公开(公告)号：WO2015083033A1

公开(公告)日：2015-06-11

申请号：PCT/IB2014/066279

申请日：2014-11-24

申请人： PIRAMAL ENTERPRISES LIMITED

发明人： KRISHNAMURTHY, Dhileepkumar ,  MORTHALA, Raghavendar Rao ,  JAGTAP, Ashutosh ,  LADKAT, Prashant ,  KUMBHAR, Ajay

IPC分类号： C07F9/6558

CPC分类号： C07F9/65583

摘要： The present invention relates to an improved process for the preparation of [3-{[(2 R ,3 S )-2- [(1 R )-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholin-4- yl]methyl}-5-oxo-2 H -1,2,4-triazol-1-yl]phosphonic acid (Fosaprepitant or the compound of formula I) or its pharmaceutically acceptable salt, having palladium (Pd) content less than 1 ppm comprising catalytic hydrogenation of the compound of formula II with Pd catalyst optionally in the presence of base, to give the compound of formula I or the pharmaceutically acceptable salt thereof, optionally isolating the compound of formula I or the pharmaceutically acceptable salt and treating the compound of formula I or the pharmaceutically acceptable salt thereof twice with the metal scavenger to obtain the compound of formula I or the pharmaceutically acceptable salt thereof having Pd content less than 1 ppm.

摘要翻译： 本发明涉及制备[3 - {[（2R，3S）-2 - [（1R）-1- [3,5-双（三氟甲基）苯基]乙氧基] -3-（4 - 氟苯基）吗啉-4-基]甲基} -5-氧代-2H-1,2,4-三唑-1-基]膦酸（Fosaprepitant或式I化合物）或其药学上可接受的盐，其具有钯（ Pd）含量小于1ppm，包括式Pd化合物与Pd催化剂任选在碱存在下的催化氢化，得到式I化合物或其药学上可接受的盐，任选分离式I化合物或其药学上可接受的盐 可接受的盐，并且用金属清除剂将式I化合物或其药学上可接受的盐进行两次处理，得到具有Pd含量小于1ppm的式I化合物或其药学上可接受的盐。

公开(公告)号：WO2016151464A1

公开(公告)日：2016-09-29

申请号：PCT/IB2016/051562

申请日：2016-03-21

申请人： PIRAMAL ENTERPRISES LIMITED

发明人： JAGTAP, Ashutosh ,  GHARPURE, Milind ,  SHINDE, Navnath ,  PATIL, Navnath ,  SHAH, Chirag ,  RAUT, Changdev ,  KRISHNMURTHY, Dhileepkumar

IPC分类号： C07D243/12 ,  C07C231/02 ,  C07C233/43 ,  C07B43/06

CPC分类号： C07D243/12 ,  C07B37/10 ,  C07B2200/13 ,  C07C231/02 ,  C07C233/43

摘要： The present invention provides an improved process for the preparation of 8-chloro-1-phenyl- 1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione (hereafter referred to as the compound (IV)), which is useful as a key intermediate for the synthesis of Clobazam (referred to as the compound (I)) 7-chloro-1-methyl-5-phenyl-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione. The process of the present invention further involves transformation of the compound (IV) into Clobazam (I), comprising (a) reacting the compound (II) (as described herein) with monoalkyl malonate in the presence of a coupling agent to obtain the compound (III) (as described herein); followed by the cyclization using a base; (b) reacting the compound-IV (as described herein) obtained from step (a) with methylating agent. The process of the present invention involves formation of novel intermediates methyl 3-((4- chloro-2-(phenylamino)phenyl)amino)-3-oxopropanoate (IlIa) and 3-((4-chloro-2- (phenylamino)phenyl)amino)-3-oxopropanoic acid (V).

摘要翻译： 本发明提供了制备8-氯-1-苯基-1H-苯并[b] [1,4]二氮杂卓-2,4（3H，5H） - 二酮（以下称为化合物（ IV）），其可用作合成Clobazam（称为化合物（I））的关键中间体7-氯-1-甲基-5-苯基-1H-苯并[b] [1,4]二氮杂 -2,4（3H，5H） - 二酮。 本发明的方法还包括将化合物（IV）转化为氯氮平（I），其包含（a）在偶联剂存在下使化合物（II）（如本文所述）与丙烯酸单烷基酯反应，得到化合物 （III）（如本文所述）; 其次是使用碱的环化; （b）使得自步骤（a）获得的化合物IV（如本文所述）与甲基化试剂反应。 本发明的方法包括形成新的中间体3 - （（4-氯-2-（苯基氨基）苯基）氨基）-3-氧代丙酸甲酯（IIIa）和3 - （（4-氯-2-（苯基氨基） 苯基）氨基）-3-氧代丙酸（V）。

公开(公告)号：WO2019135189A1

公开(公告)日：2019-07-11

申请号：PCT/IB2019/050048

申请日：2019-01-03

申请人： PIRAMAL ENTERPRISES LIMITED

发明人： GHARPURE, Milind ,  JAGTAP, Ashutosh ,  RAUT, Changdev ,  PATIL, Navnath ,  LADKAT, Prashant ,  KRISHNAPILLAI, Jaisankar ,  MANOHARAN, Nirmal Kumar ,  KANDASAMY, Kumaravel

IPC分类号： C07C227/40 ,  C07C229/36 ,  C07D207/16

摘要： The present invention provides an improved process for preparation of the L- threo -(2S,3R)-3-(3,4-dihydroxyphenyl)serine (I) or a salt thereof, which is known as Droxidopa; comprising (a) recovery of the by-product compound (V) (as described herein) from the crude compound (I), and (b) recycling and re-use it for the preparation of droxidopa. Accordingly, the present invention relates to an improved economical process for the preparation of L- threo -(2S,3R)-3-(3.4-dihydroxyphenyl)serine (I) or its pharmaceutically acceptable salts; wherein the process relates to recovery and recycling of the by-product compound (V) and also to re-use it for the preparation of droxidopa.

公开(公告)号：WO2013124823A1

公开(公告)日：2013-08-29

申请号：PCT/IB2013/051440

申请日：2013-02-22

申请人： PIRAMAL ENTERPRISES LIMITED

发明人： LADKAT, Prashant ,  WAGH, Ganesh ,  JAGTAP, Ashutosh ,  ROY, Mita ,  HARIHARAN, Sivaramakrishnan ,  CHOUKEKAR, Milind

IPC分类号： C07D413/06 ,  C07D265/32 ,  A61K31/5377

CPC分类号： C07D413/06 ,  C07D265/32

摘要： The present invention provides a process for the preparation of 5-[[(2R,3S)-2-[(1R)-1-[3,5- bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro- 3H-1,2,4-triazol-3-one (Aprepitant) comprising condensation of 2-(R)-[(1R)-1-[3,5- bis(trifluoromethyl)phenyl]ethoxy]-3-(S)-(4-fluorophenyl)morpholine hydrochloride salt with 2-(2-chloro-1-iminoethyl)hydrazinecarboxylic acid methyl ester to obtain the reaction mixture containing 2-[2-[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4- fluorophenyl)-4-morpholinyl]-1-iminoethyl]hydrazinecarboxylic acid methyl ester, which is in-situ cyclized in the presence of dimethylsulfoxide and a polar protic solvent at a low temperature to yield aprepitant having purity ≥ 99.5%.

摘要翻译： 本发明提供了制备5 - [[（2R，3S）-2 - [（1R）-1- [3,5-双（三氟甲基）苯基]乙氧基] -3-（4-氟苯基） （R） - [（1R）-1- [3,5-二（三氟甲基）苯基）-1,2-二氢-3H-1,2,4-三唑-3-酮 - 双（三氟甲基）苯基]乙氧基] -3-（S） - （4-氟苯基）吗啉盐酸盐与2-（2-氯-1-亚氨基乙基）肼甲酸甲酯反应，得到含有2- [2 - [（2R，3S）-2 - [（1R）-1- [3,5-双（三氟甲基）苯基]乙氧基] -3-（4-氟苯基）-4-吗啉基] -1-亚氨基乙基] 甲酯，其在二甲基亚砜和极性质子溶剂的存在下在低温下原位环化，得到纯度> 99.5％的糊剂。

公开(公告)号：WO2017093899A1

公开(公告)日：2017-06-08

申请号：PCT/IB2016/057194

申请日：2016-11-30

申请人： PIRAMAL ENTERPRISES LIMITED

发明人： GHARPURE, Milind ,  LADKAT, Prashant ,  SHINDE, Navnath ,  JAGTAP, Ashutosh

IPC分类号： C07B63/00 ,  C07B47/00

CPC分类号： C07F9/65583

摘要： The present invention relates to a novel process for the preparation of intermediate of fosaprepitant dimeglumine. The present invention particularly relates to a process for the preparation of fosaprepitant dibenzyl ester, an intermediate of fosaprepitant dimeglumine, which is simple, easy to handle on commercial scale and efficient.

摘要翻译： 本发明涉及一种用于制备司舒那坦二葡甲胺中间体的新方法。 本发明特别涉及一种制备司替吡坦二苄基酯的中间体司舒地尔二苄基酯的方法，该方法简单易行，易于在商业规模上操作并且高效。

公开(公告)号：WO2017009753A1

公开(公告)日：2017-01-19

申请号：PCT/IB2016/054101

申请日：2016-07-08

申请人： PIRAMAL ENTERPRISES LIMITED

发明人： JAGTAP, Ashutosh ,  GHARPURE, Milind ,  SHINDE, Navnath ,  PATIL, Navnath ,  RAUT, Changdev ,  KRISHNAMURTHY, Dhileepkumar

IPC分类号： C07C253/30 ,  C07C227/06 ,  C07C255/41

CPC分类号： C07C227/06 ,  C07C253/30 ,  C07C255/41 ,  C07C229/34

摘要： The present invention provides an improved process for the preparation of 3-(4-chlorophenyl)-3- cyanopropanoic acid (compound (A)) and further its transformation to Baclofen (I). The process comprises reaction of compound (II) with Glyoxylic acid to obtain 3-(4-chlorophenyl)-3- cyanoacrylic acid (III); followed by the 'in- situ' reduction of (III) in the presence of a reducing agent to provide the compound (A). Alternatively, the compound (A) is obtained by the process comprising reacting 2-(4- chlorophenyl)acetonitrile (II) with haloacetic acid (IV) in the presence of a base. The compound 3-(4-chlorophenyl)-3-cyanopropanoic acid (A) undergoes hydrogenation in the presence of a metal catalyst and ammonia solution to provide Baclofen (I).

摘要翻译： 本发明提供了制备3-（4-氯苯基）-3-氰基丙酸（化合物（A））并进一步转化为巴氯芬（I）的改进方法。 该方法包括使化合物（II）与乙醛酸反应得到3-（4-氯苯基）-3-氰基丙烯酸（III）; 然后在还原剂存在下“（”）原位还原以提供化合物（A）。 或者，化合物（A）通过包括在碱存在下使2-（4-氯苯基）乙腈（II）与卤代乙酸（IV）反应的方法获得。 化合物3-（4-氯苯基）-3-氰基丙酸（A）在金属催化剂和氨溶液存在下进行氢化，得到巴氯芬（I）。

公开(公告)号：WO2016135616A1

公开(公告)日：2016-09-01

申请号：PCT/IB2016/050949

申请日：2016-02-23

申请人： PIRAMAL ENTERPRISES LIMITED

发明人： MORTHALA, Raghavendar Rao ,  GHARPURE, Milind ,  JAGTAP, Ashutosh ,  MHASKAR, Mahesh ,  KRISHNMURTHY, Dhileepkumar

IPC分类号： C07C41/09 ,  C07C41/46 ,  C07C43/164

CPC分类号： C07C41/09 ,  C07C43/1785

摘要： The present invention provides an improved process for the preparation of 4-((2-isopropoxy ethoxy) methyl) phenol compound (I), used as an intermediate in many organic synthesis; particularly a key intermediate for the synthesis of l-[4[2(l-methylethoxy) ethoxy methyl] phenoxy]-3-(l-methylethylamino)-propan-2-ol; commonly known as Bisoprolol or its pharmaceutically acceptable salts. The process comprises reacting the 4-hydroxybenzyl alcohol (II) with the 2-isopropoxyethanol (III) in the presence of activated silica and optionally, in the presence of solvent.

摘要翻译： 本发明提供了制备用于许多有机合成中的中间体的4 - （（2-异丙氧基乙氧基）甲基）苯酚化合物（I）的改进方法。 特别是合成1- [4 [2-（1-甲基乙氧基）乙氧基甲基]苯氧基] -3-（1-甲基乙基氨基） - 丙-2-醇的关键中间体; 通常称为比索洛尔或其药学上可接受的盐。 该方法包括在活化二氧化硅和任选地，在溶剂存在下，使4-羟基苄醇（II）与2-异丙氧基乙醇（III）反应。

公开(公告)号：WO2015155704A1

公开(公告)日：2015-10-15

申请号：PCT/IB2015/052542

申请日：2015-04-08

申请人： PIRAMAL ENTERPRISES LIMITED

发明人： PATIL, Pravin ,  PANSARE, Prakash ,  JAGTAP, Ashutosh ,  KRISHNAMURTHY, Dhileepkumar

IPC分类号： C07D277/82 ,  C07B31/00

CPC分类号： C07D277/82 ,  C07D277/60

摘要： The present invention relates to an improved process for the preparation of the dihydrochloride monohydrate salt of (S)-2-amino-4,5,6,7-tetrahydro-6- (propylamino)benzothiazole (the compound of formula I) comprising reacting the compound of formula II with n-propanal and sodium borohydride using a mixture of methanol and dichloromethane (DCM) as the solvent to obtain the compound of formula I; followed by converting the compound of formula I into its monohydrochloride salt; purifying the monohydrochloride salt of the compound of formula I; and finally converting the pure monohydrochloride salt of the compound of formula I into the dihydrochloride monohydrate salt.

摘要翻译： 本发明涉及一种制备（S）-2-氨基-4,5,6,7-四氢-6-（丙基氨基）苯并噻唑（式I化合物）的二盐酸盐一水合物盐的改进方法，包括使 使用甲醇和二氯甲烷（DCM）的混合物作为溶剂，使式Ⅱ化合物与正丙醛和硼氢化钠反应，得到式I化合物; 然后将式I化合物转化成其单盐酸盐; 纯化式I化合物的一盐酸盐; 最后将式I化合物的纯一盐酸盐转化为二盐酸盐一水合物盐。

公开(公告)号：WO2017168313A1

公开(公告)日：2017-10-05

申请号：PCT/IB2017/051757

申请日：2017-03-28

申请人： PIRAMAL ENTERPRISES LIMITED

发明人： GHARPURE, Milind ,  JAGTAP, Ashutosh ,  RAUT, Changdev ,  KANSAGARA, Nainesh ,  KRISHNAPILLAI, Jaisankar ,  MANOHARAN, Nirmal Kumar ,  PATIL, Navnath

IPC分类号： C07C227/32 ,  C07C229/36 ,  C07B53/00 ,  C07F15/04 ,  C07D317/54 ,  C07C227/40

摘要： The present invention provides an improved process for preparation of L-threo-(2S,3R)-3-(3.4- dihydroxyphenyl)serine (I) (Droxidopa) and its salts; comprising (a) reaction of the aldehyde compound (III) (as described herein) with Metal complex (II) (as described herein), and (b) hydrolysis of the compound (IV) obtained from step (a) in presence of acid. The present invention also relates to a novel intermediates metal chiral complex (IV) for the preparation of Droxidopa.

摘要翻译： 本发明提供了制备L-苏 - （2S，3R）-3-（3,4-二羟基苯基）丝氨酸（I）（屈昔多巴）及其盐的改进方法; （a）醛化合物（III）（如本文所述）与金属络合物（II）（如本文所述）反应，和（b）使步骤（a）中得到的化合物（IV）在酸存在下 。 本发明还涉及用于制备屈昔多巴的新型中间体金属手性络合物（IV）。

公开(公告)号：WO2014057404A1

公开(公告)日：2014-04-17

申请号：PCT/IB2013/059112

申请日：2013-10-04

申请人： PIRAMAL ENTERPRISES LIMITED

发明人： WAGH, Ganesh ,  JAGTAP, Ashutosh ,  ROY, Mita ,  HARIHARAN, Sivaramakrishnan

IPC分类号： C07D209/42

CPC分类号： C07D209/42 ,  C07K5/06026

摘要： The present invention relates to an improved process for the preparation of (2S,3aS,7aS)-1-[(2S)-2-[[(1S)-1-(ethoxycarbonyl)butyl]amino]-1-oxopropyl]octahydro-lH-indole-2-carboxylic acid benzyl ester( the compound of formula II) comprising reacting (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid phenylmethyl ester 4-methylbenzenesulfonate (the compound of formula III) with N-[(S)-ethoxycarbonyl-1-butyl]-(S)-alanine (the compound of formula IV), using 1-hydroxybenzotriazole (HOBT), dicyclohexylcarbodiimide (DCC) and triethylamine in the presence of toluene as a solvent at a temperature of 5°C to 40°C.

摘要翻译： 本发明涉及制备（2S，3aS，7aS）-1 - [（2S）-2 - [[（1S）-1-（乙氧羰基）丁基]氨基] -1-氧代丙基]八氢 （2S，3aS，7aS） - 八氢-1H-吲哚-2-羧酸苯基甲酯（式III化合物）与式（II）化合物反应， 使用1-羟基苯并三唑（HOBT），二环己基碳二亚胺（DCC）和三乙胺在甲苯作溶剂存在下与N - [（S） - 乙氧基羰基-1-丁基] - （S） - 丙氨酸（式IV化合物） 在5℃至40℃的温度下。