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1. 发明申请

WO2011006455A3 METHOD OF PREPARING DESVENLAFAXINE AND ITS SALTS 审中-公开
公开(公告)号：WO2011006455A3
公开(公告)日：2011-01-20
申请号：PCT/CZ2010/000074
申请日：2010-07-08
申请人： ZENTIVA, K.S. , HRUBY, Petr , RIDVAN, Ludek , RADL, Stanislav , PLACEK, Lukas
发明人： HRUBY, Petr , RIDVAN, Ludek , RADL, Stanislav , PLACEK, Lukas
IPC分类号： C07C213/00 , C07C213/10 , C07C215/64
摘要： A method for the preparation of 4-(2-(dimethylamino)-l-(l-hydroxycyclohexyl)ethyl) phenol of formula (I), known under generic name desvenlafaxine, and its pharmaceutically acceptable salts, which comprises (a) mixing of the starting material O -benzyldesvenlafaxine or its derivative of formula (II), wherein R is H, 4-methyl, 4-methoxy, 3,4-dimethoxy, 2-nitro, 4-nitro, 4-chloro, 4- bromo, 2,6-dichloro or 2,6-difluoro, in an organic solvent or a mixture of solvents, and subsequent dissolving of the starting material by decreasing the pH to a value of 3 to 8 by addition of an inorganic or organic acid, or dissolving of O -benzyldesvenlafaxine or its derivative of formula (II) in an organic solvent or a mixture of solvents, wherein the compound of formula (II) is in the form of a salt with an inorganic or organic acid and the pH of the solution has a value of 3 to 8, (b) converting O -benzyldesvenlafaxine or its derivative of formula (II) to desvenlafaxine I by catalytic hydrogenation on a Raney catalyst, (c) removing the catalyst from the desvenlafaxine solution by filtration and subsequent increasing the pH to a value of 8 to 11 by addition of an inorganic or organic base, (d) isolating the desvenlafaxine base I by filtration, (e) converting the desvenlafaxine base I to a pharmaceutically acceptable salt. Formulae (I), (II)

2. 发明申请

WO2007009405A1 A METHOD FOR THE PREPARATION OF (R)-N-METHYL-3-(2-METHYLPHENOXY)-3-PHENYLPROPYLAMINE HYDROCHLORIDE (ATOMOXETINE) 审中-公开
标题翻译：制备（R）-N-甲基-3-（2-甲基苯氧基）-3-苯基丙烯酰胺氯化氢（ATOMOXETINE）的方法
公开(公告)号：WO2007009405A1
公开(公告)日：2007-01-25
申请号：PCT/CZ2005/000091
申请日：2005-12-01
申请人： ZENTIVA, A.S. , RIDVAN, Ludek , HRUBY, Petr , RADL, Stanislav , ZATOPKOVA, Monika , PLACEK, Lukas
发明人： RIDVAN, Ludek , HRUBY, Petr , RADL, Stanislav , ZATOPKOVA, Monika , PLACEK, Lukas
IPC分类号： C07C213/06 , C07C215/30
CPC分类号： C07C213/06 , C07C217/44
摘要： Racemic N -benzyl- N -methyl-3-(2-methylphenoxy)-3-phenylproρylamine (VIII) is an intermediate for obtaining atomoxetine. Racemic N -benzyl- N -methyl-3-(2-methylphenoxy)-3- phenylpropylamine (VIII) further reacts in a solution of an organic solvent with an optically active acid producing a mixture of diastereoisomers, which are subsequently resolved by crystallization and converted to the respective (R) and (S) enantiomers of N-benzyl-N-methyl- 3-(2-methylphenoxy)-3-phenylpropylamine by treatment with an organic or inorganic base. The (R)-enantiomer of N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine ((R)-VIII) is further subjected to debenzylation by means of an alkyl or aryl chloro formate yielding an alkyl/aryl (R)-3-(2-methylphenoxy)-3-phenylpropylmethylcarbamate ((R)-IX), which is then hydrolyzed in the basic environment yielding the base of (R)-N-methyl-3-(2-methylphenoxy)- 3-phenylpropaneamine, which is finally converted to (R)-N-methyl-3-(2-methylphenoxy)-3- phenylpropanamine hydrochloride ((R)-I) by treatment with hydrochloric acid.
摘要翻译：外消旋N-苄基-N-甲基-3-（2-甲基苯氧基）-3-苯基丙基胺（VIII）是获得阿托西汀的中间体。外消旋N-苄基-N-甲基-3-（2-甲基苯氧基）-3-苯基丙胺（VIII）进一步在有机溶剂与光学活性酸的溶液中反应，产生非对映异构体的混合物，其随后通过结晶和通过用有机或无机碱处理转化成N-苄基-N-甲基-3-（2-甲基苯氧基）-3-苯基丙胺的各自的（R）和（S）对映异构体。 N-甲基-3-（2-甲基苯氧基）-3-苯基丙基胺（（R）-VIII）的（R） - 对映异构体进一步通过烷基或芳基氯甲酸酯进行脱苄基，得到烷基/芳基（R ）-3-（2-甲基苯氧基）-3-苯基丙基甲基氨基甲酸酯（（R）-IX），然后在碱性环境中水解，得到（R）-N-甲基-3-（2-甲基苯氧基） - 苯基丙胺，最后通过用盐酸处理转化为（R）-N-甲基-3-（2-甲基苯氧基）-3-苯基丙胺盐酸盐（（R）-I）。

3. 发明申请

WO2012069025A1 (5-METHYL-2-OXO-1,3-DIOXOL-4-YLMETHYL)-4-(1-HYDROXY-1-METHYL-PROPYL)-2-PROPYL-1-[2'- (1H-TETRAZOL-5-YL)BIPHENYL-4-YL-METHYL]IMIDAZOLE-5-CARBOXYLATE AS AN IMPURITY OF OLMESARTAN MEDOXOMIL AND A METHOD OF ITS PREPARATION 审中-公开
标题翻译：（5-甲基-2-氧代-1,3-二氧代-4-甲基乙基）-4-（1-羟基-1-甲基 - 丙基）-2-丙基-1- [2' - （1H-四唑-5 -YL）联苯-4-基甲基]咪唑-5-羧酸甲酯作为奥美沙坦的消毒剂及其制备方法
公开(公告)号：WO2012069025A1
公开(公告)日：2012-05-31
申请号：PCT/CZ2011/000112
申请日：2011-11-23
申请人： ZENTIVA, K.S. , STACH, Jan , PLACEK, Lukas , KRULIS, Radim , RADL, Stanislav , CERNY, Josef
发明人： STACH, Jan , PLACEK, Lukas , KRULIS, Radim , RADL, Stanislav , CERNY, Josef
IPC分类号： C07D233/90 , C07D403/10 , C07D405/14 , G01N30/00
CPC分类号： C07D405/14 , C07D233/90 , C07D403/10
摘要： The compound of formula VI and a method of its preparation, and intermediates of its preparation. Use of these intermediates as standards in analysis of the angiotensin II antagonist olmesartan medoxomil of formula I and of intermediates of its production.
摘要翻译：式Ⅵ化合物及其制备方法及其制备中间体。使用这些中间体作为分析式I的血管紧张素II拮抗剂奥美沙坦酯和其制备中间体的标准。

4. 发明申请

WO2006045255A1 METHOD OF MANUFACTURING (S)-N-METHYL-3-(1-NAPHTHYLOXY)-3-(2-THIENYL)PROPYLAMINE HYDROCHLORIDE (DULOXETINE) 审中-公开
标题翻译：制备（S）-N-甲基-3-（1-萘基）-3-（2-苯乙基）丙酰胺氢氯化物（DULOXETINE）的方法
公开(公告)号：WO2006045255A1
公开(公告)日：2006-05-04
申请号：PCT/CZ2005/000079
申请日：2005-10-21
申请人： ZENTIVA, A.S. , RIDVAN, Ludek , HRUBY, Petr , PLACEK, Lukas , KUCHAR, Miroslav
发明人： RIDVAN, Ludek , HRUBY, Petr , PLACEK, Lukas , KUCHAR, Miroslav
IPC分类号： C07D333/20 , A61K31/38
CPC分类号： C07D333/20
摘要： A method of preparation of ( S )-N-methyl-3-(l-naphthyloxy)-3-(2-thienyl)propylamine of formula (I) or its pharmaceutically acceptable salt, in which ( RS )- N , N -dimethyl-3-(l-naphthyloxy)-3-(2-thienyl)propylamine of formula (III) is reacted with an optically active acid, after which a crystallization is made of that diastereoisomer which yields, by reaction with an inorganic or organic base, ( S )- N , N -dimethyl-3-(l-naphthyloxy)-3-(2-thienyl)propylamine of formula (S)-III, which is then demethylated using alkylchloroformates, followed by a hydrolysis and optional conversion of the compound of formula (I) to its salt.
摘要翻译：制备式（I）的（S）-N-甲基-3-（1-萘氧基）-3-（2-噻吩基）丙胺或其药学上可接受的盐的方法，其中（RS）-N，使式（III）的2-（3-甲氧基）-3-（1-萘氧基）-3-（2-噻吩基）丙胺与光学活性酸反应，然后通过与无机或有机物反应产生非对映异构体，碱，（S）-N，N-二甲基-3-（1-萘氧基）-3-（2-噻吩基）丙胺，然后使用氯甲酸烷基酯脱甲基，然后进行水解和任选的转化的式（I）化合物与其盐反应。

5. 发明申请

WO2008067781A2 A METHOD OF PURIFICATION OF (S)-N-METHYL-3-(1-NAPHTYLOXY)-3-(2-THIENYL) PROPYLAMINE HYDROCHLORIDE (DULOXETINE) 审中-公开
标题翻译：（S）-N-甲基-3-（1-萘基）-3-（2-苯乙基）丙酰胺氢氯化物（DULOXETINE）的纯化方法
公开(公告)号：WO2008067781A2
公开(公告)日：2008-06-12
申请号：PCT/CZ2007/000109
申请日：2007-12-05
申请人： ZENTIVA, A.s. , RIDVAN, Ludek , CINIBULK, Josef , ZATOPKOVA, Monika , PLACEK, Lukas
发明人： RIDVAN, Ludek , CINIBULK, Josef , ZATOPKOVA, Monika , PLACEK, Lukas
IPC分类号： C07D333/20 , A61K31/381 , A61P25/24
CPC分类号： C07D333/20
摘要： A method of purification of (5)-7V-methyl-3-(l-naphtyloxy)-3-(2-thienyl) propylamine hydrochloride of formula I, comprising (a) transformation of the substance of formula I to its free base by the action of an organic or inorganic base in an aqueous environment; and (b) transformation of the base of the substance of formula I to crystalline hydrochloride by the action of hydrochloric acid or gaseous HCl in an organic solvent or a mixture of organic solvents. A method of purification of (S)-N-methyl-3-(l-naphtyloxy)-3-(2-thienyl) propylamine hydrochloride of formula I, comprising dissolution of this substance in a minimum quantity of methanol containing 0 to 50% of water and its transformation back to the solid phase (precipitation) by addition of a less polar solvent.
摘要翻译：一种纯化式（I）的（5）-N-甲基-3-（1-萘氧基）-3-（2-噻吩基）丙胺盐酸盐的方法，该方法包括：（a）将式I物质转化为游离碱由式有机或无机碱在水性环境中的作用; 和（b）通过盐酸或气态HCl在有机溶剂或有机溶剂的混合物中的作用将式I的物质的碱转化为结晶盐酸盐。一种纯化式（I）的（S）-N-甲基-3-（1-萘基氧基）-3-（2-噻吩基）丙胺盐酸盐的方法，包括将该物质溶解在含有0至50％的水，并通过加入极性较小的溶剂将其转化回固相（沉淀）。

6. 发明申请

WO2007076733A2 A METHOD FOR THE PREPARATION OF (S)-N-METΗYL-3-(l-NAPHTHYLOXY)-3-(2-THIENYL)PROPYLAMINE HYDROCHLORIDE (DULOXETINE) 审中-公开
标题翻译：制备（S）-N-METγY-3-（1-萘基）-3-（2-噻吩基）丙酰胺氢氯化物（DULOXETINE）的方法
公开(公告)号：WO2007076733A2
公开(公告)日：2007-07-12
申请号：PCT/CZ2006/000096
申请日：2006-12-22
申请人： ZENTIVA a.s. , RIDVAN, Ludek , JARRAH, Kamal , CINIBULK, Josef , ZATOPKOVA, Monika , PLACEK, Lukas
发明人： RIDVAN, Ludek , JARRAH, Kamal , CINIBULK, Josef , ZATOPKOVA, Monika , PLACEK, Lukas
IPC分类号： C07D333/20
CPC分类号： C07D333/20
摘要： A method of preparation of (S)-N-methyl-3-(l-naphthyloxy)-3-(2-mienyl)propylamine of Formula(I) and its pharmaceutically acceptable salts, comprising a) reaction of (RS)-N,N-dimethyl-3-(l-naphthyloxy)-3-(2-thienyl)propylamine of formula (III) with optically active D-tartaric acid or an acid salt derived from D-tartaric acid forming a mixture of diastereoisomeric salts of N,N-dimethyl-3-(l-naphthyloxy)- 3-(2-thienyl)propylamine and D-tartaric acid (2:1), b) isolation of the salt (S)-N,N-dimethyl-3-(naphthyloxy)-3-(2- thienyl)propylamine/D-tartrate (2:1) from the mixture of diastereoisomeric salts in an organic solvent, water or a mixture thereof and release of (S)-N,N-dimethyl-3-(l- naphthyloxy)-3-(2-thienyl)ρropylamine of formula (S)-(III) by action of an inorganic or organic base, c) demethylation of (S)-N,N-dimethyl-3-(l-naphthyloxy)-3-(2-thienyl)propylamine by action of an alkylchloroformate of formula ClCOOR (R = C 1 - C 5 alkyl, or C 6 - C 12 aryl or alkylaryl), especially phenyl, ethyl or methyl chloroformate, and d) hydrolytic release of the duloxetine base of formula (I) and optionally conversion of the base to a salt with the respective acid, or salt of a weak base, wherein one uses, as the optically active substance in step (a), D-tartaric acid in the molar ratio 1:2 relative to the substance of formula (III), or an alkali metal acid D-tartrate or ammonium tartrate, or alternatively alkylammonium tartrate of formula (IV) in the molar ratio 1:1 relative to the substance of formula (III).
摘要翻译：制备式（I）的（S）-N-甲基-3-（1-萘氧基）-3-（2-甲基）丙胺及其药学上可接受的盐的方法，包括：a）（RS）-N ，式（III）的N-二甲基-3-（1-萘氧基）-3-（2-噻吩基）丙胺与光学活性的D-酒石酸或衍生自D-酒石酸的酸盐形成混合物，形成非对映异构体盐 N，N-二甲基-3-（1-萘氧基）-3-（2-噻吩基）丙胺和D-酒石酸（2:1），b）分离盐（S）-N，N-二甲基-3 - （萘氧基）-3-（2-噻吩基）丙胺/ D-酒石酸盐（2:1），由有机溶剂，水或其混合物中的非对映异构体盐的混合物和（S）-N，N-二甲基（S） - （III）的3-（1-萘氧基）-3-（2-噻吩基）-3-戊胺通过无机或有机碱的作用，c）（S）-N，N-二甲基 - 3-（1-萘氧基）-3-（2-噻吩基）丙胺通过式ClCOOR（R = C 1 -C 5烷基）的氯甲酸烷基酯或C 12 芳基或烷基芳基），特别是氯甲酸苯基，乙基或甲基酯，和d）式（I）的度洛西汀碱的水解释放和任选地将碱与弱碱的相应酸或盐转化成盐，其中作为步骤（a）中的光学活性物质，使用相对于式（III）物质的摩尔比为1:2的D-酒石酸或酒石酸碱金属酸酒石酸盐或酒石酸铵酒石酸盐（IV）的摩尔比相对于式（III）的物质为1:1。

7. 发明申请

WO2007147374A2 PROCESS FOR THE PREPARATION OF SOLIFENACIN 审中-公开
标题翻译：制备辛伐他汀的方法
公开(公告)号：WO2007147374A2
公开(公告)日：2007-12-27
申请号：PCT/CZ2007/000061
申请日：2007-06-21
申请人： ZENTIVA A.S. , JIRMAN, Josef , JUNEK, Richard , LUSTIG, Petr , RICHTER, Jindrich , PLACEK, Lukas
发明人： JIRMAN, Josef , JUNEK, Richard , LUSTIG, Petr , RICHTER, Jindrich , PLACEK, Lukas
IPC分类号： C07D453/02
CPC分类号： C07D453/02
摘要： A process for the preparation of (1S)-(3R)-1-azabicyclo[2.2.2.]oct-3-yl 3,4-dihydro-1-phenyl-2(1H)-isoquinoline carboxylate by reacting (1S)-alkyl 1-phenyl-1,2,3,4-tetrahydro-2- isoquinoline carboxylate with 3-(R)-quinuclidol in an inert solvent, where a primary alkyl ester of the carboxylate whose alkyl length is C 1 -C 4 is used and the reaction is catalyzed by a non-nucleophilic base.
摘要翻译：（1S） - （3R）-1-氮杂双环[2.2.2]辛-3-基3,4-二氢-1-苯基-2（1H） - 异喹啉羧酸酯的制备方法， - 烷基1-苯基-1,2,3,4-四氢-2-异喹啉羧酸酯与3-（R） - 奎宁环醇在惰性溶剂中反应，其中烷基长度为C 1的羧酸烷基酯使用C 4 S 4并且反应由非亲核碱催化。

8. 发明授权

EP1968965B1 A METHOD FOR THE PREPARATION OF (S)-N-METHYL-3-(l-NAPHTHYLOXY)-3-(2-THIENYL)PROPYLAMINE HYDROCHLORIDE (DULOXETINE) 有权
标题翻译：工艺用于制备（S）-N-甲基-3-（1-萘氧基）-3-（2-噻吩基）丙胺盐酸盐（度洛西汀）
公开(公告)号：EP1968965B1
公开(公告)日：2011-09-07
申请号：EP06840860.8
申请日：2006-12-22
申请人： Zentiva, k.s.
发明人： RIDVAN, Ludek , JARRAH, Kamal , CINIBULK, Josef , ZATOPKOVA, Monika , PLACEK, Lukas
IPC分类号： C07D333/20
CPC分类号： C07D333/20
摘要： A method of preparation of (S)-N-methyl-3-(l-naphthyloxy)-3-(2-mienyl)propylamine of Formula(l) and its pharmaceutically acceptable salts, comprising a) reaction of (RS)-N, N-dimethyl-3-(l-naρhthyloxy)-3-(2-th1enyl)propylamine with optically active D-tartaric acid or an acid salt derived from D-tartaric acid forming a mixture of diastereoisomeric salts of N,N-dimethyl-3-(l-naphthyloxy)- 3-(2-thienyl)propylamine and D- tartaric acid (2:1), b) isolation of the salt (S)-N, N-dimethyl-3-(naphthyloxy)-3-(2- thienyl)propylamine/D- tartrate (2:1) from the mixture of diastereoisomeric salts in an organic solvent, water or a mixture thereof and release of (S)-N, N-dimethyl-3-(l- naphthyloxy)-3-(2-thienyl) propylamine by action of an inorganic or organic base, c) demethylation of (S)-N,N-dimethyl-3-(1-naphthyloxy)-3-(2- thienyl) propylamine by action of an alkylchloroformate of formula C1COOR (R=C1-C5 alkyl, or C6-C12 aryl or alkylraryl), especially phenyl, ethyl or methyl chloroformate, and d) hydrolytic release of the duloxetine base of formula I and optionally conversion of the base to a salt with the respective acid, or salt of a weak base.

9. 发明公开

EP2089375A2 A METHOD OF PURIFICATION OF (S)-N-METHYL-3-(1-NAPHTYLOXY)-3-(2-THIENYL) PROPYLAMINE HYDROCHLORIDE (DULOXETINE) 有权
标题翻译：法的纯化（S）-N-甲基-3-（1-萘氧基）-3-（2-噻吩基）丙胺盐酸盐（度洛西汀）
公开(公告)号：EP2089375A2
公开(公告)日：2009-08-19
申请号：EP07846243.9
申请日：2007-12-05
申请人： Zentiva, k.s.
发明人： RIDVAN, Ludek , CINIBULK, Josef , ZATOPKOVA, Monika , PLACEK, Lukas
IPC分类号： C07D333/20 , A61K31/381 , A61P25/24
CPC分类号： C07D333/20
摘要： A method of purification of (5)-7V-methyl-3-(l-naphtyloxy)-3-(2-thienyl) propylamine hydrochloride of formula I, comprising (a) transformation of the substance of formula I to its free base by the action of an organic or inorganic base in an aqueous environment; and (b) transformation of the base of the substance of formula I to crystalline hydrochloride by the action of hydrochloric acid or gaseous HCl in an organic solvent or a mixture of organic solvents. A method of purification of (S)-N-methyl-3-(l-naphtyloxy)-3-(2-thienyl) propylamine hydrochloride of formula I, comprising dissolution of this substance in a minimum quantity of methanol containing 0 to 50% of water and its transformation back to the solid phase (precipitation) by addition of a less polar solvent.

10. 发明授权

EP2089375B1 A METHOD OF PURIFICATION OF (S)-N-METHYL-3-(1-NAPHTYLOXY)-3-(2-THIENYL) PROPYLAMINE HYDROCHLORIDE (DULOXETINE) 有权
标题翻译：法的纯化（S）-N-甲基-3-（1-萘氧基）-3-（2-噻吩基）丙胺盐酸盐（度洛西汀）
公开(公告)号：EP2089375B1
公开(公告)日：2013-07-31
申请号：EP07846243.9
申请日：2007-12-05
申请人： Zentiva, k.s.
发明人： RIDVAN, Ludek , CINIBULK, Josef , ZATOPKOVA, Monika , PLACEK, Lukas
IPC分类号： C07D333/20 , A61K31/381 , A61P25/24
CPC分类号： C07D333/20

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