公开(公告)号：US06248882B1

公开(公告)日：2001-06-19

申请号：US09689209

申请日：2000-10-12

申请人： Jollie D. Godfrey, Jr. ,  David R. Kronenthal ,  Mark D. Schwinden ,  Sushil K. Srivastava ,  Keith Ramig ,  John J. Venit ,  Paul A. Jass ,  Saibaba Racha ,  John L. Dillon, Jr. ,  Nachimuthu Soundararajan ,  Gerald L. Powers ,  Atul S. Kotnis

发明人： Jollie D. Godfrey, Jr. ,  David R. Kronenthal ,  Mark D. Schwinden ,  Sushil K. Srivastava ,  Keith Ramig ,  John J. Venit ,  Paul A. Jass ,  Saibaba Racha ,  John L. Dillon, Jr. ,  Nachimuthu Soundararajan ,  Gerald L. Powers ,  Atul S. Kotnis

IPC分类号： C07D26702

CPC分类号： C07C229/22 ,  C07D317/30

摘要： The glycinamide of the formula is reacted with the dioxolane of the formula wherein L is a leaving group such as iodo, bromo, alkylsulfonyloxy, or arylsulfonyloxy to give the dioxolane of the formula Treating the dioxolane of formula III under aqueous refluxing conditions followed by exchanging the dioxolane acetal with a dimethoxy acetal and introduction of the methyl ester gives (S)-2-amino-6,6-dimethoxyhexanoic acid, methyl ester which is an intermediate in the preparation of the dual inhibitor [4S-[4&agr;(R*),7&agr;, 10a&bgr;]]-)octahydro-4-[(2-mercapto-1-oxo-3-phenylpropy)-amino]-5-oxo-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylic acid. Also disclosed are storage stable salts of (S)-2-amino-6,6-dimethoxyhexanoic acid, methyl ester.

摘要翻译： 式中的甘氨酰胺与二氢呋喃的反应是离去基团如碘，溴，烷基磺酰氧基或芳基磺酰氧基，得到下式的二氧戊环：在含水回流条件下，将式III的二氧戊环，然后与二氧戊环缩醛交换， 得到（S）-2-氨基-6,6-二甲氧基己酸甲酯，其是制备双重抑制剂[4S- [4α（R *），7α， 10]] - ）八氢-4 - [（2-巯基-1-氧代-3-苯基丙基） - 氨基] -5-氧代-7H-吡啶并[2,1-b] [1,3] 羧酸。 还公开了（S）-2-氨基-6,6-二甲氧基己酸甲酯的储存稳定盐。

公开(公告)号：US07388098B2

公开(公告)日：2008-06-17

申请号：US09961932

申请日：2001-09-24

申请人： John J. Venit ,  Gary D. Madding ,  Victor W. Rosso ,  Francis J. Okuniewicz ,  Robert P. Discordia ,  Susanne Kiau ,  Atul S. Kotnis ,  Michael E. Randazzo ,  D. David Hennings ,  Jingyang Zhu ,  Jason G. Chen

发明人： John J. Venit ,  Gary D. Madding ,  Victor W. Rosso ,  Francis J. Okuniewicz ,  Robert P. Discordia ,  Susanne Kiau ,  Atul S. Kotnis ,  Michael E. Randazzo ,  D. David Hennings ,  Jingyang Zhu ,  Jason G. Chen

IPC分类号： C07C53/134 ,  C07D233/00 ,  C07D277/00 ,  C07B55/00

CPC分类号： C07D233/78 ,  C07C51/412 ,  C07C51/43 ,  C07C213/08 ,  C07C213/10 ,  C07D233/74 ,  C07C57/58

摘要： Provided is a dynamic resolution method of enriching a desired isomer of an alpha-substituted carboxylic acid relative to an undesired isomer, the method comprising: (a) in a solvent, contacting the alpha-substituted carboxylic acid, wherein the alpha substitution is with a leaving group and wherein the alpha carbon is chiral, with a homochiral amine to form a salt that is partially insoluble under selected reaction conditions, wherein the homochiral amine is selected so that the solubility of the amine salt of the undesired alpha-substituted carboxylic acid is greater than that of the amine salt of the desired alpha-substituted carboxylic acid under the selected reaction conditions; (b) reacting under the selected reaction conditions the salt with a nucleophile, wherein the reacting is effective in producing a net increase in the less soluble amine salt of the alpha-substituted carboxylic acid, and wherein the selected conditions are selected to (i) promote nucleophilic substitution of the nucleophile and the leaving group or (ii) to produce the increase in the less soluble amine salt in the absence of a strong base; and (c) maintaining the reaction for a period of time effective to increase the amount of the desired alpha-substituted carboxylic acid isomer.

摘要翻译： 提供了相对于不期望的异构体富集α-取代的羧酸的所需异构体的动态拆分方法，该方法包括：（a）在溶剂中使α-取代的羧酸接触，其中α取代为 离去基团，其中所述α碳是手性的，与同基因胺形成在所选择的反应条件下部分不溶的盐，其中选择所述同基因胺，使得不需要的α-取代羧酸的胺盐的溶解度为 在选择的反应条件下大于所需α-取代羧酸的胺盐的浓度; （b）在所选择的反应条件下使所述盐与亲核试剂反应，其中所述反应有效地产生所述α-取代羧酸的较不溶性胺盐的净增加，并且其中所选择的条件选择为：（i） 促进亲核试剂和离去基团的亲核取代，或（ii）在没有强碱的情况下产生较不溶性胺盐的增加; 和（c）保持反应一段时间有效以增加所需的α-取代的羧酸异构体的量。

公开(公告)号：US06897309B2

公开(公告)日：2005-05-24

申请号：US10636070

申请日：2003-08-07

申请人： Jeffrey Depue ,  Atul S. Kotnis ,  Simon Leung ,  Eric D. Dowdy ,  Daniel J. Watson

发明人： Jeffrey Depue ,  Atul S. Kotnis ,  Simon Leung ,  Eric D. Dowdy ,  Daniel J. Watson

IPC分类号： A61K31/495 ,  C07D401/12 ,  C07D401/14

CPC分类号： C07D401/12

摘要： This invention describes a process for preparing hydroxyazapirones of Formula I from azapirones of Formula II. The process comprises treating azapirones with a strong base, monitoring enolate formation of the azapirone by IR spectroscopy, and reacting the enolate with a source of molecular oxygen in the presence of a reductant. The process is suitable for large scale production of hydroxyazapirones.

摘要翻译： 本发明描述了由式II的氮杂环庚烷制备式I的羟基氮杂环庚烷的方法。 该方法包括用强碱处理唑吡酮，通过红外光谱监测阿扎地隆的烯醇化物形成，并在还原剂存在下使烯醇化物与分子氧源反应。 该方法适用于大规模生产羟基氮杂环庚烷。

公开(公告)号：US06329542B1

公开(公告)日：2001-12-11

申请号：US09689215

申请日：2000-10-12

申请人： Jollie D. Godfrey, Jr. ,  David R. Kronenthal ,  Mark D. Schwinden ,  Sushil K. Srivastava ,  Keith Ramig ,  John J. Venit ,  Paul A. Jass ,  Saibaba Racha ,  John L. Dillon, Jr. ,  Nachimuthu Soundararajan ,  Gerald L. Powers ,  Atul S. Kotnis

发明人： Jollie D. Godfrey, Jr. ,  David R. Kronenthal ,  Mark D. Schwinden ,  Sushil K. Srivastava ,  Keith Ramig ,  John J. Venit ,  Paul A. Jass ,  Saibaba Racha ,  John L. Dillon, Jr. ,  Nachimuthu Soundararajan ,  Gerald L. Powers ,  Atul S. Kotnis

IPC分类号： C07C6966

CPC分类号： C07C229/22 ,  C07D317/30

摘要： The glycinamide of the formula is reacted with the dioxolane of the formula wherein L is a leaving group such as iodo, bromo, alkylsulfonyloxy, or arylsulfonyloxy to give the dioxolane of the formula Treating the dioxolane of formula III under aqueous refluxing conditions followed by exchanging the dioxolane acetal with a dimethoxy acetal and introduction of the methyl ester gives (S)-2-amino-6,6-dimethoxyhexanoic acid, methyl ester which is an intermediate in the preparation of the dual inhibitor [4S-[4&agr;(R*),7&agr;,10a&bgr;]]-octahydro-4-[(2-mercapto-1-oxo-3-phenylpropyl)-amino]-5-oxo-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylic acid. Also disclosed are storage stable salts of (S)-2-amino-6, 6-dimethoxyhexanoic acid, methyl ester.

摘要翻译： 式中的甘氨酰胺与二氢呋喃的反应是离去基团如碘，溴，烷基磺酰氧基或芳基磺酰氧基，得到下式的二氧戊环：在含水回流条件下，将式III的二氧戊环，然后与二氧戊环缩醛交换， 得到（S）-2-氨基-6,6-二甲氧基己酸甲酯，其是制备双重抑制剂[4S- [4α（R *），7α， 10]] - 八氢-4 - [（2-巯基-1-氧代-3-苯基丙基） - 氨基] -5-氧代-7H-吡啶并[2,1-b] [1,3]硫氮杂-7-羧酸 酸。 还公开了（S）-2-氨基-6,6-二甲氧基己酸甲酯的储存稳定的盐。