公开(公告)号：US20050080277A1

公开(公告)日：2005-04-14

申请号：US10048553

申请日：2001-06-05

申请人： Akira Nishiyama ,  Miho Horikawa ,  Yoshihiko Yasohara ,  Noboru Ueyama ,  Kenji Inoue

发明人： Akira Nishiyama ,  Miho Horikawa ,  Yoshihiko Yasohara ,  Noboru Ueyama ,  Kenji Inoue

IPC分类号： C07D319/06 ,  C12P7/42 ,  C12P17/06

CPC分类号： C07D319/06 ,  C12P7/42 ,  C12P17/06

摘要： The present invention is to provide a production technology by which an optically active 2-[6-(hydroxymethyl)-1,3-dioxan-4-yl]acetic acid derivative, which are of value as pharmaceutical intermediates, can be produced from inexpensive and readily available starting materials without using any extraordinary equipment such as an ultra-low-temperature reactor. The present invention is a production process of an optically active 2-[6-(hydroxymethyl)-1,3-dioxan-4-yl]acetic acid derivative which comprises reacting an enolate, prepared by permitting a base or a 0-valent metal to act on an acetic acid ester derivative with (S)-β-hydroxy-γ-butyrolactone at a temperature not lower than −30° C. to give a dihydroxyoxohexanoic acid derivative, treating the same with an acylating agent in the presence of a base to produce a dihydroxyoxohexanoic acid monoacyl derivative, reducing this compound with a microorganism to produce a trihydroxyhexanoic acid monoacyl derivative, treating this compound with an acetal-forming reagent in the presence of an acid catalyst to produce an acyloxymethyldioxanylacetic acid derivative, and finally, subjecting this compound to solvolysis in the presence of a base.

摘要翻译： 本发明提供一种生产技术，通过该技术，可以以廉价的方式生产价值为医药中间体的光学活性的2- [6-（羟甲基）-1,3-二恶烷-4-基]乙酸衍生物 和容易获得的起始材料，而不使用任何非常设备，例如超低温反应器。 本发明是光学活性的2- [6-（羟甲基）-1,3-二恶烷-4-基]乙酸衍生物的制备方法，该方法包括使通过使碱或0价金属 在不低于-30℃的温度下用（S）-β-羟基-γ-丁内酯在乙酸酯衍生物上作用，得到二羟基氧代己酸衍生物，在酰化剂存在下用酰化剂处理 碱化以制备二羟基氧己基单酰基衍生物，用微生物还原该化合物以产生三羟基己酸单酰基衍生物，在酸催化剂存在下用缩醛形成试剂处理该化合物，得到酰氧基甲基二恶烷基乙酸衍生物，最后， 该化合物在碱存在下溶剂解。

公开(公告)号：US07094594B2

公开(公告)日：2006-08-22

申请号：US10048553

申请日：2001-06-05

申请人： Akira Nishiyama ,  Miho Horikawa ,  Yoshihiko Yasohara ,  Noboru Ueyama ,  Kenji Inoue

发明人： Akira Nishiyama ,  Miho Horikawa ,  Yoshihiko Yasohara ,  Noboru Ueyama ,  Kenji Inoue

IPC分类号： C12P41/00

CPC分类号： C07D319/06 ,  C12P7/42 ,  C12P17/06

摘要： The present invention is to provide a production technology by which an optically active 2-[6-(hydroxymethyl)-1, 3-dioxan-4-yl]acetic acid derivative, which are of value as pharmaceutical intermediates, can be produced from inexpensive and readily available starting materials without using any extraordinary equipment such as an ultra-low-temperature reactor.The present invention is a production process of an optically active 2-[6-(hydroxymethyl)-1,3-dioxan-4-yl]acetic acid derivative which comprises reacting an enolate, prepared by permitting a base or a 0-valent metal to act on an acetic acid ester derivative with (S)-β-hydroxy-γ-butyrolactone at a temperature not lower than −30° C. to give a dihydroxyoxohexanoic acid derivative, treating the same with an acylating agent in the presence of a base to produce a dihydroxyoxohexanoic acid monoacyl derivative, reducing this compound with a microorganism to produce a trihydroxyhexanoic acid monoacyl derivative, treating this compound with an acetal-forming reagent in the presence of an acid catalyst to produce an acyloxymethyldioxanylacetic acid derivative, and finally, subjecting this compound to solvolysis in the presence of a base.

摘要翻译： 本发明提供一种生产技术，通过该技术，可以从廉价的方式制备价值为药物中间体的光学活性的2- [6-（羟甲基）-1,3-二恶烷-4-基]乙酸衍生物 和容易获得的起始材料，而不使用任何非常设备，例如超低温反应器。 本发明是光学活性的2- [6-（羟甲基）-1,3-二恶烷-4-基]乙酸衍生物的制备方法，该方法包括使通过使碱或0价金属 在不低于-30℃的温度下用（S）-β-羟基-γ-丁内酯在乙酸酯衍生物上作用，得到二羟基氧代己酸衍生物，在酰化剂存在下用酰化剂处理 碱化以制备二羟基氧己基单酰基衍生物，用微生物还原该化合物以产生三羟基己酸单酰基衍生物，在酸催化剂存在下用缩醛形成试剂处理该化合物，得到酰氧基甲基二恶烷基乙酸衍生物，最后， 该化合物在碱存在下溶剂解。

公开(公告)号：US06903225B2

公开(公告)日：2005-06-07

申请号：US10242453

申请日：2002-09-13

申请人： Noriyuki Kizaki ,  Yukio Yamada ,  Yoshihiko Yasohara ,  Akira Nishiyama ,  Makoto Miyazaki ,  Masaru Mitsuda ,  Takeshi Kondo ,  Noboru Ueyama ,  Kenji Inoue

发明人： Noriyuki Kizaki ,  Yukio Yamada ,  Yoshihiko Yasohara ,  Akira Nishiyama ,  Makoto Miyazaki ,  Masaru Mitsuda ,  Takeshi Kondo ,  Noboru Ueyama ,  Kenji Inoue

IPC分类号： C07C67/343 ,  C07C253/30 ,  C07C255/21 ,  C07D319/06 ,  C12P7/62 ,  C12P1/04 ,  C12P17/06

CPC分类号： C07D319/06 ,  C07B2200/07 ,  C07C67/343 ,  C07C253/30 ,  C12P7/62 ,  C07C69/716 ,  C07C255/21

摘要： This invention provides a process for producing optically active 2-[6-(hydroxymethyl)-1,3-dioxan-4-yl]acetic acid derivatives, which are of value as intermediates of drugs, from inexpensive starting materials without using any special equipment such as that required for super-low temperature reactions.A process for producing optically active 2-[6-(hydroxymethyl)-1,3-dioxan-4-yl]acetic acid derivatives which comprises reacting an acetic acid derivative at a temperature of not less than −30° C. with an enolate prepared by permitting either a base or a metal having a valency of 0 to act on the derivative to produce a hydroxyoxohexanoic acid derivative, reducing this compound with the aid of a strain of microorganism to provide a halomethyldioxanylacetic acid derivative, treating this compound with an acetalizing agent in the presence of an acid catalyst to provide a halomethyl-dioxanylacetic acid derivative, reacted with an acyloxylating agent to provide a acyloxymethyldioxanylacetic acid derivative, and subjecting this compound to solvolysis in the presence of a base.

摘要翻译： 本发明提供了从廉价起始原料生产具有价值作为药物中间体的光学活性的2- [6-（羟甲基）-1,3-二恶烷-4-基]乙酸衍生物的方法，而不使用任何特殊设备 例如超低温反应所需的。 一种制备光学活性的2- [6-（羟基甲基）-1,3-二恶烷-4-基]乙酸衍生物的方法，其包括使不饱和-30℃的乙酸衍生物与烯醇化物 通过使碱金属或0价金属作用于衍生物以制备羟基己酸衍生物而制备，借助于微生物菌株还原该化合物以提供卤代甲基二恶烷基乙酸衍生物，用缩醛化处理该化合物 在酸催化剂存在下，提供卤代甲基 - 二恶烷基乙酸衍生物，与酰氧基化剂反应，得到酰氧基甲基二恶烷基乙酸衍生物，并在碱的存在下使其溶解。

公开(公告)号：US06472544B1

公开(公告)日：2002-10-29

申请号：US09509998

申请日：2000-08-16

申请人： Noriyuki Kizaki ,  Yukio Yamada ,  Yoshihiko Yasohara ,  Akira Nishiyama ,  Makoto Miyazaki ,  Masaru Mitsuda ,  Takeshi Kondo ,  Noboru Ueyama ,  Kenji Inoue

发明人： Noriyuki Kizaki ,  Yukio Yamada ,  Yoshihiko Yasohara ,  Akira Nishiyama ,  Makoto Miyazaki ,  Masaru Mitsuda ,  Takeshi Kondo ,  Noboru Ueyama ,  Kenji Inoue

IPC分类号： C07D31906

CPC分类号： C07D319/06 ,  C07B2200/07 ,  C07C67/343 ,  C07C253/30 ,  C12P7/62 ,  C07C69/716 ,  C07C255/21

摘要： This invention provides a process for producing optically active 2-[6-(hydroxymethyl)-1,3-dioxan-4-yl]acetic acid derivatives, which are of value as intermediates of drugs, from inexpensive starting materials without using any special equipment such as that required for super-low temperature reactions. A process for producing optically active 2-[6-(hydroxymethyl)-1,3-dioxan-4-yl]acetic acid derivatives which comprises reacting an acetic acid derivative at a temperature of not less than −30° C. with an enolate prepared by permitting either a base or a metal having a valency of 0 to act on the derivative to produce a hydroxyoxohexanoic acid derivative, reducing this compound with the aid of a strain of microorganism to provide a halomethyldioxanylacetic acid derivative, treating this compound with an acetalizing agent in the presence of an acid catalyst to provide a halomethyldioxanylacetic acid derivative, reacted with an acyloxylating agent to provide a acyloxymethyldioxanylacetic acid derivative, and subjecting this compound to solvolysis in the presence of a base.

摘要翻译： 本发明提供了从廉价起始原料生产具有价值作为药物中间体的光学活性的2- [6-（羟甲基）-1,3-二恶烷-4-基]乙酸衍生物的方法，而不使用任何特殊设备 例如超低温反应所需的方法。一种制备光学活性的2- [6-（羟甲基）-1,3-二恶烷-4-基]乙酸衍生物的方法，其包括在不是的温度下使乙酸衍生物反应 小于-30℃，通过使碱金属或化合价为0的金属作用于衍生物以制备羟基氧代己酸衍生物而制备的烯醇化物，借助于微生物菌株还原该化合物以提供 卤甲基二恶烷基乙酸衍生物，在酸催化剂存在下用缩醛化剂处理该化合物，得到卤代甲基二恶烷基乙酸衍生物，与酰氧基化剂反应，得到酰氧基甲基二恶烷基乙酸 在碱的存在下，将该化合物施用于溶剂分解。

公开(公告)号：US20060246557A1

公开(公告)日：2006-11-02

申请号：US11477322

申请日：2006-06-30

申请人： Akira Nishiyama ,  Miho Horikawa ,  Yoshihiko Yosohara ,  Noboru Ueyama ,  Kenji Inoue

发明人： Akira Nishiyama ,  Miho Horikawa ,  Yoshihiko Yosohara ,  Noboru Ueyama ,  Kenji Inoue

IPC分类号： C12P7/64 ,  C12P7/62 ,  C07C51/00

CPC分类号： C07D319/06 ,  C12P7/42 ,  C12P17/06

摘要： The present invention is to provide a production technology by which an optically active 2-[6-(hydroxymethyl)-1,3-dioxan-4-yl]acetic acid derivative, which are of value as pharmaceutical intermediates, can be produced from inexpensive and readily available starting materials without using any extraordinary equipment such as an ultra-low-temperature reactor. The present invention is a production process of an optically active 2-[6-(hydroxymethyl)-1,3-dioxan-4-yl]acetic acid derivative which comprises reacting an enolate, prepared by permitting a base or a 0-valent metal to act on an acetic acid ester derivative with (S)-β-hydroxy-γ-butyrolactone at a temperature not lower than −30° C. to give a dihydroxyoxohexanoic acid derivative, treating the same with an acylating agent in the presence of a base to produce a dihydroxyoxohexanoic acid monoacyl derivative, reducing this compound with a microorganism to produce a trihydroxyhexanoic acid monoacyl derivative, treating this compound with an acetal-forming reagent in the presence of an acid catalyst to produce an acyloxy-methyldioxanylacetic acid derivative, and finally, subjecting this compound to solvolysis in the presence of a base.

摘要翻译： 本发明提供一种生产技术，通过该技术，可以以廉价的方式生产价值为医药中间体的光学活性的2- [6-（羟甲基）-1,3-二恶烷-4-基]乙酸衍生物 和容易获得的起始材料，而不使用任何非常设备，例如超低温反应器。 本发明是光学活性的2- [6-（羟甲基）-1,3-二恶烷-4-基]乙酸衍生物的制备方法，该方法包括使通过使碱或0价金属 在不低于-30℃的温度下用（S）-β-羟基-γ-丁内酯在乙酸酯衍生物上作用，得到二羟基氧代己酸衍生物，在酰化剂存在下用酰化剂处理 制备二羟基氧基己酸单酰基衍生物，用微生物还原该化合物以产生三羟基己酸单酰基衍生物，在酸催化剂存在下用缩醛形成试剂处理该化合物以产生酰氧基 - 甲基二恶烷基乙酸衍生物，最后 使该化合物在碱的存在下溶剂解。

公开(公告)号：US20050153408A1

公开(公告)日：2005-07-14

申请号：US10496639

申请日：2002-11-28

申请人： Tatsuya Honda ,  Akio Fujii ,  Kenji Inoue ,  Yoshihiko Yasohara ,  Yoshifumi Itagaki ,  Katsuji Maehara ,  Toshihiro Takeda ,  Yasuyoshi Ueda

发明人： Tatsuya Honda ,  Akio Fujii ,  Kenji Inoue ,  Yoshihiko Yasohara ,  Yoshifumi Itagaki ,  Katsuji Maehara ,  Toshihiro Takeda ,  Yasuyoshi Ueda

IPC分类号： C07C213/02 ,  C07C217/74 ,  C07C303/28 ,  C07C309/66 ,  C07C309/73 ,  C12P7/42 ,  C12P7/62

CPC分类号： C12P7/42 ,  C07B2200/07 ,  C07C213/02 ,  C07C303/28 ,  C07C309/66 ,  C07C309/73 ,  C07C217/74

摘要： The present invention is to efficiently and simply prepare an optically active 7-substituted-2-aminotetralin with industrial advantage. In the process, a 7-substituted-2-tetralone or its bisulfite adduct is reduced with a microorganism to an optically active 7-substituted-2-tetralol. Then, a sulfonyl group is introduced to the hydroxy group to form an optically active 7-substituted-2-sulfonyloxytetralin. Then, with inversion of the configuration, a nitrogen substituent is introduced using a nitrogen nucleophile to form an optically active 2,7-substituted tetralin. Furthermore, if necessary, the nitrogen substituent is converted into a non-substituted amino group. Thus, an optically active 7-substituted-2-aminotetralin or its salt is prepared.

摘要翻译： 本发明是有效且简单地制备具有工业优势的光学活性7-取代-2-氨基四氢萘酚。 在此过程中，7-取代-2-四氢萘酮或其亚硫酸氢盐加合物与微生物一起还原成光学活性的7-取代-2-四氢萘酚。 然后，将磺酰基引入羟基以形成光学活性的7-取代-2-磺酰氧基四氢萘酮。 然后，通过配置的倒置，使用氮亲核试剂引入氮取代基以形成光学活性的2,7-取代的四氢化萘。 此外，如果需要，氮取代基转化为未取代的氨基。 因此，制备光学活性的7-取代-2-氨基四氢萘或其盐。

公开(公告)号：US5079382A

公开(公告)日：1992-01-07

申请号：US617345

申请日：1990-11-23

申请人： Naoaki Taoka ,  Kenji Inoue ,  Shigeo Hayashi ,  Noboru Ueyama ,  Satomi Takahashi

发明人： Naoaki Taoka ,  Kenji Inoue ,  Shigeo Hayashi ,  Noboru Ueyama ,  Satomi Takahashi

IPC分类号： C07C303/30 ,  C07C309/65 ,  C07C309/66 ,  C07C309/73 ,  C07D303/40

CPC分类号： C07D303/40 ,  C07C309/65 ,  C07C309/73

摘要： A 3,4-epoxybutyrate of the formula: ##STR1## wherein R.sup.1 is an alkyl or aralkyl group is efficiently prepared by a process comprising steps of:(a) reacting 3,4-dihydroxybutyronitrile of the formula: ##STR2## with a sulfonyl chloride of the formula: R.sup.2 --SO.sub.2 --Cl wherein R.sup.2 is an alkyl group or a phenyl group which may be substituted in the presence of a base to obtain a compound of the formula: ##STR3## (b) reacting the compound prepared in the step (a) with an alcohol of the formula: R.sup.1 --OH in the presence of an acid to obtain a compound of the formula: ##STR4## and (c) reacting the compound prepared in the step (b) with a base to obtain the 3,4-epoxybutyrate.

公开(公告)号：US5214199A

公开(公告)日：1993-05-25

申请号：US755496

申请日：1991-08-30

申请人： Teruyoshi Koga ,  Noboru Ueyama ,  Kenji Inoue ,  Satomi Takahashi

发明人： Teruyoshi Koga ,  Noboru Ueyama ,  Kenji Inoue ,  Satomi Takahashi

IPC分类号： B01J31/02 ,  C07B61/00 ,  C07C67/08 ,  C07C67/287 ,  C07C69/38 ,  C07C69/635

CPC分类号： C07C67/08

摘要： A malonic monoester is prepared in a good yield by a single step reaction by reacting malonic acid with an alcohol in the presence of a base and an activator of malonic acid selected from the group consisting of an acyl halide or halocarbonate and an acid anhydride or dicarbonate.

公开(公告)号：US4983759A

公开(公告)日：1991-01-08

申请号：US452470

申请日：1989-12-20

申请人： Kenji Inoue ,  Satomi Takahashi ,  Keiichi Yonetsu ,  Noboru Ueyama

发明人： Kenji Inoue ,  Satomi Takahashi ,  Keiichi Yonetsu ,  Noboru Ueyama

IPC分类号： B01J23/06 ,  B01J23/80 ,  C07B61/00 ,  C07C67/317 ,  C07C67/343 ,  C07C69/675 ,  C07C69/708 ,  C07C69/716 ,  C07C69/78 ,  C07C255/13 ,  C07C255/14 ,  C07D317/30 ,  C07D319/06 ,  C07D319/08 ,  C07F7/18

CPC分类号： C07D319/08 ,  C07C255/13 ,  C07C255/14 ,  C07D317/30 ,  C07D319/06 ,  Y02P20/55

摘要： A compound of a 3,5,6-trihydroxyhexanoic acid derivative of the formula: ##STR1## wherein P.sup.1 and P.sup.2 are independently hydrogen atoms or hydroxy-protecting groups, or together form a ring, and R is an alkyl group is effectively prepared by a process comprising steps of:reacting a butyronitrile derivative of the formula: ##STR2## wherein P.sup.1 and P.sup.2 are the same as defined above with an .alpha.-haloacetate of the formula:X--CH.sub.2 --COOR (III) wherein X is a halogen atom, and R is the same as defined above in the presence of a metallic catalyst selected from the group consisting zinc and zinc-copper to form a keto acid derivative of the formula: ##STR3## wherein P.sup.1, P.sup.2 and R are the same as defined above, and then reducing the obtained keto-acid derivative of the formula (IV).

公开(公告)号：US5214197A

公开(公告)日：1993-05-25

申请号：US724728

申请日：1991-07-02

申请人： Shigeo Hayashi ,  Noboru Ueyama ,  Kenji Inoue ,  Teruyoshi Koga ,  Satomi Takahashi

发明人： Shigeo Hayashi ,  Noboru Ueyama ,  Kenji Inoue ,  Teruyoshi Koga ,  Satomi Takahashi

IPC分类号： C07C69/675 ,  C07C69/738

CPC分类号： C07C69/738 ,  C07C69/675 ,  Y02P20/55

摘要： A novel 2,4-dihydroxyadipic acid derivative of the formula: ##STR1## wherein R.sup.1 and R.sup.4 are the same or different and each a hydrogen atom, an alkyl group, an aralkyl group, an aryl group or a silyl group, and R.sup.2 and R.sup.3 are the same or different and each a hydrogen atom or a protective group of a hydroxy group or together form a ring, which is useful as a common intermediate in the synthesis of HMG-CoA reductase inhibitor.