WO2017104782A1 - Procédé de préparation d'un composé d'oxadiazole - Google Patents

Procédé de préparation d'un composé d'oxadiazole Download PDF

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WO2017104782A1
WO2017104782A1 PCT/JP2016/087486 JP2016087486W WO2017104782A1 WO 2017104782 A1 WO2017104782 A1 WO 2017104782A1 JP 2016087486 W JP2016087486 W JP 2016087486W WO 2017104782 A1 WO2017104782 A1 WO 2017104782A1
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formula
compound represented
compound
added
acid
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PCT/JP2016/087486
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Japanese (ja)
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斉大 武田
岳志 金田
亮 糸岡
学 原
和夫 久保田
臣 内藤
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第一三共株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
    • C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • 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 present invention has the formula (1):
  • Compound (1) or a pharmaceutically acceptable salt thereof is expected as a new therapeutic agent for diabetes because it has a hypoglycemic action and a ⁇ -cell or pancreatic protective action (see Patent Document 1).
  • Example 3 of Patent Document 1 describes a method for synthesizing compound (1). Specifically, it is as follows.
  • the overall yield is about 22%, and the yield needs to be improved.
  • the object of the present invention is to improve the yield, use of readily available and inexpensive raw materials and cost reduction by efficient recovery of unnecessary stereoisomers, a compound (1) that can reduce the burden on the environment, etc.
  • a method for producing a pharmaceutically acceptable salt thereof is provided.
  • R represents a protecting group for a carboxy group.
  • the method according to (2) or (3) above comprising a step of obtaining a compound represented by formula (4) using an organic amine salt of a compound represented by formula (1) and an acid; (5) The method according to (4) above, wherein the organic amine is benzylamine, cyclohexylamine or n-butylamine; (6) The method according to (4) above, wherein the organic amine is benzylamine; (7) The method according to any one of (4) to (6) above, wherein the acid is sulfuric acid, hydrochloric acid or hydrobromic acid; (8) The method according to any one of (4) to (6) above, wherein the acid is sulfuric acid; (9) Equation (8):
  • the method according to (2) or (3) comprising a step of obtaining a compound represented by: (10) The method according to (9) above, further using a base; (11) The method according to (10) above, wherein the base is imidazole, triethylamine, diisopropylethylamine, tributylamine or pyridine; (12) The method according to (10) above, wherein the base is imidazole; (13) The method according to (9) to (12) above, comprising a heating step; (14) The method according to (13) above, comprising a step of adding water after heating; (15)
  • the condensing agent is N, N′-carbonyldiimidazole, N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride, N, N′-dicyclohexylcarbodiimide, 4- (4,6-dimethoxy) -1,3,5-triazin-2-yl) -4-methylmorpholin
  • the present invention provides a method for producing a compound (1) or a pharmaceutically acceptable salt thereof by improving yield, using readily available and inexpensive raw materials, and efficiently recovering unnecessary stereoisomers. There are effects such as reduction and reduction of environmental load.
  • compound (x) refers to a compound represented by the formula (x).
  • the compound (1) is 4- (5- ⁇ (1R) -1- [4- (cyclopropylcarbonyl) phenoxy] propyl ⁇ -1,2,4-oxadiazol-3-yl) 2-Fluoro-N-[(2R) -1-hydroxypropan-2-yl] benzamide.
  • “pharmaceutically acceptable salt” refers to a salt formed by reacting compound (1) with an acid or a base.
  • the salt include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide; hydrochloride, nitrate, perchlorate, sulfate, phosphate, etc.
  • Inorganic acid salts lower alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate and ethane sulfonate; aryl sulfonates such as benzene sulfonate and p-toluene sulfonate; acetate and malic acid Organic salts such as salts, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate; alkali metal salts such as sodium salt, potassium salt, lithium salt; calcium salt Alkaline earth metal salts such as magnesium salts; metal salts such as aluminum salts and iron salts; inorganic salts such as ammonium salts; t-octylamine salts, benzylamine salts, dibenzines Ruamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglu
  • the compound (1) for example, may be left in the air to absorb moisture and adsorb water, resulting in a hydrate. Such a hydrate may also be a salt of the compound (1). Is included.
  • the compound represented by the general formula (II), the compound represented by the general formula (III), the compound (11) and the compound (13) may have geometric isomers (EZ form), and these compounds Is represented in the chemical structural formula as one of the isomers, but may exist in any form of E isomer and Z isomer and mixtures thereof.
  • examples of the ⁇ carboxy group protecting agent '' include T. H. Greene, P. G. Wuts, Protective Groups in Organic Synthesis, Fifth Edition, 2014, John Wiley & Sons,
  • the protective groups described are mentioned, preferably tert-butyl, p-methoxybenzyl, 2,6-dimethoxybenzyl, 2,4,6-trimethoxybenzyl or 2,4,6-trimethylbenzyl
  • a diphenylmethyl group more preferably a tert-butyl group.
  • the optical resolution agent is (R)-( ⁇ )-phenylglycinol, (1S, 2S)-(+)-2-amino-1-phenyl-1,3-propanediol or (D). -(-)-Threo-2-amino-1- (4-nitrophenyl) -1,3-propanediol, preferably (R)-(-)-phenylglycinol.
  • the organic amine that forms a salt with compound (4) includes n-octylamine salt, n-butylamine salt, t-butylamine salt, cyclohexylamine salt, benzylamine salt, dibenzylamine salt, diphenylmethyl Amine, morpholine, glucosamine, phenylglycine alkyl ester, ethylenediamine, N-methylglucamine, guanidine, diethylamine, triethylamine, dicyclohexylamine, N, N'-dibenzylethylenediamine, chloroprocaine Salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt, tris (hydroxymethyl) aminomethane salt, etc., preferably benzylamine salt or cyclohexylamine salt, Ri is preferably benzyl amine salt.
  • Compound (1) or a pharmaceutically acceptable salt thereof can be produced by the following reaction scheme.
  • R represents a protecting group for a carboxy group.
  • Step A is a step of obtaining an organic amine salt of compound (4) from compound (2).
  • Step A-I is a step in which compound (2) and ethyl 2-bromobutyrate are reacted to obtain compound (3).
  • solvent used examples include acetone, acetonitrile, N, N-dimethylacetamide, tetrahydrofuran, ethyl acetate, and the like, preferably acetone, acetonitrile, or tetrahydrofuran, and more preferably acetone or tetrahydrofuran.
  • Examples of the reagent used include tripotassium phosphate, trisodium phosphate, potassium carbonate, sodium carbonate and the like, preferably tripotassium phosphate, trisodium phosphate or potassium carbonate, more preferably , Tripotassium phosphate or potassium carbonate.
  • the reaction temperature is 20 to 100 ° C., preferably 45 to 75 ° C. or 35 to 65 ° C., more preferably 55 to 65 ° C. or 45 to 55 ° C.
  • the reaction time is 0.5 to 24 hours, preferably 1 to 6 hours, and more preferably 2 to 3 hours.
  • Step A-II is a step of obtaining compound (4) from compound (3).
  • solvent used examples include acetone, tetrahydrofuran, acetonitrile, N, N-dimethylacetamide, methanol, ethanol, water and the like, preferably acetone, tetrahydrofuran, methanol, ethanol or water, more preferably , Acetone, methanol or water.
  • Examples of the reagent used include sodium hydroxide, potassium hydroxide, lithium hydroxide, tripotassium phosphate, potassium carbonate and the like, preferably sodium hydroxide, potassium hydroxide or lithium hydroxide, More preferred is sodium hydroxide or potassium hydroxide.
  • the reaction temperature is 0 to 50 ° C., preferably 10 to 40 ° C., and more preferably 20 to 30 ° C.
  • the reaction time is 0.25 to 24 hours, preferably 0.5 to 4 hours, more preferably 1 to 2 hours.
  • Step A-III is a step of obtaining an organic amine salt of compound (4) from compound (4).
  • solvent used examples include isopropyl acetate, ethyl acetate, acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, toluene, tetrahydrofuran, methanol, ethanol, N, N-dimethylacetamide, etc., preferably isopropyl acetate, Ethyl acetate, acetonitrile or acetone is preferable, and isopropyl acetate or ethyl acetate is more preferable.
  • organic amine to be used examples include benzylamine, cyclohexylamine, n-butylamine, dibenzylamine, diphenylmethylamine and the like, preferably benzylamine, cyclohexylamine or n-butylamine, more preferably Benzylamine or cyclohexylamine.
  • the crystallization temperature is 0 to 120 ° C., preferably 50 to 90 ° C., and more preferably 65 to 75 ° C.
  • the crystallization time is from 0.25 to 24 hours, preferably from 0.5 to 12 hours, more preferably from 1 to 2 hours.
  • the aging temperature before filtration is -20 to 70 ° C, preferably 0 to 50 ° C, and more preferably 20 to 30 ° C.
  • the aging time before filtration is 0.25 to 48 hours, preferably 0.5 to 24 hours, and more preferably 1 to 3 hours.
  • Step B is a step of obtaining a salt of compound (12) and an optical resolution agent (compound (7)) from an organic amine salt of compound (4).
  • Step B-I is a step of obtaining the compound (4) from the organic amine salt of the compound (4).
  • solvent used examples include isopropyl acetate, water, ethyl acetate, toluene, cyclopentyl methyl ether, and the like, preferably isopropyl acetate, water, ethyl acetate, and / or toluene, and more preferably isopropyl acetate. And water.
  • Examples of the reagent to be used include sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid and the like, preferably sulfuric acid or hydrochloric acid, more preferably sulfuric acid.
  • the reaction temperature is 0 to 50 ° C., preferably 10 to 40 ° C., and more preferably 20 to 30 ° C.
  • the reaction time is 5 to 120 minutes, preferably 10 to 80 minutes, and more preferably 20 to 40 minutes.
  • Step B-II is a step of obtaining a salt (compound (7)) of compound (12) and an optical resolution agent from compound (4).
  • optical resolution agent used is, for example, (R)-( ⁇ )-phenylglycinol, (1S, 2S)-(+)-2-amino-1-phenyl-1,3-propanediol, (D) -(-)-Threo-2-amino-1- (4-nitrophenyl) -1,3-propanediol and the like, preferably (R)-(-)-phenylglycinol.
  • the crystallization temperature is 0 to 120 ° C., preferably 50 to 90 ° C., and more preferably 65 to 75 ° C.
  • the crystallization time is 0.25 to 24 hours, preferably 0.5 to 12 hours, and more preferably 1 to 4 hours.
  • the aging temperature before filtration is -20 to 50 ° C, preferably -10 to 40 ° C or -10 to 20 ° C, more preferably 0 to 30 ° C or 0 to 5 ° C.
  • the aging time before filtration is 0.25 to 48 hours, preferably 0.5 to 24 hours, and more preferably 1 to 3 hours.
  • optical purity of the salt of the obtained compound (12) and optical resolution agent (compound (7)) is 90% ee or more, preferably 97 to 100% ee, more preferably 99 to 100%. ee.
  • Step C is a step of racemizing compound (8) by-produced by optical resolution of compound (4) in step B to obtain an organic amine salt of compound (4).
  • Step C-I is a step of obtaining compound (8) from compound (4), and compound (8) can be obtained from the filtrate in the same step as step B-II.
  • Step C-II is a step of mixing compound (8) and a condensing agent, heating and racemizing, and then adding water to obtain compound (4), preferably compound (8), In this step, the condensing agent and the base are mixed, heated and racemized, and then water is added to obtain the compound (4).
  • solvent used examples include isopropyl acetate, ethyl acetate, toluene, cyclopentyl methyl ether, and the like, preferably isopropyl acetate, ethyl acetate, or toluene, and more preferably isopropyl acetate or ethyl acetate.
  • Examples of the condensing agent used include N, N′-carbonyldiimidazole, N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride, N, N′-dicyclohexylcarbodiimide, 4- (4, 6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride, 1H-benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, ⁇ [ (1-cyano-2-ethoxy-2-oxoethylidene) amino] oxy ⁇ -4-morpholinomethylene ⁇ dimethylammonium hexafluorophosphate, and the like, preferably N, N′-carbonyldiimidazole or N— (3-Dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride, more preferably N
  • Examples of the base used include imidazole, triethylamine, diisopropylethylamine, tributylamine, pyridine and the like, preferably imidazole or triethylamine, and more preferably imidazole.
  • the reaction temperature is 0 to 120 ° C., preferably 50 to 100 ° C., more preferably 75 to 85 ° C.
  • the reaction time is 1 to 72 hours, preferably 4 to 20 hours, and more preferably 8 to 10 hours.
  • the reaction time is 1 to 72 hours, preferably 2 to 8 hours, and more preferably 3 to 4 hours.
  • Step C-III is a step of obtaining an organic amine salt of compound (4) from compound (4), and can be obtained by the same method as in step A-III.
  • Step D is a step of obtaining a compound represented by general formula (II) from compound (9).
  • Step D-I is a step of protecting the carboxy group of compound (9).
  • Step D-II is a step of obtaining a compound represented by the general formula (II) by reacting the compound represented by the general formula (I) with hydroxylamine.
  • solvent used examples include ethanol, tetrahydrofuran, methanol, tert-butyl alcohol, toluene, cyclopentyl methyl ether, 1,2-dimethoxyethane, and the like, and preferably ethanol, tetrahydrofuran and / or 1,2- Dimethoxyethane, more preferably ethanol and tetrahydrofuran.
  • the reaction temperature is 0 to 100 ° C., preferably 40 to 70 ° C., and more preferably 50 to 60 ° C.
  • the reaction time is 0.5 to 24 hours, preferably 1 to 5 hours, and more preferably 1.5 to 2.5 hours.
  • Step E is a step of obtaining a compound represented by general formula (III) from a salt of compound (12) and an optical resolution agent (compound (7)).
  • Step EI is a step of obtaining the compound (12) from a salt of the compound (12) and an optical resolution agent (compound (7)).
  • Examples of the solvent used include ethyl acetate, water, isopropyl acetate, toluene, cyclopentyl methyl ether, tetrahydrofuran, tert-butyl methyl ether, and the like, and preferably ethyl acetate, water, isopropyl acetate and / or tert- Butyl methyl ether, more preferably ethyl acetate and water.
  • Examples of the reagent to be used include sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid and the like, preferably sulfuric acid or hydrochloric acid, more preferably sulfuric acid.
  • the reaction temperature is 0 to 50 ° C., preferably 5 to 40 ° C., more preferably 10 to 20 ° C.
  • the reaction time is 5 to 120 minutes, preferably 10 to 80 minutes, and more preferably 20 to 40 minutes.
  • Step E-II is a step of obtaining the compound represented by the general formula (III) using the compound (12) and the compound represented by the general formula (II).
  • solvent to be used examples include acetonitrile, N, N-dimethylacetamide, tetrahydrofuran, ethyl acetate, and the like, preferably acetonitrile or N, N-dimethylacetamide, and more preferably acetonitrile.
  • Examples of the reagent used include N, N′-carbonyldiimidazole, N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride, N, N′-dicyclohexylcarbodiimide, 4- (4,6 -Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride, 1H-benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, ⁇ [( 1-cyano-2-ethoxy-2-oxoethylidene) amino] oxy ⁇ -4-morpholinomethylene ⁇ dimethylammonium hexafluorophosphate, and the like, preferably N, N′-carbonyldiimidazole or 1-ethyl -3- (3-Dimethylaminopropyl) -carbodiimide hydrochloride, more preferably N,
  • the reaction temperature is ⁇ 20 to 60 ° C., preferably 0 to 40 ° C., and more preferably 10 to 20 ° C.
  • the reaction time is 0.25 to 24 hours, preferably 0.5 to 4 hours, more preferably 1 to 2 hours.
  • Step F is a step of obtaining compound (15) from the compound represented by formula (III).
  • Step F-I is a step of obtaining the compound represented by the general formula (IV) from the compound represented by the general formula (III).
  • solvent to be used examples include toluene, acetonitrile, tetrahydrofuran, N, N-dimethylacetamide, butyl acetate, cyclopentyl methyl ether and the like, preferably toluene, acetonitrile or cyclopentyl methyl ether, more preferably Toluene or acetonitrile.
  • the reaction temperature is 20 to 150 ° C., preferably 70 to 130 ° C., more preferably 90 to 110 ° C.
  • the reaction time is 1 to 72 hours, preferably 4 to 10 hours, and more preferably 6 to 8 hours.
  • Step F-II is a step of obtaining the compound (15) from the compound represented by the general formula (IV).
  • solvent used examples include acetonitrile, toluene, cyclopentyl methyl ether, N, N-dimethylacetamide, and the like, preferably acetonitrile, toluene, or cyclopentyl methyl ether, more preferably acetonitrile or toluene. .
  • Examples of the reagent used include sulfuric acid, hydrochloric acid, hydrobromic acid, trifluoroacetic acid and the like, preferably sulfuric acid or trifluoroacetic acid, and more preferably sulfuric acid.
  • the reaction temperature is 0 to 120 ° C., preferably 50 to 100 ° C., more preferably 75 to 85 ° C.
  • the reaction time is 0.25 to 24 hours, preferably 0.5 to 4 hours, more preferably 1 to 2 hours.
  • Step G is a step of obtaining compound (1) using compound (15) and (R)-( ⁇ )-2-amino-1-propanol.
  • Examples of the solvent used include N, N-dimethylacetamide, ethyl acetate, water, acetonitrile, acetone, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, and preferably N , N-dimethylacetamide, ethyl acetate, water and / or acetonitrile, more preferably N, N-dimethylacetamide, ethyl acetate and water.
  • Examples of the condensing agent used include N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide, N, N′-carbonyldiimidazole hydrochloride, N, N′-dicyclohexylcarbodiimide, 4- (4, 6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride, 1H-benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, ⁇ [ (1-cyano-2-ethoxy-2-oxoethylidene) amino] oxy ⁇ -4-morpholinomethylene ⁇ dimethylammonium hexafluorophosphate, and the like, preferably N- (3-dimethylaminopropyl) -N '-Ethylcarbodiimide hydrochloride or N, N'-carbonyldiimidazole, more preferably
  • Additives used include 1-hydroxybenzotriazole monohydrate, 1-hydroxyazabenzotriazole, 4-dimethylaminopyridine, 3,5-dihydro-3-hydroxy-4-oxo-1,2,3 -Benzotriazine, ethyl cyano (hydroxyimino) acetate, etc., preferably 1-hydroxybenzotriazole monohydrate or 4-dimethylaminopyridine, more preferably 1-hydroxybenzotriazole monohydrate It is.
  • the reaction temperature is 0 to 100 ° C., preferably 20 to 60 ° C., and more preferably 35 to 45 ° C.
  • the reaction time is 0.5 to 48 hours, preferably 1 to 6 hours, and more preferably 2 to 3 hours.
  • the pharmaceutically acceptable salt of compound (1) can be produced by reacting compound (1) with an acid or base using a method known in the art.
  • the production method of compound (1) is preferably the following reaction scheme:
  • t-Bu represents a tert-butyl group
  • Example 1-1 Ethyl 2- [4- (cyclopropylcarbonyl) phenoxy] butanoate A solution of cyclopropyl (4-hydroxyphenyl) methanone (50.0 g, 308 mmol) in acetone (500 mL, 10 v / w) To the mixture, tripotassium phosphate (85.1 g, 401 mmol) and ethyl 2-bromobutyrate (49.7 mL, 339 mmol) were added and heated to about 60 ° C. The mixture was heated to reflux at the same temperature for 3 hours, cooled to room temperature, and water (250 mL, 5 v / w) was added to separate the layers. The obtained organic layer was directly used in the next step.
  • Example 1-2 2- [4- (Cyclopropylcarbonyl) phenoxy] butanoic acid The organic layer obtained in Example 1-1 was concentrated under reduced pressure to 6 v / w, and then water (150 mL, 3 v / w w) and 25% aqueous sodium hydroxide solution (74.0 mL, 462 mmol) were added, and the mixture was stirred at room temperature for 1 hr. Water (350 mL, 7 v / w) was added to the reaction solution, adjusted to pH 6.5 with concentrated sulfuric acid, and then concentrated under reduced pressure to 14 v / w.
  • Example 1-3 2- [4- (cyclopropylcarbonyl) phenoxy] butanoic acid benzylamine
  • the filtrate obtained in Example 1-2 was heated to 70 ° C., and benzylamine (10.1 mL, 92.5 mmol) was added. The mixture was added and stirred at the same temperature for 30 minutes. Benzylamine (10.1 mL, 92.5 mmol) was added again and stirred for 30 minutes, and benzylamine (15.2 mL, 139 mmol) was further added and stirred for 1 hour. Thereafter, the mixture was allowed to cool to room temperature and further stirred at the same temperature for 2.5 hours.
  • Example 2-1 2- [4- (Cyclopropylcarbonyl) phenoxy] butanoic acid Concentrated sulfuric acid (12.8 mL, 232 mmol) and isopropyl acetate (375 mL, 5 v / w) in water (375 mL, 5 v / w) / w) was added, and the compound obtained in Example 1 (75.0 g, 211 mmol) was added thereto. After vigorous stirring for 10 minutes, the layers were separated, and the organic layer was washed twice with a sodium sulfate decahydrate (93.8 g, 1.25 wt) / water (315 mL, 4.2 v / w) solution. The obtained organic layer was directly used in the next step.
  • Example 2-2 (2R) -2- [4- (Cyclopropylcarbonyl) phenoxy] butanoic acid (1R) -2-hydroxy-1-phenylethanamine
  • the organic layer obtained in Example 2-1 Add isopropyl acetate (150 mL, 2 v / w), heat to 70 ° C., add (R)-(-)-phenylglycinol (5.79 g, 42.2 mmol) and seed crystals (1 mg, 0.001 wt %) was added. After confirming the precipitation of crystals, the mixture was stirred at the same temperature for 1 hour.
  • the seed crystal is obtained by heating the organic layer obtained in Example 2-1 to 70 ° C., adding (R)-( ⁇ )-phenylglycinol all at once, and then cooling to room temperature.
  • Example 3-1 (2S) -2- [4- (cyclopropylcarbonyl) phenoxy] butanoic acid
  • water 225 mL, 3 v / w
  • concentrated sulfuric acid 2.32 mL, 42.2 mmol
  • the organic layer was washed with a sodium sulfate decahydrate (60.0 g, 0.8 wt) / water (225 mL, 3 v / w) solution.
  • the obtained organic layer was directly used in the next step.
  • the organic layer obtained in Example 3-1 was concentrated under reduced pressure to 4 v / w, and then isopropyl acetate (300 mL, 4 v / w) was added and the mixture was again concentrated under reduced pressure to 4 v / w.
  • N, N′-carbonyldiimidazole (27.4 g, 169 mmol) was added to the residue, and the mixture was heated to 80 ° C. and stirred at the same temperature for 10 hours.
  • Example 3-3 2- [4- (Cyclopropylcarbonyl) phenoxy] butanoic acid benzylamine
  • the organic layer obtained in Example 3-2 was heated to 70 ° C. and benzylamine (4.61 mL, 42.2 mmol). Was added and stirred at the same temperature for 1 hour.
  • Benzylamine (4.61 mL, 42.2 mmol) was added again and stirred for 1 hour, and benzylamine (5.76 mL, 52.8 mmol) was further added and stirred for 1 hour. Thereafter, the mixture was allowed to cool to room temperature and stirred overnight.
  • Example 4-1 1,1-dimethylethyl 4-cyano-2-fluorobenzoate 4-Cyano-2-fluorobenzoic acid (1300 g, 7.87 mol) in tetrahydrofuran (5200 mL, 4 v / w) 4-Dimethylaminopyridine (96.2 g, 0.79 mol) was added to the mixture and heated to 60 ° C. A solution of di-tert-butyl dicarbonate (2062 g, 9.45 mol) / tetrahydrofuran (1300 mL, 1 v / w) was added dropwise at about 60 ° C. over 2 hours, and the mixture was stirred at the same temperature for 1 hour. The obtained reaction solution was directly used in the next step.
  • Example 4-2 1,1-dimethylethyl 2-fluoro-4- (N′-hydroxycarbamimidoyl) benzoate
  • ethanol 6500 mL, 5 v / w
  • 50% aqueous hydroxylamine solution 780 mL, 13.2 mol
  • the reaction mixture was concentrated under reduced pressure to 5 v / w
  • ethanol (6500 mL, 5 v / w) was added, and the mixture was concentrated again under reduced pressure to 5 v / w.
  • Example 5-1 (2R) -2- [4- (cyclopropylcarbonyl) phenoxy] butanoic acid Concentrated sulfuric acid (15.2 mL, 285 mmol) and ethyl acetate (500 mL, 5 v / w) mL, 5 v / w) was added, and the compound obtained in Example 2 (100.0 g, 259 mmol) was added thereto. After vigorous stirring for 10 minutes, the solution was separated, and the organic layer was washed with a sodium sulfate decahydrate (125 g, 1.25 wt) / water (420 mL, 4.2 v / w) solution.
  • a sodium sulfate decahydrate 125 g, 1.25 wt
  • water 420 mL, 4.2 v / w
  • the organic layer was concentrated under reduced pressure to 3 v / w, acetonitrile (500 mL, 5 v / w) was added, and the mixture was concentrated under reduced pressure to 3 v / w.
  • Acetonitrile (500 mL, 5 v / w) was added again, and the mixture was concentrated under reduced pressure to 3 v / w.
  • the obtained residue was directly used in the next step.
  • Example 5-2 4- [N ′-( ⁇ (2R) -2- [4- (cyclopropylcarbonyl) phenoxy] butanoyl ⁇ oxy) carbamimidoyl] -2-fluorobenzoic acid 1,1-dimethyl Ethyl
  • N, N′-carbonyldiimidazole 48.4 g, 298 mmol
  • the compound (75.9 g, 298 mmol) obtained in Example 4 was added thereto in 4 portions and stirred at 15 ° C. for 30 minutes.
  • Example 6 4- (5- ⁇ (1R) -1- [4- (cyclopropylcarbonyl) phenoxy] propyl ⁇ -1,2,4-oxadiazol-3-yl) -2-fluorobenzoic acid
  • Example 6-1 4- (5- ⁇ (1R) -1- [4- (cyclopropylcarbonyl) phenoxy] propyl ⁇ -1,2,4-oxadiazol-3-yl) -2-fluoro 1,1-dimethylethyl benzoate
  • a toluene (40 mL, 2 v / w) solution of the compound (20.0 g, 41.3 mmol) obtained in Example 5 was heated to 100 ° C. and stirred for 6 hours.
  • Example 6-2 4- (5- ⁇ (1R) -1- [4- (cyclopropylcarbonyl) phenoxy] propyl ⁇ -1,2,4-oxadiazol-3-yl) -2-fluoro Benzoic acid
  • acetonitrile 40 mL, 2 v / w
  • concentrated sulfuric acid 2.50 mL, 45.4 mmol
  • Acetonitrile 120 mL, 6 v / w was added, and the mixture was again concentrated under reduced pressure to 2 v / w.
  • isopropyl alcohol 40 mL, 2 v / w
  • water 40 mL, 2 v / w
  • seed crystals (1 mg, 0.005 wt%) were added.
  • the mixture was stirred for 2 hours.
  • Water 40 mL, 2 v / w
  • the seed crystal can be obtained according to the method described in Patent Document 1.
  • Example 7 4- (5- ⁇ (1R) -1- [4- (cyclopropylcarbonyl) phenoxy] propyl ⁇ -1,2,4-oxadiazol-3-yl) -2-fluoro-N -[(2R) -1-Hydroxypropan-2-yl] benzamide
  • Activated carbon (0.50 g, 0.05 wt) was added to the organic layer, stirred at room temperature for 1 hour, filtered, and washed with ethyl acetate (20 mL, 2 v / w). The filtrate was concentrated under reduced pressure to 4 v / w, n-propanol (100 mL, 10 v / w) was added, and the mixture was concentrated under reduced pressure to 4 v / w. The residue was heated to 50 ° C.
  • n-heptane 50 mL, 5 v / w
  • 4- 5- ⁇ (1R) -1- [4- (cyclopropylcarbonyl) phenoxy] propyl ⁇ -1 , 2,4-oxadiazol-3-yl) -2-fluoro-N-[(2R) -1-hydroxypropan-2-yl] benzamide (0.5 mg, 0.005 wt%) and added to the same temperature And stirred for 1 hour. Thereafter, the mixture was gradually cooled to room temperature and stirred overnight.
  • n-Heptane 150 mL, 15 v / w
  • Example 8-1 Ethyl 2- [4- (cyclopropylcarbonyl) phenoxy] butanoate A solution of cyclopropyl (4-hydroxyphenyl) methanone (100 g, 617 mmol) in acetone (300 mL, 3 v / w) Tripotassium phosphate (170 g, 802 mmol) was added to the mixture, and the mixture was stirred at room temperature for 30 minutes. Then, ethyl 2-bromobutyrate (132 g, 678 mmol) was added and heated to about 50 ° C. After stirring at the same temperature for 2 hours, the mixture was cooled to room temperature, and water (300 mL, 3 v / w) was added to separate the layers. The obtained organic layer was directly used in the next step.
  • Example 8-2 2- [4- (Cyclopropylcarbonyl) phenoxy] butanoic acid
  • water 270 mL, 2.7 v / w
  • a 25% aqueous sodium hydroxide solution 148 mL, 925 mmol
  • the reaction solution was adjusted to pH 2.7 with concentrated sulfuric acid, isopropyl acetate (600 mL, 6 v / w) was added, the pH was adjusted again to 2.2 with concentrated sulfuric acid, and the solution was separated.
  • the organic layer was washed with 10% aqueous sodium sulfate solution (300 mL, 3 v / w), and the organic layer was concentrated to 3 v / w under reduced pressure.
  • the obtained filtrate was directly used in the next step.
  • Example 8-3 2- [4- (Cyclopropylcarbonyl) phenoxy] butanoic acid benzylamine Isopropyl acetate (300 mL, 3 v / w) was added to the filtrate obtained in Example 8-2, and 70 Heated to ° C. Benzylamine (66.1 g, 617 mmol) was added dropwise over 2 hours, and the mixture was further stirred at the same temperature for 2 hours. Thereafter, the mixture was allowed to cool to room temperature and further stirred at the same temperature for 3 hours. The crystals were filtered, washed with isopropyl acetate (300 mL, 3 v / w), and dried under reduced pressure at 45 ° C.
  • Example 9-1 2- [4- (Cyclopropylcarbonyl) phenoxy] butanoic acid
  • isopropyl acetate 810 mL, 4.5 v / w.
  • Concentrated sulfuric acid 54.6 g, 557 mmol
  • water 540 mL, 3 v / w
  • the obtained organic layer was directly used in the next step.
  • Example 9-2 (2R) -2- [4- (cyclopropylcarbonyl) phenoxy] butanoic acid (1R) -2-hydroxy-1-phenylethanamine
  • the organic layer obtained in Example 9-1 After heating to 70 ° C, a solution of (R)-(-)-phenylglycinol (38.2 g, 279 mmol) in isopropyl acetate (450 mL, 2.5 v / w) / water (14.0 mL, 0.08 v / w) It was added dropwise over time. After confirming the precipitation of crystals, the mixture was stirred at the same temperature for 2 hours.
  • Example 10-1 (2S) -2- [4- (Cyclopropylcarbonyl) phenoxy] butanoic acid
  • water 540 mL, 3 v / w
  • concentrated sulfuric acid (10.0 g, 98.9 mmol) were added for liquid separation.
  • the organic layer was washed with 10% aqueous sodium sulfate solution (540 mL, 3 v / w). The obtained organic layer was directly used in the next step.
  • Example 10-2 2- [4- (Cyclopropylcarbonyl) phenoxy] butanoic acid
  • the organic layer obtained in Example 9-1 was concentrated under reduced pressure to 4 v / w, and imidazole (69.0 g, 1013) was then added to the residue.
  • imidazole (69.0 g, 1013) was then added to the residue.
  • mmol) and N, N′-carbonyldiimidazole (49.3 g, 304 mmol) were added, heated to 80 ° C., and stirred at the same temperature for 3 hours.
  • the reaction mixture was cooled to room temperature, water (540 mL, 3 v / w) was added, the pH was adjusted to 2.1 with concentrated sulfuric acid, and the mixture was separated.
  • Example 10-3 2- [4- (Cyclopropylcarbonyl) phenoxy] butanoic acid benzylamine
  • benzylamine 32.6 g, 304 mmol
  • the mixture was allowed to cool to room temperature and stirred overnight.
  • the crystals were filtered, washed with isopropyl acetate (270 mL, 1.5 v / w), and dried under reduced pressure at 45 ° C. to give the title compound (96.9 g, yield: 53.9%).
  • Example 11 4- (5- ⁇ (1R) -1- [4- (cyclopropylcarbonyl) phenoxy] propyl ⁇ -1,2,4-oxadiazol-3-yl) -2-fluorobenzoic acid
  • Example 11-1 (2R) -2- [4- (Cyclopropylcarbonyl) phenoxy] butanoic acid Concentrated sulfuric acid (1.57 mL, 28.5 mmol) and ethyl acetate (50 mL, 50 v, 5 v / w) mL, 5 v / w) was added, and the compound obtained in Example 9 (10.0 g, 25.9 mmol) was added thereto. After vigorous stirring for 10 minutes, the layers were separated, and the organic layer was washed with a sodium sulfate decahydrate (12.5 g, 1.25 wt) / water (42 mL, 4.2 v / w) solution.
  • a sodium sulfate decahydrate (12.5 g, 1.25 wt) / water (42 mL, 4.2 v / w) solution.
  • the organic layer was concentrated under reduced pressure to 3 v / w, acetonitrile (50 mL, 5 v / w) was added, and the mixture was concentrated under reduced pressure to 3 v / w.
  • Acetonitrile (50 mL, 5 v / w) was added again, and the mixture was concentrated under reduced pressure to 3 v / w.
  • the obtained residue was directly used in the next step.
  • Example 11-2 4- [N ′-( ⁇ (2R) -2- [4- (cyclopropylcarbonyl) phenoxy] butanoyl ⁇ oxy) carbamimidoyl] -2-fluorobenzoic acid 1,1-dimethyl N, N′-carbonyldiimidazole (4.84 g, 29.8 mmol) was added to ethyl acetonitrile (20 mL, 2 v / w), and the mixture was cooled to 15 ° C. The residue obtained in Example 11-1 was added dropwise thereto over 15 minutes, and the mixture was stirred at 15 ° C. for 45 minutes.
  • Example 4 To this solution, the compound obtained in Example 4 (7.59 g, 29.8 mmol) was added in four portions and stirred at 15 ° C. for 1 hour. Water (5 mL, 0.5 v / w) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours, and then toluene (10 mL, 1 v / w) and sodium sulfate decahydrate (2.50 g, 0.25 wt) / water (35 mL, 3.5 v / w) solution was added for liquid separation.
  • Example 11-3 4- (5- ⁇ (1R) -1- [4- (cyclopropylcarbonyl) phenoxy] propyl ⁇ -1,2,4-oxadiazol-3-yl) -2-fluoro 1,1-Dimethylethyl benzoate
  • the residue obtained in Example 11-2 was heated to 100 ° C. and stirred for 6 hours.
  • the reaction mixture was cooled to room temperature, acetonitrile (50 mL, 5 v / w) was added, and the mixture was concentrated under reduced pressure to 3 v / w.
  • Acetonitrile (50 mL, 5 v / w) was added again, and the mixture was concentrated under reduced pressure to 3 v / w.
  • Acetonitrile 50 mL, 5 v / w was added, and the mixture was stirred at room temperature for 15 minutes. The insoluble material was filtered off and washed with acetonitrile (20 mL, 2 v / w). The filtrate was concentrated under reduced pressure to 3 v / w and the resulting residue was used as such in the next step.
  • Example 11-4 4- (5- ⁇ (1R) -1- [4- (cyclopropylcarbonyl) phenoxy] propyl ⁇ -1,2,4-oxadiazol-3-yl) -2-fluoro Benzoic acid Acetonitrile (10 mL, 1 v / w) and concentrated sulfuric acid (1.57 mL, 28.5 mmol) were added to the residue obtained in Example 11-3 and heated to 80 ° C. After stirring for 1 hour, the reaction solution was cooled to 40 ° C. The mixture was stirred at the same temperature. After confirming the precipitation of crystals, the mixture was further stirred for 1 hour.
  • Example 12 4- (5- ⁇ (1R) -1- [4- (cyclopropylcarbonyl) phenoxy] propyl ⁇ -1,2,4-oxadiazol-3-yl) -2-fluoro-N -[(2R) -1-Hydroxypropan-2-yl] benzamide
  • Activated carbon (0.50 g, 0.05 wt) was added to the organic layer, stirred for 30 minutes at room temperature, filtered, and washed with ethyl acetate (20 mL, 2 v / w). The filtrate was concentrated under reduced pressure to 4 v / w, n-propanol (100 mL, 10 v / w) was added, and the mixture was concentrated under reduced pressure to 4 v / w. After adding n-heptane (80 mL, 8 v / w) to the residue, it was heated to 85 ° C. or higher.
  • n-heptane (10 mL, 1 v / w) was added and cooled to 60 ° C.
  • 4- (5- ⁇ (1R) -1- [4- (cyclopropylcarbonyl) phenoxy] propyl ⁇ -1,2,4-oxadiazol-3-yl) -2-fluoro-N-[( 2R) -1-Hydroxypropan-2-yl] benzamide (0.5 mg, 0.005 wt%) was added and stirred at the same temperature for 1 hour.
  • n-Heptane 70 mL, 7 v / w was added dropwise over 50 minutes, stirred for 30 minutes, gradually cooled to room temperature, and stirred overnight.
  • Table 2 shows the yield when compound (1) was synthesized according to the method of the present invention.
  • the overall yield was improved by about 1.6 times compared to the method described in Patent Document 1.
  • (2S) -2- [4- (cyclopropylcarbonyl) phenoxy] butanoic acid which is an unnecessary stereoisomer is converted into 2- [4- ( Since the cyclopropylcarbonyl) phenoxy] butanoic acid benzylamine can be efficiently recovered and reused in Step B, the substantial yield can be further improved.

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Abstract

L'invention concerne un procédé de préparation d'un composé (1) ou d'un sel pharmaceutiquement acceptable correspondant, permettant d'améliorer le rendement, de réduire le coût, par l'utilisation d'un matériau de départ facilement obtenu, bon marché et par la récupération efficace de stéréoisomères inutiles, et de diminuer la charge environnementale. L'invention concerne un procédé de préparation d'un composé représenté par la formule (1) ou d'un sel pharmaceutiquement acceptable correspondant, le procédé comprenant une étape d'obtention d'un composé représenté par la formule générale (III) (dans laquelle R représente un groupe de protection de la fonction carboxyle) à l'aide d'un composé représenté par la formule (12) et d'un composé représenté par la formule générale (II) (dans laquelle R représente un groupe de protection de la fonction carboxyle).
PCT/JP2016/087486 2015-12-17 2016-12-16 Procédé de préparation d'un composé d'oxadiazole WO2017104782A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5829719A (ja) * 1981-08-14 1983-02-22 Hiroyuki Nohira 光学活性フエニルグリシノ−ルを用いるキラルカルボン酸の光学分割法
JPS6183144A (ja) * 1984-09-28 1986-04-26 Nissan Chem Ind Ltd ２−（４−ヒドロキシフエノキシ）プロピオン酸の光学分割法
WO2010067824A1 (fr) * 2008-12-12 2010-06-17 第一三共株式会社 Procédé de synthèse d'un acide carboxylique optiquement actif
WO2012050151A1 (fr) * 2010-10-14 2012-04-19 第一三共株式会社 Dérivé d'acylbenzène
WO2013108800A1 (fr) * 2012-01-18 2013-07-25 第一三共株式会社 Dérivé de phénylazole substitué

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5829719A (ja) * 1981-08-14 1983-02-22 Hiroyuki Nohira 光学活性フエニルグリシノ−ルを用いるキラルカルボン酸の光学分割法
JPS6183144A (ja) * 1984-09-28 1986-04-26 Nissan Chem Ind Ltd ２−（４−ヒドロキシフエノキシ）プロピオン酸の光学分割法
WO2010067824A1 (fr) * 2008-12-12 2010-06-17 第一三共株式会社 Procédé de synthèse d'un acide carboxylique optiquement actif
WO2012050151A1 (fr) * 2010-10-14 2012-04-19 第一三共株式会社 Dérivé d'acylbenzène
WO2013108800A1 (fr) * 2012-01-18 2013-07-25 第一三共株式会社 Dérivé de phénylazole substitué

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BOSTROM J. ET AL.: "Oxadiazoles in Medicinal Chemistry", JOURNAL OF MEDICINAL CHEMISTRY, vol. 55, 2012, pages 1817 - 1830, XP055050959, DOI: doi:10.1021/jm2013248 *
DATABASE Database [online] 9 August 2013 (2013-08-09), retrieved from STN Database accession no. 1448004-30-5 *

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