WO2015037460A1 - PROCÉDÉ DE PRODUCTION DE 3-(BIPHÉNYLE-4-YL)-2-[(t-BUTOXYCARBONYL)AMINO]PROPAN-1-OL OPTIQUEMENT ACTIF - Google Patents

PROCÉDÉ DE PRODUCTION DE 3-(BIPHÉNYLE-4-YL)-2-[(t-BUTOXYCARBONYL)AMINO]PROPAN-1-OL OPTIQUEMENT ACTIF Download PDF

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WO2015037460A1
WO2015037460A1 PCT/JP2014/072854 JP2014072854W WO2015037460A1 WO 2015037460 A1 WO2015037460 A1 WO 2015037460A1 JP 2014072854 W JP2014072854 W JP 2014072854W WO 2015037460 A1 WO2015037460 A1 WO 2015037460A1
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formula
optically active
reaction
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compound
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淳一 友川
秋山　雅紀
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住友化学株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • 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
    • 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
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to a method for producing optically active 3- (biphenyl-4-yl) -2-[(t-butoxycarbonyl) amino] propan-1-ol.
  • R a , R b and R c represent a C1-C6 alkyl group or a benzyl group
  • Z represents a leaving group such as a chlorine atom or a bromine atom
  • Ac represents an acetyl group
  • Boc represents t- Represents a butoxycarbonyl group.
  • the present invention uses optically active N-acyl-4-biphenylalanine (for example, N-acetyl-4-biphenylalanine), which is relatively inexpensive and easily available, as a raw material, and has high optical purity 3- (biphenyl-4-yl)-.
  • N-acyl-4-biphenylalanine for example, N-acetyl-4-biphenylalanine
  • the present invention is as follows. [1] A process for producing optically active 3- (biphenyl-4-yl) -2-[(t-butoxycarbonyl) amino] propan-1-ol, comprising the following steps 1 and 2.
  • Step 1 Formula [I] (In the formula, R 1 represents an alkyl group having 1 to 4 carbon atoms or an optionally substituted phenyl group, R 2 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and * represents S- or R- Indicates the carbon atom that is the configuration.) Is reacted with an optically active biphenylalanine represented by the formula [II] (In the formula, R 1 and R 2 have the same meaning as described above, and * represents a carbon atom in the S- or R-configuration as in the formula [I].) Obtaining an optically active biphenylalaninol represented by: Step 2: The optically active biphenylalaninol represented by the formula [II] obtained in Step 1 is hydrolyzed under acidic conditions, and then the product is reacted with di-t-butyl dicarbonate to obtain the formula [III].
  • a step of obtaining optically active 3- (biphenyl-4-yl) -2-[(t-butoxycarbonyl) amino] propan-1-ol (hereinafter referred to as Compound C) represented by the formula: [2]
  • R 1 is a methyl group.
  • R 1 is a methyl group.
  • R 2 is a methyl group.
  • an optically active biphenylalanine (hereinafter referred to as Compound A) represented by the formula [I] is used as a starting material, and a compound C having high optical purity is efficiently obtained through a plurality of steps from Step 1 to Step 2. It is a manufacturing method.
  • the alkyl group having 1 to 4 carbon atoms include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, and a sec-butyl group.
  • an optionally substituted phenyl group for example, a phenyl group 4-methoxyphenyl group and 2-chlorophenyl group.
  • the group represented by R 1 —C ( ⁇ O) in the formula [I] and the formula [II] has a role as a protecting group for the amino group, but in the present invention, the group represented by R 1 Is preferably a methyl group or a phenyl group, more preferably a methyl group.
  • the R 2 group in the formula [I] is preferably an alkyl group having 1 to 4 carbon atoms, and more preferably a methyl group.
  • the compound A is appropriately selected from the viewpoints of availability of raw materials, reactivity in the step 1 and step 2 in the present invention, N-acylbiphenylalanine methyl ester is preferable, and N-acetylbiphenylalanine is preferred. Methyl ester or N-benzoylbiphenylalanine methyl ester is more preferred.
  • acyl means a group represented by R—C ( ⁇ O) (R is an alkyl group having 1 to 4 carbon atoms or an optionally substituted phenyl group).
  • boron hydride such as lithium borohydride, sodium borohydride, borane (diborane or borane complex), and sodium borohydride and an alcohol solvent Or a composite system such as a combination of sodium borohydride and a Lewis acid.
  • the reaction substrate is N-acylbiphenylalanine methyl ester (a compound in which R 2 is a methyl group in Formula [I])
  • the reducing agent is preferably a combination of sodium borohydride and methanol.
  • the amount of the reducing agent is usually 1 mol or more of the reducing agent as a hydride source with respect to 1 mol of Compound A.
  • the amount of sodium borohydride or lithium borohydride is usually 0.5 to 5 moles relative to 1 mole of Compound A. Mole is preferred.
  • the amount of sodium borohydride is usually 0.5 to 5 mol, preferably 1 to 1.5 mol, relative to 1 mol of compound A.
  • the amount of methanol is usually 1 to 10 mol, preferably 2 to 4 mol.
  • the reaction of step 1 is performed in a solvent.
  • the solvent examples include aromatic hydrocarbon solvents such as benzene, toluene, and xylene, halogenated hydrocarbon solvents such as chlorobenzene, and organic solvents such as ether solvents such as diethyl ether, dibutyl ether, tetrahydrofuran, 1,4-dioxane, and tetrahydropyran.
  • aromatic hydrocarbon solvents such as benzene, toluene, and xylene
  • halogenated hydrocarbon solvents such as chlorobenzene
  • organic solvents such as ether solvents such as diethyl ether, dibutyl ether, tetrahydrofuran, 1,4-dioxane, and tetrahydropyran.
  • ether solvents such as diethyl ether, dibutyl ether or tetrahydrofuran, and it is more preferable to use tetrahydrofuran.
  • the amount of the solvent is usually 1 to 20 parts by weight with respect to 1 part by weight of Compound A, and preferably 2 to 5 parts by weight.
  • Step 1 when a combination of sodium borohydride and methanol is used as a reducing agent, a method of gradually adding methanol to a mixture of Compound A, sodium borohydride and a solvent at 0 to 30 ° C. preferable.
  • the reaction in step 1 is usually carried out in the temperature range of 0 to 80 ° C, preferably in the range of 0 to 30 ° C, more preferably in the range of 5 to 25 ° C.
  • the reaction time in step 1 is usually 1 to 20 hours, and the reaction is usually continued until it is confirmed by the reaction check that compound A has disappeared.
  • the reaction mixture is preferably added with an acid such as hydrochloric acid and water to decompose excess reducing agent, and then subjected to a usual post-treatment operation to obtain an optical activity represented by the formula [II].
  • Biphenylalaninol hereinafter referred to as Compound B
  • the normal post-treatment operation is, for example, an operation for extracting the product compound B from the reaction mixture with an organic solvent, and if necessary, salting out extraction is performed.
  • the obtained compound B can be purified by recrystallization or the like.
  • Examples of the organic solvent used for extraction in the post-treatment operation in Step 1 include aromatic hydrocarbon solvents such as benzene, toluene, and xylene, halogenated hydrocarbon solvents such as chlorobenzene, ester solvents such as ethyl acetate, diethyl ether, and dibutyl ether. , Ether solvents such as tetrahydrofuran, or a mixed solvent composed of two or more of them if necessary. If the organic solvent used in the reaction sufficiently dissolves Compound B and can be separated from the aqueous layer containing reaction by-products, it is not necessary to newly use an organic solvent for extraction in the post-treatment operation.
  • aromatic hydrocarbon solvents such as benzene, toluene, and xylene
  • halogenated hydrocarbon solvents such as chlorobenzene
  • ester solvents such as ethyl acetate, diethyl ether, and dibutyl ether.
  • Ether solvents such
  • Step 1 the solution containing Compound B obtained by the extraction operation is partially concentrated as necessary, and then an aliphatic hydrocarbon solvent such as heptane or hexane is added to obtain crystals of Compound B. It can be deposited. Subsequently, the precipitated crystals of compound B are separated by filtration, and then washed and dried as necessary, whereby crystals of compound B with high optical purity can be obtained.
  • the solvent used for washing include nonpolar solvents such as heptane and hexane. The amount of the solvent used for washing is 0.1 to 5 parts by weight with respect to 1 part by weight of Compound B.
  • Compound B used in Step 2 can be an isolated crystal of Compound B, but in some cases, after completion of the reaction in Step 1, a reaction mixture containing Compound B is isolated without isolating Compound B.
  • step 1 and step 2 can be carried out continuously.
  • the post-treatment operation of compound B becomes unnecessary, and the amount of extraction solvent and the like used can be reduced.
  • the reaction system is preferably made acidic by adding an inorganic acid to the reaction system, and hydrochloric acid is added to the reaction system. More preferably, the acidic condition is set.
  • Step 2 When Step 2 is continuously performed without isolating Compound B after completion of the reaction in Step 1, the reaction mixture in Step 1 is hydrolyzed by adding an inorganic acid such as hydrochloric acid and water. A decomposition reaction is carried out. At this time, you may add the reaction mixture of the process 1 with respect to the mixture of an inorganic acid and water.
  • the excess reducing agent used at the process 1 remains in the reaction mixture after completion
  • the quantity of the inorganic acid to be used should be added more than the quantity required for decomposition
  • the amount of the inorganic acid is not particularly limited, but the pH in the reaction mixture for the hydrolysis reaction is usually 2 or less, and preferably 1 or less.
  • the hydrolysis reaction in Step 2 is usually performed within a temperature range of 0 to 80 ° C, preferably within a range of 40 to 80 ° C, and more preferably within a range of 50 to 70 ° C.
  • the reaction time in Step 2 is usually 1 to 20 hours, and the reaction is usually continued until the disappearance of Compound B is confirmed by a reaction check.
  • compound C is obtained by reacting the product with di-t-butyl dicarbonate. Usually, after completion of the hydrolysis reaction without isolating the product after hydrolysis.
  • T-Butoxycarbonylation reaction is carried out by adding di-t-butyl dicarbonate to the reaction mixture.
  • the t-butoxycarbonylation reaction in step 2 is preferably performed under alkaline conditions, and more preferably adjusted to alkaline conditions by adding a base of sodium hydroxide or potassium hydroxide to the reaction system.
  • the hydrolysis reaction in step 2 is preferably carried out under acidic conditions by adding hydrochloric acid. Therefore, when the t-butoxycarbonylation reaction is carried out subsequent to the hydrolysis reaction, the acid remaining after the hydrolysis reaction is reduced. It is necessary to use an excess of base.
  • the amount of the base is not particularly defined, but the pH in the reaction mixture of the t-butoxycarbonylation reaction is usually 8 or more at the start of the t-butoxycarbonylation reaction, and 10 at the start of the t-butoxycarbonylation reaction.
  • the amount of di-t-butyl dicarbonate is usually 0.9 to 1.5 mol, preferably 1.0 to 1.1 mol, relative to 1 mol of Compound B.
  • the amount of di-t-butyl dicarbonate is usually 0.9 to 1.5 with respect to 1 mole of Compound A. Mol, preferably 1.0 to 1.1 mol.
  • the t-butoxycarbonylation reaction in Step 2 is usually performed within a temperature range of 0 to 80 ° C, preferably within a range of 10 to 60 ° C, and more preferably within a range of 20 to 50 ° C.
  • the reaction time is usually 1 to 10 hours.
  • compound C can be obtained by subjecting the reaction mixture to conventional post-treatment operations.
  • the usual post-treatment operation is, for example, an operation of extracting the product compound C from the reaction mixture with an organic solvent. If necessary, the pH of the reaction mixture is adjusted or salting-out extraction is performed.
  • Examples of the organic solvent used for extraction in the post-treatment operation after completion of the t-butoxycarbonylation reaction in Step 2 include aromatic hydrocarbon solvents such as benzene, toluene and xylene, halogenated hydrocarbon solvents such as chlorobenzene, and ethyl acetate. Ester solvents, ether solvents such as diethyl ether, dibutyl ether, and tetrahydrofuran, and mixed solvents of two or more thereof. If the organic solvent used in the reaction sufficiently dissolves Compound C and can be separated from the aqueous layer containing reaction by-products, it is not necessary to newly use an organic solvent for extraction in the post-treatment operation.
  • Step 2 by distilling off the organic solvent from the solution containing Compound C obtained by the extraction operation, for example, by solvent substitution with 2-propanol, Crystals of compound C can be precipitated from the solution.
  • the obtained compound C can be purified by recrystallization or the like.
  • the amount of 2-propanol used is usually 2 to 10 parts by weight per 1 part by weight of compound C.
  • the precipitated crystals of compound C are separated by filtration, and then washed and dried as necessary to obtain crystals of compound C with high optical purity.
  • Examples of the solvent used for washing include an alcohol solvent such as 2-propanol and a mixed solvent of an alcohol solvent and water in an arbitrary ratio.
  • the amount of the solvent used for washing is 0.1 to 5 parts by weight with respect to 1 part by weight of Compound C.
  • the reducing agent sodium borohydride, etc.
  • acid hydroochloric acid, etc.
  • base sodium hydroxide, potassium hydroxide
  • di-t-butyl dicarbonate, solvent, etc. used in the production method of the present invention are industrial. A commercial product of the grade used in the above can be used.
  • Compound A used in the production method of the present invention can be produced, for example, by a known method shown below or a method according to a known method.
  • ⁇ -acetamino-4-phenylcinnamic acid represented by the formula [VI-1] is described in, for example, Org. Synth. , Coll. Vol. 2, 1 (1943).
  • the ⁇ -acetamino-4-phenylcinnamic acid represented by the formula [VI-1] is methyl esterified, for example, by the method described in Chemische Berichte 28, 3252, or Org. Synth. , Coll. Vol.
  • An ⁇ -acetamino-4-phenylcinnamic acid represented by the formula [VI-1] or an ⁇ -acetamino-4-phenylcinnamic acid methyl ester represented by the formula [VI-2] can be prepared by, for example, Advanced Synthesis & Catalysis (2003), 345 (1 + 2), 308, Journal of Organometallic Chemistry (2003), 687 (2), 494, and JP-A No. 2003-261522, a catalyst comprising a combination of an optically active phosphine compound and a rhodium compound is used.
  • optically active phosphine compound used in the asymmetric hydrogenation reaction examples include 1-[(R) -ferrocenyl-2- (S) -ethyl-1- (dimethylamino) phenyl]-(R) -phosphino-1 ′.
  • SL-F356-1 1-[(S) -ferrocenyl-2- (R) -ethyl-1- (dimethylamino) phenyl]-(S) -phosphino-1 '-Dicyclohexylphosphinoferrocene (hereinafter referred to as SL-F356-2), (-)-1,2-bis [(2R, 5R) -2,5-dimethylphosphorano] benzene (hereinafter referred to as (R, R ) -Me-DuPhos), (+)-1,2-bis [(2S, 5S) -2,5-dimethylphosphorano] benzene (hereinafter referred to as (S, S) -Me-DuPhos) ( ⁇ )-1,2-bis [(2R, 5R) -2,5-diethylphosphorano] benzene
  • (S, S) -1,2-bis [(2-methoxyphenyl) (phenylphosphino)] ethane (hereinafter referred to as (S, S) -DIPAMP), preferably SL— F356-1, S -F356-2, (R, R) -Et-DuPhos, (S, S) -Et-DuPhos, (R, R) -DIPAMP or (S, S) -DIPAMP, particularly preferably SL-F356-1, SL-F356-2, (R, R) -DIPAMP or (S, S) -DIPAMP can be used.
  • the amount of the optically active phosphine compound used in the asymmetric hydrogenation reaction is usually 1 to 5 mol, preferably 1.01 to 2 mol, per 1 mol of the rhodium compound.
  • rhodium compounds used in the asymmetric hydrogenation reaction include [Rh (nbd) 2 ] X, [Rh (cod) 2 ] X, [Rh (nbd) Cl] 2 , and [Rh (cod) Cl] 2.
  • [Rh (nbd) 2 ] BF 4 is used.
  • rhodium compound used is 1 mol of compound D
  • the amount is usually 0.00001 to 0.01 mol, preferably 0.00005 to 0.001 mol.
  • the asymmetric hydrogenation reaction is performed in a solvent.
  • the solvent examples include alcohol solvents such as methanol, ethanol and 2-propanol, polar organic solvents such as acetonitrile, dimethylformamide and dimethyl sulfoxide, ether solvents such as tetrahydrofuran, dioxane and dimethyl ether, dichloromethane, chloroform and 1,1,1-trichloroethane.
  • Alcohol solvents such as methanol, ethanol and 2-propanol
  • polar organic solvents such as acetonitrile, dimethylformamide and dimethyl sulfoxide
  • ether solvents such as tetrahydrofuran, dioxane and dimethyl ether, dichloromethane, chloroform and 1,1,1-trichloroethane.
  • Halogenated hydrocarbon solvents such as toluene, aromatic hydrocarbon solvents such as toluene and xylene, and mixed solvents of two or more of these.
  • the asymmetric hydrogenation reaction can be appropriately selected depending on the reaction conditions such as the solvent, the specifications of the autoclave as a reduction device, etc., but is usually carried out within a temperature range of 0 to 150 ° C.
  • the reaction is usually performed within 1 to 12 hours within a range of 20 MPa.
  • the compound A can be isolated by adding water to the reaction mixture and then filtering the precipitated crystals, or performing an ordinary post-treatment operation such as extraction operation in an organic solvent.
  • Compound A can be purified by recrystallization or the like.
  • the product has a chemical purity of 99.1% and an optical purity of 99.8% e.e. e. Met.
  • the NMR spectrum of the product crystal is shown below.
  • Example 7 Instead of (R) -N-acetylbiphenylalanine methyl ester of Example 1, chemical purity 99.9%, optical purity 100.0% e.e. e. (S) -N-benzoylbiphenylalanine ethyl ester was used in the same manner as in Example 1 to obtain (S) -N-benzoylbiphenylalaninol (yield 98.5%). The product has a chemical purity of 99.7% and an optical purity of 99.9% e.e. e. Met.
  • Example 8 In a test tube type reaction vessel, chemical purity 99.3%, optical purity 100.0% e.e. e.
  • optically active optically active formula [III] 3- (biphenyl-4-yl) -2-[(t-butoxycarbonyl) amino] represented by the optically active optically active formula [III], which is a compound useful as a pharmaceutical intermediate compound Propan-1-ol can be produced efficiently.

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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé de production du 3-(biphényle-4-yl)-2-[(t-butoxycarbonyl)amino]propan-1-ol optiquement actif par une étape de réaction d'un composé biphénylalanine optiquement actif représenté par la formule [I] avec un agent réducteur pour produire un composé biphénylalaninol optiquement actif représenté par la formule [II]; et par une étape d'hydrolyse du composé biphénylalaninol optiquement actif représenté par la formule [II], qui est produit au cours de l'étape précédente, dans des conditions acides, puis de réaction du produit obtenu avec du dicarbonate de tert-butyle pour produire le 3-(biphényle-4-yl)-2-[(t-butoxycarbonyl)amino]propan-1-ol optiquement actif représenté par la formule [III].
PCT/JP2014/072854 2013-09-10 2014-08-26 PROCÉDÉ DE PRODUCTION DE 3-(BIPHÉNYLE-4-YL)-2-[(t-BUTOXYCARBONYL)AMINO]PROPAN-1-OL OPTIQUEMENT ACTIF WO2015037460A1 (fr)

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CN105017082A (zh) * 2015-07-31 2015-11-04 上海皓元化学科技有限公司 一种心衰药Entresto 关键中间体(R)-叔丁基 (1-([1,1`-联苯]-4-基)-3-羟基丙烷-2-基)氨基甲酸酯的制备方法
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
WO2016199688A1 (fr) * 2015-06-10 2016-12-15 住友化学株式会社 Procédé de production d'un composé à base de carbamate
WO2017059759A1 (fr) * 2015-10-10 2017-04-13 Chiral Quest (Suzhou) Co., Ltd. Procédé de préparation de n-boc alaninol biphénylique
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
WO2017203474A1 (fr) * 2016-05-27 2017-11-30 Dr. Reddy's Laboratories Limited Procédé de préparation d'intermédiaire de sacubutril
WO2018116203A1 (fr) 2016-12-23 2018-06-28 Novartis Ag Nouveau procédé pour des intermédiaires de sacubitril précoces

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JP2005082524A (ja) * 2003-09-08 2005-03-31 Ihara Chem Ind Co Ltd アミノアルコール誘導体の製造方法
JP2007537163A (ja) * 2004-05-06 2007-12-20 サイトキネティクス・インコーポレーテッド 化合物、組成物、および方法
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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016199688A1 (fr) * 2015-06-10 2016-12-15 住友化学株式会社 Procédé de production d'un composé à base de carbamate
CN107635959A (zh) * 2015-06-10 2018-01-26 住友化学株式会社 氨基甲酸酯化合物的制造方法
CN105017082A (zh) * 2015-07-31 2015-11-04 上海皓元化学科技有限公司 一种心衰药Entresto 关键中间体(R)-叔丁基 (1-([1,1`-联苯]-4-基)-3-羟基丙烷-2-基)氨基甲酸酯的制备方法
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
WO2017059759A1 (fr) * 2015-10-10 2017-04-13 Chiral Quest (Suzhou) Co., Ltd. Procédé de préparation de n-boc alaninol biphénylique
EP3359522A4 (fr) * 2015-10-10 2018-09-26 Chiral Quest (suzhou) Co., Ltd. Procédé de préparation de n-boc alaninol biphénylique
US10183909B2 (en) 2015-10-10 2019-01-22 Chiral Quest (Suzhou) Co., Ltd. Process for preparation of N-Boc biphenyl alaninol
WO2017203474A1 (fr) * 2016-05-27 2017-11-30 Dr. Reddy's Laboratories Limited Procédé de préparation d'intermédiaire de sacubutril
WO2018116203A1 (fr) 2016-12-23 2018-06-28 Novartis Ag Nouveau procédé pour des intermédiaires de sacubitril précoces
CN110088079A (zh) * 2016-12-23 2019-08-02 诺华股份有限公司 用于早期沙卡布曲中间体的新方法
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

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