Showing posts with label New patent. Show all posts
Showing posts with label New patent. Show all posts

Wednesday, 4 October 2017

WO 2017163257, NEW PATENT, IBRUTINIB, IND-SWIFT LABORATORIES LIMITED

WO2017163257) PROCESS FOR PREPARING PURE LH-PYRAZOLO[3,4-D] PYRIMIDINE DERIVATIVE
IND-SWIFT LABORATORIES LIMITED
ARUL, Ramakrishnan; (IN).
SARIN, Gurdeep Singh; (IN).
WAS, Sandeep; (IN).
KUMAR, Vishal; (IN)
The present invention relates to an efficient and industrially advantageous process for the preparation of pure lH-pyrazolo[3,4-d] pyrimidine derivative. In particular the present invention provides a process for the preparation of pure 4-amino-3-(4- phenoxyphenyl)-lH-pyrazolo[3,4-d] pyrimidine, a key intermediate of ibrutinib. Particularly, the present invention provides a process for the preparation of 3-amino-4-cyano-5-(4-phenoxy phenyl)pyrazole, wherein none of the intermediates have been isolated, an important precursor for the preparation of 4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d] pyrimidine.
The present invention relates to an efficient and industrially advantageous process for the preparation of pure lH-pyrazolo[3,4-d] pyrimidine derivative. In particular the present invention provides a process for the preparation of pure 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d] pyrimidine, a key intermediate of ibrutinib, wherein none of the intermediates have been isolated to prepare 3-amino-4-cyano-5-(4-phenoxy phenyl)pyrazole, an important precursor.
Ibrutinib (IMBRUVICA), chemically known as l-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin- 1 -yl]piperidin- 1 -yl] prop-2-en- 1 -one is an orally administered drug that targets Bruton’s tyrosine kinase (BTK). Ibrutinib may be used for treating both B cell-related hematological cancers/ B cell chronic lymphocytic leukemia, and autoimmune diseases such as rheumatoid arthritis, Sjogrens syndrome, lupus and asthma and is represented by following chemical formula:
Ibrutinib and its pharmaceutically acceptable salts were first disclosed in US patent US7,514,444. This patent discloses a process for the preparation of Ibrutinib by involving use of 4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidine, as intermediate as shown below:
4-Amino-3-(4-phenoxyphenyl)- l H-pyrazolo[3,4-d]pyrimidine, a key intermediate of ibrutinib, and its preparation from 3-amino-4-cyano-5-(4-phenoxyphenyl) pyrazole was first disclosed in a PCT patent publication WO2001/019829 A2 as shown in below scheme.
Various other publications like US patents US7,514,444; US7.718,662; US8,883,803 and PCT publications WO2012/158843 A2; WO2013/010136A2 follow the same process for the preparation of 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidine as described above.
The process comprises the conversion of 4-phenoxybenzoic acid to the corresponding acid chloride, which is then taken up in mixture of toluene and tetrahydrofuran and further reacted with malononitrile in the presence of diisopropylethylethylamine in toluene. The reaction mixture is stirred overnight and after completion of reaction, followed by work up 1 , 1 -dicyano-2-hydroxy-2-(4-phenoxyphenyl)ethene is isolated as a residue and which is further purified.
The resulting l, l-dicyano-2-hydroxy-2-(4-phenoxyphenyl)ethene is reacted with trimethylsilyldiazomethane in a mixture of acetonitrile and methanol in the presence of diisopropylethylamine as a base. The resulting reaction mixture is stirred for 2 days to give l, l-dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene (O-methylated product) as an oil, which is purified by flash chromatography.
The O-methylated product is treated with hydrazine hydrate to give 3-amino-4-cyano- 5-(4-phenoxyphenyl)pyrazole, which is further reacted with formamide at a temperature of 180°C to give 4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4- d]pyrimidine as pale brown-grey solid.
Since, the above process involves the isolation of intermediates and takes long time during reaction completion. Therefore, it is lengthy, not efficient. Further publication is silent about the purity of 4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidine. Acetonitrile solvent has been used in methylation reaction, which is carcinogenic.
The cyclization reaction has been carried out at 180°C and it is observed that the cyclization reaction at high temperature of 180°C, results in grey brown solid colour of 4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidine, may be due to presence of inorganic impurities.
The said process also requires the use of expensive (trimethylsilyl)diazomethane to obtain O-methylated product, which is sensitive to air and water, and hence, the methylation reaction has to be carried out in the absence of water, under anaerobic conditions; silica and flash chromatography are also used for purifying O-methylated product. Since the above process involves complicated operation processes, which leads to high production cost and therefore is not an attractive option at industrially scale.
PCT publication WO2014/173289A1 discloses a process for preparation of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole as shown below and its conversion into 4- amino-3-(4-phenoxy phenyl)- lH-pyrazolo[3,4-d]pyrimidine has not been disclosed.
The process involves conversion of 4-phenoxybenzoic acid to the corresponding acid chloride, followed by reaction with malononitrile in the presence of diisopropylethylethylamine in tetrahydrofuran. The reaction mixture has been stirred for 16 hours and thereafter l, l -dicyano-2-hydroxy-2-(4-phenoxyphenyl) ethene is isolated from reaction mixture. A solution of l, l-dicyano-2-hydroxy-2-(4- phenoxyphenyl)ethene in trimethoxymethane has been heated for 16 hours to give l, l-dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene (O-methylated product), which is then reacted with hydrazine hydrate to give 3-amino-4-cyano-5-(4-phenoxy phenyl)pyrazole.
The above process is inefficient, since it involves isolation of intermediates and takes long time to complete the reactions and purity of 3-amino-4-cyano-5-(4- phenoxypheny pyrazole has not been disclosed.
A similar approach has been described in a PCT publication WO2014/082598 A 1 for preparation of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole and is presented as below:
The process involves conversion of 4-phenoxybenzoic acid to the corresponding acyl chloride by using sulfurous dichloride, followed by reaction with malononitrile in the presence of sodium hydride to obtain l, l-dicyano-2-hydroxy-2-(4-phenoxy phenyl)ethene, which is recrystallized from 1,4-dioxane. The hydroxy moiety is then methylated using dimethyl sulphate to give l, l-dicyano-2-methoxy-2-(4-phenoxy phenyl)ethene (O-methylated product) which is recrystallized from a mixture of hexane and ethylactetate. The solution of resulting O-methylated product in ethanol was treated with hydrazine hydrate at reflux temperature to give 3-amino-4-cyano-5- (4-phenoxy phenyl)pyrazole, followed by its recrystallization in hexane and further, its conversion into 4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidine was not disclosed.
The above process also involves isolation of intermediates; their purification which leads to longer time in reaction completion, and it does not disclose the purity of 3- amino-4-cyano-5-(4-phenoxyphenyl)pyrazole. Further the above process involves use of sodium hydride, which is a hazardous reagent and can ignite in air during scale up. Several alternative methods have been reported in literature, wherein process for the preparation of 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidine has been disclosed and are discussed herein.
A Chinese patent application CN103121999A discloses a process of preparation of 4- amino-3 -(4-phenoxy phenyl)- 1 H-pyrazolo[3 ,4-d] pyrimidine, as below :
The process involves reaction of 3-bromo-lH-pyrazolo[3,4-d]pyrimidin-4-amine with (4-phenoxyphenyl)boronic acid in the presence of alkali agents and aprotic solvents to give 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidine.
The said Chinese application is also silent about the purity of target compound and even starts with the advance intermediates, which are expensive and make the process unattractive from industrial point of view.
A similar approach has been described in US patent US8,940,893; PCT publication WO2013/1 13097A1 and WO2015/018333 A 1 for preparing 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidine .
In US patent US8,940,893 and PCT publication WO2013/1 13097A1, 4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidine is purified by using Combi-flash chromatography on silica gel. In PCT publication WO2015/018333A1, 4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidine is purified by recrystallization in ethyl acetate.
The purity of 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidine has not been reported in above publications too. Further two of the above processes involve tedious step of chromatographic purification, which is not industrial viable.
Another Chinese patent application CN 103965201 A discloses a process for the preparation of 4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidine, wherein 3-bromo-lH-pyrazolo[3,4-d]pyrimidin-4-amine was reacted with trimethyl tin (4- phenoxy phenyl) to give 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- d]pyrimidine and followed by its recrystallization in isopropanol, as shown below:
The said Chinese application is also silent about the purity of 4-amino-3-(4- phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidine and is not cost-effective because it starts with advance intermediates, which are expensive. Therefore, said route of synthesis is not industrially applicable.
Purity of an API as well as intermediates is of great importance in the field of pharmaceutical chemistry. It is well documented in the art that direct product of a chemical reaction is rarely a single compound with sufficient purity to comply with pharmaceutical standards. The impurities that can be present in pharmaceutical compounds are starting materials, by-products of the reaction, products of side reactions, or degradation products.
According to ICH guidelines, process impurities should be maintained below set limits by specifying the quality of raw materials, their stoichiometric ratios, controlling process parameters, such as temperature, pressure, time and including purification steps, such as crystallization, distillation and liquid-liquid extraction etc., in the manufacturing process. Typically, these limits should less than about 0.15 % by weight of each identified impurity. Limits for unidentified and/or uncharacterized impurities are obviously lower, typically less than 0.10 % by weight. The limits for genotoxic impurities could be much lower depending upon the daily dose of the drug and duration of the treatment. Therefore, in the manufacture of a drug substance, the purity of the starting materials is also important, as impurities may carry forward to the active pharmaceutical ingredient such as ibrutinib.
In view of the above, most of the prior art processes involve isolation of intermediates, additional purification steps and silent about the purity or the assay of 4-amino-3-(4-phenoxy phenyl)- lH-pyrazolo[3,4-d]pyrimidine.
Thus, there is an urgent need for the development of a synthetic process which produces pure 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidine or its acid addition salts.
The present invention fulfills the need in the art and provides an improved, industrially advantageous process for the synthesis of pure 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d] pyrimidine, a key intermediate in the preparation of ibrutinib, through preparation of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole from 4-phenoxy benzoic acid using same organic solvent and none of the intermediates have been isolated.
Examples:
Example 1: Preparation of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole
4-Phenoxybenzoic acid (200g) was slowly added to thionyl chloride (400ml) at a temperature of 25-30°C and resulting reaction mixture was heated under stirring to a temperature of 60-65°C for 5 hours. Thionyl chloride was distilled off under vacuum at temperature below 60°C. Toluene (2x400ml) was added to the resulting oily residue and thereafter distilled out completely under vacuum below 60°C to remove traces of thionyl chloride to obtain 4-phenoxybenzoyl chloride as a viscous oil. The resulting viscous oil of 4-phenoxybenzoyl chloride was dissolved in toluene (2000ml). Malononitile (80g) and diisopropylethylamine (320ml) were sucessively added to the reuslting solution at a temperature of 25-30°C slowly, maintaining reaction temperature 50-55°C. The reaction mass was further stirred for 30 minutes. After completion of the reaction, the reaction mass was cooled to 25-30°C and a solution of sulfuric acid ( 1.25 M) was added. The reaction mixture was then stirred at a temperature of 25-30°C for 30 minutes, and the layers were separated. The organic layer was washed with a solution of sodium chloride ( 10%) and the resulting organic layer was used directly in next reaction.
Dimethyl sulfate (200ml) and sodium bicarbonate (200g) were added to the resulting organic layer at a temperature of 25-30°C. Thereafter, temperature of reaction mass was raised to 80-90°C and reaction mass was stirred for 1-2 hours. After completion of reaction, the reaction mass was cooled to a temperature of 25-30°C, demineralized water (2000ml) was added and stirred for 10-15 minutes. The layers were separated and the aqueous layer was extracted with toluene (1000ml). All the organic layers were combined and washed with sodium chloride solution ( 10%). Activated carbon (20g) was added and reaction mixture was stirred for 30 minutes. The solution was filtered through hyflo bed and to the resulting organic layer hydrazine hydrate ( 120ml) was added at a temperature of 25-30°C. During the addition exothermicity was observed, and temperature of the reaction mass was rose up to 40-50°C. Thereafter, the reaction mass was stirred at a temperature of 25-30°C for 1 -2 hours. The resulting precipitated solid was filtered, slurry washed with dichloromethane (400ml) and finally, dried to obtain title compound of formula V ( 140g) purity 93.28% measured by HPLC.
Example 2: Preparation of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole
4-Phenoxybenzoic acid (lOOg) was slowly added to thionyl chloride (200ml) at a temperature of 25-30°C and resulting reaction mixture was heated under stirring to a temperature of 50-55°C for 5 hours. Thionyl chloride was distilled off under vacuum at temperature below 50°C. Toluene (250ml) was added to the resulting oily residue and thereafter distilled out completely under vacuum below 50°C to remove traces of thionyl chloride to obtain 4-phenoxybenzoyl chloride as a viscous oil. The resulting viscous oil of 4-phenoxybenzoyl chloride was dissolved in toluene (500ml). Malononitile (35.58ml) and diisopropylethylamine (160ml) were sucessively added to the reuslting solution at a temperature of 25-30°C slowly, maintaining reaction temperature around 50-55°C. The reaction mass was further stirred for 10 minutes. After completion of the reaction, the reaction mass was cooled to 25-30°C and a solution of sulfuric acid (70 ml in 1000 ml water) was added. The reaction mixture was then stirred at a temperature of 25-30°C for 30 minutes, and the layers were separated. The organic layer was washed with a solution of sodium chloride (10%) and the resulting organic layer was used directly in next reaction.
Dimethyl sulfate (95.1 1ml) and sodium bicarbonate (96.16g) were added to the resulting organic layer at a temperature of 25-30°C. Thereafter, temperature of reaction mass was raised to 80-90°C and reaction mass was stirred for 1-2 hours. After completion of reaction, the reaction mass was cooled to a temperature of 55- 60°C, demineralized water ( 1000ml) was added. The reaction mass was cooled to a temperature of 25-30°C and stirred for 10- 15 minutes. The layers were separated and the aqueous layer was extracted with toluene (500ml). All the organic layers were combined and washed with sodium chloride solution ( 10%). To the resulting organic layer hydrazine hydrate (50ml) was added at a temperature of 25-30°C. During the addition exothermicity was observed, and temperature of the reaction mass was rose up to 40-45°C. Thereafter, the reaction mass was stirred at a temperature of 25-30°C for 1-2 hours. The resulting precipitated solid was filtered, suck dried to obtain 3- amino-4-cyano-5-(4-phenoxyphenyl)pyrazole compound of formula V ( 123g) purity 86.96% measured by HPLC.
Example 3: Purification of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole
3-Amino-4-cyano-5-(4-phenoxyphenyl)pyrazole (36g) was suspended in isopropanol (350ml) and temperature of the reaction mixture was raised and allowed to reflux to dissolve the solid completely to provide a clear solution. Then, solvent was distilled off under vacuum to obtain a residue and isopropanol (50ml) was added and after stirring for hours the solid was filtered and dried to afford 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole compound of formula V (26g) and having purity of 97.54 % by HPLC .
Example 4: Purification of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole
3-Amino-4-cyano-5-(4-phenoxyphenyl)pyrazole (36g) was suspended in isopropanol (350ml) and temperature of the reaction mixture was raised upto reflux to dissolve the solid completely upto clear solution. Water (1050ml) was added to the solution and the reaction mixture was gradually cooled to crystallize the product. The resulting solid was filtered, washed with two volumes of isopropanol, dried in vacuum oven at a temperature of 40-45 °C to afford 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole compound of formula V (20g) and having a HPLC purity of 97.23% .
Example 5: Preparation of pure 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- d] pyrimidine compound of formula I
3-Amino-4-cyano-5-(4-phenoxyphenyl)pyrazole (20g) was suspended in formamide (100 ml) and heated at a temperature of 130°C, after completion of reaction, the reaction mixture was cooled to a temperature of 30-35°C and demineralized water (500ml) was added and the reaction mixture was stirred at a temperature of 25-30°C for 45 minutes. The resulting solid was filtered and acetone (200ml) was added stirred the reaction mixture for 30-45 minutes. The resulting solid was filtered, washed, dried to afford pure 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidine compound of formula 1 (12g) having purity 99.6% measured by HPLC.
Example 6: Preparation of pure 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- d] pyrimidine compound of formula I
3-Amino-4-cyano-5-(4-phenoxyphenyl)pyrazole (lOOg) was suspended in formamide (500ml) and heated at a temperature of 135-140°C, after completion of reaction, the reaction mixture was cooled to a temperature of 30-35°C and demineralized water (1000ml) was added and the reaction mixture was stirred at a temperature of 20-25°C for 1 hour. The resulting solid was filtered, washed with water (500ml) then successively slurry washed with toluene (2 x 500ml) and dried to afford pure 4- amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d] pyrimidine compound of formula I
(70g) having purity 99.8% measured by HPLC; assay > 98%; residue on ignition 0.05%; heavy metals < 20ppm.
Example 7: Preparation of (lS)-l-[(3R)-3-piperidyl]-3-(p-phenoxyphenyl)-l,2,5,7-tetraza-lH-inden-4-ylamine
Diisopropyl diazodicarboxylate (DAID, 1.2 ml,) was added to a solution of 1-tert-butyloxycarbonyl-3-(S)-hydroxypiperidine ( l .Og,) and triphenylphosphine (2.59g) in tetrahydrofuran (50.0ml). To the resulting yellow solution, 3-(p-phenoxyphenyl)-l ,2,5,7-tetraza- lH-inden-4-ylamine (l .Og). was added and warmed till dissolution, and stirred overnight at room temperature. The reaction mixture was filtered and the solvent was distilled under vacuum to get an oily residue, which was further purified by flash chromatography (30-50 % ethyl acetate/ hexane) on silicagel to give 0.3 g (0.3 w/w) of tert-butyloxycarbonyl-( l S)- l-[(3R)-3-piperidyl]-3-(p-phenoxyphenyl)- l,2,5,7-tetraza- lH-inden-4-ylamine as a light brown solid. The resulting solid was dissolved in dichloromethane (5 ml) and trifluoroacetic acid (0.6 ml) was added to it. After completion of reaction, water was added to reaction mass, followed by addition of methyl tert-butyl ether (20.0 ml). The layers were separated and the aqueous layer was basified with potassium carbonate and extracted with dichloromethane (15.0 ml x 2). The organic layer dried over sodium sulfate, filtered and evaporated to yield 0.2 g (0.6 w/w) of title compound as light yellow oil.
Example 8: Preparation of l-(3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo [3,4- d]pyrimidin-l-yl)piperidin-l-yI)prop-2-en-l-one (Ibrutinib)
To a solution of acryloyl chloride (0.06g) in tetrahydrofuran (15.0 ml), a mixture of triethylamine (O. lg) and (lS)-l-[(3R)-3-piperidyl]-3-(p-phenoxyphenyl)-l,2,5,7- tetraza- lH-inden-4-ylamine (0.2g) in tetrahydrofuran (7.8 ml) was added. The reaction mixture was stirred at 25-30°C for 18 hous and filtered. The solvent was removed under vacuum to obtain crude ibrutinib, which was further purified by column chromatography on silica gel to obtain pure ibrutinib as crystalline solid.
Formula VI
Formula VII
Formula I
Formula II

Formula III

Formula IV

Formula V
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Tuesday, 4 July 2017

NEW PATENT, PONESIMOD, CRYSTAL PHARMATECH, WO 2017107972

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NEW PATENT, PONESIMOD CRYSTAL PHARMATECH, WO 2017107972

Novel crystalline forms I, II and III of ponesimod . Useful as a selective sphingosine-1-phosphate receptor-1 (S1P1) receptor agonist, for the treatment of psoriasis. Appears to be first filing from Crystal Pharmatech claiming ponesimod. Johnson & Johnson , following its acquisition of Actelion , is developing ponesimod (phase III clinical trial), a S1P1 agonist, for the treatment of autoimmune disorders. 


Applicants:CRYSTAL PHARMATECH CO., LTD. [CN/CN]; B4-101, Biobay, 218 Xinghu Street,
Suzhou Industrial Park Suzhou, Jiangsu 215123 (CN)
Inventors:CHEN, Minhua; (CN).
ZHANG, Yanfeng; (CN).
LI, Jiaoyang; (CN).
ZHANG, Xiaoyu; (CN)

Most of the family members of the product case ( WO2005054215 ) of ponesimod expire in European countries until November, 2023 and in the US by December, 2024 with US154 extension.


Disclosed are crystalline forms 1, 2, and 3 of a selective S1P1 receptor agonist, namely Ponesimod, and a method for preparing the same. An X-ray powder diffraction pattern of the crystalline form 1 has characteristic peaks at 2 theta values of 18.1° ± 0.2°, 14.6° ± 0.2°, and 11.3° ± 0.2°. An X-ray powder diffraction pattern of the crystalline form 2 has characteristic peaks at 2 theta values of 3.8° ± 0.2°, 10.8° ± 0.2°, and 6.1° ± 0.2°. An X-ray powder diffraction pattern of the crystalline form 3 has characteristic peaks at 2 theta values of 12.2° ± 0.2°, 6.2° ± 0.2°, and 5.6° ± 0.2°. Compared with existing crystalline forms, the present invention has better stability and a greatly increased solubility, and is more suitable for development of a pharmaceutical preparation containing Ponesimod


front page image
Ponesimod (compound of formula I) is a selective S1P1 receptor antagonist developed by Actelion. The drug was used to treat moderate to severe chronic plaque psoriasis in the two medium-term trial was successful, and will carry out the treatment of psoriasis in 3 clinical trials.


The present invention discloses a process for the preparation of a compound of formula I, which is disclosed in patent CN 102177144B, which is an amorphous form prepared by the process of CN100567275C, and discloses a process for the preparation of a compound of formula I, crystalline form C, crystalline form III, Type II. The results show that the crystallinity of crystalline form III is poor and it is converted to crystalline form II at room temperature. The crystalline form II is difficult to repeat and prepare a certain amount of propionic acid. The thermodynamics stability of crystalline form A is inferior to that of crystal form C. In contrast, For the crystal form suitable for the development of the drug, the solubility of the crystalline form C is not ideal.


Example 1
[0060]
Preparation of Ponesimod Form 1:
[0061]
48.1 mg of Ponesimod was added to 0.40 mL of 1,4-dioxane and the filtrate was filtered. To the solution was stirred at room temperature, 1.20 mL of n-heptane was added dropwise to precipitate the crystals and stirred overnight. The supernatant was filtered off by centrifugation Liquid to obtain Ponesimod crystal form 1.



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    Follow "'2014' Suzhou International Elite Entrepreneurship Week" with interest Over 88 billion venture capital investment helps your pioneering dreams come true


    Since 2009, there have been 1267 overseas high-level talent projects settled in Suzhou through International Elite Entrepreneurship Week and 54 talents have been introduced and fostered for the national "Thousand Talents Plan". Among these 53 talents, Dr. Chen Minhua, the founder of Suzhou Crystal Pharmatech Co., Ltd., was deeply impressed by thoughtful services in Suzhou for innovative pioneering talents when he recalled the development in Suzhou. "Investment and financing services are placed with particular importance. Everything is thoroughly considered for fear that enterprise
      In 2010, Chen Minhua quitted his job in a well-known pharmaceutical company in the United States and returned with his core 4-people R&D team. He founded Crystal Pharmatech Co., Ltd. in Suzhou Biobay through the Entrepreneurship Week. Till 2013, Crystal Pharmatech has made profits year by year. The yearly output value in 2013 reached 18 million Yuan, while the profits reached as high as 4 million Yuan. His clients involve half of top 20 pharmaceutical companies globally. Chen Minhua longs to fill the vacancy of drug crystals in China and take the lead in the international drug crystal research. Chen Minhua introduced that government service is an integral part to his growth. "Since it was settled down, Suzhou public sector organized several investment and financing activities and offered training and services in various aspects like the mode of financing, finance docking and enterprise strategic investment, which laid a solid foundation for Crystal Pharmatech's capital expansion", said by Chen Minhua.

      To help high-level talents solve financial difficulty, Suzhou lays stress on the docking of science & technology and finance. The person in charge of the Municipal Science and Technology Bureau said that Suzhou guides and integrates social capital for equity investment of hi-tech enterprises at the start-up stage via the guiding funds set up by the government and follow-up investment, etc, thus evolving the venture capital investment cluster based on Shahu Equity Investment Center. After the national "Thousand Talents Plan" venture capital investment center was set up, pioneering talents and venture capital are further converging here. As of the end of 2013, there are 270 effective organizations engaged in various venture capital investment in Suzhou that manage the funds in excess of 88 billion Yuan. 30 million Yuan will be appropriated from the municipal science and technology fund budget for the newly established FOF of Angel Investment this year, so as to take avail of social capital for the development of small and medium-sized hi-tech enterprises.

      Meanwhile, Suzhou sets up the special compensation fund against credit risks and offers "Kedaitong" with "low threshold and low interest rate", so as to solve financial difficulty of small and medium-sized hi-tech enterprises and create favorable financing environment for the pioneering work of talents and corporate development. At present, the fund of credit risk pool has reached 500 million Yuan and "Kedaitong" loans of 8.52 billion Yuan have been granted for 1023 small and medium-sized hi-tech enterprises. Particularly, 120 pioneering enterprises that feature independent intellectual property, high content of technology and light assets were backed up with 1.314 billion Yuan, the special risk compensation fund of "Kedaitong", thus vigorously supporting innovation and pioneering work of leading talents in the science and technology community in Suzhou.

      Reporter Qian Yi
      Quoted from Suzhou Daily on July 6, 2014





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Monday, 3 July 2017

Imigliptin dihydrochloride, Xuanzhu Pharma Co Ltd, NEW PATENT, WO 2017107945


Imigliptin dihydrochloride, Xuanzhu Pharma Co Ltd, NEW PATENT, WO 2017107945
Applicants:XUANZHU PHARMA CO.,LTD. [CN/CN]; 2518, Tianchen Street, National High-tech Development Zone Jinan, Shandong 250101 (CN)
Inventors:SHU, Chutian; (CN).
WANG, Zhenhua; (CN)
str1
The present invention relates to a crystalline form of benzoate of a dipeptidyl peptidase-IV inhibitor, a method for preparing the same, a pharmaceutical composition,and a use thereof. Specifically, the present invention relates to a crystalline form of benzoate of a compound used as a dipeptidyl peptidase-IV inhibitor and represented by formula (1), namely (R)-2-((7-(3-aminopiperidine-1-yl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazo(4,5-b)pyridine-1-yl)methyl)benzonitrile, a method for preparing the same, a pharmaceutical composition, and a use thereof.
Novel crystalline form I of imigliptin dihydrochloride as dipeptidyl peptidase IV inhibitor (DPP-IV) for the treatment of and/or prevention of non-insulin dependent diabetes, hyperglycemia and hyperlipidemia. In June 2017, KBP Biosciences and Xuanzhu Pharma , subsidiaries of Sihuan Pharmaceutical , are developing an imigliptin dihydrochloride (phase II clinical trial), a DPP-IV inhibitor and a hypoglycemic agent,, for the treatment of type II diabetes. Follows on from WO2013007167 , claiming similar composition.
Dipeptidyl peptidase-IV (DPP-IV) inhibitor is a new generation of oral type 2 diabetes treatment drugs, by enhancing the role of intestinal insulin to play a role, non-insulin therapy drugs. Compared with conventional drugs for the treatment of diabetes, DPP-IV inhibitors do not have weight gain and edema and other adverse reactions.
 
The compound (R) -2 - ((7- (3-aminopiperidin-1-yl) -3,5-dimethyl-2-oxo-2,3-dihydro- 1H-imidazo [4,5-b] pyridin-1-yl) methyl) benzonitrile (described in the specification as a compound of formula (1), as described in patent application PCT / CN2011 / 000068) Inhibitors of compounds, DPP-IV has a strong inhibitory effect and a high selectivity.
 

 
The study of crystal form plays an important role in drug development process. Application No. PCT / CN2012 / 078294 discloses the dihydrochloride crystal form I of the compound of formula (1), in order to meet the requirements of formulation, production and transportation , We further studied the crystal form of the compound of formula (1) in order to find a better crystal form.
Example 1 Preparation of benzoate form I of compound of formula (1)
 
 
40 g (0.1 mol) of the compound of the formula (1) was added to a 2 L round bottom flask, suspended in 1428 mL of acetonitrile, and the temperature was raised to 60 ° C. The free solution was dissolved, 14.3 g (0.1 mol) of benzoic acid was added, The precipitate was dried at 60 ° C for 1 hour and then allowed to stand at room temperature. The filter cake was dried in vacuo at 40 ° C for 10 hours and weighed 51.6 g in 97.4% yield. By XRPD test, for the benzoate crystal type Ⅰ.

////////////////Imigliptin dihydrochloride, Xuanzhu Pharma Co Ltd, NEW PATENT, WO 2017107945
CFDA Granted Approval of Phase II/III Clinical Trials for Imigliptin Hydrochloride
2016-08-04 15:25:37 Author:admin
        Phase II/ III Clinical Trials of Imigliptin Hydrochloride (KBP-3853) have been approved by CFDA; the Clinical Approval Numbers are 2016L05997 and 2016L06137.
 
        As we know, in Phase I study both single and multiple doses of Imigliptin Hydrochloride were safe and well tolerated in healthy volunteers and in Type 2 diabetes patients. Imigliptin Hydrochloride demonstrated good pharmacokinetic (PK) characteristics and exhibited dose-proportional plasma exposure. The potent and long duration inhibition of DPP-4 was validated in the PK/PD study. The results of Phase I study of Imigliptin Hydrochloride warranted its long-term safety and efficacy studies in Phase II/ III.
 
        Currently, the Imigliptin Hydrochloride team has completed the production of clinical trial drug product, as well as finalized the clinical protocols and the study sites. Phase II clinical trial of Imigliptin Hydrochloride will begin in the near future.
 
       The approval of Imigliptin Hydrochloride for the phase II/ III clinical trials represents another milestone in the SiHuan/ XuanZhu’s new drug discovery history. We enter into a new clinical stage of the development process, and we have many works remaining before us. It is still an urgent task for us to accelerate the clinical development, and to launch the drug product in the China market as soon as possible.

Wednesday, 29 March 2017

QUILSECONAZOLE, VT 1129, New Patent, WO, 2017049080, Viamet


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VT 1129 BENZENE SULFONATE
CAS 1809323-18-9

Image result for VT1129

VT 1129

1340593-70-5 CAS
MF C22 H14 F7 N5 O2, MW 513.37
2-Pyridineethanol, α-(2,4-difluorophenyl)-β,β-difluoro-α-(1H-tetrazol-1-ylmethyl)-5-[4-(trifluoromethoxy)phenyl]-, (αR)-
R ISOMER
ROTATION +
QUILSECONAZOLE, VT-1129
Viamet, in collaboration with Therapeutics for Rare and Neglected diseases, is investigating quilseconazole benzenesulfonate (VT-1129), a small-molecule lanosterol demethylase (CYP51) inhibitor, developed using the company's Metallophile technology, for treating fungal infections, including Cryptococcus neoformans meningitis.
WO-2017049080
  

////////////QUILSECONAZOLE, VT-1129, New Patent, WO, 2017049080, Viamet