公开(公告)号：WO2004080959A3

公开(公告)日：2004-11-25

申请号：PCT/US2004006565

申请日：2004-03-04

Applicant: ISP INVESTMENTS INC

Inventor： GUTMAN ARIE ,  ZALTSMAN IGOR ,  SHALIMOV ANTON ,  SOTRIHIN MAXIM ,  NISNEVICH GENNADY ,  YUDOVICH LEV ,  FEDOTEV IRINA

IPC: A61K31/445 ,  A61K31/4458 ,  C07D20060101 ,  C07D211/22 ,  C07D211/34

CPC classification number: C07D211/34

Abstract: The present invention provides a new and efficient process for the preparation of the dexmethylphenidate hydrochloride with high optical purity, the process comprising: (a) reacting a solution of threo-N-Boc-ritalinic acid with (S)-1-phenylethylamine, separating precipitated solid salt of (R,R)-enriched N-Boc-ritalinic acid with (S)-1-phenylethylamine from the reaction mixture and recrystallizing, reslurring and/or trituring of said salt; (b) mixing the solid salt of (R,R)-N-Boc-ritalinic acid and (S)-1- phenylethylamine obtained in step (a) with aqueous acid and separating (R,R)-N-Boc-ritalinic acid from the mixture; and (c) reacting the (R,R)-N-Boc-ritalinic acid prepared in step (b) with hydrogen chloride and methanol to give dexmethylphenidate hydrochloride with optical purity of at least 99% ee. The present invention further provides salt of (R,R)-N-Boc-ritalinic acid with (S)-1-phenylethylamine as new intermediate in the preparation of dexmethylphenidate hydrochloride.

Abstract translation: 本发明提供了一种制备高光学纯度右旋哌甲酯盐酸盐的新颖有效的方法，该方法包括：（a）使苏-N-Boc-利他宁酸与（S）-1-苯乙胺溶液反应，分离 （R，R） - 富集的N-Boc-利他宁酸与（S）-1-苯乙胺的固体盐从反应混合物中沉淀出来，并对所述盐进行重结晶，再润湿和/或研磨; （b）将步骤（a）中得到的（R，R）-N-Boc-利他宁酸和（S）-1-苯乙基胺的固体盐与酸水溶液混合并分离（R，R）-N-Boc-利他尼酸 来自混合物的酸; （c）使步骤（b）中制备的（R，R）-N-Boc-利他宁酸与氯化氢和甲醇反应，得到光学纯度为至少99％ee的右旋哌甲酯盐酸盐。 本发明进一步提供了（R，R）-N-Boc-利他宁酸与（S）-1-苯乙基胺的盐作为制备右旋哌甲酯盐酸盐的新中间体。

公开(公告)号：WO2004080583A3

公开(公告)日：2005-03-24

申请号：PCT/US2004006567

申请日：2004-03-04

Applicant: ISP INVESTMENTS INC

Inventor： GUTMAN ARIE ,  ZALTSMAN IGOR ,  SHALIMOV ANTON ,  SOTRIHIN MAXIM ,  NISNEVICH GENNADY

IPC: A61K31/445 ,  C07D211/34 ,  C07D463/00 ,  C07D211/06

CPC classification number: C07D211/34 ,  A61K31/445

Abstract: The present invention provides a process for the preparation of threo-methylphenidate hydrochloride. According to a preferred embodiment, the process comprises the following steps: (a) contacting 1-(phenylglyoxylyl)piperidine arenesulfonylhydrazone of the wherein Ar denotes an aryl group, where the aryl group may be substituted by a C 1-C6 alkyl, halo or nitro group; with an inorganic base in the presence of a water immiscible organic solvent and a phase transfer catalyst to obtain (R*,R*)-enriched 7-phenyl- 1-azabicyclo[4.2.0]octan-8-one of the formula: (b) reacting the (R*,R*)-enriched 7-phenyl- 1-azabicyclo[4.2.0]octan-8-one prepared in step (a) with a solution of hydrogen chloride in methanol to obtain threo-enriched methylphenidate hydrochloride; (c) crystallizing the threo-enriched methylphenidate hydrochloride prepared in step (b) to give the desired threo-methylphenidate hydrochloride. Preferably, the threo-methylphenidate hydrochloride produced by the process of the present invention contains no more than 1 % of the erythro-isomer.

Abstract translation: 本发明提供了制备苏哌甲酸盐酸盐的方法。 根据优选的实施方案，该方法包括以下步骤：（a）使1-（苯基乙酰氧基）哌啶芳烃磺酰腙与其中Ar表示芳基的芳基磺酰腙接触，其中芳基可以被C 1 -C 6烷基，卤素或 硝基; 在无水碱存在下与水不混溶的有机溶剂和相转移催化剂反应，得到（R *，R *）富集的7-苯基-1-氮杂双环[4.2.0]辛-8-酮，其具有下式： （b）将步骤（a）中制备的（R *，R *）富集的7-苯基-1-氮杂双环[4.2.0]辛-8-酮与氯化氢的甲醇溶液反应，得到富含 哌甲酯盐酸盐; （c）使在步骤（b）中制备的富含苏氨酸的哌甲酯盐酸盐盐酸盐结晶，得到所需的苏哌甲酯盐酸盐。 优选地，通过本发明的方法制备的苏哌甲酸盐酸盐含有不超过1％的赤式异构体。