 16.66 mol) were heated in DMSO (0.8 L) at 100-105 °C for 7 hours. The solution was then cooled to 20-25 °C and toluene (2 L) and water (4 L) were added and stirred for 30 minutes. After phase separation, the aqueous layer was extracted with toluene (1 L). Organic layers were combined and washed twice with water (2 x 1 L). Distillation of toluene provided 4-(2-methyl-1 H-imidazol-1-yl)-2,2-diphenylbutanenitrile as a brown oil (0.915 Kg), which was, then, dissolved in dry acetone (3 L) and water (0.1 L), heated to 40-45°C and seeded with 4-(2-methyl-1 H-imidazol-1 -yl)-2,2-diphenylbutanenitrile phosphate. A solution of orthophosphoric acid (0.391 Kg, 3.39 mol) in acetone (2 L) was then added dropwise, maintaining temperature at 40-45 °C. Once the addition was finished, the reaction mixture was maintained 1 hour at 40-45 °C, cooled to 20-25 °C and stirred for 1 hour. The solid was filtered, washed with acetone (1 L), suspended in 2-propanol (10 L), heated at 80 °C and 2 L of solvent were distilled. The obtained suspension was then seeded with 4-(2-methyl-1 H-imidazol-1 -yl)-2,2-diphenylbutanenitrile phosphate solid Form I and maintained at 80 °C for 5 hours. The suspension was cooled down to 20-25°C, filtered off, washed with 2-propanol (1 L) and, finally, dried (45 °C, 0.5 torr, 12 hours).

Yield: 0.967 Kg (73%)

HPLC: 99.5 %

KF: 0.2 %

Optical microscopy: plate-shaped crystal habit as substantially in accordance to Figure 2.

PSD: D90 of 105 m

PXRD: Crystalline solid form as substantially in accordance to Figure 3.

DSC (10 °C/min): Endothermic peak with onset at 177 °C (-1 18 J/g), as substantially in accordance to Figure 4.

TGA (10 °C/min): Decomposition starting at 180 °C.

DVS: No significant weight gain up to 90% of relative humidity. At this humidity, a total increase of only 0.45% in weight was observed.

SCXRD: Crystal structure substantially in accordance to Figure 5. There are not water or solvent molecules in the crystal structure.

PATENT

https://www.google.com/patents/CN103351344A?cl=en

Overactive Bladder (symptomatic overactive bladder, 0AB) is a common chronic lower urinary tract dysfunction. Its incidence, United States and Europe over 75 year-old male incidence up to 42%, slightly lower incidence of women 31%; the incidence of domestic in Beijing 50 years of age for men was 16.4% for women over the age of 18 mixed The overall incidence of urinary incontinence and urge incontinence was 40.4 percent, seriously affecting the physical and mental health of the patient, reduced quality of life. Common antimuscarinic drugs in vivo and in vivo M receptor in some or all of binding with different affinities to improve the symptoms of OAB, but will also cause many side effects, such as dry mouth, constipation, cognitive impairment , tachycardia, blurred vision and so on. Imidafenacin have diphenylbutanoic amide structure, is a new high anticholinergic drugs, which selectively acts on the M3 and Ml receptors, blocking the contraction of the detrusor choline, so detrusor relaxation, reduce side effects of drugs. Meanwhile imidafenacin inhibit smooth muscle of the bladder and inhibiting acetylcholine free dual role, and selectivity for the bladder stronger than the salivary glands.

imidafenacin is a new diphenylbutanoic amides from Japan Ono Pharmaceutical Co., Ltd. jointly developed with Kyorin Pharmaceutical anticholinergics, structure (I) as follows:

Figure CN103351344AD00031

The goods listed in June 2007 in Japan under the trade name: STAYBLA, chemical name: 4- (2-methyl-1-imidazolyl) _2,2- diphenylbutyric amide.

At present the preparation imidafenacin few reports, can be summed up as the following ways:

China Patent CN10699098 reported to bromoethyl diphenyl acetonitrile and 2-methylimidazole as a raw material, at 150 ° C condition, after the reaction DMF / triethylamine system, sulfuric acid hydrolysis reuse imidafenacin. The reaction equation is as follows:

Figure CN103351344AD00032

BACKGROUND OF THE INVENTION This two-step method was 24% overall yield is too low, and the second step of the reaction is difficult to control. And the reaction product was purified by column chromatography required to obtain a purified product, is not conducive to industrial production.

Chinese patent CN101362721A referred to as the hydrolysis conditions for the preparation of sulfuric acid and organic acid mixed use imidafenacin yield have mentioned the smell.

Figure CN103351344AD00041

 Although this method increases the yield, but still more by-product of the reaction, the product is not easy purification.

 Japanese Patent No. JP2005 / 023216 proposes hydrolysis under alkaline environment, and the use of products and solutions of salts hydrochloride salt and then purified product.

Figure CN103351344AD00042

This method improves the yield of the second step of the hydrolysis reaction and simplified purification methods. But the need to use this method to purify salt activated carbon, and filtration devices require more stringent; and a need to be re-crystallized salt solution salt after the operation, a total of four steps of unit operations. Process more cumbersome and more stringent requirements for equipment, it is not conducive to industrial scale production. In addition, the product is dried for a long time, still remaining after solvent treatment product obtained, the purity of the product is still low.

Figure CN103351344AD00051

DETAILED DESCRIPTION

 The following typical examples are intended to illustrate the present invention, simple replacement of skill in the art of the present invention or improvement made in all part of the present invention within the protection of technical solutions.

Example 1

4- (2-methyl-1-imidazolyl) -2,2-diphenyl butanamide hydrobromide. The 16.5 g (52 mmol) 4- (2- methyl-1-imidazolyl) -2,2-diphenyl butyramide crude into 100 mL of isopropanol, stirring was added 8.0 mL hydrobromic acid and isopropyl alcohol mixed solution (volume ratio of 1: 1), the solid gradually dissolved, was nearly colorless and transparent liquid. After maintaining the reaction mixture was stirred for half an hour, the reaction mixture was added to 100 mL of ethyl acetate, stirred for I hour at room temperature, solid precipitated. Filtration, and the cake was rinsed with an appropriate amount of ethyl acetate. The solid was collected, 40 ° C drying oven and dried to constant weight to give 19.5 g white 4- (2-methyl-1-imidazolyl) -2,2-diphenyl butyramide hydrobromide, yield 98.9%. ?] \ 1 .228.4-229.00C0MS (m / z): 320 [M + 1] +. 1H-NMR (DMS0-1 / 6, 400 MHz) δ: 2.25 (3H, s), 2.73-2.74 (2H, m), 3.68-3.91 (2H, m), 6.81 (1H, s), 7.28-7.35 (I OH, m), 7.39 (1H, s), 7.49 (1H, d, /=2.4 Hz), 7.55 (1H, d, J = 2.2 Hz), 14.39 (1¾ br s).

Example 2

4- (2-methyl-1-imidazolyl) -2,2-diphenyl butyramide. -2,2-Diphenyl butyric acid amide acetate was dissolved in 900 mL of water to 19.5 g (0.051mmol) obtained in Example 1 4- (2-methyl-1-imidazolyl) embodiment. Extracted with 900mL diethyl ether solution, collecting the inorganic layer. Was added to an aqueous solution of 200 mL of ethanol, was added to the system with stirring in an aqueous solution of KOH 2mol / L, there is a solid precipitated. The reaction was stirred I h after filtration. Cake was washed with 40% ethanol solution rinse, rinsed with water several times. Collect the cake, put 40 ° C drying oven dried to constant weight to give 14.8 g white 4- (2-methyl-1-imidazolyl) -2,2-diphenyl methylbutanamide, yield 91.0% (total yield 90% two steps). Μ.p.192.3-193.00C (CN101076521A 191-193O). MS (m / z): 320 [M + l] +. 1H-NMR (DMSO-J6, 400MHz) δ: 2.11 (3Η, s), 2.69-2.73 (2H, m), 3.61-3.65 (2H, m), 6.75 (1H, d, J = L OMHz), 7.01 (1H, br s), 7.04 (1H, d, J = L 0 MHz), 7.34-7.49 (11H, m).

Example 3

4- (2-methyl-1-imidazolyl) -2,2-diphenyl butyramide. The 14.5 g (0.045mmol) obtained in Example 4- (2-methyl-1-imidazolyl) -2,2-diphenyl butanamide 2 was added 116 mL of ethyl acetate was slowly heated to reflux reflux for 30 min, cooled to room temperature for crystallization 5 h. Suction filtered, the filter cake was rinsed with a small amount of ethanol, collected cake was put 40 ° C drying oven and dried to constant weight to give 13.4 g white 4- (2-methyl-1-imidazolyl) -2,2- diphenyl methylbutanamide refined products, yield 92.4% (three-step total yield 83.1%). Mp192.5-193 (TC (CN101076521A 191_193 ° C) .MS (m / z):.. 320 [M + 1] + 1H-NMR (DMSO-J6, 400 MHz) δ

2.11 (3H, 7.01 (1H,

s), 2.69-2.73 (2H, br s), 7.04 (1H, d,

m), 3.61-3.65 (2H, m), 6.75 (1H, J = L 0 MHz), 7.34-7.49 (11H, m).

Image result for Imidafenacin

PATENT

CN103772286A.

imidafenacin (Imidafenacin) is a new diphenylbutanoic amides from Japan Ono Pharmaceutical Co., Ltd. jointly developed with Kyorin Pharmaceutical anticholinergic drugs, bladder is highly selective for the treatment of overactive bladder, in 2007 in June in Japan. Its chemical name is 4- (2-methyl -1H- imidazol-1-yl) -2,2-diphenyl butyramide chemical structure shown by the following formula I:

Figure CN103772286AD00031

Reported in U.S. Patent No. US5932607 imidafenacin preparation method, the method is based on 4-bromo-2 ‘2 ~ phenyl butyronitrile, 2-methylimidazole, triethylamine as raw materials, with DMF as a solvent at 150 ° C reaction 30h, to give the intermediate 4- (2-methyl-imidazol-1-yl) -2,2-diphenyl-butyronitrile, 77% yield, then body 140 ~ 150 ° C with 70% sulfuric acid The resulting intermediate hydrolyzed to the amide, after completion of the reaction required excess soda and sulfuric acid, the reaction is as follows:

Figure CN103772286AD00032

Which preclude the use of the dilute sulfuric acid hydrolysis, although succeeded in getting the product, but the yield is very low, only 32%, greatly increasing the production cost, mainly due to 70% sulfuric acid, the reaction is difficult to control amide phase, the product will continue to acid hydrolysis byproducts, resulting in decreased yield.

 European Patent No. EP1845091 reports imidafenacin Another preparation method, the method using potassium hydroxide and isopropyl alcohol 4- (2-methyl-imidazol-1-yl) diphenyl _2,2- Hydrolysis of nitrile to amide phosphates, and the crude product was converted to the hydrochloride or phosphate, and recrystallized to remove impurities and then basified imidafenacin obtained, which reaction is as follows:

Figure CN103772286AD00041

This method uses a lot of bases, product purification is too much trouble, and the total yield of 45%.

 Chinese Patent Publication No. CN102746235 also disclosed imidafenacin preparation method of 4- (2-methyl-1-yl) -2,2-diphenyl phosphate or nitrile salt in methanol / ethanol, dimethyl sulfoxide, and the presence of a base, with hydrogen peroxide in 40 ~ 60 ° C under through improved Radziszewski the target compound, the reaction is as follows:

Figure CN103772286AD00042

The method used in the hydrogen peroxide solution, but a solution of hydrogen peroxide has strong oxidizing, and has a certain corrosive, inhalation of the vapor or mist respiratory irritation strong, direct eye contact with the liquid may cause irreversible damage and even blindness, security It is not high on the human body and environmentally unfriendly. Alkaline environment, easily decomposed hydrogen peroxide, as the temperature increases, the decomposition reaction increased, and therefore reaction requires a large excess of hydrogen peroxide solution.

Figure CN103772286AC00021

The method comprises the steps of: (1) 4-Bromo-2,2-diphenyl-butyronitrile is hydrolyzed to the amide under basic conditions; (2) The obtained 4-bromo-2,2-diphenylbutyric amide is reacted with 2-methylimidazole to give the desired product.

Example 1

2L reaction flask was added 400mL of dry tetrahydrofuran, under a nitrogen atmosphere was added 60% sodium hydride (82.8g, 2.06mol), stirred to obtain a gray turbid solution A. With 400mL dry tetrahydrofuran was sufficiently dissolved diphenyl acetonitrile (200g, 1.04mol), I, 2- dibromoethane (204.2g, 1.08mol), to give a colorless clear liquid B; 5 ~ 15 ° C, a solution of turbid solution B dropwise to solution A, 10 ~ 15 ° C the reaction was incubated 6h, TLC until the reaction was complete, to the reaction system a small amount of water was added dropwise until no bubbles. After addition of 800mL water, 400mL ethyl acetate and stirred, liquid separation, the organic layer was washed with water, saturated sodium chloride solution, respectively, and the organic layer was dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure to give a yellow liquid 310g.

[0018] The resulting yellow liquid with 800mL 90% ethanol and stirred to dissolve at 40 ° C, then cooling and crystallization, filtration, 45 ° C and concentrated under reduced pressure to give a white solid 232.8g, 75% yield.

Preparation of bromo-2,2-diphenyl 4_ butanamide: [0019] Example 2

3L reaction flask was added 4-bromo-2,2-diphenyl-butyronitrile (15 (^, 0.511101), 7501 ^ 6mol / L KOH solution, 750mL dimethylsulfoxide and heated to 100 ~ 120 ° C under stirring The reaction, the reaction lh, until the reaction was complete by TLC after cooling to 40 V, add 2000mL water, 2000mL of methylene chloride was stirred, liquid separation, the organic layer was washed with water, washed with saturated sodium bicarbonate and sodium chloride solution, separated, dried over anhydrous The organic layer was dried over sodium sulphate, filtration, concentrated under reduced pressure to give brown oily liquid 161.92g, 96% yield.

Preparation of bromo-2,2-diphenyl 4_ butanamide: [0020] Example 3

3L reaction flask was added 4-bromo-2,2-diphenyl-butyronitrile (150g, 0.5mol), 666mL 6mol / L NaOH solution, 750mL dimethylsulfoxide, the reaction mixture was stirred and heated to 100 ~ 120 ° C under The reaction lh, until the reaction was complete by TLC after cooling to 40 ° C, add water 2000mL, 2000mL of methylene chloride was stirred, liquid separation, the organic layer was washed with water, washed with saturated sodium bicarbonate and sodium chloride solution, separated, dried over anhydrous sulfate sodium organic layer was dried, filtration, concentrated under reduced pressure to give brown oily liquid 146.73g, 87% yield.

Preparation of bromo-2,2-diphenyl 4_ butanamide: [0021] Example 4

The reaction was stirred 3L reaction flask was added 4-bromo-2,2-diphenyl-butyronitrile (15 (^, 0.511101), 8331 ^ 36% Na2CO3 solution, 750mL dimethylsulfoxide and heated to 100 ~ 120 ° C under The reaction lh, until the reaction was complete by TLC after cooling to 40 ° C, add water 2000mL, 2000mL of methylene chloride was stirred, liquid separation, the organic layer was washed with water, washed with saturated sodium bicarbonate and sodium chloride solution, separated, dried over anhydrous The organic layer was dried over sodium sulphate, filtration, concentrated under reduced pressure to give brown oily liquid 153.48g, yield 91%.

`[0022] Example 5: 4- (2-methyl-imidazol _1_ -1H- yl) butyramide _2,2_ diphenyl (imidafenacin) Preparation 5L reaction flask was added 4-bromo-2 2-diphenyl butyric amide (160g, L 5mol), 2- methyl imidazole (123g,

1.5mol), triethylamine (50.6g, 0.5mol), potassium iodide (5g, 0.03mol), fully dissolved with 1000mL DMF solution was heated to 120 ° C at a reaction 5h, until completion of the reaction by TLC, heating was stopped, to be After cooling, water was added 3000mL system stirred 0.5h, filtration, washed with water until the filtrate is neutral, concentrated under reduced pressure and dried to give a brown solid 146.14g, a yield of 91%.

[0023] Example 6: 4- (2-methyl-imidazol _1_ -1H- yl) butyramide _2,2_ diphenyl (imidafenacin) Preparation 5L reaction flask was added 4-bromo-2, 2- diphenyl butyramide (160g, 0.5mol), 2- methyl imidazole (82.1g,

1.011101), triethylamine (50.68,0.5mol), potassium iodide (5g, 0.03mol), fully dissolved with 1000mL DMF solution was heated to 120 ° C at a reaction 5h, until completion of the reaction by TLC, heating was stopped, the system was cooled until After adding 3000mL water, stirring 0.5h, filtration, washed with water until the filtrate is neutral, concentrated under reduced pressure and dried to give a brown solid 120.45g, 80% yield.

[0024] Example 7: 4- (2-methyl-imidazol _1_ -1H- yl) butyramide _2,2_ diphenyl (imidafenacin) Preparation 5L reaction flask was added 4-bromo-2, 2- diphenyl butyramide (160g, 0.5mol), 2_ methylimidazole (164.2g,

2.011101), triethylamine (50.68,0.5mol), potassium iodide (5g, 0.03mol), fully dissolved with 1000mL DMF solution was heated to 120 ° C at a reaction 5h, until completion of the reaction by TLC, heating was stopped, the system was cooled until After adding water, stirring 3000mL

0.5h, suction filtered, washed with water until the filtrate was neutral, and concentrated under reduced pressure, and dried to give a brown solid 141.33g, yield 88%.

[0025] Example 8: 4- (2-methyl imidazole -1H- _1_ group) _2,2_ diphenylbutanoic amide (imidafenacin) refining up to 80g microphone said that new crude added 300mL of absolute ethanol, the system was warmed to reflux, refluxed

0.5h, after cooling the ethanol was distilled off to IOOmL about 500mL of ethyl acetate was added to precipitate a white solid, a small amount of ethyl acetate and wash the filter cake, 45 ° C and dried in vacuo to give 74.6g of white crystals, yield 93%.

CLIP

EP 0733621; US 5932607; US 6103747; WO 9515951

Image result for Imidafenacin

Alkylation of diphenylacetonitrile (I) with dibromoethane provided bromide (II). This was condensed with 2-methylimidazole (III) in the presence of Et3N in DMF to afford the substituted imidazole (IV). Finally, hydrolysis of the cyano group of (IV) with 70% sulfuric acid produced the target amide.

Treatment of acetonitrile derivative (I) with dibromoethane (II) in toluene in the presence of NaNH2 affords bromo compound (III), which is then condensed with imidazole derivative (IV) by means of Et3N in DMF to provide compound (V). Hydrolysis of the cyano group of (V) with aqueous H2SO4 yields amide derivative (VI), which is finally subjected to alkyl quaternization by reaction with bromobenzyl bromide (VI) in acetone to furnish the desired product.

Paper

Bioorganic & Medicinal Chemistry Letters 9 (1999) 3003-3008

PAPER

Bioorganic & Medicinal Chemistry 7 (1999) 1151±1161

 4-(2-methyl-1-imidazolyl)- 2,2-diphenylbutyramide (2.02 g, 24%) as a colorless needle:

mp 189.0±190.0 C (from ethyl acetate:ethanol);

High MS (EI+) m/z calcd for C20H21N3O 319.1685, found 319.1671;

1 H NMR (400 MHz, CDCl3) d 2.23 (3H, s), 2.69±2.74 (2H, m), 3.77±3.82 (2H, m), 5.33 (1H, s), 5.49 (1H, s), 6.73 (1H, s), 6.85 (1H, s), 7.31±7.42 (10H, m).

PATENT

CN103880751A.

imidafenacin chemical name 4- (2-methyl–1H–1-yl) -2,2-diphenyl methylbutanamide (I).

Figure CN103880751AD00031

In Patent JP93-341467, JP94-319355 and literature Bioorganic & Medicinal ChemistryLetters, 1999, vol.9,3003 – 3008 reported in the chemical synthesis routes to diphenyl acetonitrile (4) as the starting material,

Condensation and hydrolysis reaction step to give imidafenacin (1).

Figure CN103880751AD00041

The new method is simple, mild reaction conditions, easy to control, good high yield and purity of the product, do not pollute the environment, suitable for industrial production.

[0012] The first method from 2-methylimidazole and I, 2- dibromoethane under phase transfer catalyst is tetrabutylammonium bromide (TBAB) and inorganic base catalyzed generate 1- (2-bromoethyl) – methyl -1H- imidazole (5), and diphenyl acetonitrile (4) a phase transfer catalyst and an inorganic base catalyzed condensation of 4- (2-methyl–1H- imidazol-1-yl) -2,2 – diphenylbutyronitrile hydrochloride (2), and then hydrolyzed to imidafenacin (I)

Figure CN103880751AD00042
Figure CN103880751AD00051

FIG. 1 imidafenacin IH-NMR spectrum

FIG. 2 imidafenacin 13C-NMR spectra

 Examples I

1- (2-bromoethyl) -1H- -2_ methyl-imidazole (5) Preparation of

The 1,2_ dibromoethane (50ml), 2- methylimidazole (2.5g, 30.5mmol), tetrabutylammonium bromide (TBAB) (0.5g) and K2C03 (3.6g), K0H ( 4.6g) were added sequentially 100mL three-necked flask and stirred and heated to 50 ° C reaction 7h. Cooling to room temperature, the reaction solution was filtered, and the filtrate was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate. Concentrated, added to a mixed solvent of isopropyl ether and ethyl acetate (3: 1) was stirred resolved crystal dissolved, to give the product 5.lg, yield 88.5%, mp.79_80 ° C.

Preparation of 4- (2-methyl-1-imidazolyl) -2,2-diphenyl-butyronitrile hydrochloride (2)

 The diphenyl acetonitrile (5.8g, 30mmol) and 50% aqueous KOH (15ml), dimethyl sulfoxide (DMSO) (100ml), tetrabutylammonium bromide (TBAB) (0.9g) in toluene 50ml was added to the reaction flask and stirred for 0.5h in the 40 ° C. 1- (2-bromoethyl) -2-methyl -1H- imidazole (4) (5.lg, 27mmol), was heated to 20 ° C, the reaction was stirred, TLC tracking and monitoring the reaction was complete, the mixture was poured into 100mL water, extracted three times with ethyl acetate 240ml water phase. Washed three times with 300ml of water The organic phase was dried over anhydrous sodium sulfate, the organic phase was concentrated. Analytical crystal solution with hydrogen chloride ether solution, filtered crystals with a mixed solvent of isopropyl ether and recrystallized from ethyl acetate to give the condensation product of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyric carbonitrile hydrochloride (2) of a white solid 7.lg, yield 77.8%, mp: 156.5-158 ° C. 1H-NMR (400MHz, CDCl3), δ (ppm): 7.35-7.42 (IOH, m), 6.90 (1H, s), 6.77 (1H, s), 3.90-3.94 (2H, m), 2.75-2.79 ( 2H, m), 2.25 (3H, s).

The preparation imidafenacin (I),

 4- (2-methyl-1-imidazolyl) -2,2_ diphenyl butyronitrile hydrochloride (2) (8.78g, 26mmol) in 70% concentrated sulfuric acid (25ml) was added to the reaction bottle, the reaction was stirred at 90 ° C, the end of the reaction was monitored by TLC tracking. The reaction solution was poured into 120ml of water, solid sodium carbonate was added to adjust PH to weakly alkaline, sufficiently stirred. With 180ml of dichloromethane and 35ml of ethanol mixed solvent was extracted three times, the organic phase was washed with water, dried over anhydrous sodium sulfate, the organic phase was concentrated. The residue was mixed with a solvent of ethyl acetate and recrystallized from ethanol to give 4- (2-methyl-1-imidazolyl) 2,2-diphenyl butyramide 7.0g, yield 84.5%, mp: 188.0-190 (. TC.1H-NMR and 13C-NMR data are as follows (see Figure 1-2 spectra):

 1H-NMR (CDC13,400ΜΗζ) δ: 2.209 (s, 3H, -CH3), 2.666-2.707 (t, 2H, -CH2-CH2-),

3.747-3.788 (t, 2H, -CH2-CH2 -), 5.341 (s, 1H, -NH -), 5.757 (s, 1H, -NH -), 6.699 (s, 1H, Ar-H)

, 6.828 (s, 1H, Ar-H), 7.287-7.390 (m, I OH, Ar-H).

[0030] 13C-NMR (CDC13,400MHz) δ: 12.17 (-CH3), 41.00 (-CH2 -), 43.74 (-CH2-), 59.44 (quaternary carbon, coupled with strong electron-withdrawing group), 119.08 (-C = C -), 126.95 (aromatic carbon), 127.88 (aromatic carbon), 128.52 (aromatic carbon), 129.10 (aromatic carbon), 142.61 (= CN), 144.54 (-C = N), 176.21 (carbonyl carbon).

Example 2

[0032] 1- (2-bromoethyl) -1H- -2_ methyl-imidazole (5) Preparation of

[0033] The 1,2_ dibromoethane (50ml), 2- methylimidazole (2.5g, 30.5mmol), tetrabutylammonium chloride (0.43g) and Na2CO3 (2.8g), NaOH (3.3g) followed by adding 100mL three-necked flask, stirred and heated to 40 ° C reaction 5h.Cooling to room temperature, the reaction solution was filtered, and the filtrate was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate. Concentrated, added to a mixed solvent of isopropyl ether and ethyl acetate (3: 1) was dissolved with stirring parsing crystal give the product 4.9g, yield 85.1%, mp.79-80 ° C.

Preparation of [0034] 4- (2-methyl-1-imidazolyl) -2,2-diphenyl-butyronitrile hydrochloride (2)

[0035] A two phenylethyl chest (5.8g, 30mmol) and 50% aqueous NaOH (15ml), dimethylethylene Bitterness (DMSO) (100ml), tetrabutylammonium chloride (0.8g) was added to a toluene 50ml The reaction flask, stirred 0.5h in the 40 ° C. Join

1- (2-bromoethyl) -2-methyl -1H- imidazole (4) (5.lg, 27mmol), was heated to 60 ° C, the reaction was stirred, TLC tracking and monitoring the reaction was complete, the mixture was poured into 100mL of water and extracted three times with ethyl acetate 240ml water phase. Washed three times with 300ml of water The organic phase was dried over anhydrous sodium sulfate, the organic phase was concentrated. Solution of hydrogen chloride in ether solution with analytical crystal, crystals were filtered with a mixed solvent of isopropyl ether and recrystallized from ethyl acetate to give the condensation product of 4- (2-methyl-1-imidazolyl) -2,

2-phenyl-butyronitrile hydrochloride (2) as a white solid 7.0g, yield 76.8%, mp: 156.5-158 ° C. 1H-NMR (400MHz, CDCl3), δ (ppm): 7.35-7.42 (IOH, m), 6.90 (1H, s), 6.77 (1H, s), 3.90-3.94 (2H, m), 2.75-2.79 ( 2H, m), 2.25 (3H, s).

Preparation imidafenacin (I),

[0037] 4- (2-methyl-1-imidazolyl) -2,2_ diphenyl butyronitrile hydrochloride (2) (8.78g, 26mmol) in 70% concentrated sulfuric acid (25ml) was added to the reaction bottle, the reaction was stirred at 110 ° C, the end of the reaction was monitored by TLC tracking. The reaction solution was poured into 120ml of water, solid sodium carbonate was added to adjust PH to weakly alkaline, sufficiently stirred. With 180ml of dichloromethane and 35ml of ethanol mixed solvent was extracted three times, the organic phase was washed with water, dried over anhydrous sodium sulfate, the organic phase was concentrated. The residue was mixed with a solvent of ethyl acetate and recrystallized from ethanol to give 4- (2-methyl-1-imidazolyl) 2,2-diphenyl butyramide 7.2g, yield 86.8%, mp: 188.0-190 (. TC.1H-NMR and 13C-NMR data are as follows (see Figure 1-2 spectra):

 1H-NMR (CDC13,400ΜΗζ) δ: 2.209 (s, 3H, -CH3), 2.666-2.707 (t, 2H, -CH2-CH2-),

3.747-3.788 (t, 2H, -CH2-CH2 -), 5.341 (s, 1H, -NH -), 5.757 (s, 1H, -NH -), 6.699 (s, 1H, Ar-H), 6.828 ( s, 1H, Ar-H), 7.287-7.390 (m, I OH, Ar-H).

 13C-NMR (CDC13,400MHz) δ: 12.17 (-CH3), 41.00 (-CH2 -), 43.74 (-CH2-), 59.44 (quaternary carbon, coupled with strong electron-withdrawing group), 119.08 (-C = C -), 126.95 (aromatic carbon), 127.88 (aromatic carbon), 128.52 (aromatic carbon), 129.10 (aromatic carbon), 142.61 (= CN), 144.54 (-C = N), 176.21 (carbonyl carbon).

 Example 3

[0041] 1- (2-bromoethyl) -1H- -2_ methyl-imidazole (5) Preparation of

[0042] The 1,2_ dibromoethane (50ml), 2- methylimidazole (2.5g, 30.5mmol), benzyltriethylammonium chloride (TEBA) (0.35g) and Na2CO3 (2.8g), Na0H (3.3g) were added sequentially 100mL three-necked flask, stirred and heated to 45 ° C reaction 4h. Cooling to room temperature, the reaction solution was filtered, washed with a saturated aqueous sodium bicarbonate paint filtrate was dried over anhydrous sodium sulfate. Concentrated, added to a mixed solvent of isopropyl ether and ethyl acetate (3: 1) was dissolved with stirring parsing crystal give the product 5.0g, yield 86.8%, mp.79-80. . .

Preparation of [0043] 4- (2-methyl-1-imidazolyl) -2,2-diphenyl-butyronitrile hydrochloride (2)

 The diphenyl acetonitrile (5.8g, 30mmol) and 50% aqueous KOH (15ml), dimethyl sulfoxide (DMSO) (100ml), benzyltriethylammonium chloride (TEBA) (0.66g) 50ml Toluene was added to the reaction flask and stirred at 40 ° C under

0.5h0 was added 1- (2-bromoethyl) -2-methyl -1H- imidazole (4) (5.lg, 27mmol), was heated to 60 ° C, the reaction was stirred, TLC tracking and monitoring the reaction was complete, the mixture was poured into 100mL of water and extracted three times with ethyl acetate 240ml water phase. Washed three times with 300ml of water The organic phase was dried over anhydrous sodium sulfate, the organic phase was concentrated. Analytical crystal solution with hydrogen chloride ether solution, filtered crystals with a mixed solvent of isopropyl ether and recrystallized from ethyl acetate to give the condensation product of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyric carbonitrile hydrochloride (2) as a white solid 7.0g, yield 76.8%, mp: 156.5-158. . . 1H-NmrgoomHzADCI3), δ (ppm): 7.35-7.42 (10H, m), 6.90 (1H, s), 6.77 (1H, s), 3.90-3.94 (2H, m), 2.75-2.79 (2H, m) , 2.25 (3H, s).

 Preparation imidafenacin (I),

[0046] 4- (2-methyl-1-imidazolyl) -2,2_ diphenyl butyronitrile hydrochloride (2) (8.78g, 26mmol) in 70% concentrated sulfuric acid (25ml) was added to the reaction bottle, the reaction was stirred at 100 ° C, the end of the reaction was monitored by TLC tracking. The reaction solution was poured into 120ml of water, solid sodium carbonate was added to adjust PH to weakly alkaline, sufficiently stirred. With 180ml of dichloromethane and 35ml of ethanol mixed solvent was extracted three times, the organic phase was washed with water, dried over anhydrous sodium sulfate, the organic phase was concentrated. The residue was mixed with a solvent of ethyl acetate and recrystallized from ethanol to give 4- (2-methyl-1-imidazolyl) 2,2-diphenyl butyramide 7.lg, yield 85.5%, mp: 188.0-190. (TC.1H-NMR and 13C-NMR data are as follows (see Figure 1-2 spectra):

[0047] 1H-NMR (CDC13,400ΜΗζ) δ: 2.209 (s, 3H, -CH3), 2.666-2.707 (t, 2H, -CH2-CH2-),

3.747-3.788 (t, 2H, -CH2-CH2 -), 5.341 (s, 1H, -NH -), 5.757 (s, 1H, -NH -), 6.699 (s, 1H, Ar-H)

, 6.828 (s, 1H, Ar-H), 7.287-7.390 (m, I OH, Ar-H).

13C-NMR (CDC13,400MHz) δ: 12.17 (-CH3), 41.00 (-CH2 -), 43.74 (-CH2-), 59.44 (quaternary carbon, coupled with strong electron-withdrawing group), 119.08 (-C = C -), 126.95 (aromatic carbon), 127.88 (aromatic carbon), 128.52 (aromatic carbon), 129.10 (aromatic carbon), 142.61 (= CN), 144.54 (-C = N), 176.21 (carbonyl carbon).

Example 41- (2-bromoethyl) -1H- -2_ methyl-imidazole (5) Preparation of

[0051] The 1,2_ dibromoethane (50ml), 2- methylimidazole (2.5g, 30.5mmol), tetrabutylammonium bromide (TBAB) (0.5g) and K2C03 (3.6g), K0H ( 4.6g) were added sequentially 100mL three-necked flask, stirred and heated to 60 ° C reaction 4h.Cooling to room temperature, the reaction solution was filtered, and the filtrate was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate. Concentrated, added to a mixed solvent of isopropyl ether and ethyl acetate (3: 1) was dissolved with stirring parsing crystal give the product 4.5g, yield 78.1%, mp.79_80 ° C.

Preparation of [0052] 4- (2-methyl-1-imidazolyl) -2,2-diphenyl-butyronitrile hydrochloride (2)

[0053] The diphenyl acetonitrile (5.8g, 30mmol) and 50% aqueous KOH (15ml), dimethyl sulfoxide (DMSO) (100ml), tetrabutylammonium bromide (TBAB) (0.9g) in toluene 50ml was added to the reaction flask and stirred for 0.5h in the 40 ° C. Plus Λ 1- (2- bromoethyl) -2-methyl -1H- imidazole (4) (5.lg, 27mmol), was heated to 100 ° C, the reaction was stirred, TLC tracking and monitoring the reaction was complete, the mixture was poured into 100mL of water and extracted three times with ethyl acetate 240ml water phase. Washed three times with 300ml of water The organic phase was dried over anhydrous sodium sulfate, the organic phase was concentrated. Analytical crystal solution with hydrogen chloride ether solution, filtered crystals with a mixed solvent of isopropyl ether and recrystallized from ethyl acetate to give the condensation product of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyric carbonitrile hydrochloride (2) as a white solid 6.7g, yield 73.4%, mp: 156.5-158 ° C. 1H-NMR (400MHz, CDCl3), δ (ppm): 7.35-7.42 (IOH, m), 6.90 (1H, s), 6.77 (1H, s), 3.90-3.94 (2H, m), 2.75-2.79 ( 2H, m), 2.25 (3H, s).

The preparation imidafenacin (I),

 4- (2-methyl-1-imidazolyl) -2,2_ diphenyl butyronitrile hydrochloride (2) (8.78g, 26mmol) in 70% concentrated sulfuric acid (25ml) was added to the reaction bottle, the reaction was stirred at 150 ° C at the end of the reaction was monitored TLC tracking. The reaction solution was poured into 120ml of water, solid sodium carbonate was added to adjust PH to weakly alkaline, sufficiently stirred. With 180ml of dichloromethane and 35ml of ethanol mixed solvent was extracted three times, the organic phase was washed with water, dried over anhydrous sodium sulfate, the organic phase was concentrated. The residue was mixed with a solvent of ethyl acetate and recrystallized from ethanol to give 4- (2-methyl-1-imidazolyl) 2,2-diphenyl butyramide 6.2g, yield 74.8%, mp: 188.0-190 (. TC.1H-NMR and 13C-NMR data are as follows (see Figure 1-2 spectra):

[0056] 1H-NMR (CDC13,400ΜΗζ) δ: 2.209 (s, 3H, -CH3), 2.666-2.707 (t, 2H, -CH2-CH2 -), 3.747-3.788 (t, 2H, -CH2-CH2 -), 5.341 (s, 1H, -NH -), 5.757 (s, 1H, -NH -), 6.699 (s, 1H, Ar-H)

, 6.828 (s, 1H, Ar-H), 7.287-7.390 (m, I OH, Ar-H).

 13C-NMR (CDC13,400MHz) δ: 12.17 (-CH3), 41.00 (-CH2 -), 43.74 (-CH2-), 59.44 (quaternary carbon, coupled with strong electron-withdrawing group), 119.08 (-C = C -), 126.95 (aromatic carbon), 127.88 (aromatic carbon), 128.52 (aromatic carbon), 129.10 (aromatic carbon), 142.61 (= CN), 144.54 (-C = N), 176.21 (carbonyl carbon).

Example 5

1- (2-bromoethyl) -1H- -2_ methyl-imidazole (5) Preparation of

 The 1,2_ dibromoethane (50ml), 2- methylimidazole (2.5g, 30.5mmol), tetrabutylammonium bromide (TBAB) (0.5g) and K2CO3 (3.6g), K0H ( 4.6g) were added sequentially 100mL three-necked flask, stirred and heated to 20 ° C reaction 10h. Cooling to room temperature, the reaction solution was filtered, washed with a saturated aqueous sodium bicarbonate paint filtrate was dried over anhydrous sodium sulfate. Concentrated, added to a mixed solvent of isopropyl ether and ethyl acetate (3: 1) was dissolved with stirring parsing crystal give the product 4.1g, yield 71.2%, mp.79-80. . .

Preparation of [0061] 4- (2-methyl-1-imidazolyl) -2,2-diphenyl-butyronitrile hydrochloride (2)

[0062] The diphenyl acetonitrile (5.8g, 30mmol) and 50% aqueous KOH (15ml), dimethyl sulfoxide (DMSO) (100mL), tetrabutylammonium bromide (TBAB) (0.9g) in toluene 50ml was added to the reaction flask and stirred at 20 ° C in Ih. Join

1- (2-bromoethyl) -2-methyl -1H- imidazole (4) (5.lg, 27mmol), was heated to 60 ° C, the reaction was stirred, TLC tracking and monitoring the reaction was complete, the mixture was poured into 100mL of water and extracted three times with ethyl acetate 240ml water phase. Washed three times with 300ml of water The organic phase was dried over anhydrous sodium sulfate, the organic phase was concentrated. Solution of hydrogen chloride in ether solution with analytical crystal, crystals were filtered with a mixed solvent of isopropyl ether and recrystallized from ethyl acetate to give the condensation product of 4- (2-methyl-1-imidazolyl) -2,

2-phenyl-butyronitrile hydrochloride (2) as a white solid 6.5g, yield 71.2%, mp: 156.5-158 ° C. 1H-NMR (400MHz, CDCl3), δ (ppm): 7.35-7.42 (IOH, m), 6.90 (1H, s), 6.77 (1H, s), 3.90-3.94 (2H, m), 2.75-2.79 ( 2H, m), 2.25 (3H, s).

[0063] Preparation of imidafenacin (I), [0064] 4- (2-methyl-1-imidazolyl) -2,2-diphenyl-butyronitrile hydrochloride (2) (8.78g, 26mmol ) and 70% of concentrated sulfuric acid (25ml) was added to the reaction flask, and stirred in at 50 ° C, the end of the reaction was monitored by TLC tracking. The reaction solution was poured into 120ml of water, solid sodium carbonate was added to adjust PH to weakly alkaline, sufficiently stirred. With 180ml of dichloromethane and 35ml of ethanol mixed solvent was extracted three times, the organic phase was washed with water, dried over anhydrous sodium sulfate, the organic phase was concentrated. The residue was mixed with a solvent of ethyl acetate and recrystallized from ethanol to give 4- (2-methyl-1-imidazolyl) 2,2-diphenyl butyramide 6.6g, yield 79.7%, mp: 188.0-190 (. TC.1H-NMR and 13C-NMR data are as follows (see Figure 1-2 spectra):

[0065] 1H-NMR (CDC13,400ΜΗζ) δ: 2.209 (s, 3H, -CH3), 2.666-2.707 (t, 2H, -CH2-CH2-),

3.747-3.788 (t, 2H, -CH2-CH2 -), 5.341 (s, 1H, -NH -), 5.757 (s, 1H, -NH -), 6.699 (s, 1H, Ar-H)

, 6.828 (s, 1H, Ar-H), 7.287-7.390 (m, I OH, Ar-H).

[0066] 13C-NMR (CDC13,400MHz) δ: 12.17 (-CH3), 41.00 (-CH2 -), 43.74 (-CH2-), 59.44 (quaternary carbon, coupled with strong electron-withdrawing group), 119.08 (-C = C -), 126.95 (aromatic carbon), 127.88 (aromatic carbon), 128.52 (aromatic carbon), 129.10 (aromatic carbon), 142.61 (= CN), 144.54 (-C = N), 176.21 (carbonyl carbon).

[0067] Example 6

[0068] 1- (2-bromoethyl) -1H- -2_ methyl-imidazole (5) Preparation of

[0069] The 1,2_ dibromoethane (50ml), 2- methylimidazole (2.5g, 30.5mmol), benzyltriethylammonium chloride (TEBA) (0.35g) and Na2CO3 (2.8g), Na0H (3.3g) were added sequentially 100mL three-necked flask and stirred and heated to 40 ° C reaction 8h. Cooling to room temperature, the reaction solution was filtered, washed with a saturated aqueous sodium bicarbonate paint filtrate was dried over anhydrous sodium sulfate. Concentrated, added to a mixed solvent of isopropyl ether and ethyl acetate (3: 1) was dissolved with stirring parsing crystal give the product 4.4g, yield 76.4%, mp.79-80. . .

Preparation of [0070] 4- (2-methyl-1-imidazolyl) -2,2-diphenyl-butyronitrile hydrochloride (2)

[0071] The diphenyl acetonitrile (5.8g, 30mmol) and 50% aqueous KOH (15ml), dimethyl sulfoxide (DMSO) (100ml), benzyltriethylammonium chloride (TEBA) (0.66g) 50ml Toluene was added to the reaction flask and stirred 0.5h0 1- (2-bromoethyl) -2-methyl -1H- imidazole (4) at 40 ° C (5.lg, 27mmol), was heated to 50 ° C, the reaction mixture was stirred, TLC tracking and monitoring the reaction was complete, the mixture was poured into 100mL of water and extracted three times with ethyl acetate. The aqueous phase was 240ml. Washed three times with 300ml of water The organic phase was dried over anhydrous sodium sulfate, the organic phase was concentrated. Analytical crystal solution with hydrogen chloride ether solution, filtered crystals with a mixed solvent of isopropyl ether and recrystallized from ethyl acetate to give the condensation product of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyric carbonitrile hydrochloride (2) as a white solid 6.8g, yield 74.6%, mp: 156.5-158. . . 1H-NmrgoomHzADCI3), δ (ppm): 7.35-7.42 (10H, m), 6.90 (1H, s), 6.77 (1H, s), 3.90-3.94 (2H, m), 2.75-2.79 (2H, m) , 2.25 (3H, s).

[0072] Preparation imidafenacin (I),

[0073] 4- (2-methyl-1-imidazolyl) -2,2_ diphenyl butyronitrile hydrochloride (2) (8.78g, 26mmol) in 70% concentrated sulfuric acid (25ml) was added to the reaction bottle, the reaction was stirred at 80 ° C, the end of the reaction was monitored by TLC tracking. The reaction solution was poured into 120ml of water, solid sodium carbonate was added to adjust PH to weakly alkaline, sufficiently stirred. With 180ml of dichloromethane and 35ml of ethanol mixed solvent was extracted three times, the organic phase was washed with water, dried over anhydrous sodium sulfate, the organic phase was concentrated. The residue was mixed with a solvent of ethyl acetate and recrystallized from ethanol to give 4- (2-methyl-1-imidazolyl) 2,2-diphenyl butyramide 6.Sg, yield 81.8%, mp: 188.0-190. (TC.1H-NMR and 13C-NMR data are as follows (see Figure 1-2 spectra):

[0074] 1H-NMR (CDC13,400ΜΗζ) δ: 2.209 (s, 3H, -CH3), 2.666-2.707 (t, 2H, -CH2-CH2-),

3.747-3.788 (t, 2H, -CH2-CH2 -), 5.341 (s, 1H, -NH -), 5.757 (s, 1H, -NH -), 6.699 (s, 1H, Ar-H)

, 6.828 (s, 1H, Ar-H), 7.287-7.390 (m, I OH, Ar-H). [0075] 13C-NMR (CDC13,400MHz) δ: 12.17 (_CH3), 41.00 (-CH2 -), 43.74 (-CH2-), 59.44 (quaternary carbon, coupled with strong electron-withdrawing group), 119.08 (-C = C -), 126.95 (aromatic carbon), 127.88 (aromatic carbon), 128.52 (aromatic carbon), 129.10 (aromatic carbon), 142.61 (= CN), 144.54 (-C = N), 176.21 (carbonyl carbon).

 

PATENT

CN 105399678

https://www.google.com/patents/CN105399678A?cl=en

CLIP

http://dmd.aspetjournals.org/content/35/9/1624/T3.expansion.html

TABLE 3

Chemical shifts of protons and carbons in 1H NMR and 13C NMR spectra of major (M-11b) and minor (M-11a) constituents of reference products obtained from imidafenacinGraphic


Position of Proton



1H NMR Data (in D2O)


Major Constituent (M-11b)


Minor Constituent (M-11a)


1 2.18a (3Hb, sc) 2.11a (3Hb, sc)
2 2.82 (2H, m) 2.79 (2H, m)
3 3.45 (2H, m) 3.41 (2H, m)
5 5.26 (1H, s) 5.43-5.47d (1H, d, J = 8.1e)
6 5.33 (1H, s) 5.43-5.47d (1H, d, J = 8.1e)
8, 9, and 10 7.39-7.49 (10H, m) 7.40-7.48 (10H, m)
13


8.45 (1.3H, s)


8.45 (2H, s)


Position of Carbon


13C-NMR Data (in D2O)xc


Major Constituent (M-11b)


Minor Constituent (M-11a)


1 14.61a 14.48a
2 39.04 38.49
3 43.49 42.90
4 61.95-61.99f 61.95-61.99f
5 87.61 80.22 or 85.78f
6 93.10 80.22 or 85.78f
7 144.2-144.4f 144.2-144.4f
8, 9, and 10 130.7-131.8f 130.7-131.8f
11 170.8 169.5
12 181.9-182.2f 181.9-182.2f
13


173.8


173.8


  • a Chemical shifts are reported in parts per million.

  • b Intensities are represented as number of protons.

  • c Multiplicity: s, singlet; d, doublet; m, multiplet.

  • d These proton signals could not be distinguished.

  • e Coupling constants (J) are given in Hertz.

  • f These carbon signals could not be distinguished.

Fig. 1.

FIG. 1.

Chemical structures of [14C]imidafenacin and postulated metabolites, and their fragment ions. *, 14C labeled position; broken line, precursor and product ions obtained by collision-induced dissociation in LC/MS/MS.

 

 

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US2013211352 2013-08-15 PERCUTANEOUSLY ABSORBED PREPARATION
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US8343544 2013-01-01 Oral sustained-release tablet
US2012289563 2012-11-15 COMBINATIONS OF IMIDAFENACIN AND SALIVARY STIMULANTS FOR THE TREATMENT OF OVERACTIVE BLADDER
US8247415 2012-08-21 Hydroxymethyl pyrrolidines as [beta]3 adrenergic receptor agonists
US8158152 2012-04-17 Lyophilization process and products obtained thereby
US8124633 2012-02-28 HYDROXYMETHYL ETHER HYDROISOINDOLINE TACHYKININ RECEPTOR ANTAGONISTS
  1. Kobayashi F, Yageta Y, Segawa M, Matsuzawa S: Effects of imidafenacin (KRP-197/ONO-8025), a new anti-cholinergic agent, on muscarinic acetylcholine receptors. High affinities for M3 and M1 receptor subtypes and selectivity for urinary bladder over salivary gland. Arzneimittelforschung. 2007;57(2):92-100. [PubMed:17396619 ]
  2. Miyachi H, Kiyota H, Uchiki H, Segawa M: Synthesis and antimuscarinic activity of a series of 4-(1-Imidazolyl)-2,2-diphenylbutyramides: discovery of potent and subtype-selective antimuscarinic agents. Bioorg Med Chem. 1999 Jun;7(6):1151-61. [PubMed:10428387 ]

Reference

Imidafenacin
Imidafenacin.png
Systematic (IUPAC) name
4-(2-methyl-1H-imidazol-1-yl)-2,2-diphenylbutanamide
Clinical data
Routes of
administration
Oral
Legal status
Legal status
  • ℞ (Prescription only)
Identifiers
CAS Number 170105-16-5 Yes
ATC code none
PubChem CID 6433090
ChemSpider 4938278 
UNII XJR8Y07LJO Yes
ChEMBL CHEMBL53366 
Chemical data
Formula C20H21N3O
Molar mass 319.40 g/mol

//////////イミダフェナシン , D06273, KRP-197, KRP 197, ONO-8025, ONO 8025, UNII:XJR8Y07LJO, Kyorin, Ono ,Imidafenacin, 170105-16-5, JAPAN 2015,  Uritos® , Staybla®

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Pemafibrate


 

 

img

Pemafibrate

NDA Filing Japan, Phase 2 in EU, US

A PPAR-α agonist potentially for the treatment of dyslipidemia.

K-877, K-13675, (R)-

CAS No. 848259-27-8,

Molecular Formula,C28-H30-N2-O6,Molecular Weight,490.553

(2R)-2-[3-({(1,3-benzoxazol-2-yl)[3-(4-methoxyphenoxy)propyl]amino}methyl)phenoxy]butanoic acid
(R)-2-{3-[N-(benzoxazole-2-yl)-N-(3-(4-methoxyphenoxy)propyl)aminomethyl]phenyloxy}butyric acid
  • Originator Kowa Pharmaceutical
  • Class Antihyperlipidaemics
  • Mechanism of Action Peroxisome proliferator-activated receptor alpha agonists
  • Preregistration Dyslipidaemias

Most Recent Events

  • 01 Feb 2016 Kowa Research Institute completes a phase I drug-interaction trial in Healthy volunteers in USA (PO) (NCT02719431)
  • 12 Jan 2016 Kowa Research Institute plans the phase III PROMINENT trial for Dyslipidaemia (In patients with diabetes mellitus) in countries worldwide
  • 01 Jan 2016 Kowa Research Institute initiates a phase I drug-interaction trial in Healthy volunteers in USA (PO) (NCT02719431)

Pemafibrate, also known as K-877 and (R)-K 13675, is a PPAR alpha agonist. (R)-K-13675 decreases the secretion of inflammatory markers without affecting cell proliferation or tube formation. Peroxisome proliferator-activated receptor-alpha (PPAR-alpha) is a key regulator of lipid and glucose metabolism and has been implicated in inflammation. (R)-K-13675 was associated with the inhibition of inflammatory responses without affecting cell proliferation or angiogenesis, and subsequently may induce an anti-atherosclerotic effect.

Pemafibrate had been filed NDA by Kowa for the treatment of dyslipidemia in the Japan in 2015.

Pemafibrate is in phase II clinical trials for the treatment of dyslipidemia in the US and EU.

 

 

Route 1
Reference:1. US2009023944A1.

Route 2
Reference:1. US2009076280A1.

http://www.google.com/patents/US20090076280

Example 5 Synthesis of (R)-2-{3-[N-(benzoxazole-2-yl)-N-(3-(4-methoxyphenoxy)propyl)aminomethyl]phenyloxy}butyric acid (Compound (6))

  • Ethyl (R)-2-{3-[N-(benzoxazole-2-yl)-N-(3-(4-methoxyphenoxy)propyl)aminomethyl]phenyloxy}butylate (26.0 g) was dissolved in ethanol (200 mL), and 1.5N NaOH (50 mL) was added to the solution, followed by stirring for 1 hour at room temperature. The reaction mixture was washed with diethyl ether, and the formed aqueous layer was acidified with 4N HCl under ice cooling. The thus-treated aqueous layer was extracted with ethyl acetate, and the extract was washed sequentially with water and saturated brine. The washed extract was dried over sodium sulfate anhydrate and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol=10/1), to thereby yield the target product (21.3 g, 87%, 98% ee).

Optical Purity:

  • Measurement conditions: HPLC
  • Column: CHIRALPAK AD
  • Solvent: n-hexane/IPA/TFA=100/30/0.1
  • Flow rate: 2 mL/min
  • Retention time: 4.19 min (S-form; 3.68 min)
  • 1H-NMR (400 MHz, CD3OD) δ ppm: 0.94 (t, J=7 Hz, 3H), 1.81 (m, 2H), 1.99 (quintet, J=6 Hz, 2H), 3.60 (t, J=7 Hz, 2H), 3.61 (s, 3H), 3.85 (t, J=6 Hz, 2H), 4.40 (t, J=6 Hz, 1H), 4.65 (s, 2H), 6.69-6.80 (m, 7H), 6.91 (dt, J=7, 1 Hz, 1H), 7.05 (dt, J=7, 1 Hz, 1H), 7.12-7.18 (m, 4H).

 

Route 3
Reference:1. Bioorg. Med. Chem. Lett. 200717, 4689-4693.

 

Landmark Trial Entitled “PROMINENT” To Explore The Prevention Of Heart Disease In Diabetic Patients With High Triglycerides And Low HDL-C

Trial will evaluate if lowering triglycerides and increasing functional HDL with Kowa’s potent selective peroxisome proliferator activator receptor-alpha (PPAR-alpha) modulator, K-877 (pemafibrate) can reduce the elevated risk of cardiovascular disease in high-risk diabetic patients who are already taking statins

Jan 12, 2016, 09:00 ET from Kowa Research Institute, Inc.

RESEARCH TRIANGLE PARK, N.C., Jan. 12, 2016 /PRNewswire/ — Kowa Research Institute, Inc., announced plans to conduct an international, multi-center cardiovascular outcomes trial evaluating triglyceride reduction and increasing functional HDL with K-877 (pemafibrate), in high-risk diabetic patients with high triglyceride and low HDL-C levels who are already taking statins.  K-877 is a highly potent and selective peroxisome proliferator activator receptor-alpha (PPAR-alpha) modulator (SPPARMalpha), a promising category of metabolic therapy.

Paul Ridker, MD, director of the Center for Cardiovascular Disease Prevention (CCVDP) at Brigham and Women’s Hospital (BWH), a teaching affiliate of Harvard Medical School, and Aruna Pradhan, MD, a cardiologist at BWH, will be co-Principal Investigators of the planned trial.

“This trial is unprecedented,” said Gary Gordon, MD, President, Kowa Research Institute, Inc. “Statins are effective in lowering cardiovascular risk among patients with high cholesterol, but residual risk remains, particularly in patients with high triglyceride levels and low HDL-C levels.  Kowa will be the first company to run a major, randomized clinical trial investigating whether modulating PPAR-alpha to lower triglycerides and increase functional HDL in diabetic patients can reduce cardiovascular risk when added to statin therapy.”

Evidence supports a role for triglyceride-rich lipoproteins and low HDL-C as important contributors to atherosclerosis.  Kowa specifically set out to create the most potent and selective PPAR-alpha modulator ever developed, and succeeded with K-877, which is at least 1,000 times as potent and selective as other drugs.  Kowa has completed clinical development of K-877 for hyperlipidemia in Japan, and has submitted it to the PMDA for approval as a new drug.  Kowa’s clinical studies have shown K-877 significantly reduces triglycerides, ApoC3, and remnant cholesterol and increases functional HDL and FGF21.

The Pemafibrate to Reduce cardiovascular OutcoMes by reducing triglycerides IN diabetic patiENTs (PROMINENT) Phase 3 K-877 cardiovascular outcomes trial will recruit an estimated 10,000 high-risk diabetic patients worldwide.  All participants will receive aggressive, standard of care management of cardiovascular risk factors including treatment with high-intensity statins.  In addition, patients will receive either K-877 or placebo.  The trial will include diabetic patients with and without established cardiovascular disease and will test whether K-877 reduces the occurrence of heart attacks, hospitalizations for unstable angina requiring unplanned revascularization, stroke, or death from cardiovascular causes.

“Cardiovascular disease remains the number one cause of death worldwide,” said Dr. Gordon.  “Reducing residual cardiovascular risk with K-877 would be valuable to physicians managing patients’ cardiovascular disease.”

About Kowa Company, Ltd. and Kowa Research Institute, Inc.
Kowa Company, Ltd. (Kowa) is a privately held multinational company headquartered in Nagoya, Japan. Established in 1894, Kowa is actively engaged in various manufacturing and trading activities in the fields of pharmaceuticals, life science, information technology, textiles, machinery and various consumer products. Kowa’s pharmaceutical division is focused on research and development for cardiovascular therapeutics (dyslipidemia, type 2 diabetes and atherosclerosis), ophthalmology and anti-inflammatory agents. The company’s flagship product, LIVALO® (pitavastatin), is approved in 45 countries around the world.

Kowa Research Institute, Inc., headquartered in Research Triangle Park, NC, is the division of Kowa responsible for the clinical development of Kowa’s new drugs in the United States. Kowa Research Institute was established in 1997 in California and began operations at the current location in 2003.  For more information about Kowa Research Institute, visit www.kowaus.com.

1 NCT00610441 Dose Finding Study in Adults With Attention-Deficit/Hyperactivity Disorder (ADHD)(174007/P05805/MK-8777-003) Completed Drug: MK-8777|Drug: Placebo Phase 2 Merck Sharp & Dohme Corp.
2 NCT00610649 Trial to Determine the Maximum Tolerated Dose (MTD) Based on Safety and Tolerability, of Org 26576 in Participants With Major Depressive Disorder (174001/P05704/MK-8777-001) Completed Drug: MK-8777|Drug: Placebo Phase 2 Merck Sharp & Dohme Corp.
3 NCT02073084 A Thorough Corrected QT Interval Trial Completed Drug: K-877 Low Dose|Drug: Moxifloxacin|Other: Placebo|Drug: K-877 High Dose Phase 1 Kowa Research Institute, Inc.
4 NCT02273986 Drug-Drug Interaction Study in Health Adult Volunteers Completed Drug: Digoxin|Drug: K-877 Phase 1 Kowa Research Institute, Inc.
5 NCT02275962 Drug-Drug Interaction Study in Healthy Adult Volunteers Active, not recruiting Drug: K-877|Drug: Rifampin Phase 1 Kowa Research Institute, Inc.
6 NCT02275975 Drug-Drug Interaction Study in Healthy Adult Volunteers Completed Drug: K-877|Drug: Fluconazole Phase 1 Kowa Research Institute, Inc.
7 NCT02275988 Drug-Drug Interaction Study in Healthy Adult Volunteers Completed Drug: K-877|Drug: Clarithromycin Phase 1 Kowa Research Institute, Inc.
8 NCT02276001 Drug-Drug Interaction Study in Healthy Adult Volunteers Completed Drug: K-877|Drug: Cyclosporine Phase 1 Kowa Research Institute, Inc.

2D chemical structure of 848259-27-8

US6653334 * Dec 27, 2002 Nov 25, 2003 Kowa Co., Ltd. Benzoxazole compound and pharmaceutical composition containing the same
US7109226 * Sep 3, 2004 Sep 19, 2006 Kowa Co., Ltd. PPAR-activating compound and pharmaceutical composition comprising the compound
US7183295 * Apr 20, 2006 Feb 27, 2007 Kowa Co., Ltd. PPAR-activating compound and pharmaceutical composition comprising the compound

///////Pemafibrate, NDA,  Kowa, dyslipidemia,  Japan, 2015, phase II clinical trials,  US and EU, K-877, K-13675, (R)-

CC[C@H](C(=O)O)Oc1cccc(c1)CN(CCCOc2ccc(cc2)OC)c3nc4ccccc4o3

CC[C@@H](OC1=CC=CC(CN(C2=NC3=CC=CC=C3O2)CCCOC4=CC=C(OC)C=C4)=C1)C(O)=O

 

Vonoprazan Fumarate


 

img

1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine fumarate

 

Vonoprazan Fumarate

(Takecab®) Approved

Vonoprazan Fumarate
CAS#: 1260141-27-2 (fumarate); 881681-00-1 (free base).
Chemical Formula: C21H20FN3O6S
Molecular Weight: 461.46

A potassium-competitive acid blocker (P-CAB) used to treat gastric ulcer, duodenal ulcer and reflux esophagitis.

Research Code TAK-438

CAS No. 881681-00-1

 Cas 1260141-27-2(Vonoprazan Fumarate)

1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine fumarate

Molecular Weight 461.46
Formula C17H16FN3O2S ● C4H4O4
Drug Name:Vonoprazan FumarateResearch
Code:TAK-438Trade Name:Takecab®MOA:Potassium-competitive acid blocker (P-CAB)Indication:Gastric ulcer; Duodenal ulcer; Reflux esophagitisStatus:ApprovedCompany:Takeda (Originator) , Otsuka
Company Takeda Pharmaceutical Co. Ltd.
Description Small molecule potassium-competitive acid blocker
Molecular Target H+/K ATPase pump

Vonoprazan (Takecab(®)) is an orally bioavailable potassium-competitive acid blocker (P-CAB) being developed by Takeda for the treatment and prevention of acid-related diseases. The drug is approved in Japan for the treatment of acid-related diseases, including erosive oesophagitis, gastric ulcer, duodenal ulcer, peptic ulcer, gastro-oesophageal reflux, reflux oesophagitis and Helicobacter pylori eradication. Phase III development is underway for the prevention of recurrence of duodenal and gastric ulcer in patients receiving aspirin or NSAID therapy. Phase I development was conducted in the UK for gastro-oesophageal reflux; however, no further development has been reported. This article summarizes the milestones in the development of vonoprazan leading to this first approval for acid-related diseases.

Vonoprazan Fumarate was approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on December 26, 2014. It was co-developed and marketed as Takecab® by Takeda & Otsuka.
Vonoprazan has a novel mechanism of action called potassium-competitive acid blockers (P-CABs) which competitively inhibits the binding the potassium ions to H+, K+-ATPase (also known as the proton pump) in the final step of gastric acid secretion in gastric parietal cells. Vonoprazan provides a strong and sustained acid section inhibitory effect. It is indicated for the treatment of gastric ulcer, duodenal ulcer and reflux esophagitis.
Cometriq® is available as tablet for oral use, containing 10 or 20 mg of free Vonoprazan, and the recommended dose is 20 mg orally once daily for adluts.

Vonoprazan fumarate (Takecab(®)) is a first-in-class potassium-competitive acid blocker that has been available in the market in Japan since February 2015. Vonoprazan is administered orally at 20 mg once daily for the treatment of gastroduodenal ulcer, at 20 and 10 mg once daily for the treatment and secondary prevention of reflux esophagitis, respectively, at 10 mg once daily for the secondary prevention of low-dose aspirin- or non-steroidal anti-inflammatory drug-induced peptic ulcer, and at 20 mg twice daily in combination with clarithromycin and amoxicillin for the eradication of Helicobacter pylori. It inhibits H(+),K(+)-ATPase activities in a reversible and potassium-competitive manner with a potency of inhibition approximately 350 times higher than the proton pump inhibitor, lansoprazole. Vonoprazan is absorbed rapidly and reaches maximum plasma concentration at 1.5-2.0 h after oral administration. Food has minimal effect on its intestinal absorption. Oral bioavailability in humans remains unknown. The plasma protein binding of vonoprazan is 80 % in healthy subjects. It distributes extensively into tissues with a mean apparent volume of distribution of 1050 L. Being a base with pKa of 9.6 and with acid-resistant properties, vonoprazan is highly concentrated in the acidic canaliculi of the gastric parietal cells and elicited an acid suppression effect for longer than 24 h after the administration of 20 mg. The mean apparent terminal half-life of the drug is approximately 7.7 h in healthy adults. Vonoprazan is metabolized to inactive metabolites mainly by cytochrome P450 (CYP)3A4 and to some extent by CYP2B6, CYP2C19, CYP2D6, and SULT2A1. A mass balance study showed that 59 and 8 % of the orally administered radioactivity was recovered in urine as metabolites and in an unchanged form, respectively, indicating extensive metabolism. Genetic polymorphism of CYP2C19 may influence drug exposure but only to a clinically insignificant extent (15-29 %), according to the population pharmacokinetic study performed in Japanese patients. When vonoprazan was co-administered with clarithromycin, the mean AUC from time 0 to time of the next dose (dosing interval) of vonoprazan and clarithromycin were increased by 1.8 and 1.5 times, respectively, compared with the corresponding control values, indicating mutual metabolic inhibition. The mean area under the curve from time zero to infinity obtained from patients with severe liver and renal dysfunction were elevated by 2.6 and 2.4 times, respectively, compared with healthy subjects, with no significant changes in plasma protein binding. Vonoprazan increases intragastric pH above 4.0 as early as 4 h after an oral dose of 20 mg, and the extensive anti-secretory effect is maintained up to 24 h post-dose. During repeated dosing of 20 mg once daily, the 24-h intragastric pH >4 holding time ratios were 63 and 83 % on days 1 and 7, respectively. Because vonoprazan elicited a more extensive gastric acid suppression than the proton pump inhibitor, lansoprazole, it also gave rise to two to three times greater serum gastrin concentrations as compared with lansoprazole. In pre-approval clinical studies for the treatment of acid-related disorders, mild to moderate adverse drug reactions (mostly constipation or diarrhea) occurred at frequencies of 8-17 %. Neither severe liver toxicity nor neuroendocrine tumor has been reported in patients receiving vonoprazan.

 

Vonoprazan fumarate is a first-in-class potassium-competitive acid blocker. It was approved in the Japanese market in February, 2015.[1]

Vonoprazan can be used for the treatment of gastroduodenal ulcer, reflux esophagitis, and for some drug-induced peptic ulcers. It can be combined with other antibiotics for the eradication of Helicobacter pylori.[2]

PATENT

CN102421753B

Figure CN102421753BD00401

Figure CN102421753BD00421

 

Route 1

Reference:1. WO2006036024A1 / US8048909B2.

2. WO2007026916A1 / US7498337B2.

3. CN104327051A.

1- [5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -IH- pyrrol-3-yl] -N- methylmethanamine fumarate Takeda single An R & D for the gastric acid secretion inhibitors (codename: TAK-438, generic name: vonoprazan fumarate), the drug belongs to the potassium ion (K +) competitive acid blocker (P-CAB) for a new inhibitors, with a strong, long-lasting inhibition of gastric acid secretion, while the gastric parietal cells in the final stage of gastric acid secretion by inhibiting K + for H +, K + -ATP enzyme (proton pump) binding effect on gastric acid secretion also advance termination action.

Its molecular formula is: C17H16FN3O2S · C4H4O4, MW: 461.46, the chemical structure of formula I as shown.

 

Figure CN104327051AD00031

CN101300229A discloses 1- [5- (2_-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1Η- pyrrol -3-yl] -N- methylmethanamine fumarate alone, but not related to its crystalline form.

The present invention discloses a I- [5- (2- fluorophenyl) -I- (pyridin-3-ylsulfonyl) -IH- pyrrol-3-yl] -N- methylmethanamine single rich fumarate A method for preparing a crystalline form. 1- [5- (2_-fluorophenyl) -1- (Batch-3-ylsulfonyl) -IH- pyrrol-3-yl] -N- methylmethanamine fumarate single crystalline form A, according to prepared by the following routes:

Figure CN104327051AD00051

Example 1

  A method of preparing polymorph having pyrrole derivatives maleate described in detail below.

Step I: 5- (2- fluorophenyl) -1- (pyridin-3-ylsulfonyl) -IH- pyrrole-3-carbaldehyde Synthesis of

Compound II (260mg) was dissolved in tetrahydrofuran (50ml) was added 60% NaH, the reaction was stirred for 30 minutes at room temperature. Was added 15-crown–5 (I. 5g), the reaction mixture was stirred at room temperature for 1 hour and then pyridine-3-sulfonyl chloride was added, stirred at room temperature for 2 hours until complete reaction was followed by thin layer chromatography, and then was added to the reaction system 20mL saturated brine with ethyl acetate (IOOmLX2) and the combined organic phase was washed with saturated brine 50ml organic phase, an appropriate amount of anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude compound IV (200mg) administered directly in the next reaction.

Synthesis 1_ [5- (2-fluorophenyl) -1- (piperidin-3-sulfonyl batch) -IH- pyrrol-3-yl] -N- methylmethanamine of: Step 2

The brown residue obtained in the previous step IV compound (200mg) was dissolved in 30mL methanol was added 27% -33% methyl amine solution, the reaction was stirred for 1.5 hours. Sodium borohydride (68mg), the reaction was stirred for 20 minutes, was added lmol / LHCl to an acidic aqueous solution, and stirred until complete reaction was followed by thin layer chromatography. To the reaction mixture was added saturated sodium bicarbonate solution until weakly basic system was extracted with ethyl acetate (IOOmLX2), the combined organic phases with saturated brine (50mL), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product ( 208mg, yellow oil). Yield: 100%.

  Step 3: 1_ [5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -IH- pyrrol-3-yl] -N- methylmethanamine fumarate single synthesis

Compound V obtained in the previous step was dissolved in 20mL of ethyl acetate, taking the mass fraction of equivalents of fumaric acid was dissolved in 2ml of methanol. Added dropwise with stirring to a solution of compound V in ethyl acetate, stirred for 30 minutes at room temperature. Then warmed to 55-65 degrees reflux one hour, cooled to room temperature and filtered to give an off-white solid was washed with cold ethyl acetate IOml and dried in vacuo to give 170mg of crystalline Compound I, about 20% overall yield. X- ray diffraction spectrum of the crystalline sample is shown in Figure 1. DSC spectrum shown in Figure 2, this polymorph is defined as A crystalline form.

Route 2

Reference:1. CN105085484A.

http://www.google.com/patents/CN105085484A?cl=en

Fumaric Wonuo La Like (TAK-438, Vonoprazan fumarate) is Takeda Pharmaceuticals and Otsuka Pharmaceutical to launch a new type of oral anti-acid drugs. As a potassium ion (K +) competitive acid blocker (P-CAB), Wonuo La Like gastric acid secretion in the gastric parietal cells play a role in the final step, by inhibiting K + for H +, K + -ATP enzyme (proton chestnut) combine to inhibit gastric acid secretion and early termination. Compared to the current power of the proton chestnut inhibitors (PPIs), due to the absence of praise Wonuo La CYP2C19 metabolism, so the performance in clinical trials showing good effect: the treatment of gastric ulcer / duodenal ulcer, reflux esophagitis eradication of H. pylori and other effects are better than lansoprazole, while having a similar security.

  fumarate Wonuo La Like chemical name: I- [5_ (2_ gas) -1- (pyridin _3_ cross-acyl group) -IH- P ratio slightly 3-yl] – N- methylmethanamine fumarate, structured as follows:

 

Figure CN105085484AD00051

  Preparation of fumaric Wonuo La Like synthetic route mainly follows:

  Takeda patent CN200680040789 original study discloses a 5- (2-fluorophenyl) -lH- pyrrole-3-carbaldehyde as a starting material, the solvent is tetrahydrofuran, sodium hydride doing acid binding agent, crown ethers do a phase transfer catalyst, with 3-pyridine sulfonyl chloride to give the intermediate 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -IH- pyrrole-3-carbaldehyde, then to form a Schiff base with methylamine boron sodium hydride reduction to give Wonuo La Like the free base and then fumaric acid salt formation, generate fumaric Wonuo La Chan, the reaction equation is as follows:

 

Figure CN105085484AD00061

  Takeda company disclosed in 2010 it 0 01,080,018,114 in improved synthetic route: Intermediate 5- (2-fluorophenyl) -I- (pyridine-3-ylsulfonyl) -IH–3 formaldehyde synthesis, instead of acetonitrile as solvent, DIEA do acid-binding agent, DMAP as catalyst, but side reactions, tedious post-processing operation, the lower the yield, the overall yield of less than 40%.

CN201080018114 improved synthetic route to 5- (2-fluorophenyl) -IH- pyrrole-3-carbonitrile as a starting material of the synthesis route, but this route is converted to the cyano aldehyde used Raney catalytic hydrogenation, industrial scale there is a big security risk, its reaction equation is as follows:

Figure CN105085484AD00062

  Y. Arikawa et J. Med Chem 2012, 55, 4446-4456 reported the following synthetic route.:

In phenyl pyrrole-3-carbaldehyde and methylamine alcohol imine by metal borohydride reduction, to give further protection to give Boc ((5-phenyl -IH- pyrrol-3-yl) -N -) methyl carbamate; the above product with an arylsulfonyl chloride, and then de-Boc protection to give 1- (5-phenyl-1 aromatic sulfonyl -IH- pyrrol-3-yl) – N- methyl methylamine;

Figure CN105085484AD00063

Y. Arikawa et al reported that the above process step is prolonged, the probability g [J reacting a corresponding increase in the above reaction scheme conditional optimization, control side reactions is one of the present invention is to solve the problem. On the other hand the above literature after the synthesis process used in chromatography, is not conducive to fumaric Wonuo La Like industrial production. Therefore, the development of fumaric acid Wonuo La Like New synthesis process, simplify the synthesis operations, reduce costs, improve productivity, it has important implications for fumaric Wonuo La Like this one which attract anti-acid drugs.

str1

PAPER

J. Med Chem 2012, 55, 4446-4456

http://pubs.acs.org/doi/abs/10.1021/jm300318t

Discovery of a Novel Pyrrole Derivative 1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine Fumarate (TAK-438) as a Potassium-Competitive Acid Blocker (P-CAB)

Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., 26-1, Muraokahigashi-2-chome, Fujisawa, Kanagawa 251-8555, Japan
CMC Research Center, Takeda Pharmaceutical Company Ltd., 17-85, Jusohonmachi-2-chome, Yodogawa-ku, Osaka 532-8686, Japan
J. Med. Chem., 2012, 55 (9), pp 4446–4456
DOI: 10.1021/jm300318t

 

Abstract Image

In our pursuit of developing a novel and potent potassium-competitive acid blocker (P-CAB), we synthesized pyrrole derivatives focusing on compounds with low log D and high ligand-lipophilicity efficiency (LLE) values. Among the compounds synthesized, the compound 13e exhibited potent H+,K+-ATPase inhibitory activity and potent gastric acid secretion inhibitory action in vivo. Its maximum efficacy was more potent and its duration of action was much longer than those of proton pump inhibitors (PPIs). Therefore, compound 13e (1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate, TAK-438) was selected as a drug candidate for the treatment of gastroesophageal reflux disease (GERD), peptic ulcer, and other acid-related diseases.

 

 

SYNTHESIS

Presentation of Highlight Results from recent Phase 3 Trials of Vonoprazan Fumarate for the Treatment of Acid-related Diseases at the DDW 2014 Meeting

Osaka, Japan, May 7, 2014 — Takeda Pharmaceutical Company Limited (“Takeda”) announced today that the results of five Phase 3 trials for Vonoprazan Fumarate (development code:TAK-438) were presented at the poster session of Digestive Disease Week (DDW) being held May 3-6, 2014 in Chicago, Illinois.

Vonoprazan Fumarate, discovered by Takeda, belongs to a new class of acid secretion inhibitors called potassium-competitive acid blockers (P-CAB). It competitively inhibits the binding of potassium ion to H+, K+-ATPase (proton pump) in the final step of gastric acid secretion in gastric parietal cells. Vonoprazan Fumarate has strong and sustained acid secretion inhibitory effects and shows efficacy from the early stages of dosing. Takeda submitted a New Drug Application in Japan in February 2014. These highlight results presented at DDW include the Phase 3 results that were submitted with the New Drug Application.

Takeda aims to achieve better treatment outcomes in the field of gastrointestinal diseases and is striving to meet the medical needs of more patients.

# # #

<A Phase 3, Randomized, Double-Blind, Multicenter Study to Evaluate the Efficacy and Safety of TAK-438 (20 mg Once-Daily) Compared to AG-1749 (Lansoprazole; LPZ) (30 mg Once-Daily) in Patients With Erosive Esophagitis (EE) (Abstract #Tu1059)>
Objective To evaluate the efficacy and safety of TAK-438 (20 mg Once-Daily) compared to LPZ (30 mg Once-Daily) in Japanese patients with EE
Study Design Multicenter, randomized, double-blind, active-controlled, Phase 3 trial
Population Patients with EE of Los Angeles Classification Grade (LA Grade) A to D
Patients 409
Description This study consisted of 2 periods; an observation period of 3 to 7 days and a double-blind treatment period of 8 weeks.
The subjects were stratified by the baseline LA Grades (A/B or C/D) and randomized in a ratio of 1:1 to receive TAK-438 20 mg or LPZ 30 mg, once daily. The subjects with endoscopically confirmed healing of EE at Week 2, 4, or 8 were regarded as having completed the study.
Primary endpoint Proportion of healed patients at Week 8
* EE healing was defined as endoscopically confirmed Grade O (i.e. no mucosal breaks) by investigators.
Results Efficacy
Ÿ・   For the primary endpoint, the proportion of healed patients at Week 8, the non-inferiority of TAK-438 to LPZ was verified (99.0% vs. 95.5%, p<0.0001).
・Ÿ   The superiority of TAK-438 to LPZ was also verified for the proportion of healed patients at Week 8 based on the post-hoc analysis results (p=0.0337).
Ÿ・   The difference in the proportion of healed patients between the 4-week treatment of TAK-438 and the 8-week treatment of LPZ (TAK-438 group – LPZ group) was 1.1% (96.6% vs. 95.5%). The lower limit of the 95% CI of the difference was above -10% (=the lower limit of the non-inferiority margin for the primary analysis), which indicated the non-inferiority of TAK-438 4W to LPZ 8W.
Ÿ・   Notably, the differences in the proportion of healed patients between TAK-438 group and LPZ group were large in the subgroups of CYP2C19-EM (98.9% vs. 94.5%) and LA Grade C/D (98.7% vs. 87.5%) .
Safety
・Ÿ   The incidences of AEs, drug-related AEs, AEs leading to study drug discontinuation, and serious AEs were comparable between the groups.
Ÿ・   Nasopharyngitis was most commonly reported TEAE in both groups (TAK-438, LPZ: 3.4%, 4.0%). The incidences of other TEAEs by PT were ≦ 2%.
<A Phase 3, Randomized, Double-Blind, Multicenter Study to Evaluate the Efficacy and Safety of TAK-438 (10 mg or 20 mg Once-Daily) Compared to AG-1749 (Lansoprazole; LPZ) (15 mg Once-Daily) in a 24-week Maintenance Treatment in Patients With Healed Erosive Esophagitis (EE) (Abstract #Tu1052)>
Objective To evaluate the efficacy and safety of TAK-438 (10 mg or 20 mg Once-Daily) compared to LPZ (15 mg Once-Daily) in a 24-week maintenance treatment for healed EE
Study Design Multicenter, randomized, double-blind, active-controlled, phase 3 trial
Population Patients with EE of Los Angeles Classification Grade (LA Grade) A to D
Patients 607
Description Subjects with EE of LA Grade A to D received TAK-438 20 mg once daily for 2, 4, or 8 weeks during the treatment period. If EE healing was confirmed, the subject was stratified by the baseline LA grade (A/B or C/D) and randomized in a ratio of 1:1:1 to receive TAK-438 in doses of 10 mg, 20 mg, or LPZ 15mg, once daily, in a 24-week maintenance period. Once EE recurrence was endoscopically confirmed, the subject discontinued the study.
Primary endpoint Proportion with recurrence at Week 24 *EE recurrence was defined as endoscopically confirmed LA Grade A to D by investigators.
Results Efficacy
Ÿ・   For the primary endpoint, the proportion with recurrence at Week 24, the non-inferiority to LPZ was verified for both TAK-438 groups. The proportion was 16.8%, 5.1%, 2.0% in the LPZ 15 mg, TAK-438 10 mg and TAK-438 20 mg, respectively (p<0.0001).
・Ÿ   The superiority to LPZ was also verified for both TAK-438 groups for the proportion with recurrence at Week 24 based on the post-hoc analysis results. (LPZ 15 mg vs. TAK-438 10 mg: p=0.0002, LPZ 15 mg vs. TAK-438 20 mg: p<0.0001).
Ÿ・   Notably, the differences in the proportion with recurrence between each TAK-438 group and LPZ group were large in the subgroups of CYP2C19-EM (LPZ 15 mg, TAK-438 10 mg, TAK-438 20 mg: 19.6%, 5.4%, 1.8%) and LA Grade C/D (LPZ 15 mg, TAK-438 10 mg, TAK-438 20 mg: 39.0%, 13.2%, 4.7%).
Safety
Ÿ・   The incidences of AEs, drug-related AEs, AEs leading to study drug discontinuation, and serious AEs in the maintenance period were comparable among the groups.
Ÿ・   Nasopharyngitis was the most commonly reported TEAE in all groups (LPZ 15 mg, TAK-438 10 mg, TAK-438 20 mg: 13.9%, 16.8%, 13.2%).
Ÿ・   Serum gastrin increased to the greatest degree in TAK-438 20 mg group, followed by TAK-438 10 mg group, and LPZ group. On the other hand, no obvious difference among the groups in gastric mucosa histopathologic tests were observed during the study. The increase in serum gastrin observed during the study did not cause any adverse effects on the gastric mucosa as evidenced by histopathological testing.
<A Phase 3, Multicenter, Randomized, Double-blind, AG-1749 (Lansoprazole; LPZ) -controlled, Parallel-group, Comparison Study to Evaluate the Efficacy and Safety of TAK-438 (10 mg or 20 mg, Orally, Once Daily) for the Prevention of Recurrent Gastric or Duodenal Ulcers During Long-term Therapy of Non-steroidal Anti-inflammatory Drug (NSAID) (Abstract #Tu1054)>
Objective To evaluate the efficacy and safety of TAK-438 (10 mg or 20 mg Once-Daily) compared to LPZ (15 mg Once-Daily) for secondary prevention of peptic ulcers associated with NSAID therapy
Study Design Multicenter, randomized, double-blind, double-dummy, non-inferiority, active-controlled Phase 3 trial
Population Patients with a history of gastric ulcers (GU) or duodenal ulcers (DU) who require long-term NSAID therapy
Patients 642
Description Patients receive NSAID with TAK-438 in doses of 10 mg, 20 mg, or LPZ 15 mg, once daily.
Primary Endpoint The proportion of patients with recurrent GU or DU confirmed with endoscopy at Week 24.
Secondary Endpoints The proportion of patients with the development of hemorrhagic lesion confirmed with endoscopy in stomach or duodenum
Exploratory Analysis Time to event of ulcer recurrence or hemorrhagic lesion occurrence in stomach or duodenum
Results Efficacy
Ÿ・   At Week 24, non-inferiority of TAK-438 10 mg and 20 mg to LPZ 15 mg was verified for the proportion of patients with recurrent peptic ulcers (LPZ 15 mg, TAK-438 10 mg, TAK-438 20 mg: 5.5%, 3.3%, 3.4% : p<0.0001 vs.  LPZ 15 mg). The proportion of patients with recurrent peptic ulcers in the TAK-438 10 mg and 20 mg through week 24 was slightly lower than in the LPZ 15 mg, although no statistically significant differences were observed.
Ÿ・   The proportion of patients with the development of hemorrhagic lesion in stomach or duodenum was slightly lower in each TAK-438 group than in LPZ 15 mg through 24 weeks, but no statistically significant differences were observed (LPZ 15 mg, TAK-438 10 mg, TAK-438 20 mg at Week 24 : 2.0%, 1.4%, 1.0%). Ÿ   The proportion of cumulative incidences of GU/DU or hemorrhagic lesion was lower in each TAK-438 group than in LPZ 15 mg group.
Safety
・Ÿ   The incidence of treatment emergent adverse events (TEAEs) was almost similar across the treatment groups.
Ÿ・   The most commonly reported TEAE was nasopharyngitis in all the treatment groups (LPZ 15 mg, TAK-438 10 mg, TAK-438 20 mg: 18.6%, 22.9%, 18.4%).
Ÿ・   Serum gastrin of patients in each TAK-438 group was higher compared to that in LPZ 15 mg group, and degree of increase was dose-dependent. Serum gastrin increased at Week 4 in all treatment groups, no obvious increasing tendency was observed thereafter, and it was almost stable until Week 24.
<A Phase 3, Multicenter, Randomized, Double-blind, AG-1749 (Lansoprazole; LPZ) -controlled, Parallel-group, Comparison Study to Evaluate the Efficacy and Safety of TAK-438 (10 mg or 20 mg, Orally, Once Daily) for the Prevention of Recurrent Gastric or Duodenal Ulcers During Long-term Therapy of Low-dose Aspirin (LDA) (Abstract #Tu1055)>
Objective To evaluate the efficacy and safety of TAK-438 (10 mg or 20 mg Once-Daily) compared to Lansoprazole (LPZ) (15 mg Once-Daily) for secondary prevention of peptic ulcers associated with LDA therapy
Study Design Multicenter, randomized, double-blind, double-dummy, non-inferiority, active-controlled phase 3 trial
Population Patients with a history of gastric ulcers (GU) or duodenal ulcers (DU) who require long-term LDA therapy
Patients 621
Description Patients receive LDA with TAK-438 in doses of 10 mg, 20 mg, or Lansoprazol (LPZ) 15 mg, once daily.
Primary Endpoint The proportion of patients with recurrent GU or DU confirmed with endoscopy at Week 24
Secondary Endpoints The proportion of patients with the development of hemorrhagic lesion confirmed with endoscopy in stomach or duodenum
Exploratory Analysis Time to event of ulcer recurrence or hemorrhagic lesion occurrence in stomach or duodenum
Results Efficacy
Ÿ・   At Week 24, non-inferiority of TAK-438 10 mg and 20 mg to LPZ 15 mg was verified for the proportion of patients with recurrent peptic ulcers (LPZ 15 mg, TAK-438 10 mg, TAK-438 20 mg: 2.8%, 0.5%, 1.5% : p<0.0001 vs. LPZ 15 mg). The proportion of patients with recurrent peptic ulcers in the TAK-438 10 mg and 20 mg through 24 weeks was slightly lower than in the LPZ 15 mg, although no statistically significant differences were observed.
Ÿ・   The proportion of patients with the development of hemorrhagic lesion in stomach or duodenum was significantly lower in each TAK-438 groups than in LPZ 15 mg through 24 weeks, and higher prevention effect on hemorrhagic lesion was observed (LPZ 15 mg, TAK-438 10 mg, TAK-438 20 mg at Week 24 : 2.9%, 0.0%, 0.0% : p=0.0129 vs. LPZ 15 mg).
Ÿ・   The proportion of cumulative incidences of GU/DU or hemorrhagic lesion at Week 24 was lower in each TAK-438 group than in LPZ 15 mg group, and statistically significant differences were observed (p=0.0066: TAK-438 10 mg vs. LPZ 15 mg, p=0.0471: TAK-438 20 mg vs. LPZ 15 mg).
Safety
Ÿ・   The incidence of treatment emergent adverse events (TEAEs) was almost similar across the treatment groups.
Ÿ・   The mostly commonly reported TEAE was nasopharyngitis in all the treatment groups (LPZ 15 mg, TAK-438 10 mg, TAK-438 20 mg: 17.1%, 14.9%, 20.3%).
Ÿ・   Serum gastrin of patients in each TAK-438 group was higher compared to that in LPZ 15 mg group, and degree of increase was dose-dependent. Serum gastrin increased at Week 4 in all treatment groups, no obvious increasing tendency was observed thereafter, and it was almost stable until Week 24.
<A Phase 3, Randomized, Double-Blind, Double Dummy, Multicenter, Parallel Group Comparison Study to Evaluate Efficacy and Safety of a Triple Therapy With TAK-438, Amoxicillin (AMPC) and Clarithromycin (CAM) by Comparison With a Triple Therapy With AG-1749 (Lansoprazole; LPZ), AMPC and CAM for the First Line Eradication of H.Pylori (Abstract#Tu1056)>
Objective To evaluate the efficacy and safety of a Triple Therapy with TAK-438, AMPC, and CAM as First Line Eradication of H. pylori and a Triple Therapy with TAK-438, AMPC, and Metronidazole (MNDZ) as Second Line Eradication of H. pylori
Study Design Multicenter, randomized, double-blind, active-controlled, phase 3 trial
Population H. pylori-positive patients with cicatrized gastric or duodenal ulcer
Patients 650
Description 650 eligible subjects were randomly allocated at a 1:1:1:1 ratio to receive one of four 7-day courses as the first line therapy; TAK-438 (20 mg b.i.d.), AMPC (750 mg b.i.d.) and CAM (200 mg b.i.d. or 400 mg b.i.d.), or LPZ (30 mg b.i.d.), AMPC (750 mg b.i.d.) and CAM (200 mg b.i.d. or 400 mg b.i.d.). 50 of 101 subjects for whom the first line eradication had failed in this study received additional 7-day course of TAK-438 (20 mg b.i.d.), AMPC (750 mg b.i.d.) and MNDZ (250 mg b.i.d.) as the second line therapy. More than 4 weeks after the treatment, eradication was evaluated by using 13C urea breath test.
Primary Endpoint H. pylori eradication rate with the first line therapy
Secondary Endpoint H. pylori eradication rate with the second line therapy
Results Efficacy
・   In the analysis of primary endpoint, H. pylori eradication rate, the non-inferiority of the first line therapy with TAK-438 to that with LPZ was verified using the Farrington and Manning test with a non-inferiority margin of 10% (Eradication rate: with TAK-438: 92.6% [300/324], with LPZ: 75.9% [243/320], p < 0.0001). Based on the additional analysis, the superiority of the first line therapy with TAK-438 to that with LPZ was confirmed (p < 0.0001). In the subjects who were treated by the second line therapy with TAK-438, the H. pylori eradication rate was also high (98.0% [49/50]).
Ÿ・   The H. pylori eradication rates were significantly higher in the first line therapy with TAK-438 than that with LPZ in the subjects with EMs for CYP2C19 (with TAK-438: 92.9% [250/269], with LPZ: 75.0% [204/272]) and the subjects with a CAM MIC of ≥ 1 μg/mL, CAM resistance (with TAK-438: 82.0% [82/100], with LPZ: 40.0% [46/115]). The doses of CAM did not affect the H. pylori eradication rate with the first line therapy (200 mg b.i.d: with TAK-438: 93.3% [152/163], with LPZ: 78.7% [129/164], 400 mg b.i.d : with TAK-438: 91.9% [148/161], with LPZ: 73.1% [114/156]).
Safety
Ÿ・   In the first line therapies, the overall incidences of Treatment-Emergent Adverse Events (TEAEs), drug-related TEAEs, TEAEs leading to study drug discontinuation and serious TEAEs were comparable between both therapies. In the second line therapy, those were similar to those of the first line therapies.
Ÿ・   The TEAEs with ≥ 2% incidence were diarrhoea, nasopharyngitis, and dysgeusia in both of the first line therapies (LPZ 15 mg,: 15.3%, 4.7%, 3.1%, TAK-438:  12.5%, 5.5%, 4.0%). No remarkable differences between both therapies were observed in the incidences of TEAEs by Preferred Term. The incidence of dysgeusia seemed to be related to daily CAM dose. The TEAEs reported in 2 subjects treated by the second line therapy with TAK-438 were diarrhoea (4.0%), flatulence (4.0%), nasopharyngitis (4.0%), ALT increased (4.0%), and AST increased (4.0%)
Ÿ・   Serious TEAEs were reported from 6 subjects in the first line therapies and 1 subject in the second line therapy. In the first line therapy with TAK-438, 1 serious TEAE, acute myocardial infarction, was assessed as related to the study drug. All the other serious TEAEs in the first line therapies and all the serious TEAEs in the second line therapy were assessed as not related to the study drug by the investigators.

References

References

1: Arikawa Y, Nishida H, Kurasawa O, Hasuoka A, Hirase K, Inatomi N, Hori Y, Matsukawa J, Imanishi A, Kondo M, Tarui N, Hamada T, Takagi T, Takeuchi T, Kajino M. Discovery of a novel pyrrole derivative 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamin e fumarate (TAK-438) as a potassium-competitive acid blocker (P-CAB). J Med Chem. 2012 May 10;55(9):4446-56. doi: 10.1021/jm300318t. Epub 2012 Apr 30. PubMed PMID: 22512618.

2: Kondo M, Kawamoto M, Hasuoka A, Kajino M, Inatomi N, Tarui N. High-throughput screening of potassium-competitive acid blockers. J Biomol Screen. 2012 Feb;17(2):177-82. doi: 10.1177/1087057111421004. Epub 2011 Sep 22. PubMed PMID: 21940711.

3: Shin JM, Inatomi N, Munson K, Strugatsky D, Tokhtaeva E, Vagin O, Sachs G. Characterization of a novel potassium-competitive acid blocker of the gastric H,K-ATPase, 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamin e monofumarate (TAK-438). J Pharmacol Exp Ther. 2011 Nov;339(2):412-20. doi: 10.1124/jpet.111.185314. Epub 2011 Aug 9. PubMed PMID: 21828261; PubMed Central PMCID: PMC3199995.

4: Hori Y, Matsukawa J, Takeuchi T, Nishida H, Kajino M, Inatomi N. A study comparing the antisecretory effect of TAK-438, a novel potassium-competitive acid blocker, with lansoprazole in animals. J Pharmacol Exp Ther. 2011 Jun;337(3):797-804. doi: 10.1124/jpet.111.179556. Epub 2011 Mar 16. PubMed PMID: 21411494.

5: Matsukawa J, Hori Y, Nishida H, Kajino M, Inatomi N. A comparative study on the modes of action of TAK-438, a novel potassium-competitive acid blocker, and lansoprazole in primary cultured rabbit gastric glands. Biochem Pharmacol. 2011 May 1;81(9):1145-51. doi: 10.1016/j.bcp.2011.02.009. Epub 2011 Mar 1. PubMed PMID: 21371447.

6: Hori Y, Imanishi A, Matsukawa J, Tsukimi Y, Nishida H, Arikawa Y, Hirase K, Kajino M, Inatomi N. 1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamin e monofumarate (TAK-438), a novel and potent potassium-competitive acid blocker for the treatment of acid-related diseases. J Pharmacol Exp Ther. 2010 Oct;335(1):231-8. doi: 10.1124/jpet.110.170274. Epub 2010 Jul 12. PubMed PMID: 20624992.

 

“The First-in-Class Potassium-Competitive Acid Blocker, Vonoprazan Fumarate: Pharmacokinetic and Pharmacodynamic Considerations. – PubMed – NCBI”. Ncbi.nlm.nih.gov. 2015-09-28. Retrieved 2016-03-30.

 

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Trelagliptin


File:Trelagliptin.svg

TRELAGLIPTIN.png

Trelagliptin

865759-25-7; UNII-Q836OWG55H

Molecular Formula: C18H20FN5O2
Molecular Weight: 357.382103 g/mol

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

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

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

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

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

1029877-94-8 (Trelagliptin Succinate)

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

GLP-I (7-36) is a 29 amino-acid peptide derived by post-translational processing of proglucagon in the small intestine. GLP-I (7-36) has multiple actions in vivo including the stimulation of insulin secretion, inhibition of glucagon secretion, the promotion of satiety, and the slowing of gastric emptying. Based on its physiological profile, the actions of GLP-I (7-36) are believed to be beneficial in the prevention and treatment of type II diabetes and potentially obesity. For example, exogenous administration of GLP-I (7-36) (continuous infusion) in diabetic patients has been found to be efficacious in this patient population. Unfortunately, GLP-I (7-36) is degraded rapidly in vivo and has been shown to have a short half -life in vivo (t1/2=1.5 minutes).
Based on a study of genetically bred DPP-IV knock out mice and on in vivo I in vitro studies with selective DPP-IV inhibitors, DPP-IV has been shown to be the primary degrading enzyme of GLP-I (7-36) in vivo. GLP-I (7-36) is degraded by DPP-IV efficiently to GLP-I (9-36), which has been speculated to act as a physiological antagonist to GLP-I (7-36). Inhibiting DPP-TV in vivo is therefore believed to be useful for potentiating endogenous levels of GLP-I (7-36) and attenuating the formation of its antagonist GLP-I (9-36). Thus, DPP-IV inhibitors are believed to be useful agents for the prevention, delay of progression, and/or treatment of conditions mediated by DPP-IV, in particular diabetes and more particularly, type 2 diabetes mellitus, diabetic dislipidemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose (WG), metabolic acidosis, ketosis, appetite regulation and obesity.

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

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

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

Indications for Medical Use

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

Biochemistry

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

Development

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

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

Administration and Dosing

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

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

SYNTHESIS …………….

 

PAPER

J. Med .Chem.,2011, 54, 510-524
Synthesis started with selective alkylation of chlorouracil 80, followed by methylation provided compound153via152.
The displacement of chloride with 3-(R)-aminopiperidine83afforded trelagliptin154..

Abstract Image

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

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

A mixture of 3-methyl-6-chlorouracil (0.6 g, 3.8 mmol), 2-bromomethyl-4-fluorobenzonitrile (0.86 g, 4 mmol), and K2CO3 (0.5 g, 4 mmol) in DMSO (10 mL) was stirred at 60 °C for 2 h. The mixture was diluted with water and extracted with EtOAc. The organics were dried over MgSO4, and the solvent was removed. The residue was purified by column chromatography to give 0.66 g of 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluorobenzonitrile (60%). 1H NMR (400 MHz, CDCl3): δ 7.73 (dd, J = 7.2, 8.4 Hz, 1H), 7.26 (d, J = 4.0 Hz, 1H), 7.11−7.17 (m, 1H), 6.94 (dd, J = 2.0, 9.0 Hz, 1H), 6.034 (s, 2H), 3.39 (s, 3H). MS (ES) [M + H] calcd for C13H9ClFN3O2, 293; found 293.
2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluorobenzonitrile (300 mg, 1.0 mmol), 3-(R)-aminopiperidine dihydrochloride (266 mg, 1.5 mmol), and sodium bicarbonate (500 mg, 5.4 mmol) were stirred in a sealed tube in EtOH (3 mL) at 100 °C for 2 h. The final compound (367 mg, 81% yield) was obtained as a TFA salt after HPLC purification. 1H NMR (400 MHz, CD3OD): δ 7.77−7.84 (m, 1H), 7.16−7.27 (m, 2H), 5.46 (s, 1H), 5.17−5.34 (ABq, 2H, J = 35.2, 15.6 Hz), 3.33−3.47 (m, 2H), 3.22 (s, 3H), 2.98−3.08 (m, 1H), 2.67−2.92 (m, 2H), 2.07−2.17 (m, 1H), 1.82−1.92 (m, 1H), 1.51−1.79 (m, 2H). MS (ES) [M + H] calcd for C18H20FN5O2, 357; found, 357.

PATENT

WO 2007035629

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

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

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

PATENT

US 2008227798

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

    EXAMPLES
      Example 1Preparation of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile succinate (Compound I)

    • Figure US20080227798A1-20080918-C00004
      Compound I may be prepared by the follow synthetic route (Scheme 1)
    • Figure US20080227798A1-20080918-C00005

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

    • Figure US20080227798A1-20080918-C00006
    • Compound B was prepared by refluxing a mixture of 2-bromo-5-fluoro-toluene (Compound A) (3.5 g, 18.5 mmol) and CuCN (2 g, 22 mmol) in DMF (100 mL) for 24 hours. The reaction was diluted with water and extracted with hexane. The organics were dried over MgSO4 and the solvent removed to give product B (yield 60%). 1H-NMR (400 MHz, CDCl3): δ 7.60 (dd, J=5.6, 8.8 Hz, 1H), 6.93-7.06 (m, 2H), 2.55 (s, 3H).

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

    • Figure US20080227798A1-20080918-C00007
    • Compound C was prepared by refluxing a mixture of 4-fluoro-2-methylbenzonitrile (Compound B) (2 g, 14.8 mmol), N-bromosuccinimide (NBS) (2.64 g, 15 mmol) and azo-bis-isobutyronitrile (AIBN) (100 mg) in CCl4 under nitrogen for 2 hours. The reaction was cooled to room temperature. The solid was removed by filtration. The organic solution was concentrated to give the crude product the form of an oil, which was used in the next step without further purification. 1H-NMR (400 MHz, CDCl3): δ 7.68 (dd, J=5.2, 8.4 Hz, 1H), 7.28 (dd, J=2.4, 8.8 Hz, 1H), 7.12 (m, 1H), 4.6 (s, 2H).

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

    • Figure US20080227798A1-20080918-C00008
    • Compound E was prepared by stirring a mixture of crude 3-methyl-6-chlorouracil D (0.6 g, 3.8 mmol), 2-bromomethyl-4-fluorobenzonitrile (0.86 g, 4 mmol) and K2CO3 (0.5 g, 4 mmol) in DMSO (10 mL) at 60° C. for 2 hours. The reaction was diluted with water and extracted with EtOAc. The organics were dried over MgSO4 and the solvent removed. The residue was purified by column chromatography. 0.66 g of the product was obtained (yield: 60%). 1H-NMR (400 MHz, CDCl3): δ 7.73 (dd, J=7.2, 8.4 Hz, 1H), 7.26 (d, J=4.0 Hz, 1H), 7.11-7.17 (m, 1H), 6.94 (dd, J=2.0, 9.0 Hz, 1H), 6.034 (s, 2H), 3.39 (s, 3H). MS (ES) [m+H] calc’d for C13H9ClFN3O2, 293.68; found 293.68.

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

    • Figure US20080227798A1-20080918-C00009
    • Compound F was prepared by mixing and stirring 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile (Compound E) (300 mg, 1.0 mmol), (R)-3-amino-piperidine dihydrochloride (266 mg, 1.5 mmol) and sodium bicarbonate (500 mg, 5.4 mmol) in a sealed tube in EtOH (3 mL) at 100° C. for 2 hrs. The final compound was obtained as trifluoroacetate (TFA) salt after HPLC purification. 1H-NMR (400 MHz, CD3OD): δ. 7.77-7.84 (m, 1H), 7.16-7.27 (m, 2H), 5.46 (s, 1H), 5.17-5.34 (ABq, 2H, J=35.2, 15.6 Hz), 3.33-3.47 (m, 2H), 3.22 (s, 3H), 2.98-3.08 (m, 1H), 2.67-2.92 (m, 2H), 2.07-2.17 (m, 1H), 1.82-1.92 (m, 1H), 1.51-1.79 (m, 2H). MS (ES) [m+H] calc’d for C18H20FN5O2, 357.38; found, 357.38.

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

  • Figure US20080227798A1-20080918-C00010
  • The TFA salt prepared in the above step (Example 1, Step D) was suspended in DCM, and then washed with saturated Na2CO3. The organic layer was dried and removed in vacuo. The benzonitrile product (approximately 10 mg) was dissolved in MeOH (1 mL) and to which succinic acid in THF (1.05 equivalents) was added. The solutions were allowed to stand for three days open to the air. If a precipitate formed, the solid was collected by filtration. If no solid formed, the mixture was concentrated in vacuo, and the succinate salt was obtained after removing the solvent. 1H-NMR (400 MHz, CD3OD): δ. 7.77-7.84 (m, 1H), 7.12-7.26 (m, 2H), 5.47 (s, 1H), 5.21-5.32 (ABq, 2H, J=32.0, 16.0 Hz), 3.35-3.5 (m, 2H), 3.22 (s, 3H), 3.01-3.1 (m, 1H), 2.69-2.93 (m, 2H), 2.07-2.17 (m, 1H), 1.83-1.93 (m, 1H), 1.55-1.80 (m, 2H). MS (ES) [m+H] calc’d for C18H20FN5O2, 357.38; found, 357.38.
  • Compound I such prepared was found to be crystalline as determined by x-ray powder diffraction analysis (FIG. 1). The crystal material was designated Form A.
TABLE A
Approximate Solubilities of Compound I
Solubility
Solvent (mg/mL)a
Acetone 2
Acetonitrile (ACN) <1
Dichloromethane (DCM) <1
Dimethyl Formamide (DMF) 68
1,4-Dioxane <1
Ethanol (EtOH) 2
Ethyl Acetate (EtOAc) <1
di-Ethyl ether <1
Hexanes <1
2-Propanol (IPA) <1
Methanol (MeOH) 20
Tetrahydrofuran (THF) <1
Toluene <1
Trifluoroethanol (TFE) >200
Water (H2O) 51
ACN:H2O (85:15) 101
EtOH:H2O (95:5) 5
IPA:H2O (88:12) 11
aApproximate solubilities are calculated based on the total solvent used to give a solution; actual solubilities may be greater because of the volume of the solvent portions utilized or a slow rate of dissolution. Solubilities are reported to the nearest mg/mL.

 PATENT

WO2012118180

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

[Formula 2]

str1

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

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

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

PATENT

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

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

As shown below.

 

Figure CN103030631AD00051

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

 

Figure CN103030631AD00061

Scheme I

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

 

 PATENT

WO 2015137496

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

str1

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

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

13 C NMR (126 MHz, CDCl 3 ) ppm 28.0, 33.4, 46.1, 51.9, 59.7, 90.8, 114.6,114.7, 115.6, 115.8, 116.4, 135.4, 135.5, 144.6, 152.7, 159.5, 162.9.
Reference Example 4
(R) -2 – ((6 (3-amino-piperidin-1-yl) -3-methyl-2,4-dioxo-3,4-dihydropyrimidine -1 (2H) – yl) methyl) synthesis of 4-fluoro-benzonitrile succinate
str1
50mL eggplant-shaped flask (R) -2 – ((6- (3- amino-1-yl) -3-methyl-2,4-dioxo-3,4-dihydro-pyrimidine -1 (2H) – yl) methyl) -4-fluorobenzonitrile 1.0g [mw.357.38, 2.8mmol], it was added tetrahydrofuran 4.5mL and water 2 drops. After heated and dissolved at 65 ℃, was dropped to the solution was dissolved at the same temperature 0.331g succinic acid [mw.118.09, 2.8mmol] with tetrahydrofuran 4mL and isopropanol 2.5mL. Aged for 16 hours at room temperature after stirring for 30 min at 65 ℃, and stirred for a further 2 hours at 0 ℃. The crystallization product was collected by terrorism to vacuum filtration. To obtain the desired compound after drying under reduced pressure at 45 ℃. White crystalline powder, 1.2g, 93% yield.

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

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

 

PATENT

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

PATENT

WO 2016024224,

New Patent, Trelagliptin, SUN PHARMA

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

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

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

front page image

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

Formula I

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

Formula la

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

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

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

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

EXAMPLES

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Yield: 38.0 g

Sun Pharma managing director Dilip Shanghvi.

References

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

 

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

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

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

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

Fosfluconazole


Fosfluconazole.png

Fosfluconazole

Fosfluconazole; 194798-83-9; UNII-3JIJ299EWH; 3JIJ299EWH; NCGC00182029-01;

2-(2,4-difluorophenyl)-1,3-di(1h-1,2,4-triazol-1-yl)propan-2-yl dihydrogen phosphate;

2,4-difluoro-α,α-bis(1H-1,2,4-triazol-1-ylmethyl) benzyl alcohol, dihydrogen phosphate

Molecular Formula: C13H13F2N6O4P
Molecular Weight: 386.250688 g/mol

Agouron Pharmaceuticals, Inc.

Research Code:UK-292663, UK 292663, F-FLCZ, F FLCZ

Trade Name:Prodif® PFIZER

MOA:Azole antifungal

Indication:Cryptococcus neoformans; Candidiasis

Status:Approved, Japan PMDA OCT 16 2003

Company:Pfizer (Originator)

Candidiasis,Cryptococcus neoformans, Injection, Solution, Eq. 100 mg/200 mg/400 mg fluconazole per vial

Fosfluconazole (INN) is a water-soluble phosphate prodrug of fluconazole – a triazole antifungal drug used in the treatment and prevention of superficial and systemic fungal infections. The phosphate ester bond is hydrolysed by the action of a phosphatase – an enzyme that removes a phosphate group from its substrate by hydrolysing phosphoric acid monoesters into a phosphate ion and a molecule with a free hydroxyl group (see dephosphorylation).

Fosfluconazole was approved by Pharmaceuticals and Medicals Devices Agency of Japan (PMDA) on Oct 16, 2003. It was developed and marketed as Prodif® by Pfizer in Japan.

Fosfluconazole is a water-soluble phosphate prodrug of fluconazole – a triazole antifungal drug. It is indicated for the treatment of candida and cryptococcus infections.

Prodif® is available as solution for intravenous use, containing 100, 200 or 400 mg of free Fosfluconazole per vial. The recommended dose is 50 to 100 mg administered intravenously once daily for candidiasis. Another dose is 50 to 200 mg fluconazole once daily for cryptococcosis.

 

Route 1

Reference:1. WO9728169A1 / US6977302B2.

2. Org. Process Res. Dev.2002, 6, 109-112.

http://pubs.acs.org/doi/pdf/10.1021/op010064%2B

2-(2,4-Difluorophenyl)-1,3-bis(1H-1,2,4-triazole-1-yl)- 2-propyl dihydrogen phosphate (2). A slurry of dibenzyl 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazole-1-yl)-2-propyl phosphate (30.1 kg, 53.13 mol), 5% palladium-on-carbon catalyst (50% wet, type 5R39, 1.5 kg), and sodium hydroxide (4.36 kg, 108.9 mol) in low-endotoxin water (75.7 L) was hydrogenated at ambient temperature and 414 kPa (60 psi) for 12 h. The slurry was filtered, and the catalyst was washed with low-endotoxin water (9.8 L). After separating the toluene by-product, the aqueous phase was slurried with carbon (3.1 kg) for 30 min. After the carbon was removed by filtration, the aqueous phase was acidified to pH 1.45 by that addition of sulfuric acid (6.69 kg) in low-endotoxin water (25 L) over 2 h. The resulting slurry was granulated at ambient temperature for 1 h and then filtered. The product was sequentially washed with filtered low-endotoxin water (103 L) and filtered acetone (103 L). The product was dried under vacuum at 50 °C for 12 h to give the title compound (18.1 kg, 88%) a white powder: mp 223-224 °C.

1H NMR (DMSO) δ 5.07 (2H, d), 5.24 (2H, d), 6.77-6.83 (1H, m), 7.00-7.18 (2H, m), 7.75 (2H, s), 8.53 (2H, s).

Found: C, 40.28; H, 3.39; N, 21.63;

[MH]+ 387.0786. C13H13F2N6O4P requires: C, 40.43; H, 3.39; N, 21.78; [MH]+ 387.0782.

 

US6977302

https://www.google.com/patents/US6977302

EXAMPLE 1 1-(2,4-Difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)-2-propyl dihydrogen phosphate

(a) Dibenzyl 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)-2-propyl phosphate

Method A

A solution of 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol (also known as fluconazole, 10.0 g, 32.6 mmol), 1H-tetrazole (6.85 g, 97.8 mmol), dibenzyl diisopropyl phosphoramidite (22.55 g, 65.2 mmol) in methylene chloride (100 ml) was stirred at room temperature under a nitrogen atmosphere for 2 hours. The mixture was then cooled to 0° C., and a solution of 3-chloroperoxybenzoic acid (13.5 g, 50-55% w/w, 39.1 mmol) in methylene chloride (50 ml) was added maintaining the temperature at 0° C. The resulting mixture was allowed to warm to room temperature for 1 hour before washing with aqueous sodium metabisulphite and sodium bicarbonate. After drying (MgSO4) the solvent was removed and replaced with methyl isobutyl ketone (37 ml) and tert-butyl methyl ether (74 ml). After granulating at −10° C. for 1 hour the product was filtered and washed with ice cold methyl isobutyl ketone and tert-butyl methyl ether (1:3, 15 ml) and dried at 50° C. under vacuum for 18 hours to give the subtitle compound (16.05 g, 87%), m.p. 93° C.

Found: C, 57.12; H, 4.46; N, 14.85. C27H25F2N6O4P requires C, 57.24; H, 4.46; N, 14.84%. m/z 567 (MH+) 1H NMR (300 MHz, CDCl3) δ=4.90 (d, 2H), 4.95 (d, 2H), 5.05 (d, 2H), 5.19 (d, 2H), 6.58-6.73 (m, 2H), 6.88-6.95 (m, 1H), 7.20-7.30 (m, 4H) 7.32-7.38 (m; 6H), 7.80 (s, 2H), 8.36 (s, 2H).

Method B

To stirred ethyl acetate (1530 ml) was added 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol (also known as fluconazole, 306 g, 1.00 mol) and pyridine (237.3 g, 3.00 mol) before cooling to 0° C. Phosphorus trichloride (137.4 g, 1.00 mol) was added dropwise to the reaction mixture maintaining the temperature between 0-5° C. before allowing the reaction mixture to warm to 15° C. over 30 minutes. Benzyl alcohol (216 g, 2.00 mol) was then added over 30 minutes at 15-20° C. After a further 30 minutes hydrogen peroxide (27.5% w/w in water, 373 g) was added maintaining the temperature at 15-20° C. After 30 minutes the aqueous phase was removed and the organic phase washed with aqueous sodium metabisulphite, dilute hydrochloric acid and water. The solvent was removed at reduced pressure and replaced with methyl isobutyl ketone (850 ml) and tert-butyl methyl ether (1132 ml). After granulating at 20° C. for 1 hour and at 0° C. for 1 hour, the product was filtered and washed with ice cold tert-butyl methyl ether (2×220 ml) and dried at 50° C. under vacuum for 18 hours to give the subtitle compound (358 g, 63%). The melting point and spectroscopic data was identical to that stated in method A.
(b) 2-(2,4-Difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)-2-propyl dihydrogen phosphate

A slurry of the compound of step (a) (9.80 g, 17.3 mmol), 5% palladium on carbon catalyst (50% wet, 1.0 g) and sodium hydroxide (1.38 g, 34.6 mmol) in water (26 ml) was hydrogenated at room temperature and 414 kPa (60 p.s.i.) for 20 hours. The solution was filtered through a pad of celite (trade mark) and washed with water (5 ml). The toluene was separated and the aqueous phase cooled to 0° C. whereupon sulphuric acid (1.70 g, 17.3 mmol) was added. The resulting slurry was granulated at 0° C. for 1 hour and then filtered, washed with water (2×5 ml) and dried under vacuum at 50° C. to give the title compound (5.80 g, 87%). m.p. 223-224° C.

Found: C, 40.28; H, 3.39; N, 21.63. C13H13F2N6O4P requires C, 40.43; H, 3.39; N, 21.76%. 1H NMR (300 MHz, DMSO) δ=5.07 (d, 2H) 5.24 (d, 2H), 6.77-6.83 (m, 1H), 7.00-7.18 (m, 2H), 7.75 (s, 2H), 8.53 (s, 2H).

EXAMPLE 2 2-(2,4-Difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)-2-propyl disodium phosphate

A solution of the compound of Example 1(a) (10.0 g, 17.7 mmol) and sodium acetate (2.90 g, 35.3 mmol) in ethanol (160 ml) and water (20 ml) was hydrogenated over Pearlman’s catalyst (1.00 g) at room temperature and at 345 kPa (50 p.s.i.) for 16 hours. The solution was filtered through a pad of celite (trade mark) and the solvents removed at reduced pressure to leave a thick syrup. This was dissolved in ethanol (100 ml) with the aid of sonication and warmed to reflux. The resulting solution was allowed to cool slowly and granulate for 1 hour at room temperature. The product was filtered, washed with ethanol (10 ml) and dried under vacuum at 50° C. to give the title compound (4.48 g, 59%). m.p. 160-162° C.

1H NMR (300 MHz, D2O) δ=5.01 (d, 2H), 5.40 (d, 2H), 6.60 (m, 1H), 6.79 (m, 1H), 7.11 (m, 1H), 7.63 (s, 2H), 8.68 (s, 2H).

 

Route 2

Reference:1. CN103864844A.

http://www.google.com/patents/CN103864844A?cl=en

TRANSLATED BY MACHINE…….TEXT MAY VARY

forskolin fluconazole (fosf Iuconazole, Formula I) is fluconazole (Formula IV) of monophosphate prodrugs, fluconazole in the tertiary alcohol into a phosphate ester, not only did not introduce a chiral center, also increased water solubility, because a long time to overcome the low water solubility of fluconazole resulting larger infusion volume defects. After intravenous administration in the role of phosphatases in vivo hydrolysis into fluconazole, pharmacological effect. Blessing from the Central Institute of the United States Secretary of fluconazole Fai end developed, launched in Japan in 2004 I May 15, for the treatment of candidiasis and cryptococcal infections caused deep as true bacteremia, respiratory fungal disease, fungal peritoneum

Inflammation, gastrointestinal fungal disease, fungal urinary tract infections, fungal meningitis.

 

Figure CN103864844AD00031

Synthesis gas itraconazole on forskolin in W09728169, Organic Process Research & Development (200 2), 6 (2), 109-112, CN1789270, Art of Drug Synthesis (2007), 71-82, etc. have been reported in the literature . Which Organic Process Research & Development (2002) described in detail in the first blessing Secretary fluconazole and improved synthetic route for the route problems to adapt to industrial mass production of synthetic routes.

  Document Organic Process Research & Development (2002), 6,109-112 discloses the following two synthetic routes.

Route One:

 

Figure CN103864844AD00032

Route two:

 

Figure CN103864844AD00041

  The final step is a route to the removal of benzyl group in a methanol solvent by palladium on carbon catalyzed hydrogenation reaction yield was 65%. Since forskolin fluconazole final product insoluble in methanol, and therefore there is a route following shortcomings: a catalyst poisoning, the final product is easy to form methanol solvate, removing the catalyst in the loss of product, the final product are difficult to separate, low yield not suitable for industrial production.

Two routes still using palladium on carbon hydrogenation debenzylation, except that the solvent was changed to sodium hydroxide solution, the product of soluble and stable in aqueous sodium hydroxide solution, after filtering off the catalyst, forskolin fluoro itraconazole by acidification of sodium sulfate can be easily obtained blessing Secretary of fluconazole, the reaction yield of 85-90%.

  In the prior art, the removal of benzyl preparation blessing Secretary of fluconazole, the use of a pressure hydrogenation, relatively harsh reaction conditions; and blessing Secretary of fluconazole in water and slightly soluble in methanol, for blessing Secretary fluconazole further refined and purified more difficult. The present invention aims to provide a new and suitable for industrial production methods blessing Secretary fluconazole.

Example 1

  2- (2,4-gas-phenyl) -1,3-bis (1H-1, 2,4- two P sat 1-yl) -2-propyl-di-benzyl-pity Cool ( Preparation blessing Secretary fluconazole dibenzyl ester)

Step  The method according to CN1210540A in Example 1 A or Method B of (a), was prepared to give the title compound, having 1H-NMR shown in Figure 1 (SOi) MHz, DMS0-D6) spectrum.

  Example 2

2_ (2,4_ two gas-phenyl) -1, double 3_ (1H-1, 2,4_ two 1-yl) propyl pity _2_ di press (forskolin gas

Itraconazole ammonium salt) Preparation

 

Figure CN103864844AD00071

  Formula III blessing Secretary fluconazole two benzyl ester (566g, lmol), 120g of dry Pd / C (containing 5% palladium) and ammonium formate (315g, 5mol) in methanol (6L), and stirred under reflux for 5h , TLC monitoring completion of the reaction was filtered, 50 ° C the solvent was distilled off under reduced pressure, ethanol was added (566ml), stirred for beating, and filtered to give a solid forskolin fluconazole salt 415g, yield 98.8%.

] lH-Mffi (500MHz, DMS0-D6) δ: 4.87-4.90, 5.58-5.61,6.56-6.60, 6.94-7.03,7.52-7.61,8.96, having 1H-NMR shown in Figure 2 (500MHz, DMS0 -D6) spectrum.

  Example 3

2- (2,4-gas-phenyl) -1,3-bis (1H-1, 2,4- two 1-yl) -2-propyl-pity acid dioxide Cool (forskolin

Fluconazole) Preparation of

 

Figure CN103864844AD00072

[0052] Formula II forskolin fluconazole salt (420g, Imol), in water (IL) while stirring, filtered, 2mol / L sulfuric acid aqueous solution (500ml), 5 ° C under stirring for lh, filtered, cold water ( 200ml) wash, 50 ° C under dry blessed Division fluconazole 379g, yield 98%.

  1H-Mffi (SOOMHz) DMSO-De) δ:. 5.09-5.12,5.25-5.28,6.80-6.84,7.05-7.16,7.77,8.55,10.32 [0054] Example 4

  2_ (2,4_ two gas-phenyl) -1, double 3_ (1Η-1, 2,4_ two 1-yl) propyl pity _2_ di press (forskolin gas itraconazole salt) Preparation

  Under nitrogen, forskolin fluconazole dibenzyl ester (566g, lmol), 84g of dry Pd / C (5% containing button) and ammonium formate (189g, 3mol) in anhydrous methanol (5L) in the mixture was stirred at reflux for 5h, TLC monitoring completion of the reaction was filtered, 50 ° C the solvent was distilled off under reduced pressure, ethanol was added (300ml), stirred for beating, and filtered to give a solid forskolin fluconazole salt 410g, yield 97.5%.

Example 5

2_ (2,4_ two gas-phenyl) -1, double 3_ (1H-1, 2,4_ two 1-yl) propyl pity _2_ di press (forskolin gas itraconazole salt) Preparation

Under nitrogen, forskolin fluconazole dibenzyl ester (566g, lmol), 30g of dry Pd / C (containing 10% palladium) and ammonium formate (315g, 5mol) in anhydrous methanol (5L) in the mixture was stirred at reflux for 5h, TLC monitoring completion of the reaction was filtered, 50 ° C the solvent was distilled off under reduced pressure, ethanol was added (300ml), stirred for beating, and filtered to give a solid forskolin fluconazole salt 405g, yield 96.4%.

  Example 6

2_ (2,4_ two gas-phenyl) -1, double 3_ (1H-1, 2,4_ two 1-yl) propyl pity _2_ di press (forskolin gas itraconazole salt) Preparation

  Under nitrogen, forskolin fluconazole dibenzyl ester (566g, lmol), 30g of dry Pd / C (containing 10% palladium) and ammonium formate (315g, 5mol) in ethanol (12L) and stirred was refluxed for 5h, TLC monitoring completion of the reaction, was filtered, 50 ° C the solvent was distilled off under reduced pressure, ethanol was added (300ml), stirred for beating, and filtered to give a solid forskolin fluconazole salt 395g, 94% yield.

  Example 7

2_ (2,4_ two gas-phenyl) -1, double 3_ (1H-1, 2,4_ two 1-yl) propyl pity _2_ di press (forskolin gas itraconazole salt) Preparation

  forskolin fluconazole dibenzyl ester (566g, lmol), 170g of dry Pd / C (containing 5% of palladium) and ammonium formate (315g, 5mol) in ethanol (16L) was stirred under reflux for 5h, TLC monitoring completion of the reaction was filtered, 50 ° C the solvent was distilled off under reduced pressure, ethanol was added (300ml), stirred for beating, and filtered to give a solid forskolin fluconazole salt 398g, yield 94.7%.

  Example 8

2_ (2,4_ two gas-phenyl) -1, double 3_ (1H-1, 2,4_ two 1-yl) propyl pity _2_ di press (forskolin gas itraconazole salt) Preparation

Under nitrogen, forskolin fluconazole dibenzyl ester (566g, lmol), 120g of dry Pd / C (containing 5% palladium) and ammonium formate (315g, 5mol) in isopropanol (12L) in the mixture was stirred at reflux for 5h, TLC monitoring completion of the reaction was filtered, 50 ° C the solvent was distilled off under reduced pressure, ethanol was added (300ml), stirred for beating, and filtered to give a solid forskolin fluconazole salt 402g, a yield of 95.7%.

Example 9

  2_ (2,4_ two gas-phenyl) -1, double 3_ (1H-1, 2,4_ two 1-yl) propyl pity _2_ di press (forskolin gas itraconazole salt) Preparation

[0071] under nitrogen blessing Secretary fluconazole dibenzyl ester (566g, lmol), 60g of dry Pd / C (containing 5% palladium) and ammonium formate (504g, 8mol) in methanol (8L) in, 50 ° C under stirring reaction 40h, TLC monitoring completion of the reaction, was filtered, 50 ° C the solvent was distilled off under reduced pressure, ethanol was added ^ OOml), stirred for beating, and filtered to give a solid forskolin fluconazole salt 398g, yield 94.8%.

Example 10

2_ (2,4_ two gas-phenyl) -1, double 3_ (1H-1, 2,4_ two 1-yl) propyl pity _2_ di press (forskolin gas itraconazole salt) Preparation

  Under nitrogen, forskolin fluconazole dibenzyl ester (5668,111101), 8 (^ dry? (1 / (:( containing palladium 5%) and ammonium formate (315g, 5mol) for n-propyl alcohol (12L) in, 60 ° C the reaction was stirred 20h, TLC monitoring completion of the reaction was filtered, 50 ° C the solvent was distilled off under reduced pressure, ethanol was added (300ml), stirred for beating, and filtered to give a solid forskolin fluconazole salt 398g 95% yield.

Example 11

2- (2,4-gas-phenyl) -1,3-bis (1H-1, 2,4- sit two P-1-yl) -2-propyl-pity acid dioxide Cool (forskolin fluconazole) Preparation of [0077] under nitrogen blessing Secretary fluconazole dibenzyl ester 566 g (Imol) adding 56g of dry Pd / C (containing 5% palladium), methanol 6L, 315 g of ammonium formate, stirring boil under reflux for 5h, TLC after completion of the reaction was filtered, 50 ° C the solvent was distilled off under reduced pressure, addition of IL of water and dissolved with stirring, filtered, 2mol / L sulfuric acid 500mL, 5 ° C with stirring to precipitate lh, filtered, 200mL cold water, 50 ° C drying 365 g, 95% yield.

  Example 12 forskolin fluconazole salt and HPLC detection methods blessing Secretary fluconazole:

  High performance liquid chromatography (Chinese Pharmacopoeia 2010 edition two Appendix VD): octadecylsilane bonded silica as a filler, Column: Thermo BDS C18 (4.6 X 150mm, 3.5 μ m); methanol as mobile phase A, phosphate buffer (take potassium dihydrogen phosphate 0.68g, set 1000ml water, triethylamine 6ml, adjusted to pH 5.0 with phosphoric acid) as the mobile phase B, a flow rate of 1.0ml / min; column temperature 35 ° C; detection wavelength was 210nm, linear gradient.

 

Figure CN103864844AD00091

 

  After the examination, according to the peak area calculation, purity prepared in Example 2-11 was the implementation of the target product of 99.5%.

Patent Submitted Granted
Nanoparticulate Anidulafungin Compositions and Methods for Making the Same [US2009238867] 2009-09-24
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TOPICAL TERBINAFINE FORMULATIONS AND METHODS OF ADMINISTERING SAME FOR THE TREATMENT OF FUNGAL INFECTIONS [US7820720] 2010-04-29 2010-10-26
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Patent Submitted Granted
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IMPURITIES

1

Impurity Name:Molecular Formula:Molecular Weight:CAS No.:
Fosfluconazole Impurity A C13H12F2N6O306.2786386-73-4
2
Impurity Name:Molecular Formula:Molecular Weight:CAS No.:
Fosfluconazole Impurity B C13H13F2N6O4P386.25
3
Impurity Name:Molecular Formula:Molecular Weight:CAS No.:
Fosfluconazole Impurity C C13H14FN6O4P368.26
4
Impurity Name:Molecular Formula:Molecular Weight:CAS No.:
Fosfluconazole Impurity D C13H14FN6O4P368.26
5
Impurity Name:Molecular Formula:Molecular Weight:CAS No.:
Fosfluconazole Impurity E C27H25F2N6O4P566.5
6
Impurity Name:Molecular Formula:Molecular Weight:CAS No.:
Fosfluconazole Impurity F C20H19F2N6O4P476.37
7
Impurity Name:Molecular Formula:Molecular Weight:CAS No.:
Fosfluconazole Impurity G C13H13F2N6O5P402.25
8
Impurity Name:Molecular Formula:Molecular Weight:CAS No.:
Fosfluconazole Impurity H C13H15N6O4P350.27
9
Impurity Name:Molecular Formula:Molecular Weight:CAS No.:
Fosfluconazole Impurity I C13H14FN6O4P368.26
Fosfluconazole
Fosfluconazol.svg
Systematic (IUPAC) name
{[2-(2,4-Difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-yl]oxy}phosphonic acid
Clinical data
AHFS/Drugs.com International Drug Names
Legal status
  • (Prescription only)
Routes of
administration
IV
Identifiers
CAS Number 194798-83-9 Yes
ATC code None
PubChem CID 214356
ChemSpider 185843 Yes
UNII 3JIJ299EWH Yes
ChEMBL CHEMBL1908301 Yes
Chemical data
Formula C13H13F2N6O4P
Molar mass 386.25 g/mol

 

CN1210540A * Jan 27, 1997 Mar 10, 1999 辉瑞研究开发公司 Triazole derivatives useful in therapy
CN1789270A * Dec 16, 2005 Jun 21, 2006 西安新安医药科技有限公司 Mycotic ingection-resisting fosfluconazole hydrate and preparation method thereof
CN101890028A * Feb 22, 2007 Nov 24, 2010 卫材R&D管理有限公司 Stabilized pharmaceutical composition
CN102439018A * Mar 3, 2010 May 2, 2012 塞普斯制药有限公司 Fosfluconazole derivatives, synthesis, and use in long acting formulations
US20040007689 * Jun 23, 2003 Jan 15, 2004 Pfizer Inc. Process for controlling the hydrate mix of a compound
1 * ARTHUR BENTLEY等: “The Discovery and Process Development of a Commercial Route to the Water Soluble Prodrug, Fosfluconazole“, 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》, vol. 6, no. 2, 18 December 2001 (2001-12-18), XP002491526, DOI: doi:10.1021/op010064+
2 * 国大亮 等: “福司氟康唑“, 《齐鲁药事》, vol. 24, no. 1, 30 January 2005 (2005-01-30), pages 60
3 * 村上尚道: “fosfluconazole“, 《NEW DRUGS OF THE WORLD:2003》, vol. 33, no. 10, 15 September 2004 (2004-09-15), pages 56

//////UK-292663, UK 292663, F-FLCZ, F FLCZ, Fosfluconazole,  194798-83-9, UNII-3JIJ299EWH, 3JIJ299EWH, NCGC00182029-01

Fc1ccc(c(F)c1)C(OP(=O)(O)O)(Cn2ncnc2)Cn3ncnc3

MARIZEV® (Omarigliptin), Merck’s Once-Weekly DPP-4 Inhibitor for Type 2 Diabetes, Approved in Japan


MARIZEV® (Omarigliptin), Merck’s Once-Weekly DPP-4 Inhibitor for Type 2 Diabetes, Approved in Japan

KENILWORTH, N.J.–(BUSINESS WIRE)–Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced that the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) has approved MARIZEV® (omarigliptin) 25 mg and 12.5 mg tablets, an oral, once-weekly DPP-4 inhibitor indicated for the treatment of adults with type 2 diabetes. Japan is the first country to have approved omarigliptin……….http://www.mercknewsroom.com/news-release/prescription-medicine-news/marizev-omarigliptin-mercks-once-weekly-dpp-4-inhibitor-type

syn…….https://newdrugapprovals.org/2014/04/18/omarigliptin-mk-3102-in-phase-3-for-type-2-diabetes/

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/////////////MARIZEV,  (Omarigliptin), Merck’s,  Once-Weekly,  DPP-4 Inhibitor,   Type 2 Diabetes, Approved, Japan

Firategrast, T-0047


Japan

Firategrast.png

Firategrast, 402567-16-2;

Firategrast, MS, Alpha4beta1 integrin

PHASE 2 GSK

Mitsubishi Tanabe Pharma INNOVATOR

Tanabe Seiyaku Co

Glaxo Group Limited, Mitsubishi Tanabe Pharma Corporation

SB 683699, SB-683699, UNII-OJY3SK9H5F
Firategrast; UNII-OJY3SK9H5F; SB-683699; Firategrast (USAN); 402567-16-2; SB683699; T-0047  
Molecular Formula: C27H27F2NO6
Molecular Weight: 499.503186 g/mol
SYSTEMATIC NAME:
1,1′-Biphenyl)-4-propanoic acid, alpha-((2,6-difluorobenzoyl)amino)-4′-(ethoxymethyl)-2′,6′-dimethoxy-, (alphaS)-
N-(2,6-Difluorobenzoyl)-4-[4-(ethoxymethyl)-2,6-dimethoxyphenyl]-L-phenylalanine
N- (2 , 6-Difluorobenzoyl) -4- (2 , 6-dimethoxy-4- ethoxymethylphenyl) -L-phenylalanine .
2S)-2-((2,6-Difluorobenzoyl)amino)-3-(4′-(ethoxymethyl)-2′,6′-dimethoxybiphenyl-4- yl)propanoic acid
(2S)-2-{[(2,6- difluorophenyl)carbonyl]amino}-3-[4′-[(ethyloxy)methyl]-2′,6′-bis(methyloxy)-4- biphenylyl]propanoic acid
(2S)-2-[[2,6-bis(fluoranyl)phenyl]carbonylamino]-3-[4-[4-(ethoxymethyl)-2,6-dimethoxy-phenyl]phenyl]propanoic acid

Pharmacological half-life is 2.5 – 4.5 hours, compared to 11 days for natalizumab, a drug in the same class

Orally bioavailable small molecule α4-integrin antagonist
see

http://www.msdiscovery.org/node/1377#node-biblio-1338

http://multiple-sclerosis-research.blogspot.com/2012/01/research-oral-tysabri-analogue.html

SB683699 is an alpha4 integrin antagonist that had been studied in phase II trials at GlaxoSmithKline under a license from Mitsubishi Tanabe Pharma for the oral treatment of multiple sclerosis (MS) in Europe. GlaxoSmithKline and Tanabe Seiyaku (now Mitsubishi Tanabe Pharma) had been studying the drug candidate for the treatment of asthma, rheumatoid arthritis (RA) and Crohn’s disease

MECHANISMS/EFFECTS

HUMAN:

Similar mechanism of action to natalizumab (α4-integrin blocker), but its faster elimination could improve safety profile

 Firategrast
Firategrast
SYNTHESIS
………………….
PATENT

Scheme 1

Figure imgf000010_0001

Scheme 2

Figure imgf000012_0001

In a further aspect the present invention provides for a process for the preparation of compound of formula (II) which comprises coupling the compound of formula (V)

Figure imgf000012_0002

Suitable coupling conditions for the compound of formula (V) and the compound of formula (VI) include those shown in Scheme 2. In a further aspect of the invention there is provided the compound of formula (V):

Figure imgf000013_0001

1H NMR characterisation data for the compound of formula (V) were generated on an isolated and purified batch. 1H-NMR spectra were recorded on a Bruker Avance 400 at 400MHz, using TMS as an internal reference.1H NMR (400 MHz, DMSO-D6) δ ppm 1.17 (t, J=7.09 Hz, 3 H) 2.96 (dd, J=13.82, 9.90 Hz, 1 H) 3.1 1 (dd, J=13.82, 5.26 Hz, 1 H) 4.12 (q, J=7.09 Hz, 2 H) 4.63 (ddd, J=9.78, 7.82, 5.38 Hz, 1 H) 7.15 (t, J=7.95 Hz, 2 H) 7.25 (d, J=8.31 Hz, 2 H) 7.47 – 7.55 (m, 3 H) 9.23 (d, J=7.83 Hz, 1 H).

The present invention provides a process for the preparation of the compound of formula

Figure imgf000003_0001

which process comprises the steps: a) hydrolysis of an ester of formula (I la):

Figure imgf000004_0001

Recrvstallisation of (2S)-2-{r(2,6-difluorophenyl)carbonyllamino)-3-r4′-r(ethyloxy)methyll- 2′,6′-bis(methyloxy)-4-biphenylyllpropanoic acid

(2S)-2-{[(2,6-difluorophenyl)carbonyl]amino}-3-[4′-[(ethyloxy)methyl]-2′,6′-bis(methyloxy)- 4-biphenylyl]propanoic acid (9.38Kg) was charged into a clean reactor, followed by ethyl acetate (46.9L). The solution was heated to 50°C and filtered into the pre-warmed (35°C) crystallizing vessel. A line-wash with ethyl acetate (9.4L) was carried out. The combined ethyl acetate solutions were heated to 50°C, stirred to ensure complete dissolution. Filtered heptane (9.4L) was added maintaining the temperature at 50°C then the solution cooled to 30°C and seeded with (2S)-2-{[(2,6-difluorophenyl)carbonyl]amino}-3-[4 – [(ethyloxy)methyl]-2′,6′-bis(methyloxy)-4-biphenylyl]propanoic acid (47g) slurried in 1 :9 ethyl acetate:heptane (0.47L). The slurry was aged for 2 hours at 30°C. Filtered heptane (75L) was added over 3 hours. The slurry was then cooled to 0°C over 1 hour. The mixture was aged at 0°C for 1 hour then the solid was filtered off, washed with isopropyl ether (29.6L and dried under vacuum at 50±3°C to give the product (8.55Kg, 91 %). Characterised by having an infrared absorption spectrum with significant absorption bands at about 754, 768, 800, 820, 849, 866, 1006, 1 100, 1 122, 1 157, 1 188, 1225, 1242, 1268, 1292, 1317, 1352, 1417, 1466, 1530, 1580, 1624, 1650, 1662, 171 1 , 1728, 2938, 3302cm

…………………………………..
PATENT

Example 10: N- (2 , 6-Difluorobenzoyl) -4- (2 , 6-dimethoxy-4- ethoxymethylphenyl) -L-phenylalanine ethyl ester.

(1) The product obtained in Example l-(4) (2.1 g) was acylated with 2 , 6-difluorobenzoyl chloride in a similar manner as described in Example 1 -(5) to give N- (2, 6-difluorobenzoyl) – 4- (2 , 6-dimethoxy-4-hydroxymethylphenyl) -L-phenylalanine ethyl ester (2.75 g) . mp . 70-72 °C; IR (Nujol) 3400, 3263, 1735, 1654, 1624 cm“1; MS (APCI) m/z 500 (M+H) . (2) To a solution of the product obtained above (1.72 g) in DMSO (20 ml) were added Et3N (4.8 ml) and S03«pyridine (5.6 g) successively at room temperature. The whole mixture was stirred at room temperature for 25 minutes. The reaction mixture was poured into ice-water, and then the mixture was extracted with EtOAc. The organic layer was sequentially washed with 5% aqueous HCl, H20 and brine, dried (Na2S04) and then evaporated. The residue was purified by column chromatography (silica gel; eluent: n-hexane/EtOAc 5:1 to 1:1) to yield N-(2,6- difluorobenzoyl) -4- (2 , 6-dimethoxy-4-formylphenyl) -L- phenylalanine ethyl ester (1.54 g) . mp. 114-116°C; IR (Nujol)

3332, 1735, 1695, 1657, 1644, 1623 cm“1; MS (APCI) m/z 498 (M+H) .

(3) The product obtained above (716 mg) was converted into the title compound (428 mg) in a similar manner as described in Example 1- (7) . mp . 87-89°C; IR (Neat+CHC13) 3300, 1739, 1668 cm 1; MS (APCI) m/z 528 (M+H) .

Example 11: N- (2 , 6-Difluorobenzoyl) -4- (2 , 6-dimethoxy-4- ethoxymethylphenyl ) -L-phenylalanine methyl ester.

(1) The product obtained in Example 2- (4) (1.00 g) was acylated with 2 , 6-difluorobenzoyl chloride to give N-(2,6- difluorobenzoyl) -4- (2 , 6-dimethoxy-4-hydroxymethylphenyl) -L- phenylalanine methyl ester (873 mg) in a similar manner as described in Example l-(5). IR (Nujol) 3257, 1743, 1655, 1624 cm 1; MS (APCI +Q1MS) m/z 503 (M+NH4) , 486 (M+H) . (2) The product obtained above (860 mg) was converted into the title compound (220 mg) in a similar manner as described in Example 2- (6) and (7).

Example 12: N- (2 , 6-Difluorobenzoyl) -4- (2 , 6-dimethoxy-4- ethoxymethylphenyl) -L-phenylalanine .

The product obtained in Example 10 (200 mg) was hydrolyzed in a similar manner as described in Example 3 to give the title compound (160 mg) . The product obtained in Example 11 (220 mg) was also hydrolyzed in a similar manner as described in Example 3 to give the title compound (167 mg) . mp. 156-158°C; IR (Nujol) 1735, 1655 cm“1; MS (ESI) m/z 498 (M-H) .

…………………….

PATENT

 https://www.google.com/patents/WO2003072536A1?cl=en

OUT LINE

phenylalanine derivative of the formula (I) :

Figure imgf000003_0001

wherein X1 is a halogen atom, X2 is a halogen atom, Q is a group of the formula -CH2– or -(CH2)2– and Y is a lower alkyl group, or a pharmaceutically acceptable salt thereof, which has excellent inhibitory activity against α4 integrin-mediated cell adhesion.

Thus, the present invention relates to a process for preparing a compound of the formula (I) :

Figure imgf000004_0001

wherein the symbols are the same as defined above, or a pharmaceutically acceptable salt thereof, comprising : (1) coupling a compound of the formula (VI) :

Figure imgf000004_0002

wherein Z is a leaving group, R1NH is a protected amino group and C02R is a protected carboxyl group with a compound of the formula (V) :

Figure imgf000004_0003

wherein the symbols are the same as defined above, removing the protecting group from the protected amino group, and if necessary, converting the resulting compound into a salt, to yield a compound of the formula (IV) :

Figure imgf000005_0001

wherein the symbols are the same as defined above, or a salt thereof,

(2) condensing the compound (IV) or a salt thereof with a compound of the formula (III) :

Figure imgf000005_0002

wherein the symbols are the same as defined above, a salt or a reactive derivative thereof to yield a compound of the formula (II) :

Figure imgf000005_0003

Ethyl (ocS) – – [ [ (1, 1-dimethylethoxy) carbonyl] amino] -4- hydroxybenzene propionate and ethyl (otS) -α- [ [ (1, 1- dimethylethoxy) carbonyl] amino] -4-

(trifluoromethanesulfonyloxy) benzene propionate are described in J. Med. Chem. , 33: 1620 (1990) and JP-A-7- 157472, respectively. 4-Bromo-3, 5-dimethoxybenzyl alcohol is described in, for example, J. Med. Chem. , 20: 299 (1977), and can also be prepared according to the following process.

Figure imgf000019_0001

Firstly, 4-bromo-3, 5-dihydroxybenzoic acid is methylated to give methyl 4-bromo-3, 5-dimethoxybenzoate, which is then reduced to yield 4-bromo-3, 5-dimethoxy benzyl alcohol. The methylation can be carried out by reacting with dimethyl sulfate in the presence of a base in a suitable solvent (e.g., ethyl acetate). The reduction can be carried out by reacting with an reducing agent (e.g., lithium alminium hydride, sodium borohydride and calcium borohydride) in a suitable solvent (e.g., tetrahydrofuran) .

EXAMPLES

The following Examples are provided to further illustrate the process of preparation according to the present invention. In the following examples, some compounds may be referred to by different compound name depending on the nomenclature, as illustrated below.

Ethyl (αS) -α-amino-4′ -ethoxymethyl-2′ , 6′ – dimethoxy (1, 1′ -biphenyl) -4-propionate

Another name: ethyl (2S) -2-amino-3- [4- (4-ethoxymethyl- 2, 6-dimethoxyphenyl) phenyl]propanoate

Ethyl (αS) – [ [1, 1-dimethylethoxy] carbonyl] amino] -4′ – ethoxymethyl-2′ , 6′ -dimethoxy (1,1′ -biphenyl) -4-propionate

Another name 1: ethyl (2S) -2- [ (t-butoxycarbonyl) – amino] -3- [4- (4-ethoxymethyl-2, 6-dimethoxyphenyl) – phenyl]propanoate

Another name 2: Ethyl N- (t-butoxycarbonyl) -4- (4- ethoxymethyl-2, 6-dimethoxyphenyl) -L-phenylalanine

Ethyl (αS) – – [ (2, 6-difluorobenzoyl) amino] -4′ – ethoxymethyl-2′ , 6′ -dimethoxy (1, 1′ -biphenyl) -4-propionate Another name 1: Ethyl (2S) -2- [ (2, 6- difluorobenzoyl) amino] -3- [4- (4-ethoxymethyl-2, 6- di ethoxyphenyl) phenyl] propanoate

Another name 2: Ethyl N- [2 , 6-difluorobenzoyl) -4- (4- ethoxymethyl-2, 6-dimethoxyphenyl) -L-phenylalanine

(ocS) – – [ (2, 6-Difluorobenzoyl) amino] -4′ -ethoxymethyl- 2′ , 6′ -dimethox (1,1′ -biphenyl) -4-propionic acid

Another name 1: (2S) -2- [ (2, 6-difluorobenzoyl) amino] -3- [4- (4-ethoxymethyl-2, 6-dimethoxyphenyl) phenyl]propanoic acid

Another name 2: N- [ 2 , 6-difluorobenzoyl) -4- (4- ethoxymethyl-2, 6-dimethoxyphenyl) -L-phenylalanine

EXAMPLE 1 (1) Under nitrogen atmosphere, pyridine (130.3 g) and trifluoromethanesulfonic anhydride (170.4 g) were added dropwise to a solution of ethyl (αS) -α- [ [ (1, 1- dimethylethoxy) carbonyl] amino] -4-hydroxybenzenepropionate

(170.0 g) in dichloromethane (1.7 L) at 10 ° C or below. After stirring for 1 hour at the same temperature, water

(850 ml) was added dropwise to the mixture and the mixture was stirred for 2 hours at the same temperature. The organic layer was washed with 10 % aqueous citric acid solution and aqueous saturated sodium hydrogen carbonate solution, and dried over magnesium sulfate. The solvent was removed in vacuo to yield ethyl (αS) -α- [ [ (1, 1- dimethylethoxy) carbonyl] amino] -4-

(trifluoromethanesulfonyloxy)benzenepropionate (242.5 g) as oil . MS (m/z) : 441 (M+) (2) Under nitrogen atmosphere, to a mixture of ethyl (αS)- – [ [ (1, 1-dimethylethoxy) carbonyl] amino] -4-

(trifluoromethanesulfonyloxy) benzenepropionate (66.2g), 4- ethoxymethyl-2, 6-dimethoxyphenylboric acid (54.0 g) , triphenylphosphine (9.83 g) and N-methylpyrrolidone (330 ml) were added palladium acetate (1.68 g) and diisopropylamine (24.9 g ), and the mixture was heated at 90 °C. After stirring for 1 hour at the same temperature, the mixture was cooled and toluene and water were added. The organic layers were washed with 10% aqueous citric acid solution and saturated aqueous NaCl solution and dried over magnesium sulfate. The solvent was removed in vacuo to yield ethyl (αS) -α- [[ (1, 1-dimethylethoxy) carbonyl] amino] – 4′ -ethoxymethyl-2′ , 6′ -dimethox (1,1′ -biphenyl) -4-propionate (90.1 g) as oil.

The product was dissolved in ethanol (330 ml) , and after addition of p-toluenesulfonic acid monohydrate (28.5 g) , the mixture was stirred for 2 hours at 75 °C. After cooling to room temperature, the mixture was filtrated over charcoal and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate with heating. After cooling, the crystalline precipitates were collected by filtration and dried to yield ethyl (αS)-α- amino-4′ -ethoxymethyl-2′ , 6′ -dimethoxy (1, 1′ -biphenyl) -4- propionate p-toluenesulfonate (63.4 g) .

MS (m/z) : 387 (M+-p-toluenesulfonic acid), M.p. 127-129°C

(3) To a mixture of ethyl (αS) -α-amino-4′ -ethoxymethyl- 2′ , 6′ -dimethox (1, 1′ -biphenyl) -4-propionate p- toluenesulfonate (29.0 g) , sodium hydrogen carbonate (15. 2 g) , water (290 ml) and ethyl acetate (290 ml) was added dropwise 2, 6-difluorobenzoyl chloride (9. 6 g) at 15 °C or below and the mixture was stirred for 30 minutes at the same temperature. The ethyl acetate layer was washed with saturated aqueous NaCl solution and dried over magnesium sulfate. The solvent was removed in vacuo. The residue was recrystallized from isopropanol-water to yield ethyl (αS) -oi- [ (2, 6-difluorobenzoyl) amino] -4′ -ethoxymethyl-2′ , 6′ – dimethox (1, 1′ -biphenyl) -4-propionate (26.4 g) . MS (m/z) : 527 (M+) , M.p. 87-89°C (4) To a solution of sodium hydroxide (2.9 g) in water- tetrahydrofuran (317 ml-159 ml) was added ethyl (oιS)-α- [ (2, 6-difluorobenzoyl) amino] -4′ -ethoxymethyl-2′ , 6′ – dimethoxy (1, 1′ -biphenyl) -4-propionate (31.7 g) at 15°C and the mixture was stirred for 4 hours at the same temperature. After neutralizing with IN HC1, the organic solvent was removed in vacuo. The aqueous layer was cooled, the crystalline precipitates were collected by filtration and recrystallized from ethanol-water to yield (αS) -a- [ (2, 6- difluorobenzoyl) amino] -4′ -ethoxymethyl-2′ , 6′ – dimethoxy (1, 1′ -biphenyl) -4-propionic acid (28.8 g) . MS (m/z): 499 (M+) , M.p. 154-155°C

EXAMPLE 2 (1) Under nitrogen atmosphere, a mixture of ethyl (oιS)-o:- [[ (1, 1-dimethylethoxy) carbonyl] amino] -4-bromobenzene propanoate (11.17 g) , 4-ethoxymethyl-2, 6- dimethoxyphenylboronic acid (10.80 g ), palladium acetate (0.34 g), triphenylphosphine (1.57 g) , anhydrous potassium carbonate (12.44 g) , iV-methylpyrrolidone (56 ml) and water (11 ml) was stirred for 50 minutes at 80 °C. After completion of the reaction, the mixture was cooled to room temperature and extracted with ethyl acetate and water. The organic layer was washed with 10% aqueous citric acid solution and saturated aqueous NaCl solution, dried over magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure to yield ethyl (αS)-α- [ [ (1, 1-dimethylethoxy) carbonyl] amino] -4′ -ethoxymethyl- 2′ , 6′ -dimethox (1, 1′ -biphenyl) -4-propionate (20.4 g) as oil. The product was dissolved in ethanol (100 ml) , and after addition of p-toluenesulfonic acid monohydrate (5.7 g) , the mixture was stirred for 1.5 hours at 75 °C. After cooling, the mixture was filtrated over charcoal and the filtrate was concentrated under reduced pressure. The residue was suspended in toluene with heating. After cooling, the crystalline precipitates were collected by filtration and dried to yield ethyl (αS) – -amino-4′ – ethoxymethyl-2′ , 6′ -dimethoxy (1,1′ -biphenyl) -4-propionate p- toluenesulfonate (13.80 g) . (2) The compound obtained in the above step (1) was treated in the same manner as described in Example 1 (2) to (4) to yield (αS) -a- [ [2 , 6-difluorobenzoyl) amino] -4′ – ethoxymethyl-2′ , 6′ -dimethoxy (1, 1′ -biphenyl) -4-propionic acid. The physicochemical data were the same as that obtained in Example 1.

EXAMPLE 3

To a solution of ethyl (αS) -α- [ (2, 6- difluorobenzoyl) amino] -4′ -ethoxymethyl-2′ , 6′ – dimethox (1, 1′ -biphenyl) -4-propionate (500 g ) in water (12.6 ml) and dioxane (50 ml) was added hydrochloric acid (12.4 g) and the mixture was stirred for 60 hours at 60 “C. The organic solvent was removed in vacuo and the aqueous layer was cooled. The crystalline precipitates were collected by filtration and recrystallized from ethanol- water to yield (αS) – – [ (2, 6-difluorobenzoyl) amino] -4′ – ethoxymethyl-2′ , 6′ -dimethoxy (1,1′ -biphenyl) -4-propionic acid (426 mg) . The physicochemical data were the same as that obtained in Example 1.

REFERENCE EXAMPLE 1

(1) To a mixture of 4-bromo-3, 5-dimethoxybenzylalcohol (44.5 g) , triethylammonium benzyl chloride (2.05 g) and 20% aqueous sodium hydroxide solution (288 g) was added diethyl sulfate (41.7 g) under ice-cooling, and the mixture was stirred overnight at 25-30 °C. After stirring for 1 hour at 70 °C, the mixture was cooled and extracted with toluene. The toluene layer was washed with water and saturated aqueous NaCl solution and dried over magnesium sulfate. The solvent was removed in vacuo to yield 4-bromo-3, 5- dimethoxybenzyl ethyl ether (49.5 g) as colorless oil. MS (m/z): 276 (M++2) , 274 (M+)

(2) Under nitrogen atmosphere, to a solution of 4-bromo- 3, 5-dimethoxybenzyl ethyl ether (440.0 g) in tetrahydrofuran (4.0 L) was added dropwise n-butyl lithium (1.6 M n-hexane solution, 1.1 L) at -60°C. After stirring for 15 minutes at the same temperature, trimethyl borate (249.3 g) was added. The temperature of the mixture was gradually elevated, followed by stirring for 1 hour under ice-cooling. To the mixture was added dropwise 10% aqueous sulfuric acid solution (835 g ) . The mixture was extracted with ethyl acetate and the organic layer was washed with water and saturated aqueous NaCl solution. After drying over magnesium sulfate, the solvent was removed in vacuo. The residue was dissolved in isopropyl ether with heating and cooled. The crystalline precipitates were collected by filtration and dried to yield 4-ethyoxymethyl-2, 6- dimetoxyphenylboronic acid (312.9 g) . M.p. 59-61°C

REFERENCE EXAMPLE 2

(1) To a suspension of 4-bromo-3, 5-dihydroxybenzoic acid (95.0 kg) in ethyl acetate (950 L) were added anhydrous potassium carbonate (270.8 kg) and dimethyl sulfate (174.7 kg) . The mixture was heated at 50-80 ‘C for about 4 hours and partitioned by adding water. The organic layer was washed with water and saturated aqueous NaCl solution and concentrated under reduced pressure. The residue was suspended into methanol, stirred under heating and cooled. The crystalline precipitates were collected by filtration and dried to yield methyl 4-bromo-3, 5-dimethoxybenzoate (98.8 kg) as pale yellow crystals. MS (m/z): 277 (M++2) , 275 (M+) , M.p. 120-122°C

(2) To a solution of calcium chloride (46.5 kg) in ethanol (336 L) were added tetrahydrofuran (672 L) and methyl 4- bromo-3, 5-dimethoxybenzoate (96.0 kg) to obtain a suspension. To the suspension was added sodium borohydride

(31.7 kg) by portions at room temperature, and the mixture was stirred for about 9 hours at temperature of room temperature to 45 °C. The reaction mixture was added dropwise to aqueous HC1 solution and stirred for about 16 hours at room temperature. Organic solvent was removed in vacuo, and water (1440 L) was added to the residue and stirred for 1 hour at 50 °C. After cooling, the crystalline precipitates were collected by filtration and dried to yield 4-bromo-3, 5-dimethoxybenzyl alcohol (83.3 kg) as colorless crystals. MS (m/z): 249 (M++2), 247 (M+) , M.p. 100-102°C.

INDUSTRIAL APPLICABILITY The process for preparation of the present invention makes it possible to afford a compound of the formula (I) or a pharmaceutically acceptable salt thereof with high- purity, in a high yield and inexpensively, and, therefore, the process of the present invention is industrially very useful.

References

GlaxoSmithKline website
US8822527 16 Out 2012 2 Set 2014 Biotheryx, Inc. Substituted biaryl alkyl amides
WO2002018320A2 27 Ago 2001 7 Mar 2002 Tanabe Seiyaku Co INHIBITORS OF α4 MEDIATED CELL ADHESION
WO2003072536A1 27 Fev 2003 4 Set 2003 Tanabe Seiyaku Co A process for preparing a phenylalanine derivative and intermediates thereof
WO2003072537A2 6 Fev 2003 4 Set 2003 Abbott Lab Selective protein tyrosine phosphatatase inhibitors

Mitsubishi Tanabe Pharma Corporation

Mitsubishi Tanabe Pharma Corporation
Pharmacological research building

Mitsubishi Tanabe Pharma Corporation
■Mitsubishi Tanabe Pharma Corporation
Pharmacological research building

 

 

 

 

 

 

 

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.

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.

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.

 

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.

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.

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.

K 912, NC 6300, Epirubicin nano


Epirubicin.png

PHASE 1 JAPAN SOLID TUMOURS

DNA/RNA Synthesis Inhibitor

WITH Nano Carrier Co.,Ltdhttp://pdf.irpocket.com/C4571/qnwX/eFou/vG1J.pdf

KOWA COMPANY LTD

CAS FREE FORM. 56420-45-2

Smiles

NC-6300, an epirubicin-incorporating micelle, extends the antitumor effect and reduces the cardiotoxicity of epirubicin.

Epirubicin is widely used to treat various human tumors. However, it is difficult to achieve a sufficient antitumor effect because of dosage limitation to prevent cardiotoxicity. We hypothesized that epirubicin-incorporating micelle would reduce cardiotoxicity and improve the antitumor effect. NC-6300 comprises epirubicin covalently bound to PEG polyaspartate block copolymer through an acid-labile hydrazone bond. The conjugate forms a micellar structure of 40-80 nm in diameter in an aqueous milieu. NC-6300 (10, 15 mg/kg) and epirubicin (10 mg/kg) were given i.v. three times to mice bearing s.c. or liver xenograft of human hepatocellular carcinoma Hep3B cells. Cardiotoxicity was evaluated by echocardiography in C57BL/6 mice that were given NC-6300 (10 mg/kg) or epirubicin (10 mg/kg) in nine doses over 12 weeks. NC-6300 showed a significantly potent antitumor effect against Hep3B s.c. tumors compared with epirubicin. Moreover, NC-6300 also produced a significantly longer survival rate than epirubicin against the liver orthotopic tumor of Hep3B. With respect to cardiotoxicity, epirubicin-treated mice showed significant deteriorations in fractional shortening and ejection fraction. In contrast, cardiac functions of NC-6300 treated mice were no less well maintained than in control mice. This study warrants a clinical evaluation of NC-6300 in patients with hepatocellular carcinoma or other cancers.

K-912(NC-6300)の概要 K-912(NC-6300)は、世界的に幅広く使用されているアントラサイクリン系の抗が ん剤の一つであるエピルビシンを内包したミセル化ナノ粒子製剤で、その特性により、 エピルビシンの有する心毒性の軽減が期待できます。さらに、pH 応答性システムを採 用することで、腫瘍細胞内でのエピルビシンの放出量を高め、既存のエピルビシンに比 べより強力な抗腫瘍効果が期待できます。

Epirubicin is an anthracycline drug used for chemotherapy. It can be used in combination with other medications to treat breast cancer in patients who have had surgery to remove the tumor. It is marketed by Pfizer under the trade name Ellence in the US andPharmorubicin or Epirubicin Ebewe elsewhere.

Similarly to other anthracyclines, epirubicin acts by intercalating DNA strands. Intercalation results in complex formation which inhibits DNA and RNA synthesis. It also triggers DNA cleavage by topoisomerase II, resulting in mechanisms that lead to cell death. Binding to cell membranes and plasma proteins may be involved in the compound’s cytotoxic effects. Epirubicin also generates free radicalsthat cause cell and DNA damage.

Epirubicin is favoured over doxorubicin, the most popular anthracycline, in some chemotherapy regimens as it appears to cause fewer side-effects. Epirubicin has a different spatial orientation of the hydroxyl group at the 4′ carbon of the sugar – it has the opposite chirality – which may account for its faster elimination and reduced toxicity. Epirubicin is primarily used against breast and ovarian cancer, gastric cancer, lung cancer and lymphomas.

Development history

The first trial of epirubicin in humans was published in 1980.[1] Upjohn applied for approval by the U.S. Food and Drug Administration(FDA) in node-positive breast cancer in 1984, but was turned down because of lack of data.[2] It appears to have been licensed for use in Europe from around this time however.[3] In 1999 Pharmacia (who had by then merged with Upjohn) received FDA approval for the use of epirubicin as a component of adjuvant therapy in node-positive patients.

Patent protection for epirubicin expired in August 2007.

References

  1.  Bonfante, V; Bonadonna, G; Villani, F; Martini, A (1980). “Preliminary clinical experience with 4-epidoxorubicin in advanced human neoplasia”. Recent results in cancer research 74: 192–9. PMID 6934564. PM6934564.
  2.  “On Target”.
  3.  According to the proprietary database iddb.com

External links

1H NMR PREDICT

Epirubicin NMR spectra analysis, Chemical CAS NO. 56420-45-2 NMR spectral analysis, Epirubicin H-NMR spectrum

 

 

13C NMR PREDICT

Epirubicin NMR spectra analysis, Chemical CAS NO. 56420-45-2 NMR spectral analysis, Epirubicin C-NMR spectrum

 

COSY

 

COSY NMR prediction EPI

 

 

1H NMR

 

1H  NMR prediction EPI

 

 

 

1H  NMR prediction EPI 2

 

 

 

Epirubicin
Epirubicin.png
Epirubicin ball-and-stick.png
Systematic (IUPAC) name
(8R,10S)-10-((2S,4S,5R,6S)-4-amino-5-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)-6,8,11-trihydroxy-8-(2-hydroxyacetyl)-1-methoxy-7,8,9,10-tetrahydrotetracene-5,12-dione
Clinical data
Trade names Ellence
AHFS/Drugs.com monograph
MedlinePlus a603003
  • ℞-only (U.S.), POM (UK)
Intravenous
Pharmacokinetic data
Bioavailability NA
Protein binding 77%
Metabolism Hepatic glucuronidationand oxidation
Excretion Biliary and renal
Identifiers
56420-45-2 Yes
L01DB03
PubChem CID 41867
DrugBank DB00445 Yes
ChemSpider 38201 Yes
UNII 3Z8479ZZ5X Yes
KEGG D07901 Yes
ChEBI CHEBI:47898 Yes
ChEMBL CHEMBL417 Yes
Chemical data
Formula C27H29NO11
543.519 g/mol

 

 

KOWA COMPANY LTD

Nano Carrier Co

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.

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.

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.

PRI-724, ICG 001, What is correct structure?


 

 

PRI 724 AND ICG001  do confuse us, my efforts to unlock this confusion

STR 4

STRUCTURE 4

4-(((6S,9S,9aS)-l-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-ylmethyl)octahydro- 1 H-pyrazino[2, 1 -c] [ 1 ,2,4]triazin-6-yl)methyl)phenyl dihydrogen phosphate……………seems most likely PRI 724

STR 5

STRUCTURE 5

Cas 1422253-37-9

(6S,9S,9aS)-N-benzyl-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-yImethyl)octahydro- 1 H-pyrazino[2, 1 -c] [ 1 ,2,4]triazine- 1 -carboxamide.

pri 724 2

compd 2 and 1

OR

COMPD 3

http://www.medkoo.com/Anticancer-trials/PRI-724.htm and similar/Same

http://www.nature.com/nrc/journal/v14/n4/fig_tab/nrc3690_T1.html

compd 3.both above str are same

One of compd 1,2, 3, 4, 5 see at the end as an update ,  CAN BE ICG001,  PRI-724,

Prism Biolab Corporation

Beta-catenin (CTNNB1) inhibitor

ICG001, also known as PRI-724, is a potent, specific inhibitor of the canonical Wnt signaling pathway in cancer stem cells with potential antineoplastic activity. Wnt signaling pathway inhibitor PRI-724 specifically inhibits the recruiting of beta-catenin with its coactivator CBP (the binding protein of the cAMP response element-binding protein CREB); together with other transcription factors beta-catenin/CBP binds to WRE (Wnt-responsive element) and activates transcription of a wide range of target genes of Wnt/beta-catenin signaling. Blocking the interaction of CBP and beta-catenin by this agent prevents gene expression of many proteins necessary for growth, thereby potentially suppressing cancer cell growth. The Wnt/beta-catenin signaling pathway regulates cell morphology, motility, and proliferation; aberrant regulation of this pathway leads to neoplastic proliferation.

JAPAN

4-(((6S,9S)-l-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinoline-8-ylmethyl) octahy- dro-1H-pyrazino[2,1-c][1,2,4]triazine-6-yl)methyl) phenyl dihydrogen phosphate

(6S,9S)-N-benzyl-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxo-8-(quinoline-8-ylmethyl) octahydro-1H-pyrazino[2,1-c] [I,z,4]triazine-1-carboxamide,

4-(((6S,9S,9aS)-l-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-ylmethyl)octahydro- 1 H-pyrazino[2, 1 -c] [ 1 ,2,4]triazin-6-yl)methyl)phenyl dihydrogen phosphate

(6S,9S,9aS)-N-benzyl-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-yImethyl)octahydro- 1 H-pyrazino[2, 1 -c] [ 1 ,2,4]triazine- 1 -carboxamide.

Compound A  as in wo 2014061827……..4-(((6S,9S,9aS)-l-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-ylmethyl)octahydro- 1 H-pyrazino[2, 1 -c] [ 1 ,2,4]triazin-6-yl)methyl)phenyI dihydrogen phosphate in     WO2014061827

4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinoline-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-6-yl)methyl)phenyl dihydrogen phosphate (presumed to be PRI-724; first disclosed in WO2009148192), useful for treating cancer, neurodegenerative diseases, glaucoma and idiopathic pulmonary fibrosis.

Eisai, under license from PRISM Pharma, is developing PRI-724, an inhibitor of CREB binding protein or beta-catenin complex formation, for treating cancer (phase 1, as of March 2015) and HCV-induced cirrhosis (preclinical trial).

Follows on from WO2014061827, claiming the use of PRI-724 for treating pulmonary fibrosis.

IS IT

PRI-724 structure

cas 847591-62-2…………http://www.medkoo.com/Anticancer-trials/PRI-724.htm

(6S,9aS)-N-Benzyl-6-(4-hydroxybenzyl)-8-(naphthalen-1-ylmethyl)-4,7-dioxoperhydropyrazino[1,2-a]pyrimidine-1-carboxamide

 COMPD 3

OR

pri 724 5

COMPD 2

PRI724

1198780-43-6, 578.66, C33 H34 N6 O4

(6S,9S)-N-benzyl-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxo-8-(quinoline-8-ylmethyl) octahydro-1H-pyrazino[2,1-c] [I,z,4]triazine-1-carboxamide,
pri 724 6

COMPD1

PRI 724

4-(((6S,9S)-l-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinoline-8-ylmethyl) octahy- dro-1H-pyrazino[2,1-c][1,2,4]triazine-6-yl)methyl) phenyl dihydrogen phosphate

COMPD 1

SEE

 http://www.google.co.in/patents/WO2009148192A1?cl=en

About PRI-724
PRI-724 is an antiproliferative small molecule that selectively inhibits the CBP/beta-catenin complex, which modulates the beta-catenin dependent pathway of Wnt signaling. Activation of the Wnt/beta-catenin signaling pathway is observed in various tumor cells and results in proliferation and metastasis. PRI-724 exhibits a selective antiproliferative effect, inhibiting various cancer cell lines in vitroand substantially inhibiting tumor growth in animal studies. PRI-724 is currently in clinical trials in oncology indications, partnered with Eisai Co., Ltd. PRI-724 also has potential to provide therapeutic benefit in non-oncology areas such as fibrosis and clinical trials in that indication are targeted to start in the second half of 2013.

About PRISM Pharma Co., Ltd.
PRISM Pharma Co., Ltd. has developed its platform technology to modulate inter-cellular protein-protein interactions using peptide mimetic small molecules and found various hit compounds including PRI-724.

SEE

WO 2015037587

Eisai Research Institute; PRISM Pharma Co Ltd

出願人:エ_ ザイ■ ア_ ル■ アンド■ ディ_ ■
マネジメン卜株式会社(EISAI R&D MANAGEMENT
CO., LTD.) [JP /JP ];亍1128088 東京都文京区
小石川四丁目6 番1 O 号Tokyo (JP).株式会社P
R I S M P h a r m a (PRISM PHARMA CO.,
LTD.) [JP /JP ];亍2268510神奈川県横浜市緑区長津
田町 4 2 5 9 — 3 Kanagawa (JP)

(IO) 国際公開番号
2 0 1 5 ^ ® S 3 .2 0 1 5 )

WO 2015/037587 Al

This method of producing 4-(((6S,9S)-l-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinoline-8-ylmethyl) octahy- dro-1H-pyrazino[2,1-c][1,2,4]triazine-6-yl)methyl) phenyl dihydrogen phosphate involves a step for adding a reaction solution (I) comprising (6S,9S)-N-benzyl-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxo-8-(quinoline-8-ylmethyl) octahydro-1H-pyrazino[2,1-c] [I,z,4]triazine-1-carboxamide, triethylamine and a solvent to a reaction solution (2) comprising a phosphorylating agent and a solvent.

1

1H-NMR (600MHz, METHAN0L-d4) δ (ppm):1.15 (d, J=6 Hz, 3H), 2.65 (s, 3H), 3.12 (d, J=18 Hz, 1H), 3.35 (d, J=7 Hz, 2H), 3.48 (d, J=18 Hz,1H), 4.15 (m,1H), 4.32 (d, J=15 Hz, 1H), 4.40 (d, J=15 Hz, 1H), 5.33(d, J=16 Hz, 1H), 5.41(d, J=16 Hz, 1H), 5.44 (d, J=7 Hz, 1H), 5.64 (d, J=10 Hz, 1H), 7.07 (dd, J=9,1 Hz, 2H), 7.15 (d, J=9 Hz, 2H), 7.24 (t, J=7 Hz, 1H), 7.27 (d, J=7 Hz, 2H), 7.34 (t, J=8 Hz, 2H), 7.55 (d d, J=8, 4 Hz, 1H), 7.60 (brd, J=6 Hz, 1H), 7.62 (dd, J=8, 7 Hz, 1H), 7.88 (dd, J=8,1 Hz, 1H), 8.38 (dd, J=8, 2 Hz, 1H), 8.90 (dd, J =4, 2 Hz, 1H).

…………………………………………………………………….

SEE

 http://www.google.co.in/patents/WO2009148192A1?cl=en

SYNTHESIS OF COMPD 2

PART A

PRI 724 A

Synthesis  Part A

step A

(S)-benzyl 1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate

Reaction   of the foll……………….N-methoxy-N-methylamine hydrochloride,   1N sodium hydroxide , (S)-2-(benzyloxycarbonylamino)propanoic acidand 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride to obtain
(S)-benzyl 1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate.

STEP B

(S)-benzyl 1,1-diethoxypropan-2-ylcarbamate

Reaction   of the foll……………….(S)-benzyl 1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate, 2M lithium aluminium hydride in tetrahydrofuran solution to obtain (S)-benzyl 1,1-diethoxypropan-2-ylcarbamate

STEP C

(S)-1,1-diethoxypropan-2-amine

Reaction   of the foll……………….(S)-benzyl 1,1-diethoxypropan-2-ylcarbamate,  5% palladium on carbon title compound . (S)-1,1-diethoxypropan-2-amine,

STEP D

 (S)-1,1-diethoxy-N-(quinolin-8-ylmethyl)propan-2-amine,
Reaction   of the foll……………….(S)-1,1-diethoxypropan-2-amine,was reacted with 8-Quinolinecarboaldehyde  to obtain the title
compound (S)-1,1-diethoxy-N-(quinolin-8-ylmethyl)propan-2-amine

 PART B

PRI 724 B

STEP E

 (9H-fluoren-9-yl)methyl (S)-3-(4-tert-butoxyphenyl)-1-(((S)-1,1-diethoxypropan-2-yl)(quinolin-8-ylmethyl)amino)-1-oxopropan-2-ylcarbamate

Reaction   of the foll………………. (S)-1,1-diethoxy-N-(quinolin-8-ylmethyl)propan-2-amine,  (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tertbutoxyphenyl)propanoic acid  to obtain the title compound (9H-fluoren-9-yl)methyl (S)-3-(4-tert-butoxyphenyl)-1-(((S)-1,1-diethoxypropan-2-yl)(quinolin-8-ylmethyl)amino)-1-oxopropan-2-ylcarbamate

STEP f

 (S)-2-amino-3-(4-tertbutoxyphenyl)-N-((S)-1,1-diethoxypropan-2-yl)-N-(quinolin-8-ylmethyl)propanamide        INT A

Reaction   of the foll……………….  (9H-fluoren-9-yl)methyl (S)-3-(4-tert-butoxyphenyl)-1-(((S)-1,1-diethoxypropan-2-yl)(quinolin-8-ylmethyl)amino)-1-oxopropan-2-ylcarbamate and  piperidine  to
obtain the title compound (S)-2-amino-3-(4-tertbutoxyphenyl)-N-((S)-1,1-diethoxypropan-2-yl)-N-(quinolin-8-ylmethyl)propanamide INT A

PART C

PRI 724 C

STEP g

 ethyl 2-(1-methylhydrazinyl)acetate

Reaction   of the foll……………….methylhydrazine 7 was reacted with ethyl 2-bromoacetate 1to obtain the title compound

STEP h
ethyl 2-(1-Methyl-2-(benzylcarbamoyl)hydrazinyl)acetate

Reaction   of the foll………………. ethyl 2-(1-methylhydrazinyl)acetateand  benzyl isocyanate  to obtain the title
compound ethyl 2-(1-Methyl-2-(benzylcarbamoyl)hydrazinyl)acetate

STEP i
2-(2-(benzylcarbamoyl)-1-methylhydrazinyl)acetic acid

Reaction   of the foll………………. ethyl 2-(1-allyl-2-
(benzylcarbamoyl)hydrazinyl)acetate and lithium hydroxide monohydrate to obtain the title compound 2-(2-(benzylcarbamoyl)-1-methylhydrazinyl)acetic acid

STEP j
N-benzyl-2-(2-((S)-3-(4-tert-butoxyphenyl)-1-(((S)-1,1-
diethoxypropan-2-yl)(quinolin-8-ylmethyl)amino)-1-oxopropan-2-ylamino)-2-oxoethyl)-2-
methylhydrazinecarboxamide……… precursor

Reaction   of the foll………………. 2-(2-(benzylcarbamoyl)-1-methylhydrazinyl)acetic acid and  (S)-2-amino-3-(4-tert-butoxyphenyl)-N-((S)-1,1-diethoxypropan-2-yl)-N-(quinolin-8-ylmethyl)propanamide ( INT A )yielded the title compound ie the precursor

PART D

THIS PRECURSOR GIVES FINAL PRODUCT

pri 724 5

Synthesis of (6S,9S)-N-benzyl-6-(4-hydroxybenzyl)-2,9-
dimethyl-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-
carboxamide ……….final

fOLL reactants……….. N-benzyl-2-(2-((S)-3-(4-tert-butoxyphenyl)-1-(((S)-1,1-diethoxypropan-2-yl)(naphthalen-1-ylmethyl)amino)-1-oxopropan-2-ylamino)-2-oxoethyl)-2-methylhydrazinecarboxamide, ie the precursor  and 10%-water/HCOOH gave (6S,9S)-N-benzyl-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-ylmethyl)octahydro-1Hpyrazino[2,1-c][1,2,4]triazine-1-carboxamide

RT 4.22; Mass 578.9

COMPD 3

(6S,9aS)-N-Benzyl-6-(4-hydroxybenzyl)-8-(naphthalen-1-ylmethyl)-4,7-dioxoperhydropyrazino[1,2-a]pyrimidine-1-carboxamide

SEE

US 6762185

……………………………..

SEE

http://www.google.com/patents/WO2012141038A1?cl=en

novel compounds, agent for inducing differentiation into hepatocytes of mesenchymal stem cells, Wnt / β- catenin signaling pathway inhibitor, method for producing hepatocytes with them on hepatocytes such as by their production.

Liver disease is said to be Japan’s national disease, a large number of patients suffering from liver disease. In addition, the annual number of deaths from hepatocellular carcinoma amounts to about 30 004 thousand people. Recently, hepatocellular cancer outcome is improved by advances in treatment, but the increase of advanced cancer, with hepatic dysfunction cirrhosis to merge, so-called hepatic failure death has increased. Liver failure therapy, although liver transplantation is ideal, it is difficult in Japan to obtain sufficient donors, it is necessary to develop a liver regeneration therapy with stem cells.

As stem cells that have the potential to differentiate into liver cells, bone marrow cells, tissue stem cells, such as umbilical cord blood cells can be expected.Therefore, a number of research institutions, for the realization of by regenerative medicine liver cell transplantation treatment of chronic liver failure patient, to differentiate human tissue stem cells into functional hepatocytes, truly clinically applicable efficient differentiation induction technology you are conducting research and development with the goal of developing a.

For example, in the laboratory of Shioda Professor of Tottori University Graduate School of Medicine, reported that the Wnt / β- catenin signaling pathway were differentiated into hepatocytes showed that suppressed by RNA interference at the time of induction of differentiation from human mesenchymal stem cells into hepatocytes you are (Non-Patent Document 1 and Non-Patent Documents 3-5).Furthermore, studies to induce differentiation of hepatocytes in other institutions have been conducted (Non-Patent Document 2, Patent Documents 1 and 2).

On the other hand, recently, from 4,000 or more screening of large compound libraries, Wnt / β- catenin signaling pathway inhibitory low molecular compound 5 types have been identified (Non-Patent Documents 6-9).

Kohyo 2009-535035 JP Patent Publication No. 2010-75631

Atsushi Yanagitani et al., ” retinoic Acid Receptor Dominant Level Negative Form Causes steatohepatitis and Liver Tumors in Transgenic Mice “, Hepatology, Vol. 40, No. 2, 2004, P. 366-375 Seoyoung Park et al.,”Hexachlorophene Inhibits Wnt / beta-catenin Pathway by Promoting Siah-Mediated beta-catenin Degradation “, Mol Pharmacol Vol. 70, No. 3, 960-966, 2006 Yoko Yoshida et al.,” A role of Wnt / beta-catenin Signals in hepatic fate Specification of human umbilical cord blood-derived mesenchymal stem cells “, Am J Physiol Gastrointest Liver Physiol 293:. G1089-G1098, 2007 Shimomura T et al,” Hepatic differentiation of human bone marrow-derived UE7T-13 cells: Effects of cytokines and CCN family Gene expression “, Hepatol Res., 37, 1068-79, 2007 Ishii K et al.,” Hepatic differentiation of human bone marrow-derived mesenchymal stem cells by tetracycline-regulated Hepatocyte Nuclear factor 3Beta “Hepatology, 48, 597- 606, 2008 Maina Lepourcelet et al., ” Small-molecule Antagonists of the oncogenic Tcf / beta-catenin protein complex “, CANCER CELL, JANUARY 2004, VOL. 5, 91-102 Emami KH et al.,” A Small molecule inhibitor of beta-catenin / CREB-binding protein Transcription “, Proc Natl Acad Sci US A. 2004 Aug 24; 101 (34):.. 12682-7 Jufang Shan et al,”Identification of a Specific Inhibitor of the Dishevelled PDZ Domain ” , Biochemistry 2005 Nov 29; 44 (47):.. 15495-503 Trosset JY et al, ” Inhibition of protein-protein Interactions: the discovery of beta-catenin Druglike Inhibitors by combining virtual and Biophysical Screening . “, Proteins 2006 Jul 1 ; 64 (1): 60-7

However, the conventional techniques described above literature, had a room for improvement in the following points.
Patent Documents 1 and 2, it has been described for proteins to induce stem cells from Hikimomiki cells, due to the use of the protein formulation as a differentiation inducing agent, a room for further improvement in terms of stability and safety and there was.

Non-Patent Document 1 and Non-Patent Document 3 to 5, and have reported that induced differentiated hepatocytes from human mesenchymal stem cells, the use of siRNA as a differentiation inducing agent, such as stability and safety there is room for further improvement in the surface. Non-Patent Document 2, 6 to 9, is not described with respect to method of inducing differentiation into hepatocytes.

The present invention has been made in view of the above circumstances, and an object thereof is to provide an effective low-molecular compounds that induce differentiation into hepatocytes from mesenchymal stem cells. Or, it is intended that the low-molecular compound was used to provide a secure differentiation inducing method is excellent from the mesenchymal stem cell differentiation efficiency of liver cells.

According to the present invention, there is provided formula (1) and one or more compounds selected from the group of compounds represented by the formula (2), a salt thereof or a solvate thereof.

Figure JPOXMLDOC01-appb-C000010
 
 

<Example 1> synthetic ICG-001 of synthesis (1) ICG-001 of the IC-2 is an oligopeptide having two rings of β- turn mimic structure in central skeleton, and transcription by β-catenin / Tcf complex can function as a potent antagonist for activation has been reported (Drug Discov. Today 2005, 10, 1467-1474). Synthesis of ICG-001 in accordance with the literature (Tetrahedron 2007, 63, 12912-12916), was subjected to examination.

Figure JPOXMLDOC01-appb-C000019

(1-1) of Compound 1 Synthesis 1-naphtaldehyde (Wako Pure Chemical) (1.56 g, 10 mmol) and 2,2-diethoxyethanamine (Tokyo Kasei Kogyo) (1.33 g, 10 mmol) were mixed 100 I was stirred 20 min at o C. After cooling to room temperature, diluted with EtOH (20 mL), was added portionwise NaBH 4 (0.38 g, 10 mmol), at room temperature, and stirred for 16 h. After completion of the reaction, was distilled off by concentration under reduced pressure EtOH, the product was extracted with AcOEt. The resulting product was purified by silica gel column chromatography (hexane / AcOEt = 5/1) to give the to give compound 1 (2.29 g, 8.5 mmol, 85%).

Figure JPOXMLDOC01-appb-C000020

(1-2) Synthesis of Compound 3 Fmoc-L-Tyr (t-Bu) -OH (0.87 g, 1.9 mmol) in DMF (7 mL) solution of a condensing agent HATU (0.76 g, 2.0 mmol) and diisopropylethylamine (DIEA) (0.35 mL, 2.0 mmol) was added and after stirring for 20 min, compound 1 (0.54 g, a 2.0 mmol) was added, at room temperature, 16 h the mixture was stirred. After the reaction, DMF was distilled off by concentration under reduced pressure, and the resulting product was purified by column chromatography (hexane / AcOEt = 10/1), compound 2 was obtained (1.33 g, 1.9 mmol, 93%). The resulting compound 2 (1.33 g, 1.9 mmol) was dissolved in CH 2 Cl 2 (20 mL), was added diethylamine (DEA) (10 ml, excess), at room temperature, was 2 h stirring.After confirming the completion of the reaction by TLC, vacuum was distilled off CH 2 Cl 2 by concentration, the resulting product was purified by silica gel column chromatography (AcOEt), to give compound 3 (0.92 g, 1. 8 mmol, 92%).

Figure JPOXMLDOC01-appb-C000021

(1-3) Synthesis Fmoc-β-Ala-OH (0.53 g, 1.7 mmol) of compound 5 in DMF (8 mL) solution of a condensing agent HATU (0.70 g, 1.8 mmol) and diisopropylethylamine (DIEA) (0.32 mL, 1.8 mmol) was added and after stirring for 20 min, compound 3 (0.92 g, 1.8 mmol) was added, at room temperature, and stirred for 14 h. After the reaction, DMF was distilled off by concentration under reduced pressure, the resulting product was purified by column chromatography (hexane / AcOEt = 1/1), compound 4 was obtained (1.2 g, 1.5 mmol, 82%). Obtained compound 4 (1.2 g, 1.5 mmol) was dissolved in CH 2 Cl 2 (20 mL), was added diethylamine (DEA) (9 mL, excess), at room temperature, and stirred for 1 h. After confirming the completion of the reaction by TLC, was distilled off CH 2 Cl 2 by concentration under reduced pressure, and the resulting product was purified by silica gel column chromatography (AcOEt / EtOH = 1/1), to give compound 5 (0 .66 g, 1.2 mmol, 80%).

Figure JPOXMLDOC01-appb-C000022

(1-4) synthetic compounds 5 (0.66 g, 1.2 mmol) of compound 7 CH 2 Cl 2 of solution (8 mL) to benzylisocyanate (0.16 g, 1.2 mmol) of CH 2 Cl 2 solution (8 mL) was added, at room temperature, and stirred for 12 h. After confirming the completion of the reaction by TLC, was distilled off CH 2 Cl 2 by concentration under reduced pressure, and the resulting product was purified by column chromatography (AcOEt / EtOH = 1/1), to give compound 6 (0. 59 g, 0.85 mmol, 73%). The obtained compound 6 (0.59 g, 0.85 mmol) at room temperature in the formic acid (9 ml), I was stirred 20 h. Was evaporated formic acid by concentration under reduced pressure, the resulting product was purified by column chromatography (AcOEt), Compound 7a to (ICG-001) was obtained as a white solid (0.26 g, 0.48 mmol, 57 %).
The resulting product, MS spectra and were identified from the 1 H NMR spectrum (with the literature value) (Fig. 1).

Figure JPOXMLDOC01-appb-C000023
WO2006101858A1 * Mar 15, 2006 Sep 28, 2006 Inst Chemical Genomics Alpha-helix mimetics and methods relating to the treatment of fibrosis
WO2009148192A1 * Jun 5, 2009 Dec 10, 2009 Prism Biolab Corporation Alpha helix mimetics and methods relating thereto
WO2012068299A2 * Nov 16, 2011 May 24, 2012 University Of Southern California Cbp/catenin antagonists for enhancing asymmetric division of somatic stem cells

SEE      https://www.google.com/patents/WO2014061827A1?cl=en

one more compd
compd 4
Compound A  as in wo 2014061827……..4-(((6S,9S,9aS)-l-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-ylmethyl)octahydro- 1 H-pyrazino[2, 1 -c] [ 1 ,2,4]triazin-6-yl)methyl)phenyI dihydrogen phosphate in     WO2014061827

 STR 4

STRUCTURE 4

4-(((6S,9S,9aS)-l-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-ylmethyl)octahydro- 1 H-pyrazino[2, 1 -c] [ 1 ,2,4]triazin-6-yl)methyl)phenyl dihydrogen phosphate

STRUCTURE  5

STR 5

STRUCTURE 5

(6S,9S,9aS)-N-benzyl-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-yImethyl)octahydro- 1 H-pyrazino[2, 1 -c] [ 1 ,2,4]triazine- 1 -carboxamide.

Cas 1422253-37-9

2H-​Pyrazino[2,​1-​c]​[1,​2,​4]​triazine-​1(6H)​-​carboxamide, hexahydro-​6-​[(4-​hydroxyphenyl)​methyl]​-​2,​9-​dimethyl-​4,​7-​dioxo-​N-​(phenylmethyl)​-​8-​(8-​quinolinylmethyl)​-​, (6S,​9S,​9aS)​-

Structure can represented as

PRI 724 CAAS

 

coming
coming
coming
 CONCLUSION ………………….SEEMS TO ME THAT COMPD 4 IS PRI 724  NAD COMPD 3 IS ICG 001……ERROR EMAIL ME  amcrasto@gmail.com, call +919323115463 india

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.

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.

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.

Vibegron, MK-4618 for for the treatment of overactive bladder


Chemical structure for Vibegron (USAN)

 

Vibegron, MK-4618, KRP 114V

UNII-M5TSE03W5U; M5TSE03W5U; D10433
Molecular Formula: C26H28N4O3   Molecular Weight: 444.52552
phase 2 for the treatment of overactive bladder
 (6S)-N-[4-([(2S,5R)-5-[(R)-Hydroxy(phenyl)methyl]pyrrolidin-2-yl]methyl)phenyl]-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide
(6S)-N-[4-[[(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl]methyl]phenyl]-4-oxo-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6-carboxamide

Target-based Actions Beta 3 adrenoceptor agonist
Indications Overactive bladder; Urinary incontinence

 

Kyorin Pharmaceutical, under license from Merck, is developing vibegron (phase II, September 2014) for the treating of overactive bladder. In July 2014, Merck has granted to Kyorin an exclusive license to develop, manufacture and commercialize vibegron in Japan.

MK-4618 is being developed in phase II clinical trials at Merck & Co. for the treatment of overactive bladder. The company had been developing the compound for the treatment of endocrine disorders and hypertension; however, recent progress reports are not available at present.

In 2014, Merck licensed the product to Kyorin for development and commercialization in Japan.

The function of the lower urinary tract is to store and periodically release urine. This requires the orchestration of storage and micturition reflexes which involve a variety of afferent and efferent neural pathways, leading to modulation of central and peripheral neuroeffector mechanisms, and resultant coordinated regulation of sympathetic and parasympathetic components of the autonomic nervous system as well as somatic motor pathways. These proximally regulate the contractile state of bladder (detrusor) and urethral smooth muscle, and urethral sphincter striated muscle.

β Adrenergic receptors (βAR) are present in detrusor smooth muscle of various species, including human, rat, guinea pig, rabbit, ferret, dog, cat, pig and non-human primate. However, pharmacological studies indicate there are marked species differences in the receptor subtypes mediating relaxation of the isolated detrusor; β1AR predominate in cats and guinea pig, β2AR predominate in rabbit, and β3AR contribute or predominate in dog, rat, ferret, pig, cynomolgus and human detrusor. Expression of βAR subtypes in the human and rat detrusor has been examined by a variety of techniques, and the presence of β3AR was confirmed using in situ hybridization and/or reverse transcription-polymerase chain reaction (RT-PCR). Real time quantitative PCR analyses of β1AR, β2AR and β3AR mRNAs in bladder tissue from patients undergoing radical cystectomy revealed a preponderance of β3AR mRNA (97%, cf 1.5% for β1AR mRNA and 1.4% for β2AR mRNA). Moreover, β3AR mRNA expression was equivalent in control and obstructed human bladders. These data suggest that bladder outlet obstruction does not result in downregulation of β3AR, or in alteration of β3AR-mediated detrusor relaxation. β3AR responsiveness also has been compared in bladder strips obtained during cystectomy or enterocystoplasty from patients judged to have normal bladder function, and from patients with detrusor hyporeflexia or hyperreflexia. No differences in the extent or potency of β3AR agonist mediated relaxation were observed, consistent with the concept that the β3AR activation is an effective way of relaxing the detrusor in normal and pathogenic states.

Functional evidence in support of an important role for the β3AR in urine storage emanates from studies in vivo. Following intravenous administration to rats, the rodent selective β3AR agonist CL316243 reduces bladder pressure and in cystomeric studies increases bladder capacity leading to prolongation of micturition interval without increasing residual urine volume.

Overactive bladder is characterized by the symptoms of urinary urgency, with or without urgency urinary incontinence, usually associated with frequency and nocturia. The prevalence of OAB in the United States and Europe has been estimated at 16 to 17% in both women and men over the age of 18 years. Overactive bladder is most often classified as idiopathic, but can also be secondary to neurological condition, bladder outlet obstruction, and other causes. From a pathophysiologic perspective, the overactive bladder symptom complex, especially when associated with urge incontinence, is suggestive of detrusor overactivity. Urgency with or without incontinence has been shown to negatively impact both social and medical well-being, and represents a significant burden in terms of annual direct and indirect healthcare expenditures. Importantly, current medical therapy for urgency (with or without incontinence) is suboptimal, as many patients either do not demonstrate an adequate response to current treatments, and/or are unable to tolerate current treatments (for example, dry mouth associated with anticholinergic therapy). Therefore, there is need for new, well-tolerated therapies that effectively treat urinary frequency, urgency and incontinence, either as monotherapy or in combination with available therapies. Agents that relax bladder smooth muscle, such as β3AR agonists, are expected to be effective for treating such urinary disorders.

PATENT

http://www.google.com/patents/WO2013062881A1?cl=en

Figure imgf000013_0001

EXAMPLE 3

To a three neck flask equipped with a N2 inlet, a thermo couple probe was charged pyrrolidine i-11 (10.0 g), sodium salt i-12 (7.87 g), followed by IPA (40 mL) and water (24 mL). 5 N HC1 (14.9 mL) was then slowly added over a period of 20 min to adjust pH = 3.3- 3.5, maintaining the batch temperature below 35 °C. Solid EDC hydrochloride (7.47 g) was charged in portions over 30 min. The reaction mixture was aged at RT for additional 0.5 – 1 h, aqueous ammonia (14%) was added dropwise to pH ~8.6. The batch was seeded and aged for additional 1 h to form a slurry bed. The rest aqueous ammonia (14%, 53.2 ml total) was added dropwise over 6 h. The resulting thick slurry was aged 2-3 h before filtration. The wet-cake was displacement washed with 30% IPA (30 mL), followed by 15% IPA (2 x 20mL) and water (2 X 20mL). The cake was suction dried under N2 overnight to afford 14.3 g of compound of Formula (I)-

1H NMR (DMSO) δ 10.40 (s, NH), 7.92 (d, J = 6.8, 1H), 7.50 (m, 2H), 7.32 (m, 2H), 7.29 (m, 2H), 7.21 (m, 1H), 7.16 (m, 2H), 6.24 (d, J = 6.8, 1H), 5.13 (dd, J = 9.6, 3.1, 1H), 5.08 (br s, OH), 4.22 (d, J = 7.2, 1H), 3.19 (p, J = 7.0, 1H), 3.16-3.01 (m, 3H), 2.65 (m, 1H), 2.59-2.49 (m, 2H), 2.45 (br s, NH), 2.16 (ddt, J = 13.0, 9.6, 3.1, 1H), 1.58 (m, 1H), 1.39 (m, 1H), 1.31-1.24 (m, 2H).

13C NMR (DMSO) δ 167.52, 165.85, 159.83, 154.56, 144.19, 136.48, 135.66, 129.16, 127.71, 126.78, 126.62, 119.07, 112.00, 76.71, 64.34, 61.05, 59.60, 42.22, 31.26, 30.12, 27.09, 23.82.

HPLC method – For monitoring conversion

Column: XBridge C18 cm 15 cm x 4.6 mm, 3.5 μιη particle size;

Column Temp. : 35 °C; Flow rate: 1.5 mL/min; Detection: 220 nm;

Mobile phase: A. 5 mM Na2B407.10 H20 B: Acetonitrile

Gradient:

HPLC method – For level of amide epimer detection

Column: Chiralpak AD-H 5 μηι, 250 mm x 4.6 mm.

Column Temp: 35 °C; Flow rate: 1.0 mL/min; Detection: 250 nm;

Mobile phase: Isocratic 30% Ethanol in hexanes + 0.1% isobutylamine

PATENT

WO 2009124167

http://www.google.com/patents/WO2009124167A1?cl=en

 

EXAMPLE 103

(6y)-N-r4-({(25′. 5R)-5-r(R)-hvdroxy(phenvnmethyl1pyrrolidin-2-yl}methvnphenyl1-4-oxo- 4,6J,8-tetrahydropyiτolori,2-α1pyrimidine-6-carboxamide

ter?-butyl(2R. 55f)-2-rCR)-hvdroxy(phenvnmethyl1-5-r4-({r(65f)-4-oxo-4.6.7.8-

tetrahydropyrrolof 1.2-alpyrimidin-6- yl]carbonyl} amino)benzyl]pyrrolidine- 1 – carboxylate

To a solution of i-13a (21.4 g, 55.9 mmol) in N,N-dimethylformamide (100 ml) at O0C was added [(65)-4-oxo-4,6,7,8-tetrahydropyrrolo[l,2-α]pyrimidine-6-carboxylic acid (11.1 g, 61.5 mmol), followed by 1 -hydroxybenzotriazole (i-44, 7.55 g, 55.9 mmol), N-(3- dimethylaminopropyl)-Nl-ethylcarbodiimide hydrochloride (16.1 g, 84.0 mmol) and N,N- diisopropylethylamine (29.2 ml, 168 mmol). The reaction mixture was stirred from O0C to ambient temperature for 2 h. Water (600 ml) was added and it was extracted with dichloromethane (600 ml x 2). The combined organic layers were dried over Na2SO4. After removal of the volatiles, the residue was purified by using a Biotage Horizon® system (0-5% then 5% methanol with 10% ammonia/dichloromethane mixture) to afford the title compound which contained 8% of the minor diastereomer. It was further purified by supercritical fluid chromatography (chiral AS column, 40% methanol) to afford the title compound as a pale yellow solid (22.0 g, 72%). 1H NMR (CDCl3): δ 9.61 (s, IH), 7.93 (d, J = 6.6 Hz, IH), 7.49 (d, J = 8.4 Hz, 2H), 7.35-7.28 (m, 5H), 7.13 (d, J = 8.5 Hz, 2H), 6.40 (d, J = 6.7 Hz, IH), 5.36 (d, J = 8.6 Hz, IH), 4.38 (m, IH), 4.12-4.04 (m, 2H), 3.46 (m,lH), 3.15-3.06 (m, 2H), 2.91 (dd, J = 13.1, 9.0 Hz, IH), 2.55 (m, IH), 2.38 (m, IH), 1.71-1.49 (m, 13H). LC-MS 567.4 (M+23).

(6S)-N-\4-( U2S. 5R)-5-r(R)-hvdroxy(phenyl)methyl1pyrrolidin-2-

yl}methyl)phenyl1-4-oxo-4,6J,8-tetrahvdropyrrolori,2-α1pyrimidine-6- carboxamide

To a solution of the intermediate from Step A (2.50 g, 4.59 mmol) in dichloromethane (40 ml) was added trifluoroacetic acid (15 ml). The reaction mixture was stirred at ambient temperature for 1.5 h. After removal of the volatiles, saturated NaHCCh was added to make the PH value to 8-9. The mixture was then extracted with dichloromethane. The combined organic layers were dried over Na2SO4. After concentration, crystallization from methanol/acetonitrile afforded the title compound as a white solid (1.23g, 60%). 1H NMR (DMSO-Cl6): δ 10.40 (s, IH), 7.91 (d, J = 6.7 Hz, IH), 7.49 (d, J = 8.3 Hz, 2H), 7.32-7.26 (m, 4H), 7.21 (m, IH), 7.15 (d, J = 8.4 Hz, 2H), 6.23 (d, J = 6.7 Hz, IH), 5.11 (dd, J = 9.6, 2.9 Hz, IH), 5.10 (br, IH), 4.21 (d, J = 7.1 Hz, IH), 3.20-3.00 (m, 4H), 2.66-2.51 (m, 3H), 2.16 (m, IH), 1.57 (m, IH), 1.38 (m, IH), 1.29-1.23 (m, 2H). LC-MS 445.3 (M+l).

Using the Biological Assays described above, the human β3 functional activity of Example 103 was determined to be between 11 to 100 nM.

 

PATENT

CHECK STRUCTURE…………….CAUTION

 

http://www.google.com/patents/US8247415

Figure US08247415-20120821-C00547

 

Figure US08247415-20120821-C00015

CAUTION…………….

Example 103(6S)-N-[4-({(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)phenyl]-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-α]pyrimidine-6-carboxamide

Step A: tert-butyl(2R,5S)-2-[(R)-hydroxy(phenyl)methyl]-5-[4-({[(6S)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-α]pyrimidin-6-yl]carbonyl}amino)benzyl]pyrrolidine-1-carboxylate

To a solution of i-13a (21.4 g, 55.9 mmol) in N,N-dimethylformamide (100 ml) at 0° C. was added [(6S)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-α]pyrimidine-6-carboxylic acid (11.1 g, 61.5 mmol), followed by 1-hydroxybenzotriazole (i-44, 7.55 g, 55.9 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (16.1 g, 84.0 mmol) and N,N-diisopropylethylamine (29.2 ml, 168 mmol). The reaction mixture was stirred from 0° C. to ambient temperature for 2 h. Water (600 ml) was added and it was extracted with dichloromethane (600 ml×2). The combined organic layers were dried over Na2SO4. After removal of the volatiles, the residue was purified by using a Biotage Horizon® system (0-5% then 5% methanol with 10% ammonia/dichloromethane mixture) to afford the title compound which contained 8% of the minor diastereomer. It was further purified by supercritical fluid chromatography (chiral AS column, 40% methanol) to afford the title compound as a pale yellow solid (22.0 g, 72%). 1H NMR (CDCl3): δ 9.61 (s, 1H), 7.93 (d, J=6.6 Hz, 1H), 7.49 (d, J=8.4 Hz, 2H), 7.35-7.28 (m, 5H), 7.13 (d, J=8.5 Hz, 2H), 6.40 (d, J=6.7 Hz, 1H), 5.36 (d, J=8.6 Hz, 1H), 4.38 (m, 1H), 4.12-4.04 (m, 2H), 3.46 (m, 1H), 3.15-3.06 (m, 2H), 2.91 (dd, J=13.1, 9.0 Hz, 1H), 2.55 (m, 1H), 2.38 (m, 1H), 1.71-1.49 (m, 13H). LC-MS 567.4 (M+23).

Step B: (6S)-N-[4-({(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)phenyl]-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-α]pyrimidine-6-carboxamide

To a solution of the intermediate from Step A (2.50 g, 4.59 mmol) in dichloromethane (40 ml) was added trifluoroacetic acid (15 ml). The reaction mixture was stirred at ambient temperature for 1.5 h. After removal of the volatiles, saturated NaHCO3 was added to make the PH value to 8-9. The mixture was then extracted with dichloromethane. The combined organic layers were dried over Na2SO4. After concentration, crystallization from methanol/acetonitrile afforded the title compound as a white solid (1.23 g, 60%). 1H NMR (DMSO-d6): δ 10.40 (s, 1H), 7.91 (d, J=6.7 Hz, 1H), 7.49 (d, J=8.3 Hz, 2H), 7.32-7.26 (m, 4H), 7.21 (m, 1H), 7.15 (d, J=8.4 Hz, 2H), 6.23 (d, J=6.7 Hz, 1H), 5.11 (dd, J=9.6, 2.9 Hz, 1H), 5.10 (br, 1H), 4.21 (d, J=7.1 Hz, 1H), 3.20-3.00 (m, 4H), 2.66-2.51 (m, 3H), 2.16 (m, 1H), 1.57 (m, 1H), 1.38 (m, 1H), 1.29-1.23 (m, 2H). LC-MS 445.3 (M+1).

Using the Biological Assays described above, the human β3 functional activity of Example 103 was determined to be between 11 to 100 nM.

PATENT

WO2014150639

http://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014150639&recNum=4&docAn=US2014023858&queryString=EN_ALL:nmr%20AND%20PA:merck&maxRec=11148

Step 6. Preparation of Compound 1-7 from Compound 1-6 and Compound A-2

To a three neck flask equipped with a N2 inlet, a thermo couple probe was charged pyrrolidine hemihydrate 1-6 (10.3 g), sodium salt A-2 (7.87 g), followed by IPA (40 mL) and water (24 mL). 5 N HC1 (14.9 mL) was then slowly added over a period of 20 minutes to adjust pH = 3.3-3.5, maintaining the batch temperature below 35°C. Solid EDC hydrochloride (7.47 g) was charged in portions over 30 minutes. The reaction mixture was aged at RT for additional 0.5 – 1 hour, aqueous ammonia (14%) was added dropwise to pH -8.6. The batch was seeded and aged for additional 1 hour to form a slurry bed. The rest aqueous ammonia (14%, 53.2 ml total) was added dropwise over 6 hours. The resulting thick slurry was aged 2-3 hours before filtration. The wet-cake was displacement washed with 30% IPA (30 mL), followed by 15% IPA (2 x 20mL) and water (2 X 20mL). The cake was suction dried under N2 overnight to afford 14.3 g of compound 1-7.

1H NMR (DMSO) δ 10.40 (s, NH), 7.92 (d, J = 6.8, 1H), 7.50 (m, 2H), 7.32 (m, 2H), 7.29 (m, 2H), 7.21 (m, 1H), 7.16 (m, 2H), 6.24 (d, J = 6.8, 1H), 5.13 (dd, J = 9.6, 3.1, 1H), 5.08 (br s, OH), 4.22 (d, J = 7.2, 1H), 3.19 (p, J = 7.0, 1H), 3.16-3.01 (m, 3H), 2.65 (m, 1H), 2.59-2.49 (m, 2H), 2.45 (br s, NH), 2.16 (ddt, J = 13.0, 9.6, 3.1, 1H), 1.58 (m, 1H), 1.39 (m, 1H), 1.31-1.24 (m, 2H).

13C NMR (DMSO) δ 167.52, 165.85, 159.83, 154.56, 144.19, 136.48, 135.66, 129.16, 127.71, 126.78, 126.62, 119.07, 112.00, 76.71, 64.34, 61.05, 59.60, 42.22, 31.26, 30.12, 27.09, 23.82.

The crystalline freebase anhydrous form I of Compound 1-7 can be characterized by XRPD by

 

 

PATENT

WO-2014150633
Merck Sharp & Dohme Corp
Process for preparing stable immobilized ketoreductase comprises bonding of recombinant ketoreductase to the resin in a solvent. Useful for synthesis of vibegron intermediates. For a concurrent filling see WO2014150639, claiming the method for immobilization of ketoreductase. Picks up from WO2013062881, claiming the non enzymatic synthesis of vibegron and intermediates.

 

PAPER

Discovery of Vibegron: A Potent and Selective β3 Adrenergic Receptor Agonist for the Treatment of Overactive Bladder

Merck Research Laboratories, 2015 Galloping Hill Road, PO Box 539, Kenilworth, New Jersey 07033, United States
J. Med. Chem., Article ASAP
DOI: 10.1021/acs.jmedchem.5b01372
Publication Date (Web): December 27, 2015
Copyright © 2015 American Chemical Society
*Telephone: (908) 740-0287. E-mail scott.edmondson@merck.com.

http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5b01372

http://pubs.acs.org/doi/suppl/10.1021/acs.jmedchem.5b01372/suppl_file/jm5b01372_si_001.pdf

 

Abstract Image

The discovery of vibegron, a potent and selective human β3-AR agonist for the treatment of overactive bladder (OAB), is described. An early-generation clinical β3-AR agonist MK-0634 (3) exhibited efficacy in humans for the treatment of OAB, but development was discontinued due to unacceptable structure-based toxicity in preclinical species. Optimization of a series of second-generation pyrrolidine-derived β3-AR agonists included reducing the risk for phospholipidosis, the risk of formation of disproportionate human metabolites, and the risk of formation of high levels of circulating metabolites in preclinical species. These efforts resulted in the discovery of vibegron, which possesses improved druglike properties and an overall superior preclinical profile compared to MK-0634. Structure–activity relationships leading to the discovery of vibegron and a summary of its preclinical profile are described.

Reference
1 H.P. Kaiser, et al., “Catalytic Hydrogenation of Pyrroles at Atmospheric Pressure“, J. Org. Chem., vol. 49, No. 22, p. 4203-4209 (1984).
A study of the efficacy and safety of MK-4618 in patients with overactive bladder (OAB) (MK-4618-008 EXT1) (NCT01314872)
ClinicalTrials.gov Web Site 2011, April 28

WO2011043942A1 * Sep 27, 2010 Apr 14, 2011 Merck Sharp & Dohme Corp. Combination therapy using a beta 3 adrenergic receptor agonist and an antimuscarinic agent
US20090253705 * Apr 2, 2009 Oct 8, 2009 Richard Berger Hydroxymethyl pyrrolidines as beta 3 adrenergic receptor agonists
US20110028481 * Apr 2, 2009 Feb 3, 2011 Richard Berger Hydroxymethyl pyrrolidines as beta 3 adrenergic receptor agonists
 
Citing Patent Filing date Publication date Applicant Title
US8642661 Aug 2, 2011 Feb 4, 2014 Altherx, Inc. Pharmaceutical combinations of beta-3 adrenergic receptor agonists and muscarinic receptor antagonists
US8653260 Jun 20, 2012 Feb 18, 2014 Merck Sharp & Dohme Corp. Hydroxymethyl pyrrolidines as beta 3 adrenergic receptor agonists
US20120202819 * Sep 27, 2010 Aug 9, 2012 Merck Sharp & Dohme Corporation Combination therapy using a beta 3 adrenergic receptor agonists and an antimuscarinic agent
US20020028835 Jul 12, 2001 Mar 7, 2002 Baihua Hu Cyclic amine phenyl beta-3 adrenergic receptor agonists
US20070185136 Feb 2, 2007 Aug 9, 2007 Sanofi-Aventis Sulphonamide derivatives, their preparation and their therapeutic application
US20110028481 Apr 2, 2009 Feb 3, 2011 Richard Berger Hydroxymethyl pyrrolidines as beta 3 adrenergic receptor agonists
WO2003072572A1 Feb 17, 2003 Sep 4, 2003 Jennifer Anne Lafontaine Beta3-adrenergic receptor agonists
8-22-2012
Hydroxymethyl pyrrolidines as [beta]3 adrenergic receptor agonists

 

 

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