WO2013137330A1 - Procédé de production d'un ester d'acide 2-vinylcyclopropane-1,1- dicarboxylique optiquement actif - Google Patents

Procédé de production d'un ester d'acide 2-vinylcyclopropane-1,1- dicarboxylique optiquement actif Download PDF

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Publication number
WO2013137330A1
WO2013137330A1 PCT/JP2013/057035 JP2013057035W WO2013137330A1 WO 2013137330 A1 WO2013137330 A1 WO 2013137330A1 JP 2013057035 W JP2013057035 W JP 2013057035W WO 2013137330 A1 WO2013137330 A1 WO 2013137330A1
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Prior art keywords
formula
compound
vinylcyclopropane
group
optically active
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English (en)
Japanese (ja)
Inventor
麻美 斎藤
俊也 瀧澤
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Sekisui Medical Co Ltd
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Sekisui Medical Co Ltd
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Priority to JP2014504967A priority Critical patent/JP6158168B2/ja
Publication of WO2013137330A1 publication Critical patent/WO2013137330A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/317—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
    • C07C67/327—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups by elimination of functional groups containing oxygen only in singly bound form
    • 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
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/30—Preparation of optical isomers
    • C07C227/32—Preparation of optical isomers by stereospecific synthesis
    • 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
    • C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
    • C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/74—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C69/757—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • the present invention relates to a process for producing optically active 2-vinylcyclopropane-1,1-dicarboxylic acid and 1-amino-2-vinylcyclopropane-1-carboxylic acid ester useful as intermediates or raw materials for production of pharmaceuticals and the like. .
  • Optically active 1-amino-2-vinylcyclopropane-1-carboxylic acid ester and 2-vinylcyclopropane-1,1-dicarboxylic acid ester are important as intermediates for the manufacture of pharmaceuticals such as a therapeutic agent for hepatitis C.
  • Patent Document 1 Non-Patent Documents 1 to 3.
  • An optically active 1-amino-2-vinylcyclopropane-1-carboxylic acid ester is prepared by reacting malonic acid diester with 1,4-dibromo-2-butene in the presence of a base.
  • a method is known in which a propane-1,1-dicarboxylic acid ester is obtained and this is subjected to Curtius rearrangement (Non-patent Documents 1 and 3).
  • an object of the present invention is to provide an optically active 1-amino-2-vinylcyclopropane-1-carboxylic acid ester that uses an optically active raw material that is inexpensive and easily available as a starting material and that does not undergo isomerization during the reaction. And a process for producing 2-vinylcyclopropane-1,1-dicarboxylic acid ester.
  • the present inventor has studied a process for producing optically active 1-amino-2-vinylcyclopropane-1-carboxylic acid ester from readily available optically active raw materials. As a result, isopropylidene easily obtained from D-tartaric acid has been studied. When -D-threitol is used as a raw material, optically active 2-vinylcyclopropane-1,1-carboxylic acid ester and 1-amino-2-vinylcyclopropane-1-carboxylic acid are produced without isomerization during the reaction. The present inventors have found that an acid ester can be obtained efficiently and completed the present invention.
  • R 1 represents an arylsulfonyl group or an alkylsulfonyl group
  • R 2 represents an alkyl group
  • R 4 represents a hydrogen atom, an alkylsulfonyl group or an arylsulfonyl group, or two R 4 together represent an isopropylidene group
  • isopropylidene-D-threitol obtained from easily available D-tartaric acid is used as a raw material, and isomerization does not occur in the reaction process, and optically active 2-vinylcyclopropane-1, 1-dicarboxylic acid ester and 1-amino-2-vinylcyclopropane-1-carboxylic acid ester can be obtained efficiently.
  • the optically active substance of the formula (A) is a compound of the formula (3), the formula (4) and the formula (5), which is a novel compound and useful as an intermediate of the method of the present invention.
  • the method of the present invention can be illustrated as a reaction formula from D-tartaric acid to 1-amino-2-vinylcyclopropane-1-carboxylic acid ester as follows.
  • R 1 and R 3 each represent an arylsulfonyl group or an alkylsulfonyl group
  • R 2 and R 5 represent an alkyl group
  • Ph represents a phenyl group
  • Bn represents a benzyl group
  • the method of the present invention is a method for producing a compound of formula (6) from a compound of formula (1) and a method of producing a compound of formula (8) from a compound of formula (1).
  • the compound of Formula (3), Formula (4), and Formula (5) is a novel compound, and this invention provides these compounds.
  • the reaction from D-tartaric acid (B) to 2-O-benzyl-3,4-O-isopropylidene-D-threitol (E) is carried out according to the method described in J. Org. Chem. 2004, 69, 5433-5438.
  • Can be implemented according to Compound (C) can be obtained by esterifying D-tartaric acid (B) and then reacting with benzaldehyde.
  • This reaction can be performed, for example, by reacting D-tartaric acid (B) with thionyl chloride in an alcohol such as methanol to obtain an alkyl ester, and then reacting benzaldehyde with an acid catalyst such as p-toluenesulfonic acid.
  • Compound (D) is obtained by reacting compound (C) with a reducing agent such as LiAlH 4 in the presence of a Lewis acid such as aluminum chloride, or with diisobutylaluminum hydride.
  • a reducing agent such as LiAlH 4
  • a Lewis acid such as aluminum chloride
  • diisobutylaluminum hydride This reaction can be performed, for example, in an ether solvent such as tetrahydrofuran and dichloromethane, a halogenated hydrocarbon solvent, or a mixed solvent thereof under ice-cooling to 100 ° C. conditions.
  • Compound (E) can be obtained by reacting compound (D) with acetone. This reaction can be performed in a solvent such as 2,2-dimethoxypropane in the presence of a dehydrating agent such as molecular sieves 4 ⁇ . At this time, p-toluenesulfonic acid can also be added.
  • compound (1) (3,4-O-isopropylidene-D-threitol) is obtained.
  • This reduction reaction can be performed by a method of hydrogenation (catalytic reduction) in the presence of a catalyst such as palladium or platinum.
  • a catalyst such as palladium or platinum.
  • hydrogen may be introduced in an alcohol such as ethanol.
  • the reaction may be performed at 100 ° C. for 1 hour to 20 hours under ice cooling.
  • the compound of the formula (2) is obtained.
  • the sulfonyl compound to be used alkylsulfonyl halide or arylsulfonyl halide is used.
  • the alkylsulfonyl halide include C 1 -C 6 alkylsulfonyl halide and halogeno C 1 -C 6 alkylsulfonyl halide.
  • arylsulfonyl halide examples include benzenesulfonyl halide, C 1 -C 6 alkylbenzenesulfonyl halide, nitrobenzenesulfonyl halide, and the like.
  • alkylsulfonyl halide or arylsulfonyl halide examples include methanesulfonyl chloride, methanesulfonyl bromide, toluenesulfonyl chloride, toluenesulfonyl bromide, nitrobenzenesulfonyl chloride, nitrobenzenesulfonyl bromide, trifluoromethanesulfonyl chloride, trifluoromethanesulfonyl bromide and the like.
  • the reaction is preferably carried out by reacting compound (1) with a sulfonyl compound in the presence of an amine such as triethylamine or dimethylaniline in a solvent such as a halogenated hydrocarbon such as dichloromethane or an aromatic hydrocarbon such as benzene. .
  • the reaction may be performed under ice-cooling to room temperature for 1 to 10 hours.
  • R 1 in the formula (2) is an arylsulfonyl group or an alkylsulfonyl group, but a benzenesulfonyl group, a substituted (C 1-6 alkyl, nitro, etc.) benzenesulfonyl group, a C 1 -C 6 alkylsulfonyl group, a halogeno C 1 -C 6 alkylsulfonyl group. More specifically, it is a group derived from the sulfonyl compound.
  • Compound (3) is obtained by reacting compound (2) with malonic acid diester in the presence of a base.
  • the base used include alkali metal hydrides, alkali metal alkoxides, alkali metal bis (trialkylsilyl) amides, and specific examples include sodium hydride, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide. Lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, and potassium bis (trimethylsilyl) amide.
  • malonic acid diester examples include a malonic acid dialkyl ester, more preferably a malonic acid di (C 1 -C 6 alkyl), specifically, diethyl malonate and diisopropyl malonate.
  • the reaction is carried out by reacting compound (2) with malonic acid diester in the presence of a base in an ether solvent such as tetrahydrofuran or an aromatic solvent such as toluene at ice-cooling to reflux temperature for 1 hour to 2 days. Good.
  • R 2 in the formula (3) is preferably a C 1 -C 6 alkyl group, particularly preferably an isopropyl group.
  • Compound (4) can be obtained by hydrolyzing compound (3).
  • This hydrolysis reaction is preferably carried out using an acid such as a cation exchange resin or hydrochloric acid in order to decompose only the isopropylidene group.
  • the reaction is preferably carried out under ice cooling to room temperature for 1 to 20 hours.
  • Compound (5) is obtained by reacting compound (4) with a sulfonyl compound. This reaction can be carried out in the same manner as the reaction for obtaining the compound (2) from the compound (1). The same applies to the sulfonyl compound to be used, and R 3 in the formula (5) is the same as R 1 in the formula (2).
  • Compound (6) is obtained by reacting compound (5) with a metal halide.
  • the metal halide used is preferably an alkali metal halide, and more preferably sodium iodide. This reaction is preferably carried out in the presence of a quaternary ammonium salt such as tetrabutylammonium iodide or zinc. The reaction is preferably carried out in an amide solvent such as dimethylformamide or a ketone solvent such as 2-butanone at room temperature to reflux temperature for 1 hour to 20 hours.
  • the reaction from compound (6) to compound (8) can be carried out according to, for example, the description of Org. Process Res. Dev., 2011, 15 (5), p1207-1211. If the compound (6) is hydrolyzed, the compound (7) is obtained. This hydrolysis is carried out in the presence of a base such as tetramethylammonium hydroxide. When this is reacted with dibenzylamine, the dibenzylamine salt of compound (7) is obtained.
  • the reaction of the compound (7) to the compound (8) is a Curtius rearrangement in which conversion from a carboxy group to an amine is carried out at once.
  • an acid such as phosphoric acid or hydrochloric acid is reacted, and then a halogenoformate such as alkyl chloroformate and the like
  • An acid addition salt of compound (8) can be obtained by reacting sodium azide or diphenylphosphoric acid azide and further reacting an acid such as p-toluenesulfonic acid.
  • the reaction for reacting the halogenoformate ester and sodium azide may be carried out in an aliphatic alcohol having 1 to 6 carbon atoms.
  • the method of the present invention is industrially advantageous because most of the process proceeds under mild conditions, and isomerization does not occur. Moreover, since reaction advances on mild conditions, there are few side reactions and a highly purified compound (8) can be obtained efficiently.
  • the separated organic layer was concentrated under reduced pressure, and then the concentrated residue was dissolved in acetone (56 mL) and cooled to ⁇ 5 ° C.
  • Triethylamine (3.89 mL, 27.8 mmol) was added thereto, and ethyl chloroformate (2.65 mL, 27.8 mmol) was further added dropwise.
  • sodium azide (3.29 g, 50.6 mmol) dissolved in water (33 mL) was added dropwise to the cooled to ⁇ 5 ° C. again. The mixture was further stirred at ⁇ 5 to 0 ° C. for 10 minutes, diluted with water, and extracted with toluene.

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

Abstract

Cette invention concerne un procédé de production d'un ester d'acide 1-amino-2-vinylcyclopropane-1-carboxylique et d'un ester d'acide 2-vinylcyclopropane-1,1- dicarboxylique optiquement actifs, qui utilisent un matériau optiquement actif qui peut être obtenu à bon marché et facilement à titre de matériau de départ, et ne s'isomérisent pas au milieu d'une réaction. L'ester d'acide 2-vinylcyclopropane-1,1-dicarboxylique optiquement actif selon l'invention est produit selon les formules de réaction suivantes.
PCT/JP2013/057035 2012-03-14 2013-03-13 Procédé de production d'un ester d'acide 2-vinylcyclopropane-1,1- dicarboxylique optiquement actif Ceased WO2013137330A1 (fr)

Priority Applications (1)

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JP2014504967A JP6158168B2 (ja) 2012-03-14 2013-03-13 光学活性２−ビニルシクロプロパン−１，１−ジカルボン酸エステルの製造法

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JP2012056635 2012-03-14
JP2012-056635 2012-03-14

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WO2013137330A1 true WO2013137330A1 (fr) 2013-09-19

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117964499A (zh) * 2024-03-26 2024-05-03 泽升科技(广州)有限公司 一种胺类化合物的制备及纯化方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010517972A (ja) * 2007-02-01 2010-05-27 テイボテク・フアーマシユーチカルズ・リミテツド Ｈｃｖの大員環状プロテアーゼ阻害剤の製造のための方法及び中間体
WO2011102388A1 (fr) * 2010-02-16 2011-08-25 株式会社エーピーアイ コーポレーション Procédé de production de 1-amino-1-alcoxycarbonyl-2-vinylcyclopropane
WO2012029819A1 (fr) * 2010-08-31 2012-03-08 株式会社エーピーアイ コーポレーション Nouvelle protéine hydrolase

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010517972A (ja) * 2007-02-01 2010-05-27 テイボテク・フアーマシユーチカルズ・リミテツド Ｈｃｖの大員環状プロテアーゼ阻害剤の製造のための方法及び中間体
WO2011102388A1 (fr) * 2010-02-16 2011-08-25 株式会社エーピーアイ コーポレーション Procédé de production de 1-amino-1-alcoxycarbonyl-2-vinylcyclopropane
WO2012029819A1 (fr) * 2010-08-31 2012-03-08 株式会社エーピーアイ コーポレーション Nouvelle protéine hydrolase

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ELENA MURAY ET AL., THE JOURNAL OF ORGANIC CHEMISTRY, vol. 68, 2003, pages 4906 - 4911 *
JEAN RANCOURT ET AL., JOURNAL OF MEDICINAL CHEMISTRY, vol. 47, 2004, pages 2511 - 2522 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117964499A (zh) * 2024-03-26 2024-05-03 泽升科技(广州)有限公司 一种胺类化合物的制备及纯化方法

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JPWO2013137330A1 (ja) 2015-08-03

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