公开(公告)号：US4914199A

公开(公告)日：1990-04-03

申请号：US156873

申请日：1988-02-18

申请人： Isao Sada ,  Kazunori Kan ,  Noboru Ueyama ,  Shingo Matsumoto ,  Takehisa Ohashi ,  Kiyoshi Watanabe

发明人： Isao Sada ,  Kazunori Kan ,  Noboru Ueyama ,  Shingo Matsumoto ,  Takehisa Ohashi ,  Kiyoshi Watanabe

IPC分类号： C07D205/08 ,  C07F7/18

CPC分类号： C07F7/186 ,  C07D205/08 ,  Y02P20/55

摘要： A process for preparing a 4-acetoxy-3-hydroxyethylazetidin-2-one derivative having the formula (II): ##STR1## wherein R.sup.1 is a protective group for the hydroxyl group, which comprises reactig a .beta.-lactam compound having the formula (I): ##STR2## wherein R.sup.1 is as difined above and R.sup.2, R.sup.3 and R.sup.4 are the same or different and each is a lower alkyl group having 1 to 4 carbon atoms or an aralkyl group, with acetic anhydride in the presence of a base and a catalyst selected from the group consisting of an organic strong acid, a mineral acid, a Lewis acid, a halogenated acyl compound having the formula (IV):R.sup.8 --CO--X (IV)wherein R.sup.8 is an alkyl group, an aralkyl group or phenyl group and X is a halogen atom, a halogenated sulfonyl compound having the formula (V):R.sup.9 --SO.sub.2 --X (V)wherein R.sup.9 is an alkyl group, an aralkyl group or phenyl group and X is a halogen atom, and a compound having the formula (VI):(R.sup.10).sub.4-n --Si(X').sub.n (VI)wherein R.sup.10 is a lower alkyl group having 1 to 6 carbon atoms or phenyl group, X' is a halogen atom or CF.sub.3 SO.sub.2 O group and n is an integer of 1 to 4. According to the present invention, there can be obtained 4-acetoxy-3-hydroxyethylazetidin-2-one derivatives, which are useful intermediates for preparing carbapenem .beta.-lactam antibiotics, in high yield.

公开(公告)号：US4914200A

公开(公告)日：1990-04-03

申请号：US309935

申请日：1989-02-14

申请人： Kazunori Kan ,  Noboru Ueyama ,  Isao Sada ,  Takehisa Ohashi ,  Kiyoshi Watanabe

发明人： Kazunori Kan ,  Noboru Ueyama ,  Isao Sada ,  Takehisa Ohashi ,  Kiyoshi Watanabe

IPC分类号： C07D205/08 ,  C07F7/18

CPC分类号： C07D205/08 ,  C07F7/186 ,  Y02P20/55

摘要： A process for preparing a 4-acetoxy-3-hydroxyethylazetidin-2-one derivative having the formula (II): ##STR1## wherein R.sup.1 is a protective group for the hydroxyl group, which comprises reacting a .beta.-lactam compound having the formula (I): ##STR2## wherein R.sup.1 is as defined above, and R.sup.2, R.sup.3 and R.sup.4 are a lower alkyl group having 1 to 6 carbon atoms, phenyl group or an aralkyl group, with acetic anhydride in an organic solvent in the presence of a low concentration of a substituted pyridine. According to the present invention, there can be obtained 4-acetoxy-3-hydroxyethylazetidin-2-one derivatives, which are useful intermediates for preparing carbapenem .beta.-lactam antibiotics.

公开(公告)号：US4791198A

公开(公告)日：1988-12-13

申请号：US810

申请日：1987-01-06

申请人： Takehisa Ohashi ,  Kazunori Kan ,  Noboru Ueyama ,  Isao Sada ,  Akimasa Miyama ,  Kiyoshi Watanabe

发明人： Takehisa Ohashi ,  Kazunori Kan ,  Noboru Ueyama ,  Isao Sada ,  Akimasa Miyama ,  Kiyoshi Watanabe

IPC分类号： C07D205/08 ,  C07F7/18

CPC分类号： C07D205/08 ,  C07F7/186

摘要： The present invention relates to .beta.-lactam compound having the formula (I): ##STR1## wherein R.sup.1 is a trialkylsilyl group, dimethyl-1,1,2-trimethylpropylsilyl group, acetyl group, benzyloxycarbonyl group, O-nitrobenzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group or t-butyl group, R.sup.2, R.sup.3 and R.sup.4 are a member selected from the group consisting of a lower alkyl group having 1 to 6 carbon atoms, phenyl group and an aralkyl group and a process for preparing the compound which comprises reacting enolsilylethers having the formula (III): ##STR2## wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as above, with chlorosulfonylisocyanate and then reducing the obtained product. The .beta.-lactam compound of the present invention is a useful intermediate for preparing carbapenem .beta.-lactam compound.

摘要翻译： 本发明涉及具有式（I）的β-内酰胺化合物：其中R1是三烷基甲硅烷基，二甲基-1,1,2-三甲基丙基甲硅烷基，乙酰基，苄氧基羰基，O-硝基苄氧基羰基 对硝基苄氧羰基或叔丁基，R2，R3和R4是选自具有1至6个碳原子的低级烷基，苯基和芳烷基的成员，以及制备该化合物的方法 包括使具有式（III）的烯醇醚：其中R 1，R 2，R 3和R 4如上所述与式（III）化合物反应，得到产物。 本发明的β-内酰胺化合物是制备碳青霉烯类β-内酰胺化合物的有用中间体。

公开(公告)号：US4861877A

公开(公告)日：1989-08-29

申请号：US809

申请日：1987-01-06

申请人： Takehisa Ohashi ,  Kazunori Kan ,  Noboru Ueyama ,  Isao Sada ,  Akimasa Miyama ,  Kiyoshi Watanabe

发明人： Takehisa Ohashi ,  Kazunori Kan ,  Noboru Ueyama ,  Isao Sada ,  Akimasa Miyama ,  Kiyoshi Watanabe

IPC分类号： C07D205/08 ,  C07F7/18

CPC分类号： C07D205/08 ,  C07F7/186 ,  Y02P20/55

摘要： A process for preparing a 4-acetoxy-3-hydroxyethylazetidin-2-one derivative having the formula (II): ##STR1## wherein R.sup.1 is a protective group for the hydroxyl group, which comprises reacting a .beta.-lactam compound having the formula (I): ##STR2## wherein R.sup.1 is as defined above, R.sup.2, R.sup.3 and R.sup.4 are a lower alkyl group having 1 to 6 carbon atoms, phenyl group or an aralkyl group and R is a protective group for N, with acetic anhydride in an organic solvent in the presence of a base, and removing the protective group for N.4-Acetoxy-3-hydroxyethylazetidin-2-one derivatives are useful intermediates for preparing carbapenem .beta.-lactam antibiotics such as thienamycin and penem .alpha.-lactam antibiotics.

摘要翻译： 制备具有式（II）的4-乙酰氧基-3-羟乙基氮杂环丁-2-酮衍生物的方法：其中R1是羟基的保护基，其包括使具有 式（I）：其中R 1如上定义，其中R 1，R 3和R 4为具有1至6个碳原子的低级烷基，苯基或芳烷基，R为N的保护基 在乙酸酐的存在下，在有机溶剂中，在碱的存在下，除去N-（4-乙酰氧基-3-羟乙基氮杂环丁烷-2-酮）衍生物的保护基是制备碳青霉烯类β-内酰胺抗生素如噻吩霉素和青霉素的有用中间体 α-内酰胺抗生素。

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。

公开(公告)号：US4384139A

公开(公告)日：1983-05-17

申请号：US294028

申请日：1981-08-18

申请人： Takehisa Ohashi ,  Masami Shimazaki ,  Kenji Nomura ,  Kazunori Kan ,  Kiyoshi Watanabe

发明人： Takehisa Ohashi ,  Masami Shimazaki ,  Kenji Nomura ,  Kazunori Kan ,  Kiyoshi Watanabe

IPC分类号： C07B53/00 ,  C07B31/00 ,  C07C53/19 ,  C07C53/50 ,  C07C67/00 ,  C07C313/00 ,  C07C319/02 ,  C07C319/14 ,  C07C323/52 ,  C07C51/363

CPC分类号： C07C53/50 ,  C07C323/00 ,  C07C53/19

摘要： A process is disclosed wherein an optically active .beta.-mercaptoalkanoic acid represented by formula (I): ##STR1## wherein R.sub.1 is lower alkyl having from 1 to 4 carbon atoms, is prepared by(1) reacting an optically active .beta.-hydroxyalkanoic acid represented by formula (II): ##STR2## wherein R.sub.1 is the same as defined above, with a halogenating reagent to prepare an optically active .beta.-haloalkanoyl halide represented by formula (III): ##STR3## wherein X is halogen and R.sub.1 is the same as defined above; (2) reacting the .beta.-haloalkanoyl halide with water or an aqueous alkaline solution to prepare an optically active .beta.-haloalkanoic acid represented by formula (IV): ##STR4## wherein X and R.sub.1 are each the same as defined above, or a salt thereof, respectively; and(3) reacting the .beta.-haloalkanoic acid or the salt thereof with a reagent capable of converting the halogen into the thiol group, the configuration of the compound (II), (III), and (IV) being retained throughout the process to prepare the compound represented by formula (I). The product of the present invention is useful as an intermediate for preparation of an antihypertensive agent such as N-(3-mercapto-2-D-methylpropanoyl)-L-proline.

摘要翻译： 公开了一种方法，其中式（I）表示的光学活性β-巯基链烷酸：其中R1是具有1-4个碳原子的低级烷基，其通过以下步骤制备：（1）使光学活性β- （II）表示的羟基链烷酸：其中R1与上述定义相同，与卤化试剂反应，制备式（III）表示的光学活性β-卤代烷酰基卤化物：（III） 其中X是卤素且R 1与上述定义相同; （2）使β-卤代烷酰基卤化物与水或碱性水溶液反应以制备由式（Ⅳ）表示的光学活性β-卤代链烷酸：其中X和R 1各自与上述定义相同， 或其盐; 和（3）使β-卤代烷酸或其盐与能够将卤素转化成硫醇基的试剂反应，化合物（II），（III）和（IV）的构型在整个过程中被保留 制备由式（I）表示的化合物。 本发明的产品可用作制备抗高血压药如N-（3-巯基-2-D-甲基丙酰基）-L-脯氨酸的中间体。

公开(公告)号：US4371699A

公开(公告)日：1983-02-01

申请号：US214780

申请日：1980-12-09

申请人： Takehisa Ohashi ,  Masami Shimazaki ,  Kazunori Kan ,  Hideo Kondo ,  Kiyoshi Watanabe

发明人： Takehisa Ohashi ,  Masami Shimazaki ,  Kazunori Kan ,  Hideo Kondo ,  Kiyoshi Watanabe

IPC分类号： C07C51/60 ,  C07D207/16 ,  C07D211/60 ,  C07D277/06 ,  C07K5/078

CPC分类号： C07K5/06165 ,  C07C51/60 ,  C07D207/16 ,  C07D211/60 ,  C07D277/06

摘要： A process is disclosed wherein an optically active N-mercaptoalkanoylamino acid is prepared by(1) reacting an optically active .beta.-hydroxyalkanoic acid, with a halogenating reagent to prepare an optically active .beta.-haloalkanoyl halide(2) reacting the .beta.-haloalkanoyl halide with an amino acid to produce an optically active N-.beta.-haloalkanoylamino acid and(3) reacting the N-.beta.-haloalkanoylamino acid with a reagent capable of converting the halogen into the thiol group, the configuration of the formulas (II), (III), (IV), (V), and (VI) being retained in all the optically active compounds throughout the process to prepare the compound represented by formula (I). The product of the present invention, for example, N-(3-mercapto-2-D-methylpropanoyl)-L-proline inhibits the enzymatic conversion of angiotensin I into angiotensin II and therefore is useful for relieving angiotensin-related hypertension.

摘要翻译： 公开了一种方法，其中光学活性N-巯基烷酰基氨基酸通过（1）使光学活性β-羟基链烷酸与卤化试剂反应制备光学活性β-卤代烷酰基卤化物（2）使β-卤代烷酰卤与 氨基酸以产生光学活性的N-β-卤代烷酰基氨基酸和（3）使N-β-卤代烷酰基氨基酸与能够将卤素转化成硫醇基团的试剂反应，式（II），（III ），（IV），（V）和（VI）在整个过程中保留在所有光学活性化合物中以制备由式（I）表示的化合物。 本发明的产物，例如N-（3-巯基-2-D-甲基丙酰基）-L-脯氨酸抑制血管紧张素I的酶促转化为血管紧张素II，因此可用于缓解血管紧张素相关的高血压。

公开(公告)号：US5616726A

公开(公告)日：1997-04-01

申请号：US392826

申请日：1995-06-21

申请人： Masaru Mitsuda ,  Shigeo Hayashi ,  Junzo Hasegawa ,  Noboru Ueyama ,  Takehisa Ohashi ,  Masakatsu Shibasaki

发明人： Masaru Mitsuda ,  Shigeo Hayashi ,  Junzo Hasegawa ,  Noboru Ueyama ,  Takehisa Ohashi ,  Masakatsu Shibasaki

IPC分类号： C07C213/02 ,  C07C215/28 ,  C07C227/02 ,  C07C229/34 ,  C07C269/02 ,  C07C271/16

CPC分类号： C07C269/02 ,  C07C213/02 ,  C07C215/28 ,  C07C227/02 ,  C07C229/34 ,  C07C271/16 ,  Y02P20/55

摘要： An object of the present invention is to provide a safe method of commercially producing optically active aminoalcohol derivatives, which serve as intermediates for the synthesis of medicinal chemicals such as the immunopotentiating anticancer agent bestatin, in a simple and easy manner in high yields and with high levels of selectivity.The present invention consists in a method of producing 3-amino-1-nitro-4-phenyl-2-butanol derivatives of the general formula (1) ##STR1## wherein R.sup.1 and R.sup.2 each independently represents a hydrogen atom or an amino group protecting group, and a method of producing 3-amino-2-hydroxy-4-phenylbutyric acid derivatives derivable therefrom.

摘要翻译： PCT No.PCT / JP94 / 01049 Sec。 371日期：1995年6月21日 102（e）1995年6月21日PCT PCT 1994年6月29日PCT公布。 出版物WO95 / 01323 日本1995年1月12日本发明的目的是提供一种安全的商业生产光学活性氨基醇衍生物的方法，其用作合成药物的中间体，例如免疫增强抗癌药的美白蛋白，简单易用 高产量和高选择性。 本发明在于制备通式（1）的3-氨基-1-硝基-4-苯基-2-丁醇衍生物的方法，其中R1和R2各自独立地表示氢原子或 氨基保护基，以及由其衍生的3-氨基-2-羟基-4-苯基丁酸衍生物的方法。

公开(公告)号：USRE36718E

公开(公告)日：2000-05-30

申请号：US280853

申请日：1999-03-30

申请人： Masaru Mitsuda ,  Shigeo Hayashi ,  Junzo Hasegawa ,  Noboru Ueyama ,  Takehisa Ohashi ,  Masakatsu Shibasaki

发明人： Masaru Mitsuda ,  Shigeo Hayashi ,  Junzo Hasegawa ,  Noboru Ueyama ,  Takehisa Ohashi ,  Masakatsu Shibasaki

IPC分类号： C07C213/02 ,  C07C215/28 ,  C07C227/02 ,  C07C229/34 ,  C07C269/02 ,  C07C271/16

CPC分类号： C07C269/02 ,  C07C213/02 ,  C07C215/28 ,  C07C227/02 ,  C07C229/34 ,  C07C271/16 ,  Y02P20/55

摘要： An object of the present invention is to provide a safe method of commercially producing optically active aminoalcohol derivatives, which serve as intermediates for the synthesis of medicinal chemicals such as the immunopotentiating anticancer agent bestatin, in a simple and easy manner in high yields and with high levels of selectivity.The present invention consists in a method of producing 3-amino-1-nitro-4-phenyl-2-butanol derivatives of the general formula (1) ##STR1## wherein R.sup.1 and R.sup.2 each independently represents a hydrogen atom or an amino group protecting group, and a method of producing 3-amino-2-hydroxy-4-phenylbutyric acid derivatives derivable therefrom.

摘要翻译： PCT No.PCT / JP94 / 01049 Sec。 371日期：1995年6月21日 102（e）1995年6月21日PCT PCT 1994年6月29日PCT公布。 出版物WO95 / 01323 日本1995年1月12日本发明的目的是提供一种安全的商业生产光学活性氨基醇衍生物的方法，其用作合成药物的中间体，例如免疫增强抗癌药的美白蛋白，简单易用 高产量和高选择性。 本发明在于制备通式（1）的3-氨基-1-硝基-4-苯基-2-丁醇衍生物的方法，其中R 1和R 2各自独立地表示氢原子或氨基保护基，和 制备可从其衍生的3-氨基-2-羟基-4-苯基丁酸衍生物的方法。

公开(公告)号：US4898822A

公开(公告)日：1990-02-06

申请号：US846436

申请日：1986-03-31

申请人： Masanori Asada ,  Shigeki Hamaguchi ,  Hidetoshi Katsuki ,  Yoshio Nakamura ,  Hideyuki Takahashi ,  Kenji Takahara ,  Yoshio Shimada ,  Takehisa Ohashi ,  Kiyoshi Watanabe

发明人： Masanori Asada ,  Shigeki Hamaguchi ,  Hidetoshi Katsuki ,  Yoshio Nakamura ,  Hideyuki Takahashi ,  Kenji Takahara ,  Yoshio Shimada ,  Takehisa Ohashi ,  Kiyoshi Watanabe

IPC分类号： C12P17/10 ,  C12P41/00

CPC分类号： C12P17/10 ,  C12P41/005 ,  Y10S435/83 ,  Y10S435/839 ,  Y10S435/843 ,  Y10S435/874 ,  Y10S435/897 ,  Y10S435/911 ,  Y10S435/921 ,  Y10S435/925

摘要： A process for preparing optically active indoline-2-carboxylic acid by an optical resolution, which comprises subjecting a racemic ester of (R,S)-indoline-2-carboxylic acid having the general formula [(R,S)-I] to the action of an enzyme or a microorganism having a stereo-selective esterase activity, which is capable of asymmetrically hydrolyzing the racemic ester [(R,S)-I] to give optically active indoline-2-carboxylic acid having the formula [II*] so as to produce the hydrolysis product, i.e. optically active indoline-2-carboxylic acid [II*] and an unreacted optically active ester of indoline-2-carboxylic acid having the general formula [I*], isolating each optically active form, and further, if necessary, hydrolyzing the obtained optically active ester [I*] to give an optical antipode of the acid [II*].According to the process of the present invention, optically active indoline-2-carboxylic acid with a high optical purity can be prepared in a simple process with a good yield.

摘要翻译： 通过光学拆分制备光学活性二氢吲哚-2-羧酸的方法，其包括使具有通式[（R，S）-I]的（R，S） - 二氢吲哚-2-羧酸的外消旋酯与 具有立体选择性酯酶活性的酶或微生物的作用，其能够不对称地水解外消旋酯[（R，S）-I]，得到具有式[II *]的光学活性二氢吲哚-2-羧酸， ]以产生水解产物，即具有通式[I *]的光学活性二氢吲哚-2-羧酸[II *]和未反应的二氢吲哚-2-羧酸的光学活性酯，分离每种光学活性形式， 此外，如果需要，水解得到的光学活性酯[I *]，得到酸[II *]的光学对映体。 根据本发明的方法，可以以简单的方法制备具有高光学纯度的光学活性二氢吲哚-2-羧酸，产率高。