公开(公告)号：US06720449B2

公开(公告)日：2004-04-13

申请号：US09926346

申请日：2002-02-05

申请人： Masanobu Sugawara ,  Akio Fujii ,  Kazumi Okuro ,  Yasuhiro Saka ,  Nobuo Nagashima ,  Kenji Inoue ,  Toshihiro Takeda ,  Koichi Kinoshita ,  Tadashi Moroshima ,  Yoshihide Fuse ,  Yasuyoshi Ueda

发明人： Masanobu Sugawara ,  Akio Fujii ,  Kazumi Okuro ,  Yasuhiro Saka ,  Nobuo Nagashima ,  Kenji Inoue ,  Toshihiro Takeda ,  Koichi Kinoshita ,  Tadashi Moroshima ,  Yoshihide Fuse ,  Yasuyoshi Ueda

IPC分类号： C07D20308

CPC分类号： C07D203/08 ,  C07B2200/07 ,  C07C227/10 ,  C07C227/32 ,  C07C227/42 ,  C07C229/30 ,  C07C303/36 ,  C07D203/20 ,  C07D203/24 ,  C07C311/19 ,  C07C229/26

摘要： An optically active amino acid derivative is produced by N-protecting an optically active 3-haloalanine derivative followed by cyclization, or cyclizing this derivative followed by N-protection to thereby give an optically active N-protected-aziridine-2-carboxylic acid derivative which is protected by a benzenesulfonyl group substituted by nitro at the 2- and/or 4-positions and then treating this product with an organic metal reagent, or by N-protecting an optically active 3-haloalanine derivative to thereby give N-protected-aziridine-2-carboxylic acid which is protected by a benzenesulfonyl group substituted by nitro at the 2- and/or 4-positions and then treating this product with an organic metal reagent. According to this process, natural and unnatural optically active amino acids can be produced from inexpensive materials by using simple procedures.

摘要翻译： 光学活性氨基酸衍生物通过N-保护光学活性3-卤代丙氨酸衍生物进行环化生成，或使该衍生物环化，接着进行N-保护，从而得到光学活性N-保护的氮丙啶-2-羧酸衍生物， 在2-和/或4-位被硝基取代的苯磺酰基保护，然后用有机金属试剂处理该产物，或通过N-保护光学活性3-卤代丙氨酸衍生物，由此得到N-保护的氮丙啶 -2-羧酸，其在2-和/或4-位被硝基取代的苯磺酰基保护，然后用有机金属试剂处理该产物。根据该方法，天然和非天然旋光氨基酸可以是 通过简单的程序从便宜的材料生产。

公开(公告)号：US20060105435A1

公开(公告)日：2006-05-18

申请号：US10515658

申请日：2003-06-05

申请人： Takahiro Ohishi ,  Hirokazu Nanba ,  Masanobu Sugawara ,  Masashi Izumida ,  Tatsuya Honda ,  Kohei Mori ,  Satohiro Yanagisawa ,  Nobuo Nagashima ,  Kenji Inoue

发明人： Takahiro Ohishi ,  Hirokazu Nanba ,  Masanobu Sugawara ,  Masashi Izumida ,  Tatsuya Honda ,  Kohei Mori ,  Satohiro Yanagisawa ,  Nobuo Nagashima ,  Kenji Inoue

IPC分类号： C12P13/12 ,  C12P17/00

CPC分类号： C12P13/12 ,  C07C319/06 ,  C07D233/76 ,  C12P17/04 ,  C12P17/10 ,  C12P41/009 ,  C07C323/58

摘要： The present invention provides a simple industrial process for producing an L- or D-optically active α-methylcysteine derivative or its salt, which is a useful pharmaceutical intermediate, from readily available, inexpensive raw materials. In a process for producing an L- or D-optically active α-methylcysteine derivative or its salt, a racemic N-carbamoyl-α-methylcysteine derivative or its salt is D-selectively cyclized with hydantoinase to produce a D-5-methyl-5-thiomethylhydantoin derivative or its salt and an N-carbamoyl-α-methyl-L-cysteine derivative or its salt, which are then subjected to deprotection of the amino group and the sulfur atom, and hydrolysis.

摘要翻译： 本发明提供了一种用于从容易得到的廉价原料生产L-或D-光学活性α-甲基半胱氨酸衍生物或其盐的简单工业方法，其是有用的药物中间体。 在制备L-或D-光学活性α-甲基半胱氨酸衍生物或其盐的方法中，外消旋的N-氨基甲酰基-α-甲基半胱氨酸衍生物或其盐与乙内酰脲酶D选择性环化以产生D-5-甲基 - 5-硫代甲基乙内酰脲衍生物或其盐和N-氨基甲酰基-α-甲基-L-半胱氨酸衍生物或其盐，然后对氨基和硫原子进行脱保护和水解。

公开(公告)号：US06998495B2

公开(公告)日：2006-02-14

申请号：US10492507

申请日：2002-10-24

申请人： Masanobu Sugawara ,  Kenji Inoue

发明人： Masanobu Sugawara ,  Kenji Inoue

IPC分类号： C07C51/36

CPC分类号： C07C67/31 ,  C07B2200/07 ,  C07C67/29 ,  C07C69/78 ,  C07C69/675

摘要： A method for producing an optically active 3,5-dihydroxyhexanoic acid derivative by stereoselectively reducing an optically active 3-oxo-5-hydroxyhexanoic acid derivative is provided. The method, which requires neither an ultralow-temperature reactor, an incubator, nor protection of the 5-position hydroxy group, is simple and economical.An optically active 3,5-dihydroxyhexanoic acid derivative is produced by asymmetrical hydrogenation of an optically active 3-oxo-5-hydroxyhexanoic acid derivative catalyzed by an RuBr2BINAP complex prepared from a ruthenium complex and a ruthenium-optically active phosphine complex, i.e., 2,2′-bisdiarylphosphino-1,1′-binaphthyl (BINAP), while using extremely inexpensive hydrogen as the reductant.

摘要翻译： 提供了通过立体选择性还原旋光性3-氧代-5-羟基己酸衍生物制备光学活性3,5-二羟基己酸衍生物的方法。 既不需要超低温反应器，培养箱也不需要保护5位羟基的方法简单经济。

公开(公告)号：US06281379B1

公开(公告)日：2001-08-28

申请号：US09578446

申请日：2000-05-26

申请人： Akio Fujii ,  Masanobu Sugawara ,  Kenji Inoue

发明人： Akio Fujii ,  Masanobu Sugawara ,  Kenji Inoue

IPC分类号： C07C22900

CPC分类号： C07C227/16 ,  C07B2200/07 ,  C07C227/02 ,  C07C227/18 ,  C07C227/32 ,  C07C315/04 ,  C07C317/28 ,  C07C229/34

摘要： This invention to provide a process for producing an optically active threo-phenylnorstatin derivative which does not require a toxic cyanating agent or a costly reagent, or a complicated procedure, and can be practiced on a commercial scale. This invention is directed to a process for producing a &bgr;-amino-&agr;-hydroxy acid derivative which comprises treating either a &ggr;-amino-&bgr;-keto sulfoxide derivative with a halogenating agent to produce a &ggr;-amino-&agr;-halo-&bgr;-keto sulfoxide derivative, treating the same with an acid and an alcohol to produce a &bgr;-amino-&agr;-keto ester derivative or &bgr;-amino-&agr;-keto acid derivative, and followed by reducing.

摘要翻译： 本发明提供一种不需要有毒的氰化剂或昂贵的试剂的光学活性的苏氨酸苯基抑制素衍生物的制备方法或复杂的方法，并且可以以商业规模实施。本发明涉及一种用于 产生β-氨基-α-羟基酸衍生物，其包括用卤化剂处理γ-氨基-β-酮亚砜衍生物以产生γ-氨基-α-卤代-β-酮亚砜衍生物，用 酸和醇，生成β-氨基-α-酮酯衍生物或β-氨基-α-酮酸衍生物，然后还原。

公开(公告)号：US20100197934A1

公开(公告)日：2010-08-05

申请号：US12757947

申请日：2010-04-09

申请人： Takahiro Ohishi ,  Hirokazu Nanba ,  Masanobu Sugawara ,  Masashi Izumida ,  Tatsuya Honda ,  Kohei Mori ,  Satohiro Yanagisawa ,  Nobuo Nagashima ,  Kenji Inoue

发明人： Takahiro Ohishi ,  Hirokazu Nanba ,  Masanobu Sugawara ,  Masashi Izumida ,  Tatsuya Honda ,  Kohei Mori ,  Satohiro Yanagisawa ,  Nobuo Nagashima ,  Kenji Inoue

IPC分类号： C12P17/10 ,  C12P13/12 ,  C07C321/00 ,  C07D233/02

CPC分类号： C12P13/12 ,  C07C319/06 ,  C07D233/76 ,  C12P17/04 ,  C12P17/10 ,  C12P41/009 ,  C07C323/58

摘要： The present invention provides a simple industrial process for producing an L- or D-optically active α-methylcysteine derivative or its salt, which is a useful pharmaceutical intermediate, from readily available, inexpensive raw materials. In a process for producing an L- or D-optically active α-methylcysteine derivative or its salt, a racemic N-carbamoyl-α-methylcysteine derivative or its salt is D-selectively cyclized with hydantoinase to produce a D-5-methyl-5-thiomethylhydantoin derivative or its salt and an N-carbamoyl-α-methyl-L-cysteine derivative or its salt, which are then subjected to deprotection of the amino group and the sulfur atom, and hydrolysis.

摘要翻译： 本发明提供了一种简单的工业方法，用于从容易获得的便宜的原料制备作为有用的药物中间体的L-或D-光学活性的α-甲基半胱氨酸衍生物或其盐。 在制备L-或D-光学活性α-甲基半胱氨酸衍生物或其盐的方法中，外消旋的N-氨基甲酰基-α-甲基半胱氨酸衍生物或其盐与乙内酰脲酶D选择性环化以产生D-5-甲基 - 5-硫代甲基乙内酰脲衍生物或其盐和N-氨基甲酰基-α-甲基-L-半胱氨酸衍生物或其盐，然后进行氨基和硫原子的脱保护和水解。

公开(公告)号：US20060051846A1

公开(公告)日：2006-03-09

申请号：US10526888

申请日：2003-08-27

申请人： Takahiro Ohishi ,  Hirokazu Nanba ,  Masanobu Sugawara ,  Masashi Izumida ,  Tatsuya Honda ,  Kouhei Mori ,  Satohiro Yanagisawa ,  Kenji Inoue

发明人： Takahiro Ohishi ,  Hirokazu Nanba ,  Masanobu Sugawara ,  Masashi Izumida ,  Tatsuya Honda ,  Kouhei Mori ,  Satohiro Yanagisawa ,  Kenji Inoue

IPC分类号： C12P17/16

CPC分类号： C12P17/10 ,  C07B2200/07 ,  C07C319/06 ,  C07C319/14 ,  C07C323/58 ,  C07C327/34 ,  C07D233/76 ,  C12P41/009

摘要： A process for easily producing an L-α-methylcysteine derivative or its salt, which is useful as a drug intermediate, from a cheap easily procurable raw material through an enzymatic D-stereoselective hydrolysis of racemic 5-halomethyl-5-methyl-hydantoin. L-α-methylcysteine derivative or its salt is produced by converting racemic 5-halomethyl-5-methylhydantoin to L-5-halomethyl-5-methylhydantoin through an enzymatic D-stereoselective hydrolysis, reacting the L-5-halomethyl-5-methylhydantoin with a sulfurizing agent into L-5-methyl-5-thiomethylhydantoin and hydrolyzing the L-5-methyl-5-thiomethylhydantoin.

摘要翻译： 通过外消旋5-卤代甲基-5-甲基乙内酰脲的酶促D-立体选择性水解，从便宜的可原始的原料容易地制备可用作药物中间体的L-α-甲基半胱氨酸衍生物或其盐的方法。 通过酶促D-立体选择性水解将外消旋5-卤代甲基-5-甲基乙内酰脲转化为L-5-卤代甲基-5-甲基乙内酰脲来制备L-α-甲基半胱氨酸衍生物或其盐，使L-5-卤代甲基-5-甲基乙内酰脲 用硫化剂加入到L-5-甲基-5-硫代甲基乙内酰脲中并水解L-5-甲基-5-硫代甲基乙内酰脲。

公开(公告)号：US07109352B2

公开(公告)日：2006-09-19

申请号：US10716430

申请日：2003-11-20

申请人： Masanobu Sugawara ,  Akio Fujii ,  Kazumi Okuro ,  Yasuhiro Saka ,  Nobuo Nagashima ,  Kenji Inoue ,  Toshihiro Takeda ,  Koichi Kinoshita ,  Tadashi Moroshima ,  Yoshihide Fuse ,  Yasuyoshi Ueda

发明人： Masanobu Sugawara ,  Akio Fujii ,  Kazumi Okuro ,  Yasuhiro Saka ,  Nobuo Nagashima ,  Kenji Inoue ,  Toshihiro Takeda ,  Koichi Kinoshita ,  Tadashi Moroshima ,  Yoshihide Fuse ,  Yasuyoshi Ueda

IPC分类号： C07D203/02 ,  C07D203/08

CPC分类号： C07D203/08 ,  C07B2200/07 ,  C07C227/10 ,  C07C227/32 ,  C07C227/42 ,  C07C229/30 ,  C07C303/36 ,  C07D203/20 ,  C07D203/24 ,  C07C311/19 ,  C07C229/26

摘要： An optically active amino acid derivative is produced by N-protecting an optically active 3-haloalanine derivative followed by cyclization, or cyclizing this derivative followed by N-protection to thereby give an optically active N-protected-aziridine-2-carboxylic acid derivative which is protected by a benzenesulfonyl group substituted by nitro at the 2- and/or 4-positions and then treating this product with an organic metal reagent, or by N-protecting an optically active 3-haloalanine derivative to thereby give N-protected-aziridine-2-carboxylic acid which is protected by a benzenesulfonyl group substituted by nitro at the 2- and/or 4-positions and then treating this product with an organic metal reagent. According to this process, natural and unnatural optically active amino acids can be produced from inexpensive materials by using simple procedures.

摘要翻译： 光学活性氨基酸衍生物是通过N-保护光学活性3-卤代丙氨酸衍生物进行环化，或环化该衍生物进行N-保护而得到光学活性N-保护的氮丙啶-2-羧酸衍生物 在2-和/或4-位被硝基取代的苯磺酰基保护，然后用有机金属试剂处理该产物，或通过N-保护光学活性3-卤代丙氨酸衍生物，由此得到N-保护的氮丙啶 -2-羧酸，其在2-和/或4-位被硝基取代的苯磺酰基保护，然后用有机金属试剂处理该产物。 根据该方法，可以通过简单的方法从便宜的材料制备天然和非天然旋光氨基酸。

公开(公告)号：US20050143586A1

公开(公告)日：2005-06-30

申请号：US10716430

申请日：2003-11-20

申请人： Masanobu Sugawara ,  Akio Fujii ,  Kazumi Okuro ,  Yasuhiro Saka ,  Nobuo Nagashima ,  Kenji Inoue ,  Toshihiro Takeda ,  Koichi Kinoshita ,  Tadashi Moroshima ,  Yoshihide Fuse ,  Yasuyoshi Ueda

发明人： Masanobu Sugawara ,  Akio Fujii ,  Kazumi Okuro ,  Yasuhiro Saka ,  Nobuo Nagashima ,  Kenji Inoue ,  Toshihiro Takeda ,  Koichi Kinoshita ,  Tadashi Moroshima ,  Yoshihide Fuse ,  Yasuyoshi Ueda

IPC分类号： C07C227/10 ,  C07C227/32 ,  C07C227/42 ,  C07C229/26 ,  C07C229/30 ,  C07C303/36 ,  C07C311/19 ,  C07D203/08 ,  C07D203/20 ,  C07D203/24 ,  C07D203/16

CPC分类号： C07D203/08 ,  C07B2200/07 ,  C07C227/10 ,  C07C227/32 ,  C07C227/42 ,  C07C229/30 ,  C07C303/36 ,  C07D203/20 ,  C07D203/24 ,  C07C311/19 ,  C07C229/26

摘要： An optically active amino acid derivative is produced by N-protecting an optically active 3-haloalanine derivative followed by cyclization, or cyclizing this derivative followed by N-protection to thereby give an optically active N-protected-aziridine-2-carboxylic acid derivative which is protected by a benzenesulfonyl group substituted by nitro at the 2- and/or 4-positions and then treating this product with an organic metal reagent, or by N-protecting an optically active 3-haloalanine derivative to thereby give N-protected-aziridine-2-carboxylic acid which is protected by a benzenesulfonyl group substituted by nitro at the 2- and/or 4-positions and then treating this product with an organic metal reagent. According to this process, natural and unnatural optically active amino acids can be produced from inexpensive materials by using simple procedures.

摘要翻译： 光学活性氨基酸衍生物通过N-保护光学活性3-卤代丙氨酸衍生物进行环化生成，或使该衍生物环化，接着进行N-保护，从而得到光学活性N-保护的氮丙啶-2-羧酸衍生物， 在2-和/或4-位被硝基取代的苯磺酰基保护，然后用有机金属试剂处理该产物，或通过N-保护光学活性3-卤代丙氨酸衍生物，由此得到N-保护的氮丙啶 -2-羧酸，其在2-和/或4-位被硝基取代的苯磺酰基保护，然后用有机金属试剂处理该产物。 根据该方法，可以通过简单的方法从便宜的材料制备天然和非天然旋光氨基酸。

公开(公告)号：US07223859B2

公开(公告)日：2007-05-29

申请号：US10801141

申请日：2004-03-16

申请人： Tatsuyoshi Tanaka ,  Masanobu Sugawara ,  Hirofumi Maeda ,  Akira Nishiyama ,  Yoshihiko Yasohara ,  Nobuo Nagashima

发明人： Tatsuyoshi Tanaka ,  Masanobu Sugawara ,  Hirofumi Maeda ,  Akira Nishiyama ,  Yoshihiko Yasohara ,  Nobuo Nagashima

IPC分类号： C07D205/02 ,  C07C233/00

CPC分类号： C07D205/08 ,  C07C231/02 ,  C07C309/66 ,  C07C309/73

摘要： The present invention provides a method for easily producing an (R)-3-[4-(trifluoromethyl)phenylamino]-pentanoic acid amide derivative useful for an intermediate for pharmaceutical products, particularly an inhibitor of a cholesteryl ester transfer protein (CETP) from easily available raw materials. In the present invention, (S)-N-[4-(trifluoromethyl)phenyl]-3-hydroxypentanoic acid amide prepared from easily available raw materials leads a production of (R)-4-ethyl-1-[4-(trifluoromethyl)phenyl]-2-azetidinone to give (R)-3-[4-(trifluoromethyl)phenylamino]-pentanoic acid amide. Furthermore, (R)-4-ethyl-1-[4-(trifluoromethyl)phenyl]-2-azetidinone is reacted with a carbamic acid ester to give an (R)-3-[4-(trifluoromethyl)phenylamino]-pentanoic acid amide derivative.

摘要翻译： 本发明提供了一种容易地制备用于药物产品中间体（特别是胆固醇酯转移蛋白（CETP）抑制剂）的（R）-3- [4-（三氟甲基）苯基氨基] - 戊酸酰胺衍生物的方法， 容易获得的原料。 在本发明中，由容易获得的原料制备的（S）-N- [4-（三氟甲基）苯基] -3-羟基戊酸酰胺导致（R）-4-乙基-1- [4-（三氟甲基） ）苯基] -2-氮杂环丁酮，得到（R）-3- [4-（三氟甲基）苯基氨基] - 戊酸酰胺。 此外，将（R）-4-乙基-1- [4-（三氟甲基）苯基] -2-氮杂环丁酮与氨基甲酸酯反应，得到（R）-3- [4-（三氟甲基）苯基氨基] - 戊酸 酰胺衍生物。