WO2017104782A1

WO2017104782A1 - Method for manufacturing oxadiazole compound

Info

Publication number: WO2017104782A1
Application number: PCT/JP2016/087486
Authority: WO
Inventors: 斉大武田; 岳志金田; 亮糸岡; 学原; 和夫久保田; 臣内藤
Original assignee: 第一三共株式会社
Priority date: 2015-12-17
Filing date: 2016-12-16
Publication date: 2017-06-22

Abstract

In order to provide a method for manufacturing a compound (1) or a pharmaceutically acceptable salt thereof, whereby yield can be improved, cost can be reduced by using an easily obtained, inexpensive starting material and efficiently recovering unnecessary stereoisomers, and environmental burden can be decreased, the present invention is a method for manufacturing a compound represented by formula (1) or a pharmaceutically acceptable salt thereof, the method including a step for obtaining a compound represented by general formula (III) (in which R represents a carboxyl-protecting group) using a compound represented by formula (12) and a compound represented by general formula (II) (in which R represents a carboxyl-protecting group).

Description

Method for producing oxadiazole compound

The present invention has the formula (1):

Or a pharmaceutically acceptable salt thereof, an intermediate thereof, and a method of producing the intermediate.

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 β-cell or pancreatic protective action (see Patent Document 1).

WO2012 / 050151

Example 3 of Patent Document 1 describes a method for synthesizing compound (1). Specifically, it is as follows.

In Reference Example 1 of Patent Document 1, tert-butyl 4-cyano-2-fluorobenzoate is prepared. However, in this step, there is an operation for distilling off tert-butyl alcohol having a high melting point under reduced pressure, and in the case of large-scale synthesis, there is a problem in operability because it is necessary to take measures such as avoiding clogging of the capacitor.

In Reference Example 4 of Patent Document 1, (2S) -2-acetoxybutyric acid is prepared (yield: 60%). However, in this step, there are problems in that the yield is moderate and the availability of (2S) -2-aminobutyric acid, which is an expensive optically active compound.

In Reference Example 3 of Patent Document 1, cyclopropyl (4-hydroxyphenyl) methanone is prepared (yield: 86%).

In Reference Example 7 of Patent Document 1, 4- (5-{(1R) -1- [4- (cyclopropyl) is obtained by using the compound obtained in Reference Example 6 and the compound obtained in Reference Example 3 above. Tert-butylcarbonyl) phenoxy] propyl} -1,2,4-oxadiazol-3-yl) -2-fluorobenzoate has been prepared (yield: 55%). However, in this step, there are problems with the medium yield and waste liquid treatment including di-tert-butyl azodicarboxylate and triphenylphosphine.

In Reference Example 8 of Patent Document 1, 4- (5-{(1R) -1- [4- (cyclopropylcarbonyl) phenoxy] propyl} -1,2, using the compound obtained in Reference Example 7 above. 4-Oxadiazol-3-yl) -2-fluorobenzoic acid is prepared (yield: 94%). However, in this process, since dichloromethane and trifluoroacetic acid are used in large quantities, there is a problem from the viewpoint of the environment.

Column purification is performed in each step of Patent Document 1, and there are problems in terms of environment and application to mass synthesis.

When trying to synthesize the compound (1) according to the synthesis method described in Patent Document 1, the yield is as follows.

When these values are used, the overall yield is about 22%, and the yield needs to be improved.

Therefore, 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. Alternatively, a method for producing a pharmaceutically acceptable salt thereof is provided.

The present invention
(1) Formula (12):

And a compound represented by the general formula (II):

(In the formula, R represents a protecting group for a carboxy group.)
General formula (III):

(In the formula, R represents a protecting group for a carboxy group.)
Comprising a step of obtaining a compound represented by formula (1):

Or a pharmaceutically acceptable salt thereof;
(2) Formula (4):

(R)-(-)-phenylglycinol, (1S, 2S)-(+)-2-amino-1-phenyl-1,3-propanediol and (D)-(- ) -Threo-2-amino-1- (4-nitrophenyl) -1,3-propanediol and an optical resolution agent selected from the group consisting of formula (12):

The method as described in said (1) including the process of obtaining the compound represented by these;
(3) The method according to (2) above, wherein the optical resolution agent is (R)-(−)-phenylglycinol;
(4) Formula (4):

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):

Using a compound represented by the formula and a condensing agent:

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-methylmorpholinium chloride, 1H-benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate or {{[(1- The method according to any one of (9) to (14) above, which is cyano-2-ethoxy-2-oxoethylidene) amino] oxy} -4-morpholinomethylene} dimethylammonium hexafluorophosphate;
(16) The method according to any one of (9) to (14), wherein the condensing agent is N, N′-carbonyldiimidazole;
(17) Formula (4):

The method according to any one of (4) to (8) above, comprising a step of obtaining an organic amine salt of the compound represented by the formula (4) using the compound represented by
(18) General formula (IV) using a compound represented by general formula (III) and a solvent:

(Wherein R represents a protecting group for a carboxy group;), and a step of obtaining a compound represented by:
By removing the protecting group of the carboxy group in the compound represented by the general formula (IV), the formula (15):

The method according to any one of (1) to (14) above, which comprises a step of obtaining a compound represented by:
(19) A compound represented by formula (1) or a pharmaceutically acceptable salt thereof using a compound represented by formula (15) and (R)-(-)-2-amino-1-propanol The method according to (18), comprising a step of producing a salt;
(20) Formula (4):

A process for producing a compound represented by:
(21) Formula (12):

Or an organic amine salt thereof;
(22) Formula (8):

And a condensing agent represented by formula (4):

(23) The method according to (22) above, further using a base;
(24) Formula (4):

Or a pharmaceutically acceptable salt thereof; and
(25) General formula (III):

(In the formula, R represents a protecting group for a carboxy group.)
Or a pharmaceutically acceptable salt thereof.

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.

In this specification, “compound (x)” refers to a compound represented by the formula (x).

In the present specification, 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.

As used herein, “pharmaceutically acceptable salt” refers to a salt formed by reacting compound (1) with an acid or a base. Examples of 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-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, chloroprocaine Amine salts such as organic salts such as salts, procaine salts, diethanolamine salts, N-benzylphenethylamine salts, piperazine salts, tetramethylammonium salts, tris (hydroxymethyl) aminomethane salts; glycine salts, lysine salts, arginine salts, ornithine salts Amino acid salts such as glutamate and aspartate.

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.

In this specification, 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.

In the present specification, 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.

In this specification, 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.

(In the scheme, R represents a protecting group for a carboxy group.)

(Process A)
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).

Examples of the solvent used 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).

Examples of the solvent used 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).

Examples of the solvent used 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.

Examples of the organic amine to be used 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.

(Process B)
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).

Examples of the solvent used 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 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).

The 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 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 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.

(Process C)
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).

Examples of the solvent used 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, N′-carbonyldiimidazole.

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.

When no base is used, the reaction time is 1 to 72 hours, preferably 4 to 20 hours, and more preferably 8 to 10 hours.

When a base is used, 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.

(Process D)
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).

This process can be performed according to the method described in T. H. Greene, P. G. Wuts, Protective Groups in Organic Synthesis, FifthifEdition, 2014, John Wiley & Sons, Inc.

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.

Examples of the solvent used 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.

(Process E)
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.

The reaction temperature is 0 to 50 ° C., preferably 5 to 40 ° C., more preferably 10 to 20 ° C.

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).

Examples of the solvent to be used 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, N′-carbonyldiimidazole.

The reaction temperature is −20 to 60 ° C., preferably 0 to 40 ° C., and more preferably 10 to 20 ° C.

(Process F)
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).

Examples of the solvent to be used 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).

Examples of the solvent used 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.

(Process G)
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 N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride.

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:

(In the scheme, t-Bu represents a tert-butyl group).

Hereinafter, the present invention will be described in more detail with reference to examples, but the scope of the present invention is not limited thereto.

Example 1 2- [4- (Cyclopropylcarbonyl) phenoxy] butanoic acid benzylamine

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. To the residue was added isopropyl acetate (200 mL, 4 v / w), adjusted to pH 2.3 with concentrated sulfuric acid, and separated. Isopropyl acetate (250 mL, 5 v / w) was added to the organic layer, and the mixture was washed with a sodium sulfate decahydrate (37.5 g, 0.75 wt) / water (125 mL, 2.5 v / w) solution. Activated carbon (5.0 g, 0.1 wt) was added to the organic layer, stirred for 15 minutes at room temperature, filtered, and washed with isopropyl acetate (250 mL, 5 v / w). The obtained filtrate was directly used in the next step.

(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. The crystals were filtered, washed with isopropyl acetate (100 mL, 2 v / w), and dried under reduced pressure at 40 ° C. to obtain the title compound (107 g, yield: 97.9%).
¹ H-NMR (500MHz, CDCl ₃ ) δppm:
7.98 (2H, dt, J = 9.5, 2.6 Hz), 7.45-7.37 (5H, m), 6.98 (2H, dt, J = 9.6, 2.5 Hz), 4.42 (1H, dd, J = 7.3, 5.0 Hz) , 4.07 (2H, s), 2.81-2.74 (1H, m), 2.01-1.89 (2H, m), 1.11-1.00 (7H, m);

Example 2 (2R) -2- [4- (Cyclopropylcarbonyl) phenoxy] butanoic acid (1R) -2-hydroxy-1-phenylethanamine

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. Add (R)-(-)-phenylglycinol (5.79 g, 42.2 mmol) again and stir for 1 minute, then add (R)-(-)-phenylglycinol (4.34 g, 31.7 mmol). Stir for 2 hours. Thereafter, the mixture was gradually cooled to room temperature and stirred overnight. The crystals were filtered, washed with isopropyl acetate (150 mL, 2 v / w), and dried under reduced pressure at 40 ° C. to obtain the title compound (34.1 g, yield: 41.2%). 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. Can do.
^{1 H-NMR (400MHz, CDCl} 3) δppm:
7.98 (2H, dt, J = 9.6, 2.5 Hz), 7.46-7.38 (5H, m), 6.98 (2H, dt, J = 9.5, 2.6 Hz), 4.42 (1H, dd, J = 7.3, 5.0 Hz) , 4.30 (1H, dd, J = 8.4, 4.2 Hz), 3.86 (1H, dd, J = 11.5, 4.4 Hz), 3.78 (1H, dd, J = 11.7, 8.4 Hz), 2.81-2.75 (1H, m ), 2.01-1.90 (2H, m), 1.12-1.00 (7H, m);
Chemical purity: HPLC> 99% (excluding (R)-(-)-phenylglycinol peak)
(Measurement conditions; column: Waters XBridge C18 (3.5 μm, 4.6 mm I.D. × 150 mm), mobile phase: 0.1% trifluoroacetic acid / acetonitrile = 60/40, flow rate: 1.0 ml / min, column oven: 40 ° C. , Detection (UV): 250 nm, retention time: (2R) -2- [4- (cyclopropylcarbonyl) phenoxy] butanoic acid (about 5.6 min))
Optical purity:> 98% ee
(Measurement conditions; column: Daicel Chiralpak IA-3 (3 μm, 4.6 mm I.D. × 150 mm), mobile phase: 0.1% trifluoroacetic acid / acetonitrile = 65/35, flow rate: 1.0 ml / min, column oven: 35 ° C., detection (UV): 250 nm, retention time: (2R) -2- [4- (cyclopropylcarbonyl) phenoxy] butanoic acid (about 8.6 min), (2S) -2- [4- (cyclopropyl) Carbonyl) phenoxy] butanoic acid (about 10.4 minutes))

Example 3 Benzylamine 2- [4- (cyclopropylcarbonyl) phenoxy] butanoate

Example 3-1 (2S) -2- [4- (cyclopropylcarbonyl) phenoxy] butanoic acid To the filtrate (about 675 mL) obtained in Example 2-2 was added water (225 mL, 3 v / w ) And concentrated sulfuric acid (2.32 mL, 42.2 mmol) were added for liquid separation. 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.

Example 3-2 2- [4- (Cyclopropylcarbonyl) phenoxy] butanoic acid 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. The reaction solution was cooled to room temperature, water (150 mL, 2 v / w) was added, and the mixture was stirred for 1.5 hours, adjusted to pH 2.0 with concentrated sulfuric acid, and separated. The organic layer was washed with a sodium sulfate decahydrate (40.5 g, 0.54 wt) / water (225 mL, 3 v / w) solution. The obtained organic layer was directly used in the next step.
Optical purity: 0 ± 3% ee
(Measured under the optical purity measurement conditions described in Example 2-2)

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. The crystals were filtered, washed with isopropyl acetate (75 mL, 1 v / w), and dried under reduced pressure at 40 ° C. to obtain the title compound (40.1 g, yield: 53.4%).
¹ H-NMR (500MHz, CDCl ₃ ) δppm:
7.98 (2H, dt, J = 9.5, 2.6 Hz), 7.45-7.37 (5H, m), 6.98 (2H, dt, J = 9.6, 2.5 Hz), 4.42 (1H, dd, J = 7.3, 5.0 Hz) , 4.07 (2H, s), 2.81-2.74 (1H, m), 2.01-1.89 (2H, m), 1.11-1.00 (7H, m)

(Example 4) 1,1-dimethylethyl 2-fluoro-4- (N′-hydroxycarbamimidoyl) benzoate

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 To the reaction solution obtained in Example 4-1, ethanol (6500 mL, 5 v / w) and 50% aqueous hydroxylamine solution (780 mL, 13.2 mol) were added, and the mixture was stirred at 60 ° C. for 2 hours, and then cooled to room temperature. 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. Water (6500 mL, 5 v / w) was added to the residue, and the mixture was stirred overnight at room temperature. Water (11700 mL, 9 v / w) was added dropwise over 1 hour, and the mixture was further stirred for 5 hours. The crystals were filtered, washed with ethanol / water = 4/14 (2600 mL, 2 v / w), and dried under reduced pressure at 40 ° C. to obtain the title compound (1937 g, yield: 96.8%).
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
7.89 (1H, t, J = 8 Hz), 7.44 (2H, dd, J = 8, 2 Hz), 7.39 (2H, dd, J = 11, 2 Hz), 4.90 (2H, s), 1.60 (9H , s)

Example 5 4- [N ′-({(2R) -2- [4- (cyclopropylcarbonyl) phenoxy] butanoyl} oxy) carbamimidoyl] -2-fluorobenzoic acid 1,1-dimethylethyl

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. 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 The residue obtained in Example 5-1 was cooled to 15 ° C., N, N′-carbonyldiimidazole (48.4 g, 298 mmol) was added in four portions, and the mixture was stirred at the same temperature for 1 hour. 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. The reaction solution was dropped into an isopropyl alcohol (250 mL, 2.5 v / w) / water (300 mL, 3 v / w) solution at room temperature over 1 hour and 40 minutes, and the reaction solution adhering to the reaction vessel was further added to acetonitrile ( 25 mL, 0.25 v / w). After stirring at room temperature for 30 minutes, water (700 mL, 7 v / w) was added dropwise over 1 hour and 15 minutes, and the mixture was stirred at the same temperature overnight. The crystals were filtered, washed with isopropyl alcohol / water = 35/65 (200 mL, 2 v / w), and dried under reduced pressure at 40 ° C. to obtain the title compound (122.3 g, yield: 97.3%).
¹ H-NMR (500MHz, CDCl ₃ ) δppm:
8.04-8.00 (2H, m), 7.89-7.85 (1H, m), 7.47-7.41 (2H, m), 7.05-7.00 (2H, m), 4.91-4.82 (3H, m), 2.65-2.58 (1H , m), 2.20-2.11 (2H, m), 1.59 (9H, s), 1.23-1.14 (5H, m), 1.04-0.99 (2H, m)

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 The reaction solution obtained in Example 6-1 was cooled to room temperature, acetonitrile (40 mL, 2 v / w) and concentrated sulfuric acid (2.50 mL, 45.4 mmol) were added, and the mixture was heated to 80 ° C. After stirring for 30 minutes, acetonitrile (80 mL, 4 v / w) was added, and the mixture was concentrated under reduced pressure to 2 v / w. Acetonitrile (120 mL, 6 v / w) was added, and the mixture was again concentrated under reduced pressure to 2 v / w. At room temperature, isopropyl alcohol (40 mL, 2 v / w) and water (40 mL, 2 v / w) were added to the residue, and seed crystals (1 mg, 0.005 wt%) were added. After confirming the precipitation of crystals, the mixture was stirred for 2 hours. Water (40 mL, 2 v / w) was added dropwise over 15 minutes, and the mixture was stirred overnight at room temperature, then ice-cooled, and further stirred for 3.5 hours. The crystals were filtered, washed with cold isopropyl alcohol / water = 1/2 (50 mL, 2.5 v / w), and dried under reduced pressure at 40 ° C. to obtain the title compound (16.1 g, yield: 95.2%). . The seed crystal can be obtained according to the method described in Patent Document 1.
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
8.14 (1H, t, J = 8 Hz), 8.01-7.89 (4H, m), 7.04 (2H, dd, J = 7, 2 Hz), 5.54 (1H, dd, J = 7, 6 Hz), 2.63 -2.57 (1H, m), 2.35-2.21 (2H, m), 1.22-1.18 (2H, m), 1.15 (3H, q, J = 5 Hz), 1.02-0.99 (2H, m)

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

A solution of the compound obtained in Example 6 (10.0 g, 24.4 mmol) in N, N-dimethylacetamide (50 mL, 5 v / w) / ethyl acetate (50 mL, 5 v / w) in water (2.0 mL, 0.2 v / w), 1-hydroxybenzotriazole monohydrate (1.49 g, 9.75 mmol), (R)-(-)-2-amino-1-propanol (3.23 mL, 41.4 mmol) and N- (3 -Dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride (6.07 g, 31.7 mmol) was sequentially added and heated to 40 ° C. and stirred for 1 hour 30 minutes. After cooling to room temperature, a sodium chloride (10.7 g, 1.07 wt) / water (96.3 mL, 9.63 v / w) solution was added to the reaction mixture, and the aqueous layer was separated with ethyl acetate (50 mL, 5 v / w). Re-extracted. The matched organic layer was washed with a sodium bicarbonate (2.60 g, 0.26 wt) / water (49.4 mL, 4.94 v / w) solution and further with water (50 mL, 5 v / w). 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. and n-heptane (50 mL, 5 v / w) was added followed by 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) was added dropwise over 45 minutes, heated to 80 ° C., and stirred for 1 hour. The mixture was gradually cooled to room temperature and stirred for 2 hours, then ice-cooled and further stirred for 3 hours. The solid was filtered, washed with cold n-propanol / n-heptane = 13/87 (20 mL, 2 v / w), and dried under reduced pressure at 40 ° C. to give the title compound (10.9 g, yield: 96.0% ) In addition, 4- (5-{(1R) -1- [4- (cyclopropylcarbonyl) phenoxy] propyl} -1,2,4-oxadiazol-3-yl) -2-fluoro-N added -[(2R) -1-hydroxypropan-2-yl] benzamide can be obtained according to the method described in Patent Document 1.
^{1 H-NMR (400MHz, CDCl} 3) δppm:
8.20 (1H, t, J = 8 Hz), 8.01-7.97 (3H, m), 7.85 (1H, dd, J = 12, 1 Hz), 7.06-7.03 (2H, m), 6.90 (1H, dd, J = 12, 7 Hz), 5.52 (1H, t, J = 6 Hz), 4.38-4.31 (1H, m), 3.81 (1H, dd, J = 11, 4Hz), 3.68 (1H, dd, J = 11, 6Hz), 2.63-2.56 (1H, m), 2.44 (1H, brs), 2.34-2.20 (2H, m), 1.32 (3H, d, J = 7 Hz), 1.22-1.18 (2H, m) , 1.14 (3H, t, J = 7 Hz), 1.02-0.97 (2H, m)

Example 8 2- [4- (Cyclopropylcarbonyl) phenoxy] butanoic acid benzylamine

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 To the organic layer obtained in Example 8-1 was added water (270 mL, 2.7 v / w) and a 25% aqueous sodium hydroxide solution. (148 mL, 925 mmol) was added and stirred at room temperature for 1 hour. 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. Add isopropyl acetate (700 mL, 7 v / w) and activated carbon (10.0 g, 0.1 wt) to the residue, stir at room temperature for 1.5 hours, filter, and wash with isopropyl acetate (200 mL, 2 v / w) . 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. to obtain the title compound (209 g, yield: 95.2%).
¹ H-NMR (500MHz, CDCl ₃ ) δppm:
7.98 (2H, dt, J = 9.5, 2.6 Hz), 7.45-7.37 (5H, m), 6.98 (2H, dt, J = 9.6, 2.5 Hz), 4.42 (1H, dd, J = 7.3, 5.0 Hz) , 4.07 (2H, s), 2.81-2.74 (1H, m), 2.01-1.89 (2H, m), 1.11-1.00 (7H, m);

Example 9 (2R) -2- [4- (Cyclopropylcarbonyl) phenoxy] butanoic acid (1R) -2-hydroxy-1-phenylethanamine

(Example 9-1) 2- [4- (Cyclopropylcarbonyl) phenoxy] butanoic acid To the compound obtained in Example 8 (180 g, 506 mmol) was added isopropyl acetate (810 mL, 4.5 v / w). Concentrated sulfuric acid (54.6 g, 557 mmol) / water (540 mL, 3 v / w) solution was added dropwise thereto. The mixture was vigorously stirred for 40 minutes and then separated, and the organic layer was washed with a 10% aqueous sodium sulfate solution (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. Thereafter, the mixture was gradually cooled to room temperature, stirred overnight, and further stirred for 3 hours under ice cooling. The crystals were filtered, washed with isopropyl acetate (540 mL, 3 v / w), and dried under reduced pressure at 45 ° C. to obtain the title compound (84.1 g, yield: 43.1%).
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
7.98 (2H, dt, J = 9.6, 2.5 Hz), 7.46-7.38 (5H, m), 6.98 (2H, dt, J = 9.5, 2.6 Hz), 4.42 (1H, dd, J = 7.3, 5.0 Hz) , 4.30 (1H, dd, J = 8.4, 4.2 Hz), 3.86 (1H, dd, J = 11.5, 4.4 Hz), 3.78 (1H, dd, J = 11.7, 8.4 Hz), 2.81-2.75 (1H, m ), 2.01-1.90 (2H, m), 1.12-1.00 (7H, m);
Chemical purity: HPLC> 99% (excluding (R)-(-)-phenylglycinol peak)
(Measurement conditions; column: Waters XBridge C18 (3.5 μm, 4.6 mm I.D. × 150 mm), mobile phase: 0.1% trifluoroacetic acid / acetonitrile = 60/40, flow rate: 1.0 ml / min, column oven: 40 ° C. , Detection (UV): 250 nm, retention time: (2R) -2- [4- (cyclopropylcarbonyl) phenoxy] butanoic acid (about 5.6 min))
Optical purity:> 99% ee
(Measurement conditions; column: Daicel Chiralpak IA-3 (3 μm, 4.6 mm I.D. × 150 mm), mobile phase: 0.1% trifluoroacetic acid / acetonitrile = 65/35, flow rate: 1.0 ml / min, column oven: 35 ° C., detection (UV): 250 nm, retention time: (2R) -2- [4- (cyclopropylcarbonyl) phenoxy] butanoic acid (about 8.6 min), (2S) -2- [4- (cyclopropyl) Carbonyl) phenoxy] butanoic acid (about 10.4 minutes))

Example 10 2- [4- (Cyclopropylcarbonyl) phenoxy] butanoic acid benzylamine

Example 10-1 (2S) -2- [4- (Cyclopropylcarbonyl) phenoxy] butanoic acid To the filtrate (about 1800 mL) obtained in Example 9-2 was added water (540 mL, 3 v / w ) And 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. 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. 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.
Optical purity: 0 ± 1% ee
(Measured under the optical purity measurement conditions described in Example 9-2)

(Example 10-3) 2- [4- (Cyclopropylcarbonyl) phenoxy] butanoic acid benzylamine The organic layer obtained in Example 10-2 was heated to 70 ° C. to obtain benzylamine (32.6 g, 304 mmol). Was added dropwise over 2 hours and stirred at the same temperature for 2.5 hours. Thereafter, 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%).
¹ H-NMR (500MHz, CDCl ₃ ) δppm:
7.98 (2H, dt, J = 9.5, 2.6 Hz), 7.45-7.37 (5H, m), 6.98 (2H, dt, J = 9.6, 2.5 Hz), 4.42 (1H, dd, J = 7.3, 5.0 Hz) , 4.07 (2H, s), 2.81-2.74 (1H, m), 2.01-1.89 (2H, m), 1.11-1.00 (7H, m)

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. 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. 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. Organic layer with acetonitrile (20 mL, 2 v / w), potassium dihydrogen phosphate (2.00 g, 0.20 wt) / dipotassium hydrogen phosphate (2.00 g, 0.20 wt) / water (35 mL, 3.5 v / w) The solution was added and separated. Once again the organic layer was acetonitrile (10 mL, 1 v / w), potassium dihydrogen phosphate (2.00 g, 0.20 wt) / dipotassium hydrogen phosphate (2.00 g, 0.20 wt) / water (35 mL, 3.5 v / w) ) The solution was added and separated. Furthermore, toluene (20 mL, 2 v / w) and sodium sulfate decahydrate (0.10 g, 0.01 wt) were added to the organic layer for liquid separation. Toluene (20 mL, 2 v / w) was added to the organic layer, and the mixture was concentrated under reduced pressure to 3 v / w. The obtained residue was directly used in the next step.

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. Water (20 mL, 2 v / w) was added at 40 ° C., and the mixture was stirred at the same temperature for 1 hour. Further, water (40 mL, 2 v / w) was added dropwise over 30 minutes, and the mixture was stirred at 40 ° C. for 30 minutes. Thereafter, the mixture was gradually cooled to room temperature and stirred overnight. The crystals were filtered, washed with acetonitrile / water = 2/3 (30 mL, 3 v / w), and dried under reduced pressure at 40 ° C. to obtain the title compound (9.79 g, yield: 91.9%).
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
8.14 (1H, t, J = 8 Hz), 8.01-7.89 (4H, m), 7.04 (2H, dd, J = 7, 2 Hz), 5.54 (1H, dd, J = 7, 6 Hz), 2.63 -2.57 (1H, m), 2.35-2.21 (2H, m), 1.22-1.18 (2H, m), 1.15 (3H, q, J = 5 Hz), 1.02-0.99 (2H, m)

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

A solution of the compound obtained in Example 11 (10.0 g, 24.4 mmol) in N, N-dimethylacetamide (50 mL, 5 v / w) / ethyl acetate (50 mL, 5 v / w) in water (2.0 mL, 0.2 v / w), 1-hydroxybenzotriazole monohydrate (0.93 g, 6.09 mmol), (R)-(-)-2-amino-1-propanol (3.23 mL, 41.4 mmol) and N- (3 -Dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride (6.07 g, 31.7 mmol) was sequentially added and heated to 40 ° C. and stirred for 2 hours 30 minutes. The mixture was cooled to room temperature, and a sodium chloride (10.7 g, 1.07 wt) / water (96.3 mL, 9.63 v / w) solution was added to the reaction solution to separate the layers. The organic layer was washed with a sodium bicarbonate (2.60 g, 0.26 wt) / water (49.4 mL, 4.94 v / w) solution, and further washed twice with water (50 mL, 5 v / w). 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. After confirming complete dissolution, 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. Thereafter, the mixture was further cooled with ice and stirred for 3 hours. The solid was filtered, washed with cold n-propanol / n-heptane = 3/16 (30 mL, 3 v / w), and dried under reduced pressure at 40 ° C. to give the title compound (10.8 g, yield: 94.6% ) In addition, 4- (5-{(1R) -1- [4- (cyclopropylcarbonyl) phenoxy] propyl} -1,2,4-oxadiazol-3-yl) -2-fluoro-N added -[(2R) -1-hydroxypropan-2-yl] benzamide can be obtained according to the method described in Patent Document 1.
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
8.20 (1H, t, J = 8 Hz), 8.01-7.97 (3H, m), 7.85 (1H, dd, J = 12, 1 Hz), 7.06-7.03 (2H, m), 6.90 (1H, dd, J = 12, 7 Hz), 5.52 (1H, t, J = 6 Hz), 4.38-4.31 (1H, m), 3.81 (1H, dd, J = 11, 4Hz), 3.68 (1H, dd, J = 11, 6Hz), 2.63-2.56 (1H, m), 2.44 (1H, brs), 2.34-2.20 (2H, m), 1.32 (3H, d, J = 7 Hz), 1.22-1.18 (2H, m) , 1.14 (3H, t, J = 7 Hz), 1.02-0.97 (2H, m)

Table 2 shows the yield when compound (1) was synthesized according to the method of the present invention.

In 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. Further, in the method of the present invention, from step C (Examples 3 and 10), (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.

Claims

Formula (12):

And a compound represented by the general formula (II):

(In the formula, R represents a protecting group for a carboxy group.)
General formula (III):

(In the formula, R represents a protecting group for a carboxy group.)
Comprising a step of obtaining a compound represented by formula (1):

Or a pharmaceutically acceptable salt thereof.
Formula (4):

(R)-(-)-phenylglycinol, (1S, 2S)-(+)-2-amino-1-phenyl-1,3-propanediol and (D)-(- ) -Threo-2-amino-1- (4-nitrophenyl) -1,3-propanediol and an optical resolution agent selected from the group consisting of formula (12):

The method of Claim 1 including the process of obtaining the compound represented by these.
The method according to claim 2, wherein the optical resolving agent is (R)-(-)-phenylglycinol.
Formula (4):

The method of Claim 2 or 3 including the process of obtaining the compound represented by Formula (4) using the organic amine salt of the compound represented by these, and an acid.
The method according to claim 4, wherein the organic amine is benzylamine, cyclohexylamine or n-butylamine.
The method according to claim 4, wherein the organic amine is benzylamine.
The method according to any one of claims 4 to 6, wherein the acid is sulfuric acid, hydrochloric acid or hydrobromic acid.
The method according to any one of claims 4 to 6, wherein the acid is sulfuric acid.
Formula (8):

Using a compound represented by the formula and a condensing agent:

The method of Claim 2 or 3 including the process of obtaining the compound represented by these.
The method according to claim 9, further using a base.
The method according to claim 10, wherein the base is imidazole, triethylamine, diisopropylethylamine, tributylamine or pyridine.
The method according to claim 10, wherein the base is imidazole.
The method according to any one of claims 9 to 12, comprising a heating step.
The method of Claim 13 including the process of adding water after heating.
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-methylmorpholinium chloride, 1H-benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate or {{[(1-cyano-2 The method according to any one of claims 9 to 14, which is -ethoxy-2-oxoethylidene) amino] oxy} -4-morpholinomethylene} dimethylammonium hexafluorophosphate.
The method according to any one of claims 9 to 14, wherein the condensing agent is N, N'-carbonyldiimidazole.
Formula (4):

The method according to any one of claims 4 to 8, which comprises the step of obtaining an organic amine salt of the compound represented by the formula (4) using the compound represented by the formula (1) and an organic amine.
Using a compound represented by the general formula (III) and a solvent, the general formula (IV):

(Wherein R represents a protecting group for a carboxy group), and a step of obtaining a compound represented by:
By removing the protecting group of the carboxy group in the compound represented by the general formula (IV), the formula (15):

The method according to any one of claims 1 to 17, comprising a step of obtaining a compound represented by the formula:
A compound represented by formula (1) or a pharmaceutically acceptable salt thereof is produced using a compound represented by formula (15) and (R)-(-)-2-amino-1-propanol The method of claim 18, comprising the step of:
Formula (4):

(R)-(-)-phenylglycinol, (1S, 2S)-(+)-2-amino-1-phenyl-1,3-propanediol and (D)-(- ) -Threo-2-amino-1- (4-nitrophenyl) -1,3-propanediol and an optical resolution agent selected from the group consisting of formula (12):

The method to manufacture the compound represented by these.
Formula (12):

Or an organic amine salt thereof.
Formula (8):

And a condensing agent represented by formula (4):

The method to manufacture the compound represented by these.
The method according to claim 22, further using a base.
Formula (4):

Or a pharmaceutically acceptable salt thereof.
General formula (III):

(In the formula, R represents a protecting group for a carboxy group.)
Or a pharmaceutically acceptable salt thereof.