WO2015037243A1 - Procédé pour la production d'un composé d'hydantoïne optiquement actif - Google Patents

Procédé pour la production d'un composé d'hydantoïne optiquement actif Download PDF

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WO2015037243A1
WO2015037243A1 PCT/JP2014/004702 JP2014004702W WO2015037243A1 WO 2015037243 A1 WO2015037243 A1 WO 2015037243A1 JP 2014004702 W JP2014004702 W JP 2014004702W WO 2015037243 A1 WO2015037243 A1 WO 2015037243A1
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compound
acid
potassium
sodium
formula
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PCT/JP2014/004702
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Japanese (ja)
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稔 小浦
寿史 住田
公幸 渋谷
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興和株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
    • C07D233/76—Two oxygen atoms, e.g. hydantoin with substituted hydrocarbon radicals attached to the third ring carbon atom
    • C07D233/78—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered

Definitions

  • the present invention relates to a method for producing an optically active hydantoin compound having an LXR ⁇ activation action and a production intermediate thereof.
  • the method of this document does not mention the production of optically active (a3), and does not describe the production method of the optical isomers of the compounds (A) to (J). Therefore, in the above production method, two diastereomers with different stereochemistry of the asymmetric carbon atom of the 4,4-disubstituted imidazolidine-2,5-dione moiety are produced for the compounds (A) to (J). The problem that it was not possible was left.
  • Patent Documents 2 and 3 As a method for optical resolution of 4,4-disubstituted imidazolidine-2,5-dione derivatives, a preferential crystallization method using optically active benzylamine (Patent Documents 2 and 3) and a method using lipase (non-patent document) Although literature 7) has been reported, it has been found that all of them have a narrow substrate application range and are not suitable for the production of the compounds (A) to (J).
  • Patent Document 5 Furthermore, a method for producing an optically active 1,4,4-trisubstituted imidazolidine-2,5-dione derivative represented by the following formula has also been reported (Patent Document 5).
  • compound (c2) By reacting 2,5-dimethylpiperazine-1-carboxylic acid (2S, 5R) -tert-butyl produced by the method described in the pamphlet, compound (c2) is obtained, and this is subjected to Wittig reaction to give compound (c3 to), an unsaturated bond and a compound by the hydrogenation reaction (c4), which compounds by hydrolyzing the (c5), by reacting it with the compound (c6), ribs with tmsCF 3
  • Compound (c7) is obtained by a nolation reaction, and the optically active 2- [4- (2,5-dimethylpiperazi is obtained by deprotecting the piperazine compound.
  • R 1 , R 2 and R 3 may be the same or different and each represents a C 1-3 alkyl group, * represents an asymmetric carbon atom, and R 4 represents
  • the compound represented by the formula (1) is (S) -3- (2- ⁇ (2S, 5R) -4- [4- (1,1,1,3,3,3-hexafluoro- 2-Hydroxypropan-2-yl) -2-propylphenyl] -2,5-dimethylpiperazin-1-yl ⁇ -2-oxoethyl) -5- [4- (1-methylethoxy) phenyl] -5-methyl
  • the method of the present invention can produce the target compound (1) in a higher yield than the conventional method, as shown in the Examples below.
  • the asymmetric carbon atom of the imidazolidine-2,4-dione (3) can be constructed without racemization by following this method. Therefore, by using the method of the present invention, compound (1) useful as an LXR ⁇ selective agonist can be produced with high yield and high optical purity.
  • the C 1-3 alkyl group means a linear or branched alkyl group having 1 to 3 carbon atoms, and examples thereof include a methyl group, an ethyl group, a propyl group, and an isopropyl group.
  • the C 1-3 alkyl group for R 1 is preferably an ethyl group or a propyl group, and more preferably a propyl group.
  • the C 1-3 alkyl group for R 2 is preferably a methyl group.
  • the C 1-3 alkyl group for R 3 is preferably a methyl group.
  • the C 1-3 alkyl group for R 6 is preferably a methyl group or an ethyl group.
  • (1b) is preferable.
  • the steric structure is (1b), R 1 is a propyl group, R 2 and R 3 are methyl groups, and R 4 is 4- (1- Mention may be made of compounds that are methylethoxy) phenyl groups.
  • reaction process diagrams are shown, and the reaction of each process will be described in detail.
  • the base is not particularly limited.
  • alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride
  • alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide
  • Alkali metal carbonates such as lithium, sodium carbonate, potassium carbonate, cesium carbonate
  • metal salts of alcohols such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, tert-butoxy sodium, tert-butoxy potassium
  • lithium Metal amides such as diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide
  • n-butyllithium, sec- Organometallic compounds such as til lithium and tert-butyl lithium; triethylamine, N, N-diiso
  • the reaction conditions are ⁇ 80 to 150 ° C., preferably 0 to 100 ° C., and 1 minute to 48 hours, preferably 1 hour to 24 hours.
  • Step 2 In this step, compound (3) and compound (4) are reacted in a solvent in the presence of a condensing agent, in the presence or absence of a reaction accelerator, and in the presence or absence of a base.
  • a condensing agent in the presence or absence of a reaction accelerator
  • a base in the presence or absence of a base.
  • the solvent is not particularly limited.
  • dimethyl sulfoxide, acetonitrile, and methylene chloride are preferable.
  • the condensing agent is not particularly limited.
  • carbodiimide reagents such as dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC), diisopropylcarbodiimide (DIPCDI), (1H- Benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate (BOP), (1H-benzotriazol-1-yloxy) tris (pyrrolidino) phosphonium hexafluorophosphate (PyBOP), 1- [bis (dimethyl) Amino) methylene] -1H-1,2,3-triazolo (4,5-b) pyridium-3-oxodohexafluorophosphate (HATU),
  • the reaction accelerator is not particularly limited.
  • 1-hydroxybenzotriazole (HOBt) 6-chloro-1-hydroxybenzotriazole (6-Cl-HOBt), 3,4-dihydro-3-hydroxy-4 -Oxo-1,2,3-benzotriazine (HOOBt), 1-hydroxy-7-azabenzotriazole (HOAt) and the like can be used.
  • the base is not particularly limited.
  • alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride
  • alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide
  • Alkali metal carbonates such as lithium, sodium carbonate, potassium carbonate, cesium carbonate
  • metal salts of alcohols such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, tert-butoxy sodium, tert-butoxy potassium
  • lithium Metal amides such as diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide
  • n-butyllithium, sec- Organometallic compounds such as til lithium and tert-butyl lithium; triethylamine, N, N-diisopropylethylamine, N
  • phosphine reagents include trialkylphosphine such as trimethylphosphine, triethylphosphine, tripropylphosphine, triisopropylphosphine, tributylphosphine, triisobutylphosphine, and tricyclohexylphosphine, and triarylphosphine such as diphenylphosphinophenylpolystyrene Etc. can be used.
  • trialkylphosphine such as trimethylphosphine, triethylphosphine, tripropylphosphine, triisopropylphosphine, tributylphosphine, triisobutylphosphine, and tricyclohexylphosphine
  • triarylphosphine such as diphenylphosphinophenylpolystyrene Etc.
  • Examples of the azo reagent or ethylenedicarboxylic acid reagent include diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), 1,1′-azobis (N, N-dimethylformamide) (TMAD), 1,1′- (Azodicarbonyl) dipiperidine (ADDP), 1,1′-azobis (N, N-diisopropylformamide) (TIPA), 1,6-dimethyl-1,5,7-hexahydro-1,4,6,7- Tetrazocine-2,5-dione (DHTD) or the like can be used.
  • the reaction conditions are ⁇ 80 to 150 ° C., preferably 0 to 100 ° C., for 1 minute to 5 days, preferably 1 hour to 3 days.
  • compound (3) is reacted with an acid halogenating agent in a solvent to produce an acid halide derivative, and this is then combined with compound (4) in a solvent in the presence or absence of a base.
  • the hydantoin derivative (1) can also be produced by reacting.
  • Examples of the acid halogenating agent include N, N-diethylaminosulfur trifluoride (DAST), selenium tetrafluoride or its pyridine adduct, thionyl chloride, oxalyl chloride, pyrocatekylphosphotrichloride, dichlorotriphenylphosphorane, Thionyl bromide, dibromotriphenylphosphorane, 1-dimethyl-1-iodo-2-methylpropene and the like can be used.
  • DAST N-diethylaminosulfur trifluoride
  • selenium tetrafluoride or its pyridine adduct thionyl chloride
  • oxalyl chloride oxalyl chloride
  • pyrocatekylphosphotrichloride dichlorotriphenylphosphorane
  • Thionyl bromide Thionyl bromide
  • dibromotriphenylphosphorane 1-dimethyl-1-i
  • alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride
  • alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide
  • Alkali metal carbonates such as lithium, sodium carbonate, potassium carbonate, cesium carbonate
  • metal salts of alcohols such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, tert-butoxy sodium, tert-butoxy potassium
  • lithium Metal amides such as diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide
  • n-butyllithium, sec- Organometallic compounds such as til lithium and tert-butyl lithium; triethylamine, N, N-diisopropylethylamine, N
  • Step 3 is a step for producing a compound (7) by reacting the compound (5) with a compound (6) in a solvent in the presence or absence of a base.
  • a compound (6) a commercially available compound can be used, and for example, a compound produced according to the method described in WO2010 / 12581 can be used, but the compound (6) is particularly limited to this. is not.
  • the solvent is not particularly limited, but for example, tetrahydrofuran, toluene, dioxane, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, propionitrile, acetone, methyl ethyl ketone, water, etc.
  • alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride, Alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide; Alkali metal carbonates such as lithium, sodium carbonate, potassium carbonate, cesium carbonate; metal salts of alcohols such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, tert-butoxy sodium, tert-butoxy potassium; lithium Metal amides such as diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide; n-butyllithium, sec- Organometallic compounds such as til lithium and tert-butyl lithium;
  • Step 4 is a step for producing compound (8) by reacting compound (7) with a Wittig reagent or Horner-Wadsworth-Emmons (HWE) reagent in a solvent in the presence or absence of a base.
  • the solvent is not particularly limited, and for example, N, N-dimethylformamide, tetrahydrofuran, dioxane, acetonitrile, nitromethane, acetone, ethyl acetate, benzene, chlorobenzene, toluene, chloroform, methylene chloride and the like can be used.
  • Tetrahydrofuran, ethyl acetate, toluene, chloroform and methylene chloride are preferred.
  • phosphonium salts such as stable ylide and unstable ylide (methyltriphenylphosphonium bromide, ethyltriphenylphosphonium bromide) can be used.
  • HWE reagent a phosphonic acid ester can be used.
  • the base is not particularly limited.
  • alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride
  • alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide
  • Alkali metal carbonates such as lithium, sodium carbonate, potassium carbonate, cesium carbonate, metal salts of alcohols such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, tert-butoxy sodium, tert-butoxy potassium
  • lithium Metal amides such as diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide
  • n-butyllithium, sec- Organometallic compounds such as til lithium and tert-butyl lithium
  • This process is a process of manufacturing a compound (10) by making a compound (9) react in a solvent in presence of a base or an acid.
  • the solvent is not particularly limited.
  • the base is not particularly limited.
  • alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide
  • alkali carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate
  • an acid For example, hydrochloric acid, a sulfuric acid, an acetic acid, a tosylic acid etc. can be used.
  • the reaction conditions are ⁇ 80 to 150 ° C., preferably 0 to 100 ° C., for 1 minute to 5 days, preferably 1 hour to 3 days.
  • Step 7 is a step of removing the compound (10) in a solvent or in the absence of a solvent, in the presence or absence of a condensing agent, in the presence or absence of a reaction accelerator, in the presence or absence of an acid or base.
  • compound (11) is produced by the reaction below.
  • the substituent represented by R 9 can be converted into an acid halide, an acid anhydride or an ester with reference to, for example, literature (Comprehensive Organic Transformations Second Edition, John Wiley & Sons, Inc.).
  • acid halides include acid fluorides and acid chlorides.
  • Examples of the acid anhydride include an acid anhydride with an aliphatic carboxylic acid such as acetic acid, an acid anhydride with an aromatic carboxylic acid such as benzoic acid, and the like.
  • Examples of the ester include an ester with an aliphatic alcohol such as methanol, an ester with an aromatic alcohol such as pentafluorophenol, and the like.
  • R 9 is a pentafluorophenoxy group
  • the solvent is not particularly limited.
  • tetrahydrofuran, toluene, dioxane, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, propionitrile, acetone, Methyl ethyl ketone, ethyl acetate and the like can be used alone or in combination.
  • the condensing agent is not particularly limited, and examples thereof include carbodiimide reagents such as dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC), and diisopropylcarbodiimide (DIPCDI). Of these, dicyclohexylcarbodiimide and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide are preferable.
  • DEC dicyclohexylcarbodiimide
  • EDC 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide
  • DIPCDI diisopropylcarbodiimide
  • Step 8 is a step for producing the compound (11) into the hexafluorocarbinol compound (12) using a trifluoromethylating reagent in a solvent in the presence of a base.
  • the solvent is not particularly limited, and examples thereof include dimethoxyethane, tetrahydrofuran, toluene, dioxane, ethylene glycol dimethyl ether, N, N-dimethylformamide, N-methylpyrrolidone, tetramethylurea, dimethyl sulfoxide, acetonitrile, propionitrile and the like. They can be used alone or in combination, and ethylene glycol dimethyl ether is particularly preferable.
  • Trifluoromethylating reagents include (trifluoromethyl) trimethylsilane, triethyl (trifluoromethyl) silane, triisopropyl (trifluoromethyl) silane, methyldiphenyl (trifluoromethyl) silane, dimethyl (diphenyl) trifluoromethylsilane Etc.
  • the reaction conditions are ⁇ 80 to 150 ° C., preferably ⁇ 30 to 50 ° C., for 1 minute to 5 days, preferably 1 hour to 3 days.
  • compound (4) can be produced by reacting compound (12) with an acid in a solvent or without a solvent.
  • the solvent is not particularly limited.
  • N, N-dimethylformamide, tetrahydrofuran, dioxane, acetonitrile, nitromethane, acetone, ethyl acetate, benzene, chlorobenzene, toluene, chloroform, methylene chloride, water, methanol, ethanol, 1- Propanol, 2-propanol and the like can be used alone or in combination.
  • the production method of the compound (2) used in the present invention is not particularly limited, but can be synthesized, for example, by the method shown below.
  • alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide
  • alkali carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate
  • an acid For example, hydrochloric acid, a sulfuric acid, an acetic acid, a tosylic acid etc. can be used.
  • the reaction conditions are ⁇ 80 to 200 ° C., preferably 0 to 150 ° C., for 1 minute to 7 days, preferably 1 hour to 2 days.
  • Step 12 is a step for producing a compound (16) by reacting the compound (15) in a solvent or in the absence of a solvent in the presence of an optical resolution agent.
  • the solvent is not particularly limited.
  • esters such as isobutyl acetate, alcohols such as water, methanol, ethanol, 1-propanol, and 2-propanol can be used alone or in combination.
  • the optical resolution agent is not particularly limited.
  • (L)-(+)-mandelic acid, (D)-( ⁇ )-mandelic acid, malic acid, tartaric acid, lactic acid, camphorsulfonic acid, (1S) — (+)-Ketopic acid or commercially available optically pure compounds can also be used.
  • the reaction conditions are -80 to 150 ° C, preferably -10 to 100 ° C, 1 minute to 48 hours, preferably 1 hour to 24 hours.
  • the base is not particularly limited.
  • alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride
  • alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide
  • Alkali metal carbonates such as lithium, sodium carbonate, potassium carbonate, cesium carbonate
  • metal salts of alcohols such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, tert-butoxy sodium, tert-butoxy potassium
  • Specific examples of the salt allowed in the optically active compound represented by the general formula (3) of the present invention include acid addition salts with inorganic acids and organic acids, or base addition salts with inorganic bases and organic bases. Etc.
  • solvate of the optically active compound represented by the general formula (3) of the present invention and its acceptable salt include hydrates and various solvates.
  • N, N-dimethylformamide 50 mL of 2,5-dimethylpiperazine-1-carboxylic acid (2S, 5R) -tert-butyl (14.2 g, 61.26 mmol) produced according to the pamphlet of WO2010 / 12581
  • the solution and 4-fluoro-3-formylbenzoic acid methyl ester 11.15 g, 61.26 mmol
  • toluene and water were added to the reaction solution at 0 ° C.
  • Step II 4- [4- (Methoxycarbonyl) -2- (prop-1-en-1-yl) phenyl] -2,5-dimethylpiperazine-1-carboxylic acid (2S, 5R) -tert-butyl ( c3)
  • Ethyltriphenylphosphonium bromide 25.8 g, 69.46 mmol
  • potassium methoxide 4.87 g, 69.46 mmol
  • trans-c3 4- ⁇ 4- (methoxycarbonyl) -2-[(E) -prop-1-en-1-yl] phenyl ⁇ -2,5-dimethylpiperazine-1-carboxylic acid (2S, 5R) -tert-butyl
  • Step III Preparation of 4- [4- (methoxycarbonyl) -2-propylphenyl] -2,5-dimethylpiperazine-1-carboxylic acid (2S, 5R) -tert-butyl (c4): 4- [4- (Methoxycarbonyl) -2- (prop-1-en-1-yl) phenyl] -2,5-dimethylpiperazine-1-carboxylic acid (2S, 5R) -tert-butyl (4.76 g) , 12.25 mmol) was dissolved in methanol (123 mL), and palladium on carbon was added under an argon atmosphere. Thereafter, the mixture was stirred at room temperature for 24 hours under a hydrogen atmosphere.
  • Step IV Preparation of 4-[(2R, 5S) -4- (tert-butoxycarbonyl) -2,5-dimethylpiperazin-1-yl] -3-propylbenzoic acid (c5): 4- [4- (Methoxycarbonyl) -2-propylphenyl] -2,5-dimethylpiperazine-1-carboxylic acid (2S, 5R) -tert-butyl (4.72 g, 12.09 mmol) in methanol (121 mL) 4N-aqueous sodium hydroxide solution (18.1 mL, 72.52 mmol) was added at 0 ° C., and the mixture was stirred at 60 ° C. for 2 hours.
  • Step V Preparation of 2,5-dimethyl-4- ⁇ 4-[(perfluorophenoxy) carbonyl] -2-propylphenyl ⁇ piperazine-1-carboxylic acid (2S, 5R) -tert-butyl (c6): 4-[(2R, 5S) -4- (tert-butoxycarbonyl) -2,5-dimethylpiperazin-1-yl] -3-propylbenzoic acid (1.0 g, 2.656 mmol) was added to ethyl acetate (18 mL).
  • Step VI 4- [4- (1,1,1,3,3,3-Hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl] -2,5-dimethylpiperazine-1-carboxyl
  • 2S, 5R 2,5-dimethyl-4- ⁇ 4-[(perfluorophenoxy) carbonyl] -2-propylphenyl ⁇ piperazine-1-carboxylic acid (2S, 5R) -tert-butyl (5.75 g, 10.6 mmol) under reduced pressure After drying at 100 ° C.
  • Step VII 2- ⁇ 4-[(2R, 5S) -2,5-dimethylpiperazin-1-yl] -3-propylphenyl ⁇ -1,1,1,3,3,3-hexafluoropropane-2 -Manufacture of all (c8): 4- [4- (1,1,1,3,3,3-Hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl] -2,5-dimethylpiperazine-1-carboxylic acid (2S , 5R) -tert-butyl (4.53 g, 9.08 mmol) was dissolved in methanol (14 mL), 2N hydrochloric acid methanol solution (41 mL, 81.7 mmol) was added at 0 ° C., and 5 hours at 35 ° C.
  • Step IX Preparation of methyl 2-amino-2- [4- (1-methylethoxy) phenyl] propanoate (c11): 2-Amino-2- [4- (1-methylethoxy) phenyl] propanoic acid hydrochloride (70.0 g, 270 mmol) was dissolved in methanol (225 mL), concentrated sulfuric acid (70 mL) was sequentially added at room temperature, and 24 Heated to reflux for hours. After confirming the completion of the reaction, the reaction solution was brought to room temperature and concentrated under reduced pressure to distill off methanol. The obtained residue was dissolved in dichloromethane and extracted with dichloromethane. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (44.8 g, yield 70%) as a colorless oil.
  • Step XI Preparation of 2- [3- (2-ethoxy-2-oxoethyl) ureido] -2- [4- (1-methylethoxy) phenyl] propanoic acid (S) -methyl ((S) -c12): 2-Amino-2- [4- (1-methylethoxy) phenyl] propanoic acid (S) -methyl (53.0 mg, 0.223 mmol) was dissolved in dichloromethane (740 ⁇ L) and ethyl isocyanatoacetate (0 ° C.) 29 mg, 0.223 mmol) was added, and the mixture was stirred at 0 ° C. for 1 hour. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain 91.5 mg (yield> 99%) of the title compound as a colorless oil.
  • Steps XI & XII (S) -2- ⁇ 4- [4- (1-methylethoxy) phenyl] -4-methyl-2,5-dioxoimidazolidin-1-yl ⁇ acetic acid ((S) -c13) Manufacturing: 2-Amino-2- [4- (1-methylethoxy) phenyl] propanoic acid (S) -methyl (2.90 g, 12.2 mmol) was dissolved in dimethyl sulfoxide (15 mL) and ethyl isocyanatoacetate at 15 ° C. (1.74 g, 13.4 mmol) was added, and the mixture was stirred at 15 ° C. for 1 hour.
  • Oxoimidazolidin-1-yl ⁇ acetic acid (169 mg, 0.552 mmol) was added. Thereafter, O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HBTU) (228 mg, 0.602 mmol), diisopropylethylamine ( 156 mg, 1.20 mmol). The reaction solution was stirred at 0 ° C. for 10 minutes, and then stirred at room temperature for 20 hours.
  • HBTU hexafluorophosphate
  • Step XIII-2 (S) -3- (2- ⁇ (2S, 5R) -4- [4- (1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl) ) -2-Propylphenyl] -2,5-dimethylpiperazin-1-yl ⁇ -2-oxoethyl) -5- [4- (1-methylethoxy) phenyl] -5-methylimidazolidine-2,4-dione Production of ((S) -B): (S) -2- ⁇ 4- [4- (1-methylethoxy) phenyl] -4-methyl-2,5-dioxoimidazolidin-1-yl ⁇ acetic acid was dissolved in toluene (2.0 mL), N, N-dimethylformamide (2.6 mg) and thionyl chloride (77.7 mg) were sequentially added, and the mixture was stirred at 120 ° C.
  • Step XIV Preparation of 2-amino-2- [4- (1-methylethoxy) phenyl] propanoic acid (R) -methyl ((R) -c11): (D)-( ⁇ )-Mandelic acid was used for the reaction and treatment in the same manner as in Step X to obtain the title compound as a colorless oil (99.4% ee).
  • Step XV (R) -2- ⁇ 4- [4- (1-methylethoxy) phenyl] -4-methyl-2,5-dioxoimidazolidin-1-yl ⁇ acetic acid ((R) -c13) Manufacturing: 2-Amino-2- [4- (1-methylethoxy) phenyl] propanoic acid (R) -methyl (1.00 g, 4.21 mmol) was dissolved in ethanol (5.0 mL), and Ethyl isocyanatoacetate (599 mg, 4.64 mmol) was added, and the mixture was stirred at 20 ° C. for 1 hr 30 min.
  • Step XVI (R) -3- (2- ⁇ (2S, 5R) -4- [4- (1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)- 2-propylphenyl] -2,5-dimethylpiperazin-1-yl ⁇ -2-oxoethyl) -5- [4- (1-methylethoxy) phenyl] -5-methylimidazolidine-2,4-dione (( Production of R) -B): 2- ⁇ 4-[(2R, 5S) -2,5-dimethylpiperazin-1-yl] -3-propylphenyl ⁇ -1,1,1,3,3,3-hexafluoropropan-2-ol ( 43.8 mg, 0.112 mmol) is dissolved in dimethyl sulfide (500 ⁇ L) and (R) -2- ⁇ 4- [4- (1-methylethoxy) phenyl] -4-methyl-2,5-
  • the present invention provides a production method applicable to mass synthesis of the optically active hydantoin compound (1) represented by the general formula (1).
  • Compound (1) has an LXR ⁇ agonistic action, and atherosclerosis such as atherosclerosis, arteriosclerosis, and diabetes caused by diabetes; dyslipidemia; hypercholesterolemia; lipid-related disease; inflammation Inflammatory diseases caused by sex cytokines; skin diseases such as allergic skin diseases; diabetes; or Alzheimer's disease preventive and / or therapeutic agents, etc. Has the above applicability.

Abstract

　La présente invention porte sur un procédé pour la production d'un composé d'hydantoïne optiquement actif ayant un effet d'activation de LXRβ et sur un intermédiaire de production correspondant. Dans la présente invention, un composé carbinol optiquement actif représenté par la formule (1) est produit par réaction d'un composé représenté par la formule (3) et d'un composé représenté par la formule (4). Dans les formules (1), (3) et (4), R1, R2 et R3 représentent des groupes alkyle en C1-3 identiques ou différents, * désigne un atome de carbone asymétrique et R4 représente une structure quelconque choisie parmi les structures A-E.
PCT/JP2014/004702 2013-09-12 2014-09-11 Procédé pour la production d'un composé d'hydantoïne optiquement actif WO2015037243A1 (fr)

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Citations (6)

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Publication number Priority date Publication date Assignee Title
DE335993C (de) * 1916-02-02 1921-04-20 Chem Fab Von Heyden Aktien Ges Verfahren zur Herstellung von Hydantoinen
JPH05503718A (ja) * 1990-11-16 1993-06-17 ジュヴェイナル　エス　アー 光学異性ヒダントインの分割方法
JPH07330737A (ja) * 1993-06-18 1995-12-19 Rhone Poulenc Agrochim 殺菌性の光学活性な２−イミダゾリン−５−オンおよび２−イミダゾリン−５−チオン誘導体
JPH1059947A (ja) * 1996-06-20 1998-03-03 Hoechst Ag キラルで、非ラセミの（４−アリール−２，５−ジオキソイミダゾリジン−１−イル）酢酸の製造方法
JPH11504024A (ja) * 1995-04-28 1999-04-06 ヘキスト・アクチエンゲゼルシヤフト 薬学的に活性な化合物の中間体としてのヒダントイン誘導体
WO2010125811A1 (fr) * 2009-04-29 2010-11-04 興和株式会社 Composé carbinol ayant un groupe de liaison hétérocyclique

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Publication number Priority date Publication date Assignee Title
DE335993C (de) * 1916-02-02 1921-04-20 Chem Fab Von Heyden Aktien Ges Verfahren zur Herstellung von Hydantoinen
JPH05503718A (ja) * 1990-11-16 1993-06-17 ジュヴェイナル　エス　アー 光学異性ヒダントインの分割方法
JPH07330737A (ja) * 1993-06-18 1995-12-19 Rhone Poulenc Agrochim 殺菌性の光学活性な２−イミダゾリン−５−オンおよび２−イミダゾリン−５−チオン誘導体
JPH11504024A (ja) * 1995-04-28 1999-04-06 ヘキスト・アクチエンゲゼルシヤフト 薬学的に活性な化合物の中間体としてのヒダントイン誘導体
JPH1059947A (ja) * 1996-06-20 1998-03-03 Hoechst Ag キラルで、非ラセミの（４−アリール−２，５−ジオキソイミダゾリジン−１−イル）酢酸の製造方法
WO2010125811A1 (fr) * 2009-04-29 2010-11-04 興和株式会社 Composé carbinol ayant un groupe de liaison hétérocyclique

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DATABASE REGISTRY CHEMICAL ABSTRACTS SERVICE; 17 April 2011 (2011-04-17), accession no. 281562-68-2 *
DATABASE REGISTRY CHEMICAL ABSTRACTS SERVICE; 25 September 2008 (2008-09-25), accession no. 052555-32-4 *

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