公开(公告)号：US07002016B2

公开(公告)日：2006-02-21

申请号：US10793600

申请日：2004-03-04

申请人： Arie Gutman ,  Igor Zaltsman ,  Anton Shalimov ,  Maxim Sotrihin ,  Gennady Nisnevich

发明人： Arie Gutman ,  Igor Zaltsman ,  Anton Shalimov ,  Maxim Sotrihin ,  Gennady Nisnevich

IPC分类号： C07D221/02

CPC分类号： C07D211/34 ,  A61K31/445

摘要： 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 formula wherein Ar denotes an aryl group, where the aryl group may be substituted by a C1–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.

摘要翻译： 本发明提供了制备苏哌甲酸盐酸盐的方法。 根据优选实施例，该方法包括以下步骤

公开(公告)号：US07247730B2

公开(公告)日：2007-07-24

申请号：US10793080

申请日：2004-03-04

申请人： Arie Gutman ,  Igor Zaltsman ,  Anton Shalimov ,  Maxim Sotrihin ,  Gennady Nisnevich ,  Lev Yudovich ,  Irina Fedotev

发明人： Arie Gutman ,  Igor Zaltsman ,  Anton Shalimov ,  Maxim Sotrihin ,  Gennady Nisnevich ,  Lev Yudovich ,  Irina Fedotev

IPC分类号： C07D211/22

CPC分类号： C07D211/34

摘要： 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-phenylethylamnine 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.

摘要翻译： 本发明提供了一种用于制备具有高光学纯度的右哌醋酸盐酸盐的新型和有效的方法，该方法包括：（a）使苏氨酸-N-Boc-色氨酸与（S）-1-苯基乙胺的溶液，分离 （R，R）富含N-Boc-异戊酸的沉淀固体盐与（S）-1-苯乙基胺在反应混合物中的沉淀，并重结晶，再沉淀和/或研磨所述盐; （b）将步骤（a）中得到的（R，R）-N-Boc-异戊酸和（S）-1-苯基乙胺的固体盐与酸水溶液和（R，R）-N-Boc-活化后 酸从混合物中; 和（c）使步骤（b）中制备的（R，R）-N-Boc-异戊酸与氯化氢和甲醇反应，得到光学纯度为至少99％ee的盐酸偏苯甲酸酯。 本发明进一步提供（R，R）-N-Boc-异戊酸与（S）-1-苯基乙胺的盐作为制备右哌甲酯盐酸盐的新中间体。