WO2023029235A1 - Procédé de préparation d'un intermédiaire de sacubitril - Google Patents

Procédé de préparation d'un intermédiaire de sacubitril Download PDF

Info

Publication number
WO2023029235A1
WO2023029235A1 PCT/CN2021/132938 CN2021132938W WO2023029235A1 WO 2023029235 A1 WO2023029235 A1 WO 2023029235A1 CN 2021132938 W CN2021132938 W CN 2021132938W WO 2023029235 A1 WO2023029235 A1 WO 2023029235A1
Authority
WO
WIPO (PCT)
Prior art keywords
preparation
acid
hydroxyl
formula
compound
Prior art date
Application number
PCT/CN2021/132938
Other languages
English (en)
Chinese (zh)
Inventor
马保德
郑勇鹏
余弘毅
赵金辉
肖烨
Original Assignee
凯特立斯（深圳）科技有限公司
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by 凯特立斯（深圳）科技有限公司 filed Critical 凯特立斯（深圳）科技有限公司
Publication of WO2023029235A1 publication Critical patent/WO2023029235A1/fr

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
    • C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/16—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
    • C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/17—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D203/04—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D203/06—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D203/22—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
    • C07D203/24—Sulfur atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of medicinal chemical synthesis, and in particular relates to a preparation method of a sacubitril intermediate.
  • the method has short steps, simple operation, low cost and great industrial application value.
  • Sacubitril (AHU-377) is one of the main components of LCZ696 (CAS: 936623-90-4), an anti-heart failure drug developed by Novartis.
  • the drug is a supramolecular complex (complex) formed by non-covalent bonding of valsartan and AHU-377, which has dual effects of angiotensin receptor blocking and neutral endopeptidase inhibition, and reduces cardiovascular
  • the risk of disease mainly used to treat heart failure, can also be used for high blood pressure.
  • Sacubitril (AHU-377) usually needs to be prepared through the key intermediate N-Boc amino alcohol (I).
  • the chemical name of this intermediate is: N-[(1R)-2-[1,1'-biphenyl ]-4-yl-1-(hydroxymethyl)ethyl]tert-butyl carbamate; CAS: 1426129-50-1; Molecular formula: C20H25NO3; Molecular weight: 327.42; Structural formula:
  • Patent WO2014032627 and patent EP1903027 disclose the preparation method of N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester, synthesis The route looks like this:
  • triphenylphosphine a large amount of triphenoxyphosphine compounds are generated after the reaction, which makes separation and purification difficult
  • azodicarboxylate compounds are also used, and these compounds are sensitive to light, heat and vibration. Sensitive and potentially explosive when heated.
  • Chinese patent CN 105985225 discloses a preparation method of an intermediate of Shakubiqu, which is as follows
  • Chinese patent CN 105884656 discloses a preparation method of Shakubiqu intermediate, as follows:
  • benzylmagnesium bromide is used as a raw material to react with monomethyl oxalyl chloride to generate the required methyl ketoate; then under the action of a brominating reagent, the 4-position of the benzene ring is brominated; Copper-catalyzed coupling with phenylboronic acid to obtain biphenone ester; in the system of glucose, NADP + and reductase CGKR2 and GDH, catalyzed asymmetric reductive amination of keto ester to obtain chiral amino acid methyl ester; After Boc protects the amino group, under the action of sodium borohydride and Lewis acid, the methyl carboxylate is reduced to alcohol to obtain the key intermediate N-Boc amino alcohol
  • the above-mentioned method firstly, has the problem of a relatively long synthetic route, and secondly, it is inconvenient to use acid chloride and bromine reagent, and copper-catalyzed coupling and asymmetric reductive amination steps require the use of more metal copper and reductase; in addition, the patent The enantiomeric excess of the product after reductive amination is not indicated. Moreover, enzymes are expensive and have high requirements for reactions, so they are not suitable for industrial production.
  • the D-tyrosine used in this method is a non-natural amino acid, which is expensive; the reaction process also uses an expensive trifluoromethanesulfonic anhydride reagent, and this reagent is very active and corrosive, and has high requirements for production equipment and operation. Good for industrial applications.
  • Chinese patent CN103764624 discloses a method for preparing sacubitril intermediate amino alcohol by using p-phenylbenzaldehyde as a raw material, and its synthetic route is as follows:
  • This method uses the precious metals Rh and Pd, resulting in high production costs; and the operation of lithium aluminum hydride is potentially dangerous
  • the present invention aims to provide a simple and efficient method for preparing the intermediate of sacubitril.
  • the method has the characteristics of low cost, easy operation, environmental friendliness and the like, and is suitable for industrialized production and the like.
  • a preparation method of a sacubitril intermediate which relates to a preparation method of a sacubitril intermediate N-Boc amino alcohol (I), including steps a to f in the synthetic route:
  • X is a halogen, hydroxyl or protected hydroxyl
  • the activated reagent of hydroxyl is acid chloride, sulfonyl chloride, chlorosilane, etc.
  • the base (Base) is selected from sodium salt and potassium salt
  • the acid (acid) is an inorganic acid.
  • the compound of formula 7, the compound of formula 8 and the compound of formula I are the intermediates of sacubitril required by the present invention.
  • the compound of formula 5 can be prepared by a step-by-step method, and can also be synthesized by a one-pot method.
  • the step a is to prepare the corresponding N-Ts amino alcohol (formula 3) from chloramine-T trihydrate (formula 1) and propylene oxide derivatives (formula 2) in a solvent.
  • the X group in the propylene oxide derivative (Formula 2) is selected from chlorine, bromine, hydroxyl, siloxy, alkoxy, acyloxy, more preferably chlorine, hydroxyl , acyloxy and siloxy.
  • the molar ratio of the propylene oxide derivative (Formula 2) to chloramine-T trihydrate (Formula 1) is 1-2:1, more preferably 1-1.2:1 .
  • the reaction solvent is selected from tetrahydrofuran, dichloromethane, toluene, acetonitrile, N,N-dimethylformamide or solvent-free conditions, more preferably acetonitrile or solvent-free.
  • the reaction temperature is selected from 0-100°C, more preferably 20-50°C, and still more preferably 25-37°C.
  • the step b is to use an activated reagent to activate the secondary alcohol on the N-Ts amino alcohol (Formula 3) in the presence of a base.
  • the activated reagent is selected from sulfuryl chloride, chlorosilane and acid chloride, more preferably sulfuryl chloride, and even more preferably MsCl, TsCl and NsCl.
  • the molar ratio of the activated reagent to the N-Ts amino alcohol is 1 to 2:1, more preferably 1.0 to 1.2:1, and even more preferably 1.05- 1.15:1.
  • the base is selected from triethylamine, trimethylamine, tri-n-butylamine, N,N-diethylpropylamine, N,N-diethylmethylamine, 2-ethoxy Any of ethylamine, N-isopropylethylenediamine, pyridine, piperidine, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide One, more preferably triethylamine, N,N-diethylpropylamine, sodium hydroxide, potassium tert-butoxide, more preferably triethylamine, sodium hydroxide.
  • the molar ratio of the base to the activated reagent (activated reagent) is 1-2:1, more preferably 1.05-1.3:1, still more preferably 1.1-1.2:1.
  • the reaction temperature is selected from -20-60°C, more preferably -10-35°C, still more preferably -5-30°C.
  • the reaction solvent is selected from tetrahydrofuran, dichloromethane, toluene, acetonitrile, N,N-dimethylformamide or solvent-free conditions, more preferably acetonitrile or solvent-free.
  • the step c is to cyclize the compound of formula 4 under the action of a base to generate the compound of acridine formula 5.
  • the base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, bis(trimethyl Any one of silicon-based) lithium amide (LiHMDS), bis(trimethylsilyl) potassium amide (KHMDS), and lithium diisopropylamide (LDA), more preferably bis(trimethylsilyl) Any one of potassium amide (KHMDS), more preferably sodium hydroxide, potassium hydroxide or cesium carbonate.
  • LiHMDS silicon-based lithium amide
  • KHMDS bis(trimethylsilyl) potassium amide
  • LDA lithium diisopropylamide
  • the molar ratio of the amount of base to the compound of formula 4 is 1-2:1, more preferably 1.0-1.2:1, and still more preferably 1.05-1.15:1.
  • the reaction temperature is selected from -20-60°C, more preferably -10-35°C, still more preferably -5-30°C.
  • the reaction solvent is selected from tetrahydrofuran, dichloromethane, toluene, acetonitrile, N,N-dimethylformamide or solvent-free conditions, more preferably acetonitrile or solvent-free.
  • the compound of the formula 6 of the Grignard reagent performs nucleophilic addition to the compound of the formula 5 of the acridine to generate the compound of the formula 7.
  • the molar ratio of the Grignard reagent formula 6 compound to the formula 5 compound is 1-2:1, more preferably 1-1.5:1, further preferably 1.05-1.20:1.
  • the reaction temperature is selected from -20-100°C, more preferably -10-75°C, still more preferably -5-60°C.
  • the reaction solvent is selected from any one of tetrahydrofuran, dichloromethane, toluene, acetonitrile, and N,N-dimethylformamide, more preferably tetrahydrofuran or toluene.
  • the base (Base) described in step c is selected from sodium hydroxide or potassium hydroxide.
  • the solvent used in step d is THF, and the temperature is -30-10°C.
  • the additive used in step d is cuprous iodide, and the added mass is 5%-25%.
  • the compound of formula 7 is removed from the Ts protecting group on the nitrogen under the action of acid to generate the compound of formula 8 amino alcohol.
  • the acid is selected from any one of hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid, phosphoric acid, acetic acid, perchloric acid, nitrous acid, hypochlorous acid, lactic acid, propionic acid, further Hydrochloric acid, sulfuric acid, hydrobromic acid are preferred.
  • the amount of acid used is preferably 1-10 equivalents, more preferably 1-5 equivalents.
  • step e the reaction is performed under heating reflux, ultrasonic or microwave conditions, more preferably heating reflux or microwave.
  • the reaction solvent is selected from methanol, ethanol, isopropanol, toluene, acetonitrile, tetrahydrofuran, DMF, 1,4-dioxane or water, more preferably 1,4-dioxane ring or water.
  • the amino alcohol compound of formula 8 reacts with Boc 2 O in a base and a solvent to generate the N-Boc amino alcohol compound of formula I.
  • the base is selected from any one of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide and lithium hydroxide, more preferably sodium hydroxide and potassium hydroxide.
  • the molar ratio of Boc 2 O to the compound of amino alcohol formula 8 is 1-2:1, more preferably 1.05-1.5:1, and even more preferably 1.05-1.15:1.
  • the molar ratio of alkali to Boc 2 O is 1-2:1, more preferably 1.05-1.20:1, and even more preferably 1.05-1.10:1.
  • the reaction solvent is selected from methanol, ethanol, isopropanol, toluene, acetonitrile, tetrahydrofuran, DMF, 1,4-dioxane or water, more preferably methanol, 1,4-dioxane Oxyhexane, tetrahydrofuran
  • the reaction temperature is selected from -20-55°C, more preferably -10-45°C, still more preferably -5-35°C.
  • the present invention also provides a novel intermediate compound: a compound 7 whose chemical structural formula is:
  • X is halogen, hydroxyl or protected hydroxyl, preferably X is chlorine, bromine, hydroxyl, siloxy, alkoxy, acyloxy;
  • the present invention has the following advantageous effects:
  • the starting material chloramine-T trihydrate (formula 1) and the compound of propylene oxide formula 2 are easily and easily obtained, and the key aza three-membered ring compound 5 is generated through a three-step reaction, and then biphenyl is introduced through the Grignard reaction group, and then change the Ts on the nitrogen into a Boc group to complete the preparation of the N-Boc aminoalcohol formula I compound.
  • the entire route is simple to operate, safe and pollution-free, has no special requirements for equipment, and has low production costs. It is suitable for industrial production and has significant progress compared with the existing technology.
  • Fig. 1 is a schematic diagram of the synthetic route of the present invention
  • Fig. 2 is the proton NMR spectrum collection of compounds 5a;
  • Fig. 3 is the proton NMR spectrum collection of compounds 7a
  • Figure 4 is the H NMR spectrum of compound I.
  • Embodiment 1 (R)-N-(3-chloro-2-hydroxypropyl)-4-methylbenzenesulfonamide (R)-N-(3-chloro-2-hydroxypropyl)-4-methylbenzenesulfonamide (formula 3a) Preparation

Landscapes

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

Abstract

La présente invention relève du domaine technique de la synthèse chimique et concerne un procédé de préparation d'un intermédiaire de sacubitril. Le procédé comprend la production d'un composé 5 aza-tricyclique clé par l'utilisation de matières premières, de trihydrate de chloramine-T (formule 1) et d'un composé époxypropane tel que représenté dans la formule 2 qui sont simples et faciles à obtenir, au moyen d'une réaction en trois étapes, puis par introduction de biphényle au moyen d'une réaction de Grignard, ensuite la conversion de Ts sur l'azote en un groupe Boc, et la préparation du composé d'alcool aminé N-Boc de formule I. L'ensemble du procédé est simple à utiliser, sans danger et sans pollution, ne présente pas d'exigences particulières pour l'équipement, a un faible coût de production, est approprié pour une production industrielle, et a une progression notable par rapport à l'état de la technique.
PCT/CN2021/132938 2021-09-03 2021-11-25 Procédé de préparation d'un intermédiaire de sacubitril WO2023029235A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202111033114.2A CN115745841B (zh) 2021-09-03 2021-09-03 一种沙库必曲中间体的制备方法
CN202111033114.2 2021-09-03

Publications (1)

Publication Number Publication Date
WO2023029235A1 true WO2023029235A1 (fr) 2023-03-09

Family

ID=85332615

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/132938 WO2023029235A1 (fr) 2021-09-03 2021-11-25 Procédé de préparation d'un intermédiaire de sacubitril

Country Status (2)

Country Link
CN (1) CN115745841B (fr)
WO (1) WO2023029235A1 (fr)

Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105330569A (zh) * 2015-09-11 2016-02-17 天台宜生生化科技有限公司 一种(r)-2-(n-叔丁氧羰基氨基)联苯丙醇的制备方法
CN106397273A (zh) * 2015-07-31 2017-02-15 四川海思科制药有限公司 一种沙库比曲中间体的改进制备方法
CN106496055A (zh) * 2016-10-09 2017-03-15 杭州科巢生物科技有限公司 一种抗心衰新药的关键组分沙库比曲的新合成方法
CN106905192A (zh) * 2017-03-09 2017-06-30 常州沃腾化工科技有限公司 一种沙库必曲中间体的纯化方法
CN107382779A (zh) * 2017-07-27 2017-11-24 江苏中邦制药有限公司 一种沙库必曲中间体的制备方法
CN107382785A (zh) * 2017-08-09 2017-11-24 常州制药厂有限公司 一种沙库必曲关键中间体的制备方法
WO2017203474A1 (fr) * 2016-05-27 2017-11-30 Dr. Reddy's Laboratories Limited Procédé de préparation d'intermédiaire de sacubutril
CN107540574A (zh) * 2017-09-19 2018-01-05 成都西岭源药业有限公司 R‑联苯丙氨醇的制备方法
CN108675943A (zh) * 2018-06-13 2018-10-19 常州亚邦制药有限公司 一种沙库巴曲关键中间体的制备方法
CN109415308A (zh) * 2016-07-05 2019-03-01 诺华股份有限公司 用于早期沙卡布曲中间体的新方法
CN110183357A (zh) * 2019-06-13 2019-08-30 甘肃皓天医药科技有限责任公司 一种用于制备沙库比曲中间体的制备方法
CN111943862A (zh) * 2019-05-16 2020-11-17 上海迪赛诺药业股份有限公司 一种抗心衰新药Entresto关键成分沙库巴曲的制备方法
CN113135841A (zh) * 2020-01-20 2021-07-20 鲁南制药集团股份有限公司 一种沙库巴曲中间体的制备方法
CN113387829A (zh) * 2020-03-13 2021-09-14 凯特立斯（深圳）科技有限公司 一种沙库必曲的制备方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105254589B (zh) * 2015-10-15 2018-07-31 上海博氏医药科技有限公司 一种制备心力衰竭药物中间体的方法
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

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106397273A (zh) * 2015-07-31 2017-02-15 四川海思科制药有限公司 一种沙库比曲中间体的改进制备方法
CN105330569A (zh) * 2015-09-11 2016-02-17 天台宜生生化科技有限公司 一种(r)-2-(n-叔丁氧羰基氨基)联苯丙醇的制备方法
WO2017203474A1 (fr) * 2016-05-27 2017-11-30 Dr. Reddy's Laboratories Limited Procédé de préparation d'intermédiaire de sacubutril
CN109415308A (zh) * 2016-07-05 2019-03-01 诺华股份有限公司 用于早期沙卡布曲中间体的新方法
CN106496055A (zh) * 2016-10-09 2017-03-15 杭州科巢生物科技有限公司 一种抗心衰新药的关键组分沙库比曲的新合成方法
CN106905192A (zh) * 2017-03-09 2017-06-30 常州沃腾化工科技有限公司 一种沙库必曲中间体的纯化方法
CN107382779A (zh) * 2017-07-27 2017-11-24 江苏中邦制药有限公司 一种沙库必曲中间体的制备方法
CN107382785A (zh) * 2017-08-09 2017-11-24 常州制药厂有限公司 一种沙库必曲关键中间体的制备方法
CN107540574A (zh) * 2017-09-19 2018-01-05 成都西岭源药业有限公司 R‑联苯丙氨醇的制备方法
CN108675943A (zh) * 2018-06-13 2018-10-19 常州亚邦制药有限公司 一种沙库巴曲关键中间体的制备方法
CN111943862A (zh) * 2019-05-16 2020-11-17 上海迪赛诺药业股份有限公司 一种抗心衰新药Entresto关键成分沙库巴曲的制备方法
CN110183357A (zh) * 2019-06-13 2019-08-30 甘肃皓天医药科技有限责任公司 一种用于制备沙库比曲中间体的制备方法
CN113135841A (zh) * 2020-01-20 2021-07-20 鲁南制药集团股份有限公司 一种沙库巴曲中间体的制备方法
CN113387829A (zh) * 2020-03-13 2021-09-14 凯特立斯（深圳）科技有限公司 一种沙库必曲的制备方法

Also Published As

Publication number Publication date
CN115745841B (zh) 2024-04-16
CN115745841A (zh) 2023-03-07

Similar Documents

Publication Publication Date Title
CN104230978B (zh) 依折麦布的制备中间体及其制备方法
CN110526859B (zh) 一种瑞维那新中间体及其制备方法和瑞维那新的制备方法
JP5115477B2 (ja) 水酸基を有する３−エチルオキセタン化合物及びその製法
CN107216307A (zh) 一种高效合成1,1‑二芳基烷烃类化合物的方法
CN104177331B (zh) 比拉斯汀的制备方法
WO2020207129A1 (fr) Préparation et utilisation d'un sel d'ammonium
WO2023029235A1 (fr) Procédé de préparation d'un intermédiaire de sacubitril
CN103073492A (zh) 2-[3-(s)-[3-[2-(7-氯-2-喹啉基)乙烯基]苯基]-3-羟基丙基]苯甲酸酯的合成方法
JP4161290B2 (ja) ピリミジニルアルコール誘導体の製造方法及びその合成中間体
US7368608B2 (en) 1-amido-3-(2-hydroxyphenoxy)-2-propanol derivatives and a process for preparing 2-amidomethyl-1,4-benzodioxane derivatives
CN113548982A (zh) 一种4-氰基-2-氟苄醇的制备方法
JP4899385B2 (ja) ３−アミノメチルオキセタン化合物の製法
JP2007291010A (ja) 光学活性２−メチルエピハロヒドリン等の製造法
WO2005021465A1 (fr) Procede de production de compose insature aromatique
CN102993116A (zh) 一种苯并噁嗪类激动剂的制备方法
CN113493388B (zh) 一种盐酸布替萘芬的合成方法
CN112759542B (zh) 一种药物中间体及其制备和应用
TWI397527B (zh) 合成ｎ-〔３-〔（２-甲氧苯基）硫烷基〕-２-甲基丙基〕-３，４-二氫-２ｈ-１，５-苯並噻庚因-３-胺之方法
CN113493385B (zh) 一种合成盐酸布替萘芬的方法
JP2022035954A (ja) Ｎ－Ｂｏｃ－ラクタム誘導体及びその製造方法、並びに、環状アミン誘導体の製造方法
CN106432003A (zh) 一种3‑砜基腈类化合物的合成方法
JP2009126784A (ja) ２−ヨード−３，４−ジメトキシベンゾニトリルの製造方法。
JP4750286B2 (ja) 反応活性な基を有する新規なビフェニル化合物の製造方法
WO2023206874A1 (fr) Intermédiaire du sacubitril, son procédé de préparation et son utilisation
WO2004011451A1 (fr) Procede de production industrielle de derives de 1,4-benzodioxane optiquement actifs

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21955763

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE