WO2015037243A1

WO2015037243A1 - Method for producing optically active hydantoin compound

Info

Publication number: WO2015037243A1
Application number: PCT/JP2014/004702
Authority: WO
Inventors: 稔小浦; 寿史住田; 公幸渋谷
Original assignee: 興和株式会社
Priority date: 2013-09-12
Filing date: 2014-09-11
Publication date: 2015-03-19
Also published as: JPWO2015037243A1

Abstract

　The present invention provides a method for producing an optically active hydantoin compound having an LXRβ-activating effect and a production intermediate thereof. In the present invention, an optically active carbinol compound represented by formula (1) is produced by reacting a compound represented by formula (3) and a compound represented by formula (4). In formulas (1), (3), and (4), R¹, R², and R³ show the same or different C_1-3 alkyl groups, * shows an asymmetric carbon atom, and R⁴ shows any one structure selected from A-E.

Description

Method for producing optically active hydantoin compound

The present invention relates to a method for producing an optically active hydantoin compound having an LXRβ activation action and a production intermediate thereof.

Liver X receptor (LXR) is a nuclear receptor in which a part of oxysterols including 22-R-hydroxycholesterol acts as a ligand (Non-Patent Documents 1 to 3). In mammals, the presence of two LXR genes (α and β) is known. LXRα is specifically expressed in tissues involved in cholesterol metabolism such as liver, small intestine, adipose tissue, and LXRβ is ubiquitously expressed in almost all tissues examined. It recognizes similar sequences and activates transcription of nearby target genes (Non-Patent Documents 4 and 5). Many of the genes identified as LXR target genes are genes involved in reverse cholesterol transport (RCT) (ApoE, CETP, and LPL) including ABC transporters (ABCA1, ABCG1, ABCG5, ABCG8). is there. Thus, activation of LXR increases the expression of these genes and activates the reverse cholesterol transport pathway to increase peripheral cholesterol efflux and increase HDL cholesterol, thereby reducing the cholesterol content at the site of atherosclerotic lesions. It is expected (Non-Patent Document 6).

Under such circumstances, the present inventors have expressed the following formula as a compound having an LXRβ selective activation action:

The compounds (A) to (J) having the chemical structure represented by the above have been found and a patent application has been filed (Patent Document 1). These compounds are common in that they have a 4,4-disubstituted imidazolidine-2,5-dione structure having an asymmetric carbon atom.

Examples of the method for producing the above compounds (A) to (J) include the production of a racemic 4,4-disubstituted imidazolidine-2,5-dione derivative (a3) as shown in the following reaction process diagram. The way through is reported. That is, the compound (a2) is produced by alkylating the hydroxyl group of 1- (4-hydroxyphenyl) ethanone (a1), and undergoes the Bucherer-Bergs reaction, thereby forming a 4,4-diphenyl which becomes a common intermediate. A method is known in which a substituted imidazolidine-2,5-dione derivative (a3) is produced and then reacted with (a4) to obtain (B).

However, the method of this document does not mention the production of optically active (a3), and does not describe the production method of the optical isomers of the compounds (A) to (J). Therefore, in the above production method, two diastereomers with different stereochemistry of the asymmetric carbon atom of the 4,4-disubstituted imidazolidine-2,5-dione moiety are produced for the compounds (A) to (J). The problem that it was not possible was left.

Although a method using optically active column chromatography is known as a general optical resolution method for racemates, it is not suitable for mass synthesis from the viewpoint of work efficiency and cost.

As a method for optical resolution of 4,4-disubstituted imidazolidine-2,5-dione derivatives, a preferential crystallization method using optically active benzylamine (Patent Documents 2 and 3) and a method using lipase (non-patent document) Although literature 7) has been reported, it has been found that all of them have a narrow substrate application range and are not suitable for the production of the compounds (A) to (J).

Further, as a method for producing an optically active 1,4,4-trisubstituted imidazolidine-2,5-dione derivative, a racemate of a 1,4,4-trisubstituted imidazolidine-2,5-dione derivative is used. Although a preferential crystallization method using an optically active compound (Patent Document 4) has been reported, it has been found that the substrate application range is narrow and is not suitable for the production of the compounds (A) to (J).

Furthermore, a method for producing an optically active 1,4,4-trisubstituted imidazolidine-2,5-dione derivative represented by the following formula has also been reported (Patent Document 5).

However, when the method described in this document is applied to the production of the compounds (A) to (J), the substrate is decomposed in the step vi), and 1,4,4-trisubstituted imidazolidine-2, It was found that a 5-dione ring could not be obtained.

WO2010 / 12581 pamphlet WO1992 / 08702 pamphlet JP 7-330737 A JP-A-10-59947 WO1996 / 033976 pamphlet

The present invention provides a production method applicable to a large-scale synthesis of an optically active hydantoin compound having an LXRβ selective activation action via an optically active 1,4,4-trisubstituted imidazolidine-2,5-dione ring. The purpose is to provide. The present invention also provides an optically active 2- (4-aryl-4-methyl-2,5-dioxoimidazolidin-1-yl) acetic acid derivative compound useful as an intermediate for the production of an optically active hydantoin compound. With the goal.

As described above, it is considered that production of an optically active hydantoin compound efficiently and with high optical purity is very useful in the production of pharmaceuticals, particularly LXRβ selective activators. Therefore, as a result of intensive studies on a useful method for producing an optically active hydantoin compound represented by the compound (B), the present inventors have found that a benzoate ester compound (c1) and WO2010 / 12581 are shown in the figure below. By reacting 2,5-dimethylpiperazine-1-carboxylic acid (2S, 5R) -tert-butyl produced by the method described in the pamphlet, compound (c2) is obtained, and this is subjected to Wittig reaction to give compound (c3 to), an unsaturated bond and a compound by the hydrogenation reaction (c4), which compounds by hydrolyzing the (c5), by reacting it with the compound (c6), ribs with tmsCF ₃ Compound (c7) is obtained by a nolation reaction, and the optically active 2- [4- (2,5-dimethylpiperazi is obtained by deprotecting the piperazine compound. N-1-yl) -3-propylphenyl] -1,1,1,3,3,3-hexafluoropropan-2-ol compound (c8). Next, the hydantoin body (c9) produced by the method described in the pamphlet of WO2010 / 12581 is hydrolyzed to obtain a compound (c10), which is esterified to obtain a compound (c11). An optically active amino acid form ((S) -c11) is obtained by preferential crystallization with — (+)-mandelic acid, and this is reacted with isocyanatoacetate to give compound ((S) -c12). Optically active compound (S) -2- {4- [4- (1-methylethoxy) phenyl] -4-methyl-2,5-dioxoimidazolidin-1-yl by ring-closing reaction in the presence of a base } Acetic acid compound ((S) -c13) and this compound (c8) are condensed to form an optically active hydantoin compound (( ) -B) it was found that the resulting. In addition, optically active amino acid form ((R) -c11) is produced by preferential crystallization of (c11) using (D)-(−)-mandelic acid, and optically active hydantoin form ((R ) -B) was obtained analogously. The present invention has been completed based on this finding.

That is, the present invention relates to the following inventions.
[1] Formula (1):

[Wherein R ¹ , R ² and R ³ may be the same or different and each represents a C _1-3 alkyl group, * represents an asymmetric carbon atom, and R ⁴ represents

A method for producing an optically active compound represented by any one of the structures selected from:
i) Formula (2):

[Wherein R ⁴ and * are as defined above, and R ⁵ and R ⁶ may be the same or different and each represents a C _1-3 alkyl group] By reacting, the formula (3):

[Wherein R ⁴ and * are as defined above]
ii) a compound represented by formula (3) and formula (4):

[Wherein R ¹ , R ² , R ³ , * are as defined above] are reacted to produce a compound represented by the formula (1). Method.

[2] The production method according to [1], wherein R ^{1 in} formula (1) is a propyl group, and R ² and R ³ are methyl groups.

[3] The compound represented by the formula (1) is (S) -3- (2-{(2S, 5R) -4- [4- (1,1,1,3,3,3-hexafluoro- 2-Hydroxypropan-2-yl) -2-propylphenyl] -2,5-dimethylpiperazin-1-yl} -2-oxoethyl) -5- [4- (1-methylethoxy) phenyl] -5-methyl The production method according to the above [1] or [2], which is imidazolidine-2,4-dione. *

[4] Formula (3):

[Wherein, * represents an asymmetric carbon atom and R ⁴ represents

An optically active compound represented by the formula: or a salt thereof, or a solvate thereof.

The method of the present invention can produce the target compound (1) in a higher yield than the conventional method, as shown in the Examples below. In addition, the asymmetric carbon atom of the imidazolidine-2,4-dione (3) can be constructed without racemization by following this method. Therefore, by using the method of the present invention, compound (1) useful as an LXRβ selective agonist can be produced with high yield and high optical purity.

The definitions of the terms of the present invention are as follows.

In the present invention, the C _1-3 alkyl group means a linear or branched alkyl group having 1 to 3 carbon atoms, and examples thereof include a methyl group, an ethyl group, a propyl group, and an isopropyl group.

In general formulas (1) and (4), the C _1-3 alkyl group for R ¹ is preferably an ethyl group or a propyl group, and more preferably a propyl group.

In general formulas (1) and (4), the C _1-3 alkyl group for R ² is preferably a methyl group.

In general formulas (1) and (4), the C _1-3 alkyl group for R ³ is preferably a methyl group.

In general formulas (1) to (3), as R ⁴ ,

Is preferred.

In general formula (2), the C _1-3 alkyl group for R ⁵ is preferably a methyl group or an ethyl group.

In general formula (2), the C _1-3 alkyl group for R ⁶ is preferably a methyl group or an ethyl group.

In the present invention, * represents an asymmetric carbon atom. The general formula (1) of the present invention includes the following (1a) to (1h):

8 structures are included.

As the three-dimensional structure of the general formula (1) of the present invention, (1b) is preferable.

As a particularly preferred structure of the general formula (1) of the present invention, the steric structure is (1b), R ¹ is a propyl group, R ² and R ³ are methyl groups, and R ⁴ is 4- (1- Mention may be made of compounds that are methylethoxy) phenyl groups.

Hereinafter, with respect to the production method of the present invention, reaction process diagrams are shown, and the reaction of each process will be described in detail.

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and * are the same as described above)

Step 1: This step is a step for producing a compound (3) by subjecting the compound (2) to a ring-closing reaction in a solvent or in the absence of a solvent in the presence of a base. The solvent is not particularly limited. For example, tetrahydrofuran, ethylene glycol dimethyl ether, toluene, dioxane, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, propionitrile, acetone, methyl ethyl ketone; ethyl acetate, acetic acid Esters such as propyl, isopropyl acetate, and isobutyl acetate; alcohols such as methanol, ethanol, 1-propanol, and 2-propanol can be used alone or in combination, among which ethanol, ethanol / water, ethylene glycol dimethyl ether, Ethylene glycol dimethyl ether / water, dimethyl sulfoxide, and dimethyl sulfoxide / water are preferred. The base is not particularly limited. For example, alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; Alkali metal carbonates such as lithium, sodium carbonate, potassium carbonate, cesium carbonate; metal salts of alcohols such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, tert-butoxy sodium, tert-butoxy potassium; lithium Metal amides such as diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide; n-butyllithium, sec- Organometallic compounds such as til lithium and tert-butyl lithium; triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine, 3,4-lutidine, 2,6-lutidine, 2,4,6-collidine, etc. Among them, sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate are preferable. The reaction conditions are −80 to 150 ° C., preferably 0 to 100 ° C., and 1 minute to 48 hours, preferably 1 hour to 24 hours.

Step 2: In this step, compound (3) and compound (4) are reacted in a solvent in the presence of a condensing agent, in the presence or absence of a reaction accelerator, and in the presence or absence of a base. This is a process for producing a hydantoin derivative (1). The solvent is not particularly limited. For example, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, dioxane, acetonitrile, nitromethane, acetone, ethyl acetate, benzene, chlorobenzene, toluene, chloroform, methylene chloride, etc. Among them, dimethyl sulfoxide, acetonitrile, and methylene chloride are preferable. The condensing agent is not particularly limited. For example, carbodiimide reagents such as dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC), diisopropylcarbodiimide (DIPCDI), (1H- Benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate (BOP), (1H-benzotriazol-1-yloxy) tris (pyrrolidino) phosphonium hexafluorophosphate (PyBOP), 1- [bis (dimethyl) Amino) methylene] -1H-1,2,3-triazolo (4,5-b) pyridium-3-oxodohexafluorophosphate (HATU), 1- [bis (dimethylamino) methylene] -1H-benzotriazoly 3-oxide hexafluorophosphate (HBTU), 1- [bis (dimethylamino) methylene] -1H-benzotriazolium-3-oxide tetrafluoroborate (TBTU), 1- [bis (dimethylamino) Methylene] -5-chloro-1H-benzotriazolium-3-oxide hexafluorophosphate (HCTU), 1- [bis (dimethylamino) methylene] -5-chloro-1H-benzotriazolium-3-oxide Examples thereof include phosphonium salt or guanidinium salt type reagents such as tetrafluoroborate (TCTU), among which 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC), (1H-benzotriazol-1-yloxy) ) Tris (dimethylamino) phosphonium hexafluorophor Sulfate (BOP), (1H-benzotriazol-1-yloxy) tris (pyrrolidino) phosphonium hexafluorophosphate (PyBOP), 1- [bis (dimethylamino) methylene] -1H-1,2,3-triazolo (4 , 5-b) pyridium-3-oxodohexafluorophosphate (HATU), 1- [bis (dimethylamino) methylene] -1H-benzotriazolium-3-oxide hexafluorophosphate (HBTU). The reaction accelerator is not particularly limited. For example, 1-hydroxybenzotriazole (HOBt), 6-chloro-1-hydroxybenzotriazole (6-Cl-HOBt), 3,4-dihydro-3-hydroxy-4 -Oxo-1,2,3-benzotriazine (HOOBt), 1-hydroxy-7-azabenzotriazole (HOAt) and the like can be used. The base is not particularly limited. For example, alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; Alkali metal carbonates such as lithium, sodium carbonate, potassium carbonate, cesium carbonate; metal salts of alcohols such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, tert-butoxy sodium, tert-butoxy potassium; lithium Metal amides such as diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide; n-butyllithium, sec- Organometallic compounds such as til lithium and tert-butyl lithium; triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine, 3,4-lutidine, 2,6-lutidine, 2,4,6-collidine, etc. Can be used. The reaction conditions are −80 to 150 ° C., preferably 0 to 100 ° C., for 1 minute to 5 days, preferably 1 hour to 3 days.

This step can also be carried out by adapting Mitsunobu reaction in which compound (3) and compound (4) are reacted with an azo reagent or ethylenedicarboxylic acid reagent in a solvent in the presence of a phosphine reagent. Can be manufactured. The solvent is not particularly limited. For example, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, dioxane, acetonitrile, nitromethane, acetone, ethyl acetate, benzene, chlorobenzene, toluene, chloroform, methylene chloride, etc. Can be used. Examples of phosphine reagents include trialkylphosphine such as trimethylphosphine, triethylphosphine, tripropylphosphine, triisopropylphosphine, tributylphosphine, triisobutylphosphine, and tricyclohexylphosphine, and triarylphosphine such as diphenylphosphinophenylpolystyrene Etc. can be used. Examples of the azo reagent or ethylenedicarboxylic acid reagent include diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), 1,1′-azobis (N, N-dimethylformamide) (TMAD), 1,1′- (Azodicarbonyl) dipiperidine (ADDP), 1,1′-azobis (N, N-diisopropylformamide) (TIPA), 1,6-dimethyl-1,5,7-hexahydro-1,4,6,7- Tetrazocine-2,5-dione (DHTD) or the like can be used. The reaction conditions are −80 to 150 ° C., preferably 0 to 100 ° C., for 1 minute to 5 days, preferably 1 hour to 3 days.

In this step, compound (3) is reacted with an acid halogenating agent in a solvent to produce an acid halide derivative, and this is then combined with compound (4) in a solvent in the presence or absence of a base. The hydantoin derivative (1) can also be produced by reacting. Examples of the acid halogenating agent include N, N-diethylaminosulfur trifluoride (DAST), selenium tetrafluoride or its pyridine adduct, thionyl chloride, oxalyl chloride, pyrocatekylphosphotrichloride, dichlorotriphenylphosphorane, Thionyl bromide, dibromotriphenylphosphorane, 1-dimethyl-1-iodo-2-methylpropene and the like can be used. The solvent is not particularly limited, and for example, toluene, N, N-dimethylformamide, N-methylpyrrolidone, acetonitrile, dichloromethane, 1,2-dichloroethane and the like can be used alone or in combination. The base is not particularly limited. For example, alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; Alkali metal carbonates such as lithium, sodium carbonate, potassium carbonate, cesium carbonate; metal salts of alcohols such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, tert-butoxy sodium, tert-butoxy potassium; lithium Metal amides such as diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide; n-butyllithium, sec- Organometallic compounds such as til lithium and tert-butyl lithium; triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine, 3,4-lutidine, 2,6-lutidine, 2,4,6-collidine, etc. Can be used. The reaction conditions are −80 to 150 ° C., preferably 0 to 100 ° C., for 1 minute to 5 days, preferably 1 hour to 3 days.

The production method of the compound (4) used in the present invention is not particularly limited, but can be synthesized, for example, by the method shown below.

(Wherein R ¹ , R ² , R ³ and * represent the same as above, P ¹ represents an amine protecting group, R ⁷ represents a C _1-3 alkyl group, and R ⁸ represents Represents a hydrogen atom or a methyl group, R ⁹ represents a leaving group such as a halogen atom or a pentafluorophenoxy group, X represents a halogen atom, the wavy line is a single bond, and (The configuration for a heavy bond is independently an E configuration or a Z configuration, or a mixture thereof)

Step 3: This step is a step for producing a compound (7) by reacting the compound (5) with a compound (6) in a solvent in the presence or absence of a base. As the compound (6), a commercially available compound can be used, and for example, a compound produced according to the method described in WO2010 / 12581 can be used, but the compound (6) is particularly limited to this. is not. The solvent is not particularly limited, but for example, tetrahydrofuran, toluene, dioxane, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, propionitrile, acetone, methyl ethyl ketone, water, etc. are used alone or in combination. can do. Although there is no restriction | limiting in particular as a base, For example, alkali metal hydrides, such as lithium hydride, sodium hydride, potassium hydride, Alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide; Alkali metal carbonates such as lithium, sodium carbonate, potassium carbonate, cesium carbonate; metal salts of alcohols such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, tert-butoxy sodium, tert-butoxy potassium; lithium Metal amides such as diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide; n-butyllithium, sec- Organometallic compounds such as til lithium and tert-butyl lithium; lithium fluoride, lithium chloride, lithium bromide, lithium iodide, sodium fluoride, sodium chloride, sodium bromide, sodium iodide, potassium fluoride, potassium chloride Alkali metal halides such as potassium bromide, potassium iodide, cesium fluoride, cesium chloride, cesium bromide, cesium iodide; triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine, 3,4 -Organic amines such as lutidine, 2,6-lutidine, 2,4,6-collidine, among them, triethylamine and N, N-diisopropylethylamine are preferred. The reaction conditions are −80 to 150 ° C., preferably 0 to 100 ° C., for 1 minute to 5 days, preferably 1 hour to 3 days.

Step 4: This step is a step for producing compound (8) by reacting compound (7) with a Wittig reagent or Horner-Wadsworth-Emmons (HWE) reagent in a solvent in the presence or absence of a base. is there. The solvent is not particularly limited, and for example, N, N-dimethylformamide, tetrahydrofuran, dioxane, acetonitrile, nitromethane, acetone, ethyl acetate, benzene, chlorobenzene, toluene, chloroform, methylene chloride and the like can be used. Tetrahydrofuran, ethyl acetate, toluene, chloroform and methylene chloride are preferred. As the Wittig reagent, phosphonium salts such as stable ylide and unstable ylide (methyltriphenylphosphonium bromide, ethyltriphenylphosphonium bromide) can be used. As the HWE reagent, a phosphonic acid ester can be used. The base is not particularly limited. For example, alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; Alkali metal carbonates such as lithium, sodium carbonate, potassium carbonate, cesium carbonate, metal salts of alcohols such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, tert-butoxy sodium, tert-butoxy potassium; lithium Metal amides such as diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide; n-butyllithium, sec- Organometallic compounds such as til lithium and tert-butyl lithium; lithium chloride, lithium bromide, lithium iodide, sodium fluoride, sodium chloride, sodium bromide, sodium iodide, potassium chloride, potassium bromide, potassium iodide Alkali metal halides such as cesium chloride, cesium bromide, and cesium iodide can be used. The reaction conditions are −80 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C., for 1 minute to 5 days, preferably 1 hour to 3 days.

Step 5: This step is a step for producing the compound (9) by reacting the compound (8) in a solvent in the presence of metallic carbon under a hydrogen atmosphere. The solvent is not particularly limited, and may be used alone or in combination with toluene, esters such as methyl acetate and ethyl acetate, and alcohols such as methanol, ethanol, 1-propanol and 2-propanol. Examples of the metal carbon include palladium carbon, platinum carbon, rhodium carbon, ruthenium carbon and the like. The reaction conditions are −80 to 150 ° C., preferably 0 to 100 ° C., for 1 minute to 5 days, preferably 1 hour to 3 days.

Process 6: This process is a process of manufacturing a compound (10) by making a compound (9) react in a solvent in presence of a base or an acid. The solvent is not particularly limited. For example, tetrahydrofuran, toluene, dioxane, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, propionitrile, acetone, methyl ethyl ketone, water, methanol, ethanol, 1- Alcohols such as propanol and 2-propanol can be used alone or in combination. The base is not particularly limited. For example, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, alkali carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate are used. can do. Although there is no restriction | limiting in particular as an acid, For example, hydrochloric acid, a sulfuric acid, an acetic acid, a tosylic acid etc. can be used. The reaction conditions are −80 to 150 ° C., preferably 0 to 100 ° C., for 1 minute to 5 days, preferably 1 hour to 3 days.

Step 7: This step is a step of removing the compound (10) in a solvent or in the absence of a solvent, in the presence or absence of a condensing agent, in the presence or absence of a reaction accelerator, in the presence or absence of an acid or base. In this step, compound (11) is produced by the reaction below. The substituent represented by R ⁹ can be converted into an acid halide, an acid anhydride or an ester with reference to, for example, literature (Comprehensive Organic Transformations Second Edition, John Wiley & Sons, Inc.). Examples of acid halides include acid fluorides and acid chlorides. Examples of the acid anhydride include an acid anhydride with an aliphatic carboxylic acid such as acetic acid, an acid anhydride with an aromatic carboxylic acid such as benzoic acid, and the like. Examples of the ester include an ester with an aliphatic alcohol such as methanol, an ester with an aromatic alcohol such as pentafluorophenol, and the like.

When R ⁹ is a pentafluorophenoxy group, the solvent is not particularly limited. For example, tetrahydrofuran, toluene, dioxane, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, propionitrile, acetone, Methyl ethyl ketone, ethyl acetate and the like can be used alone or in combination. The condensing agent is not particularly limited, and examples thereof include carbodiimide reagents such as dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC), and diisopropylcarbodiimide (DIPCDI). Of these, dicyclohexylcarbodiimide and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide are preferable. The base is not particularly limited, and examples thereof include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; alkali carbonate metals such as lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate; triethylamine, Organic amines such as N, N-diisopropylethylamine, N-methylmorpholine, pyridine, 3,4-lutidine, 2,6-lutidine, 2,4,6-collidine and the like can be used. Although there is no restriction | limiting in particular as an acid, For example, hydrochloric acid, a sulfuric acid, an acetic acid, a tosylic acid etc. can be used. The reaction conditions are −80 to 150 ° C., preferably 0 to 100 ° C., for 1 minute to 5 days, preferably 1 hour to 3 days.

Step 8: This step is a step for producing the compound (11) into the hexafluorocarbinol compound (12) using a trifluoromethylating reagent in a solvent in the presence of a base. The solvent is not particularly limited, and examples thereof include dimethoxyethane, tetrahydrofuran, toluene, dioxane, ethylene glycol dimethyl ether, N, N-dimethylformamide, N-methylpyrrolidone, tetramethylurea, dimethyl sulfoxide, acetonitrile, propionitrile and the like. They can be used alone or in combination, and ethylene glycol dimethyl ether is particularly preferable. Examples of the base include tetraalkylammonium salts such as tetramethylammonium fluoride, tetraethylammonium fluoride and tetrabutylammonium fluoride, and alkali metal fluoride salts such as lithium fluoride, sodium fluoride, potassium fluoride and cesium fluoride. Etc. Trifluoromethylating reagents include (trifluoromethyl) trimethylsilane, triethyl (trifluoromethyl) silane, triisopropyl (trifluoromethyl) silane, methyldiphenyl (trifluoromethyl) silane, dimethyl (diphenyl) trifluoromethylsilane Etc. The reaction conditions are −80 to 150 ° C., preferably −30 to 50 ° C., for 1 minute to 5 days, preferably 1 hour to 3 days.

Process 9: This process is a process of manufacturing a compound (4) by deprotecting the amino group of a compound (12). The protecting group represented by P ¹ can be deprotected with reference to literature (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.), for example.

When P ¹ is a tert-butoxycarbonyl group, compound (4) can be produced by reacting compound (12) with an acid in a solvent or without a solvent. The solvent is not particularly limited. For example, N, N-dimethylformamide, tetrahydrofuran, dioxane, acetonitrile, nitromethane, acetone, ethyl acetate, benzene, chlorobenzene, toluene, chloroform, methylene chloride, water, methanol, ethanol, 1- Propanol, 2-propanol and the like can be used alone or in combination. The acid is not particularly limited, but hydrochloric acid, hydrochloric acid / ethyl acetate solution, hydrochloric acid / dioxane solution, hydrochloric acid / methanol solution, hydrobromic acid, sulfuric acid, nitric acid, etc. can be used. Among them, hydrochloric acid / ethyl acetate solution A hydrochloric acid / methanol solution is preferred. The reaction conditions are −20 ° C. to 100 ° C., preferably 0 ° C. to 50 ° C., for 1 minute to 24 hours, preferably 5 minutes to 12 hours.

The production method of the compound (2) used in the present invention is not particularly limited, but can be synthesized, for example, by the method shown below.

(In the formula, R ⁴ , R ⁵ , R ⁶ and * are the same as described above.)

Step 10: This step is a step for producing the compound (14) by subjecting the compound (13) to a hydrolysis reaction in a solvent in the presence of water and a base or acid. The solvent is not particularly limited. For example, tetrahydrofuran, toluene, dioxane, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, propionitrile, acetone, methyl ethyl ketone, water, methanol, ethanol, 1- Alcohols such as propanol and 2-propanol can be used alone or in combination. The base is not particularly limited. For example, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, alkali carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate are used. can do. Although there is no restriction | limiting in particular as an acid, For example, hydrochloric acid, a sulfuric acid, an acetic acid, a tosylic acid etc. can be used. The reaction conditions are −80 to 200 ° C., preferably 0 to 150 ° C., for 1 minute to 7 days, preferably 1 hour to 3 days.

Step 11: In this step, the compound (14) is added in the presence of an alcohol (R ⁵ —OH), in another solvent or in the absence of a solvent, in the presence or absence of a condensing agent, in the presence of a reaction accelerator or In this step, the compound (15) is produced by reacting in the absence or presence of an acid or a base. For example, it can be converted into an ester with reference to literature (Comprehensive Organic Transformations Second Edition, John Wiley & Sons, Inc.). Examples of the alcohol include aliphatic alcohols such as methanol and ethanol. The base is not particularly limited. For example, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, alkali carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate are used. can do. Although there is no restriction | limiting in particular as an acid, For example, hydrochloric acid, a sulfuric acid, an acetic acid, a tosylic acid etc. can be used. The reaction conditions are −80 to 200 ° C., preferably 0 to 150 ° C., for 1 minute to 7 days, preferably 1 hour to 2 days.

Step 12: This step is a step for producing a compound (16) by reacting the compound (15) in a solvent or in the absence of a solvent in the presence of an optical resolution agent. The solvent is not particularly limited. For example, tetrahydrofuran, toluene, dioxane, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, propionitrile, acetone, methyl ethyl ketone, ethyl acetate, propyl acetate, isopropyl acetate In addition, esters such as isobutyl acetate, alcohols such as water, methanol, ethanol, 1-propanol, and 2-propanol can be used alone or in combination. The optical resolution agent is not particularly limited. For example, (L)-(+)-mandelic acid, (D)-(−)-mandelic acid, malic acid, tartaric acid, lactic acid, camphorsulfonic acid, (1S) — (+)-Ketopic acid or commercially available optically pure compounds can also be used. The reaction conditions are -80 to 150 ° C, preferably -10 to 100 ° C, 1 minute to 48 hours, preferably 1 hour to 24 hours.

Step 13: This step is a step for producing a compound (2) by reacting the compound (16) with an isocyanate derivative (17) in a solvent or without a solvent in the presence or absence of a base. The solvent is not particularly limited, but for example, tetrahydrofuran, ethylene glycol dimethyl ether, toluene, dioxane, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, propionitrile, acetone, methyl ethyl ketone, ethyl acetate, acetic acid Esters such as propyl, isopropyl acetate and isobutyl acetate, alcohols such as methanol, ethanol, 1-propanol and 2-propanol can be used alone or in combination. The base is not particularly limited. For example, alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; Alkali metal carbonates such as lithium, sodium carbonate, potassium carbonate, cesium carbonate; metal salts of alcohols such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, tert-butoxy sodium, tert-butoxy potassium; lithium Diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, n-butyllithium, sec-butyllithium, ert- butyl lithium, triethylamine, N, N- diisopropylethylamine, N- methylmorpholine, pyridine, 3,4-lutidine, 2,6-lutidine, can be used 2,4,6-collidine. The reaction conditions are −80 to 150 ° C., preferably 0 to 100 ° C., for 1 minute to 5 days, preferably 1 hour to 3 days.

Further, the compound (2) obtained in the step 13 can be continuously subjected to the reaction in the step 1 without isolation and purification to obtain the compound (3).

Specific examples of the salt allowed in the optically active compound represented by the general formula (3) of the present invention include acid addition salts with inorganic acids and organic acids, or base addition salts with inorganic bases and organic bases. Etc.

Specific examples of the solvate of the optically active compound represented by the general formula (3) of the present invention and its acceptable salt include hydrates and various solvates.

Hereinafter, the present invention will be described in more detail with reference to examples.
Example 1: (S) -3- (2-{(2S, 5R) -4- [4- (1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl] -2,5-dimethylpiperazin-1-yl} -2-oxoethyl) -5- [4- (1-methylethoxy) phenyl] -5-methylimidazolidine-2,4-dione ( Production of (S) -B)

Step I: Preparation of 4- [2-formyl-4- (methoxycarbonyl) phenyl] -2,5-dimethylpiperazine-1-carboxylic acid (2S, 5R) -tert-butyl (c2):
Cesium fluoride (14.0 g, 91.89 mmol) was dried under reduced pressure at 120 ° C. for 2 hours, and N, N-dimethylformamide (52 mL) was added at room temperature under an argon atmosphere. Thereafter, N, N-dimethylformamide (50 mL) of 2,5-dimethylpiperazine-1-carboxylic acid (2S, 5R) -tert-butyl (14.2 g, 61.26 mmol) produced according to the pamphlet of WO2010 / 12581 The solution and 4-fluoro-3-formylbenzoic acid methyl ester (11.15 g, 61.26 mmol) were added in this order, and the mixture was stirred at 100 ° C. for 18 hours. After confirming the completion of the reaction, toluene and water were added to the reaction solution at 0 ° C. Thereafter, extraction with toluene was performed, and the organic layer was washed with saturated brine, dried using anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography (hexane / ethyl acetate) to obtain 19.57 g (yield 85%) of the title compound as a yellow amorphous.

¹ H-NMR (CDCl ₃ ) δ: 1.00 (3H, d, J = 6.0 Hz), 1.28 (3H, d, J = 6.4 Hz), 1.49 (9H, s), 2.86 (1H, d, J = 11.6 Hz), 3.63-3.70 (3H, m), 3.77 (1H, d, J = 12.6 Hz), 3.91 (3H, s), 4.44-4.49 (1H, m), 6.99 (1H, d, J = 8.8 Hz ), 8.13 (1H, dd, J = 2.4, 8.8 Hz), 8.45 (1H, d, J = 2.4 Hz), 10.12 (1H, s).

Step II: 4- [4- (Methoxycarbonyl) -2- (prop-1-en-1-yl) phenyl] -2,5-dimethylpiperazine-1-carboxylic acid (2S, 5R) -tert-butyl ( c3) Production:
Ethyltriphenylphosphonium bromide (25.8 g, 69.46 mmol) was dissolved in tetrahydrofuran (140 mL), and potassium methoxide (4.87 g, 69.46 mmol) was added at 0 ° C. under an argon atmosphere. After stirring at 0 ° C. for 1 hour and 30 minutes, 4- [2-formyl-4- (methoxycarbonyl) phenyl] -2,5-dimethylpiperazine-1-carboxylic acid (2S, 5R) -tert-butyl (5. (23 g, 13.89 mmol) in tetrahydrofuran (140 mL) was added, and the mixture was stirred at room temperature for 2 hours 30 minutes. After confirming the completion of the reaction, water was added to the reaction solution at 0 ° C. Thereafter, extraction with toluene was performed, and the organic layer was washed with saturated brine, dried using anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 4.76 g (yield 88%, cis / trans = 0.7 / 1) of the title compound as a yellow amorphous.

cis-c3: 4- {4- (methoxycarbonyl) -2-[(Z) -prop-1-en-1-yl] phenyl} -2,5-dimethylpiperazine-1-carboxylic acid (2S, 5R) -tert-butyl

¹ H-NMR (CDCl ₃ ) δ: 0.87 (3H, d, J = 6.8 Hz), 1.30 (3H, d, J = 6.8 Hz), 1.48 (9H, s), 1.90-1.92 (3H, m), 2.71 (1H, d, J = 11.6 Hz), 3.41-3.44 (1H, m), 3.53-3.58 (1H, m), 3.69-3.72 (2H, m), 3.86 (3H, s), 4.41-4.46 ( 1H, m), 5.81 (1H, dd, J = 6.8, 11.4 Hz), 6.42 (1H, dd, J = 1.6, 11.4 Hz), 6.84 (1H, d, J = 8.6 Hz), 7.84 (1H, dd , J = 2.0, 8.6 Hz), 7.90 (1H, d, J = 1.6 Hz).

trans-c3: 4- {4- (methoxycarbonyl) -2-[(E) -prop-1-en-1-yl] phenyl} -2,5-dimethylpiperazine-1-carboxylic acid (2S, 5R) -tert-butyl

¹ H-NMR (CDCl ₃ ) δ: 0.85 (3H, d, J = 6.8 Hz), 1.26 (3H, d, J = 6.8 Hz), 1.46 (9H, s), 1.87-1.89 (3H, m), 2.67 (1H, d, J = 12.0 Hz), 3.39-3.59 (3H, m), 3.67-3.73 (1H, m), 3.86 (3H, s), 4.41 (1H, brs), 6.25 (1H, dd, J = 6.4, 15.6 Hz), 6.54 (1H, dd, J = 1.6, 15.6 Hz), 6.80 (1H, d, J = 8.8 Hz), 7.80 (1H, dd, J = 1.6, 8.8 Hz), 8.03 ( (1H, d, J = 1.6 Hz).

Step III: Preparation of 4- [4- (methoxycarbonyl) -2-propylphenyl] -2,5-dimethylpiperazine-1-carboxylic acid (2S, 5R) -tert-butyl (c4):
4- [4- (Methoxycarbonyl) -2- (prop-1-en-1-yl) phenyl] -2,5-dimethylpiperazine-1-carboxylic acid (2S, 5R) -tert-butyl (4.76 g) , 12.25 mmol) was dissolved in methanol (123 mL), and palladium on carbon was added under an argon atmosphere. Thereafter, the mixture was stirred at room temperature for 24 hours under a hydrogen atmosphere. After confirming the completion of the reaction, the mixture was filtered through Celite, washed with ethyl acetate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (4.72 g, yield 99%) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 0.91 (3H, d, J = 6.4 Hz), 0.97 (3H, t, J = 7.2 Hz), 1.30 (3H, d, J = 6.4 Hz), 1.49 (9H, s), 1.70 (2H, tq, J = 7.2, 7.6 Hz), 2.49-2.56 (2H, m), 2.79 (1H, td, J = 7.6, 14.4 Hz), 3.35-3.40 (1H, m), 3.51 (1H, dd, J = 3.2, 13.2 Hz), 3.61 (1H, dd, J = 4.0, 11.4 Hz), 3.74 (1H, dd, J = 1.6, 13.2 Hz), 3.88 (3H, s), 4.38- 4.44 (1H, m), 6.90 (1H, d, J = 8.0 Hz), 7.80 (1H, dd, J = 2.0, 8.0 Hz), 7.89 (1H, d, J = 2.0 Hz).

Step IV: Preparation of 4-[(2R, 5S) -4- (tert-butoxycarbonyl) -2,5-dimethylpiperazin-1-yl] -3-propylbenzoic acid (c5):
4- [4- (Methoxycarbonyl) -2-propylphenyl] -2,5-dimethylpiperazine-1-carboxylic acid (2S, 5R) -tert-butyl (4.72 g, 12.09 mmol) in methanol (121 mL) 4N-aqueous sodium hydroxide solution (18.1 mL, 72.52 mmol) was added at 0 ° C., and the mixture was stirred at 60 ° C. for 2 hours. After confirming the completion of the reaction, the reaction solution was neutralized with an aqueous ammonium chloride solution at 0 ° C. (pH = 7). Thereafter, the mixture was extracted with chloroform, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 4.48 g (yield 99%) of the title compound as a colorless amorphous.

¹ H-NMR (CDCl ₃ ) δ: 0.92 (3H, d, J = 6.8 Hz), 0.97 (3H, t, J = 7.2 Hz), 1.30 (3H, d, J = 6.8 Hz), 1.49 (9H, s), 1.71 (2H, tq, J = 7.2, 7.6 Hz), 2.50-2.58 (2H, m), 2.79 (1H, td, J = 7.6, 14.0 Hz), 3.37-3.43 (1H, m), 3.52 (1H, dd, J = 3.6, 12.8 Hz), 3.61 (1H, dd, J = 4.0, 11.4 Hz), 3.75 (1H, dd, J = 1.6, 11.6 Hz), 4.39-4.44 (1H, m), 6.91 (1H, d, J = 8.0 Hz), 7.87 (1H, dd, J = 2.0, 8.0 Hz), 7.94 (1H, d, J = 2.0 Hz).

Step V: Preparation of 2,5-dimethyl-4- {4-[(perfluorophenoxy) carbonyl] -2-propylphenyl} piperazine-1-carboxylic acid (2S, 5R) -tert-butyl (c6):
4-[(2R, 5S) -4- (tert-butoxycarbonyl) -2,5-dimethylpiperazin-1-yl] -3-propylbenzoic acid (1.0 g, 2.656 mmol) was added to ethyl acetate (18 mL). Then, 2,3,4,5,6-pentafluorophenol (513 mg, 2.789 mmol) and N, N′-dicyclohexylcarbodiimide (575 mg, 2.789 mmol) were sequentially added at room temperature. Stir at room temperature for 18 hours. After confirming the completion of the reaction, water was added to the reaction solution at 0 ° C. Thereafter, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography (hexane / ethyl acetate) to obtain 1.43 g (yield> 99%) of the title compound as an orange oil.

¹ H-NMR (CDCl ₃ ) δ: 0.96 (3H, d, J = 6.6 Hz), 1.00 (3H, t, J = 7.3 Hz), 1.31 (3H, d, J = 6.8 Hz), 1.50 (9H, s), 1.74 (2H, tq, J = 7.2, 8.2 Hz), 2.54-2.63 (2H, m), 2.81 (1H, td, J = 8.2, 14.1 Hz), 3.45-3.51 (1H, m), 3.54 (1H, dd, J = 3.6, 12.9 Hz), 3.65 (1H, dd, J = 4.1, 11.7 Hz), 3.77 (1H, dd, J = 1.4, 12.8 Hz), 4.41-4.47 (1H, m), 6.98 (1H, d, J = 8.5 Hz), 7.98 (1H, dd, J = 2.2, 8.5 Hz), 8.03 (1H, d, J = 2.2 Hz).

Step VI: 4- [4- (1,1,1,3,3,3-Hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl] -2,5-dimethylpiperazine-1-carboxyl Preparation of acid (2S, 5R) -tert-butyl (c7):
2,5-dimethyl-4- {4-[(perfluorophenoxy) carbonyl] -2-propylphenyl} piperazine-1-carboxylic acid (2S, 5R) -tert-butyl (5.75 g, 10.6 mmol) under reduced pressure After drying at 100 ° C. for 1 hour, ethylene glycol dimethyl ether (110 mL) was added at room temperature under an argon atmosphere. Thereafter, trifluoromethyltrimethylsilane (3.32 g, 23.3 mmol) and cesium fluoride (7.08 g, 46.6 mmol) were added in this order at −15 ° C. Thereafter, the mixture was stirred at −15 ° C. for 1 hour and then at room temperature for 3 hours and 30 minutes. After confirming the completion of the reaction, a 1N hydrochloric acid aqueous solution and toluene were added to the reaction solution at 0 ° C. Thereafter, extraction with toluene was performed, and the organic layer was washed with saturated brine, dried using anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography (hexane / ethyl acetate) to obtain 4.98 g (yield 90%) of the title compound as a brown crystalline solid.

¹ H-NMR (CDCl ₃ ) δ: 0.92 (3H, d, J = 6.8 Hz), 0.97 (3H, t, J = 7.2 Hz), 1.30 (3H, d, J = 6.8 Hz), 1.48 (9H, s), 1.67 (2H, tq, J = 7.2, 8.0 Hz), 2.47-2.56 (2H, m), 2.82 (1H, td, J = 8.0, 14.0 Hz), 3.28-3.34 (1H, m), 3.50 (1H, dd, J = 3.2, 13.6 Hz), 3.53 (1H, s), 3.59 (1H, dd, J = 4.0, 11.6 Hz), 3.74 (1H, dd, J = 1.6, 12.4 Hz), 4.37- 4.43 (1H, m), 6.93 (1H, d, J = 8.4 Hz), 7.44 (1H, dd, J = 2.0, 8.4 Hz), 7.51 (1H, d, J = 2.0 Hz). Mp: 170-172 ° C.

Step VII: 2- {4-[(2R, 5S) -2,5-dimethylpiperazin-1-yl] -3-propylphenyl} -1,1,1,3,3,3-hexafluoropropane-2 -Manufacture of all (c8):
4- [4- (1,1,1,3,3,3-Hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl] -2,5-dimethylpiperazine-1-carboxylic acid (2S , 5R) -tert-butyl (4.53 g, 9.08 mmol) was dissolved in methanol (14 mL), 2N hydrochloric acid methanol solution (41 mL, 81.7 mmol) was added at 0 ° C., and 5 hours at 35 ° C. Stir. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure. Water was added to the residue, the pH was adjusted to 8-9 using an aqueous sodium hydroxide solution, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and then decompressed. Concentrated. The obtained residue was washed with heptane and dried to give 3.43 g (yield 95%) of the title compound as a pale yellow crystalline solid.

¹ H-NMR (CDCl ₃ ) δ: 0.76 (3H, d, J = 6.0 Hz), 0.95 (3H, t, J = 7.2 Hz), 1.04 (3H, d, J = 6.4 Hz), 1.63 (2H, qt, J = 7.2, 7.6 Hz), 2.17 (2H, brs), 2.30 (1H, d, J = 10.4 Hz), 2.33 (1H, d, J = 10.4 Hz), 2.63-2.77 (3H, m), 2.81 (1H, dd, J = 2.8, 11.8 Hz), 2.97-3.05 (2H, m), 7.22 (1H, d, J = 9.2 Hz), 7.52-7.54 (2H, m). Mp: 165-167 ° C .

Step VIII: Preparation of 2-amino-2- [4- (1-methylethoxy) phenyl] propanoic acid hydrochloride (c10):
5- [4- (1-Methylethoxy) phenyl] -5-methylimidazolidine-2,4-dione (110 g, 443 mmol) produced according to the pamphlet of WO2009 / 144961 is dissolved in water (700 mL) and brought to room temperature. Sodium hydroxide (90 g, 2.25 mol) was added, and the mixture was heated to reflux for 48 hours. After confirming the completion of the reaction, the reaction solution was brought to 0 ° C. and concentrated hydrochloric acid was added until pH <6. Thereafter, the crude product obtained by concentrating water under reduced pressure was used in the next step (> 99%).

¹ H-NMR (DMSO) δ: 1.22 (6H, d, J = 6.1 Hz), 1.62 (3H, s), 4.57 (1H, sept, J = 6.1 Hz), 6.68 (2H, brs), 6.84 (2H , d, J = 8.8 Hz), 7.37 (2H, d, J = 8.8 Hz).

Step IX: Preparation of methyl 2-amino-2- [4- (1-methylethoxy) phenyl] propanoate (c11):
2-Amino-2- [4- (1-methylethoxy) phenyl] propanoic acid hydrochloride (70.0 g, 270 mmol) was dissolved in methanol (225 mL), concentrated sulfuric acid (70 mL) was sequentially added at room temperature, and 24 Heated to reflux for hours. After confirming the completion of the reaction, the reaction solution was brought to room temperature and concentrated under reduced pressure to distill off methanol. The obtained residue was dissolved in dichloromethane and extracted with dichloromethane. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (44.8 g, yield 70%) as a colorless oil.

¹ H-NMR (acetone-d6) δ: 1.27 (6H, d, J = 5.8 Hz), 1.55 (3H, s), 3.63 (3H, s), 4.58 (1H, sept, J = 5.8 Hz), 6.84 (2H, d, J = 8.8 Hz), 7.39 (2H, d, J = 8.8 Hz).

Step X: Preparation of 2-amino-2- [4- (1-methylethoxy) phenyl] propanoic acid (S) -methyl ((S) -c11):
Racemic methyl 2-amino-2- [4- (1-methylethoxy) phenyl] propanoate (5.54 g, 23.3 mmol) was dissolved in ethyl acetate (52 mL) and (L)-( +)-Mandelic acid (3.55 g, 23.3 mmol) was added, ethanol (6 mL) was added, and the mixture was heated to reflux for 30 min. Thereafter, the temperature was gradually lowered, and the mixture was further left at 0 to 5 ° C. for 1 hour. The resulting precipitate was collected by filtration, washed with heptane and dried to give the title compound (L)-(+)-mandelate (3.35 g, 37%) as a white solid. Next, the obtained (L)-(+)-mandelic acid salt of the title compound was recrystallized from 95% ethanol. The obtained title compound (L)-(+)-mandelate was suspended in dichloromethane, and an aqueous sodium carbonate solution was added until pH = 8. Thereafter, the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1.12 g (yield 20%, 99.4% ee) of the title compound as a colorless oil.

Optical purity measurement:
Column: CHIRALPAK AS-H, 5μm, 0.46 * 250mm
Mobile phase: Hexane: Isopropyl alcohol = 92: 8 (0.1% DEA)
Flow rate: 1 mL / min
Temperature: 30 ° C
Wavelength: 234nm
Retention time: Compound (S) -c11; 7.36 min (Compound (R) -c11; 8.59 min)

Step XI: Preparation of 2- [3- (2-ethoxy-2-oxoethyl) ureido] -2- [4- (1-methylethoxy) phenyl] propanoic acid (S) -methyl ((S) -c12):
2-Amino-2- [4- (1-methylethoxy) phenyl] propanoic acid (S) -methyl (53.0 mg, 0.223 mmol) was dissolved in dichloromethane (740 μL) and ethyl isocyanatoacetate (0 ° C.) 29 mg, 0.223 mmol) was added, and the mixture was stirred at 0 ° C. for 1 hour. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain 91.5 mg (yield> 99%) of the title compound as a colorless oil.

¹ H-NMR; (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.1 Hz), 1.32 (6H, d, J = 6.1 Hz), 2.00 (3H, s), 3.69 (3H, s), 3.89 (1H, dd, J = 5.1, 18.6 Hz), 3.93 (1H, dd, J = 5.6, 18.6 Hz), 4.16 (2H, q, J = 7.1 Hz), 4.53 (1H, sept, J = 6.1 Hz) , 4.94 (1H, brs), 5.82 (1H, brs), 6.84 (2H, d, J = 8.8 Hz). 7.36 (2H, d, J = 8.8 Hz).

Step XII: (S) -2- {4- [4- (1-methylethoxy) phenyl] -4-methyl-2,5-dioxoimidazolidin-1-yl} acetic acid ((S) -c13) Manufacturing:
2- [3- (2-Ethoxy-2-oxoethyl) ureido] -2- [4- (1-methylethoxy) phenyl] propanoic acid (S) -methyl (49.6 mg, 0.135 mmol) was added to ethanol (500 μL). ), Sodium hydrogen carbonate (11.3 mg, 0.135 mmol) was added at room temperature, and the mixture was stirred at room temperature for 7 hours. Then, 2M potassium carbonate aqueous solution (136 μL, 0.271 mmol) was added to the reaction solution at room temperature, and the mixture was stirred at 70 ° C. for 15 hours. After confirming the completion of the reaction, the reaction solution was adjusted to pH = <2 with 1N hydrochloric acid at 0 ° C. and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (39.6 mg, yield 96%) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.32 (6H, d, J = 6.0 Hz), 1.84 (3H, s), 4.27 (1H, d, J = 18.0 Hz), 4.32 (1H, d, J = 18.0 Hz), 4.52 (1H, sept, J = 6.0 Hz), 6.50 (1H, brs), 6.87 (2H, d, J = 8.8 Hz), 7.38 (2H, d, J = 8.8 Hz).

Steps XI & XII: (S) -2- {4- [4- (1-methylethoxy) phenyl] -4-methyl-2,5-dioxoimidazolidin-1-yl} acetic acid ((S) -c13) Manufacturing:
2-Amino-2- [4- (1-methylethoxy) phenyl] propanoic acid (S) -methyl (2.90 g, 12.2 mmol) was dissolved in dimethyl sulfoxide (15 mL) and ethyl isocyanatoacetate at 15 ° C. (1.74 g, 13.4 mmol) was added, and the mixture was stirred at 15 ° C. for 1 hour. Then, 1M potassium carbonate aqueous solution (18.3 mL, 18.3 mmol) was added to the reaction solution at 15 ° C., and the mixture was stirred at 70 ° C. for 2 hours. After confirming the completion of the reaction, water and a saturated aqueous sodium bicarbonate solution were added to the reaction solution at room temperature, followed by extraction with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium bicarbonate solution. The obtained aqueous layer was adjusted to pH = <2 with 4N hydrochloric acid at 0 ° C., extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. As a result, 3.26 g (yield 87%) of the title compound was obtained as a colorless oil.

Step XIII-1: (S) -3- (2-{(2S, 5R) -4- [4- (1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl) ) -2-Propylphenyl] -2,5-dimethylpiperazin-1-yl} -2-oxoethyl) -5- [4- (1-methylethoxy) phenyl] -5-methylimidazolidine-2,4-dione Production of ((S) -B):
2- {4-[(2R, 5S) -2,5-dimethylpiperazin-1-yl] -3-propylphenyl} -1,1,1,3,3,3-hexafluoropropan-2-ol ( 200 mg, 0.502 mmol) was dissolved in dichloromethane (2.0 mL) and (S) -2- {4- [4- (1-methylethoxy) phenyl] -4-methyl-2,5-di- at room temperature. Oxoimidazolidin-1-yl} acetic acid (169 mg, 0.552 mmol) was added. Thereafter, O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HBTU) (228 mg, 0.602 mmol), diisopropylethylamine ( 156 mg, 1.20 mmol). The reaction solution was stirred at 0 ° C. for 10 minutes, and then stirred at room temperature for 20 hours. After confirming the completion of the reaction, the mixture was concentrated under reduced pressure, water and methyl-tert-butyl ether were added to the resulting residue, and the mixture was extracted with methyl-tert-butyl ether. The organic layer was washed with 20% aqueous potassium phosphate solution, 1N aqueous hydrochloric acid solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography (hexane / ethyl acetate) to obtain 294 mg (yield 85%) of the title compound as a pale yellow amorphous.

Step XIII-2: (S) -3- (2-{(2S, 5R) -4- [4- (1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl) ) -2-Propylphenyl] -2,5-dimethylpiperazin-1-yl} -2-oxoethyl) -5- [4- (1-methylethoxy) phenyl] -5-methylimidazolidine-2,4-dione Production of ((S) -B):
(S) -2- {4- [4- (1-methylethoxy) phenyl] -4-methyl-2,5-dioxoimidazolidin-1-yl} acetic acid was dissolved in toluene (2.0 mL), N, N-dimethylformamide (2.6 mg) and thionyl chloride (77.7 mg) were sequentially added, and the mixture was stirred at 120 ° C. for 1 hour. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a residue. Next, 2- {4-[(2R, 5S) -2,5-dimethylpiperazin-1-yl] -3-propylphenyl} -1,1,1,3,3,3-hexafluoropropane-2 -Ol (130 mg, 0.326 mmol) was dissolved in dichloromethane (3.9 mL) and triethylamine (66.1 mg, 0.653 mmol) was added at room temperature. The residue obtained previously at 0 ° C. was added, stirred at 0 ° C. for 5 minutes, and then stirred at room temperature for 14 hours. After confirming the completion of the reaction, water was added at 0 ° C., and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography (chloroform / methanol) to obtain 176 mg (yield 78%) of the title compound as a colorless amorphous substance.

¹ H-NMR (CDCl ₃ ) δ: 0.96-0.99 (6H, m), 1.32-1.33 (9H, m), 1.68 (2H, qt, J = 7.0, 7.6 Hz), 1.90 (3H, s), 2.48-2.63 (2H, m), 2.79-2.87 (1H, m), 3.39-3.66 (4H, m), 4.29-4.33 (2H, m), 4.54 (1H, sept, J = 5.9 Hz), 4.84 (1H, s), 5.63 (1H, s), 6.90 (2H, d, J = 8.8 Hz), 6.93 (1H, d, J = 8.8 Hz), 7.45 (1H, d, J = 8.8 Hz), 7.46 (2H, d, J = 8.8 Hz) , 7.52 (1H, d, J = 2.2 Hz).

Optical purity: 99% ee
Measurement conditions: HPLC
Column: CHIRALPAK AD-H
Solvent: hexane / isopropyl alcohol = 25/75
Flow rate: 0.6 mL / min
Retention time: Compound (S) -B; 23.4 min
(Isomer 1; 9.7 min, Isomer 2; 13.3 min, Isomer 3; 14.1 min, Isomer 4; 15.0 min, Isomer 5; 17.9 min, Isomer 6; 20.5 min, Isomer Body 7; 54.9 min)

Example 2 (R) -3- (2-{(2S, 5R) -4- [4- (1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)- 2-propylphenyl] -2,5-dimethylpiperazin-1-yl} -2-oxoethyl) -5- [4- (1-methylethoxy) phenyl] -5-methylimidazolidine-2,4-dione (( Production of R) -B)

Step XIV: Preparation of 2-amino-2- [4- (1-methylethoxy) phenyl] propanoic acid (R) -methyl ((R) -c11):
(D)-(−)-Mandelic acid was used for the reaction and treatment in the same manner as in Step X to obtain the title compound as a colorless oil (99.4% ee).

Step XV: (R) -2- {4- [4- (1-methylethoxy) phenyl] -4-methyl-2,5-dioxoimidazolidin-1-yl} acetic acid ((R) -c13) Manufacturing:
2-Amino-2- [4- (1-methylethoxy) phenyl] propanoic acid (R) -methyl (1.00 g, 4.21 mmol) was dissolved in ethanol (5.0 mL), and Ethyl isocyanatoacetate (599 mg, 4.64 mmol) was added, and the mixture was stirred at 20 ° C. for 1 hr 30 min. Then, 1M potassium hydrogen carbonate aqueous solution (4.64 mL, 4.64 mmol) was added to the reaction solution at 20 ° C., and the mixture was stirred at 20 ° C. for 2 hours. Further, 2M potassium carbonate aqueous solution (4.21 mL, 8.43 mmol) was added to the reaction solution at 0 ° C., and the mixture was stirred at 70 ° C. for 6 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution at room temperature, followed by extraction with ethyl acetate, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution. The resulting aqueous layer was adjusted to pH = <2 with 4N hydrochloric acid at 0 ° C. and extracted with ethyl acetate. The obtained organic layer was washed successively with phosphate buffer (pH = 5.8) and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1.12 g (yield 87) of the title compound. %) As a colorless oil.

Step XVI: (R) -3- (2-{(2S, 5R) -4- [4- (1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)- 2-propylphenyl] -2,5-dimethylpiperazin-1-yl} -2-oxoethyl) -5- [4- (1-methylethoxy) phenyl] -5-methylimidazolidine-2,4-dione (( Production of R) -B):
2- {4-[(2R, 5S) -2,5-dimethylpiperazin-1-yl] -3-propylphenyl} -1,1,1,3,3,3-hexafluoropropan-2-ol ( 43.8 mg, 0.112 mmol) is dissolved in dimethyl sulfide (500 μL) and (R) -2- {4- [4- (1-methylethoxy) phenyl] -4-methyl-2,5- is dissolved at room temperature. Dioxoimidazolidin-1-yl} acetic acid (40.4 mg, 0.132 mmol) was added. Then, O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HBTU) (50.1 mg, 0.132 mmol), diisopropylethylamine at room temperature (17.1 mg, 0.132 mmol) was added in this order. The reaction solution was stirred at room temperature for 3 hours. After confirming the completion of the reaction, methyl-tert-butyl ether and 20% aqueous potassium phosphate solution were sequentially added, and the mixture was extracted with methyl-tert-butyl ether. The organic layer was washed with 20% aqueous potassium phosphate solution, 1N aqueous hydrochloric acid solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography (hexane / ethyl acetate) to obtain 65.8 mg (yield 87%, 99% ee) of the title compound as a pale yellow amorphous.

¹ H-NMR (CDCl ₃ ) δ: 0.86-1.02 (3H, m), 0.96 (3H, t, J = 7.3 Hz), 1.25-1.45 (3H, m), 1.31 (6H, d, J = 5.9 Hz), 1.62-1.71 (2H, m), 1.90 (3H, s), 2.47-2.58 (2H, m), 2.77-2.85 (1H, m), 3.37-3.88 (4H, m), 4.06-4.85 (3H, m), 4.52 (1H, sept, J = 5.9 Hz), 5.85 (1H, brs), 6.88 (2H, d, J = 9.0 Hz), 6.91 (1H, d, J = 8.6 Hz), 7.43 (2H, d, J = 9.0 Hz) , 7.45 (1H, d, J = 8.6 Hz), 7.51 (1H, s).

Comparative Example Comparison of physical property data with racemic compound (B) described in WO 2010/12581 pamphlet As a result of comparing physical property data with compound ((S) -B) and compound ((R) -B), Significant differences were observed in the NMR spectra.

The present invention provides a production method applicable to mass synthesis of the optically active hydantoin compound (1) represented by the general formula (1). Compound (1) has an LXRβ agonistic action, and atherosclerosis such as atherosclerosis, arteriosclerosis, and diabetes caused by diabetes; dyslipidemia; hypercholesterolemia; lipid-related disease; inflammation Inflammatory diseases caused by sex cytokines; skin diseases such as allergic skin diseases; diabetes; or Alzheimer's disease preventive and / or therapeutic agents, etc. Has the above applicability.

Claims

Formula (1):

[Wherein R 1 , R 2 and R 3 may be the same or different and each represents a C 1-3 alkyl group, * represents an asymmetric carbon atom, and R 4 represents

A method for producing an optically active compound represented by any one of the structures selected from:
i) Formula (2):

[Wherein R 4 and * are as defined above, and R 5 and R 6 may be the same or different and each represents a C 1-3 alkyl group] By reacting, the formula (3):

[Wherein R 4 and * are as defined above]
ii) a compound represented by formula (3) and formula (4):

[Wherein R 1 , R 2 , R 3 , * are as defined above] are reacted to produce a compound represented by the formula (1). Method.
The production method according to claim 1, wherein R 1 in the formula (1) is a propyl group, and R 2 and R 3 are methyl groups.
The compound represented by the formula (1) is (S) -3- (2-{(2S, 5R) -4- [4- (1,1,1,3,3,3-hexafluoro-2-hydroxy). Propan-2-yl) -2-propylphenyl] -2,5-dimethylpiperazin-1-yl} -2-oxoethyl) -5- [4- (1-methylethoxy) phenyl] -5-methylimidazolidine The production method according to claim 1 or 2, which is 2,4-dione.
Formula (3):

[Wherein, * represents an asymmetric carbon atom and R 4 represents

An optically active compound represented by the formula: or a salt thereof, or a solvate thereof.