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WO2023097697A1 - Procédé de synthèse de (1r)-1-(2,2-diméthyl-4h-1,3-benzodioxin-6-yl)oxazolidin-2-one - Google Patents

Procédé de synthèse de (1r)-1-(2,2-diméthyl-4h-1,3-benzodioxin-6-yl)oxazolidin-2-one Download PDF

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Publication number
WO2023097697A1
WO2023097697A1 PCT/CN2021/135536 CN2021135536W WO2023097697A1 WO 2023097697 A1 WO2023097697 A1 WO 2023097697A1 CN 2021135536 W CN2021135536 W CN 2021135536W WO 2023097697 A1 WO2023097697 A1 WO 2023097697A1
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Prior art keywords
compound
dimethyl
benzodioxin
oxazolin
reaction
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PCT/CN2021/135536
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English (en)
Chinese (zh)
Inventor
叶伟平
费安杰
周章涛
吴春林
黄志宁
王道功
Original Assignee
广东莱佛士制药技术有限公司
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Priority to PCT/CN2021/135536 priority Critical patent/WO2023097697A1/fr
Publication of WO2023097697A1 publication Critical patent/WO2023097697A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • 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 organic chemical synthesis, in particular to a method for synthesizing (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)oxazoline-2- The keto approach.
  • the target molecule is obtained from the starting material after 6 steps of reaction.
  • the first step reduction reagent is borane N,N-diethylaniline
  • the chiral control is the use of chiral reagent (R)-(+)-2-methyl-CBS-oxazolidine (0.2- 0.5 equivalent) in toluene.
  • the protection and deprotection steps There are four steps in the reaction, the protection and deprotection steps.
  • this route adopts Adam's amount of chiral reagent as the chiral control agent, which is more expensive.
  • there are multiple steps of protection and deprotection and the molecular weight of the protecting group is large, which does not conform to the principle of atom economy.
  • the present invention aims at the long route and cost of the existing synthetic (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)oxazolin-2-one High, low yield, low atom economy and other problems, to provide a synthetic (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)oxazole A new approach to lin-2-ones.
  • the embodiment of the present invention provides a method for synthesizing (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)oxazolin-2-one, The method route is as follows:
  • X is Br, Cl or I
  • R and R are detachable protecting groups.
  • R and R are each independently selected from any one of H, halogen, nitro, cyano, alkyl, aryl, phenolic hydroxyl and ether;
  • X is Br
  • R1 and R2 are each independently selected from any one of H, halogen, nitro, cyano, C1-C18 alkyl, C20 or less aryl, phenolic hydroxyl and C20 or less ether.
  • Step S1 a substitution reaction occurs between the compound of formula I and the protected amino compound under basic conditions to generate the compound of formula II;
  • Step S2 the compound of formula II is reduced under the condition of asymmetric catalytic transfer hydrogenation to obtain the compound of formula III.
  • Step S3 The compound of formula III is subjected to N,N'-carbonyldiimidazole or N,N'-disuccinimidyl carbonate, or phosgene, or triphosgene to obtain the compound of formula IV.
  • step S1 further includes:
  • the base is at least one of potassium carbonate, sodium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide, triethylamine and diisopropylethylamine;
  • the organic solvent is selected from at least one of acetonitrile, acetone, DMF, DMAc, THF, more preferably, the organic solvent is acetonitrile;
  • the reaction temperature is 30°C;
  • methyl tert-butyl ether can also be replaced by ethyl acetate, isopropyl acetate, dichloromethane or toluene, etc.;
  • the organic solvent for extraction is selected from at least one of methyl tert-butyl ether, ethyl acetate, isopropyl acetate, and dichloromethane. More preferably, the organic solvent for extraction is Methyl tert-butyl ether;
  • step S1-2 the drying is drying with anhydrous sodium sulfate
  • the separation and purification is column chromatography.
  • step S2 further includes:
  • the solvent is selected from at least one of DMF, water, methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, acetonitrile and tetrahydrofuran; more preferably, the solvent is DMF;
  • the transfer hydrogenation reducing agent is a mixture of triethylamine and formic acid, ammonium formate or triethylsilane; preferably, the transfer hydrogenation reducing agent is a mixture of triethylamine and formic acid;
  • the reaction temperature is 60°C;
  • the extraction solvent is at least one selected from ethyl acetate, isopropyl acetate, dichloromethane and methyl tert-butyl ether, further preferably, the extraction solvent is ethyl acetate;
  • the drying is drying with anhydrous sodium sulfate.
  • step S3 further includes:
  • the organic solvent is selected from at least one of tetrahydrofuran, dimethyltetrahydrofuran, methyl tert-butyl ether, isopropyl ether, diethyl ether and ethylene glycol dimethyl ether, preferably tetrahydrofuran;
  • the sufficient stirring is sufficient stirring for 2 hours.
  • the protected amino compound in step S1 includes mono-protected amino compound and double-protected amino compound
  • the protected amino compound is selected from dibenzylamine, dimethylamine, t-butyl carbamate, benzyl carbamate, acetamide, phthalimide, phthalimide At least one of a metal salt, maleimide, bis-(4-methoxybenzyl)-amine and fluorenylmethoxycarbonamide;
  • the amino compound is dibenzylamine.
  • the catalyst of S2-1) is selected from at least one of the following: RuCl[(S,S)-TsDPEN](p-cymene)(cat.1), RuCl[( S,S)-TsDPEN](1,3,5-trimethyl benzene)(cat.2),RuCl[(S,S)-TsDPEN](benzene)(cat.3),RuCl[(S,S)- FsDPEN] (p-cymene) (cat.4); preferably, the catalyst is RuCl [(S, S)-TsDPEN] (p-cymene) (cat.1); the catalyst structure is as follows:
  • the excellent technical effects of the present invention include: Synthesizing (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)oxazoline-2 by the synthetic method of the present invention - Ketone, which has the advantages of novel process route, high yield and high atom economy.
  • Fig. 1 is the hydrogen NMR spectrum of compound IV prepared in the embodiment.
  • R 1 and R 2 are each independently selected from any one of H, halogen, nitro, cyano, alkyl, aryl, phenolic hydroxyl and ether.
  • R1 and R2 are each independently selected from any one of H, halogen, nitro, cyano, C1-C18 alkyl, C20 or less aryl, phenolic hydroxyl and C20 or less ether.
  • Step S1 a substitution reaction occurs between the compound of formula I and the protected amino compound under basic conditions to generate the compound of formula II;
  • Step S2 the compound of formula II is reduced under the condition of asymmetric catalytic transfer hydrogenation to obtain the compound of formula III.
  • Step S3 The compound of formula III is subjected to N,N'-carbonyldiimidazole (or N,N'-disuccinimidyl carbonate, or phosgene, or triphosgene) to obtain the compound of formula IV.
  • N,N'-carbonyldiimidazole or N,N'-disuccinimidyl carbonate, or phosgene, or triphosgene
  • the method includes the following steps:
  • Step S1 further includes S1-1) S1-2) S1-3)
  • Step S2 further includes S2-1) S2-2) S2-3)
  • S3 further includes S3-1)
  • tetrahydrofuran is used as a solvent, and the solvent may also be dimethyl tetrahydrofuran, methyl tert-butyl ether, isopropyl ether, diethyl ether or ethylene glycol dimethyl ether and the like.
  • the amino compound required in step S1 can be a mono-protected amino compound or a double-protected amino compound.
  • the amino compound is dibenzylamine, dimethylamine, t-butyl carbamate, benzyl carbamate, acetamide, phthalimide, phthalimide metal salt, horse at least one of imide, bis-(4-methoxybenzyl)-amine, and fluorenylmethoxycarbonamide.
  • the amino compound is dibenzylamine.
  • the added solvent required for step S2 is N,N-dimethylformamide (DMF), water, etc., preferably DMF, and the solvent can also be methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, Acetonitrile or tetrahydrofuran etc.;
  • the required hydrogen transfer reagent of step S2 is ammonium formate, formic acid/triethylamine, preferably formic acid/triethylamine;
  • Required catalyst is selected from following at least one: RuCl[(S, S)- TsDPEN](p-cymene)(cat.1), RuCl[(S,S)-TsDPEN](1,3,5-trimethyl benzene)(cat.2), RuCl[(S,S)-TsDPEN]( Benzene) (cat.3), RuCl[(S,S)-FsDPEN](p-cymene) (cat
  • Step S3 needs to add at least one of N,N'-carbonyldiimidazole, N,N'-disuccinimidyl carbonate, phosgene and triphosgene.
  • N,N'-carbonyldiimidazole is added to S3.
  • the method for synthesizing (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)oxazolin-2-one by the synthetic method of the present invention has a novel process route , high yield, and high atom economy.
  • the yield of the 6-step reaction route introduced in the Background Art section is about 50%. Compared with the existing route, the yield of the route of the present invention is greatly improved.
  • the original route undergoes 6-step reactions, multiple large protecting groups and deprotecting groups are added, and chiral reagents are used to construct chirality. The operation is complicated, the cost is high, and the atom economy is not good. .

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

L'invention concerne un procédé de synthèse de (1R)-1-(2,2-diméthyl -4H-1,3-benzodioxin-6-yl) oxazolidin-2-one, la voie du procédé étant la suivante : [voie 1], où X est Br, Cl ou I, et R1 et R2 sont des groupes protecteurs qui peuvent être éliminés. Le procédé de synthèse de (1R)-1-(2,2-diméthyl-4H-1,3-benzodioxin-6-yl)oxazolidin-2-one présente les avantages d'une nouvelle voie de traitement, d'un rendement élevé et d'une économie d'atomes élevée.
PCT/CN2021/135536 2021-12-03 2021-12-03 Procédé de synthèse de (1r)-1-(2,2-diméthyl-4h-1,3-benzodioxin-6-yl)oxazolidin-2-one WO2023097697A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/CN2021/135536 WO2023097697A1 (fr) 2021-12-03 2021-12-03 Procédé de synthèse de (1r)-1-(2,2-diméthyl-4h-1,3-benzodioxin-6-yl)oxazolidin-2-one

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PCT/CN2021/135536 WO2023097697A1 (fr) 2021-12-03 2021-12-03 Procédé de synthèse de (1r)-1-(2,2-diméthyl-4h-1,3-benzodioxin-6-yl)oxazolidin-2-one

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003072539A1 (fr) * 2002-02-28 2003-09-04 Glaxo Group Limited Derives de phenethanolamine pour traiter des maladies respiratoires
WO2004037773A1 (fr) * 2002-10-28 2004-05-06 Glaxo Group Limited Derive de phenethanolamine utilise dans le traitement de maladies respiratoires
CN1732152A (zh) * 2002-10-28 2006-02-08 葛兰素集团有限公司 用于治疗呼吸性疾病的苯乙醇胺衍生物
US20060205790A1 (en) * 2002-10-22 2006-09-14 Coe Diane M Medicinal arylethanolamine compounds
US20070135490A1 (en) * 2003-10-24 2007-06-14 Keith Biggadike Phenetanolamine derivatives
CN107188813A (zh) * 2016-03-14 2017-09-22 益方生物科技（上海）有限公司 苯乙醇胺衍生物及其制备方法和用途
CN111836899A (zh) * 2017-12-20 2020-10-27 欧伦股份公司 制备用于通过酶还原合成光学活性β-氨基醇的中间体的方法以及新型合成中间体

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003072539A1 (fr) * 2002-02-28 2003-09-04 Glaxo Group Limited Derives de phenethanolamine pour traiter des maladies respiratoires
US20060205790A1 (en) * 2002-10-22 2006-09-14 Coe Diane M Medicinal arylethanolamine compounds
WO2004037773A1 (fr) * 2002-10-28 2004-05-06 Glaxo Group Limited Derive de phenethanolamine utilise dans le traitement de maladies respiratoires
CN1732152A (zh) * 2002-10-28 2006-02-08 葛兰素集团有限公司 用于治疗呼吸性疾病的苯乙醇胺衍生物
US20070135490A1 (en) * 2003-10-24 2007-06-14 Keith Biggadike Phenetanolamine derivatives
CN107188813A (zh) * 2016-03-14 2017-09-22 益方生物科技（上海）有限公司 苯乙醇胺衍生物及其制备方法和用途
CN111836899A (zh) * 2017-12-20 2020-10-27 欧伦股份公司 制备用于通过酶还原合成光学活性β-氨基醇的中间体的方法以及新型合成中间体

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HANG LIAO; YAJIE CHOU; YU WANG; HAN ZHANG; TANYU CHENG; GUOHUA LIU: "Multistep Organic Transformations over Base‐Rhodium/Diamine‐Bifunctionalized Mesostructured Silica Nanoparticles", CHEMCATCHEM, JOHN WILEY & SONS, INC., HOBOKEN, USA, vol. 9, no. 16, 28 June 2017 (2017-06-28), Hoboken, USA, pages 3197 - 3202, XP072439191, ISSN: 1867-3880, DOI: 10.1002/cctc.201700436 *

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