公开(公告)号：US06593486B2

公开(公告)日：2003-07-15

申请号：US09911366

申请日：2001-07-23

申请人： Arie L. Gutman ,  Genady Nisnevich ,  Eleonora Shkolnik ,  Igor Zaltzman ,  Boris Tishin

发明人： Arie L. Gutman ,  Genady Nisnevich ,  Eleonora Shkolnik ,  Igor Zaltzman ,  Boris Tishin

IPC分类号： C07C25300

CPC分类号： C07D213/40 ,  C07C51/367 ,  C07C255/14 ,  C07D211/26 ,  C07C65/21 ,  C07C65/24

摘要： This application relates to a process for the preparation of the cyanomethyl ester which comprises reacting 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid or a salt thereof, with a haloacetonitrile of the formula XCH2CN wherein X is Cl, Br, or I.

摘要翻译： 本申请涉及制备氰甲基酯的方法，其包括使2,5-双（2,2,2-三氟乙氧基）苯甲酸或其盐与式XCH 2 CN的卤代乙腈反应，其中X为Cl，Br， 或I.

公开(公告)号：US06316627B1

公开(公告)日：2001-11-13

申请号：US09422931

申请日：1999-10-21

申请人： Arie L. Gutman ,  Genady Nisnevich ,  Eleonora Shkolnik ,  Igor Zaltzman ,  Boris Tishin

发明人： Arie L. Gutman ,  Genady Nisnevich ,  Eleonora Shkolnik ,  Igor Zaltzman ,  Boris Tishin

IPC分类号： C07D21126

CPC分类号： C07D213/40 ,  C07C51/367 ,  C07C255/14 ,  C07D211/26 ,  C07C65/21 ,  C07C65/24

摘要： A process for the preparation of trifluoroethoxy benzoic acid derivatives, in particular Flecainide, and their pharmaceutically acceptable salts, starting with commercially available halobenzoic acids and involving the use of simple reagents and low cost solvents, to afford high overall yield of the product. The above object is achieved in accordance with the present invention which, in one aspect thereof, provides a process for preparing a compound of formula (A): and pharmaceutically acceptable salts thereof, which process comprises the steps of: a) reacting a halobenzoic acid or a salt thereof of the formula [II ]  with 2,2,2-trifluoroethanol in the presence of a strong base and a copper containing material, if desired followed by acidification to obtain a compound of formula [I] b) converting the product obtained in step a) above into the compound of formula (A) or a pharmaceutically acceptable salt thereof.

摘要翻译： 制备三氟乙氧基苯甲酸衍生物，特别是氟卡尼胺及其药学上可接受的盐的方法，起始于市售的卤代苯甲酸，并涉及使用简单的试剂和低成本的溶剂，以提供产品的高总产率。 目的是根据本发明实现的，其一方面提供制备式（A）化合物及其药学上可接受的盐的方法，该方法包括以下步骤：a）使卤代苯甲酸或 如果需要，然后酸化以得到式[I]的化合物，b）将式[II]化合物与式（II）的盐与2,2,2-三氟乙醇在强碱和含铜材料存在下反应，得到式 步骤a）在式（A）化合物或其药学上可接受的盐中。

公开(公告)号：US06492522B1

公开(公告)日：2002-12-10

申请号：US09763245

申请日：2001-05-24

申请人： Arie L. Gutman ,  Eleonora Shkolnik ,  Boris Tishin ,  Genady Nisnevich ,  Igor Zaltzman

发明人： Arie L. Gutman ,  Eleonora Shkolnik ,  Boris Tishin ,  Genady Nisnevich ,  Igor Zaltzman

IPC分类号： C07D21132

CPC分类号： C07D211/32 ,  C07D211/34

摘要： The present invention relates to a new process for the preparation of acetylcholinesterase inhibitors of formula (I) or a salt thereof, wherein: R1 is N-acyl-4-piperidyl; N-alkoxycarbonyl-4-piperidyl; N-alkyl-4-piperidyl; N-benzyl-4-piperidyl; N-(&ohgr;-aralkyl)-4-piperidyl; 4-pyridyl; R4, R5, R6, and R7 are identical or different and each represents hydrogen, straight-chain or branched alkyl, aryl, hydroxy, alkoxy, aryloxy, benzyloxy, acyloxy, alkylthio, arylthio, benzylthio, acylamino, phthalimido or halogen; n is 1, 2 or 3; m is 1, 2, 3, 4, or 5. This process comprises cyclisation of a compound of formula (II) or salts thereof, wherein R1, R4, R5, R6 and R7, m and n are as defined above; R2 is selected from a derivatised or non-derivatised carboxyl, cyano, N-substituted aminocarbonyl groups or hydrogen; R3 is selected from a derivatised or non-derivatised carboxyl, cyano or N-substituted aminocarbonyl groups, optionally in the presence of acids and/or solvents. One of the most potent acetylcholinesterase inhibitors of the class of compounds prepared according to the present invention is donepezil.

摘要翻译： 本发明涉及制备式（I）的乙酰胆碱酯酶抑制剂或其盐的新方法，其中：R1是N-酰基-4-哌啶基; N-烷氧基羰基-4-哌啶基; N-烷基-4-哌啶基; N-苄基-4-哌啶基; N-（ω-芳烷基）-4-哌啶基; 4-吡啶基; R 4，R 5，R 6和R 7相同或不同，各自表示氢，直链或支链烷基，芳基，羟基，烷氧基，芳氧基，苄氧基，酰氧基，烷硫基，芳硫基，苄硫基，酰氨基，苯二酰亚胺基或卤素; n为1,2或3; 该方法包括式（II）化合物或其盐的环化，其中R 1，R 4，R 5，R 6和R 7，m和n如上所定义; R2选自衍生的或非衍生的羧基，氰基，N-取代的氨基羰基或氢; R3选自衍生化或非衍生的羧基，氰基或N-取代的氨基羰基，任选在酸和/或溶剂的存在下。 根据本发明制备的化合物类别中最有效的乙酰胆碱酯酶抑制剂之一是多奈哌齐。

公开(公告)号：US06288271B1

公开(公告)日：2001-09-11

申请号：US09403384

申请日：2000-01-18

申请人： Arie L. Gutman ,  Genady Nisnevich ,  Eleonora Shkolnik ,  Igor Zaltzman

发明人： Arie L. Gutman ,  Genady Nisnevich ,  Eleonora Shkolnik ,  Igor Zaltzman

IPC分类号： C07C6306

CPC分类号： C07C51/367 ,  C07C65/21 ,  C07C65/24

摘要： A process for producing trifluoroethoxybenzoic acids or salts thereof by reaction of halobenzoic acids or salts thereof with 2,2,2-trifluoroethanol in the presence of a strong base and copper containing materials. The compounds obtained by the process of the present invention may be used as synthetic intermediates in the pharmaceutical industry.

摘要翻译： 在强碱和含铜材料的存在下，通过卤代苯甲酸或其盐与2,2,2-三氟乙醇的反应制备三氟乙氧基苯甲酸或其盐的方法。 通过本发明的方法获得的化合物可以用作制药工业中的合成中间体。

公开(公告)号：US06538138B1

公开(公告)日：2003-03-25

申请号：US09462418

申请日：2000-04-03

申请人： Arie L. Gutman ,  Genady Nisnevich ,  Eleonora Shkolnik ,  Igor Zaltzman

发明人： Arie L. Gutman ,  Genady Nisnevich ,  Eleonora Shkolnik ,  Igor Zaltzman

IPC分类号： C07D21130

CPC分类号： C07D213/40 ,  C07C255/14 ,  C07D211/26

摘要： The invention relates to processes for the preparation of compounds of the formula wherein R is a 2-piperidyl or 2-pyridyl radical, and pharmaceutically acceptable salts thereof, the process comprising the steps of: a) reacting 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid or a salt thereof with a haloacetonitrile to form a cyanomethyl ester of formula b) reacting the ester with an amine of the formula RCH2NH2, where R is as defined above.

摘要翻译： 本发明涉及制备糠醛的化合物的方法，R是2-哌啶基或2-吡啶基，以及其药学上可接受的盐，该方法包括以下步骤：a）使2,5-双（2,2 ，2-三氟乙氧基）苯甲酸或其盐与卤代乙腈反应以形成公式的氰甲基酯）使酯与式RCH 2 NH 2的胺反应，其中R如上定义。

公开(公告)号：US20090298930A1

公开(公告)日：2009-12-03

申请号：US11791415

申请日：2005-11-18

申请人： Arie L. Gutman ,  Gennady A. Nisnevich ,  Igor Rukhman ,  Boris Tishin ,  Marina Etinger ,  Irina Fedotev ,  Boris Pertsikov ,  Ram Khanolkar

发明人： Arie L. Gutman ,  Gennady A. Nisnevich ,  Igor Rukhman ,  Boris Tishin ,  Marina Etinger ,  Irina Fedotev ,  Boris Pertsikov ,  Ram Khanolkar

IPC分类号： A61K31/35 ,  C07D311/80

CPC分类号： A61K31/352 ,  A61K9/4875 ,  C07D311/80

摘要： Methods for making trans-(−)-Δ9-tetrahydrocannabinol and trans-(+)-Δ9-tetrahydrocannabinol are disclosed herein. In one embodiment, a trans-(−)-Δ9-tetrahydrocannabinol composition is prepared by allowing a composition comprising (±)-Δ9-tetrahydrocannabinol to separate on a chiral stationary phase to provide a trans-(−)-Δ9-tetrahydrocannabinol composition comprising at least about 99% by weight of trans-(−)-Δ9-tetrahydrocannabinol based on the total amount of trans-(−)-Δ9-tetrahydrocannabinol and trans-(+)-Δ9-tetrahydrocannabinol. The invention also relates to methods for treating or preventing a condition such as pain comprising administering to a patient in need thereof an effective amount of a trans-(−)-Δ9-tetrahydrocannabinol having a purity of at least about 98% based on the total weight of cannabinoids.

摘要翻译： 本文公开了制备反 - （ - ） - Delta9-四氢大麻酚和反 - （+） - Delta9-四氢大麻酚的方法。 在一个实施方案中，通过使包含（±）-Delta9-四氢大麻酚的组合物在手性固定相上分离以提供反式 - （ - ） - Delta9-四氢大麻酚组合物来制备反 - （ - ） - Delta9-四氢大麻酚组合物，其包含 基于反 - （ - ）-Δ9-四氢大麻酚和反 - （+）-Δ9-四氢大麻酚的总量的至少约99重量％的反式 - （ - ） - Δ9-四氢大麻酚。 本发明还涉及用于治疗或预防诸如疼痛的病症的方法，其包括向有需要的患者施用有效量的基于总计的纯度为至少约98％的反 - （ - ） - Delta9-四氢大麻酚 大麻素的重量。

公开(公告)号：US08383842B2

公开(公告)日：2013-02-26

申请号：US11791415

申请日：2005-11-18

申请人： Arie L. Gutman ,  Gennady A. Nisnevich ,  Igor Rukhman ,  Boris Tishin ,  Marina Etinger ,  Irina Fedotev ,  Boris Pertsikov ,  Ram Khanolkar

发明人： Arie L. Gutman ,  Gennady A. Nisnevich ,  Igor Rukhman ,  Boris Tishin ,  Marina Etinger ,  Irina Fedotev ,  Boris Pertsikov ,  Ram Khanolkar

IPC分类号： C07D311/80

CPC分类号： A61K31/352 ,  A61K9/4875 ,  C07D311/80

摘要： Methods for making trans-(−)-Δ9-tetrahydrocannabinol and trans-(+)-Δ9-tetrahydrocannabinol are disclosed herein. In one embodiment, a trans-(−)-Δ9-tetrahydrocannabinol composition is prepared by allowing a composition comprising (±)-Δ9-tetrahydrocannabinol to separate on a chiral stationary phase to provide a trans-(−)-Δ9-tetrahydrocannabinol composition comprising at least about 99% by weight of trans-(−)-Δ9-tetrahydrocannabinol based on the total amount of trans-(−)-Δ9-tetrahydrocannabinol and trans-(+)-Δ9-tetrahydrocannabinol. The invention also relates to methods for treating or preventing a condition such as pain comprising administering to a patient in need thereof an effective amount of a trans-(−)-Δ9-tetrahydrocannabinol having a purity of at least about 98% based on the total weight of cannabinoids.

摘要翻译： 本文公开了制备反 - （ - ） - ＆Dgr; 9-四氢大麻酚和反 - （+） - ＆Dgr; 9-四氢大麻酚的方法。 在一个实施方案中，通过使包含（±） - ＆Dgr; 9-四氢大麻酚的组合物在手性固定相上分离以提供反式 - （ - ） - 基于反式 - （ - ） - ＆Dgr; 9-四氢大麻酚和反 - （+） - ＆Dgr的总量，包含至少约99重量％的反 - （ - ） - ＆Dgr; 9-四氢大麻酚的9-四氢大麻酚组合物 ; 9-四氢大麻酚。 本发明还涉及用于治疗或预防诸如疼痛的病症的方法，包括向有需要的患者施用有效量的基于以下物质的纯 - 至少约98％的反式 - （ - ） - 吗啉-4-基 - 四氢大麻酚 大麻素的总重量。

公开(公告)号：US06696568B2

公开(公告)日：2004-02-24

申请号：US09834657

申请日：2001-04-16

申请人： Arie L. Gutman ,  Gennadiy Nisnevich ,  Igor Ruchman ,  Boris Tishin ,  Alex Vilensky ,  Boris Pertsikov

发明人： Arie L. Gutman ,  Gennadiy Nisnevich ,  Igor Ruchman ,  Boris Tishin ,  Alex Vilensky ,  Boris Pertsikov

IPC分类号： C07D45704

CPC分类号： C07D457/06 ,  C07F7/10

摘要： A process for preparation of N-(ergoline-8&bgr;-carbonyl)ureas of the formula [I] their stereoisomers as well as acid addition salts thereof which process comprises silylating an ergoline-8&bgr;-carboxamide of the formula [2], their stereoisomers as well as metal or ammonium salts or acid addition salts thereof and reacting the resultant product with an isocyanates R1N═C═O [5] wherein R1 is selected from alkyl having from 1 to 4 carbon atoms, cyclohexyl, phenyl, and dimethylamino alkyl group —(CH2)nNMe2 in which n is an integer, R2 is selected from hydrogen, alkyl having from 1 to 4 carbon atoms, cyclohexyl, phenyl, dimethylamino alkyl group —(CH2)nNMe2 in which n is an integer, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazolyl or thiadiazolyl, R3 represent a hydrocarbon group having from 1 to 4 carbon atoms, and R4 is selected from hydrogen, halogen, methylthio and phenylthio group;; followed by desilylation. This novel approach provides an efficient method for preparation of N-(ergoline- 8&bgr;-carbonyl)ureas of the formula [I] which can be useful as anty-Parkisons drugs and prolactin inhibitors. One of the most potent antiprolactinic agent of the class of compounds prepared according to the present invention is Cabergoline. Silylated ergolines, which are obtained as intermediates in the process of the present invention, are novel compounds and represent a further aspect of the invention.

摘要翻译： 制备式[I]的N-（麦角灵-8-羰基）脲，其立体异构体及其酸加成盐的方法包括将式[2]的麦角灵-8β-甲酰胺甲硅烷基化，其立体异构体为 以及金属或铵盐或其酸加成盐，并使所得产物与异氰酸酯R 1 = C = O [5]反应，其中R 1选自具有1至4个碳原子的烷基，环己基， 苯基和二甲基氨基烷基 - （CH 2）n NMe 2，其中n是整数，R 2选自氢，具有1至4个碳原子的烷基，环己基，苯基，二甲基氨基烷基 - （CH 2）n NMe 2，其中 n是整数，吡啶基，嘧啶基，吡嗪基，哒嗪基，噻唑基或噻二唑基，R 3表示具有1至4个碳原子的烃基，R 4选自氢，卤素，甲硫基和苯硫基。 然后脱甲硅烷基化。该新方法提供了用于制备式（I）的N-（麦角灵-8β-羰基）脲的有效方法，其可用作无色帕金森药物和催乳素抑制剂。 根据本发明制备的化合物类别中最有效的促乳素剂之一是卡麦角林。在本发明方法中作为中间体获得的硅藻土，是新化合物，代表本发明的另一方面。

公开(公告)号：US06737518B1

公开(公告)日：2004-05-18

申请号：US09700035

申请日：2001-05-18

申请人： Arie L. Gutman ,  Genadi Nisnevitch ,  Lev Yudovitch ,  Igor Rokhman

发明人： Arie L. Gutman ,  Genadi Nisnevitch ,  Lev Yudovitch ,  Igor Rokhman

IPC分类号： C07H1500

CPC分类号： C07H17/08

摘要： Conjugation of 4,5-Epoxymorphinan-6-ols with Bromoglucuronides in the presence of Zinc containing compounds as activator under conditions capable of forming 4,5-Epoxymorphinan-6-oxyglucuronides is disclosed. This novel approach provides an efficient method for preparation of both anomers of 4,5-Epoxymorphinan-6-oxyglucuronides. The deprotected end products are useful as analgesic agents.

摘要翻译： 公开了在能够形成4,5-环氧基吗啡喃-6-氧基葡糖苷酸的条件下，在含锌化合物作为活化剂的情况下，将4,5-环氧吗啡喃-6-ols与溴葡萄糖苷酸缀合。 这种新方法提供了一种制备4,5-环氧吗啡喃-6-氧基葡糖苷酸的两种端基异构体的有效方法。 去保护的最终产物可用作止痛剂。