公开(公告)号：ES2241149T3

公开(公告)日：2005-10-16

申请号：ES98932585

申请日：1998-07-21

Applicant: KANEKA CORP

Inventor： UEDA YASUYOSHI ,  KINOSHITA KOICHI ,  MOROSHIMA TADASHI ,  YANAGIDA YOSHIFUMI ,  FUSE YOSHIHIDE

IPC: A61P9/12 ,  C07K1/02 ,  C07K1/08 ,  C07K5/02 ,  C07K5/06 ,  C07K5/062

Abstract: UN PROCEDIMIENTO PARA LA PREPARACION DE SALES DE N - (1(S) ETOXICARBONIL - 3 - FENILPROPIL) - L - ALANILAMINOACIDOS FARMACOLOGICAMENTE ACEPTABLES QUE CONSISTE EN LOS PASOS SIGUIENTES: SE CONDENSA UN AMINOACIDO CON N - CARBOXIANHIDRIDO DE N - (1(S) - ETOXICARBONIL - 3 - FENILPROPIL) - L - ALANINA BAJO CONDICIONES BASICAS; SE DESCARBOXILA EL CONDENSADO BAJO CONDICIONES DE NEUTRAS A ACIDAS PARA PREPARAR UN N - (1(S) ETOXICARBONIL 3 - FENILPROPIL) - L - ALANILAMINOACIDO; Y SE CONVIERTE EL PRODUCTO EN UNA SAL FARMACOLOGICAMENTE ACEPTABLE DEL MISMO, QUE SE CARACTERIZA PORQUE SE LLEVAN A CABO UNA SERIE DE PROCEDIMIENTOS HASTA LA FORMACION DE UNA SAL FARMACOLOGICAMENTE ACEPTABLE O HASTA LA RETIRADA DE LA SAL FARMACOLOGICAMENTE ACEPTABLE DEL MISMO EN UN LIQUIDO ACUOSO PARA INHIBIR LA PRODUCCION DE UN SUBPRODUCTO (4). SEGUN ESTE PROCEDIMIENTO, SE PUEDEN PREPARAR SALES DE N - (1(S) ETOXICARBONIL - 3 - FENILPROPIL) - L - ALANILAMINOACIDOS FARMACOLOGICAMENTE ACEPTABLES EN GRANDES CANTIDADES DE MANERA ECONOMICA A ESCALA COMERCIAL.

公开(公告)号：ES2215624T3

公开(公告)日：2004-10-16

申请号：ES00915524

申请日：2000-04-14

Applicant: KANEKA CORP

Inventor： KINOSHITA KOICHI ,  MOROSHIMA TADASHI ,  YANAGIDA YOSHIFUMI ,  NAGASHIMA NOBUO ,  SAKA YASUHIRO ,  HONDA TATSUYA

IPC: C07C29/147 ,  C07C31/42 ,  C07D307/20

Abstract: The application is concerned with a process for producing a 3-hydroxytetrahydrofuran of the formula (3): by cyclizing a 4-halo-1,3-butanediol of the general formula (2): wherein X represents a halogen atom in an aqueous solution, which comprises carrying out the cyclization reaction under weakly acidic to neutral conditions. Furthermore several methods are disclosed for the isolution of highly pure 3-hydroxytetrahydrofuran.

公开(公告)号：HU0100831A2

公开(公告)日：2001-08-28

申请号：HU0100831

申请日：1999-09-22

Applicant: KANEKA CORP

Inventor： FUSE YOSHIHIDE ,  MOROSHIMA TADASHI ,  UEDA YASUYOSHI ,  YANAGIDA YOSHIFUMI

IPC: C07K5/068 ,  A61K38/05 ,  A61P9/12 ,  C07K5/02

Abstract: The process for producing N -(1(S)-carboxy-3-phenylpropyl)-L-lysyl-L-proline in a simple, efficient and industrially advantageous manner, which comprises: the first step of subjecting the N -(1(S)-alkoxycarbonyl-3-phenylpropyl)-N -trifluoroacetyl-L-lysyl -L-proline (1) to alkali hydrolysis in a mixed solution composed of water and a hydrophilic organic solvent using an inorganic base in an amount of n molar equivalents (n >/= 3) per mole of the above compound (1), the second step of neutralizing the hydrolysis product using an inorganic acid in an amount of (n - 1) to n molar equivalents (n >/= 3) and removing the inorganic salt formed by causing the same to precipitate out from a solvent system suited for decreasing the solubility of the inorganic salt, and the third step of causing the compound (2) existing in the mixture after removal of the inorganic salt to crystallize out at the isoelectric point thereof and thereby recovering the compound (2) in the form of crystals while retaining the salts comprising the trifluoroacetic acid-derived organic acid salt in a state dissolved in the mother liquor.

公开(公告)号：PL340685A1

公开(公告)日：2001-02-26

申请号：PL34068599

申请日：1999-09-22

Applicant: KANEKA CORP

Inventor： MOROSHIMA TADASHI ,  YANAGIDA YOSHIFUMI ,  FUSE YOSHIHIDE ,  UEDA YASUYOSHI

IPC: C07K5/068 ,  A61K38/05 ,  A61P9/12 ,  C07K5/02

Abstract: The process for producing N -(1(S)-carboxy-3-phenylpropyl)-L-lysyl-L-proline in a simple, efficient and industrially advantageous manner, which comprises: the first step of subjecting the N -(1(S)-alkoxycarbonyl-3-phenylpropyl)-N -trifluoroacetyl-L-lysyl -L-proline (1) to alkali hydrolysis in a mixed solution composed of water and a hydrophilic organic solvent using an inorganic base in an amount of n molar equivalents (n >/= 3) per mole of the above compound (1), the second step of neutralizing the hydrolysis product using an inorganic acid in an amount of (n - 1) to n molar equivalents (n >/= 3) and removing the inorganic salt formed by causing the same to precipitate out from a solvent system suited for decreasing the solubility of the inorganic salt, and the third step of causing the compound (2) existing in the mixture after removal of the inorganic salt to crystallize out at the isoelectric point thereof and thereby recovering the compound (2) in the form of crystals while retaining the salts comprising the trifluoroacetic acid-derived organic acid salt in a state dissolved in the mother liquor.

公开(公告)号：SI20211A

公开(公告)日：2000-10-31

申请号：SI9920008

申请日：1999-07-19

Applicant: KANEKA CORP

Inventor： KINOSHITA KOICHI ,  MOROSHIMA TADASHI ,  YANAGIDA YOSHIFUMI ,  FUSE YOSHIHIDE ,  UEDA YASUYOSHI

IPC: A61P9/00 ,  C07K1/00 ,  C07K5/06 ,  C07K5/062 ,  C07K1/30 ,  A61P9/12

Abstract: A method for crystallizing the maleic acid salt of N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline (Enalapril) from an aqueous liquid with ease in good yield, which comprises mixing an aqueous liquid containing N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline, maleic acid and a base and having a pH of 4 or more with an acid in an amount of the acid sufficient to convert the base to a neutral salt, to thereby crystallize N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline in the form of a maleic acid salt.

公开(公告)号：EP1018516A4

公开(公告)日：2004-05-26

申请号：EP99929893

申请日：1999-07-19

Applicant: KANEKA CORP

Inventor： KINOSHITA KOICHI ,  MOROSHIMA TADASHI ,  YANAGIDA YOSHIFUMI ,  FUSE YOSHIHIDE ,  UEDA YASUYOSHI

IPC: A61P9/00 ,  C07K1/00 ,  C07K5/06 ,  C07K5/062 ,  C07K5/02

CPC classification number: C07K5/06026

Abstract: A method for crystallizing the maleic acid salt of N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline (Enalapril) from an aqueous liquid with ease in good yield, which comprises mixing an aqueous liquid containing N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline, maleic acid and a base and having a pH of 4 or more with an acid in an amount of the acid sufficient to convert the base to a neutral salt, to thereby crystallize N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline in the form of a maleic acid salt.

公开(公告)号：EP1035131A4

公开(公告)日：2002-05-02

申请号：EP99944783

申请日：1999-09-22

Applicant: KANEKA CORP

Inventor： MOROSHIMA TADASHI ,  YANAGIDA YOSHIFUMI ,  FUSE YOSHIHIDE ,  UEDA YASUYOSHI

IPC: C07K5/068 ,  A61K38/05 ,  A61P9/12 ,  C07K5/02 ,  C07K5/06

CPC classification number: C07K5/0222

Abstract: A process for preparing N -(1(S)-carboxy-3-phenylpropyl)-L-lysyl-L-proline (2) easily, efficiently and industrially advantageously, which comprises: the first step of conducting the alkaline hydrolysis of an N -(1(S)-alkoxycarbonyl-3-phenylpropyl)-N -trifluoroacetyl-L-lysyl-L-proline (1) by the use of n molar equivalents (wherein n >/= 3) of an inorganic base per mol of the compound (1) either in a mixture of water with a hydrophilic organic solvent or in water; the second step of neutralizing the resulting reaction mixture with (n-1) to n molar equivalents (wherein n >/= 3) of an inorganic acid, replacing the solvent system by a suitable one to thereby precipitate an inorganic salt formed by the above neutralization, and separating and removing the salt; and the third step of crystallizing the compound (2) present in the liquid mixture left after the above removal of the salt at its isoelectric point and recovering the compound (2) as a crystal, while salts mainly comprising organic acid salts resulting from trifluoroacetic acid remain dissolved in the mother liquor.

公开(公告)号：EP0967221A4

公开(公告)日：2002-05-02

申请号：EP98932585

申请日：1998-07-21

Applicant: KANEKA CORP

Inventor： UEDA YASUYOSHI ,  KINOSHITA KOICHI ,  MOROSHIMA TADASHI ,  YANAGIDA YOSHIFUMI ,  FUSE YOSHIHIDE

IPC: A61P9/12 ,  C07K1/02 ,  C07K1/08 ,  C07K5/02 ,  C07K5/06 ,  C07K5/062

CPC classification number: C07K5/0222 ,  C07K5/06026

Abstract: A process for preparing pharmacologically acceptable salts of N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl amino acids, comprising the steps of: condensing an amino acid with N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanine N-carboxyanhydride under basic conditions; decarboxylating the condensate under neutral to acidic conditions to prepare an N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl amino acid; and converting the product to a pharmacologically acceptable salt thereof, characterized in that a series of procedures up to the formation of a pharmacologically acceptable salt or up to the withdrawal of the pharmaceutically acceptable salt thereof are carried out in an aqueous liquid to inhibit the production of a by-product (3). According to this process, high-quality pharmacologically acceptable salts of N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl amino acids can be prepared in high yields in a cost-effective manner on a commercial scale.

Abstract translation: 制备N-（1（S） - 乙氧羰基-3-苯丙基）-L-丙氨酰氨基酸的药理学上可接受的盐的方法，包括以下步骤：使氨基酸与N-（1（S） - 乙氧羰基-3 - 苯基丙基）-L-丙氨酸N-羧酸酐在碱性条件下; 在中性至酸性条件下将缩合物脱羧基以制备N-（1（S） - 乙氧羰基-3-苯丙基）-L-丙氨酰氨基酸; 并将该产物转化成其药理学上可接受的盐，其特征在于在含水液体中进行一系列形成药理学上可接受的盐或直至其药学上可接受的盐的程序，以抑制 一个副产品（3）。 根据该方法，可以以商业规模以高成本效益的方式高产率地制备N-（1（S） - 乙氧羰基-3-苯丙基）-L-丙氨酰氨基酸的高质量药理学上可接受的盐。