WO2013089189A1 - Procédé de résolution optique pour composé bicyclique utilisant de l'acide hydroxysulfonique - Google Patents

Procédé de résolution optique pour composé bicyclique utilisant de l'acide hydroxysulfonique Download PDF

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Publication number
WO2013089189A1
WO2013089189A1 PCT/JP2012/082356 JP2012082356W WO2013089189A1 WO 2013089189 A1 WO2013089189 A1 WO 2013089189A1 JP 2012082356 W JP2012082356 W JP 2012082356W WO 2013089189 A1 WO2013089189 A1 WO 2013089189A1
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WIPO (PCT)
Prior art keywords
compound
general formula
optically active
salt
active amine
Prior art date
Application number
PCT/JP2012/082356
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English (en)
Japanese (ja)
Inventor
嘉孝 中村
隆文 北脇
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第一三共株式会社
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Publication of WO2013089189A1 publication Critical patent/WO2013089189A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds
    • 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
    • C07C227/12—Formation of amino and carboxyl groups
    • 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
    • C07C303/02—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
    • C07C45/52—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition by dehydration and rearrangement involving two hydroxy groups in the same molecule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/78—Separation; Purification; Stabilisation; Use of additives
    • C07C45/85—Separation; Purification; Stabilisation; Use of additives by treatment giving rise to a chemical modification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/14—All rings being cycloaliphatic
    • C07C2602/20—All rings being cycloaliphatic the ring system containing seven carbon atoms

Definitions

  • the present invention relates to a bicyclic ⁇ -amino acid derivative or a pharmacologically acceptable salt thereof, particularly a compound having activity as an ⁇ 2 ⁇ ligand and an optically active process for producing an intermediate thereof.
  • Non-Patent Document 1 Compounds that exhibit high affinity binding to the ⁇ 2 ⁇ subunit of the voltage-gated calcium channel have been shown to be effective, for example, in the treatment of neuropathic pain (eg, Non-Patent Document 1 and Non-Patent Document 1). Patent Document 2).
  • ⁇ 2 ⁇ ligands are known as therapeutic agents for neuropathic pain, and examples of ⁇ 2 ⁇ ligands include gabapentin and pregabalin.
  • ⁇ 2 ⁇ ligands such as these compounds are useful for the treatment of epilepsy, neuropathic pain and the like (for example, Patent Document 1).
  • Other compounds are disclosed in, for example, Patent Document 2, Patent Document 3, Patent Document 4, and the like.
  • Patent Literature 5 and Patent Literature as ⁇ 2 ⁇ ligands and methods for producing the same. 6 is reported.
  • Patent Document 7 Examples of optical resolution of hydroxysulfonates have been reported (Patent Document 7, Non-Patent Document 3), but the structure is different from the compounds split according to the present invention.
  • An object of the present invention is to provide a bicyclic ⁇ -amino acid derivative or a pharmacologically acceptable salt thereof, in particular, a compound having activity as an ⁇ 2 ⁇ ligand and an optically active method for producing an intermediate thereof. To do.
  • Patent Document 5 or Patent Document 6 reports a method for producing compound 6 as described in Scheme 1.
  • the inventors of the present application have paid attention to the method of stereocontrol of the asymmetric carbon in the production method of Compound 6, and have continued intensive research to develop an efficient method.
  • optical splitting is performed in the process (Step 4) immediately before the final process, but it is possible to establish a more efficient manufacturing method by performing optical splitting in an early process. I thought it would be possible. That is, the problem to be solved by the present invention is to develop a production method in which an intermediate thereof is an optically active compound in an early step of the production of compound 6.
  • the inventors of the present application continued intensive studies to solve this problem, and as a result, the problem was solved and the present invention was completed.
  • R 1a a hydrogen atom or a C1-C6 alkyl group
  • a racemic mixture of a compound having the general formula (I) and a compound having the general formula (II) is present in the presence of sulfur dioxide (sulfurous acid gas, hereinafter referred to as SO 2 gas), water, an optically active amine and a solvent.
  • SO 2 gas sulfurous acid gas
  • R 1 is a hydrogen atom or a C1-C6 alkyl group
  • R 1 is a hydrogen atom or a C1-C6 alkyl group
  • a process for producing a compound having the general formula (I). [3] The method according to [1] or [2], wherein R 1 is a hydrogen atom, a methyl group, or an ethyl group. [4] The method according to [2] or [3], wherein the optically active amine in (1) is any one selected from the group shown below.
  • the amount of the optically active amine used in (1) is 0.3-0.7 or 0.8 with respect to the racemic mixture of the compound having the general formula (I) and the compound having the general formula (II).
  • Any one selected from 1,2-dimethoxyethane, isopropyl ether, ethers such as tetrahydrofuran, highly polar solvents such as acetonitrile, esters such as ethyl acetate [7] [2]-[6] A method for producing a compound having the general formula (III) or a salt thereof, using the compound having the general formula (I) produced by the method.
  • the present invention is useful for optically active production of bicyclic ⁇ -amino acid derivatives or pharmacologically acceptable salts thereof, particularly compounds having activity as ⁇ 2 ⁇ ligands and intermediates thereof.
  • the present invention is efficient because it is a production method in which an intermediate is used as an optically active compound in an early step of the production.
  • the C1-C6 alkyl group is a linear or branched alkyl group having 1-6 carbon atoms, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group , A pentyl group, a hexyl group, and the like, preferably a methyl group, an ethyl group, and a propyl group.
  • the compound having the general formula (I) or general formula (II) preferably a compound in which R 1 has a hydrogen atom, a methyl group or an ethyl group.
  • Step (1) In the SO 2 gas used in the present invention, an excess amount is blown into the reaction solution with respect to the racemic mixture of the compound having the general formula (I) and the compound having the general formula (II). Added by.
  • the water used in the present invention is preferably 0.8 to 1.2 equivalents, more preferably a racemic mixture of the compound having the general formula (I) and the compound having the general formula (II). Is 0.9-1.1 equivalent.
  • the “optically active amine” used when producing the compound having the general formula (I) is preferably an optically active amine as shown in Table 1 below.
  • the compound which has general formula (II) when manufacturing the compound which has general formula (II), what is necessary is just to use the enantiomer which has a configuration opposite to the optically active amine used when manufacturing the compound which has general formula (I).
  • the amount of the optically active amine varies depending on the solvent used or the salt formation ratio with hydroxysulfonic acid, but with respect to the racemic mixture of the compound having the general formula (I) and the compound having the general formula (II), 0.3-0.7 or 0.8-1.2 equivalents are preferred, and 0.4-0.6 or 0.9-1.1 equivalents are more preferred.
  • a compound having the general formula (I) or a compound having the general formula (II) can be produced by appropriately selecting the enantiomer of the optically active amine to be used.
  • ethers such as 1,2-dimethoxyethane, isopropyl ether and tetrahydrofuran, highly polar solvents such as acetonitrile, and esters such as ethyl acetate are preferable, and 1,2-dimethoxyethane and acetonitrile are preferable. More preferred.
  • the reaction temperature is desirably cooled to about 0 ° C., and when the temperature rises above room temperature, a salt may not be formed properly.
  • the aqueous alkali solution used may be any aqueous alkaline solution that can return the salt to a free form, but it is preferable to use an aqueous sodium carbonate solution.
  • the “salt” in the present invention is a compound or the like represented by the general formula (III), and forms a salt by reacting with an acid or a base by having an amino group and a carboxyl group in its structure. Says the salt.
  • a compound having the general formula (III) may be left in the air or recrystallized to absorb moisture and have adsorbed water to form a hydrate. Such hydrates are also included in the salts of the present invention.
  • the compound having the general formula (III) or a salt thereof exhibits activity as an ⁇ 2 ⁇ ligand, has an affinity for the ⁇ 2 ⁇ subunit of the voltage-gated calcium channel, pain, central nervous disorder, and others It is useful as an active ingredient of a pharmaceutical composition used for the treatment and / or prevention of disorders.
  • 1,2-Dimethoxyethane (0.5 mL) was added to the obtained title compound (99.8 mg, 0.204 mmol), and the mixture was stirred at 0 ° C. for 12 hours, and then the crystals were filtered and cooled to 0 ° C. , 2-Dimethoxyethane, and dried under reduced pressure to obtain the title compound (70.7 mg, 90.2% ee) (yield 56.3% (N / N)).
  • 1,2-Dimethoxyethane (0.5 mL) was added to the obtained title compound (96.7 mg, 0.231 mmol), and the mixture was stirred at room temperature for 12 hours, and then the crystals were filtered and cooled to 0 ° C. Washing with 2-dimethoxyethane and drying under reduced pressure gave the title compound (70.2 mg, 80.3% ee) (yield 59% (N / N)).
  • 1,2-Dimethoxyethane (0.5 mL) was added to the obtained title compound (102 mg, 0.272 mmol), and the mixture was stirred at room temperature for 12 hours. The crystals were filtered and cooled to 0 ° C. Washing with dimethoxyethane and drying under reduced pressure gave the title compound (70.2 mg, 97.3% ee) (yield 58% (N / N)).
  • Example 5 The optical purity of the optically active compound obtained in Example 1-4 was determined by the following method. About 10 mg of the amine salt described in the title of each example was taken and dissolved in 1 mL of 5% aqueous sodium carbonate solution, 5 mL of toluene was added, and the mixture was stirred at room temperature for about 1 hour. After standing, only the toluene layer was sampled and analyzed by HPLC (analysis conditions are as described below).

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

Abstract

L'invention concerne la production efficace d'un composé bicyclique optiquement actif par réalisation d'une résolution optique en utilisant une amine optiquement active.
PCT/JP2012/082356 2011-12-16 2012-12-13 Procédé de résolution optique pour composé bicyclique utilisant de l'acide hydroxysulfonique WO2013089189A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2011275297 2011-12-16
JP2011-275297 2011-12-16

Publications (1)

Publication Number Publication Date
WO2013089189A1 true WO2013089189A1 (fr) 2013-06-20

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WO (1) WO2013089189A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4479974B2 (ja) * 2007-09-28 2010-06-09 第一三共株式会社 二環性γ−アミノ酸誘導体
WO2010084798A1 (fr) * 2009-01-21 2010-07-29 第一三共株式会社 Composé tricyclique
WO2012169474A1 (fr) * 2011-06-08 2012-12-13 第一三共株式会社 Procédé pour produire un composé bicyclique via un sel d'iminium

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4479974B2 (ja) * 2007-09-28 2010-06-09 第一三共株式会社 二環性γ−アミノ酸誘導体
WO2010084798A1 (fr) * 2009-01-21 2010-07-29 第一三共株式会社 Composé tricyclique
WO2012169474A1 (fr) * 2011-06-08 2012-12-13 第一三共株式会社 Procédé pour produire un composé bicyclique via un sel d'iminium

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
EMANUELA MAROTTA ET AL., TETRAHEDRON LETTERS, vol. 35, no. 18, 1994, pages 2949 - 2950 *
SUJU P. MATHEW ET AL., ANGEWANDTE CHEMIE INTERNATIONAL EDITION, vol. 43, 2004, pages 3317 - 3321 *

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