WO2015029447A1 - Method for manufacturing optically active carbinol compound - Google Patents

Abstract

The present invention provides a method for manufacturing an optically active carbinol compound having LXR β-activating effects and a production intermediate thereof. In the present invention, an optically active carbinol compound represented by formula (1) is manufactured by reacting a compound represented by formula (2) with a compound represented by formula (3). In the formulas (1)-(3), R¹ represents a C2 to C3 alkyl group, R² and R³ can be the same or different and represent C1 to C3 alkyl groups, * represents an asymmetric carbon atom, and R⁴ represents a structure selected from A-E.

Description

Method for producing optically active carbinol compound

The present invention relates to a method for producing an optically active carbinol compound having an LXRβ activation effect 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 (ApoE, CETP, and LPL) involved in reverse cholesterol transport (RCT) 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 are found and a patent application has been filed (Patent Document 1). These compounds are all optically active 2- (4- (2,5-dimethylpiperazin-1-yl) -3-propylphenyl) -1,1,1,3,3,3-hexafluoropropane-2. -Common in that it has an all structure.

As a method for producing the compounds (A) to (J), for example, Patent Document 1 reports a method via production of a piperazine derivative (a13) as shown in the following reaction process diagram. That is, L-alanine methyl ester (a1) is used as a starting material and compound (a3) is obtained in 13 steps in 6 steps, or trans-2,5-dimethylpiperazine (b1) is used as a starting material in 21 steps in 4 steps and compound (a3) is obtained. The compound (a5) is produced by carrying out a coupling reaction with a separately produced benzoic acid ester (a4). After that, 8 steps are taken to carry out side chain construction and protection / deprotection reaction to produce a piperazine derivative (a13) as a common intermediate.

However, in the method of this document, the total yield is reduced to 13% at the stage of producing the intermediate (a3) from the starting material (a1) and the reduction reaction of the amide of the diketopiperazine (a2) It has been known that epimerization occurs and has a problem in reproducibility. In addition, since the production of (a13) from L-alanine methyl ester is as long as 15 steps in total, and since the starting material (a1) has an asymmetric center, asymmetry is controlled in all reaction steps. There was a problem such as being necessary. In the method using the compound (b2) which can selectively protect only one amino group of trans-2,5-dimethylpiperazine (b1), the preferential crystallization is performed using (L) or (D) -tartaric acid. The total yield is reduced to 21% at the stage of producing the intermediate (a3) by the optical resolution method, the theoretical yield is 50% or less, and trans-2,5-dimethyl Piperazine (b1) is very expensive in terms of market availability, and has problems such as being unsuitable for mass production as a starting material.

In addition, although a method for producing a phenylpiperazine derivative has been reported, there is no example in which both have a substituent on the benzene ring and the piperazine ring, and it cannot be applied to stereocontrol of the substituent on the piperazine ring (Non-patent Document 7). ) And extremely low yield (Patent Documents 2 and 3), and it is difficult to say that it is an efficient method for producing a compound having a substituent on both the benzene ring and the piperazine ring.

Moreover, as a method for producing a homopiperazine derivative, a method for producing a homopiperazine body in 6 steps from an amino alcohol body having a desired steric structure has been reported, but it is applicable when a plurality of asymmetric carbon atoms are contained. It is not mentioned whether it can be done (Non-patent Document 8).

WO2010 / 12581 WO2006 / 094842 WO2012 / 027261

The present invention relates to optically active 2- (4- (2,5-dialkylpiperazin-1-yl) -3-alkylphenyl) -1,1,1,3,3,3-hexafluoropropan-2-ol. It is an object of the present invention to provide a method for obtaining an optically active carbinol compound having an LXRβ selective activation action in high yield and high optical purity. The present invention also provides optically active 2- (4- (2,5-dialkylpiperazin-1-yl) -3-alkylphenyl) -1,1,1, which is useful as an intermediate for the production of optically active carbinol compounds. An object is to provide a 3,3,3-hexafluoropropan-2-ol compound.

As described above, producing an optically active carbinol compound efficiently and with high optical purity is considered to be very useful in the production of pharmaceuticals, particularly LXRβ selective activators. Therefore, as a result of intensive studies on a useful production method of the optically active carbinol compound represented by the compound (B), the present inventors protected the amino group of the amino alcohol compound (c1) as shown in the following figure. To compound (c2) using methanesulfonic acid chloride in the presence of a base to react with optically active 2-aminopropanol compound (c4) to obtain compound (c5). Protecting the amino group to give an amino alcohol form (c6), and cyclization reaction under Fukuyama-Mitsunobu reaction conditions to form a cyclic amine compound (c7) and deprotecting the 2-nitrobenzenesulfonyl group to form a piperazine form (C8), by reacting this with a benzoic acid ester (c9) to obtain a compound (c10), which is subjected to a Wittig reaction Compound (c11) is obtained by hydrogenating the unsaturated bond to give compound (c12), which is hydrolyzed to give compound (c13), which is reacted to give compound (c14). Compound (c15) is obtained by carbinolization reaction using methyltrimethylsilane, and the optically active 2- (4- (2,5-dimethylpiperazin-1-yl) -3 is obtained by deprotecting the piperazine compound. -Propylphenyl) -1,1,1,3,3,3-hexafluoropropan-2-ol compound (c16). Next, the hydantoin compound (c17) and the compound (c18) are alkylated to give a compound (c19), which is hydrolyzed to give a compound (c20), which is then condensed with the compound (c16). The present inventors have found that the optically active carbinol compound (B) can be obtained in a total of 16 steps with a yield of 17% without impairing the optical purity. The present invention has been completed based on this finding.

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

[In the formula, R ¹ may be a C _2-3 alkyl group, R ² and R ³ may be the same or different, 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:
Formula (2):

[Wherein R ¹ , R ² , R ³ , * are as defined above], a compound represented by formula (3):

[Wherein R ⁴ and * are as defined above] to react with a compound represented by formula (1) to produce a compound represented by formula (1).

[2]
Formula (1):

[In the formula, R ¹ may be a C _2-3 alkyl group, R ² and R ³ may be the same or different, 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) Equation (4):

[Wherein R ⁵ represents a C _1-3 alkyl group and X ¹ represents a halogen atom], and a compound represented by formula (5):

[Wherein 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 P ¹ represents an amino-protecting group] The compound is reacted to give the formula (6):

[Wherein P ¹ , R ² , R ³ , R ⁵ , * are as defined above], and then,
ii) An aldehyde represented by the formula (6) is converted into an olefin, and the formula (7):

[Wherein P ¹ , R ² , R ³ , R ⁵ , * are as defined above, R ⁶ represents a hydrogen atom or a methyl group, the wavy line is a single bond, The configuration of each double bond is independently an E configuration or a Z configuration, or a mixture thereof,
iii) Reduction of the olefin represented by formula (7) to form formula (8):

[Wherein P ¹ , R ² , R ³ , R ⁵ , R ⁶ , * are the same as defined above],
iv) hydrolysis of the ester represented by formula (8) to formula (9):

[Wherein P ¹ , R ² , R ³ , R ⁶ , * are as defined above], and then,
v) Converting the carboxylic acid represented by formula (9) into an acid halide, acid anhydride or ester to give formula (10):

[Wherein P ¹ , R ² , R ³ , R ⁶ , * are as defined above, and C (O) R ⁷ represents an acid halide, an acid anhydride, or an ester] And then
vi) A compound represented by formula (10) is reacted with a trifluoromethylating reagent to form formula (11):

[Wherein P ¹ , R ² , R ³ , R ⁶ , * are as defined above], and then,
vii) By deprotecting the protecting group P ¹ of the compound represented by the formula (11), the formula (2)

Wherein R ¹ , R ² , R ³ , and * are as defined above.

[3]
The method according to [1], further comprising producing the compound represented by formula (2) by the method according to [2].

[4]
i) Equation (12):

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

[Wherein R ² and * are as defined above, and P ² represents a protecting group for an amino group],
ii) A sulfonylation reaction of the hydroxyl group of the compound represented by the formula (13) is performed to obtain the formula (14):

[Wherein P ² and R ² are as defined above, and R ⁸ represents a trifluoromethyl group, a methyl group, a toluyl group, or a nitrophenyl group],
iii) Compound represented by formula (14) and formula (15):

[Wherein R ³ may be the same or different, each represents a C _1-3 alkyl group, and * has the same definition as above], and a compound represented by formula (16):

[Wherein P ² , R ² , R ³ and * are as defined above],
iv) protecting the amino group of the compound represented by the formula (16), the formula (17):

[Wherein P ¹ represents an amino-protecting group, and P ² , R ² , R ³ and * have the same definitions as above],
v) A cyclization reaction of the compound represented by the formula (17) is performed to obtain the formula (18):

[Wherein P ¹ , P ² , R ² , R ³ and * are as defined above],
vi) The method further comprises the step of producing the compound represented by the formula (5) by deprotecting the protecting group P ² of the compound represented by the formula (18) [2] or [3 ] The manufacturing method of description.

[5]
i) Equation (19):

[Wherein R ⁴ ,

A compound selected from the group consisting of a compound represented by formula (20):

[Wherein R ⁹ represents a C _1-3 alkyl group and X ² represents a halogen atom], and a compound represented by the formula (21):

[Wherein R ⁴ , R ⁹ , * are as defined above], and then,
ii) The method further comprises the step of producing a compound represented by the formula (3) by hydrolyzing the compound represented by the formula (21), [1], [3] and [4] The production method according to any one of [4].

[6]
The compound represented by the formula (1) is 3- (2-{(2S, 5R) -4- [4- (1,1,1,3,3,3-hexafluoro-2-hydroxypropane-2- Yl) -2-propylphenyl] -2,5-dimethylpiperazin-1-yl} -2-oxoethyl) -5- [4- (1-methylethoxy) phenyl] -5-methylimidazolidine-2,4- The production method according to any one of [1] to [5], which is dione.

[7]
Formula (2)

[Wherein R ¹ represents a C _2-3 alkyl group, R ² and R ³ represent the same or different C _1-3 alkyl group, and * represents an asymmetric carbon] and a compound thereof Salts or solvates 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. The asymmetric carbon of the 2,5-dimethylpiperazine compound (3) introduced as an asymmetric center can be constructed without epimerization by following this method. Further, other than the protecting group of one amino group of the 2,5-dimethylpiperazine compound (3), it can be constructed without using a protecting group. 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 (2), the C _1-3 alkyl group for R ¹ is preferably a propyl group.

In general formulas (1) to (2), (5) to (14) and (16) to (18), the C _1-3 alkyl group for R ² is preferably a methyl group.

In general formulas (1) to (2), (5) to (11) and (15) to (18), the C _1-3 alkyl group for R ³ is preferably a methyl group.

In general formulas (1), (3), (19) and (21), as R ⁴ ,

Is preferred.

In general formulas (4) and (6) to (8), the C _1-3 alkyl group for R ⁵ is preferably a methyl group.

In general formulas (7) to (11), R ⁶ is preferably a methyl group.

In general formula (10), examples of the acid halide in C (O) R ⁷ include acid fluorides and acid chlorides.

In general formula (10), examples of the acid anhydride in C (O) R ⁷ include aliphatic carboxylic acids such as acetic acid and acid anhydrides with aromatic carboxylic acids such as benzoic acid.

In general formula (10), examples of the ester in C (O) R ⁷ include an ester with an aliphatic alcohol such as methanol, an ester with an aromatic alcohol such as pentafluorophenol, and the like.

In the general formula (10), C (O) R ⁷ is preferably an ester, and more preferably a pentafluorophenoxycarbonyl group.

In general formula (14), the C _1-3 alkyl group for R ⁸ is preferably a methyl group.

In general formulas (20) and (21), the C _1-3 alkyl group for R ⁹ is preferably a methyl group.

In the present invention, the amino-protecting group includes tert-butoxycarbonyl group (Boc), benzyloxycarbonyl group (Cbz), 9-fluorenylmethyloxycarbonyl group (Fmoc), and 2,2,2-trichloroethoxy. Carbonyl group (Troc), allyloxycarbonyl group (Alloc), trifluoroacetyl group (CF ₃ CO—), phthaloyl group (Pht), p-toluenesulfonyl group (Ts), 2-nitrobenzenesulfonyl group (Ns), trityl Group (Tr) and the like.

In the general formulas (5) to (11), (17) and (18), the amino-protecting group P ¹ includes a tert-butoxycarbonyl group, a 9-fluorenylmethyloxycarbonyl group (Fmoc), 2, 2,2-trichloroethoxycarbonyl group (Troc), allyloxycarbonyl group (Alloc), trifluoroacetyl group (CF ₃ CO-), phthaloyl group (Pht), p-toluenesulfonyl group (Ts), 2-nitrobenzenesulfonyl A group (Ns) and a trityl group (Tr) are preferable, and a tert-butoxycarbonyl group is more preferable.

In the general formulas (13), (14), (16) to (18), the amino-protecting group P ² includes a tert-butoxycarbonyl group, a 9-fluorenylmethyloxycarbonyl group (Fmoc), 2, 2,2-trichloroethoxycarbonyl group (Troc), allyloxycarbonyl group (Alloc), trifluoroacetyl group (CF ₃ CO-), phthaloyl group (Pht), p-toluenesulfonyl group (Ts), 2-nitrobenzenesulfonyl The group (Ns), 4-nitrobenzenesulfonyl group (Ns) and trityl group (Tr) are preferable, and the 2-nitrobenzenesulfonyl group (Ns) is more preferable.

In the general formula (4), examples of the halogen atom X ¹ include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. A fluorine atom and a chlorine atom are preferable, and a fluorine atom is more preferable.

In the general formula (20), the halogen atom X ^2, a chlorine atom, a bromine atom, an iodine atom.

In the present invention, * represents an asymmetric carbon atom. The general formula (2) of the present invention includes the following (2a) to (2d):

The four structures shown below are included.

As raw materials for constructing the four steric structures (2a) to (2d) of the general formula (2), specifically, amino alcohol derivatives (12a), (12b), (15a) and (15b):

Can be used. (12a) and (15b) as raw materials for constructing the three-dimensional structure (2a); (12b) and (15a); (2c) three-dimensional structures as the raw material for constructing the three-dimensional structure (2b) (12b) and (15b) may be used as raw materials for constructing the three-dimensional structure of (12a) and (15a); (2d). Specific examples include (S)-(+)-2-amino-1-propanol, (R)-(−)-2-amino-1-propanol, (S)-(+)-2-amino-1- Butanol, (R)-(−)-2-amino-1-butanol, (S)-(+)-2-amino-1-pentanol, (R)-(−)-2-amino-1-pen Tanol, L-valinol, D-valinol and the like are sold by Aldrich, Tokyo Chemical Industry, Watanabe Chemical Industry, Wako Pure Chemical Industries, Kanto Chemical, Alfa Aesar, and the like.

As the three-dimensional structure of the general formula (2) of the present invention, (2a) or (2b) is preferable, and (2b) is particularly preferable.

As a particularly preferred structure of the general formula (2) of the present invention, there can be mentioned a compound in which the steric structure is (2b), R ¹ is a propyl group, and R ² and R ³ are methyl groups.

General formula (1) of the present invention has the following (1a) to (1h):

The eight structures shown below are included.

(2a) to (2d) can be used as raw materials for constructing the eight steric structures of the general formula (1) of the present invention. As raw materials for constructing the three-dimensional structure of (1a) and (1e), (2a); (2b); (1c) and (2c) as raw materials for constructing the three-dimensional structure of (1b) and (1f) As a raw material for constructing the three-dimensional structure of (1g), (2d) may be used as a raw material for constructing the three-dimensional structure of (2c); (1d) and (1h).

The steric structure of the general formula (1) of the present invention is preferably (1a), (1b), (1e), or (1f), more preferably (1b) or (1f). A preferred structure of the formula (1) is a compound in which R ¹ is propyl, R ² and R ³ are methyl groups, and R ⁴ is a 4- (1-methylethoxy) phenyl group.

In the general formula (7) of the present invention, the wavy line is a single bond, and the configuration of the double bond to which the wavy line is bonded is independently an E configuration, a Z configuration, or a mixture thereof. It shows that. The general formula (7) of the present invention is represented by the following (7a) and (7b):

It includes the two structures shown in.

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.

Step 1: This step is a step for producing a compound (13) by protecting the amino group of the compound (12). The protecting group represented by P ² can be protected with reference to, for example, literature (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.).

When P ² is a 2-nitrobenzenesulfonyl group, compound (13) can be produced by reacting compound (12) with 2-nitrobenzenesulfonyl chloride or the like in the presence or absence of a solvent in the presence of a base. . The solvent is not particularly limited, but N, N-dimethylformamide, tetrahydrofuran, dioxane, acetonitrile, nitromethane, acetone, ethyl acetate, benzene, chlorobenzene, toluene, chloroform, methylene chloride, and the like can be used. Among these, methylene chloride is preferable. . The base is not particularly limited, and organic bases such as triethylamine, diisopropylethylamine, pyridine, lutidine, and picoline; inorganic bases such as potassium carbonate and sodium carbonate can be used, and among these, triethylamine is preferable. 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 24 hours.

Step 2: This step is a step for producing a compound (14) by carrying out a sulfonylation reaction of the compound (13). Compound (14) is produced by adding compound (13) to a leaving group such as a sulfonyloxy group by adding a sulfonic acid halide reagent or an alkyl or aralkylsulfonic acid anhydride reagent in the presence of a base in a solvent. can do. As the solvent used in this reaction, N, N-dimethylformamide, tetrahydrofuran, dioxane, acetonitrile, nitromethane, acetone, ethyl acetate, benzene, chlorobenzene, toluene, chloroform, methylene chloride and the like can be used, among which tetrahydrofuran, dioxane Acetonitrile, benzene, chlorobenzene, toluene, chloroform and methylene chloride are preferred, and methylene chloride is particularly 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. Organic amines such as triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine, 2-picoline, 3-picoline, 4-picoline, 2,3-lutidine, 2,4- Preferred are lutidine, 2,5-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 2,3,5-collidine, 2,4,6-collidine, triethylamine, N-methylmorpholine 2,6-lutidine and 2,4,6-collidine are particularly preferred. The sulfonic acid halide reagent is not particularly limited, and for example, methanesulfonic acid chloride, benzenesulfonic acid chloride, p-toluenesulfonic acid chloride, 2-nitrobenzenesulfonic acid chloride and the like are preferable. The alkyl or aralkyl sulfonic acid anhydride reagent is not particularly limited, but for example, methane sulfonic acid anhydride and trifluoromethane sulfonic acid anhydride are preferable. The reaction conditions are −78 ° C. to 100 ° C., preferably 0 ° C. to 50 ° C., for 5 minutes to 48 hours, preferably 30 minutes to 24 hours.

Step 3: This step is a step for producing a compound (16) by reacting the compound (14) with an amino alcohol form (15) in a solvent in the presence or absence of a base. The solvent is not particularly limited. For example, tetrahydrofuran, toluene, dioxane, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, propionitrile, acetone, methyl ethyl ketone, etc. may be used alone or in combination. Of these, tetrahydrofuran and acetonitrile are preferred. Examples of the base include alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; lithium carbonate, sodium carbonate and carbonate Alkali metal carbonates such as potassium and cesium carbonate; metal salts of alcohols such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, tert-butoxy sodium and tert-butoxy potassium; lithium diisopropylamide, sodium diisopropylamide Metal amides such as potassium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide; n-butyllithium, sec-butyllithium, t Organometallic compounds such as rt-butyllithium; alkali metal halides such as lithium chloride, lithium bromide, lithium iodide, sodium chloride, sodium bromide, sodium iodide, potassium chloride, potassium bromide, potassium iodide Etc. 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 4: This step is a step for producing the compound (17) by protecting the amino group of the compound (16). The protecting group represented by P ¹ can be protected with reference to, for example, literature (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.).

When P ¹ is a tert-butoxycarbonyl group, compound (17) can be produced by reacting compound (16) with di-tert-butyl dicarbonate in the presence of a base in a solvent or without a solvent. it can. The solvent is not particularly limited, and N, N-dimethylformamide, tetrahydrofuran, dioxane, acetonitrile, nitromethane, acetone, ethyl acetate, benzene, chlorobenzene, toluene, chloroform, methylene chloride and the like can be used, among which acetonitrile, Tetrahydrofuran is preferred. The base is not particularly limited, and organic bases such as triethylamine, diisopropylethylamine, pyridine, lutidine, and picoline; inorganic bases such as potassium carbonate and sodium carbonate can be used. Among them, triethylamine and potassium carbonate are preferable. 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 24 hours.

Step 5: This step is a step for producing a piperazine derivative (18) by carrying out an intramolecular ring closure reaction of the compound (17). Compound (17) is introduced into a leaving group such as a sulfonyloxy group by adding a sulfonic acid halide reagent or an alkyl or aralkylsulfonic acid anhydride reagent in a solvent in the presence of a base to advance the cyclization reaction. Can produce the piperazine derivative (18). As the solvent, N, N-dimethylformamide, tetrahydrofuran, dioxane, acetonitrile, nitromethane, acetone, ethyl acetate, benzene, chlorobenzene, toluene, chloroform, methylene chloride and the like can be used, among which tetrahydrofuran, dioxane, acetonitrile, benzene, Chlorobenzene, toluene, chloroform and methylene chloride are preferred, and toluene and tetrahydrofuran are particularly 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. Organic amines such as triethylamine, N, N-diisopropylethylamine, pyridine, 2-picoline, 3-picoline, 4-picoline, 2,3-lutidine, 2,4-lutidine, 2,5- Preferred are lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 2,3,5-collidine, 2,4,6-collidine, pyridine, 2,6-lutidine, 2,4, 6-collidine is particularly preferred. The sulfonic acid halide reagent is not particularly limited, and for example, methanesulfonic acid chloride, benzenesulfonic acid chloride, p-toluenesulfonic acid chloride, 2-nitrobenzenesulfonic acid chloride and the like are preferable. The alkyl or aralkyl sulfonic acid anhydride reagent is not particularly limited, but for example, methane sulfonic acid anhydride and trifluoromethane sulfonic acid anhydride are preferable. The reaction conditions are −78 ° C. to 100 ° C., preferably −20 ° C. to 0 ° C., for 5 minutes to 24 hours, preferably 30 minutes to 12 hours.

In this step, the piperazine derivative (18) can also be produced by reacting the compound (17) in a solvent with a phosphine reagent and an azo reagent or ethylenedicarboxylic acid reagent. As the solvent, N, N-dimethylformamide, tetrahydrofuran, dioxane, acetonitrile, nitromethane, acetone, ethyl acetate, benzene, chlorobenzene, toluene, chloroform, methylene chloride and the like can be used alone or in combination. N-dimethylformamide, tetrahydrofuran, dioxane, acetonitrile and tetrahydrofuran / toluene are preferred, and N, N-dimethylformamide, tetrahydrofuran and tetrahydrofuran / toluene are particularly preferred. Examples of the phosphine reagent include trialkylphosphine such as trimethylphosphine, triethylphosphine, tripropylphosphine, triisopropylphosphine, tributylphosphine, triisobutylphosphine, tricyclohexylphosphine, and triarylphosphine, and triarylphosphine such as diphenylphosphinopolystyrene Examples include phosphine, among which trimethylphosphine, tributylphosphine, and triphenylphosphine are preferable. 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) and the like, with diisopropyl azodicarboxylate being particularly preferred. The reaction conditions are 0 ° C. to 100 ° C., preferably 0 ° C. to room temperature, 30 minutes to 1 day.

Process 6: This process is a process of manufacturing a compound (5) by deprotecting the amino group of a compound (18). The protecting group represented by P ² can be deprotected with reference to, for example, literature (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.).

When P ² is a 2-nitrobenzenesulfonyl group, compound (5) can be produced by reacting compound (18) with a thiol compound in the presence of a base in a solvent or without a solvent. The solvent is not particularly limited, and N, N-dimethylformamide, tetrahydrofuran, dioxane, acetonitrile, nitromethane, acetone, ethyl acetate, benzene, chlorobenzene, toluene, chloroform, methylene chloride and the like can be used. N-dimethylformamide and acetonitrile are preferred. Although there is no restriction | limiting in particular as a base, Inorganic bases, such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, can be used, and potassium carbonate is especially preferable. Examples of the thiol compound include benzenethiol and 1-dodecanethiol, and benzenethiol is preferable. The reaction conditions are −20 ° C. to 100 ° C., preferably 0 ° C. to 60 ° C., for 1 minute to 24 hours, preferably 5 minutes to 24 hours.

Step 7: This step is a step for producing a compound (6) by reacting the compound (4) with a compound (5) in a solvent in the presence or absence of a base. 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. 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 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 can be used, and triethylamine and N, N-diisopropylethylamine are particularly preferable. 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 8: This step is a step for producing a compound (7) by reacting the compound (6) with a Wittig reagent or Horner-Wadsworth-Emmons (HWE) reagent in a solvent in the presence or absence of a base. is there. As the solvent, N, N-dimethylformamide, tetrahydrofuran, dioxane, acetonitrile, nitromethane, acetone, ethyl acetate, benzene, chlorobenzene, toluene, chloroform, methylene chloride and the like can be used, among which tetrahydrofuran, ethyl acetate, toluene, Chloroform and methylene chloride are preferred. As the Wittig reagent, phosphonium salts such as stable ylides and unstable ylides (methyltriphenylphosphonium bromide, ethyltriphenylphosphonium bromide, etc.) 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, cesium iodide, and the like 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 9: This step is a step for producing a compound (8) by reacting the compound (7) 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 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C., for 1 minute to 5 days, preferably 1 hour to 3 days.

Step 10: This step is a step for producing a compound (9) by reacting the compound (8) in a solvent in the 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 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C., for 1 minute to 5 days, preferably 1 hour to 3 days.

Step 11: This step is a step of removing the compound (9) 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 a base. In this step, compound (10) is produced by the reaction below. The substituent represented by R ⁷ 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 ⁷ 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. Examples of the condensing agent include carbodiimide reagents such as dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC), and diisopropylcarbodiimide (DIPCDI). Among them, dicyclohexylcarbodiimide, Ethyl-3- (3-dimethylaminopropyl) carbodiimide is preferred. The base is not particularly limited, but 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, 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 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C., for 1 minute to 5 days, preferably 1 hour to 3 days.

Step 12: This step is a step for producing the compound (10) into the hexafluorocarbinol compound (11) using a trifluoromethylating reagent in a solvent in the presence of a base. As the solvent, dimethoxyethane, tetrahydrofuran, toluene, dioxane, ethylene glycol dimethyl ether, N, N-dimethylformamide, N-methylpyrrolidone, tetramethylurea, dimethyl sulfoxide, acetonitrile, propionitrile, etc. should be used alone or in combination. Among them, ethylene glycol dimethyl ether is 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 ° C. to 150 ° C., preferably −30 ° C. to 50 ° C., for 1 minute to 5 days, preferably 1 hour to 3 days.

Step 13: This step is a step of producing the compound (2) by deprotecting the amino group of the compound (11). 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 (2) can be produced by reacting compound (11) with an acid in a solvent or without a solvent. The solvent is not particularly limited, but N, N-dimethylformamide, tetrahydrofuran, dioxane, acetonitrile, nitromethane, acetone, ethyl acetate, benzene, chlorobenzene, toluene, chloroform, methylene chloride, water, methanol, ethanol, 1-propanol, 2 -Propanol or 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.

Step 14: This step is a step for producing a compound (21) by reacting the hydantoin derivative (19) and the compound (20) in a solvent in the presence or absence of a base. 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. 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; triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine, 3,4-lutidine, 2,6-lutidine, 2,4,6-collidine, etc. Organic amines 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.

The process for producing the imidazolidine-2,4-dione derivative (19) used in this step is described in German Patent No. 335993 or WO 2010/12581 (Patent Document 1). Lysine-2,4-dione derivatives can be produced.

In addition, the imidazolidine-2,4-dione derivative (19) used in this step is converted into a diastereomeric salt with a general optically active acid such as tartaric acid, or optically resolved, or optically active column chromatography is used. Can be led to optically pure isomers by general racemic resolution methods such as

Step 15: This step is a step for producing a compound (3) by reacting the compound (21) in a solvent in the 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, ethylene glycol dimethyl ether, water or methanol, Alcohols such as ethanol, 1-propanol and 2-propanol can be used alone or in combination. 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. 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 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C., for 1 minute to 5 days, preferably 1 hour to 3 days.

Step 16: This step comprises reacting compound (2) and compound (3) in a solvent in the presence of a condensing agent, in the presence or absence of a reaction accelerator, in the presence or absence of a base. This is a process for producing a carbinol derivative (1). As the solvent, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, dioxane, acetonitrile, nitromethane, acetone, ethyl acetate, benzene, chlorobenzene, toluene, chloroform, methylene chloride and the like can be used. Dimethyl sulfoxide, acetonitrile and methylene chloride are preferred. Examples of the condensing agent include 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 (dimethylamino) methylene] -1H- 1,2,3-triazolo (4,5-b) pyridium-3-oxodohexafluorophosphate (HATU), 1- [bis (dimethylamino) methylene] -1H-benzotriazolium-3-oxidehexa Fluorophosphate (HBTU), 1- [bis (dimethylamino) methylene] -1H-benzotriazolium-3-oxidetetrafluoroborate (TBTU), 1- [bis (dimethylamino) methylene] -5 Chloro-1H-benzotriazolium-3-oxide hexafluorophosphate (HCTU), 1- [bis (dimethylamino) methylene] -5-chloro-1H-benzotriazolium-3-oxide tetrafluoroborate ( And phosphonium salt type reagents such as TCTU), of which 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC), 1H-benzotriazol-1-yloxy) tris (dimethylamino) Phosphonium hexafluorophosphate (BOP), (1 H-benzotriazol-1-yloxy) tris (pyrrolidino) phosphonium hexafluorophosphate (PyBOP), 1- [bis (dimethylamino) methylene] -1H-1,2,3-triazolo (4,5-b) pyridium -3-Oxodohexafluorophosphate (HATU) and 1- [bis (dimethylamino) methylene] -1H-benzotriazolium-3-oxide hexafluorophosphate (HBTU) are preferred. Examples of the reaction accelerator include 1-hydroxybenzotriazole (HOBt), 6-chloro-1-hydroxybenzotriazole (6-Cl-HOBt), 3,4-dihydro-3-hydroxy-4-oxo-1,2 1,3-benzotriazine (HOOBt), 1-hydroxy-7-azabenzotriazole (HOAt) and the like can be used. 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; triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine, 3,4-lutidine, 2,6-lutidine, 2,4,6-collidine, etc. Organic amines 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.

This step can also be carried out by applying a Mitsunobu reaction in which the compound (2) and the compound (3) are reacted with an azo reagent or an ethylenedicarboxylic acid reagent in a solvent in the presence of a phosphine reagent. Can be manufactured. As the solvent, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, dioxane, acetonitrile, nitromethane, acetone, ethyl acetate, benzene, chlorobenzene, toluene, chloroform, methylene chloride and the like can be used. Examples of the phosphine reagent include trialkylphosphine such as trimethylphosphine, triethylphosphine, tripropylphosphine, triisopropylphosphine, tributylphosphine, triisobutylphosphine, tricyclohexylphosphine, and triphenylphosphine, diphenylphosphinopolystyrene, and the like. 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 ° C. to 150 ° C., preferably 0 ° C. 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 (2) in a solvent in the presence or absence of a base. Carbinol 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. 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; triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine, 3,4-lutidine, 2,6-lutidine, 2,4,6-collidine, etc. Organic amines 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.

Specific examples of salts allowed in the optically active compound represented by the general formula (2) 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 (2) of the present invention and acceptable salts thereof include hydrates and various solvates.

Hereinafter, the present invention will be described in more detail with reference to examples.
[Example]
Example: (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 (R) -N- (1-hydroxypropan-2-yl) -2-nitrobenzenesulfonamide (c2):
(R) -2-Aminopropan-1-ol (2.03 g, 29.8 mmol) was dissolved in dichloromethane (27 mL). Triethylamine (3.74 g, 36.9 mmol) and 2-nitrobenzene-1-sulfonyl chloride (6.0 g, 27.1 mmol) were added at 0 ° C., and the mixture was stirred at room temperature for 16 hours. After confirming the completion of the reaction, dichloromethane and water were added to the reaction solution at 0 ° C. Thereafter, the reaction solution was extracted with dichloromethane, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (8.58 g, yield> 99%). Obtained as a brown oil.

1H-NMR (CDCl ₃ ) δ: 1.14 (3H, d, J = 6.8 Hz), 3.49-3.53 (1H, m), 1.85 (1H, brs), 3.47-3.66 (3H, m), 5.48 (1H, d, J = 6.8 Hz), 7.72-7.79 (2H, m), 7.86-7.92 (1H, m), 8.15-8.20 (1H, m).

Step II: Preparation of methanesulfonic acid (R) -2- (2-nitrophenylsulfonamido) propyl (c3):
(R) -N- (1-hydroxypropan-2-yl) -2-nitrobenzenesulfonamide (8.58 g, 27.1 mmol) was dissolved in dichloromethane (90 mL). Triethylamine (4.10 g, 40.6 mmol) and methanesulfonyl chloride (2.98 g, 29.9 mmol) were added at 0 ° C., and the mixture was stirred 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 reaction solution was extracted with chloroform, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound 9.06 g (yield> 99%). Obtained as a brown oil.

1H-NMR (CDCl ₃ ) δ: 1.25 (3H, d, J = 6.8 Hz), 3.00 (3H, s), 3.84-3.94 (1H, m), 4.11-4.19 (2H, m), 5.54 (1H, d, J = 7.6 Hz), 7.74-7.80 (2H, m), 7.88-7.94 (1H, m), 8.14-8.20 (1H, m).

Step III: Preparation of N-[(R) -1-{[(S) -1-hydroxypropan-2-yl] amino} propan-2-yl] -2-nitrobenzenesulfonamide (c5):
Methanesulfonic acid (R) -2- (2-nitrophenylsulfonamido) propyl (9.06 g, 27.1 mmol) was dissolved in tetrahydrofuran (135 mL). (S) -2-Aminopropan-1-ol (10.2 g, 135 mmol) was added at room temperature, and the mixture was stirred for 15 hours under reflux. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure. The obtained residue was purified using silica gel column chromatography (chloroform / methanol) to obtain the title compound (5.14 g, yield 60%) as a yellow oily substance.

1H-NMR (CDCl ₃ ) δ: 1.17 (3H, d, J = 6.8 Hz), 1.26 (3H, d, J = 6.4 Hz), 2.51 (1H, dd, J = 6.8, 12.4 Hz), 2.74-2.66 (1H, m), 2.79 (1H, dd, J = 4.8, 12.4 Hz), 3.23 (1H, dd, J = 6.8, 10.8 Hz), 3.59-3.67 (1H, m), 3.72 (1H, dd, J = 3.8, 10.8 Hz), 7.72-7.77 (2H, m), 7.85-7.89 (1H, m), 8.14-8.19 (1H, m).

Step IV: Preparation of [(S) -1-hydroxypropan-2-yl] [(R) -2- (2-nitrophenylsulfonamido) propyl] carbamate tert-butyl (c6):
N-[(R) -1-{[(S) -1-hydroxypropan-2-yl] amino} propan-2-yl] -2-nitrobenzenesulfonamide (7.09 g, 22.3 mmol) Dissolved in tetrahydrofuran (110 mL). At 0 ° C., triethylamine (4.97 g, 49.1 mmol), di-tert-butyl dicarbonate (Boc ₂ O) (5.36 g, 24.6 mmol) were added. Then, it stirred at 0 degreeC for 15 minutes, and also stirred at room temperature all night. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography (chloroform / methanol) to give 7.55 g (yield 81%) of the title compound as an orange oil. Got as.

1H-NMR (CDCl ₃ ) δ: 1.06 (3H, d, J = 6.8 Hz), 1.16 (3H, d, J = 7.2 Hz), 1.48 (9H, s), 3.14-3.18 (1H, m), 3.29 -3.38 (1H, m), 3.60-3.73 (2H, m), 3.76-3.84 (2H, m), 7.71-7.73 (2H, m), 7.82-7.84 (1H, m), 8.12-8.16 (1H, m).

Step V: Preparation of 2,5-dimethyl-4-[(2-nitrophenyl) sulfonyl] piperazine-1-carboxylic acid (2S, 5R) -tert-butyl (c7):
[(S) -1-Hydroxypropan-2-yl] [(R) -2- (2-nitrophenylsulfonamido) propyl] carbamate tert-butyl (3.38 g, 8.08 mmol) under vacuum After drying, it was dissolved in tetrahydrofuran (54 mL) under an argon atmosphere. At 0 ° C., triphenylphosphine (3.18 g, 12.1 mmol) and diisopropyl azodicarboxylate (DIAD) (7.1 mL, 1.7 M toluene solution 12.1 mmol) were added, and 2 at room temperature. Stir for hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography (chloroform / methanol) to give 3.11 g (yield 96%) of the title compound as an orange oil. Got as.

1H-NMR (CDCl ₃ ) δ: 1.10 (3H, d, J = 6.8 Hz), 1.32 (3H, d, J = 6.8 Hz), 1.45 (9H, s), 3.26-3.50 (3H, m), 3.67 -3.81 (1H, m), 4.13-4.18 (1H, m), 4.26-4.46 (1H, m), 7.64-7.73 (3H, m), 8.04-8.05 (1H, m).

Step VI: Preparation of 2,5-dimethylpiperazine-1-carboxylic acid (2S, 5R) -tert-butyl (c8):
2,5-Dimethyl-4-[(2-nitrophenyl) sulfonyl] piperazine-1-carboxylic acid (2S, 5R) -tert-butyl (3.21 g, 8.04 mmol) in acetonitrile (47 mL) Dissolved. At room temperature, potassium carbonate (3.33 g, 24.1 mmol) and benzenethiol (1.33 g, 12.1 mmol) were added, and the mixture was stirred at 50 ° C. for 3 hours. After confirming the completion of the reaction, water was added to the reaction solution at 0 ° C. Thereafter, the reaction solution 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 (chloroform / methanol) to obtain 1.23 g (yield 72%) of the title compound as a yellow oil.

1H-NMR (CDCl ₃ ) δ: 1.17 (3H, d, J = 6.8 Hz), 1.21 (3H, d, J = 6.8 Hz), 1.45 (9H, s), 2.48 (1H, dd, J = 2.8, 13.0 Hz), 3.09-3.16 (1H, m), 3.19 (1H, dd, J = 5.2, 5.2 Hz), 3.22 (1H, dd, J = 4.6, 5.2 Hz), 3.54 (1H, dd, J = 1.6 , 13.0 Hz), 4.08-4.15 (1H, m).

Step VII: Preparation of 4- [2-formyl-4- (methoxycarbonyl) phenyl] -2,5-dimethylpiperazine-1-carboxylic acid (2S, 5R) -tert-butyl (c10):
Cesium fluoride (14.0 g, 91.89 mmol) was dried at 120 ° C. under reduced pressure for 2 hours, and N, N-dimethylformamide (52 mL) was added at room temperature under an argon atmosphere. Then, a solution of 2,5-dimethylpiperazine-1-carboxylic acid (2S, 5R) -tert-butyl (14.2 g, 61.26 mmol) in N, N-dimethylformamide (50 mL), 4-fluoro- 3-Formylbenzoic acid methyl ester (11.15 g, 61.26 mmol) was 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.

1H-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 VIII: 4- [4- (methoxycarbonyl) -2- (prop-1-en-1-yl) phenyl] -2,5-dimethylpiperazine-1-carboxylic acid (2S, 5R) -tert-butyl ( Production of c11):
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. It was. After stirring at 0 ° C. for 1.5 hours, 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 2.5 hours. 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 using 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-c11: 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-c11: 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 IX: Preparation of 4- [4- (methoxycarbonyl) -2-propylphenyl] -2,5-dimethylpiperazine-1-carboxylic acid (2S, 5R) -tert-butyl (c12):
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 using silica gel column chromatography (hexane / ethyl acetate) to give the title compound (4.72 g, yield 99%) as a colorless oil.

1H-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 X: Preparation of 4-[(2R, 5S) -4- (tert-butoxycarbonyl) -2,5-dimethylpiperazin-1-yl] -3-propylbenzoic acid (c13):
4- [4- (methoxycarbonyl) -2-propylphenyl] -2,5-dimethylpiperazine-1-carboxylic acid (2S, 5R) -tert-butyl (4.72 g, 12.09 mmol) was added to methanol ( 121N), 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) and added. 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 the title compound (4.48 g, yield 99%) as a colorless amorphous substance.

1H-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 XI: Preparation of 2,5-dimethyl-4- {4-[(perfluorophenoxy) carbonyl] -2-propylphenyl} piperazine-1-carboxylic acid (2S, 5R) -tert-butyl (c14):
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), and 2,3,4,5,6-pentafluorophenol (513 mg, 2.789 mmol), N, N′-dicyclohexylcarbodiimide (575 mg, 2.789 mol) in this order at room temperature. added. 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.

1H-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 XII: 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 (c15):
2,5-Dimethyl-4- {4-[(perfluorophenoxy) carbonyl] -2-propylphenyl} piperazine-1-carboxylic acid (2S, 5R) -tert-butyl (5.75 g, 10.6 mmol) After drying at 100 ° C. under reduced pressure 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 stirred at room temperature for 3.5 hours. 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 obtained residue was purified using silica gel column chromatography (hexane / ethyl acetate) to give the title compound (4.98 g, yield 90%) as a brown crystalline solid.

1H-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 XIII: 2- {4-[(2R, 5S) -2,5-dimethylpiperazin-1-yl] -3-propylphenyl} -1,1,1,3,3,3-hexafluoropropane-2 -Manufacture of all (c16):
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) dissolved in methanol (14 mL), 2N hydrochloric acid methanol solution (41 mL, 81.7 mmol) was added at 0 ° C., and 35 Stir at 5 ° C. for 5 hours. 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.

1H-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 XIV: 2- {4- [4- (1-methylethoxy) phenyl] -4-methyl-2,5-dioxoimidazolidin-1-yl} acetic acid (S) -methyl ((S) -c19) Manufacturing of:
Obtained by optical resolution of 5- [4- (1-methylethoxy) phenyl-4-yl] -5-methylimidazolidine-2,4-dione produced according to WO2009 / 144961 using the optical column described below. (S) -5- [4- (1-methylethoxy) phenyl-4-yl] -5-methylimidazolidine-2,4-dione (5.0 g, 20.1 mmol) was added to acetonitrile (50 mL). ) And potassium carbonate (3.06 g, 22.2 mmol) was added at room temperature, followed by addition of bromoacetic acid methyl ester (3.12 g, 20.1 mmol) at 0 ° C. And stirred for 36 hours. After confirming the completion of the reaction, the reaction solution was filtered, and the filtrate was washed with acetonitrile and concentrated under reduced pressure to obtain 6.05 g (yield> 99%) of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ ) σ: 1.33 (6H, d, J = 5.6 Hz), 1.87 (3H, s), 3.76 (3H, s), 4.25 (1H, d, J = 17.6 Hz), 4.29 ( 1H, d, J = 17.6 Hz), 4.54 (1H, sept, J = 5.6 Hz), 5.80 (1H, brs), 6.89 (2H, d, J = 8.8 Hz), 7.40 (2H, d, J = 8.8 Hz).

The above (S) -5- [4- (1-methylethoxy) phenyl-4-yl] -5-methylimidazolidine-2,4-dione can be obtained according to the following optical resolution conditions.
Column name: CHIRALPAK AD-H
Solvent: nHexane: EtOH = 40: 60
Flow rate: 0.1 mL / min
Retention time: (S) -isomer: 9.51 min ((R) -isomer: 4.51 min)

Step XV: (S) -2- {4- [4- (1-methylethoxy) phenyl] -4-methyl-2,5-dioxoimidazolidin-1-yl} acetic acid ((S) -c20) Manufacturing:
2- {4- [4- (1-methylethoxy) phenyl] -4-methyl-2,5-dioxoimidazolidin-1-yl} acetic acid (S) -methyl (6.05 g, 18.9 mmol) Was dissolved in methanol (30 mL), 2M aqueous potassium carbonate solution (18.9 mL, 37.8 mmol) was added at 0 ° C., and the mixture was stirred at 45 ° C. for 3 hr. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure to distill off methanol. Ethyl acetate was added to the resulting residue, and the mixture was extracted with ethyl acetate. Thereafter, an aqueous hydrochloric acid solution was added to the aqueous layer at 0 ° C. to adjust to pH = 2, and the mixture was extracted with ethyl acetate. The obtained organic layers were combined, adjusted to pH = 1, extracted with ethyl acetate, washed with phosphate buffer and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (5.20 g). (Yield 90%) was obtained as a colorless oil.

¹ H-NMR (CDCl ₃ ) σ: 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).

Step XVI-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 was dissolved at room temperature. -Dioxoimidazolidin-1-yl} acetic acid (169 mg, 0.552 mmol) was added. Then, O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HBTU) (228 mg, 0.602 mmol), diisopropyl at 0 ° C. Ethylamine (156 mg, 1.20 mmol) was added in that order. 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 obtained residue was purified using silica gel column chromatography (hexane / ethyl acetate) to give the title compound (294 mg, yield 85%) as a pale yellow amorphous product.

Step XVI-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 (100 mg, 0.326 mmol) 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 obtained residue was purified using silica gel column chromatography (chloroform / methanol) to obtain the title compound (176 mg, yield 78%) 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 7; 54.9 min)

[Comparative Example 1]

In the above synthesis method described in WO2010 / 12581, the piperazine compound (a3) can be synthesized by 6 steps 13%, 98% ee.

[Comparative Example 2]
The piperazine compound (a3) obtained in Comparative Example 1 can be used to synthesize the optically active carbinol compound (B) by the above synthesis method in WO2010 / 12581, but 12 steps from the piperazine compound (a3) (5.3%) is required, which is 0.7% of 18 steps from the optically active alanine methyl ester (a1). On the other hand, in the production method of the present invention, 10 steps (50%) are required from the piperazine compound (c8), and the final product (17% (99.0% ee) is obtained from the optically active alaninol compound (c1) in 16 steps. B) can be produced. From the above, it was experimentally confirmed that the present invention is a method for producing an optically active carbinol compound (1) having a high yield and high optical purity as compared with the method described in WO2010 / 12581.

The present invention provides a method for producing a high yield and high optical purity of the optically active carbinol 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 (7)

1. Formula (1):
   

   

   [In the formula, R ¹ may be a C _2-3 alkyl group, R ² and R ³ may be the same or different, 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:
   Formula (2):
   

   

   [Wherein R ¹ , R ² , R ³ , * are as defined above], a compound represented by formula (3):
   

   

   [Wherein R ⁴ and * are as defined above] to react with a compound represented by formula (1) to produce a compound represented by formula (1).
2. Formula (1):
   

   

   [In the formula, R ¹ may be a C _2-3 alkyl group, R ² and R ³ may be the same or different, 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) Equation (4):
   

   

   [Wherein R ⁵ represents a C _1-3 alkyl group and X ¹ represents a halogen atom], and a compound represented by formula (5):
   

   

   [Wherein R ² and R ³ may be the same or different and each represent a C _1-3 alkyl group, * represents an asymmetric carbon atom, and P ¹ represents a protecting group for an amino group] To formula (6):
   

   

   [Wherein P ¹ , R ² , R ³ , R ⁵ , * are as defined above], and then,
   ii) The aldehyde represented by the formula (6) is converted into an olefin, and the formula (7):
   

   

   [Wherein P ¹ , R ² , R ³ , R ⁵ , * are as defined above, R ⁶ represents a hydrogen atom or a methyl group, the wavy line is a single bond, The configuration of each double bond is independently E or Z configuration, or a mixture thereof]
   iii) Reduction of the olefin represented by formula (7) to form formula (8):
   

   

   [Wherein P ¹ , R ² , R ³ , R ⁵ , R ⁶ , * are the same as defined above],
   iv) hydrolysis of the ester of formula (8) to give formula (9):
   

   

   [Wherein P ¹ , R ² , R ³ , R ⁶ , * are as defined above], and then,
   v) Converting the carboxylic acid represented by formula (9) into an acid halide, acid anhydride or ester to give formula (10):
   

   

   [Wherein P ¹ , R ² , R ³ , R ⁶ , * are as defined above, and C (O) R ⁷ represents an acid halide, an acid anhydride, or an ester] And then
   vi) A compound represented by formula (10) is reacted with a trifluoromethylating reagent to give formula (11):
   

   

   [Wherein P ¹ , R ² , R ³ , R ⁶ , * are as defined above], and then,
   vii) By deprotecting the protecting group P ¹ of the compound represented by the formula (11), the formula (2)
   

   

   Wherein R ¹ , R ² , R ³ , and * are as defined above.
3. The method according to claim 1, further comprising producing the compound represented by the formula (2) by the method according to claim 2.
4. i) Equation (12):
   

   

   [Wherein R ² represents a C _1-3 alkyl group which may be the same or different, and * represents an asymmetric carbon atom], and the amino group of the aminoalcohol represented by formula (13) is protected:
   

   

   
   [Wherein R ² and * are as defined above, and P ² represents a protecting group for an amino group],
   ii) A sulfonylation reaction of the hydroxyl group of the compound represented by the formula (13) is performed to obtain the formula (14):
   

   

   [Wherein P ² and R ² are as defined above, and R ⁸ represents a trifluoromethyl group, a methyl group, a toluyl group, or a nitrophenyl group],
   iii) Compound represented by formula (14) and formula (15):
   

   

   [Wherein R ³ represents a C _1-3 alkyl group which may be the same or different, and * represents the same definition as described above] and a compound represented by the formula (16):
   

   

   [Wherein P ² , R ² , R ³ and * are as defined above],
   iv) protecting the amino group of the compound represented by the formula (16), the formula (17):
   

   

   [Wherein P ¹ represents an amino-protecting group, and P ² , R ² , R ³ and * have the same definitions as above],
   v) A cyclization reaction of the compound represented by the formula (17) is performed to obtain the formula (18):
   

   

   [Wherein P ¹ , P ² , R ² , R ³ and * are as defined above],
   characterized in that it further comprises a step of producing a compound represented by the formula (5) by deprotecting the protecting group P ² of the compound represented by vi) formula (18), in claim 2 or 3 The manufacturing method as described.
5. i) Equation (19):
   

   

   [Wherein R ⁴ is
   

   

   A compound selected from the group consisting of a compound represented by formula (20):
   

   

   [Wherein R ⁹ represents a C _1-3 alkyl group and X ² represents a halogen atom], and a compound represented by the formula (21):
   

   

   [Wherein R ⁴ , R ⁹ , * are as defined above], and then,
   The method according to claim 1, 3 or 4 further comprising the step of ii) producing a compound represented by formula (3) by hydrolyzing a compound represented by formula (21). The manufacturing method in any one.
6. The compound represented by the formula (1) is 3- (2-{(2S, 5R) -4- [4- (1,1,1,3,3,3-hexafluoro-2-hydroxypropane-2- Yl) -2-propylphenyl] -2,5-dimethylpiperazin-1-yl} -2-oxoethyl) -5- [4- (1-methylethoxy) phenyl] -5-methylimidazolidine-2,4- The production method according to any one of claims 1 to 5, which is dione.
7. Formula (2)
   

   

   [Wherein R ¹ represents a C _2-3 alkyl group, R ² and R ^{3 each} represent the same or different C _1-3 alkyl group, and * represents an asymmetric carbon atom] The salt or solvate thereof.