公开(公告)号：US06388086B1

公开(公告)日：2002-05-14

申请号：US09631678

申请日：2000-08-02

申请人： Akira Nishiyama ,  Kazumi Okuro ,  Kenji Inoue

发明人： Akira Nishiyama ,  Kazumi Okuro ,  Kenji Inoue

IPC分类号： C07D21330

CPC分类号： C07D213/30

摘要： A process for producing a 3-(3-pyridyl)-1-propanol derivative of use as a pharmaceutical intermediate expediently with an inexpensive material is provided. The process is concerned with a 3-(3-pyridyl)-1-propanol derivative (3): in the formula, R1 represents an alkyl group of 1 to 20 carbon atoms, aryl group of 6 to 20 carbon atoms or aralkyl group of 7 to 20 carbon atoms, which may be substituted, and comprises reacting a 3-methylpyridine with a strong base to prepare a 3-methylpyridine metal (1): in the formula, M represents lithium, sodium, potassium or a magnesium halide, where the halide is chloride or bromide, and then reacting said metal salt with an epoxy compound (2):

摘要翻译： 提供了以便宜的材料制备用作药物中间体的3-（3-吡啶基）-1-丙醇衍生物的方法。 该方法涉及3-（3-吡啶基）-1-丙醇衍生物（3）：式中，R1表示碳原子数为1〜20的烷基，碳原子数为6〜20的芳基或芳烷基 可以被取代的7至20个碳原子，并且使3-甲基吡啶与强碱反应以制备3-甲基吡啶金属（1）：在该式中，M表示锂，钠，钾或卤化镁，其中 卤化物是氯化物或溴化物，然后使所述金属盐与环氧化合物（2）反应：

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：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：US5936104A

公开(公告)日：1999-08-10

申请号：US907461

申请日：1997-08-08

申请人： Akira Nishiyama ,  Tadashi Sugawa ,  Hajime Manabe ,  Kenji Inoue ,  Noritaka Yoshida

发明人： Akira Nishiyama ,  Tadashi Sugawa ,  Hajime Manabe ,  Kenji Inoue ,  Noritaka Yoshida

IPC分类号： C07C29/143 ,  C07C45/48 ,  C07C269/06 ,  C07C319/20 ,  C07C323/43 ,  C07D303/36 ,  C07D303/38

CPC分类号： C07D303/36 ,  C07C269/06 ,  C07C29/143 ,  C07C319/20 ,  C07C45/48

摘要： The present invention provides a process for producing 1,2-epoxy-3-amino-4-phenylbutane derivatives which comprises treating a 1-halo-2-hydroxy-3-amino-4-phenylbutane derivative with a base in an aprotic polar organic solvent or a mixed solvent composed of an aprotic polar organic solvent and water and then causing the resulting epoxide to crystallize out from a mixed solvent composed of an aprotic polar organic solvent and water.

摘要翻译： 本发明提供了1,2-环氧-3-氨基-4-苯基丁烷衍生物的制备方法，其包括用非质子极性有机物中的1-卤代-2-羟基-3-氨基-4-苯基丁烷衍生物 溶剂或由非质子极性有机溶剂和水组成的混合溶剂，然后使得到的环氧化物从由非质子极性有机溶剂和水组成的混合溶剂中结晶出来。

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：US06573399B1

公开(公告)日：2003-06-03

申请号：US09700207

申请日：2001-02-21

申请人： Akira Nishiyama ,  Kenji Inoue

发明人： Akira Nishiyama ,  Kenji Inoue

IPC分类号： C07C2600

CPC分类号： C07C269/06 ,  C07C271/18 ,  C07C271/22

摘要： The present invention provides a commercially profitable process for producing a &bgr;-amino acid ester derivative which comprises reacting an &agr;-amino acid ester derivative with a base and a dihalomethane, reacting the same with a lithium amide and an alkyllithium in succession, and treating the reaction product with an acid in an alcohol.

摘要翻译： 本发明提供了一种商业上有利可图的β-氨基酸酯衍生物的制备方法，该方法包括使α-氨基酸酯衍生物与碱和二卤甲烷反应，将其与氨基化锂和烷基锂相继反应，并进行反应 产品与酒精中的酸。

公开(公告)号：US06340767B1

公开(公告)日：2002-01-22

申请号：US09762215

申请日：2001-04-05

申请人： Akira Nishiyama ,  Kenji Inoue

发明人： Akira Nishiyama ,  Kenji Inoue

IPC分类号： C07C5100

CPC分类号： C12P7/62 ,  C07B2200/07 ,  C07C67/343 ,  C07C253/30 ,  C07D319/06 ,  C07C69/716 ,  C07C255/21 ,  C07C69/738

摘要： This invention provides a process for producing a 5-hydroxy-3-oxopentanoic acid, a useful pharmaceutical intermediate, easily from a readily available, inexpensive starting material without using any extraordinary production equipment such as a very-low-temperature reactor. Thus, this invention provides a process for producing a 5-hydroxy-3-oxopentanoic acid which comprises permitting a lithium amide to act upon a mixture of an acetic acid ester and a 3-hydroxypropionic acid derivative at not below −20° C. Further, this invention also provides a process for producing a 5-hydroxy-3-oxopentanoic acid which comprises treating a mixture of an acetic acid ester and a 3-hydroxypropionic acid derivative with a Grignard reagent to prepare a mixture of a compound and an acetic acid ester of the above formula (I), and permitting a lithium amide to act upon the mixture at a temperature not below −20° C.

摘要翻译： 本发明提供一种生产5-羟基-3-氧代戊酸的方法，该方法是一种有用的药物中间体，容易从现成的廉价起始原料中生产，而不使用任何非常低的生产设备如极低温反应器。因此， 本发明提供了一种生产5-羟基-3-氧代戊酸的方法，其包括允许氨化锂在不低于-20℃下作用于乙酸酯和3-羟基丙酸衍生物的混合物。此外，本发明还 提供了一种生产5-羟基-3-氧代戊酸的方法，其包括用格氏试剂处理乙酸酯和3-羟基丙酸衍生物的混合物，以制备上式的化合物和乙酸酯的混合物 （I）化合物，并允许在不低于-20℃的温度下使氨基化锂作用于混合物。

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：USRE39333E1

公开(公告)日：2006-10-10

申请号：US10705665

申请日：2000-06-02

申请人： Akira Nishiyama ,  Kenji Inoue

发明人： Akira Nishiyama ,  Kenji Inoue

IPC分类号： C07C69/66 ,  C07C59/185

CPC分类号： C12P7/62 ,  C07B2200/07 ,  C07C67/343 ,  C07C253/30 ,  C07D319/06 ,  C07C69/716 ,  C07C255/21 ,  C07C69/738

摘要： This invention provides a process for producing a 5-hydroxy-3-oxopentanoic acid, a useful pharmaceutical intermediate, easily from a readily available, inexpensive starting material without using any extraordinary production equipment such as a very-low-temperature reactor.Thus, this invention provides a process for producing a 5-hydroxy-3-oxopentanoic acid which comprises permitting a lithium amide to act upon a mixture of an acetic acid ester and a 3-hydroxypropionic acid derivative at not below −20° C. Further, this invention also provides a process for producing a 5-hydroxy-3-oxopentanoic acid which comprises treating a mixture of an acetic acid ester and a 3-hydroxypropionic acid derivative with a Grignard reagent to prepare a mixture of a compound and an acetic acid ester of the above formula (I), and permitting a lithium amide to act upon the mixture at a temperature not below −20° C. This invention provides a process for producing a 5-hydroxy-3-oxopentanoic acid, a useful pharmaceutical intermediate, easily from a readily available, inexpensive starting material without using any extraordinary production equipment such as a very-low temperature reactor. Thus, this invention provides a process for producing a 5-hydroxy-3-oxopentanoic acid which comprises permitting a lithium amide to act upon a mixture of an acetic acid ester and a 3-hydroxypropionic acid derivative at not below −20° C. Further, this invention also provides a process for producing a 5-hydroxy-3-oxopentanoic acid which comprises treating a mixture of an acetic acid ester and a 3-hydroxypropionic acid derivative with a Grignard reagent to prepare a mixture of a compound and an acetic acid ester of the above formula (I), and permitting a lithium amide to act upon the mixture at a temperature not below −20° C.

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。