WO2017203474A1 - Procédé de préparation d'intermédiaire de sacubutril - Google Patents

Procédé de préparation d'intermédiaire de sacubutril Download PDF

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Publication number
WO2017203474A1
WO2017203474A1 PCT/IB2017/053105 IB2017053105W WO2017203474A1 WO 2017203474 A1 WO2017203474 A1 WO 2017203474A1 IB 2017053105 W IB2017053105 W IB 2017053105W WO 2017203474 A1 WO2017203474 A1 WO 2017203474A1
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WIPO (PCT)
Prior art keywords
formula
compound
protecting group
preparation
hydrogen
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PCT/IB2017/053105
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English (en)
Inventor
Vilas Hareshwar Dahanukar
Raviram Chandrasekhar Elati
Sampath Aalla
Sreenivasulu Kurella
Phani MAMIDIPALLI
Vijay ADLA
Ganesh Varanasi
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Dr. Reddy's Laboratories Limited
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Publication of WO2017203474A1 publication Critical patent/WO2017203474A1/fr

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    • 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
    • C07C269/06—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 by reactions not involving the formation of carbamate groups
    • 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
    • C07D203/16—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 acylated ring nitrogen atoms
    • C07D203/20—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 acylated ring nitrogen atoms by carbonic acid, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

Definitions

  • the present application relates to a process for the preparation of sacubitril and salt thereof. Specifically, the present application relates to a process for the preparation of an intermediate of sacubitril and salt thereof, tert-butyl (R)-( l -([ l , l '-biphen yl]-4-yl)-3-hydroxypropan-2- yl)carbamate (IA). Specifically, the present application relates to a process for the preparation of sacubitril and salt thereof. The application also relates to a compound of formula (III)
  • Pi is selected from a group of hydrogen, and any hydroxy protecting group as known in rd
  • US Patent No. US5217996 A discloses sacubitril and its use in the treatment of cardiovascular disorders.
  • US Patent No. US8877938 B2 (hereinafter the US'938 patent) teaches a supra-molecular complex of sacubitril and valsartan. It is known in the literature as LCZ-696 (Tetrahedron Letters 53, 2012, 275-276).
  • the chemical name of the supra- molecular complex is trisodium [3-(( l S,3R)- l -biphenyl-4-ylmethyl-3-ethoxycarbonyl-l - butylcarbamoyl)propionate-(S)-3 ' -methyl -2 ' -(pentanoyl ⁇ 2 " -(tetrazol-5-ylate)-biphenyl-4 ylmethyl ⁇ amino)butyrate] hemipentahydrate (CAS # 936623-90-4).
  • First aspect of the present application relates to a com ound of formula (III)
  • Pi is selected from a group of hydrogen, and any hydroxy protecting group as known in
  • Second aspect of the present application relates to a process for preparation of compound of formula (III)
  • Third aspect of the present application relates to use of compound of formula (III) for the preparation of sacubitril and salt thereof.
  • Fourth aspect of the present application relates to use of compound of formula (III) for the preparation of LCZ-696.
  • P 2 and P 3 independently, is selected from a group of hydrogen, and any amino protecting group as known in Greene et al., "Protective Groups in Organic Synthesis", 3 rd edition, 1999.
  • P 2 and P 3 independently, is selected from a group of hydrogen, and any amino protecting group as known in Greene et al., "Protective Groups in Organic Synthesis", 3 rd edition, 1999.
  • Seventh aspect of the present application relates to use of compound of formula (IIIA) for the preparation of sacubitril and salt thereof.
  • Eighth aspect of the present application relates to use of compound of formula (IIIA) for the preparation of LCZ-696.
  • Pi is selected from a group of hydrogen, and any hydroxy protecting group as known in
  • Tenth aspect of the present application relates to a process for preparation of compound of formula (IIIB)
  • Eleventh aspect of the present application relates to use of compound of formula (IIIB) for the preparation of sacubitril and salt thereof.
  • Twelfth aspect of the present application relates to use of compound of formula (IIIB) for the preparation of LCZ-696.
  • Fifteenth aspect of the present application relates to use of compound of formula (IIIC) for the preparation of sacubitril and salt thereof.
  • Sixteenth aspect of the present application relates to use of compound of formula (IIIC) for the preparation of LCZ-696.
  • Seventeenth aspect of the present application relates to a process for the preparation of compound of formula (I)
  • Pi is selected from a group of hydrogen, and any hydroxy protecting group as known in
  • Eighteenth aspect of the present application relates to a process for the preparation of tert- butyl (i?)-(l-([l ,l'-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamate (IA)
  • Pi is selected from a group of hydrogen, and any hydroxy protecting group as known in
  • Nineteenth aspect of the present application relates to a process for the preparation of sacubitril and salt thereof comprising converting compound of formula (I) or compound of formula (IA), as prepared by the process of the present application, to sacubitril and salt thereof.
  • Twentieth aspect of the present application relates to a process for the preparation of LCZ- 696 comprising converting compound of formula (I) or compound of formula (IA), as prepared by the process of the present application, to LCZ-696.
  • Twenty first aspect of the present application relates to a process for preparation of compound of formula (IV)
  • P 4 is an amino protecting group
  • P5 is a hydroxyl protecting group
  • R is an Ci-C 6 alkyl
  • First aspect of the present application relates to a com ound of formula (III)
  • Pi is selected from a group of hydrogen, and any hydroxy protecting group as known in
  • Second aspect of the present application relates to a process for preparation of compound of formula (III)
  • Pi is selected from a group of hydrogen, and any hydroxy protecting group as known in
  • the suitable hydroxy protecting group of step (a) may be any protecting group known in the art. Specifically, the suitable hydroxy protecting group of step (a) may be any protecting group known in Greene et al., "Protective Groups in Organic Synthesis", 3rd edition, 1999. More specifically, the suitable hydroxy protecting group of step (a) may be a silyl group. Most specifically, the suitable hydroxy protecting group of step (a) may be tert-butyl dimethyl silyl.
  • the compound of formula (II) may be treated with suitable hydroxyl protecting group in a solvent including but not limited to polar aprotic solvent such as dimethyl formamide, dimethyl sulfoxide and the like; alcohol solvent such as methanol, ethanol and the like; ether solvent such as tetrahydrofuran, acetone and the like; chlorinated solvent such as dichlorome thane, chloroform and the like; hydrocarbon solvent such as toluene, xylene and the like and mixtures thereof.
  • the solvent may be a polar aprotic solvent.
  • the compound of formula (II) may be treated with suitable hydroxyl protecting group in presence of a base such as imidazole, morpholine, triethylamine, diisopropyl ethylamine and the like.
  • a base such as imidazole, morpholine, triethylamine, diisopropyl ethylamine and the like.
  • the base may be imidazole.
  • the compound of formula (A) may be treated with 4-biphenyl magnesium halide to provide compound of formula (III).
  • the compound of formula (A) may be treated with 4- biphenyl magnesium bromide to provide compound of formula (III).
  • the suitable solvent may include but not limited to an alcohol solvent such as methanol, ethanol and the like; ether solvent such as tetrahydrofuran, 1,4-dioxane and the like; ketone solvent such as acetone, methyl ethyl ketone and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; aliphatic hydrocarbon solvent such as n-hexane, cyclopentane and the like; chlorinated hydrocarbon solvent such as dichlorome thane, chloroform and the like.
  • the solvent may be an ether solvent. More specifically, the solvent may be tetrahydrofuran.
  • the reaction may be performed for about 15 minutes to about 3 hours at about 0 °C to about boiling point of the solvent. Specifically, the reaction may be performed for about 30 minutes to about 1 hour at about 20 °C to about 30 °C.
  • the product, compound of formula (III) may be isolated from the reaction mass by methods known in the art.
  • Third aspect of the present application relates to use of compound of formula (III) for the preparation of sacubitril and salt thereof.
  • Fourth aspect of the present application relates to use of compound of formula (III) for the preparation of LCZ-696.
  • IMA IMA
  • P 2 and P 3 independently, is selected from a group of hydrogen, and any amino protecting group as known in Greene et al., "Protective Groups in Organic Synthesis", 3 rd edition, 1999.
  • P 2 and P 3 independently, is selected from a group of hydrogen, and any amino protecting group as known in Greene et al., "Protective Groups in Organic Synthesis", 3 rd edition, 1999.
  • Seventh aspect of the present application relates to use of compound of formula (IIIA) for the preparation of sacubitril and salt thereof.
  • Pi is selected from a group of hydrogen, and any hydroxy protecting group as known in
  • Tenth aspect of the present application relates to a process for preparation of compound of formula (IIIB)
  • Eleventh aspect of the present application relates to use of compound of formula (IIIB) for the preparation of sacubitril and salt thereof.
  • Twelfth aspect of the present application relates to use of compound of formula (IIIB) for the preparation of LCZ-696. Thirteenth aspect of the present application relates to a compound of formula (IIIC)
  • Fifteenth aspect of the present application relates to use of compound of formula (IIIC) for the preparation of sacubitril and salt thereof.
  • Pi is selected from a group of hydrogen, and any hydroxy protecting group as known in
  • Reduction of compound of formula (III) or compound of formula (HID) in step (d) to provide compound of formula (I) may be performed by catalytic hydrogenation. Specifically, reduction of compound of formula (III) or compound of formula (HID) in step (d) to provide compound of formula (I) may be performed in presence of a heterogeneous catalyst. More specifically, reduction of compound of formula (III) or compound of formula (HID) in step (d) to provide compound of formula (I) may be performed in presence of palladium/charcoal. Optionally, the reduction of compound of formula (III) or compound of formula (HID) in step (d) to provide compound of formula (I) may be performed in presence of an acid.
  • the solvent for reduction includes but not limited to an alcohol solvent such as methanol, ethanol and the like; ether solvent such as tetrahydrofuran, 1,4-dioxane and the like; ketone solvent such as acetone, methyl ethyl ketone and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; an ester solvent such as ethyl ester, n-butyl ester and the like. More specifically, the solvent may be an alcohol solvent. More specifically, the solvent may be methanol.
  • the product, compound of formula (I) may be isolated from the reaction mass by a process known in the art.
  • One aspect of the present application relates to a compound of formula (IIIF)
  • Another aspect of the present application relates to isolation of compound of formula (IIIF) from the reaction mixture and optional purification by a process known in the art, e.g. crystallization and then further reduction of compound of formula (IIIF) to provide compound of formula (I).
  • the compound of formula (IIIF) may be directly reduced, without isolation, to provide compound of formula (I), wherein compound of formula (IIIF) may be produced as an intermediate.
  • Eighteenth aspect of the present application relates to a process for the preparation of tert- butyl (i?)-(l-([l ,l'-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamate (IA)
  • Pi is selected from a group of hydrogen, and any hydroxy protecting group as known in
  • One aspect of the present application relates to a com ound of formula (IIIG)
  • Another aspect of the present application relates to isolation of compound of formula (IIIG) from the reaction mixture and optional purification by a process known in the art, e.g. crystallization and then further reduction of compound of formula (IIIG) to provide compound of formula (IA).
  • the compound of formula (IIIG) may be directly reduced, without isolation, to provide compound of formula (IA), wherein compound of formula (IIIG) may be produced as an intermediate.
  • the compound of formula (I) or compound of formula (IA) may be converted to sacubitril and salt thereof by a process known in the art. Specifically, the compound of formula (I) or compound of formula (IA) may be converted to sacubitril by a process as known in the PCT application, WO2008/031567A1. Sacubitril and salt thereof, as produced by the process of the present application, may be converted to LCZ-696 as known in the US'938 patent.
  • Twenty first aspect of the present application relates to a process for preparation of compound of formula (IV)
  • P 4 is an amino protecting group
  • P5 is a hydroxyl protecting group
  • R is an Ci-C 6 alkyl
  • One specific aspect of the present application relates to a process for the preparation of compound of formula (IVA)
  • TBS is tert-butyl dimethylsilyl and Boc is tert-butyloxycarbonyl.
  • Step (a) may be performed in a suitable solvent including but not limited to alcohol solvent such as methanol, ethanol and the like; ether solvent such as tetrahydrofuran, 1,4-dioxane and the like; ketone solvent such as acetone, methyl ethyl ketone and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; an ester solvent such as ethyl ester, n-butyl ester and the like.
  • the solvent may be an ether solvent. More specifically, the solvent may be tetrahydrofuran.
  • Step (a) may be performed from about 0 °C to about boiling point of the solvent for about 15 minutes to about 5 hours.
  • step (a) may be performed from about 5 °C to about 10 °C for about 30 minutes to about 2 hours.
  • the product, compound of formula (VI), may be isolated by any known methods in the art. Alternatively, the product may be carried forward to the next step as such.
  • Step (al) may be performed in a suitable solvent including but not limited to ether solvent such as tetrahydrofuran, 1,4-dioxane and the like; ketone solvent such as acetone, methyl ethyl ketone and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; an ester solvent such as ethyl ester, n-butyl ester and the like.
  • the solvent may be an ester solvent. More specifically, the solvent may be ethyl acetate.
  • Step (al) may be performed from about 0 °C to about boiling point of the solvent for about 15 minutes to about 15 hours.
  • step (al) may be performed from about 0 °C to about 40 °C for about 1 hour to about 8 hours.
  • the reaction of compound of formula (V) and N-hydroxysuccinimide may be performed in presence of N,N'-dicyclohexylcarbodiimide.
  • the product, compound of formula (VIII) may be isolated by any known methods in the art. Alternatively, the product may be carried forward to the next step as such.
  • Step (b) may be performed in a suitable solvent including but not limited to alcohol solvent such as methanol, ethanol and the like; ether solvent such as tetrahydrofuran, 1 ,4-dioxane and the like; ketone solvent such as acetone, methyl ethyl ketone and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; an ester solvent such as ethyl ester, n-butyl ester and the like; mixtures thereof.
  • step (b) may be performed in a mixture of an alcohol solvent and an ether solvent. More specifically, step (b) may be performed in a mixture of methanol and tetrahydrofuran.
  • step (b) may be performed in a mixture of an ester solvent and an ether solvent.
  • step (b) may be performed in a mixture of ethyl acetate and tetrahydrofuran.
  • Step (b) may be performed from about 0 °C to about boiling point of the solvent for about 1 hour to about 25 hours. Specifically, step (b) may be performed from about 20 °C to about 50 °C for about 5 hours to about 15 hours. Alternatively, step (b) may be performed at about 0 °C to about 20 °C for about 15 minutes to about 2 hours.
  • the product, compound of formula (VII) may be isolated by any known methods in the art. Alternatively, the product may be carried forward to the next step as such.
  • the cyclization of compound of formula (VII) to provide compound of formula (IV) in step (c) may be carried out by a process as known in the art. Specifically, the step (c) may be carried out by a process as known in Tetrahedron Letters, 1998, 39(51 ), 9389.
  • the compound of formula (V) may be prepared by a process known in the art. Specifically, the compound of formula (V) may be prepared by a process as known in Tetrahedron Letters, 1984, 25(9), 91 1.
  • the compound of formula (IV) may be converted into compound of formula (I) by a process known in the art. Specifically, the compound of formula (IVA) may be converted into compound of formula (IA) by a process known in CN105237560A.
  • N-Boc-L-Serine (30 g) in dichloromethane (600 mL)
  • N-methyl morpholine (15.53 g)
  • N,0-dimethylhydroxylammonium chloride (15.69 g)
  • N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride 28.9 g
  • the reaction mass was stirred further for 2 hours at about 10-28 °C.
  • the reaction mass was quenched by 1M hydrochloric acid (150 mL).
  • the organic layer was separated and the aqueous layer was extracted with dichloromethane (2 x 300 mL).
  • the combined organic layer was washed with sodium bicarbonate solution (10 %, 150 mL), distilled under vacuum to provide solid desired compound.
  • Example 3 Preparation of tert-butyl (5)-(3,8,8,9,9-pentamethyl-4-oxo-2,7-dioxa-3-aza-8- siladecan-5-yl)carbamate (D) To a solution of (5)-tert-butyl-(3 -hydroxy- l -(metho xy(methyl)amino)-l -oxopropan -2- yl)carbamate (IIA) (10 g) in dimethyl formamide (80 mL), imidazole (5.48 g) was added at 0 °C and stirred for 5 minutes.
  • DIIA imidazole
  • Example 6 Sodium borohydride (1.18 g) was added to the filtrate of Example 6 slowly and the reaction mass was allowed to heat up to 40-45 °C. Methanol (10 mL) was added to the reaction mass. The reaction mass was stirred for about 15 hours and then quenched by the addition of ammonium chloride solution (2 g in 20 mL water). The reaction mass was extracted with ethyl acetate (150 mL), the organic layer was washed with brine (40 mL) and dried over sodium sulfate. The organic layer was distilled under vacuum to provide crude desired compound, which was purified by column chromatography over silica gel using 20% ethyl actetate/n-hexane as eluant. Yield: 3.3 g

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

Abstract

La présente invention concerne un procédé de préparation de tert-butyl (R)-(1-([1,1'-biphényl]-4-yl)-3-hydroxypropan-2-yl) carbamate (IA). Le composé de formule (IA) peut être utilisé en tant qu'intermédiaire pour la préparation de sacubitril. (I)
PCT/IB2017/053105 2016-05-27 2017-05-26 Procédé de préparation d'intermédiaire de sacubutril WO2017203474A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN201641018295 2016-05-27
IN201641018295 2016-05-27

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WO2017203474A1 true WO2017203474A1 (fr) 2017-11-30

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190256454A1 (en) * 2016-07-05 2019-08-22 Novartis Ag New process for early sacubitril intermediates
WO2020127780A1 (fr) 2018-12-20 2020-06-25 Bayer Aktiengesellschaft Hétérocyclyl-pyridazine utilisée en tant que composés fongicides
WO2021245083A1 (fr) 2020-06-04 2021-12-09 Bayer Aktiengesellschaft Hétérocyclyl pyridines en tant que nouveaux fongicides
WO2021245087A1 (fr) 2020-06-04 2021-12-09 Bayer Aktiengesellschaft Hétérocyclyl pyrimidines et triazines en tant que nouveaux fongicides
WO2021249995A1 (fr) 2020-06-10 2021-12-16 Bayer Aktiengesellschaft Hétérocycles à substitution azabicyclyle utilisés comme fongicides
WO2021255070A1 (fr) 2020-06-18 2021-12-23 Bayer Aktiengesellschaft Combinaisons de composés actifs
WO2021255071A1 (fr) 2020-06-18 2021-12-23 Bayer Aktiengesellschaft Dérivés de 3-(pyridazin-4-yl)-5,6-dihydro-4h-1,2,4-oxadiazine utilisés comme fongicides pour la protection des cultures
CN115745841A (zh) * 2021-09-03 2023-03-07 凯特立斯（深圳）科技有限公司 一种沙库必曲中间体的制备方法
WO2023099445A1 (fr) 2021-11-30 2023-06-08 Bayer Aktiengesellschaft Bis(hétéro)aryl thioéther oxadiazines utilisées en tant que composés fongicides

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015037460A1 (fr) * 2013-09-10 2015-03-19 住友化学株式会社 PROCÉDÉ DE PRODUCTION DE 3-(BIPHÉNYLE-4-YL)-2-[(t-BUTOXYCARBONYL)AMINO]PROPAN-1-OL OPTIQUEMENT ACTIF
US20150210632A1 (en) * 2012-08-31 2015-07-30 Zhejiang Jiuzhou Pharmaceutical Co., Ltd New process
CN105237560A (zh) * 2015-10-15 2016-01-13 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 (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150210632A1 (en) * 2012-08-31 2015-07-30 Zhejiang Jiuzhou Pharmaceutical Co., Ltd New process
WO2015037460A1 (fr) * 2013-09-10 2015-03-19 住友化学株式会社 PROCÉDÉ DE PRODUCTION DE 3-(BIPHÉNYLE-4-YL)-2-[(t-BUTOXYCARBONYL)AMINO]PROPAN-1-OL OPTIQUEMENT ACTIF
CN105237560A (zh) * 2015-10-15 2016-01-13 上海博氏医药科技有限公司 一种lzc696中间体及其合成方法

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190256454A1 (en) * 2016-07-05 2019-08-22 Novartis Ag New process for early sacubitril intermediates
WO2020127780A1 (fr) 2018-12-20 2020-06-25 Bayer Aktiengesellschaft Hétérocyclyl-pyridazine utilisée en tant que composés fongicides
WO2021245083A1 (fr) 2020-06-04 2021-12-09 Bayer Aktiengesellschaft Hétérocyclyl pyridines en tant que nouveaux fongicides
WO2021245087A1 (fr) 2020-06-04 2021-12-09 Bayer Aktiengesellschaft Hétérocyclyl pyrimidines et triazines en tant que nouveaux fongicides
WO2021249995A1 (fr) 2020-06-10 2021-12-16 Bayer Aktiengesellschaft Hétérocycles à substitution azabicyclyle utilisés comme fongicides
WO2021255070A1 (fr) 2020-06-18 2021-12-23 Bayer Aktiengesellschaft Combinaisons de composés actifs
WO2021255071A1 (fr) 2020-06-18 2021-12-23 Bayer Aktiengesellschaft Dérivés de 3-(pyridazin-4-yl)-5,6-dihydro-4h-1,2,4-oxadiazine utilisés comme fongicides pour la protection des cultures
CN115745841A (zh) * 2021-09-03 2023-03-07 凯特立斯（深圳）科技有限公司 一种沙库必曲中间体的制备方法
WO2023029235A1 (fr) * 2021-09-03 2023-03-09 凯特立斯（深圳）科技有限公司 Procédé de préparation d'un intermédiaire de sacubitril
CN115745841B (zh) * 2021-09-03 2024-04-16 凯特立斯（深圳）科技有限公司 一种沙库必曲中间体的制备方法
WO2023099445A1 (fr) 2021-11-30 2023-06-08 Bayer Aktiengesellschaft Bis(hétéro)aryl thioéther oxadiazines utilisées en tant que composés fongicides

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