JPWO2019189717A1 - Method for producing tetrahydronaphthylurea derivative - Google Patents

Abstract

Provided is a novel method for producing a compound represented by the formula (I). The present invention describes a method for producing a compound represented by the formula (I), a compound represented by the formula (EP-1) which is an intermediate for producing the compound represented by the formula (I), and a formula ( A method for producing a compound represented by AM-X) is provided.

Description

The present invention is for producing a method for producing a tetrahydronaphthylurea derivative having a tropomyosin receptor kinase A (TrkA) inhibitory action represented by the following Cheme 7 formula (I), and for producing a compound represented by the formula (I). The present invention relates to a compound represented by the formula (EP-1), which is an intermediate of the above, and a method for producing a compound represented by the formula (AM-X).

The tetrahydronaphthylurea derivative represented by the formula (I) is produced by a urea conversion reaction using an amino compound represented by the formula (AM-1) and an amine salt represented by the formula (AM-2-RRS). (Scheme 1) (Patent Document 1).

As shown in (Scheme 2), the amine salt represented by the formula (AM-2-RRS) is obtained through two steps using the compound represented by the formula (TH-1) as a starting material (RAM-2). ) Is converted to a salt represented by the formula (RAM-2-S) with D-tartaric acid, and then the compound can be produced by fractional recrystallization.

Although the production method using the fractional recrystallization is excellent in that the formula (AM-2-RRS) can be obtained as a compound having high optical purity, other isomers after division (for example, (1S, 2S)) are obtained. , Etc.) is a problem that it is difficult to reuse the compound, and an improved production method thereof is required for mass synthesis or industrial production of the compound represented by the formula (I). That is, when considering mass synthesis or industrial production of the compound represented by the formula (I), a novel manufacturing method different from the manufacturing method using an amine salt represented by the formula (AM-2-RRS) is found. In particular, it is an amine salt that can be used in the urea conversion reaction of Cheme 1 instead of the amine salt represented by the formula (AM-2-RRS), and is compared with the formula (AM-2-RRS). There is a demand for a compound that can easily reuse other isomers after fractional recrystallization.

(1R, 2R) -1-amino-4, which is one of the equivalents of the amine salt represented by the formula (AM-2-RRS) and is a compound having p = 0 in the following formula (AM-X). A method for producing 4-dimethyl-1,2,3,4-tetrahydronaphthalene-2-ol is disclosed in International Publication No. 2014/078454 (p165, IntermediateX2). However, since the production method is a column division method using a chiral column of the compound represented by the formula (RAM-2), the corresponding isomer (formula (AM-Y)) can be obtained even when the method is used. In that it cannot be reused, the production method is also a production method for which the above-mentioned problems have not been solved, and is not a production method capable of mass-synthesizing or industrially producing a compound represented by the formula (AM-X) (Schem 3). .. (Patent Document 2)

Therefore, since a production method for mass-synthesizing the compound represented by the formula (AM-X) in high yield and high optical purity is not yet known, the compound represented by the formula (AM-X) can be prepared in a short step. It is considered that the above-mentioned problems can be solved if a manufacturing method for mass synthesis with high chemical yield and high optical purity can be found. Further, a new production method using a compound represented by the formula (AM-X) represented by (Scheme 4) makes it possible to obtain the compound of the formula (I) in a large amount or at an industrial production level. It was desired.

[In Schema 4, p, R ¹ , Y and ring A are the same groups as those defined in the first aspect of the invention described below].

As shown in the following (Scheme 5), a method for synthesizing a compound represented by the formula (EP-1), which can be a synthetic intermediate for the compound represented by the formula (AM-X), is Chemistry Letters, (11), It is disclosed in P2231-4, 1992 (Non-Patent Document 1), or Bulletin of the Chemical Society of Japan, 67 (8), p2248-56, 1994 (Non-Patent Document 2). However, the synthesis method is an oxidation reaction using an oxygen gas or a manganese catalyst and is not suitable for mass synthesis. Furthermore, the chemical yield is as low as 35% and the optical purity is as low as 63%, which is low for use as a pharmaceutical raw material. Therefore, this reaction condition is not used in the mass synthesis or industrial production of the compound represented by the formula (AM-X). Moreover, the asymmetric aminohydroxylation reaction to the formula (AM-X) using the formula (EP-1) is not known. (However, p = 0 in the above formulas (AM-X), (EP-1), and formula (REP-1))

尚、本発明の式（ＴＨ−１）で表わされる化合物とは異なるが、式（ＴＨ−２）で表わされる化合物（式（ＴＨ−１）において、Ｐ＝０、１，２−ジヒドロナフタレン環の１位のジメチル基を除去した化合物）に対して、過酸化水素及びチタン触媒を用いる酸化反応が、Synlett,20,p3545-3547,2006年（非特許文献３）、又はSynlett,15,p2445-2447,2007年（非特許文献４）に開示されている（Ｓｃｈｅｍｅ ６）。

Although different from the compound represented by the formula (TH-1) of the present invention, the compound represented by the formula (TH-2) (in the formula (TH-1), P = 0, 1,2-dihydronaphthalene ring). The oxidation reaction using hydrogen peroxide and a titanium catalyst with respect to the compound from which the dimethyl group at the 1-position of the above was removed was Synlett, 20, p3545-3547, 2006 (Non-Patent Document 3), or Synlett, 15, p2445. -2447, disclosed in 2007 (Non-Patent Document 4) (Scheme 6).

International Publication No. 2018/199166 Pamphlet International Publication No. 2014/078454 Pamphlet

Chemistry Letters, (11), P2231-4, 1992. Bulletin of the Chemical Society of Japan, 67 (8), p2248-56, 1994. Synlett, 20, p3545-3547, 2006. Synlett, 15, p2445-2447, 2007.

An efficient production method suitable for mass synthesis or industrial production of the tetrahydronaphthylurea derivative represented by the formula (I), particularly in the mass synthesis or industrial production of the derivative, the above formula (RAM-2) is used. It is represented by the formula (I), which is different from the method for producing the compound represented by the formula (I) via the fractional recrystallization method of the represented compound, that is, the compound represented by the formula (AM-X) is used. An object of the present invention is to provide a novel production method for the compound to be used, and a production method for mass-synthesizing a compound represented by the formula (AM-X) with high chemical yield and high optical purity.

The present inventors have conducted extensive research in order to solve the above problems. As a result, in the following (Scheme 7), an asymmetric epoxidation reaction is carried out using a compound represented by the formula (TH-1) as a starting material, hydrogen peroxide as an oxygen source, and a titanium catalyst. , It has been found that an epoxy compound having a desired configuration represented by the formula (EP-1) can be obtained with a high chemical yield and high optical purity. Further, it has been found that the compound represented by the formula (AM-X) can be obtained with high chemical yield and high optical purity by the subsequent aminohydroxylation reaction. We have found a method for producing a compound of formula (AM-X), which can suppress the formation of isomers of the compound of formula (AM-X) by these continuous reactions. Furthermore, due to the urea conversion reaction with the compound of the formula (CB-1) derived from the amino compound represented by the formula (AM-1), the chemical yield is good, the optical purity is high, the process is short, and the process is easy. A method for producing a tetrahydronaphthylurea derivative represented by the following formula (I) has been found, and the present invention has been completed based on these findings.

[In Schema 7, p, R ¹ , Y and ring A are the same groups as those defined in the first aspect of the invention described below].

In the present specification, the structure of ring A is the following formula: 5-methyl-6- (2-methylpyrimidine-5-yl) -2-phenylpyridine-3-yl group.

The present invention relates to a method for producing a tetrahydronaphthylurea derivative having a tropomyosin receptor kinase A (TrkA) inhibitory action represented by the formula (I), and (1R, 2R) -1 represented by the formula (AM-X). The present invention relates to a production method for mass-synthesizing a −amino-4,4-dimethyl-1,2,3,4-tetrahydronaphthalene-2-ol derivative with high yield and high optical purity. The present invention uses an intermediate used in the production of a tetrahydronaphthylurea derivative having a tropomyosin receptor kinase A (TrkA) inhibitory action represented by the following formula (I) with good chemical yield and high optical activity purity. It is possible to provide a novel method for manufacturing in a short process, easily, and in an industrially advantageous method, and is highly industrially useful.

The present invention is a tetrahydronaphthylurea derivative represented by the following formula (I) represented by the following embodiment, represented by the formula (AM-X) (1R, 2R) -1-amino-4,4-dimethyl-. The present invention relates to a method for producing a 1,2,3,4-tetrahydronaphthalene-2-ol derivative and an epoxy derivative represented by the formula (EP-1). More specifically, exemplary embodiments of the present invention may be as follows [1]-[5].

[1] In the following (Scheme 7) [(Scheme 7), p, R ¹ , Y, and ring A are the same groups as those defined in the first aspect of the present invention described later; The reaction conditions of each step are the same as the reaction conditions of each step in the first aspect of the present invention described later], the method for producing a compound represented by the formula (I).

[2] In (Scheme 8) below [In (Scheme 8), p and R ¹ are the same groups as those defined in the second aspect of the present invention described later; the reaction conditions of each step are , The same as the reaction conditions of each step in the second aspect of the present invention described later], a method for producing a compound represented by the formula (AM-X).

[3] In the following (Scheme 9) [(Scheme 9), p, and R ¹ are the same groups as those defined in the third aspect of the present invention described later; reaction conditions of each step. Is the same as the reaction conditions of each step in the third aspect of the present invention described later], the method for producing a compound represented by the formula (EP-1).

[4] In (Scheme 10) below [In (Scheme 10), p and R ¹ are the same groups as those defined in the fourth aspect of the present invention described later; the reaction conditions of each step are , The same as the reaction conditions of each step in the fourth aspect of the present invention described later], a method for producing a compound represented by the formula (AM-X).

[5] in the following (Scheme 4) in [(Scheme 4), p, R 1, Y and Ring A is the same group as the group defined in the fifth aspect of the present invention to be described later; the The reaction conditions of the steps are the same as the reaction conditions of each step in the fifth aspect of the present invention described later], the method for producing a compound represented by the formula (I).

[Aspects of the present invention]
More specifically, the exemplary embodiment of the present invention can be as follows [1] to [5].
[1] The first aspect of the present invention is the following formula (I):

[In formula (I), p is an integer chosen from 0, 1, and 2; R ¹ is a halogen atom, a cyano group, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, a hydroxy. C _1-6 alkyl group, cyanated C _1-6 alkyl group, C _1-6 alkoxy group, halogenated C _1-6 alkoxy group, C _1-6 alkoxy C _1-6 alkyl group, mono / di C _{2- It is a substituent selected from 7} alkanoylamino group, carboxamide group, and C _1-6 alkoxycarbonyl group; ring A is 5-methyl-6- (2-methylpyrimidine-5-yl) -2-phenylpyridine-. 3-Il group], which is a method for producing a compound represented by the following steps:
(1) The following formula (TH-1):

In the formula (TH-1), p and R ¹ are the same as the definitions in the formula (I)], and a titanium catalyst (for example, titanium tetrachloride, titanium tetrabromide, titanium). Alkoxide (Titanium Tetramethoxyde, Titanium Tetraethoxydo, Titanium Tetranormal Propoxide (Ti (OCH ₂ CH ₂ CH ₃ ) ₄ ), Titanium Tetraisopropoxide (Ti (OCH (CH ₃ ) ₂ ) ₄ ), Titanium Tetra Normal butoxide (Ti (OCH ₂ CH ₂ CH ₂ CH ₃ ) ₄ ), Titanium tetraterlybutoxide (Ti (OC (CH ₃ ) ₃ ) ₄ ), etc.) and the following formula as a ligand (LG-1) ):

3,3''-((((1R, 2R) -cyclohexane-1,2-diyl) bis (azaneyl)) bis (methylene)) bis (2'-methoxy- [1,1'-biphenyl) ] -2-ol) [CAS number: 928769-12-4], hydrogen peroxide solution (eg, about 30-60% concentration), and buffer solution (eg, citrate / NaOH buffer, citrate / quen). Sodium acid acid buffer, phosphate buffer, KH ₂ PO ₄ / NaOH buffer, Tris (hydroxymethyl) aminomethane (Tris) / HCl buffer, boric acid / NaOH buffer, Na borate / HCl buffer, etc. ), And a solvent (for example, a solvent not involved in the reaction, preferably an organic solvent, more preferably a halogenated hydrocarbon solvent such as dichloromethane, 1,2-dichloroethane, chlorobenzene, fluorobenzene, etc., and an aroma such as benzene, toluene). A step of obtaining a mixed solution (1) by adding it to a group hydrocarbon solvent, an ester solvent such as ethyl acetate, an ether solvent such as tetrahydrofuran, and a nitrile solvent such as acetonitrile, (2) the mixed solution (1). The reaction was carried out at a reaction temperature (outside temperature) of 30 ° C. to 50 ° C., preferably a temperature in the range of 35 to 45 ° C., and the following formula (EP-1):

A step of obtaining a compound represented by [in the formula (EP-1), p and R ¹ are the same as the definitions in the above formula (I)], (3) represented by the above formula (EP-1). To obtain a mixed solution (3) containing the compound represented by the formula (EP-1) and aqueous ammonia, (4) the mixed solution (3) was added from 0 ° C. to the above-mentioned compound. The reaction was carried out at any temperature up to the temperature at which the mixed solution (3) refluxed, and the following formula (AM-X):

The step of obtaining the compound represented by [in the formula (AM-X), p and R ¹ are the same as the definitions in the above formula (I)].
(5) The following formula (AM-1):

[In the formula (AM-1), ring A is a 5-methyl-6- (2-methylpyrimidine-5-yl) -2-phenylpyridine-3-yl group], and triphosgene. Hosgene, trichloromethyl chlorophosphate, 2,2,2-trichloroethylchloroformate, phenylchlorophosphate, p-nitrophenyl chloroate, p-tolyl chlorogitate, N, N'-carbonyldiimidazole, and N, N' A step of adding a urelating agent selected from −discusin imidazole carbonate or the like and a base to a solvent to obtain a mixed solution (5), (6) the mixed solution (5) from 0 ° C. to the mixed solution. The reaction was carried out at any temperature up to the temperature at which (5) refluxed, and the following formula (CB-1):

[In formula (CB-1), ring A is a 5-methyl-6- (2-methylpyrimidine-5-yl) -2-phenylpyridine-3-yl group; Y is a trichloromethoxy group, chlorine. Atom, 2,2,2-trichloroethoxy group, phenoxy group, p-nitrophenoxy group, p-methylphenoxy group, imidazol-1-yl group, (2,5-dioxopyrrolidine-1-yl) oxy group, The compound represented by the above formula (CB-1) and the compound represented by the formula (AM-X) obtained in the step (7) of the step (4) and the step of obtaining the compound represented by the above formula (CB-1). And (8) the step of adding the base to the solvent to obtain the mixed solution (7), and (8) the mixed solution (7) from 0 ° C. to the temperature at which the mixed solution (7) is refluxed. This is a production method including a step of carrying out a reaction at the temperature of (I) to obtain a compound represented by the formula (I).
Here, the above formula (AM-1) is 5-methyl-6- (2-methylpyrimidine-5-yl) -2-phenylpyridine-3-amine shown below.

[1-1-1] In the step (1) of the above aspect [1], the amount of hydrogen peroxide solution is preferably 1.5 to 10 equivalents with respect to 1 equivalent of the formula (TH-1). In the range of; more preferably in the range of 1.5 to 5 equivalents; particularly preferably in the range of 1.5 or 5.0 equivalents. Here, "equal amount" means that the molar ratio is 1: 1. That is, when the amount of hydrogen peroxide solution is 1.5 to 10 equivalents with respect to 1 equivalent of the formula (TH-1), the amount of hydrogen peroxide solution is 1: 1.5 to the molar ratio. It means 1:10.

[1-1-2] In the step (1) of the above aspect [1], it is preferable to use a hydrogen peroxide solution having a concentration of about 30%.

[1-2-1] In the step (1) of the above aspect [1], the titanium catalyst is preferably titanium tetramethoxyde, titanium tetraethoxydo, titanium tetranormal propoxide, titanium tetraisopropoxide, titanium tetra. It is normal buttoxide, or titanium tetraterlary butoxide; more preferably titanium tetraisopropoxide.

[1-2-2] In the step (1) of the above aspect [1], the amount of the titanium catalyst is preferably in the range of 0.1 to 10 mol% with respect to the formula (TH-1); more preferably. It is in the range of 1.0 to 5.0 mol%; particularly preferably 1.0, 3.0, or 5.0 mol%.

[1-3] In the step (1) of the above aspect [1], the ligand is preferably in the range of 0.1 to 12 mol% with respect to the formula (TH-1); more preferably 1 It is in the range of .2 to 6.0 mol%; particularly preferably 1.2, 3.6, or 6.0 mol%.

[1-4] In the step (1) of the above aspect [1], the solvent is preferably a solvent that does not participate in the reaction, more preferably an organic solvent, and further preferably dichloromethane, 1,2-dichloroethane. , A halogenated hydrocarbon solvent such as chlorobenzene and fluorobenzene, an aromatic hydrocarbon solvent such as toluene, an ester solvent such as ethyl acetate, and an ether solvent such as tetrahydrofuran; more preferably dichloromethane.

[1-5] In the step (1) of the above aspect [1], the amount of the solvent (solvent not involved in the reaction) is preferably 1 to 20 times the mass of the formula (TH-1). It is in the range; more preferably in the range of 5 to 20 times the amount; particularly preferably in the range of 5 or 20 times the amount.

[1-6-1] In the step (1) of the above aspect [1], the buffer solution is preferably citric acid / NaOH buffer solution, citric acid / sodium citrate buffer solution, boric acid / NaOH buffer solution, phosphorus. Acid buffer, KH ₂ PO ₄ / NaOH buffer; more preferably phosphate buffer, KH ₂ PO ₄ / NaOH buffer; particularly preferably phosphate buffer. The pH of the reaction solution or the like can be adjusted with the buffer solution.
[1-6-2] In the step (1) of the above aspect [1], the pH of the reaction solution is preferably pH = 7.4 to 8.0; more preferably pH = 7.4, Or pH = 8.0.

[1-7-1] In the step (2) of the above aspect [1], the reaction time is preferably 20 hours or less; more preferably 4.0 hours or less.

[1-8-1] The reaction in step (4) of the above aspect [1] is preferably a sealing reaction using a sealing reaction bottle.

[1-8-2] The reaction temperature of the sealed tube reaction of the above aspect [1-8-1] is preferably 100 ° C.

[1-8-3] The preferable reaction time of the sealing reaction of the above aspect [1-8-1] is 2 hours.

[1-9] In the step (5) of the above aspect [1], the urea agent is preferably phenylchloroformate, p-tolyl chloroformate, or 2,2,2-trichloroethylchloroformate; More preferably, it is 2,2,2-trichloroethylchloroformate.

[1-10] In the step (5) of the above aspect [1], the base is preferably pyridine, triethylamine, or N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-. Organic bases such as undecene (DBU), inorganic bases such as sodium hydrogen carbonate, sodium carbonate, or potassium carbonate, metal alkoxides such as potassium tert-butoxide, sodium tert-butoxide, etc., sodium hydride, potassium hydride, or hydrogen. Metal hydride compounds such as calcium hydride, alkyl lithium such as methyl lithium or butyl lithium, lithium amides such as lithium hexamethyldisilazide, or lithium diisopropylamide, or mixtures thereof; more preferably pyridine. Is.

[1-11] In the step (5) of the above aspect [1], the solvent is preferably an aproton polar solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, or acetonitrile, diethyl ether. , Tetrahydrofuran, dimethoxyethane, or ether solvent such as 1,4-dioxane, ester solvent such as ethyl acetate or propyl acetate, chlorine solvent such as dichloromethane, chloroform, or 1,2-dichloroethane, or theirs. It is a mixed solvent or the like; more preferably 1,2-dichloroethane.

[1-12] In the step (6) of the above aspect [1], Y in the formula (CB-1) is preferably a phenoxy group, a p-methylphenoxy group, or a 2,2,2-trichloroethoxy group. More preferably, it is a 2,2,2-trichloroethoxy group.

[1-13] In the step (7) of the above aspect [1], the solvent is preferably an aproton polar solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, or acetonitrile, diethyl ether. , Tetrahydrofuran, dimethoxyethane, or ether solvent such as 1,4-dioxane, ester solvent such as ethyl acetate or propyl acetate, chlorine solvent such as dichloromethane, chloroform, or 1,2-dichloroethane, or theirs. A mixed solvent or the like; more preferably N-methylpyrrolidone and dimethyl sulfoxide.

[1-14] In the step (7) of the above aspect [1], the base is preferably pyridine, triethylamine, or N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-. Organic bases such as undecene (DBU), inorganic bases such as sodium hydrogen carbonate, sodium carbonate, or potassium carbonate, metal alkoxides such as potassium tert-butoxide, sodium tert-butoxide, etc., sodium hydride, potassium hydride, or hydrogen. Metal hydride compounds such as calcium tert, alkyl lithium such as methyl lithium or butyl lithium, lithium amides such as lithium hexamethyldisilazide, or lithium diisopropylamide, or mixtures thereof; more preferably triethylamine. And 1,8-diazabicyclo [5.4.0] -7-undecene (DBU).

[1-15] In each of the formulas of the above aspect [1], p is preferably an integer of 0 or 1, and more preferably an integer of 0.

[1-16] In each of the formulas of the above aspect [1], R ¹ is preferably a halogen atom, a hydroxy C _1-6 alkyl group, a C _1-6 alkoxy group, and a C _1-6 alkoxy C _1-6. It is a substituent selected from an alkyl group, a carboxamide group, and a C _1-6 alkoxycarbonyl group; more preferably a halogen atom or a C _1-6 alkoxy C _1-6 alkyl group; even more preferably a hydrogen atom. , Fluorine atom, bromine atom, or methoxymethyl group may be substituted with one or two substituents; particularly preferably unsubstituted.

２個の置換基がＲ¹によって置換する場合の部分構造式は、下記部分構造式（ＰＨ−５）ないし式（ＰＨ−１０））で表わされる置換様式をとり；

より好ましくは、１個の置換基がＲ¹によって置換する場合（ｐ＝１）は、下記部分構造式：

で表わされる置換様式をとり；より具体的な置換基との組み合わせとしては、下記部分構造式：

から選ばれる置換様式をとる。
２個の置換基がＲ¹によって置換する場合（ｐ＝２）は、下記部分構造式：

で表わされる置換様式をとり；
より具体的な置換基との組み合わせとしては、下記部分構造式：

の置換様式をとる。[1-17] In each of the formulas of the above aspect [1], the substitution mode of ^{R 1} is preferably the following partial structural formula (p = 1) when ^{one substituent is substituted by R 1 (p = 1).} It takes a substitution mode represented by PH-1) to the formula (PH-4);

When two substituents are ^{substituted by R 1} , the partial structural formula takes the substitution mode represented by the following partial structural formulas (PH-5) to (PH-10));

More preferably, when one substituent is ^{substituted by R 1} (p = 1), the following partial structural formula:

The substitution mode represented by is taken; as a combination with a more specific substituent, the following partial structural formula:

Take the replacement style chosen from.
When two substituents are ^{substituted by R 1} (p = 2), the following partial structural formula:

Takes the substitution form represented by;
As a more specific combination with a substituent, the following partial structural formula:

Take the replacement form of.

[1-18] In the step (1) of the above aspect [1], the amount of the hydrogen peroxide solution is preferably in the range of 1.5 to 5 equivalents with respect to 1 equivalent of the formula (TH-1). The amount of titanium catalyst is in the range of 1.0-5.0 mol% relative to formula (TH-1); the ligand is 1.2 relative to formula (TH-1). In the range of ~ 6.0 mol%; the titanium catalyst is titanium tetraisopropoxide; the buffer is a phosphate buffer; the solvent (solvent not involved in the reaction) is dichloromethane; the solvent (reaction). The amount of solvent not involved in the reaction is in the range of 5 to 20 times the mass of the formula (TH-1); the pH of the reaction solution is pH = 7.4 to 8.0; the reaction. The time is 20 hours or less.

[1-19] In the step (1) of the above aspect [1], more preferably, the amount of the hydrogen peroxide solution is 1.5 or 5.0 equal to 1 equal amount of the formula (TH-1). The amount of titanium catalyst is 1.0 or 3.0 mol% relative to formula (TH-1); the ligand is 1.2 or 3.6 mol% relative to formula (TH-1). %; The titanium catalyst is titanium tetraisopropoxide; the buffer is a phosphate buffer; the solvent (solvent not involved in the reaction) is dichloromethane; the solvent (solvent not involved in the reaction) The amount is 5 times the amount; the pH of the reaction solution is pH = 7.4 or pH = 8.0; the reaction time is 4 hours or less.

[2] A second aspect of the present invention is the following formula (AM-X):

[In formula (AM-X), p is an integer chosen from 0, 1, and 2; R ¹ is a halogen atom, a cyano group, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group. , Hydroxy C _1-6 alkyl group, cyanated C _1-6 alkyl group, C _1-6 alkoxy group, halogenated C _1-6 alkoxy group, C _1-6 alkoxy C _1-6 alkyl group, mono / di C _{A substituent selected from a 2-7} alkanoylamino group, a carboxamide group, and a C _1-6 alkoxycarbonyl group], which is a method for producing a compound represented by the following steps:
(1) The following formula (TH-1):

[In the formula (TH-1), p and R ¹ are the same as the definitions in the above formula (AM-X)], and a titanium catalyst (for example, titanium tetrachloride, titanium tetrabromide). , Titanium alkoxide (Titanium tetramethoxyde, Titanium tetraethoxydo, Titanium tetranormal propoxide (Ti (OCH ₂ CH ₂ CH ₃ ) ₄ ), Titanium tetraisopropoxide (Ti (OCH (CH ₃ ) ₂ ) ₄ ), Titanium Tetranormal Butoxide (Ti (OCH ₂ CH ₂ CH ₂ CH ₃ ) ₄ ), Titanium Tetrater Shaributoxide (Ti (OC (CH ₃ ) ₃ ) ₄ ), etc.) and the following formula (LG) as a ligand -1):

3,3''-((((1R, 2R) -cyclohexane-1,2-diyl) bis (azaneyl)) bis (methylene)) bis (2'-methoxy- [1,1'-biphenyl) ] -2-ol) [CAS number: 928769-12-4], hydrogen peroxide solution (eg, about 30-60% concentration), and buffer solution (eg, citrate / NaOH buffer, citrate / quen). Sodium acid acid buffer, phosphate buffer, KH ₂ PO ₄ / NaOH buffer, Tris (hydroxymethyl) aminomethane (Tris) / HCl buffer, boric acid / NaOH buffer, Na borate / HCl buffer, etc. ), And a solvent (for example, a solvent not involved in the reaction, preferably an organic solvent, more preferably a halogenated hydrocarbon solvent such as dichloromethane, 1,2-dichloroethane, chlorobenzene, fluorobenzene, etc., and an aroma such as benzene, toluene). A step of obtaining a mixed solution (1) by adding it to a group hydrocarbon solvent, an ester solvent such as ethyl acetate, an ether solvent such as tetrahydrofuran, or a nitrile solvent such as acetonitrile.
(2) The mixed solution (1) is reacted at a reaction temperature (outside temperature) in the range of 30 ° C. to 50 ° C., preferably in the range of 35 to 45 ° C., and the following formula (EP-1):

A step of obtaining a compound represented by [in formula (EP-1), p and R ¹ are the same as the definitions in the above formula (AM-X)].
(3) A step of adding the compound represented by the formula (EP-1) to aqueous ammonia to obtain a mixed solution containing the compound represented by the formula (EP-1) and aqueous ammonia, and (4) the above. A production method comprising a step of reacting a mixed solution at any temperature between 0 ° C. and the temperature at which the mixed solution (3) refluxes to obtain a compound represented by the formula (AM-X). is there.

[2-1-1] In the step (1) of the above aspect [2], the amount of hydrogen peroxide solution is preferably 1.5 to 10 equivalents with respect to 1 equivalent of the formula (TH-1). In the range of; more preferably in the range of 1.5 to 5 equivalents; particularly preferably in the range of 1.5 or 5.0 equivalents.

[2-1-2] In the step (1) of the above aspect [2], it is preferable to use a hydrogen peroxide solution having a concentration of about 30%.

[2-2-1] In the step (1) of the above aspect [2], the titanium catalyst is preferably titanium tetramethoxyde, titanium tetraethoxydo, titanium tetranormal propoxide, titanium tetraisopropoxide, titanium tetra. It is normal buttoxide, or titanium tetraterlary butoxide; more preferably titanium tetraisopropoxide.

[2-2-2] In the step (1) of the above aspect [2], the amount of the titanium catalyst is preferably in the range of 0.1 to 10 mol% with respect to the formula (TH-1); more preferably. It is in the range of 1.0 to 5.0 mol%; particularly preferably 1.0, 3.0, or 5.0 mol%.

[2-3] In the step (1) of the above aspect [2], the ligand is preferably in the range of 0.1 to 12 mol% with respect to the formula (TH-1); more preferably 1 It is in the range of .2 to 6.0 mol%; particularly preferably 1.2, 3.6, or 6.0 mol%.

[2-4] In the step (1) of the above aspect [2], the solvent is preferably a solvent that does not participate in the reaction, more preferably an organic solvent, and further preferably dichloromethane, 1,2-dichloroethane. , A halogenated hydrocarbon solvent such as chlorobenzene and fluorobenzene, an aromatic hydrocarbon solvent such as toluene, an ester solvent such as ethyl acetate, and an ether solvent such as tetrahydrofuran; more preferably dichloromethane.

[2-5] In the step (1) of the above aspect [2], the amount of the solvent (solvent not involved in the reaction) is preferably 1 to 20 times the mass of the formula (TH-1). It is in the range; more preferably in the range of 5 to 20 times the amount; particularly preferably in the range of 5 or 20 times the amount.

[2-6-1] In the step (1) of the above aspect [2], the buffer solution is preferably citric acid / NaOH buffer solution, citric acid / sodium citrate buffer solution, boric acid / NaOH buffer solution, or phosphorus. Acid buffer, KH ₂ PO ₄ / NaOH buffer; more preferably phosphate buffer, KH ₂ PO ₄ / NaOH buffer; particularly preferably phosphate buffer. The pH of the reaction solution or the like can be adjusted with the buffer solution.

[2-6-2]
In step (1) of aspect [2], the pH of the reaction solution is preferably pH = 7.4 to 8.0; more preferably pH = 7.4, or pH = 8.0. is there.

[2-7] In the step (2) of the above aspect [2], the reaction time is preferably 20 hours or less; more preferably 4.0 hours or less.

[2-8-1] The reaction in step (2) of the above aspect [2] is preferably a sealing reaction using a sealing reaction bottle.

[2-8-2] The reaction temperature of the sealed tube reaction of the above aspect [2-8-1] is preferably 100 ° C.

[2-8-3] The preferable reaction time of the sealing reaction of the above aspect [2-8-1] is 2 hours.

[2-9] In each of the formulas of the above aspect [2], p is preferably an integer of 0 or 1, and more preferably an integer of 0.

[2-10] In each of the formulas of the above aspect [2], R ¹ is preferably a halogen atom, a hydroxy C _1-6 alkyl group, a C _1-6 alkoxy group, and a C _1-6 alkoxy C _1-6. It is a substituent selected from an alkyl group, a carboxamide group, and a C _1-6 alkoxycarbonyl group; more preferably a halogen atom or a C _1-6 alkoxy C _1-6 alkyl group; even more preferably a hydrogen atom. , Fluorine atom, bromine atom, or methoxymethyl group may be substituted with one or two substituents; particularly preferably unsubstituted.

[2-11] In each of the formulas of the above aspect [2], the substitution mode of ^{R 1} is preferably the following partial structural formula (p = 1) when ^{one substituent is substituted by R 1 (p = 1).} It takes a substitution mode represented by PH-1) to the formula (PH-4);

When two substituents are ^{substituted by R 1} , the partial structural formula takes the substitution mode represented by the following partial structural formulas (PH-5) to (PH-10));

More preferably, when the substituent having one substituent is substituted ^{by R 1} (p = 1), the following partial structural formula:

The substitution mode represented by is taken; as a combination with a more specific substituent, the following partial structural formula:

Take the replacement style chosen from.
When two substituents are ^{substituted by R 1} (p = 2), the following partial structural formula:

Takes the substitution form represented by;
As a more specific combination with a substituent, the following partial structural formula:

の置換様式をとる。

Take the replacement form of.

[2-12] In the step (1) of the above aspect [2], the amount of the hydrogen peroxide solution is preferably in the range of 1.5 to 5 equivalents with respect to 1 equivalent of the formula (TH-1). The amount of titanium catalyst is in the range of 1.0-5.0 mol% relative to formula (TH-1); the ligand is 1.2 relative to formula (TH-1). In the range of ~ 6.0 mol%; the titanium catalyst is titanium tetraisopropoxide; the buffer is a phosphate buffer; the solvent (solvent not involved in the reaction) is dichloromethane; the solvent (reaction). The amount of solvent not involved in the reaction is in the range of 5 to 20 times the mass of the formula (TH-1); the pH of the reaction solution is pH = 7.4 to 8.0; the reaction. The time is 20 hours or less.

[2-13] In the step (1) of the above aspect [2], more preferably, the amount of the hydrogen peroxide solution is 1.5 or 5.0 equal to 1 equal amount of the formula (TH-1). The amount of titanium catalyst is 1.0 or 3.0 mol% relative to formula (TH-1); the ligand is 1.2 or 3.6 mol% relative to formula (TH-1). %; The titanium catalyst is titanium tetraisopropoxide; the buffer is a phosphate buffer; the solvent (solvent not involved in the reaction) is dichloromethane; the solvent (solvent not involved in the reaction) The amount is 5 times the amount; the pH of the reaction solution is pH = 7.4 or pH = 8.0; the reaction time is 4 hours or less.

[3] A third aspect of the invention is the following formula (EP-1):

[In formula (EP-1), p is an integer chosen from 0, 1, and 2; R ¹ is a halogen atom, a cyano group, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group. , Hydroxy C _1-6 alkyl group, cyanated C _1-6 alkyl group, C _1-6 alkoxy group, halogenated C _1-6 alkoxy group, C _1-6 alkoxy C _1-6 alkyl group, mono / di C _{A substituent selected from a 2-7} alkanoylamino group, a carboxamide group, and a C _1-6 alkoxycarbonyl group], which is a method for producing a compound represented by the following steps:
(1) The following formula (TH-1):

[In the formula (TH-1), p and R ¹ are the same as the definitions in the above formula (AM-X)], and a titanium catalyst (for example, titanium tetrachloride, titanium tetrabromide). , Titanium alkoxide (Titanium tetramethoxyde, Titanium tetraethoxydo, Titanium tetranormal propoxide (Ti (OCH ₂ CH ₂ CH ₃ ) ₄ ), Titanium tetraisopropoxide (Ti (OCH (CH ₃ ) ₂ ) ₄ ), Titanium Tetranormal Butoxide (Ti (OCH ₂ CH ₂ CH ₂ CH ₃ ) ₄ ), Titanium Tetrater Shaributoxide (Ti (OC (CH ₃ ) ₃ ) ₄ ), etc.) and the following formula (LG) as a ligand -1):

3,3''-((((1R, 2R) -cyclohexane-1,2-diyl) bis (azaneyl)) bis (methylene)) bis (2'-methoxy- [1,1'-biphenyl) ] -2-ol) [CAS number: 928769-12-4], hydrogen peroxide solution (eg, about 30-60% concentration), and buffer solution (eg, citrate / NaOH buffer, citrate / quen). Sodium acid acid buffer, phosphate buffer, KH ₂ PO ₄ / NaOH buffer, Tris (hydroxymethyl) aminomethane (Tris) / HCl buffer, boric acid / NaOH buffer, Na borate / HCl buffer, etc. ), And a solvent (for example, a solvent not involved in the reaction, preferably an organic solvent, more preferably a halogenated hydrocarbon solvent such as dichloromethane, 1,2-dichloroethane, chlorobenzene, fluorobenzene, etc., and an aroma such as benzene, toluene). A step of obtaining a mixed solution (1) by adding it to a group hydrocarbon solvent, an ester solvent such as ethyl acetate, an ether solvent such as tetrahydrofuran, and a nitrile solvent such as acetonitrile, (2) the mixed solution (1). , The reaction temperature (outside temperature) is in the range of 30 ° C. to 50 ° C., preferably in the range of 35 to 45 ° C., and the production method includes a step of obtaining a compound represented by the formula (EP-1). is there.

[3-1-1] In the step (1) of the above aspect [3], the amount of hydrogen peroxide solution is preferably 1.5 to 10 equivalents with respect to 1 equivalent of the formula (TH-1). In the range of; more preferably in the range of 1.5 to 5 equivalents; particularly preferably in the range of 1.5 or 5.0 equivalents.

[3-1-2] In the step (1) of the above aspect [3], it is preferable to use a hydrogen peroxide solution having a concentration of about 30%.

[3-2-1] In the step (1) of the above aspect [3], the titanium catalyst is preferably titanium tetramethoxyde, titanium tetraethoxydo, titanium tetranormal propoxide, titanium tetraisopropoxide, titanium tetra. It is normal buttoxide, or titanium tetraterlary butoxide; more preferably titanium tetraisopropoxide.

[3-2-2] In the step (1) of the above aspect [3], the amount of the titanium catalyst is preferably in the range of 0.1 to 10 mol% with respect to the formula (TH-1); more preferably. It is in the range of 1.0 to 5.0 mol%; particularly preferably 1.0, 3.0, or 5.0 mol%.

[3-3] In the step (1) of the above aspect [3], the ligand is preferably in the range of 0.1 to 12 mol% with respect to the formula (TH-1); more preferably 1 It is in the range of .2 to 6.0 mol%; particularly preferably 1.2, 3.6, or 6.0 mol%.

[3-4] In the step (1) of the above aspect [3], the solvent is preferably a solvent that does not participate in the reaction, more preferably an organic solvent, and further preferably dichloromethane, 1,2-dichloroethane. , A halogenated hydrocarbon solvent such as chlorobenzene and fluorobenzene, an aromatic hydrocarbon solvent such as toluene, an ester solvent such as ethyl acetate, and an ether solvent such as tetrahydrofuran; more preferably dichloromethane.

[3-5] In the step (1) of the above aspect [3], the amount of the solvent (solvent not involved in the reaction) is preferably 1 to 20 times the mass of the formula (TH-1). It is in the range; more preferably in the range of 5 to 20 times the amount; particularly preferably in the range of 5 or 20 times the amount.

[3-6-1] In the step (1) of the above aspect [3], the buffer solution is preferably citric acid / NaOH buffer solution, citric acid / sodium citrate buffer solution, boric acid / NaOH buffer solution, or phosphorus. Acid buffer, KH ₂ PO ₄ / NaOH buffer; more preferably phosphate buffer, KH ₂ PO ₄ / NaOH buffer; particularly preferably phosphate buffer. The pH of the reaction solution or the like can be adjusted with the buffer solution.

[3-6-2] In the step (1) of the above aspect [3], the pH of the reaction solution is preferably pH = 7.4 to 8.0; more preferably pH = 7.4, Or pH = 8.0.

[3-7] In the step (2) of the above aspect [3], the reaction time is preferably 20 hours or less; more preferably 4.0 hours or less.

[3-8] In each of the formulas of the above aspect [3], p is preferably an integer of 0 or 1, and more preferably an integer of 0.

[3-9] In each of the formulas of the above aspect [3], R ¹ is preferably a halogen atom, a hydroxy C _1-6 alkyl group, a C _1-6 alkoxy group, and a C _1-6 alkoxy C _1-6. It is a substituent selected from an alkyl group, a carboxamide group, and a C _1-6 alkoxycarbonyl group; more preferably a halogen atom or a C _1-6 alkoxy C _1-6 alkyl group; even more preferably a hydrogen atom. , Fluorine atom, bromine atom, or methoxymethyl group may be substituted with one or two substituents; particularly preferably unsubstituted.

[3-10] In each of the formulas of the above aspect [3], the substitution mode of ^{R 1} is preferably the following partial structural formula (p = 1) when ^{one substituent is substituted by R 1 (p = 1).} It takes a substitution mode represented by PH-1) to the formula (PH-4);

When two substituents are ^{substituted by R 1} , the partial structural formula takes the substitution mode represented by the following partial structural formulas (PH-5) to (PH-10));

More preferably, when one substituent is ^{substituted by R 1} (p = 1), the following partial structural formula:

The substitution mode represented by is taken; as a combination with a more specific substituent, the following partial structural formula:

Take the replacement style chosen from.
When two substituents are ^{substituted by R 1} (p = 2), the following partial structural formula:

の置換様式をとる。Takes the substitution form represented by;
As a more specific combination with a substituent, the following partial structural formula:

Take the replacement form of.

[3-11] In the step (1) of the above aspect [3], the amount of the hydrogen peroxide solution is preferably in the range of 1.5 to 5 equivalents with respect to 1 equivalent of the formula (TH-1). The amount of titanium catalyst is in the range of 1.0-5.0 mol% relative to formula (TH-1); the ligand is 1.2 relative to formula (TH-1). In the range of ~ 6.0 mol%; the titanium catalyst is titanium tetraisopropoxide; the buffer is a phosphate buffer; the solvent (solvent not involved in the reaction) is dichloromethane; the solvent (reaction). The amount of solvent not involved in the reaction is in the range of 5 to 20 times the mass of the formula (TH-1); the pH of the reaction solution is pH = 7.4 to 8.0; the reaction. The time is 20 hours or less.

[3-12] In the step (1) of the above aspect [3], more preferably, the amount of the hydrogen peroxide solution is 1.5 or 5.0 equal to 1 equal amount of the formula (TH-1). The amount of titanium catalyst is 1.0 or 3.0 mol% relative to formula (TH-1); the ligand is 1.2 or 3.6 mol% relative to formula (TH-1). %; The titanium catalyst is titanium tetraisopropoxide; the buffer is a phosphate buffer; the solvent (solvent not involved in the reaction) is dichloromethane; the solvent (solvent not involved in the reaction) The amount is 5 times the amount; the pH of the reaction solution is pH = 7.4 or pH = 8.0; the reaction time is 4 hours or less.

[4] A fourth aspect of the present invention is the following formula (AM-X):

[In formula (AM-X), p is an integer chosen from 0, 1, and 2; R ¹ is a halogen atom, a cyano group, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group. , Hydroxy C _1-6 alkyl group, cyanated C _1-6 alkyl group, C _1-6 alkoxy group, halogenated C _1-6 alkoxy group, C _1-6 alkoxy C _1-6 alkyl group, mono / di C _{A substituent selected from a 2-7} alkanoylamino group, a carboxamide group, and a C _1-6 alkoxycarbonyl group], which is a method for producing a compound represented by the following steps:
(3) The following formula (EP-1):

The compound represented by [in the formula (EP-1), p and R ¹ are the same as the definitions in the above formula (AM-X)] is added to aqueous ammonia and represented by the above formula (EP-1). Any one of the steps of obtaining a mixed solution (3) containing the compound to be used and aqueous ammonia, and (4) the mixed solution (3) from 0 ° C. to the temperature at which the mixed solution (3) is refluxed. It is a production method including a step of carrying out a reaction at temperature to obtain a compound represented by the formula (AM-X).

[4-1-1] The reaction in step (4) of the above aspect [4] is preferably a sealing reaction using a sealing reaction bottle.

[4-1-2] The preferable reaction temperature of the sealing tube reaction of the above aspect [4-1-1] is 100 ° C.

[4-1-3] The preferable reaction time of the sealing reaction of the above aspect [4-1-1] is 2 hours.

[4-2] In each of the formulas of the above aspect [4], p is preferably an integer of 0 or 1, and more preferably an integer of 0.

[4-3] In each of the formulas of the above aspect [4], R ¹ is preferably a halogen atom, a hydroxy C _1-6 alkyl group, a C _1-6 alkoxy group, and a C _1-6 alkoxy C _1-6. It is a substituent selected from an alkyl group, a carboxamide group, and a C _1-6 alkoxycarbonyl group; more preferably a halogen atom or a C _1-6 alkoxy C _1-6 alkyl group; even more preferably a hydrogen atom. , Fluorine atom, bromine atom, or methoxymethyl group may be substituted with one or two substituents; particularly preferably unsubstituted.

[4-4] In each of the formulas of the above aspect [4], the substitution mode of ^{R 1} is preferably the following partial structural formula (p = 1) when ^{one substituent is substituted by R 1 (p = 1).} It takes a substitution mode represented by PH-1) to the formula (PH-4);

When two substituents are ^{substituted by R 1} (p = 2), the partial structural formula takes the substitution mode represented by the following partial structural formulas (PH-5) to (PH-10));

More preferably, when one substituent is ^{substituted by R 1} (p = 1), the following partial structural formula:

The substitution mode represented by is taken; as a combination with a more specific substituent, the following partial structural formula:

Take the replacement style chosen from.
When two substituents are ^{substituted by R 1} (p = 2), the following partial structural formula:

の置換様式をとる。Takes the substitution form represented by;
As a more specific combination with a substituent, the following partial structural formula:

Take the replacement form of.

[5] A fifth aspect of the present invention is the following formula (I):

[In formula (I), p is an integer chosen from 0, 1, and 2; R ¹ is a halogen atom, a cyano group, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, a hydroxy. C _1-6 alkyl group, cyanated C _1-6 alkyl group, C _1-6 alkoxy group, halogenated C _1-6 alkoxy group, C _1-6 alkoxy C _1-6 alkyl group, mono / di C _{2- It is a substituent selected from 7} alkanoylamino group, carboxamide group, and C _1-6 alkoxycarbonyl group; ring A is 5-methyl-6- (2-methylpyrimidine-5-yl) -2-phenylpyridine-. 3-Il group], which is a method for producing a compound represented by the following steps:
(5) The following formula (AM-1):

[In the formula (AM-1), ring A is a 5-methyl-6- (2-methylpyrimidine-5-yl) -2-phenylpyridine-3-yl group], and triphosgene. Hosgene, trichloromethyl chlorophosphate, 2,2,2-trichloroethylchloroformate, phenylchlorophosphate, p-nitrophenyl chloroate, p-tolyl chlorogitate, N, N'-carbonyldiimidazole, and N, N' A step of adding a urelating agent selected from −discusin imidazole carbonate or the like and a base to a solvent to obtain a mixed solution (5), (6) the mixed solution (5) from 0 ° C. to the mixed solution. The reaction was carried out at any temperature up to the temperature at which (5) refluxed, and the following formula (CB-1):

[In formula (CB-1), ring A is a 5-methyl-6- (2-methylpyrimidine-5-yl) -2-phenylpyridine-3-yl group; Y is a trichloromethoxy group, chlorine. Atomic, 2,2,2-trichloroethoxy group, phenoxy group, p-nitrophenoxy group, p-methylphenoxy group, imidazol-1-yl group, (2,5-dioxopyrrolidin-1-yl) oxy group, The process of obtaining the compound represented by], which is a group selected from the above, etc.
The compound represented by the above formula (CB-1) and
The following formula (AM-X):

A step of adding a compound represented by [in the formula (AM-X), p and R ¹ are the same as the definitions in the formula (I)] and a base to a solvent to obtain a mixed solution (7). , And (8) the mixed solution (7) is reacted at any temperature between 0 ° C. and the temperature at which the mixed solution (7) refluxes to obtain a compound represented by the formula (I). It is a manufacturing method including a step.

[5-1] In step (5) of the above aspect [5], the urea agent is preferably phenylchloroformate, p-tolyl chloroformate, or 2,2,2-trichloroethylchloroformate; More preferably, it is 2,2,2-trichloroethylchloroformate.

[5-2] In step (5) of the above aspect [5], the base is preferably pyridine, triethylamine, or N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-. Organic bases such as undecene (DBU), inorganic bases such as sodium hydrogen carbonate, sodium carbonate, or potassium carbonate, metal alkoxides such as potassium tert-butoxide, sodium tert-butoxide, etc., sodium hydride, potassium hydride, or hydrogen. Metal hydride compounds such as calcium hydride, alkyl lithium such as methyl lithium or butyl lithium, lithium amides such as lithium hexamethyldisilazide, or lithium diisopropylamide, or mixtures thereof; more preferably pyridine. Is.

[5-3] In the step (5) of the above aspect [5], the solvent is preferably an aproton polar solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, or acetonitrile, diethyl ether. , Tetrahydrofuran, dimethoxyethane, or ether solvents such as 1,4-dioxane, ester solvents such as ethyl acetate or propyl acetate, chlorine solvents such as dichloromethane, chloroform, or 1,2-dichloroethane, or theirs. It is a mixed solvent or the like; more preferably tetrahydrofuran.

[5-4] In the step (5) of the above aspect [5], Y in the formula (CB-1) is preferably a phenoxy group, a p-methylphenoxy group, or a 2,2,2-trichloroethoxy group. More preferably, it is a 2,2,2-trichloroethoxy group.

[5-5] In the step (7) of the above aspect [5], the solvent is preferably an aproton polar solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, or acetonitrile, diethyl ether. , Tetrahydrofuran, dimethoxyethane, or ether solvent such as 1,4-dioxane, ester solvent such as ethyl acetate or propyl acetate, chlorine solvent such as dichloromethane, chloroform, or 1,2-dichloroethane, or theirs. It is a mixed solvent or the like; more preferably N-methylpyrrolidone.

[5-6] In (7) of the above aspect [5], the base is preferably pyridine, triethylamine, or N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene. Organic bases such as (DBU), inorganic bases such as sodium hydrogencarbonate, sodium carbonate, or potassium carbonate, metal alkoxides such as potassium tert-butoxide, sodium tert-butoxide, sodium hydride, potassium hydride, or hydrogenation. Metal hydride compounds such as calcium, alkyl lithium such as methyl lithium or butyl lithium, lithium amides such as lithium hexamethyldisilazide, or lithium diisopropylamide, or mixtures thereof; more preferably with triethylamine. is there.

[5-7] In each of the formulas of the above aspect [5], p is preferably an integer of 0 or 1, and more preferably an integer of 0.

[5-8] In each of the formulas of the above aspect [5], R ¹ is preferably a halogen atom, a hydroxy C _1-6 alkyl group, a C _1-6 alkoxy group, and a C _1-6 alkoxy C _1-6. It is a substituent selected from an alkyl group, a carboxamide group, and a C _1-6 alkoxycarbonyl group; more preferably a halogen atom or a C _1-6 alkoxy C _1-6 alkyl group; even more preferably a hydrogen atom. , Fluorine atom, bromine atom, or methoxymethyl group may be substituted with one or two substituents; particularly preferably unsubstituted.

[5-9] In each of the formulas of the above aspect [5], the substitution mode of ^{R 1} is preferably the following partial structural formula (p = 1) when ^{one substituent is substituted by R 1 (p = 1).} It takes a substitution mode represented by PH-1) to the formula (PH-4);

When two substituents are ^{substituted by R 1} , the partial structural formula takes the substitution mode represented by the following partial structural formulas (PH-5) to (PH-10));

More preferably, when one substituent is ^{substituted by R 1} (p = 1), the following partial structural formula:

The substitution mode represented by is taken; as a combination with a more specific substituent, the following partial structural formula:

Take the replacement style chosen from.
When two substituents are ^{substituted by R 1} (p = 2), the following partial structural formula:

の置換様式をとる。Takes the substitution form represented by;
As a more specific combination with a substituent, the following partial structural formula:

Take the replacement form of.

Hereinafter, each substituent in aspects [1] to [5] of the present invention will be specifically described. In the description of the compounds of the present invention, for example, "C _1-6 " indicates that the number of constituent carbon atoms is 1 to 6, and unless otherwise specified, the total carbon of a linear, branched or cyclic group is used. Represents the number of atoms. A group containing a chain group and a cyclic group means "total number of carbon atoms in the chain and ring".

Unless otherwise specified in the present specification, examples of the "halogen atom" include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.
In the present specification, unless otherwise specified, "halogenation" in "halogenated C _1-6 alkyl groups" and the like means several, preferably 1 to 5 "halogen atoms" as substituents. It means that you may have it.
In the present specification, unless otherwise specified, "cyanolation _{" in "Cyanated C 1-6} alkyl" and the like has several, preferably 1 to 5 "cyano groups" as substituents. It means that it may be.

Unless otherwise specified, the "C _1-6 alkyl group" in the present specification includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, and the like. Alternatively, a group such as hexyl can be mentioned.

Herein, unless otherwise indicated, the term "halogenated C _1-6 alkyl group", the "C _1-6 alkyl" is several, preferably substituted optionally with 1-5 halogen atoms Means that the group is, for example, a group such as fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl, or pentafluoroethyl. Can be mentioned.

In the present specification, unless otherwise specified, the "hydroxy C _1-6 alkyl group" means that the "C _1-6 alkyl" is optionally substituted with several, preferably 1 to 5 hydroxyl groups. Examples include groups such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, and 2,2-dimethyl-2-hydroxyethyl (= 2-hydroxy-2-methylpropyl).
In the present specification, unless otherwise specified, the "cyanolated C _1-6 alkyl group" is the above-mentioned "C _1-6 alkyl" optionally substituted with several, preferably 1 to 5 cyanos. Examples include groups such as cyanomethyl, 1-cyanoethyl, and 2-cyanoethyl.

In the present specification, unless otherwise specified, the "C _1-6 alkoxy group" represents an alkoxy in which the above-mentioned "C _1-6 alkyl" is bonded to an oxygen atom, and examples thereof include methoxy, ethoxy, propoxy, and iso. Groups such as propoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy and the like can be mentioned.
Unless otherwise specified in the present specification, the "halogenated C _1-6 alkoxy group" represents a halogenated alkoxy in which the above-mentioned "halogenated C _1-6 alkyl" is bonded to an oxygen atom, for example, fluoro. Groups such as methoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, or 1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy and the like can be mentioned.

In the present specification, unless otherwise specified, the "C _1-6 alkoxy C _1-6 alkyl group" means a group in which the _{"C 1-6} alkoxy" is _{replaced with the "C 1-6 alkyl".} To do. Unless otherwise specified in the present specification, "C _1-6 alkoxy C _1-6 alkyl" includes, for example, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, 1,1-dimethoxymethyl, or 1, Groups such as 1-diethoxyethyl and the like can be mentioned.

In the present specification, unless otherwise specified, the "mono / di C _2-7 alkanoylamino group" means that one or two hydrogen atoms on the nitrogen atom of the "amino group" are "C _{2-" described later. It} means an amino group substituted with "7 alkanoyl group", for example, acetamide, propionamide, butylamide, isobutyramide, barrelamide, isobarrelamide, pivalamide, hexaneamide, heptaneamide, cyclopropanecarboxamide, cyclobutanecarboxamide, cyclopentanecarboxamide, Examples thereof include groups such as cyclohexanecarboxamide, 2-methylcyclopropanecarboxamide, and diacetamide.
In the present specification, unless otherwise specified, the "C _2-7 alkanoyl group" means a "C _1-6 alkyl carbonyl group" in which a carbonyl group is bonded to the "C _1-6 alkyl group". , For example, groups such as acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyle, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cyclopropylmethylcarbonyl, or 2-methylcyclopropylcarbonyl. Can be mentioned.

In the present specification, unless otherwise specified, the "C _1-6 alkoxycarbonyl group" is a group in which the hydrogen atom of the "carboxy group (-COOH) _{" is replaced with the "C 1-6} alkyl group", that is, It means "ester group", and examples thereof include groups such as methoxycarbonyl (methyl ester), ethoxycarbonyl (ethyl ester), and tert-butoxycarbonyl (tert-butyl ester).

In the above aspects of the present specification, unless otherwise specified, the "urea agent" includes triphosgene, phosgene, trichloromethylchloroformate, 2,2,2-trichloroethylchloroformate, phenylchloroformate, p-chloroformate. Examples thereof include nitrophenyl, p-tolyl chloroformate, N, N'-carbonyldiimidazole, and N, N'-disucciniimidazole carbonate. However, it is not necessarily limited to the urea agents described above.

In the above embodiments, unless otherwise specified, the "base" includes, for example, pyridine, triethylamine, or N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene (DBU). ), 2,6-lutidine, imidazole, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine (DMAP), N, N-dimethylaniline, 1,5-diazabicyclo [4.3.0] -5-nonen, Organic bases such as 1,4-diazabicyclo [2.2.2] octane, N-methylpiperidin, N-methylpyrrolidin, or N-methylmorpholin, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, Inorganic bases such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, sodium hydrogencarbonate, tripotassium phosphate, sodium acetate, or cesium fluoride, sodium methoxydo, sodium ethoxydo, potassium tert-butoxide, sodium Metal alkoxides such as tert-butoxide, metal hydride compounds such as sodium hydride, potassium hydride, calcium hydride, or sodium amide, methyllithium, n-butyllithium, sec-butyllithium, or tert-butyllithium. Alkyllithium, lithium hexamethyldisilazide, lithium amide such as lithium diisopropylamide, or a mixture thereof. However, it is not necessarily limited to the bases described above. These bases may be used alone, or may be appropriately selected and used by mixing two or more kinds of bases in an appropriate ratio.

In the above aspects, the "solvent" or "solvent not involved in the reaction" is, for example, water, cyclohexane, hexane, benzene, chlorobenzene, toluene, xylene, methanol, ethanol, 1-propanol, 2-propanol, tert-. Butyl alcohol, N, N-dimethylformamide (DMF), N, N-dimethylacetamide, N-methylpyrrolidone (NMP), hexamethylphosphoric triamide, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide ( DMSO), acetonitrile, propionitrile, diethyl ether, diisopropyl ether, diphenyl ether, methyl tert-butyl ether (MTBE), tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, methyl acetate, ethyl acetate , Butyl acetate, acetone, methyl ethyl ketone, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like, and examples thereof include solvents that do not affect the reaction. However, it is not necessarily limited to the solvents described above. As these solvents, one kind of solvent may be used alone, or two or more kinds of solvents may be appropriately selected and used in an appropriate ratio.

In the present specification, when there is an asymmetric carbon in the structural formula of the compound, the symbol R or S indicating the configuration may be added in the vicinity of the asymmetric carbon. For example, in the following formula (AM-X) or formula (AM-Y), the 1st and 2nd positions are asymmetric carbons, and in each formula, the symbol R or S is attached in the vicinity of the asymmetric carbon. ..

Compounds herein (eg, formula (SM-2), formula (IM-6), formula (IM-7), formula (AM-1), formula (AM-X), and formula (I), Etc.) may form a salt with an inorganic or organic acid (acid addition salt) or a salt with an inorganic or organic base, depending on the type of substituent. The salt is not particularly limited as long as it is a pharmaceutically acceptable salt, and for example, a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, basicity, and the like. Alternatively, a salt with an acidic amino acid and the like can be mentioned.

Preferable examples of the metal salt include alkali metal salts such as lithium salt, sodium salt, potassium salt and cesium salt, alkaline earth metal salts such as calcium salt, magnesium salt and barium salt, and aluminum salt. (For example, in addition to monosalt, disodium salt and dipotassium salt are also included). Preferable examples of salts with organic bases include, for example, methylamine, ethylamine, t-butylamine, t-octylamine, diethylamine, trimethylamine, triethylamine, cyclohexylamine, dicyclohexylamine, dibenzylamine, ethanolamine, diethanolamine, tri. Ethanolamine, piperidine, morpholine, pyridine, picolin, lysine, arginine, ornithine, ethylenediamine, N-methylglucamine, glucosamine, phenylglycine alkyl ester, guanidine, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, N , N'-dibenzylethylenediamine and the like.

Preferable examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, enanthic acid, capric acid, myristic acid, palmitic acid, stearic acid, lactic acid, sorbic acid, etc. Salts with aliphatic monocarboxylic acids such as mandelic acid, salts with aliphatic dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, and aliphatic tricarboxylic acids such as citric acid. Salts with acids, salts with aromatic monocarboxylic acids such as benzoic acid and salicylic acid, salts of aromatic dicarboxylic acids such as phthalic acid, cinnamic acid, glycolic acid, pyruvate, oxylic acid, salicylic acid, N-acetylcysteine, etc. Examples thereof include salts with organic carboxylic acids, salts with organic sulfonic acids such as methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, and acid addition salts with acidic amino acids such as aspartic acid and glutamate.

Preferable examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like, and preferred examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. Can be mentioned. Of these, pharmaceutically acceptable salts are preferable. For example, when the compound has an acidic functional group, an inorganic salt such as an alkali metal salt (eg, sodium salt, potassium salt, etc.), an alkaline earth metal salt (eg, calcium salt, magnesium salt, barium salt, etc.), When the compound has a basic functional group such as an ammonium salt, for example, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitrate, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid, Examples thereof include salts with organic acids such as oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid and p-toluenesulfonic acid.

The salt is prepared according to a conventional method, for example, by mixing a solution containing an appropriate amount of acid or base with the compound described in the present specification to form a desired salt, and then the salt is separated and collected by filtration, or the mixed solvent is retained. It can be obtained by leaving. Further, the compound in the present specification or a salt thereof can form a solvate with a solvent such as water, ethanol, or glycerol. A review of salts, Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Stahl & Wermuth (Wiley-VCH, 2002), has been published and is detailed in this book.

The compounds herein may be present in non-solvate or solvate form. As used herein, "solvate" means a molecular complex comprising a compound herein and one or more pharmaceutically acceptable solvent molecules (eg, water, ethanol, etc.). When the solvent molecule is water, it is particularly referred to as "hydrate".

The compounds in the present specification are geometric isomers (geometric isomers), configuration isomers (configuration isomers), tautomers (toomeric isomers), optical isomers (optical isomers), and stereoisomers (diastereomers). It may have isomers such as mer), positional isomer (regioisomer), and rotational isomer (rotational isomer).

When the compound in the present specification contains a geometric isomer, an arrangement isomer, a conformation isomer, a conformation isomer, or the like, each of them can be isolated by a known means.

When the compounds in the present specification contain optical isomers, stereoisomers, positional isomers, rotational isomers, and tautomers, each isomer is simply separated by a synthesis method and a separation method known per se. It can be obtained as one compound. For example, examples of the optical resolution method include methods known per se, such as (1) fractional recrystallization method, (2) diastereomer method, and (3) chiral column method.

(1) Fractional recrystallization method: A crystalline diastereomer is obtained by ionic bonding an optical resolution agent to a racemate, which is separated by a fractional recrystallization method, and if desired, a neutralization step is performed. It is a method of obtaining a free optically pure compound. Examples of the optical resolution agent include (+)-mandelic acid, (-)-mandelic acid, (+)-tartaric acid, (-)-tartaric acid, (+)-1-phenethylamine, (-)-1-phenethylamine, and the like. Examples thereof include cinchonine, (-)-cinchonidine, brucine and the like.

(2) Diastereomer method: An optical resolution agent is covalently bonded (reacted) to a mixture of racemic compounds to obtain a mixture of diastereomers, which is then subjected to conventional separation means (eg, fractional recrystallization, silica gel column chromatography). , HPLC (High Performance Liquid Chromatography), etc.), and then separated into optically pure diastereomers, and then optically pure by removing the optical resolution agent by chemical treatment such as hydrolysis reaction. This is a method for obtaining a good optical isomer. For example, when the compound of the present invention has an intramolecular hydroxyl group or a primary or secondary amino group, the compound and an optically active organic acid (eg, MTPA [α-methoxy-α- (trifluoromethyl) phenylacetic acid]], (-)-Mentoxyacetic acid, etc.) and the like are subjected to a condensation reaction to obtain ester or amide diastereomers, respectively. On the other hand, when the compound of the present invention has a carboxy group, diastereomers of amides or esters can be obtained by subjecting the compound to an optically active amine or alcohol reagent in a condensation reaction, respectively. Each of the above separated diastereomers is converted to an optical isomer of the original compound by subjecting it to an acid hydrolysis or a basic hydrolysis reaction.

(3) Chiral column method: A method of directly optical resolution by subjecting a racemate or a salt thereof to chromatography on a chiral column (column for separating optical isomers). For example, in the case of high performance liquid chromatography (HPLC), a mixture of optical isomers is added to a chiral column such as CHIRAL series manufactured by Daicel Co., Ltd., and water, various buffers (eg, phosphate buffer), Optical isomers can be separated by developing organic solvents (eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine) alone or as a mixed solution. Further, for example, in the case of gas chromatography, separation can be performed using a chiral column such as CP-Chirasil-DeX CB (manufactured by GL Sciences).

The compounds herein may be crystalline. When it is a crystal, it may have a single crystal form or a mixture of crystal forms.

The compounds herein may be pharmaceutically acceptable co-crystals or co-crystal salts. Here, a co-crystal or a co-crystal salt is unique to two or more at room temperature, each having different physical properties (eg, structure, melting point, heat of fusion, hygroscopicity, solubility and stability). It means a crystalline substance composed of a solid solid. The co-crystal or co-crystal salt can be produced according to a co-crystallization method known per se.

The compounds herein include isotopes (eg, hydrogen isotopes: ² H and ³ H, etc., carbon isotopes: ¹¹ C, ¹³ C, and ¹⁴ C, etc., chlorine ^{isotopes: 36} Cl, etc.) , Fluorine isotopes: ¹⁸ F, etc., Iodine isotopes: ¹²³ I and ¹²⁵ I, etc., Nitrogen isotopes: ¹³ N and ¹⁵ N, ^{etc., Oxygen isotopes: 15} O, ¹⁷ O, and ¹⁸ O, etc. Also included are compounds labeled or substituted with phosphorus isotopes: ³² P, etc., and sulfur isotopes: ^{35 S, etc.).}

The compounds of the present invention labeled or substituted with certain isotopes (eg, ^{positron emitting isotopes such as 11} C, ¹⁸ F, ¹⁵ O, and ¹³ N) are, for example, positron emission tomography (PET). ) Can be used as a tracer (PET tracer), and is useful in fields such as medical diagnosis.

The compounds of the invention labeled or substituted with certain isotope labels are useful in studying the tissue distribution of drugs and / or substrates. For example, ³ H and ¹⁴ C are useful for the research purpose because they are easy to label or replace and easy to detect.

Isotope-labeled compounds of the invention can be obtained by conventional techniques known to those of skill in the art or by methods similar to the synthetic methods described in Examples below. Moreover, the obtained isotope-labeled compound can be used for pharmacological experiments instead of the unlabeled compound.

In the above aspect of the present specification or in the production method in the present specification, "any temperature between 0 ° C. and the temperature at which the mixed solution ... Refluxes" and "from 0 ° C. to the temperature at which the solvent refluxes." Where the description such as "any temperature in between" means, it means an arbitrary temperature (constant temperature) within the range from 0 ° C. to the temperature at which each mixed solution (solvent) refluxs.
In the present specification, unless otherwise specified, "room temperature" means the temperature of a laboratory, a laboratory, etc., and is usually about 1 ° C. to about 30 ° C., preferably about 5 ° C. to about 30 ° C. , More preferably usually from about 15 ° C to about 25 ° C, even more preferably 20 ± 3 ° C.

In the production method of the present invention, one kind of solvent may be used alone, or two or more kinds of solvents may be appropriately selected according to the reaction conditions and used in an appropriate ratio.
In the production method of the present invention, steps such as compound extraction, drying, and purification can be appropriately performed by a well-known method.
In the production method of the present invention, the reaction time in each step may be appropriately selected as long as the reaction proceeds sufficiently unless otherwise specified.

[Production Method A] Method for producing a compound represented by the formula (TH-1) in the present invention:
Hereinafter, in the present invention, it is represented by the formula (TH-1) [ ^{the definition of p and R 1 in} the formula (TH-1) is the same as the definition of the formula (I) in the embodiment [1]]. The method for producing the compound will be described in detail. The compound represented by the formula (TH-1) and a mixture thereof are generally known as starting materials or synthetic intermediates from commercially available compounds or compounds that can be easily obtained from commercially available compounds by a production method known in the literature. It can be easily produced by combining chemical production methods, and for example, it can be produced according to the following typical production methods.
In [Production Method A], ^RA _{is a C 1-6} alkyl group such as a methyl group, an ethyl group, a propyl group, a tert-butyl group, a phenyl group, or a benzyl group unless otherwise specified.

<Step 1> A compound represented by the formula (SM-1) [the compound of the formula (SM-1) is a commercially available compound or a compound that can be produced from a commercially available compound by a production method known in the literature] is used in the literature. According to a known method, for example, a method described in "Experimental Chemistry Course 4th Edition 22 Organic Synthetic IV Acids / Amino Acids / Peptides, pp. 1-82, 1992, Maruzen", etc., hydrochloric acid, sulfuric acid, thionyl chloride, etc. In the presence of an acidic reagent such as acetyl chloride, the reaction was carried out using a solvent such as methanol, ethanol or 2-propanol at any temperature between 0 ° C. and the temperature at which the solvent refluxed, and the formula (IM-1) was used. The compound represented by can be produced.
Further, a method known in the literature using a compound represented by the formula (SM-1), for example, the method described in "Synthetic Communications, 31 (14), pp. 2177-2183, 2001" and the like. N, N-dimethylformamide, dimethyl sulfoxide in the presence of alkyl halide agents (eg, methyl iodide, ethyl iodide, etc.) and bases such as potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, etc. , N-Methylpyrrolidone or the like, the reaction can be carried out at any temperature between 0 ° C. and the temperature at which the solvent refluxes to produce the compound represented by the formula (IM-1). it can.

Further, using a compound represented by the formula (SM-1), a method known in the literature, for example, "Chemical & Pharmaceutical Bulletin, 29 (5), 1475-1478, 1981". In accordance with the method described in the above, the reaction is carried out at 0 ° C. to room temperature in a methylating agent such as diazomethane or trimethylsilyldiazomethane, a solvent not involved in the reaction such as ether or methanol, or a mixed solvent thereof, and the formula (IM) is used. The compound represented by -1) can be produced. Further, using a compound represented by the formula (SM-1) and an alcohol (for example, methanol, ethanol, benzyl alcohol, etc.), a method known in the literature, for example, "Experimental Chemistry Course 4th Edition 22 Organic Synthetic IV Acids / Amino Acids / Peptide, pp. 191-309, 1992, Maruzen, et al., 1,3-Dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride ( WSC / HCl), 1-hydroxybenzotriazole (HOBT), benzotriazole-1-iroxytris (dimethylamino) phosphonium hexafluorophosphate (BOP reagent), bis (2-oxo-3-oxazolidinyl) phosphinic chloride (BOP) -Cl), 2-chloro-1,3-dimethylimidazolinium hexafluorophosphate (CIP), 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) -4-methylmol Holinium chloride (DTMMM), polyphosphate (PPA), 2- (1H-7-azabenzotriazole-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate methaneaminium (HATU) , (1-Cyano-2-ethoxy-2-oxoethylideneaminooxy) in the presence of condensing agents such as dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), dichloromethane, chloroform, diethyl ether, tetrahydrofuran, toluene, benzene , N, N-dimethylformamide, N-methylpyrrolidone, etc. The solvent is refluxed from 0 ° C. in the presence or absence of a base such as triethylamine or pyridine using a solvent not involved in the reaction or a mixed solvent thereof. The compound represented by the formula (IM-1) can be produced by reacting at any temperature up to the temperature.

Further, the compound represented by the formula (SM-1) can be used in a method known in the literature, for example, "Journal of the American Chemical Society", 109 (24), p7488-7494. , 1987, etc., in the presence or absence of bases such as triethylamine, N, N-diisopropylethylamine, N, N-dimethylaminopyridine, etc., thionyl chloride, oxalyl chloride, phosphoryl chloride, chloride. Halogen agents such as sulfryl, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, benzene, toluene, dichloromethane, 1,2-dichloroethane, chloroform and the like. After the reaction is carried out at any temperature between 0 ° C. and the temperature at which the solvent is refluxed using a solvent inert to the above reaction or a mixed solvent thereof to convert to acid halide, alcohol (for example, methanol, for example, methanol, etc., is used. Methods known in the literature using (ethanol, benzyl alcohol, etc.), for example, the methods described in "Experimental Chemistry Course 4th Edition 22 Organic Synthetic IV Acids / Amino Acids / Peptides, pp. 144-146, 1992, Maruzen" and the like. According to the above, in the presence of a base such as triethylamine, N, N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, dichloromethane, chloroform, 1,2-dichloroethane, diethyl ether, tetradrofuran, 1,4-dioxane, 1,2-Dimethoxyethane, toluene, benzene, N, N-dimethylformamide, N-methylpyrrolidone, etc. In a solvent not involved in the reaction, or using a mixed solvent of these, from 0 ° C. to the temperature at which the solvent returns. By reacting at any of the above temperatures, the compound represented by the formula (IM-1) can be produced in the same manner.

<Step 2> [Production Method A] Using the compound represented by the formula (IM-1) obtained in <Step 1>, a method known in the literature, for example, "Experimental Chemistry Course 4th Edition 25, Organic Synthesis VII" , Synthetic with Organic Metal Reagents, pp. 13-19, pp. 59-72, 1992, Maruzen, etc., and Grignard Reagents (eg, Methyl Magnesium Chloride, Methyl Magnesium Bromide, Ethyl Magnesium Bromide, etc.) ), Or in the presence of alkyl metal reagents (eg, methyllithium, etc.), in the reaction of diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,2-dimethoxyethane, benzene, toluene, xylene, etc. Using an inert solvent or a mixed solvent thereof, the reaction is carried out at any temperature between −78 ° C. and the temperature at which the solvent refluxes to produce a compound represented by the formula (IM-2). be able to.

<Step 3> [Production Method A] Using the compound represented by the formula (IM-2) obtained in <Step 2>, a method known in the literature, for example, "Tetrahedron Reagents, 54 (32), p4330-4332". , 2013 ”, etc., in the presence of acid reagents such as trifluoromethanesulfonic acid, diphosphorus pentoxide, phosphorus pentachloride, sulfuric acid, phosphoric acid, bismuth (III) trifluoromethanesulfonate, etc. Using a solvent inert to the reaction such as dichloromethane, chloroform, cyclohexane, benzene, toluene, xylene, diethyl ether, 2-propanol, water, etc., or a mixed solvent thereof, from 0 ° C. to the temperature at which the solvent refluxes. The reaction can be carried out at any temperature to produce the compound represented by the formula (IM-3).

<Step 4> [Production Method A] Using the compound represented by the formula (IM-3) obtained in <Step 3>, a method known in the literature, for example, "Chemistry Letters, 70 (10), p1042-1043". , 2013, etc., in the presence of oxidizing agents such as Oxone® (DuPont), tert-butyl hydroperoxide (TBHP), potassium permanganate, manganese dioxide, chromium acid, etc. , Chloroform, carbon tetrachloride, benzene, acetonitrile, tert-butyl alcohol, water and other reaction-inert solvents, or a mixed solvent of these, from 0 ° C. to the temperature at which the solvent refluxes. The reaction can be carried out at temperature to produce a compound represented by the formula (IM-4).

<Step 5> [Production Method A] Using the compound represented by the formula (IM-4) obtained in <Step 4>, a method known in the literature, for example, "Experimental Chemistry Course 4th Edition 26 Organic Synthesis VIII Non-compliance" Synthetic synthesis / reduction / sugar / labeling compounds, pp. 234-245, 1992, Maruzen, etc., according to the methods described in "Sodium hydride, lithium hydride, diisobutylaluminum hydride (DIBAH), hydrogenation". In the presence of reducing agents such as lithium aluminum (LAH), borane-tetrahydrofuran (BH ₃ · THF), bolan-dimethylsulfide (BH ₃ · Me ₂ S), diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4 -The reaction is carried out at any temperature between 0 ° C. and the temperature at which the solvent returns using a solvent such as dioxane, methanol, ethanol, 2-propanol (solvent not involved in the reaction) or a mixed solvent thereof. , The compound represented by the formula (IM-5) can be produced.

<Step 6> [Production Method A] Using the compound represented by the formula (IM-5) obtained in <Step 5>, a method known in the literature, for example, "International Publication No. 2014/078454" is described. Inactive to reactions of dichloromethane, 1,2-dichloroethane, chloroform, benzene, toluene, xylene, 1,2-dimethoxyethane, etc. as an acid in the presence of an acid reagent such as p-toluenesulfonic acid, according to the above method. The compound represented by the formula (TH-1) can be produced by carrying out the reaction at any temperature between 0 ° C. and the temperature at which the solvent refluxes using a different solvent or a mixed solvent thereof. ..

[Production Method B] Method for producing a compound represented by the formula (AM-1) in the present invention:
Hereinafter, the method for producing the compound represented by the formula (AM-1) in the present invention will be described in detail. The compound represented by the formula (AM-1) and its solvent mixture are generally known as starting materials or synthetic intermediates from commercially available compounds or compounds that can be easily obtained from commercially available compounds by a production method known in the literature. It can be easily produced by combining chemical production methods, and for example, it can be produced according to the following typical production methods.
In the following production method, [B] is boronic acid, boronic acid ester, boronic acid N-methyliminodiacetic acid (MIDA) ester or the like.

<Step 1> Formula (SM-2) and Formula (RG-1) [The compound of formula (SM-2) and formula (RG-1) can be produced from a commercially available compound or a commercially available compound by a production method known in the literature. Using the compound represented by], a method known in the literature, for example, "Experimental Chemistry Lecture 5th Edition 18 Synthesis of Organic Compounds VI-Organic Synthesis Using Metals-, pp. 327-352, 2004, Maruzen". , And "Journal of Medical Chemistry, 48 (20), p6326-6339, 2005", palladium (II) acetate (Pd (OAc) ₂ ), tetrakistriphenylphosphine palladium (Pd (Pd). PPh ₃ ) ₄ ), bis (triphenylphosphine) palladium (II) chloride (Pd (PPh ₃ ) ₂ Cl ₂ ), tris (dibenzylideneacetone) dipalladium (Pd ₂ (dba) ₃ ), bis (dibenzylideneacetone) ) Palladium (Pd (dba) ₂ ), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (PdCl ₂ (dppf)) and other palladium catalysts, triphenylphosphine, tris (tert-butyl ) Phosphine, tris (o-tolyl) phosphine, 2-dicyclohexylphosphino-2', 6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2', 4', 6'-triisopropylbiphenyl and other phosphine solvents, And in the presence of organic or inorganic bases such as triethylamine, N, N-diisopropylethylamine, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, toluene (toluene / water), xylene, N, N-dimethylformamide, N, N -Didimethylacetamide, N-methylpyrrolidone, 1,2-dimethoxyethane, acetonitrile (acetrid / water), 1,4-dioxane (1,4-dioxane / water), tetrahydrofuran (tetrakis / water), methanol, ethanol (ethanol) / Water), dichloromethane, 1,2-dichloroethane, dimethoxyethane (dimethoxyetane / water), water and other solvents (solvents that do not participate in the reaction), or a mixed solvent of these, the temperature at which the solvent refluxes from 0 ° C. The reaction can be carried out at any temperature between the above and the above to produce the compound represented by the formula (IM-6). Alternatively, it can be produced by the same method using tetramethylammonium chloride, tetrabutylammonium chloride or the like instead of the phosphine-based reagent.

<Step 2> [Production Method B] Using the compound of the formula (IM-6) obtained in <Step 1> and N-bromosuccinimide (NBS), a method known in the literature, for example, "International Publication 2009/088103" Solvents such as N-methylpyrrolidone, dimethylformamide, N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile (solvents not involved in the reaction), or a mixture thereof, according to the method described in "Pamphlet". Using a solvent, the reaction can be carried out at any temperature between 0 ° C. and the temperature at which the solvent refluxes to produce the compound represented by the formula (IM-7).
<Step 3> [Manufacturing Method B] The compounds of the formulas (IM-7) and (RG-2) [formula (RG-2) obtained in <Step 2> are commercially available compounds or known from commercially available compounds. The compound of the formula (AM-1) can be produced by carrying out the reaction according to the above [Production method B] <Step 1> using the compound represented by [It is a compound that can be produced by the production method].

In the above [Manufacturing method A] or [Manufacturing method B], the formula (SM-1), the formula (SM-2), the formula (IM-1), the formula (IM-2), the formula (IM-3), The compounds of formula (IM-4), formula (IM-5), formula (IM-6), and formula (IM-7) may form salts, such salts pharmaceutically The salt is not particularly limited as long as it is an acceptable salt, and examples thereof include a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a basic salt, or a salt with an acidic amino acid. Be done. Preferable examples of the metal salt include alkali metal salts such as lithium salt, sodium salt, potassium salt and cesium salt, alkaline earth metal salts such as calcium salt, magnesium salt and barium salt, and aluminum salt. (For example, in addition to monosalt, disodium salt and dipotassium salt are also included). Preferable examples of salts with organic bases include, for example, methylamine, ethylamine, t-butylamine, t-octylamine, diethylamine, trimethylamine, triethylamine, cyclohexylamine, dicyclohexylamine, dibenzylamine, ethanolamine, diethanolamine, tri. Ethanolamine, piperidine, morpholine, pyridine, picolin, lysine, arginine, ornithine, ethylenediamine, N-methylglucamine, glucosamine, phenylglycine alkyl ester, guanidine, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, N , N'-dibenzylethylenediamine and the like. Preferable examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, enanthic acid, capric acid, myristic acid, palmitic acid, stearic acid, lactic acid, sorbic acid, etc. Salts with aliphatic monocarboxylic acids such as mandelic acid, salts with aliphatic dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, and aliphatic tricarboxylic acids such as citric acid. Salts with acids, salts with aromatic monocarboxylic acids such as benzoic acid and salicylic acid, salts of aromatic dicarboxylic acids such as phthalic acid, cinnamic acid, glycolic acid, pyruvate, oxylic acid, salicylic acid, N-acetylcysteine, etc. Examples thereof include salts with organic carboxylic acids, salts with organic sulfonic acids such as methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, and acid addition salts with acidic amino acids such as aspartic acid and glutamate. Preferable examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like, and preferred examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. Can be mentioned. Of these, pharmaceutically acceptable salts are preferable. For example, when the compound has an acidic functional group, an inorganic salt such as an alkali metal salt (eg, sodium salt, potassium salt, etc.), an alkaline earth metal salt (eg, calcium salt, magnesium salt, barium salt, etc.), When the compound has a basic functional group such as an ammonium salt, for example, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitrate, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid, Examples thereof include salts with organic acids such as oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid and p-toluenesulfonic acid.

Further, in the above [Manufacturing method A] or [Manufacturing method B], the formula (IM-1), the formula (IM-2), the formula (IM-3), the formula (IM-4), and the formula (IM-5) ), Formula (IM-6), and formula (IM-7) can be used in the next reaction as a reaction solution or as a crude product, but can also be isolated from the reaction mixture according to a conventional method. , It can be easily purified by means known per se, for example, separation means such as extraction, concentration, neutralization, filtration, distillation, recrystallization, chromatography and the like.

Unless otherwise specified, the reaction conditions in the above-mentioned [Manufacturing Method A] or [Manufacturing Method B] are as follows. The reaction temperature is not limited as long as it is in the range of −78 ° C. to the temperature at which the solvent refluxes. Further, the reaction time is not limited as long as the reaction proceeds sufficiently unless otherwise specified.
The meaning of "the range of the temperature at which the solvent refluxes from −78 ° C." in the reaction temperature means the temperature within the range from −78 ° C. to the temperature at which the solvent (or mixed solvent) used for the reaction refluxes. .. For example, when methanol is used as the solvent, "at a temperature at which the solvent refluxes from −78 ° C." means a temperature within the range from −78 ° C. to the temperature at which methanol refluxes. Similarly, “at a temperature at which the reaction solution refluxes from −78 ° C.” means an arbitrary temperature within the range from −78 ° C. to the temperature at which the reaction solution refluxes.

Further, each of the above steps of [Production Method A] or [Production Method B] can be carried out without a solvent or by dissolving or suspending the raw material compound in an appropriate solvent before the reaction. As the solvent, a solvent that does not participate in the reaction is preferable, and for example, water, cyclohexane, hexane, benzene, chlorobenzene, toluene, xylene, methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, N, N- Dimethylformamide (DMF), N, N-dimethylacetamide, N-methylpyrrolidone (NMP), hexamethylphosphoric triamide, 1,3-dimethyl-2-imidazolidinone, dimethylsulfoxide, acetonitrile, propionitrile, diethyl Ether, diisopropyl ether, diphenyl ether, methyl tert-butyl ether (MTBE), tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, methyl acetate, ethyl acetate, butyl acetate, acetone, methyl ethyl ketone, dichloromethane, Chloroform, carbon tetrachloride, 1,2-dichloroethane, triethylamine, N, N-diisopropylethylamine, pyridine, lutidine, anhydrous acetic acid, formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid, hydrochloric acid, sulfuric acid and the like. Be done. These solvents can be used alone, or they can be appropriately selected depending on the reaction conditions and two or more kinds of solvents can be mixed and used in an appropriate ratio. These solvents are appropriately selected according to the reaction conditions.
Unless otherwise specified in the production method of the present specification, when the term "solvent", "solvent not involved in the reaction" or "solvent inert to the reaction" is described, one kind of solvent is used alone. It means that two or more kinds of solvents may be mixed and used in an appropriate ratio, which may be appropriately selected depending on the reaction conditions.

Examples of the base (or deoxidizing agent) used in each step of [Production Method A] or [Production Method B] include lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, lithium carbonate, and the like. Sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, sodium hydrogen carbonate, tripotassium phosphate, sodium acetate, cesium fluoride, triethylamine, N, N-diisopropylethylamine, tributylamine, cyclohexyldimethylamine, pyridine, lutidine, 4- Dimethylaminopyridine (DMAP), N, N-dimethylaniline, N-methylpiperidin, N-methylpyrrolidin, N-methylmorpholin, 1,5-diazabicyclo [4.3.0] -5-nonen, 1,4- Diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] -7-undecene (DBU), imidazole, sodium methoxydo, sodium ethoxydo, potassium tert-butoxide, sodium tert-butoxide, Examples thereof include sodium hydride, potassium hydride, sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, methyl lithium, n-butyllithium, sec-butyllithium, tert-butyllithium and the like. However, it is not necessarily limited to those described above. These bases are appropriately selected according to the reaction conditions.

The acid or acid catalyst used in each step of the above [Production Method A] or [Production Method B] is, for example, hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, oxalic acid, and the like. Phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, 10-campersulfonic acid, boron trifluoride ether complex, zinc iodide, aluminum anhydride, chloride anhydride. Examples include zinc and anhydrous iron chloride. However, it is not necessarily limited to those described above. These acids or acid catalysts are appropriately selected depending on the reaction conditions.

Next, examples will be given to explain the present invention in more detail, but these examples are merely embodiments, do not limit the present invention, and are changed without departing from the scope of the present invention. You may.

JEOL JNM-ECX400 FT-NMR or JEOL JNM-ECX300 FT-NMR (JEOL Ltd.) was used for the measurement of the nuclear magnetic resonance spectrum (NMR). ^{When 1} H-NMR ^{(#) is described in the 1} H-NMR data in the examples, it means that the measurement was performed using JEOL JNM-ECX300 FT-NMR (JEOL Ltd.). Liquid chromatography-mass spectrometry spectrum (LC-Mass) was measured by the following method. [UPLC] Waters AQUITY UPLC system and BEH C18 column (2.1 mm × 50 mm, 1.7 μm) (Waters) are used, and in the reference example, acetonitrile: 0.05% aqueous trifluoroacetic acid solution = 5:95 (0 minutes) to The mobile phase and gradient conditions of 95: 5 (1.0 minutes) to 95: 5 (1.6 minutes) to 5:95 (2.0 minutes) were set, and in the examples, acetonitrile: 10 mM ammonium bicarbonate aqueous solution (5%). Acetonitrile) = 5:95 (0.5 min) to 100: 0 (7.0 min) to 100: 0 (7.5 min) to 5:95 (7.51 min) for mobile phase and gradient conditions There was. Optical purity analysis by supercritical fluid liquid chromatography (SFC) was performed using Waters SFC UPC2 and the corresponding chiral column.

^{1 In 1} H-NMR data, the pattern of NMR signals, s is singlet, d is doublet, t is triplet, q is quartet, m is multiplet, br is broad, J is coupling constant, Hz is Hertz, CDCl ₃ Means deuterated chloroform, DMSO-D ₆ means deuterated dimethyl sulfoxide, and CD ₃ OD means deuterated methanol. ^{1 In the 1} H-NMR data, signals that cannot be confirmed due to broadband, such as hydroxyl group (OH), amino group (NH ₂ ), and carboxyl group (COOH) protons, are not described in the data.

In the LC-Mass data, M means molecular weight, RT means retention time, and [M + H] ⁺ and [M + Na] ⁺ mean molecular ion peaks.
The LC-Mass measurement conditions in Reference Examples, Examples, and Experimental Examples were Waters AQUITY UPLC system and BEH C18 column (2.1 mm × 50 mm, 1.7 μm) (Waters), and acetonitrile: 0.05% tri. Aqueous fluoroacetic acid solution = 5:95 (0 min) to 95: 5 (1.0 min) to 95: 5 (1.6 min) to 5:95 (2.0 min) mobile phase and gradient.

“Room temperature” in Reference Examples and Examples usually indicates a temperature of about 20 to 25 ° C.
In the table of (Example 2), DCM in the solvent column means dichloromethane, and DCE means 1,2-dichloroethane.

(Reference Example 1) Method for synthesizing 1,1-dimethyl-1,2-dihydronaphthalene (compound of p = 0 in the formula (TH-1)):

<Step 1> Synthesis of 4,4-dimethyl-1,2,3,4-tetrahydronaphthalene-1-ol:
Hydrochlorite in a solution of commercially available 4,4-dimethyl-3,4-dihydronaphthalene-1 (2H) -one (CAS No .: 2979-69-3) (1.0 g) in methanol (10 mL) under ice-water cooling. Sodium borohydride (0.24 g) was added in two portions and stirred at room temperature for 1 hour. Methanol was removed under reduced pressure, and 1N aqueous sodium hydroxide solution (30 mL) and ethyl acetate (40 mL) were added to the obtained residue and partitioned. The organic layer was washed with saturated brine (25 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (1.0 g) as a pale yellow oil.

^{1 1} H-NMR data (δ: ppm) <300MHz> :( CDCl ₃ ) δ: 7.43 (1H, dd, J = 8,2Hz), 7.35 (1H, dd, J = 8,2Hz), 7.30-7.17 ( 2H, m), 4.82-4.69 (1H, m), 2.16-2.04 (1H, m), 1.97-1.83 (2H, m), 1.74-1.54 (1H, m), 1.35 (3H, s), 1.26 ( 3H, s).
MS-ESI (m / z) [M + H] ⁺ = 159 (-OH), retention time = 1.04 (minutes).

<Step 2> Synthesis of 1,1-dimethyl-1,2-dihydronaphthalene:
(Reference Example 1) A solution of the compound (1.0 g) obtained in <Step 1> and p-toluenesulfonic acid / monohydrate (0.05 g) in toluene (10 mL) is stirred at 90 ° C. for 1.5 hours. did. After allowing to cool to room temperature, ethyl acetate (40 mL) and saturated aqueous sodium hydride solution (30 mL) were added and partitioned. The title compound (0.86 g) was obtained by washing the organic layer with saturated brine, drying the organic layer with sodium sulfate, filtering the dried organic layer, and concentrating the obtained ethyl acetate under reduced pressure. Obtained as a yellow oil.

^{1 1} H-NMR data (δ: ppm) <400MHz> :( CDCl ₃ ) δ: 7.30 (1H, d, J = 7Hz), 7.22-7.12 (2H, m), 7.04 (1H, dd, J = 7, 2Hz), 6.48-6.43 (1H, m), 5.97-5.91 (1H, m), 2.26 (2H, dd, J = 4,2Hz), 1.28 (6H, s).
MS-ESI (m / z) [M + H] ⁺ = 159, retention time = 1.25 (minutes).

(Reference Example 2) Synthesis method of 5-methyl-6- (2-methylpyrimidine-5-yl) -2-phenylpyridine-3-amine (formula (AM-1)):

<Step 1> Synthesis of 5-methyl-2-phenylpyridine-3-amine:
Commercially available 2-chloro-5-methyl-3-pyridineamine (CAS number: 34552-13-1) (1.0 g), phenylboronic acid (0.86 g) and tetrakistriphenylphosphine palladium (0.81 g). Was added to a mixed solvent of ethanol (15 mL), toluene (35 mL), and 2N aqueous potassium carbonate solution (11 mL), and stirred at 100 ° C. for 18 hours under a nitrogen atmosphere. After allowing to cool, ethyl acetate and water were added to the reaction solution obtained by stirring and distributed, and the organic layer was washed with saturated brine and dried over sodium sulfate. After filtering the dried organic layer, the obtained ethyl acetate was distilled off under reduced pressure, the obtained residue was dissolved in a mixed solvent of heptane / ethyl acetate, and silica gel column chromatography (mobile phase: heptane / ethyl acetate) was performed. The solution obtained through (= 70: 30-65: 35-60: 40) was distilled off under reduced pressure to obtain the title compound (1.2 g) as a colorless solid.

^{1 1} H-NMR data (δ: ppm) <400MHz> :( CDCl ₃ ) δ: 7.97 (1H, s), 7.69-7.63 (2H, m), 7.50-7.43 (2H, m), 7.42-7.33 (1H) , M), 6.87 (1H, s), 3.79 (2H, br s), 2.29 (3H, s).
MS-ESI (m / z) [M + H] ⁺ = 185, retention time = 0.58 (minutes).

<Step 2> Synthesis of 6-bromo-5-methyl-2-phenylpyridine-3-amine:
(Reference Example 2) N-Bromosuccinimide (0.21 g) was added to a solution of the compound (0.19 g) obtained in <Step 1> in N-methylpyrrolidone (2.0 mL), and the mixture was stirred at room temperature for 2 hours. Water (2.0 mL) was added to the reaction mixture, the mixture was extracted twice with tert-butyl methyl ether, and the organic layer was washed with water. The obtained tert-butyl methyl ether was distilled off under reduced pressure, and the obtained residue was dissolved in a mixed solvent of heptane / ethyl acetate, and silica gel column chromatography (stationary phase: amino-silica gel, mobile phase: heptane) was performed. The solution obtained through / ethyl acetate = 90: 10-30: 10) was distilled off under reduced pressure to obtain the title compound (0.20 g) as a brown solid.

^{1 1} H-NMR data (δ: ppm) <300MHz> :( CDCl ₃ ) δ: 7.67-7.61 (2H, m), 7.50-7.42 (2H, m), 7.41-7.34 (1H, m), 6.93 (1H) , d, J = 1Hz), 3.81 (2H, br s), 2.34 (3H, s).
MS-ESI (m / z) [M + H] ⁺ = 263,265, retention time = 1.02 (minutes).

<Step 3> Synthesis of 5-methyl-6- (2-methylpyrimidine-5-yl) -2-phenylpyridine-3-amine:
(Reference Example 2) 2-Methyl-5- (4,) in a mixed solution of 1,2-dimethoxyethane (10 mL) and water (2.0 mL) of the compound (0.40 g) obtained in <Step 2>. 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) pyrimidin (0.44 g), cesium carbonate (1.5 g) and dichloro [1,1'bis (diphenylphosphino) ferrocene] Palladium dichloromethane adduct (0.12 g) was added, and the mixture was stirred at 80 ° C. for 4 hours. After allowing to cool, water was added to the reaction solution. The insoluble material in the mixed solution of the reaction solution and water was filtered off with a Celite pad and washed with ethyl acetate. The organic layer was separated from the obtained filtrate, washed successively with water and saturated brine, and dried over sodium sulfate. After filtering the dried organic layer, the obtained ethyl acetate was distilled off under reduced pressure, and the obtained residue was dissolved in a mixed solvent of heptane / ethyl acetate, and silica gel column chromatography (stationary phase: amino-silicaette, The title compound (0.31 g) was obtained by distilling off the solution obtained through the mobile phase: heptane / ethyl acetate = 100: 0 to 50:50) under reduced pressure.

^{1 1} H-NMR data (δ: ppm) <300MHz> :( CDCl ₃ ) δ: 8.96 (2H, s), 7.74-7.69 (2H, m), 7.53-7.46 (2H, m), 7.44-7.38 (1H) , m), 7.02 (1H, s), 3.99 (2H, br s), 2.41 (3H, s), 1.64 (3H, s).
MS-ESI (m / z) [M + H] ⁺ = 277 (-OH), retention time = 0.66 (minutes).

(Example 1)
2,2,2-Trichloroethyl (5-methyl-6- (2-methylpyrimidine-5-yl) -2-phenylpyridine-3-yl) carbamate (Y = 2,2 in formula (CB-1)) Synthesis of 2-trichloroethoxy group compound) (steps (5) and (6) in the above embodiment):

Pyridine (0.22 mL) and 2,2,2-trichloroethylchloroformate (0.36 mL) were added to a solution of compound (0.30 g) obtained in (Reference Example 2) in 1,2-dichloroethane (100 mL). The mixture was added at room temperature and stirred at the same temperature for 1 hour. An aqueous sodium hydrogen carbonate solution was added to the reaction solution obtained by stirring, the mixture was extracted with ethyl acetate, the organic layer was washed successively with water and saturated brine, and the obtained organic layer was dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (stationary phase: amino-silica gel, mobile phase: heptane / ethyl acetate = 2: 1) to obtain the title compound (0.41 g) as a white solid. Obtained as.
^{1 1} H-NMR ^(#) (CDCl ₃ ) δ: 8.89 (2H, s), 8.41 (1H, br s), 7.67-7.61 (2H, m), 7.60-7.47 (3H, m), 7.06 (1H, 1H, br s), 4.86 (2H, s), 2.81 (3H, s), 2.50 (3H, s).
LCMS m / z [M + H] ⁺ = 451, 453, 455.UPLC retention time: 1.12 minutes

(Example 2)
Synthesis of (1aR, 7bS) -3,3-dimethyl-1a, 2,3,7b-tetrahydronaphtho [1,2-b] oxirene (compound of p = 0 in formula (EP-1)) (in the above embodiment). Steps (1) (2)):

3,3''-((((1R, 2R) -cyclohexane-1,2-) of a ligand known in the literature, for example, synthesized according to the method described in "International Publication No. 2006/087874". Diyl) bis (azanesil)) bis (methylene)) bis (2'-methoxy- [1,1'-biphenyl] -2-ol) :( CAS number: 928769-12-4), dichloromethane or 1,2 After dissolution in −dichloroethane, titanium tetraisopropoxide, which is a titanium catalyst, was added, and the mixture was stirred at 15 ° C. to 25 ° C. for 1 hour. The compound obtained in (Reference Example 1) (compound with p = 0 in the formula (TH-1)) and a phosphate buffer solution were added to the stirred mixed solution. (Hereinafter, the conditions for i-room temperature reaction or ii heating reaction will be described separately).
[I When reacting at room temperature] Then, 30% hydrogen peroxide solution was added to the reaction solution, and the mixture was stirred at room temperature. After the reaction, a saturated aqueous sodium thiosulfate solution was added at room temperature to separate the organic layer and the aqueous layer, and the aqueous layer was extracted with dichloromethane. The mixed solution of the organic layer and the extraction solution was concentrated under reduced pressure to obtain a crude product of the title compound as a brown oily substance.
[Ii When heating reaction] After that, the temperature is raised to the temperature at which the reaction solution refluxes (dichloromethane: external temperature: 40 ° C ± 5 ° C, 1,2-dichloroethane: external temperature: 60 ° C ± 5 ° C). Then, 30% hydrogen peroxide solution is added to the reaction solution, and the temperature at which the reaction solution refluxes (dichloromethane: outside temperature: 40 ° C. ± 5 ° C., 1,2-dichloroethane: outside temperature: 60 ° C. ± 5 ° C.). After the reaction, a saturated aqueous sodium thiosulfate solution was added at room temperature to separate the organic layer and the aqueous layer, and the aqueous layer was extracted with dichloromethane. The mixed solution of the organic layer and the extraction solution was concentrated under reduced pressure to obtain a crude product of the title compound as a brown oily substance.

なお、表Ａ中の溶媒のDCEは１，２−ジクロロエタンを意味し、DCMはジクロロメタンを意味する。The above reaction was carried out under various conditions in the table below (Examples 2A to 2D; Reference Examples 2a to 2c).
Table A

The solvent DCE in Table A means 1,2-dichloroethane, and DCM means dichloromethane.

なお、表Ｂ中の溶媒のDCEは１，２−ジクロロエタンを意味し、DCMはジクロロメタンを意味する。
参考例2aは、Synlett,20,p3545-3547,2006年（非特許文献３）に記載の反応条件下での反応であり、参考例2bは、Synlett,15,p2445-2447,2007年（非特許文献４）に記載の反応条件下での反応である。Table B

The solvent DCE in Table B means 1,2-dichloroethane, and DCM means dichloromethane.
Reference Example 2a is a reaction under the reaction conditions described in Synlett, 20, p3545-3547, 2006 (Non-Patent Document 3), and Reference Example 2b is Synlett, 15, p2445-2447, 2007 (Non-Patent Document 3). This is a reaction under the reaction conditions described in Patent Document 4).

The conversion rate in the above table means the ratio of the reactant (starting substance) disappeared by the reaction to the supply amount. That is, it can be understood that the higher the conversion rate, the more the reactant (starting substance) has disappeared, and the more the reaction is proceeding. The pass-through rate was measured from the 220 nm UV spectral intensity of the UPLC. The measured yield was calculated from NMR by comparison with an internal standard substance (dimethyl terephthalate).

[(1aR, 7bS) -3,3-dimethyl-1a, 2,3,7b-tetrahydronaphtho [1,2-b] oxirene data];
¹ H-NMR (CDCl ₃ ) δ: 7.42 (1H, dd, J = 8.0, 1.2 Hz), 7.37-7.30 (2H, m), 7.20 (1H, td, J = 7.2, 1.2 Hz), 3.86 (1H) , d, J = 4.1 Hz), 3.73-3.71 (1H, m), 2.21 (1H, dd, J = 15.2, 2.8 Hz), 1.84 (1H, d, J = 15.2 Hz), 1.36 (3H, s) , 1.31 (3H, s).
LCMS m / z [M + H] ⁺ = 175, UPLC retention time: 4.08 minutes
Optical purity analysis: 1% isopropanol (containing 0.1% diethylamine), 3.0 mL / min, CHIRALCEL OD-H (4.6 mm × 150 mm, 5.0 μm) (daicel), major 2.35, minor 2.20.

(Example 3)
Synthesis of (1R, 2R) -1-amino-4,4-dimethyl-1,2,3,4-tetrahydronaphthalene-2-ol (compound of p = 0 in formula (AM-X)) (in the above embodiment). Steps (3) (4)):

(1aR, 7bS) -3,3-dimethyl-1a, 2,3,7b-tetrahydronaphtho [1,2-b] oxirene (2.0 g, 51% purity) obtained by the method of (Example 2j). 25% aqueous ammonia (5.1 mL) was added to a solution of ethanol (5.1 mL), and the mixture was stirred in a sealed tube at 100 ° C. for 2 hours. After allowing to cool, water and saturated brine were added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (stationary phase: amino-silica gel, mobile phase: heptane / ethyl acetate = 100: 0 to 0: 100) to obtain the title compound (0.76 g).
[Data on (1R, 2R) -1-amino-4,4-dimethyl-1,2,3,4-tetrahydronaphthalene-2-ol];
^{1 1} H-NMR (DMSO-D ₆ ) δ: 7.62-7.60 (1H, m), 7.29-7.26 (1H, m), 7.17-7.10 (2H, m), 4.79 (1H, d, J = 4.0 Hz) 3.49-3.40 (2H, m), 1.85 (2H, br s), 1.78 (1H, dd, J = 13.2, 2.8 Hz), 1.28 (3H, s), 1.23 (3H, s).
LCMS m / z [M + H] ⁺ = 192, UPLC retention time: 2.39 minutes Optical purity analysis: 10% methanol (containing 0.1% diethylamine), 3.0 mL / min, CHIRALCEL OD-H (4.6 mm × 150 mm, 5.0 μm) ) (Daicel), major 1.90 minutes, minor 2.32 minutes. Mirror body excess rate 99%.
The obtained (1R, 2R) -1-amino-4,4-dimethyl-1,2,3,4-tetrahydronaphthalene-2-ol was combined with an organic acid as shown in the following (Experimental Example 1). Can form additional salts and hydrates.

(Experimental Example 1) (1R, 2R) -1-amino-4,4-dimethyl-1,2,3,4-tetrahydronaphthalene-2-ol (2S, 3S) -2,3-dihydrosuccinate 1 Mixing the compound (9.5 g) and D- (-)-tartaric acid (7.4 g) obtained by the method of hydrate synthesis (Example 3) with acetonitrile (113 mL) and water (12.5 mL). It was dissolved in a solvent and heated to reflux at 75 ° C. for 1 hour. The reaction mixture was cooled, stirred at room temperature for 2 hours, and the precipitated white solid was collected by filtration and washed with a mixed solution of water and acetonitrile to obtain the title compound (12 g).
[(1R, 2R) -1-amino-4,4-dimethyl-1,2,3,4-tetrahydronaphthalene-2-ol (2S, 3S) -2,3-dihydrosuccinate monohydrate data];
1H-NMR (DMSO-D6) δ: 7.48 (1H, d, J = 7.4 Hz), 7.44 (1H, dd, J = 7.6, 1.0 Hz), 7.33 (1H, t, J = 7.6 Hz), 7.27 ( 1H, td, J = 7.4, 1.0 Hz), 4.06 (1H, d, J = 9.0 Hz), 3.96 (2H, s), 1.89 (1H, dd, J = 12.8, 3.4 Hz), 1.72 (1H, t , J = 12.8 Hz), 1.32 (3H, s), 1.27 (3H, s).
LCMS m / z [M + H] + = 192, UPLC retention time: 2.43 minutes
Optical purity analysis: 10% methanol (containing 0.1% diethylamine), 3.0 mL / min, CHIRALCEL OD-H (4.6 mm × 150 mm, 5.0 μm) (daicel), major 1.89 min, minor 2.38 min. 100%.

(Example 4)
1-((1R, 2R) -2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalene-1-yl) -3- (5-methyl-6- (2-methylpyrimidine-) Synthesis of 5-yl) -2-phenylpyridine-3-yl) urea (compound of p = 0 in formula (I)) (steps (7) (8) in the above embodiment):

Diazabicycloundecene (0.59 mL) in a solution of the compound (0.75 g) obtained in (Example 3) and the compound (1.77 g) obtained in (Example 1) in dimethyl sulfoxide (10 mL). Was added and stirred overnight at room temperature. Water (10 mL) and ethanol (10 mL) were added to the reaction solution obtained by stirring, and the mixture was stirred at 55 ° C. for 1 hour. The reaction solution obtained by stirring is cooled, stirred at room temperature for 3 hours, the precipitated precipitate is collected by filtration, washed with a mixed solution of water and ethanol, and dried under reduced pressure to obtain the title compound (1.59 g, 82%). ) Was obtained.
[1-((1R, 2R) -2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalene-1-yl) -3- (5-methyl-6- (2-methylpyrimidine)) -5-yl) -2-phenylpyridine-3-yl) urea data];
^{1 1} H-NMR (DMSO-D ₆ ) δ: 8.94 (2H, s), 8.42 (1H, s), 7.79 (1H, br s), 7.65 (2H, d, J = 6.8 Hz), 7.52-7.43 ( 3H, m), 7.32 (1H, d, J = 6.8 Hz), 7.21-7.16 (4H, m), 4.94 (1H, d, J = 4.4 Hz), 4.58 (1H, t, J = 8.8 Hz), 3.75-3.68 (1H, m), 2.68 (3H, s), 2.43 (3H, s), 1.84 (1H, dd, J = 12.8, 3.6 Hz), 1.70 (1H, t, J = 12.0 Hz), 1.31 (3H, s), 1.23 (3H, s).
LCMS m / z [M + H] ⁺ = 494.UPLC retention time: 3.75 minutes Optical purity analysis: 30% ethanol, 3.0 mL / min, CHIRALPAK IC (4.6 mm × 150 mm, 5.0 μm) (daicel), major 3.34 minutes , minor 2.83 minutes. Mirror body excess rate 100%.

According to the present invention, there is provided a method for producing a compound represented by the formula (I) in a short process and suitable for industrial production. In addition, a useful method for producing a compound represented by the formula (AM-X), which is an intermediate for producing the compound represented by the formula (I), is provided.

Claims (12)

The following formula (I):

[In formula (I), p is an integer chosen from 0, 1, and 2; R ¹ is a halogen atom, a cyano group, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, a hydroxy. C _1-6 alkyl group, cyanated C _1-6 alkyl group, C _1-6 alkoxy group, halogenated C _1-6 alkoxy group, C _1-6 alkoxy C _1-6 alkyl group, mono / di C _{2- It is a substituent selected from 7} alkanoylamino group, carboxamide group, and C _1-6 alkoxycarbonyl group; ring A is 5-methyl-6- (2-methylpyrimidine-5-yl) -2-phenylpyridine-. 3-Il group], which is a method for producing a compound represented by the following steps:
(1) The following formula (TH-1):

[In the formula (TH-1), p and R ¹ are the same as the definitions in the above formula (I)], the titanium catalyst, and the following formula (LG-1):

A step of adding a ligand represented by (1), a hydrogen peroxide solution, and a buffer solution to a solvent to obtain a mixed solution (1).
(2) The mixed solution (1) was reacted at an outside temperature in the range of 30 ° C. to 50 ° C., and the following formula (EP-1):

A step of obtaining a compound represented by [in formula (EP-1), p and R ¹ are the same as the definitions in the above formula (I)].
(3) A step of obtaining a mixed solution (3) containing the compound represented by the formula (EP-1) and aqueous ammonia.
(4) The mixed solution (3) is reacted at any temperature between 0 ° C. and the temperature at which the mixed solution (3) refluxes, and the following formula (AM-X):

The step of obtaining the compound represented by [in the formula (AM-X), p and R ¹ are the same as the definitions in the above formula (I)].
(5) The following formula (AM-1):

[In the formula (AM-1), ring A is a 5-methyl-6- (2-methylpyrimidine-5-yl) -2-phenylpyridine-3-yl group], and triphosgene. Phosgene, trichloromethyl chloroformate, 2,2,2-trichloroethyl chloroformate, phenyl chloroformate, p-nitrophenyl chloroformate, p-tolyl chloroformate, N, N'-carbonyldiimidazole, and N, N' -A step of adding a urea agent selected from dysuccinimidylcarbonate and a base to a solvent to obtain a mixed solution (5).
(6) The mixed solution (5) was reacted at any temperature between 0 ° C. and the temperature at which the mixed solution (5) refluxed, and the following formula (CB-1):

[In formula (CB-1), ring A is a 5-methyl-6- (2-methylpyrimidine-5-yl) -2-phenylpyridine-3-yl group; Y is a trichloromethoxy group, chlorine. Atomic, 2,2,2-trichloroethoxy group, phenoxy group, p-nitrophenoxy group, p-methylphenoxy group, imidazol-1-yl group, or (2,5-dioxopyrrolidine-1-yl) oxy group The process of obtaining the compound represented by], which is a group selected from
(7) A step of adding a compound represented by the formula (AM-X), a compound represented by the formula (CB-1), and a base to a solvent to obtain a mixed solution (7), and (8). A step of reacting the mixed solution (7) at any temperature between 0 ° C. and the temperature at which the mixed solution (7) refluxes to obtain a compound represented by the formula (I).
A manufacturing method comprising. In formula (I), p is 0 or 1,
R ¹ is a halogen atom or a C _1-6 alkoxy C _1-6 alkyl group.
The titanium catalyst in the step (1) is titanium tetramethoxydo, titanium tetraethoxydo, titanium tetranormal propoxide, titanium tetraisopropoxide, titanium tetranormal butoxide, or titanium tetraterlybutoxide.
The solvent in step (1) is an organic solvent.
The buffer solution in the step (1) is citric acid / NaOH buffer solution, citric acid / sodium citrate buffer solution, boric acid / NaOH buffer solution, phosphate buffer solution, KH ₂ PO ₄ / NaOH buffer solution.
The urea agent in step (5) is phenyl chloroformate, p-tolyl chloroformate, or 2,2,2-trichloroethylchloroformate.
The base in step (5) is an organic base and
The solvent in step (5) is an aprotic polar solvent.
Y in the formula (CB-1) is a phenoxy group, a p-methylphenoxy group, or a 2,2,2-trichloroethoxy group.
The base in step (7) is an organic base and
The solvent in step (7) is an aprotic polar solvent.
The manufacturing method according to claim 1. In formula (I), p is 0,
The titanium catalyst in step (1) is titanium tetraisopropoxide.
The solvent in step (1) is dichloromethane,
The buffer solution in step (1) is a phosphate buffer solution.
The urea agent in step (5) is 2,2,2-trichloroethylchloroformate.
The base in step (5) is pyridine,
The solvent in step (5) is 1,2-dichloroethane.
Y in the formula (CB-1) is a 2,2,2-trichloroethoxy group.
The base in step (7) is diazabicycloundecene,
The solvent in step (7) is dimethyl sulfoxide,
The manufacturing method according to claim 1. In the step (1), the amount of hydrogen peroxide solution is in the range of 1.5 to 10 equivalents with respect to 1 equivalent of the formula (TH-1), and the amount of the titanium catalyst is the amount of the formula (TH-1). The production method according to any one of claims 1 to 3, which is in the range of 0.1 to 10 mol% with respect to -1). The production method according to any one of claims 1 to 4, wherein in the step (1), the pH of the reaction solution is pH = 7.4 to 8.0. The production method according to any one of claims 1 to 5, wherein in the step (1), the amount of the solvent is in the range of 5 to 20 times the mass of the formula (TH-1). The production method according to any one of claims 1 to 6, wherein in the step (1), the reaction temperature (outside temperature) is in the range of 35 to 45 ° C. The production method according to any one of claims 1 to 7, wherein the reaction in step (4) is a sealing reaction using a sealing reaction bottle. The following formula (AM-X):

[In formula (AM-X), p is an integer chosen from 0, 1, and 2; R ¹ is a halogen atom, a cyano group, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group. , Hydroxy C _1-6 alkyl group, cyanated C _1-6 alkyl group, C _1-6 alkoxy group, halogenated C _1-6 alkoxy group, C _1-6 alkoxy C _1-6 alkyl group, mono / di C _{A substituent selected from a 2-7} alkanoylamino group, a carboxamide group, and a C _1-6 alkoxycarbonyl group], which is a method for producing a compound represented by the following steps:
(1) The following formula (TH-1):

[In the formula (TH-1), p and R ¹ are the same as the definitions in the above formula (AM-X)], the titanium catalyst, and the following formula (LG-1):

A step of adding a ligand represented by (1), a hydrogen peroxide solution, and a buffer solution to a solvent to obtain a mixed solution (1).
(2) The mixed solution (1) was reacted at an outside temperature in the range of 30 ° C. to 50 ° C., and the following formula (EP-1):

A step of obtaining a compound represented by [in formula (EP-1), p and R ¹ are the same as the definitions in the above formula (AM-X)].
(3) A step of obtaining a mixed solution (3) containing the compound represented by the formula (EP-1) and aqueous ammonia, and (4) the mixed solution (3) is subjected to the mixed solution (3) from 0 ° C. ) Is carried out at any temperature up to the temperature at which reflux is carried out to obtain a compound represented by the above formula (AM-X).
A manufacturing method comprising. The following formula (EP-1):

[In formula (EP-1), p is an integer chosen from 0, 1, and 2; R ¹ is a halogen atom, a cyano group, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group. , Hydroxy C _1-6 alkyl group, cyanated C _1-6 alkyl group, C _1-6 alkoxy group, halogenated C _1-6 alkoxy group, C _1-6 alkoxy C _1-6 alkyl group, mono / di C _{A substituent selected from a 2-7} alkanoylamino group, a carboxamide group, and a C _1-6 alkoxycarbonyl group], which is a method for producing a compound represented by the following steps:
(1) The following formula (TH-1):

[In the formula (TH-1), p and R ¹ are the same as the definitions in the above formula (EP-1)], the titanium catalyst, and the following formula (LG-1):

A step of adding a ligand represented by (1), a hydrogen peroxide solution, and a buffer solution to a solvent to obtain a mixed solution (1), and (2) the mixed solution (1) having an outside temperature of 30 ° C. to A step of carrying out a reaction at a temperature in the range of 50 ° C. to obtain a compound represented by the above formula (EP-1).
A manufacturing method comprising. The following formula (AM-X):

[In formula (AM-X), p is an integer chosen from 0, 1, and 2; R ¹ is a halogen atom, a cyano group, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group. , Hydroxy C _1-6 alkyl group, cyanated C _1-6 alkyl group, C _1-6 alkoxy group, halogenated C _1-6 alkoxy group, C _1-6 alkoxy C _1-6 alkyl group, mono / di C _{A substituent selected from a 2-7} alkanoylamino group, a carboxamide group, and a C _1-6 alkoxycarbonyl group], which is a method for producing a compound represented by the following steps:
(3) The following formula (EP-1):

A step of obtaining a mixed solution (3) containing a compound represented by the formula (where p and R ¹ are the same as those defined in the formula (AM-X)] and aqueous ammonia. And (4) the mixed solution (3) is reacted at any temperature between 0 ° C. and the temperature at which the mixed solution (3) is refluxed, and the compound represented by the above formula (AM-X) is reacted. The process of getting
A manufacturing method comprising. The following formula (I):

[In formula (I), p is an integer chosen from 0, 1, and 2; R ¹ is a halogen atom, a cyano group, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, a hydroxy. C _1-6 alkyl group, cyanated C _1-6 alkyl group, C _1-6 alkoxy group, halogenated C _1-6 alkoxy group, C _1-6 alkoxy C _1-6 alkyl group, mono / di C _{2- It is a substituent selected from 7} alkanoylamino group, carboxamide group, and C _1-6 alkoxycarbonyl group; ring A is 5-methyl-6- (2-methylpyrimidine-5-yl) -2-phenylpyridine-. 3-Il group], which is a method for producing a compound represented by the following steps:
(5) The following formula (AM-1):

[In the formula (AM-1), ring A is a 5-methyl-6- (2-methylpyrimidine-5-yl) -2-phenylpyridine-3-yl group], and triphosgene. Phosgene, trichloromethyl chloroformate, 2,2,2-trichloroethyl chloroformate, phenyl chloroformate, p-nitrophenyl chloroformate, p-tolyl chloroformate, N, N'-carbonyldiimidazole, and N, N' -A step of adding a urea agent selected from dysuccinimidylcarbonate and a base to a solvent to obtain a mixed solution (5).
(6) The mixed solution (5) was reacted at any temperature between 0 ° C. and the temperature at which the mixed solution (5) refluxed, and the following formula (CB-1):

[In formula (CB-1), ring A is a 5-methyl-6- (2-methylpyrimidine-5-yl) -2-phenylpyridine-3-yl group; Y is a trichloromethoxy group, chlorine. Atomic, 2,2,2-trichloroethoxy group, phenoxy group, p-nitrophenoxy group, p-methylphenoxy group, imidazol-1-yl group, (2,5-dioxopyrrolidin-1-yl) oxy group, The process of obtaining the compound represented by], which is a group selected from the above, etc.
(7) The following formula (AM-X):

In the formula (AM-X), p and R ¹ are the same as the definitions in the formula (I)], the compound represented by the formula (CB-1), and the base. To obtain a mixed solution (7) by adding the mixture to a solvent, and (8) reacting the mixed solution (7) at any temperature between 0 ° C. and the temperature at which the mixed solution (7) refluxes. To obtain the compound represented by the formula (I).
A manufacturing method comprising.