WO2016119574A1 - Procédé de préparation de sacubitril - Google Patents

Procédé de préparation de sacubitril Download PDF

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Publication number
WO2016119574A1
WO2016119574A1 PCT/CN2016/070020 CN2016070020W WO2016119574A1 WO 2016119574 A1 WO2016119574 A1 WO 2016119574A1 CN 2016070020 W CN2016070020 W CN 2016070020W WO 2016119574 A1 WO2016119574 A1 WO 2016119574A1
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WO
WIPO (PCT)
Prior art keywords
methyl
reaction
biphenyl
acid
oxo
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2016/070020
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English (en)
Chinese (zh)
Inventor
许学农
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Suzhou Miracpharma Technology Co Ltd
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Suzhou Miracpharma Technology Co Ltd
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Application filed by Suzhou Miracpharma Technology Co Ltd filed Critical Suzhou Miracpharma Technology Co Ltd
Priority to KR1020177023388A priority Critical patent/KR101961897B1/ko
Publication of WO2016119574A1 publication Critical patent/WO2016119574A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/22—Separation; Purification; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton

Definitions

  • the invention belongs to the technical field of organic synthesis route design and preparation technology of raw materials and intermediates, and particularly relates to a preparation method of an enkephalinase inhibitor Sacubitril.
  • LCZ696 is a new antihypertensive drug developed by Novartis that combines two components, Novartis's Divan (general name: valsartan) and experimental drug Sacubitril (AHU-377).
  • Valsartan can improve vasodilation and stimulate the body to excrete sodium and water, while Sacubitri blocks the mechanism of action of two peptides that threaten to lower blood pressure.
  • LCZ696 is called angiotensin II receptor and enkephalinase. Double inhibitor.
  • the clinically demonstrated unique mode of action, superior antihypertensive effects of standard drugs, and reduced heart failure make the drug eligible for rapid channel review by the US FDA and the European Union EMEA.
  • Sacubitril AHU-377) does not yet have a standard Chinese translation, the applicant hereby transliterates it into "Shakubi".
  • the existing preparation scheme does not well solve the preparation of the chiral amino group of the target compound on the one hand, and on the other hand, the existing process is limited by many factors such as raw materials, cost, equipment and environmental protection, and is not easy to be industrialized. Therefore, how to use modern chiral synthesis technology and effective chiral induction reagents to design and develop a new synthetic route that is simple, fast, economical and environmentally friendly and easy to industrialize is of great significance for the economic and technological development of the drug.
  • the object of the present invention is to prepare a target product Shakubi trajectory by using a readily available industrial raw material and a chiral induction reagent "Betti base" for the defects in the prior art, which has the advantages of easy raw materials and simple process. It is economical and environmentally friendly and suitable for industrial production.
  • the present invention adopts the following main technical scheme: a preparation method of an enkephalinase inhibitor Sacubitril (I),
  • the preparation steps include: (S)-1-( ⁇ -aminobenzyl)-2-naphthol (II) is cyclized with 2R-methyl-4-oxo-butyric acid (III) (7aR, 9R,12S)-9-Methyl-10-oxo-12-phenyl-7a,8,9,10-tetrahydro-12H-naphtho[1,2-e]pyrrole[2,1- b] [1,3]oxazine (IV); the (7aR,9R,12S)-9-methyl-10-oxo-12-phenyl-7a,8,9,10-tetrahydro-12H -naphtho[1,2-e]pyrrolo[2,1-b][1,3]oxazine (IV) and Grignard reagent (1,1'-biphenyl-4-yl-methyl) Magnesium chloride or (1,1'-biphenyl-4-yl-methyl)magnesium bro
  • the molar ratio of the (S)-1-( ⁇ -aminobenzyl)-2-naphthol (II) to the 2R-methyl-4-oxo-butyric acid (III) is cyclized at a molar ratio of 1: 1-2, preferably 1:1.0-1.3; and the solvent for the cyclization reaction is toluene, 1,2-dichloroethane, N,N-dimethylformamide, acetonitrile or dimethyl sulfoxide, preferably toluene And the temperature of the cyclization reaction is 25-100 ° C, preferably 55-70 ° C.
  • the reaction system of the debenzylation reaction is a palladium carbon catalytic hydrogenation reduction system or an ammonium cerium nitrate oxidation system.
  • the solvent for the palladium on carbon catalytic hydrogenation reduction system is methanol, ethanol, isopropanol, dichloromethane, ethyl acetate or isopropyl acetate, preferably methanol.
  • the solvent of the ammonium cerium nitrate oxidation system is acetonitrile / water, dichloromethane / water or tetrahydrofuran / water, preferably acetonitrile / water; the volume ratio is 1-5:1, preferably 2:1.
  • the acid catalyst for the ring opening and esterification reaction is hydrochloric acid, sulfuric acid, trifluoroacetic acid, perchloric acid or p-toluenesulfonic acid, preferably hydrochloric acid or sulfuric acid; and the solvent for the ring opening and esterification reaction is ethanol;
  • the temperature at which the ring opening and the esterification reaction are carried out is 0-100 ° C, preferably 70-90 ° C.
  • the alkali promoter of the amidation reaction is sodium hydroxide, potassium carbonate, sodium carbonate, potassium t-butoxide, pyridine or triethylamine, preferably pyridine or triethylamine; and the solvent of the amidation reaction is dichloromethane Tetrahydrofuran, acetonitrile, N,N-dimethylformamide or dioxane, preferably dichloromethane or tetrahydrofuran; and the amidation reaction temperature is 0-90 ° C, preferably 30-50 ° C.
  • the preparation method of the Shakubiqu (I) according to the present invention has the characteristics of easy availability of raw materials, simple process and environmental protection economy, thereby facilitating the industrial production of the raw material medicine and promoting its economic technology. development of.
  • CN1348952A entitled “Chiral compounds (S)-(+) and (R) -(-)-1-( ⁇ -Aminobenzyl)-2-naphthol preparation method" Description of preparation of the compound (Publication date: May 15, 2002); raw material 2R-methyl-4-oxo
  • the -butyric acid (III) can be referred to "Journal of the American Chemical Society, 107 (2), 443-8; 1985", “Journal of the American Chemical Society, 126 (45), 14740-14745; 2004” and “ Tetrahedron, 63(26), 5754-5767; 2007” and the like for the preparation of the same compounds.
  • Embodiment 1 is a diagrammatic representation of Embodiment 1:
  • Embodiment 2 is a diagrammatic representation of Embodiment 1:
  • Embodiment 3 is a diagrammatic representation of Embodiment 3
  • Embodiment 4 is a diagrammatic representation of Embodiment 4:
  • Embodiment 5 is a diagrammatic representation of Embodiment 5:

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pyrrole Compounds (AREA)

Abstract

L'invention concerne un procédé de préparation d'un des constituants d'un nouveau médicament antihypertenseur de LCZ696, c'est-à-dire le sacubitril (sacubitril, AHU-377, I). Le procédé comprend les étapes de préparation suivantes : effectuer les étapes de cyclisation, d'addition, de débenzylation, d'ouverture de cycle, d'estérification, d'amidation et analogues sur un réactif d'induction chirale (S)-1-(alpha-aminobenzyl)-2-naphtol (base S-betti) et acide 2R-méthyl-4-oxo-butyrique pour préparer du sacubitril (I). Le procédé de préparation utilise des matières premières facilement disponibles, est un procédé simple, est économique et respectueux de l'environnement et est approprié pour une production industrielle.
PCT/CN2016/070020 2015-01-26 2016-01-04 Procédé de préparation de sacubitril Ceased WO2016119574A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
KR1020177023388A KR101961897B1 (ko) 2015-01-26 2016-01-04 사큐비톨의 제조방법

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201510039610.7A CN104557600B (zh) 2015-01-26 2015-01-26 沙库比曲的制备方法
CN201510039610.7 2015-01-26

Publications (1)

Publication Number Publication Date
WO2016119574A1 true WO2016119574A1 (fr) 2016-08-04

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PCT/CN2016/070020 Ceased WO2016119574A1 (fr) 2015-01-26 2016-01-04 Procédé de préparation de sacubitril

Country Status (3)

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KR (1) KR101961897B1 (fr)
CN (1) CN104557600B (fr)
WO (1) WO2016119574A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3272734A4 (fr) * 2015-03-20 2018-11-21 Crystal Pharmatech Co., Ltd. Forme cristalline de ahu377, procédé de préparation et utilisation de cette dernière
US11434192B2 (en) 2015-12-10 2022-09-06 Novartis Ag Process and intermediates
CN116655498A (zh) * 2023-05-24 2023-08-29 江苏福瑞康泰药业有限公司 一种沙库巴曲中间体的制备方法

Families Citing this family (23)

* Cited by examiner, † Cited by third party
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CN104557600B (zh) * 2015-01-26 2016-05-04 苏州明锐医药科技有限公司 沙库比曲的制备方法
CN106187808A (zh) * 2015-05-08 2016-12-07 苏州鹏旭医药科技有限公司 Ahu-377的制备方法、ahu-377中间体及ahu-377中间体的制备方法
CN104860894B (zh) * 2015-06-10 2017-05-17 北京博全健医药科技有限公司 一种抗心衰药lcz696的制备方法
CN106309388A (zh) * 2015-06-30 2017-01-11 深圳信立泰药业股份有限公司 一种用于心衰治疗的药物组合物及其制备方法
CN105085322B (zh) * 2015-08-15 2017-10-03 浙江永宁药业股份有限公司 Ahu‑377中间体的制备方法及其中间体和中间体的制备方法
CN105168205A (zh) * 2015-08-18 2015-12-23 泰力特医药（湖北）有限公司 一种血管紧张素ii受体和脑啡肽酶受体双重抑制剂lcz696的制备方法
CN105237560B (zh) * 2015-10-15 2018-07-06 上海博氏医药科技有限公司 一种lzc696中间体及其合成方法
CN106854187B (zh) * 2015-12-08 2020-04-14 苏州晶云药物科技股份有限公司 一种ahu-377和缬沙坦三钠盐共晶水合物晶型ii的制备方法
CN106977415B (zh) * 2016-01-15 2021-03-26 广东东阳光药业有限公司 一种沙库必曲的中间体及其制备方法
WO2017148357A1 (fr) 2016-02-29 2017-09-08 广东东阳光药业有限公司 Intermédiaire de sacubitril et procédé de préparation correspondant
CN105753733B (zh) * 2016-04-15 2019-06-18 苏州晶云药物科技股份有限公司 Ahu377的晶型及其制备方法与用途
US20190256454A1 (en) 2016-07-05 2019-08-22 Novartis Ag New process for early sacubitril intermediates
CN107602399B (zh) * 2016-07-11 2020-09-25 江西东邦药业有限公司 一种脑啡肽酶抑制剂中间体的制备方法
CN109563019A (zh) 2016-08-17 2019-04-02 诺华股份有限公司 Nep抑制剂合成的新方法和中间体
CN106380421B (zh) * 2016-08-26 2017-12-08 中国科学院上海有机化学研究所 沙库必曲的合成方法
CN108203396B (zh) * 2016-12-19 2020-12-08 江西东邦药业有限公司 一种脑啡肽酶抑制剂的合成
US10774036B2 (en) 2016-12-23 2020-09-15 Novartis Ag Process for early sacubitril intermediates
CN108238981A (zh) * 2016-12-23 2018-07-03 宁波爱诺医药科技有限公司 一种lcz-696关键中间体的制备方法
CN106699604B (zh) * 2017-01-09 2019-01-01 四川同晟生物医药有限公司 一种沙库比曲及其中间体的制备方法
CN106966926B (zh) * 2017-04-01 2018-10-19 沧州那瑞化学科技有限公司 一种lcz696中间体的制备方法
CN110878039A (zh) * 2019-12-18 2020-03-13 株洲千金药业股份有限公司 一种沙库巴曲缬沙坦钠杂质的制备方法
CN113121342B (zh) * 2019-12-31 2022-05-31 浙江医药股份有限公司新昌制药厂 一种沙库必曲中间体的制备方法及应用
CN121248547A (zh) * 2025-12-05 2026-01-02 瑞博(苏州)制药有限公司 一种联苯内酯化合物的制备方法

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CN102448928A (zh) * 2009-05-28 2012-05-09 诺瓦提斯公司 作为中性溶酶(neprilysin)抑制剂的取代的氨基丁酸衍生物
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CN103896796A (zh) * 2009-05-28 2014-07-02 诺华股份有限公司 作为脑啡肽酶抑制剂的取代的氨基丙酸衍生物
CN104230865A (zh) * 2013-06-13 2014-12-24 上海翰森生物医药科技有限公司 联芳基取代的4-氨基丁酸衍生物及其制备方法和用途
CN104557600A (zh) * 2015-01-26 2015-04-29 苏州明锐医药科技有限公司 沙库比曲的制备方法

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US5354892A (en) * 1992-01-22 1994-10-11 Ciba-Geigy Corporation Biaryl substituted 4-amino-butyric acid amides
CN101516831A (zh) * 2006-09-13 2009-08-26 诺瓦提斯公司 用于制备联芳基取代的4-氨基-丁酸或其衍生物的方法以及其在制备nep抑制剂中的应用
CN101631765A (zh) * 2007-01-12 2010-01-20 诺瓦提斯公司 用于制备5-联苯基-4-氨基-2-甲基戊酸的方法
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CN103896796A (zh) * 2009-05-28 2014-07-02 诺华股份有限公司 作为脑啡肽酶抑制剂的取代的氨基丙酸衍生物
CN103201257A (zh) * 2010-11-16 2013-07-10 诺瓦提斯公司 作为nep抑制剂的取代的氨基二苯基戊酸衍生物
CN103313708A (zh) * 2010-11-16 2013-09-18 诺瓦提斯公司 治疗造影剂诱导的肾病的方法
CN104230865A (zh) * 2013-06-13 2014-12-24 上海翰森生物医药科技有限公司 联芳基取代的4-氨基丁酸衍生物及其制备方法和用途
CN104557600A (zh) * 2015-01-26 2015-04-29 苏州明锐医药科技有限公司 沙库比曲的制备方法

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3272734A4 (fr) * 2015-03-20 2018-11-21 Crystal Pharmatech Co., Ltd. Forme cristalline de ahu377, procédé de préparation et utilisation de cette dernière
US11434192B2 (en) 2015-12-10 2022-09-06 Novartis Ag Process and intermediates
CN116655498A (zh) * 2023-05-24 2023-08-29 江苏福瑞康泰药业有限公司 一种沙库巴曲中间体的制备方法

Also Published As

Publication number Publication date
KR20170117091A (ko) 2017-10-20
CN104557600B (zh) 2016-05-04
KR101961897B1 (ko) 2019-03-25
CN104557600A (zh) 2015-04-29

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