WO2011116491A1 - Procédés de préparation du benzylate de nortropine et de ses sels et intermédiaires utilisés dans ledit procédé - Google Patents

Procédés de préparation du benzylate de nortropine et de ses sels et intermédiaires utilisés dans ledit procédé Download PDF

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Publication number
WO2011116491A1
WO2011116491A1 PCT/CN2010/000347 CN2010000347W WO2011116491A1 WO 2011116491 A1 WO2011116491 A1 WO 2011116491A1 CN 2010000347 W CN2010000347 W CN 2010000347W WO 2011116491 A1 WO2011116491 A1 WO 2011116491A1
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Prior art keywords
formula
acid
reaction
ester
compound
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PCT/CN2010/000347
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English (en)
Chinese (zh)
Inventor
罗宣德
刘玉忠
叶光
张铭锡
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北京世纪迈劲生物科技有限公司
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Priority to PCT/CN2010/000347 priority Critical patent/WO2011116491A1/fr
Priority to DE112010005112T priority patent/DE112010005112T5/de
Priority to CN2010800095410A priority patent/CN102333775A/zh
Publication of WO2011116491A1 publication Critical patent/WO2011116491A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms
    • C07D451/10—Oxygen atoms acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine

Definitions

  • This invention relates to a novel process for the preparation of decanoic acid esters of diphenylglycolic acid and salts thereof, and to novel intermediates for use in the process.
  • This method is characterized by the removal of cbz by hydrogenation with Pd-C to achieve the purpose of dethiolation, and the acid chloride used for esterification is prepared by using PC1 5 .
  • the disadvantage is that the reagents used (PC1 5 , pyridine) cause serious pollution to the environment, and the Alpha chlorine is hydrolyzed into a hydroxyl group in the process, which is extremely inconvenient to operate, high in cost, and difficult to purify the product.
  • Xu Rongsen et al. (CN 101003535A, 2007-07-25) discloses an improved method with a high yield and a total yield of about 60%.
  • This method starts from a top product, is esterified with a-hydroxy-CC-phenylphenylacetate, and is deaminated with ethyl chlororuthenate and HBr/HAc to obtain a deuterated ester of diphenylglycolic acid.
  • the reaction conditions of the method are too severe, it is difficult to control the tropine ester to be not destroyed, and the intermediate bromide is still subjected to the hydrolysis step to obtain the product, which is complicated in operation and difficult to control, and is not suitable for industrial production.
  • One of the objects of the present invention is to provide a novel method for preparing a diphenylglycolic acid deuterated ester of the following formula (1) and a salt thereof.
  • the method has the characteristics of mild reaction condition, simple operation, short reaction time, high yield, less environmental pollution, easy control of finished product quality, and is suitable for industrial production.
  • a second object of the present invention is to provide a novel intermediate for the preparation of the diphenylglycolic acid deuterated ester of the formula (1) and a salt thereof, and a process for the preparation of the intermediate.
  • the method of the invention comprises the following steps:
  • R represents dC 4 alkyl, halo d-C 4 alkyl or phenyl
  • Hal represents hydrogen, chlorine or bromine
  • the benzoate of the formula (4) is prepared according to the method described by R. Banholzer et al. (Arzneim. - Forsch, 36 (II), 8, 1161-1166, 1986); Further reacting with chlorophthalic acid ester at 0-100 ° C to obtain an intermediate of formula (5), separating the intermediate and then performing hydrolysis or alcoholysis reaction, or directly purifying the intermediate, directly proceeding to the next step
  • the hydrolysis or alcoholysis reaction gives the diphenyl alcohol acetate deuterated ester of the formula (1); then, the compound of the formula (1) is optionally reacted with an acid to obtain a salt thereof.
  • the reaction process is as follows:
  • the transesterification of the oxime of the formula (2) and the diphenyl hydroxyacetimidazole of the formula (3) for the transesterification of the benzoic acid ester of the formula (4) in a common inert solvent preferably an inert solvent From acetone, mercaptoethyl ketone, butanone, tetrahydrofuran, dichloroethane, benzene, toluene, dinonylbenzene, and mixtures thereof. More preferred inert solvents are acetone, butanone, tetrahydrofuran, benzene, and mixtures thereof.
  • the reaction temperature is from room temperature to 11 CTC, preferably from room temperature to 80 °C, more preferably from room temperature to 60 °C.
  • the reaction is from 30 minutes to 10 hours, preferably from 2 to 6 hours.
  • the reaction of the compound of the formula (4) with chlorodecanoate to prepare a compound of the formula (5) is also carried out in an inert solvent.
  • the inert solvent is selected from the group consisting of chloroform, dichloro-decane, 1,2-dichloroethane, benzene, toluene, diphenylbenzene, and mixtures thereof.
  • the preferred solvents are chloroform, dichlorodecane, 1,2-dichloroethane and mixtures thereof.
  • reaction temperature is 0-110 ° C, and the preferred reaction temperature is room temperature to 60 ° C.
  • Reaction time is 4 to 20 hours, preferably 10 to 15 hours.
  • the chlorophthalic acid ester used in the reaction is selected from the group consisting of: benzyl chlorate, ethyl chlorohydrazide, 1-chloroethyl chloroantimonate, 1-bromoethyl chloroantimonate, propyl chloroformate, chloroformic acid 1 -chloropropyl ester, 1-bromopropyl chloroantimonate, butyl chloroantimonate, 1-chlorobutyl chlorate, 1-bromobutyl chlorate, 2, 2, 2-trichloroethane Esters and mixtures thereof.
  • the chlorophthalic acid ester is used in the reaction in an amount of usually 1 to 10 equivalents, preferably 1 to 5 equivalents to the compound of the formula (4).
  • the above reaction produces an alkoxy or substituted alkoxycarbonyl deuterated intermediate of the formula (5), which is directly subjected to hydrolysis or alcoholysis without isolation to obtain a formula (1). ) compound.
  • the hydrolysis reaction is a conventional acid hydrolysis reaction, and the acid used is a usual organic or inorganic acid, preferably hydrochloric acid, sulfuric acid, acetic acid, glacial acetic acid and a mixture thereof. More preferred are concentrated hydrochloric acid, aqueous acetic acid and mixtures thereof.
  • the reaction temperature is 10-10 (TC, preferably room temperature to 7 (TC; the reaction time is 5-20 hours, preferably 8-12 hours).
  • the alcoholysis reaction is a conventional alcoholysis reaction condition.
  • Preferred solvents are decyl alcohol, ethanol, or mixtures thereof or mixtures thereof with water.
  • the reaction temperature is from 10 to 85 ° C, preferably from room temperature to 60 ° C; and the reaction time is from 0.5 to 8 hours, preferably from 1 to 4 hours.
  • Salts of the compounds of formula (1) include pharmaceutically acceptable salts with organic or inorganic acids.
  • the inorganic acid include hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid and the like.
  • the organic acid include acetic acid, citric acid, citric acid, tartaric acid, ascorbic acid and the like.
  • the method of the present invention disclosed above has mild reaction conditions, short reaction time, short reaction process, high operation rate, high yield, and easy purification of the finished product.
  • the desulfurization reaction is extremely mild, the yield is high, the cost is low, and the environment is non-polluting, which is very suitable for industrialized large-scale production.
  • Another aspect of the invention also provides a novel intermediate of the following formula (5)
  • R represents a dC alkyl group, a halogenated d_C 4 alkyl group or a phenyl group
  • Ha l represents hydrogen, chlorine or bromine.
  • a particularly preferred compound of the formula (5) is a compound wherein R represents a methyl group and Ha l represents hydrogen or chlorine.
  • the glycyl imidazole 38. 9 g (0.24 mol) was dissolved in 130 ml of dichloromethane, and the phenylglycolic acid was added in portions, 54. 8 g (0.24 mol), at 15-20. C was stirred and mixed, and after precipitation, the reaction was continued for 2-5 hours. Filtration, washing with dichloromethane (30 ml X 2 ), drying to give diphenylcarbamic acid imide 52 g (94.5%), mp 38-139 ° C (dec), recrystallized from acetone, mp 47-148 ° C.
  • the pharmaceutically acceptable product of formula (2) 14. lg (0.1 mol) was dissolved in acetone 60 ml, and diphenyl hydroxyacetimidazole (compound of formula 3) 27. 8 g (0.1 mol) was added in portions, as described above. In the solution. After the product was precipitated, the mixture was refluxed for 5 h, cooled to 0 ° C, filtered, washed with acetone, and then dried to give the title compound (3) of benzene benzoate (31.73 g) (yield 90.0%).
  • the intermediate 11.9 kg, concentrated hydrochloric acid 100 kg, and acetic acid acetic acid 62.4 kg were put into a 300 L reaction kettle, stirred, heated at 95-100 ° C for 14 h, and the reaction solution was concentrated to dryness; chloroform 88.6 kg, water was added to the residue. 47.6 kg.
  • the mixture was alkalized with aqueous sodium hydroxide solution with thorough stirring, stirred for 30 minutes, and allowed to stand for stratification.
  • the lower layer was washed with 30 kg of water, and concentrated to dryness to obtain diphenyl glycolic acid to remove the ester (1) 6.25 kg, yield 50%.
  • the content of HPLC was determined to be 99.2%;
  • benzoic acid tropine ester (compound of formula 4) 35. lg (0. lmol) is dissolved in 350 ml of 1,2-dichloroethane, and benzyl chloride chlorate (25.65 g (0.15 mol) is added under (TC) The reaction mixture was stirred at room temperature overnight, until the reaction was completed by TLC, and the solvent was evaporated under reduced pressure to give the crude product of N-(benzyloxycarbonyl) dehydrazide intermediate.
  • Example 2b (1) The decanoic acid ester of diphenylglycolate obtained in Example 2b (1) is treated with a solution of hydrogen chloride or a solution of guanidinium chloride to obtain a hydrochloride salt of decanoic acid (formula 1).
  • the filtrate is stirred and cooled to precipitate solid. It is cooled to room temperature at about 20 °C for 4h, then reduced to 5 °C, suction filtered, with 0-5 °C. After washing with ethanol, after drying, it was dried at 50 ° C to obtain 42.6 kg of diphenyl glycolic acid dehydrobenzoate hydrochloride, and the yield was 80%.
  • diphenyl glycolate (4) 35. lg (0. lmol) is dissolved in 400 ml of 1,2-dichloroethane, and chloric acid-2, 2, 2-3 is added at 0 °C. Chloroethyl ester 27.5 ml (about 42.4 g, 0.2 mol, 2 eq.).
  • Ethanol was evaporated under reduced pressure, and the residue was dissolved in 80 ml of tert-butyl oxime ether, filtered to remove insolubles, and the solvent was evaporated to give diphenylglycolic acid.
  • the ester was 38.38 g, and the yield was 89%.
  • the solution was treated with a hydrochloric acid/ethanol solution to obtain a diphenyl glycolic acid dehydrobenzoate ester.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention a trait à un procédé de préparation du benzylate de nortropine ou de ses sels, aux intermédiaires utilisés dans ledit procédé et au benzylate de nortropine ou à ses sels préparés. Le procédé de préparation du benzylate de nortropine comprend les étapes suivantes : l'utilisation de tropine comme composé de départ, la formation du benzylate de tropine par transestérification de la tropine avec le diphénylhydroxyacétylimidazole et la déméthylation du benzylate de tropine pour obtenir le benzylate de nortropine.
PCT/CN2010/000347 2010-03-22 2010-03-22 Procédés de préparation du benzylate de nortropine et de ses sels et intermédiaires utilisés dans ledit procédé WO2011116491A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
PCT/CN2010/000347 WO2011116491A1 (fr) 2010-03-22 2010-03-22 Procédés de préparation du benzylate de nortropine et de ses sels et intermédiaires utilisés dans ledit procédé
DE112010005112T DE112010005112T5 (de) 2010-03-22 2010-03-22 Verfahren zur Herstellung von Nortropylbenzilat und dessen Salzen sowie dabei verwendeten Zwischenprodukten
CN2010800095410A CN102333775A (zh) 2010-03-22 2010-03-22 制备二苯乙醇酸去甲托品酯和其盐的方法及其中所用的中间体

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2010/000347 WO2011116491A1 (fr) 2010-03-22 2010-03-22 Procédés de préparation du benzylate de nortropine et de ses sels et intermédiaires utilisés dans ledit procédé

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WO2011116491A1 true WO2011116491A1 (fr) 2011-09-29

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DE (1) DE112010005112T5 (fr)
WO (1) WO2011116491A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102718760A (zh) * 2012-06-01 2012-10-10 寿光富康制药有限公司 一种曲司氯铵合成工艺
CN102964345A (zh) * 2012-12-06 2013-03-13 四川理工学院 一种2―羟基―2,2―二苯基乙酸―3α―(8―氮杂双环[3,2,1])―3―辛酯的制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080027094A1 (en) * 2004-08-30 2008-01-31 Ono Pharmaceutical Co., Ltd. Tropane Compounds and Pharmaceutical Compositions Comprising the Same as an Active Ingredient
CN101643472A (zh) * 2008-08-07 2010-02-10 北京迈劲医药科技有限公司 2-羟基-2,2-二苯基乙酸-3α-(8-氮杂双环[3,2,1]-3-辛酯的制备方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2487340A1 (fr) * 1980-07-24 1982-01-29 Poudres & Explosifs Ste Nale Nouveau procede de dealkylation des amines tertiaires par emploi de chloroformiates a-chlores
JP3829879B2 (ja) * 1994-05-18 2006-10-04 大正製薬株式会社 キノリンカルボン酸誘導体
US6567791B2 (en) * 1998-11-03 2003-05-20 Nextcard, Inc. Method and apparatus for a verifiable on line rejection of an application for credit
CN101003535A (zh) 2006-01-17 2007-07-25 上海绿健医药技术有限公司 α－羟基－α－苯基苯乙酸 8－氮杂双环[3.2.1]－3－庚酯及中间体化合物及其制备方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080027094A1 (en) * 2004-08-30 2008-01-31 Ono Pharmaceutical Co., Ltd. Tropane Compounds and Pharmaceutical Compositions Comprising the Same as an Active Ingredient
CN101643472A (zh) * 2008-08-07 2010-02-10 北京迈劲医药科技有限公司 2-羟基-2,2-二苯基乙酸-3α-(8-氮杂双环[3,2,1]-3-辛酯的制备方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
A. B. KOSMACHEV ET AL.: "Synthesis and study of the selectivity of the M-choline eceptor blocking activity of norglipin", KHIMIKO-FARMATSEVTICHESKII ZHURNAL, vol. 32, no. 6, 1998, pages 15 - 17 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102718760A (zh) * 2012-06-01 2012-10-10 寿光富康制药有限公司 一种曲司氯铵合成工艺
CN102718760B (zh) * 2012-06-01 2014-07-02 寿光富康制药有限公司 一种曲司氯铵合成工艺
CN102964345A (zh) * 2012-12-06 2013-03-13 四川理工学院 一种2―羟基―2,2―二苯基乙酸―3α―(8―氮杂双环[3,2,1])―3―辛酯的制备方法

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CN102333775A (zh) 2012-01-25

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