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：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：US06359155B1

公开(公告)日：2002-03-19

申请号：US09719686

申请日：2001-02-15

申请人： Koichi Kinoshita ,  Tadashi Moroshima ,  Yoshifumi Yanagida ,  Nobuo Nagashima ,  Yasuhiro Saka ,  Tatsuya Honda ,  Yoshihide Fuse ,  Yasuyoshi Ueda

发明人： Koichi Kinoshita ,  Tadashi Moroshima ,  Yoshifumi Yanagida ,  Nobuo Nagashima ,  Yasuhiro Saka ,  Tatsuya Honda ,  Yoshihide Fuse ,  Yasuyoshi Ueda

IPC分类号： C07D30720

CPC分类号： C07C29/147 ,  C07B2200/07 ,  C07D307/20 ,  Y02P20/55 ,  C07C31/42

摘要： An industrial advantage process for producing high-purity 3-hydroxytetrahydrofuran easily and simply, which comprises reducing a 4-halo-3-hydroxybutyric acid ester (1) with a boron hydride compound and/or an aluminum hydride compound as a reducing agent in an organic solvent immiscible with water; treating the reaction mixture with an acid and water to thereby effect conversion to the corresponding 4-halo-1,3-butanediol and at the same time giving an aqueous solution containing said compound; carrying out the cyclization reaction of the 4-halo-1,3-butanediol in said aqueous solution; extracting the resulting 3-hydroxytetrahydrofuran from the 3-hydroxytetrahydrofuran-containing aqueous solution using an organic solvent immiscible with water; and isolating the 3-hydroxytetrahydrofuran by concentration and/or distillation of the solution obtained.

摘要翻译： 用于容易且简单地生产高纯度3-羟基四氢呋喃的工业优势方法，其包括用硼氢化合物和/或氢化铝化合物作为还原剂还原4-卤代-3-羟基丁酸酯（1） 与水不混溶的有机溶剂;用酸和水处理反应混合物，从而转化为相应的4-卤代-1,3-丁二醇，同时得到含有所述化合物的水溶液;进行环化反应 所述水溶液中的4-卤代-1,3-丁二醇;使用与水不混溶的有机溶剂从含3-羟基四氢呋喃的水溶液中萃取所得3-羟基四氢呋喃; 通过所得溶液的浓缩和/或蒸馏来使3-羟基四氢呋喃分离。

公开(公告)号：US20060089503A1

公开(公告)日：2006-04-27

申请号：US10540023

申请日：2003-12-10

申请人： Takahiro Ohishi ,  Kohei Mori ,  Koichi Kinoshita ,  Katsuji Maehara ,  Hiroaki Kawasaki ,  Nobuo Nagashima ,  Yoshihide Fuse

发明人： Takahiro Ohishi ,  Kohei Mori ,  Koichi Kinoshita ,  Katsuji Maehara ,  Hiroaki Kawasaki ,  Nobuo Nagashima ,  Yoshihide Fuse

IPC分类号： C07D305/12 ,  C07D405/02

CPC分类号： C07D305/12 ,  C07C319/14 ,  C07D317/60 ,  C07D407/06 ,  C07C323/56

摘要： The present invention provides a process for simply producing an optically active 2-thiomethyl-3-phenylpropionic acid derivative useful as an intermediate for medicines from inexpensive raw materials. An optically active 2-hydroxymethyl-3-phenylpropionic acid ester derivative which can be relatively easily obtained by asymmetric reduction reaction with an enzyme is cyclized to an optically active P-lactone derivative which is then reacted with a sulfur compound to produce an optically active 2-thiomethyl-3-phenylpropionic acid derivative in high yield.

摘要翻译： 本发明提供简单地生产用作廉价原料的药物中间体的光学活性2-硫代甲基-3-苯基丙酸衍生物的方法。 可以通过与酶的不对称还原反应相对容易地获得的光学活性的2-羟甲基-3-苯基丙酸酯衍生物环化成光学活性的P-内酯衍生物，然后与硫化合物反应以产生光学活性2 硫代甲基-3-苯基丙酸衍生物。

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：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：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。

公开(公告)号：US06747161B2

公开(公告)日：2004-06-08

申请号：US10182649

申请日：2002-11-01

申请人： Yasuhiro Saka ,  Tatsuya Honda ,  Nobuo Nagashima

发明人： Yasuhiro Saka ,  Tatsuya Honda ,  Nobuo Nagashima

IPC分类号： C07D20500

CPC分类号： C07D205/04

摘要： The invention provides a process for producing optically active azetidine-2-carboxylic acid with good efficiency, expedience, and commercial advantage, which comprises cyclizing an optically active 4-amino-2-halogenobutyric acid in an optical yield of as high as 90% or more. It is a process for producing optically active azetidine-2-carboxylic acid of the general formula (2), in which * denotes an asymmetric carbon atom, which comprises cyclizing an optically active 4-amino-2-halogenobutyric acid of the general formula (1), in which X represents a halogen atom and * denotes an asymmetric carbon atom, in the presence of an oxide of an alkaline earth metal, a hydroxide of an alkaline earth metal excepting barium, or an organic amine.

摘要翻译： 本发明提供了一种以高效率，便利和商业优点制备光学活性氮杂环丁烷-2-羧酸的方法，该方法包括使光学活性4-氨基-2-卤代丁酸以高达90％的光学收率环化;或 它是制备通式（2）的光学活性氮杂环丁烷-2-羧酸的方法，其中*表示不对称碳原子，其包括使一般的光学活性4-氨基-2-卤代丁酸环化 在碱土金属的氧化物，除了钡以外的碱土金属的氢氧化物或有机胺的存在下，式（1）中X表示卤素原子，*表示不对称碳原子。

公开(公告)号：US5071966A

公开(公告)日：1991-12-10

申请号：US576499

申请日：1990-09-10

申请人： Kazunori Kan ,  Hiroshi Murakami ,  Nobuo Nagashima ,  Noboru Ueyama ,  Takehisa Ohashi

发明人： Kazunori Kan ,  Hiroshi Murakami ,  Nobuo Nagashima ,  Noboru Ueyama ,  Takehisa Ohashi

IPC分类号： C07F7/02 ,  C07F7/18

CPC分类号： C07F7/186 ,  C07F7/1852

摘要： A process for preparing an enol silyl ether compound from a diazoacetoacetic acid ester having the general formula (IV): ##STR1## wherein R.sup.1 is a lower alkyl group having 1 to 6 carbon atoms, phenyl group, a substituted phenyl group, an aralkyl group or allyl group, and R.sup.2, R.sup.3 and R.sup.4 are the same or mutually different and each is a lower alkyl group having 1 to 6 carbon atoms, which comprises reacting a diazoacetoacetic acid ester having the general formula (I): ##STR2## wherein R.sup.1 is the same as defined above, with a trialkylsilyl chloride having the general formula (II): ##STR3## wherein R.sup.2, R.sup.3 and R.sup.4 are the same as defined above, in an inert solvent in the presence of an organic base and an alkali halide having the general formula (III):MX (III)wherein M is an alkaline metal and X is bromine atom or iodine atom. The desired compound is useful as an intermediate for synthesis of carbapenem .beta.-lactam antibiotics.

摘要翻译： PCT No.PCT / JP90 / 00038 Sec。 371 1990年9月10日第 102（e）1990年9月10日PCT 1990年1月12日PCT PCT。 公开号WO90 / 08149 日本时间1990年7月26日。一种由具有通式（IV）的重氮乙酰乙酸酯制备烯醇甲硅烷基醚化合物的方法：其中R 1为具有1至6个碳原子的低级烷基，苯基 基团，取代的苯基，芳烷基或烯丙基，R 2，R 3和R 4相同或相互不同，各自为具有1至6个碳原子的低级烷基，其包括使具有一般性基团的重氮乙酰乙酸酯 式（I）：其中R 1与上述定义相同，具有通式（II）的三烷基甲硅烷基氯：其中R2，R3和R4与上述定义相同 在有机碱和具有通式（III）的碱金属卤化物存在下，在惰性溶剂中反应：其中M是碱金属，X是溴原子或碘原子的MX（III）。 所需化合物可用作合成碳青霉烯β-内酰胺抗生素的中间体。