WO2019054450A1 - Method for producing dialkyl dihydronaphthalene derivative - Google Patents

Abstract

Provided is a novel method for producing a compound represented by formula (I). The present invention relates to a method for producing a compound represented by formula (TH-2), and a compound represented by formula (I) via formula (TH-2). Accordingly, a method for producing a 1,1-dialkyl-1,2-dihydronaphthalene derivative and an intermediate of said method are provided.

Description

Method for producing dialkyl dihydronaphthalene derivative

The present invention provides a 1,1-dialkyl-1,2,3,4-tetrahydronaphthalen-2-yl sulfonate derivative represented by the formula (TH-2), and a formula (I) via the formula (TH-2) The present invention relates to a method for producing a 1,1-dialkyl-1,2-dihydronaphthalene derivative represented by

The 1-amino-2-hydroxy-4,4-dialkyl-1,2,3,4-tetrahydronaphthalene represented by the formula (i) is a tropomyosin receptor kinase A (TrkA) represented by the formula (X) It is a compound used when producing a compound having an inhibitory action. The compound of formula (I) can be produced from the compound of formula (I) by an oxidation reaction (epoxidation) and subsequent hydroamination reaction, so the compound of formula (I) is a compound of formula (X) It is an intermediate for synthesis.

One of the compounds represented by the formula (I), 1,1-dimethyl-1,2-dihydronaphthalene (formula (I-a-1)), can be prepared by combining various prior art documents. It can manufacture by the manufacturing method shown to Scheme 2).

Reaction of each process of (Scheme 2) and cited reference:
<Step 1> Esterification Reaction: For example, "Organic Letters, 4 (18), p 3079-3081, 2002" (Non-patent Document 1)
<Step 2> Dialkylation reaction: For example, "Organic & Biomolecular Chemistry, 9 (7), p 2258-2265, 2011" (Non-Patent Document 2)
<Step 3> Cyclization reaction: Example, "Tetrahedron Letters, 54 (32), p 4330-4332, 2013" (Non-patent Document 3)
<Step 4> Oxidation Reaction: For example, “Chemistry Letters, 70 (10), p 1042-1043, 2013” (Non-patent Document 4)
<Step 5> Reductive reaction: For example, "Synlett, 27 (5), p 789-793, 2016" (Non-Patent Document 5)
<Step 6> Dehydration: For example, "International Publication 2014/078454 Pamphlet" (Patent Document 1)

The compound of the formula (I) can be produced according to the method for producing the compound of the above formula (I-a-1) represented by the above (Scheme 2). However, when the production method is used, there are steps that may cause safety problems in large-scale synthesis or industrial production (<step 2> dialkylation reaction at low temperature, <step 4> benzylic An oxidation reaction using peroxide is included. Therefore, when considering the large scale synthesis or industrial production of the compound of the formula (I), it is required to find a novel production method different from the above production method.

In addition, there is no known production method for efficiently synthesizing a large amount of 1,1-dialkyl-1,2-dihydronaphthalene derivatives represented by the formula (I) in a short step.

Accordingly, it has been desired to establish an efficient production method suitable for large-scale synthesis or industrial production of the compound of formula (I) to overcome the above-mentioned problems.

As a 1,1-dialkyl-1,2,3,4-tetrahydronaphthalen-2-yl sulfonate derivative, 7-methoxy-1,1-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl 4- Although methyl benzene sulfonate is known (Non-patent Document 6), its use as a compound for producing a derivative represented by formula (I) is not known.

International Publication 2014/078454 Brochure

An efficient production method suitable for large-scale synthesis or industrial production of a 1,1-dialkyl-1,2-dihydronaphthalene derivative represented by the formula (I), particularly, on the large-scale production or industrial production of the derivative An object of the present invention is to provide a novel production method for producing a compound represented by formula (I) without using the production method of (Scheme 2).

The present inventors have intensively studied to solve the above-mentioned problems. As a result, a 1,1-dialkyl-1,2,3,4-tetrahydronaphthalen-2-yl sulfonate derivative represented by the following formula (TH-2) is found, and the formula (TH-2) is used. A method for producing a 1,1-dialkyl-1,2-dihydronaphthalene derivative represented by the following formula (I) in a high yield, a short process, and easily, and the present invention is completed based on this finding. It came to

(In formula (I) or formula (TH-2), the definitions of p, E, R ¹ , R ^2a and R ^2b are the same as the definitions in the first aspect of the present invention described later.)

The present invention relates to a sulfonate derivative represented by the formula (TH-2) as an intermediate for synthesizing a compound having a TrkA inhibitory activity represented by the formula (X), and a compound represented by the formula (TH-2) The present invention relates to a process for producing a 1,1-dialkyl-1,2-dihydronaphthalene derivative represented by the formula (I). The present invention can provide an industrially advantageous production method with high yield, short process, and easy, and has high industrial utility.

The present invention provides a sulfonate derivative represented by the following formula (TH-2) shown in the following embodiment, and a 1,1-dialkyl-1 represented by the following formula (I) via the formula (TH-2) , A method of producing a 2-dihydronaphthalene derivative. More specifically, exemplary embodiments of the present invention may be as follows [1] to [11].

[1] the following formula (TH-2):

[Wherein p, E, R ¹ , R ^2a and R ^2b in the formula (TH-2) are the same groups as the groups defined in the first aspect of the present invention described later] Or a salt thereof, or a solvate thereof.

[2] the following formula (TH-2a):

[Wherein E, R ^1a , R ^1b , R ^2a and R ^2b in the formula (TH-2a) are the same groups as the groups defined in the second aspect of the present invention described later] A compound, or a salt thereof, or a solvate thereof.

[3] 1,1-Dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl 4-methylbenzenesulfonate, or a salt thereof, or a solvate thereof.

[4] the following formula (I):

A method for producing a compound represented by [wherein p, R ¹ , R ^2a and R ^2b in the formula (I) are the same groups as the groups defined in the fourth embodiment of the present invention described later] .

[5] the following formula (I-a):

[Wherein, in the formula (Ia), R ^1a , R ^1b , R ^2a and R ^2b are the same groups as the groups defined in the fifth aspect of the present invention described later] How to manufacture.

[6] Following Formula (TH-2):

[Wherein, in the formula (TH-2), p, E, R ¹ , R ^2a and R ^2b are the same groups as the groups defined in the sixth aspect of the present invention described later] How to manufacture.

[7] the following formula (TH-2a):

[Wherein E, R ^1a , R ^1b , R ^2a and R ^2b in the formula (TH-2a) are the same groups as the groups defined in the seventh aspect of the present invention described later] How to make a compound.

[8] The following formula (I):

[Wherein, in the formula (I), p, R ¹ , R ^2a and R ^2b are the same groups as the groups defined in the fourth embodiment of the present invention described later] A method of producing from a compound represented by TH-2).

[9] the following formula (I-a):

[Wherein, in the formula (Ia), R ^1a , R ^1b , R ^2a and R ^2b are the same groups as the groups defined in the fifth aspect of the present invention described later] A method of producing from a compound represented by formula (TH-2a).

[10] [(Scheme 4) in the following (Scheme 4), p, E, R ¹ , R ^2a and R ^2b are the same groups as the groups defined in the fourth embodiment 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 formula (I), and an intermediate in the production method .

[11] [(Scheme 5) in the following (Scheme 5), E, R ^1a , R ^1b , R ^2a and R ^2b are the same groups as the groups defined in the fifth aspect of the present invention described later A process for producing a compound represented by the formula (Ia), wherein the reaction conditions for the respective steps are the same as the reaction conditions for the respective steps in the fifth aspect of the present invention described later, and the process for the production Intermediates in.

Aspects of the Invention
An exemplary aspect of the present invention may be more specifically as the following aspects [1] to [7].
[1] A first aspect of the present invention is a compound represented by the following formula (TH-2):

[In the formula (TH-2), p is an integer of 0 to 4;
Each R ¹ independently represents 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, a cyanated C _1-6 alkyl group, a halogenated C 1 _{~ 6} alkoxy group, C 1 _{~ 6} alkoxy C _{1 ~ 6} alkyl group, a mono / di C _{2 ~ 7} alkanoylamino group, carboxamido group, or a group selected from C _{1 ~ 6} alkoxycarbonyl group; R ^2a And R ^2b is each independently a C _1-6 alkyl group;
And E is a group selected from p-toluenesulfonyl group, benzenesulfonyl group, p-nitrobenzenesulfonyl group, 2,4-dinitrobenzenesulfonyl group, methanesulfonyl group, or trifluoromethanesulfonyl group. Or a salt thereof, or a solvate thereof.

[1-1] In the compound of the above formula (TH-2) of the above aspect [1], p is preferably an integer of 0 to 3; more preferably an integer of 0 to 2; still more preferably Is an integer of 0.

[1-2] In the compound of the formula (TH-2) according to the above aspect [1], R ¹ is preferably a halogen atom, a hydroxy C _1-6 alkyl group, a C _1-6 alkoxy C _1-6 alkyl group, a carboxamide group, or a C _{1 ~ 6} alkoxycarbonyl group; more preferably, a halogen atom, or a C _{1 ~ 6} alkoxy C _{1 ~ 6} alkyl group; more preferably, a fluorine atom, a bromine atom, or methoxy It is a methyl group.

[1-3] In the compound of the formula (TH-2) according to the aspect [1], R ^2a and / or R ^2b is preferably a methyl group.

[1-4] In the compound of the above formula (TH-2) of the above aspect [1], preferably, E is a p-toluenesulfonyl group, a benzenesulfonyl group, or a methanesulfonyl group; more preferably, p -Toluenesulfonyl group.

[1-5] In the compound of the above formula (TH-2) of the above aspect [1], preferably p is an integer of 0; R ^2a and / or R ^2b is a methyl group; E is And p-toluenesulfonyl group.

[2] A second aspect of the present invention is a compound represented by the following formula (TH-2a):

[In Formula (TH-2a), R ^1a and R ^1b are each independently a hydrogen atom, 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, a halogenated C _{1 ~ 6} alkoxy group, C 1 _{~ 6} alkoxy C _{1 ~ 6} alkyl group, mono / di C _{2 ~ 7} alkanoylamino group, carboxamido group, or a C _A group selected from _{1 to 6} alkoxycarbonyl groups;
R ^2a and R ^2b are each independently a C _1-6 alkyl group;
And E is a group selected from p-toluenesulfonyl group, benzenesulfonyl group, p-nitrobenzenesulfonyl group, 2,4-dinitrobenzenesulfonyl group, methanesulfonyl group, or trifluoromethanesulfonyl group. Or a salt thereof, or a solvate thereof.

[2-1] In the compound of the formula (TH-2a) according to the above aspect [2], R ^1a and R ^1b are preferably each independently a hydrogen atom, a halogen atom, or a hydroxy C _1-6 alkyl group And C _1-6 alkoxy C _1-6 alkyl group, carboxamido group or C _1-6 alkoxycarbonyl group; more preferably, R ^1a is a hydrogen atom, a halogen atom or C _1-6 alkoxy C ₁ -C _{6 6} alkyl group, R ^1b is a hydrogen atom or a halogen atom; more preferably, R ^1a is a hydrogen atom, a fluorine atom, a bromine atom or a methoxymethyl group, and R ^1b is a hydrogen atom, a fluorine atom And the combination of R ^1a and R ^1b is (R ^1a , R ^1b ) = (hydrogen atom, hydrogen atom), (hydrogen atom, bromine atom), (bromine atom, Hydrogen atom), (methoxymethyl group, hydrogen atom) (Fluorine atom, hydrogen atom), be (hydrogen atom, a fluorine atom), (a fluorine atom, a fluorine atom); particularly preferably, R ^1a and R ^1b is hydrogen atom.

[2-2] In the compound of the formula (TH-2a) of the aspect [2], R ^2a and / or R ^2b is preferably a methyl group.

[2-3] In the compound of the above formula (TH-2a) of the above aspect [2], preferably, E is p-toluenesulfonyl group, benzenesulfonyl group or methanesulfonyl group; more preferably p -Toluenesulfonyl group.

[2-4] In the compound of the formula (TH-2) according to the above aspect [1], preferably, a combination of R ^1a and R ^1b is (R ^1a , R ^1b ) = (hydrogen atom, hydrogen atom), (Hydrogen atom, bromine atom), (bromine atom, hydrogen atom), (methoxymethyl group, hydrogen atom), (fluorine atom, hydrogen atom), (hydrogen atom, fluorine atom), (fluorine atom, fluorine atom) R ^2a and / or R ^2b is a methyl group; E is a p-toluenesulfonyl group.

[2-4-1] In the compound of the formula (TH-2) according to the aspect [2-4], more preferably, R ^1a and R ^1b are a hydrogen atom; and R ^2a and / or R ^2b are , A methyl group; E is a p-toluenesulfonyl group.

[3] A third aspect of the present invention is a method as a preferable compound in the compound of the formula (TH-2) of the aspect [1] or the compound of the formula (TH-2a) of the aspect [2] below The listed compounds, or salts thereof, or solvates thereof.
1,1-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl 4-methylbenzenesulfonate;
6-fluoro-1,1-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl 4-methylbenzenesulfonate;
7-fluoro-1,1-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl 4-methylbenzenesulfonate;
6,7-Difluoro-1,1-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl 4-methylbenzenesulfonate;
6-bromo-1,1-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl 4-methylbenzenesulfonate;
7-bromo-1,1-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl 4-methylbenzenesulfonate;
6- (Methoxymethyl) -1,1-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl 4-methylbenzenesulfonate.

[3-1] In the compound of the above aspect [3], a more preferable compound is 1,1-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl 4-methylbenzenesulfonate, or a salt thereof, or They are solvates.

[4] The fourth aspect of the present invention is a compound of the following formula (I):

[In the formula (I), p is an integer of 0 to 4;
Each R ¹ independently represents 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, a cyanated C _1-6 alkyl group, a halogenated C 1 _{~ 6} alkoxy group, C 1 _{~ 6} alkoxy C _{1 ~ 6} alkyl group, a mono / di C _{2 ~ 7} alkanoylamino group, carboxamido group, or a group selected from C _{1 ~ 6} alkoxycarbonyl group; R ^2a And R ^2b are each independently a C _1-6 alkyl group], a method of producing a compound represented by
Formula (TH-1):

[In the formula (TH-1), p, R ¹ , R ^2a and R ^2b are the same as the groups defined in the above-mentioned formula (I) (a general production method of the formula (TH-1) is A compound represented by the formula (TH-1) and a sulfonylating agent are added to a basic solvent, and the compound represented by the formula (TH-1) and the above A mixed solution containing a sulfonylating agent is formed, and the reaction is performed at a temperature at which the mixed solution containing the compound represented by the formula (TH-1) and the sulfonylating agent is refluxed from 0 ° C. -2):

[Wherein, in the formula (TH-2), p, R ¹ , R ^2a and R ^2b are the same as the groups defined in the above formula (I); E is a p-toluenesulfonyl group, a benzenesulfonyl group , A step selected from the group consisting of p-nitrobenzenesulfonyl group, 2,4-dinitrobenzenesulfonyl group, methanesulfonyl group, and trifluoromethanesulfonyl group] (step [4] -1), The compound represented by the formula (TH-2) and a base are added to a solvent not involved in the reaction to form a mixed solution containing the compound represented by the formula (TH-2) and the base, A step of reacting at 0 ° C. to a temperature at which the mixed solution containing the base and the compound represented by the formula (TH-2) refluxes to obtain a compound represented by the formula (I) (step [4] -2).

[4-1] In the method for producing a compound of the formula (I) according to the above aspect [4], p is preferably an integer of 0 to 3; more preferably an integer of 0 to 2; Preferably, it is an integer of 0.

[4-2] In the method for producing a compound of the formula (I) according to the above aspect [4], R ¹ is preferably a halogen atom, a hydroxy C _1-6 alkyl group, a C _1-6 alkoxy C _1-6 It is an alkyl group, a carboxamido group, or a C _1-6 alkoxycarbonyl group; more preferably a halogen atom or a C _1-6 alkoxy C _1-6 alkyl group; still more preferably a fluorine atom, a bromine atom, or It is a methoxymethyl group. When there are multiple R ^{1 s} , R ^{1 s} may be the same or different.

[4-3] In the method for producing the compound of the formula (I) according to the above aspect [4], R ^2a and / or R ^2b is preferably a methyl group.

[4-4] In the method for producing a compound of the formula (I) according to the above aspect [4], E is preferably p-toluenesulfonyl group, benzenesulfonyl group, or methanesulfonyl group; more preferably p-toluenesulfonyl group.

[4-5] In (Step [4] -1) of the process for producing a compound of Formula (I) according to Aspect [4], preferably, the sulfonylating agent is p-toluenesulfonyl chloride, p-toluenesulfone Acid anhydride, benzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, 2,4-dinitrobenzenesulfonyl chloride, methanesulfonyl chloride, or trifluoromethanesulfonic acid anhydride; more preferably p-toluenesulfonyl chloride, p-toluene Sulfonic acid anhydride, benzene sulfonyl chloride or methane sulfonyl chloride; more preferably p-toluene sulfonyl chloride or p-toluene sulfonic acid anhydride; and particularly preferably p-toluene sulfonyl chloride.

[4-6] In (Step [4] -1) of the process for producing a compound of Formula (I) according to Aspect [4], preferably, the basic solvent is pyridine, triethylamine, N, N-diisopropylethylamine Or 2,6-lutidine; more preferably pyridine.

[4-7] In (Step [4] -1) of the process for producing a compound of Formula (I) according to Aspect [4], preferably, the reaction temperature is 0 ° C. to room temperature.

[4-8] In (Step [4] -2) of the process for producing a compound of Formula (I) according to Aspect [4], preferably, the base is potassium tert-butoxide, sodium tert-butoxide, sodium ethoxy Sodium hydride or 1,8-diazabicyclo [5.4.0] -7-undecene (DBU); more preferably potassium tert-butoxide or sodium tert-butoxide; still more preferably It is potassium tert-butoxide.

[4-9] In (Step [4] -2) of the process for producing a compound of Formula (I) according to Aspect [4], preferably, the solvent not involved in the reaction is tert-butyl alcohol, dimethyl sulfoxide ( DMSO) or N-methyl pyrrolidone (NMP); more preferably tert-butyl alcohol.

[4-10] In (Step [4] -2) of the process for producing a compound of Formula (I) according to Aspect [4], preferably, the reaction temperature is from room temperature to 80.degree.

[4-11] In the method for producing a compound of the formula (I) according to the aspect [4], preferably, p is an integer of 0 to 2; R ¹ is a fluorine atom, a bromine atom, or a methoxymethyl group R ^2a and / or R ^2b is a methyl group; in (Step [4] -1), the sulfonylating agent is p-toluenesulfonyl chloride, the basic solvent is pyridine, and the reaction temperature is 0 C. to room temperature; (Step [4] -2), the base is potassium tert-butoxide, the solvent is tert-butyl alcohol, and the reaction temperature is room temperature to 80.degree.

[4-12] In the method for producing a compound of the formula (I) according to the aspect [4], preferably, p is an integer of 0; and R ^2a and / or R ^2b is a methyl group; In 4] -1), the sulfonylating agent is p-toluenesulfonyl chloride, the basic solvent is pyridine, and the reaction temperature is from 0 ° C. to room temperature; in (Step [4] -2), the base is potassium The solvent is tert-butyl alcohol, and the reaction temperature is from room temperature to 80.degree.

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

[In formula (I-a), R ^1a and R ^1b are each independently a hydrogen atom, 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, a halogenated C _{1 ~ 6} alkoxy group, C 1 _{~ 6} alkoxy C _{1 ~ 6} alkyl group, mono / di C _{2 ~ 7} alkanoylamino group, carboxamido group, or a C A method of producing a compound represented by the formula: R ^2a and R ^2b each independently represents a C _{1 to 6} alkyl group, which is a group selected from _{1 to 6} alkoxycarbonyl groups;
Formula (TH-1a):

[In Formula (TH-1a), R ^1a , R ^1b , R ^2a and R ^2b are the same as the groups defined in Formula (I-a) above (a method for producing Formula (TH-1a) Is the same as the method for producing formula (TH-1) described later) and a sulfonylating agent in a basic solvent, and A mixed solution containing the sulfonylating agent is formed, and the reaction is performed at a temperature at which the mixed solution containing the compound represented by the formula (TH-1a) and the sulfonylating agent is refluxed from 0 ° C. TH-2a):

[Wherein, in the formula (TH-2a), R ^1a , R ^1b , R ^2a and R ^2b are the same as the group defined in the formula (I-a); E is a p-toluenesulfonyl group, A step of obtaining a compound represented by a benzenesulfonyl group, a p-nitrobenzenesulfonyl group, a 2,4-dinitrobenzenesulfonyl group, a methanesulfonyl group, or a trifluoromethanesulfonyl group] (step [5] -1) And a compound represented by the formula (TH-2a) and the base, in a solvent which does not participate in the reaction, from 0 ° C. to the compound represented by the formula (TH-2a) and the base The reaction is carried out at a temperature at which the mixed solution refluxes to obtain a compound represented by the formula (Ia) (step [5] -2).

[5-1] In the method for producing a compound of the formula (I-a) according to the above aspect [5], R ^1a and R ^{1 b} are preferably each independently a hydrogen atom, a halogen atom, a hydroxy C _{1 6} alkyl group, C 1 _{~ 6} alkoxy C _{1 ~ 6} alkyl group, a carboxamide group, or a C _{1 ~ 6} alkoxycarbonyl group; more preferably, R ^1a is a hydrogen atom, a halogen atom, or a C _{1 ~ 6} alkoxy A C _1-6 alkyl group, R ^1b is a hydrogen atom or a halogen atom; more preferably, R ^1a is a hydrogen atom, a fluorine atom, a bromine atom or a methoxymethyl group, and R ^1b is a hydrogen atom A combination of R ^1a and R ^1b which is an atom, a fluorine atom or a bromine atom, more specifically (R ^1a , R ^1b ) = (hydrogen atom, hydrogen atom), (hydrogen atom, bromine atom), Bromine atom, hydrogen atom), (methoxymethyl group, hydrogen) Child), it is a (fluorine atom, hydrogen atom), (hydrogen atom, a fluorine atom), (a fluorine atom, a fluorine atom); Particularly preferably, R ^1a and R ^1b is hydrogen atom.

[5-2] In the method for producing a compound of the formula (Ia) according to the aspect [5], R ^2a and / or R ^2b is preferably a methyl group.

[5-3] In the method for producing a compound of the formula (I-a) according to the aspect [5], E is preferably p-toluenesulfonyl group, benzenesulfonyl group or methanesulfonyl group; more preferably Is a p-toluenesulfonyl group.

[5-4] In (Step [5] -1) of the process for producing a compound of Formula (I-a) according to Aspect [5], preferably, the sulfonylating agent is p-toluenesulfonyl chloride, p- Toluenesulfonic anhydride, benzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, 2,4-dinitrobenzenesulfonyl chloride, methanesulfonyl chloride, or trifluoromethanesulfonic anhydride; more preferably p-toluenesulfonyl chloride, p -Toluenesulfonic acid anhydride, benzenesulfonyl chloride, or methanesulfonyl chloride; more preferably p-toluenesulfonyl chloride or p-toluenesulfonic acid anhydride; particularly preferably p-toluenesulfonyl chloride .

[5-5] In (Step [5] -1) of the process for producing a compound of Formula (I-a) according to Aspect [5], preferably, the basic solvent is pyridine, triethylamine, N, N- Diisopropylethylamine or 2,6-lutidine; more preferably pyridine.

[5-6] In (Step [5] -1) of the process for producing a compound of Formula (I-a) according to Aspect [5], preferably, the reaction temperature is 0 ° C. to room temperature.

[5-7] In (Step [5] -2) of the process for producing a compound of Formula (I-a) according to Aspect [5], preferably, the base is potassium tert-butoxide, sodium tert-butoxide, Sodium ethoxide, sodium hydride or 1,8-diazabicyclo [5.4.0] -7-undecene (DBU); more preferably potassium tert-butoxide, sodium tert-butoxide or sodium ethoxide More preferably potassium tert-butoxide.

[5-8] In (Step [5] -2) of the process for producing a compound of Formula (I-a) according to Aspect [5], preferably, the solvent not involved in the reaction is tert-butyl alcohol, dimethyl Sulfoxide (DMSO) or N-methyl pyrrolidone (NMP); more preferably tert-butyl alcohol.

[5-9] In (Step [5] -2) of the method for producing a compound of Formula (I-a) according to Aspect [5], preferably, the reaction temperature is from room temperature to 80.degree.

[5-10] In the method for producing a compound of the formula (Ia) according to the above aspect [5], preferably, the combination of R ^1a and R ^1b is (R ^1a , R ^1b ) = (hydrogen atom, hydrogen Atom), (hydrogen atom, bromine atom), (bromine atom, hydrogen atom), (methoxymethyl group, hydrogen atom), (fluorine atom, hydrogen atom), (hydrogen atom, fluorine atom), (fluorine atom, fluorine atom) R ^2a and / or R ^2b is a methyl group; in (Step [5] -1), the sulfonylating agent is p-toluenesulfonyl chloride, the basic solvent is pyridine, and the reaction temperature is C. to room temperature; (Step [5] -2), the base is potassium tert-butoxide, the solvent is tert-butyl alcohol, and the reaction temperature is room temperature to 80.degree.

[5-11] In the method for producing a compound of the formula (Ia) according to the above aspect [5], preferably, R ^1a and R ^1b are hydrogen atoms; and R ^2a and / or R ^2b are methyl groups (Step [5] -1), the sulfonylating agent is p-toluenesulfonyl chloride, the basic solvent is pyridine, and the reaction temperature is from 0 ° C. to room temperature; (step [5] -2) In the above, the base is potassium tert-butoxide, the solvent is tert-butyl alcohol, and the reaction temperature is from room temperature to 80.degree.

[6] A sixth aspect of the present invention relates to a compound represented by the following formula (TH-2):

[In the formula (TH-2), p is an integer of 0 to 4;
Each R ¹ independently represents 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, a cyanated C _1-6 alkyl group, a halogenated C 1 _{~ 6} alkoxy group, C 1 _{~ 6} alkoxy C _{1 ~ 6} alkyl group, a mono / di C _{2 ~ 7} alkanoylamino group, carboxamido group, or a group selected from C _{1 ~ 6} alkoxycarbonyl group; R ^2a And R ^2b are each independently a C _1-6 alkyl group; E is a p-toluenesulfonyl group, a benzenesulfonyl group, a p-nitrobenzenesulfonyl group, a 2,4-dinitrobenzenesulfonyl group, a methanesulfonyl group Or a method selected from trifluoromethanesulfonyl group], and a method for producing a compound represented by the formula (TH-1):

[In the formula (TH-1), p, R ¹ , R ^2a and R ^2b are the same as the group defined in the above formula (TH-2)] and a sulfonylating agent In a basic solvent to form a mixed solution containing the compound represented by the formula (TH-1) and the sulfonylating agent, and from 0 ° C. to the compound represented by the formula (TH-1) The reaction is carried out at a temperature at which the mixed solution containing the sulfonylating agent is refluxed to obtain a compound represented by the formula (TH-2).

[6-1] In the method for producing a compound of the formula (TH-2) according to the above aspect [6], p is preferably an integer of 0 to 3; more preferably an integer of 0 to 2 More preferably an integer of 0.

[6-2] In the method for producing a compound of the formula (TH-2) according to the above aspect [6], R ¹ is preferably a halogen atom, a hydroxy C _1-6 alkyl group, a C _1-6 alkoxy C _{1 1-6} alkyl group, a carboxamide group, or a C _{1 - 6} alkoxycarbonyl group; more preferably, a halogen atom, or a C _{1 - 6} alkoxy C _{1 - 6} alkyl group; more preferably, a fluorine atom, a bromine atom Or a methoxymethyl group. When there are multiple R ^{1 s} , R ^{1 s} may be the same or different.

[6-3] In the method for producing a compound of the formula (TH-2) according to the above aspect [6], R ^2a and / or R ^2b is preferably a methyl group.

[6-4] In the method for producing a compound of the formula (TH-2) according to the above aspect [6], E is preferably p-toluenesulfonyl group, benzenesulfonyl group or methanesulfonyl group; more preferably Is a p-toluenesulfonyl group.

[6-5] In the method for producing a compound of the formula (TH-2) according to the above aspect [6], preferably, the sulfonylating agent is p-toluenesulfonyl chloride, p-toluenesulfonic acid anhydride, benzenesulfonyl chloride P-nitrobenzenesulfonyl chloride, 2,4-dinitrobenzenesulfonyl chloride, methanesulfonyl chloride, or trifluoromethanesulfonic acid anhydride; more preferably p-toluenesulfonyl chloride, p-toluenesulfonic acid anhydride, benzenesulfonyl More preferably, p-toluenesulfonyl chloride or p-toluenesulfonic acid anhydride; and particularly preferably p-toluenesulfonyl chloride.

[6-6] In the method for producing a compound of the formula (TH-2) according to the above aspect [6], preferably, the basic solvent is pyridine, triethylamine, N, N-diisopropylethylamine, or 2,6-lutidine More preferably pyridine.

[6-7] In the method for producing a compound of the formula (TH-2) according to the above aspect [6], preferably, the reaction temperature is 0 ° C. to room temperature.

[6-8] In the method for producing a compound of the formula (TH-2) according to the above aspect [6], preferably, p is an integer of 0 to 2; R ¹ is a fluorine atom, a bromine atom, or methoxy R ^2a and / or R ^2b is a methyl group; the sulfonylating agent is p-toluenesulfonyl chloride, the basic solvent is pyridine, and the reaction temperature is from 0 ° C. to room temperature.

[6-9] In the method for producing a compound of the formula (TH-2) according to the above aspect [6], preferably, p is an integer of 0; R ^2a and / or R ^2b is a methyl group; sulfonyl The agent is p-toluenesulfonyl chloride, the basic solvent is pyridine, and the reaction temperature is 0 ° C. to room temperature.

[7] A seventh aspect of the present invention provides a compound represented by formula (TH-2a):

[In Formula (TH-2a), R ^1a and R ^1b are each independently a hydrogen atom, 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, a halogenated C _{1 ~ 6} alkoxy group, C 1 _{~ 6} alkoxy C _{1 ~ 6} alkyl group, mono / di C _{2 ~ 7} alkanoylamino group, carboxamido group, or a C It is a group selected from _1-6 alkoxycarbonyl group; R ^2a and R ^2b are each independently a C _1-6 alkyl group; E is, p- toluenesulfonyl group, a benzenesulfonyl group, p- nitrobenzene A method of producing a compound represented by the formula (TH-1a), which is a group selected from a sulfonyl group, a 2,4-dinitrobenzenesulfonyl group, a methanesulfonyl group, and a trifluoromethanesulfonyl group;

[In the formula (TH-1a), R ^1a , R ^1b , R ^2a and R ^2b are the same as the groups defined in the above-mentioned formula (TH-2a) (a method for producing the formula (TH-1a) The compound represented by the formula (TH-1a) and the sulfonyl are added by adding a compound represented by the formula (TH-1) described below and a sulfonylating agent to a basic solvent, The reaction is performed at a temperature at which the mixed solution containing the compound represented by the formula (TH-1a) and the sulfonylating agent is refluxed from 0 ° C. It is a manufacturing method which obtains the compound represented by 2a).

[7-1] In the method for producing a compound of the formula (TH-2a) according to the above aspect [7], R ^1a and R ^1b are preferably each independently a hydrogen atom, a halogen atom, a hydroxy C _{1 6} alkyl group, C 1 _{~ 6} alkoxy C _{1 ~ 6} alkyl group, a carboxamide group, or a C _{1 ~ 6} alkoxycarbonyl group; more preferably, R ^1a is a hydrogen atom, a halogen atom, or a C _{1 ~ 6} alkoxy A C _1-6 alkyl group, R ^1b is a hydrogen atom or a halogen atom; more preferably, R ^1a is a hydrogen atom, a fluorine atom, a bromine atom or a methoxymethyl group, and R ^1b is a hydrogen atom A combination of R ^1a and R ^1b which is an atom, a fluorine atom or a bromine atom, more specifically (R ^1a , R ^1b ) = (hydrogen atom, hydrogen atom), (hydrogen atom, bromine atom), Bromine atom, hydrogen atom), (methoxymethyl group, Atom), (fluorine atom, hydrogen atom), (hydrogen atom, a fluorine atom), it is (fluorine atom, a fluorine atom); particularly preferably, R ^1a and R ^1b is hydrogen atom.

[7-2] In the method of producing a compound of the formula (TH-2a) according to the above aspect [7], R ^2a and / or R ^2b is preferably a methyl group.

[7-3] In the method for producing a compound of the formula (TH-2a) according to the above aspect [7], E is preferably p-toluenesulfonyl group, benzenesulfonyl group, or methanesulfonyl group; more preferably Is a p-toluenesulfonyl group.

[7-4] In the method for producing a compound of the formula (TH-2a) according to the above aspect [7], preferably, the sulfonylating agent is p-toluenesulfonyl chloride, p-toluenesulfonic acid anhydride, benzenesulfonyl chloride P-nitrobenzenesulfonyl chloride, 2,4-dinitrobenzenesulfonyl chloride, methanesulfonyl chloride, or trifluoromethanesulfonic acid anhydride; more preferably p-toluenesulfonyl chloride, p-toluenesulfonic acid anhydride, benzenesulfonyl More preferably, p-toluenesulfonyl chloride or p-toluenesulfonic acid anhydride; and particularly preferably p-toluenesulfonyl chloride.

[7-5] In the method for producing a compound of the formula (TH-2a) according to the above aspect [7], preferably, the basic solvent is pyridine, triethylamine, N, N-diisopropylethylamine, or 2,6-lutidine More preferably pyridine.

[7-6] In the method for producing a compound of the formula (TH-2a) according to the above aspect [7], preferably, the reaction temperature is 0 ° C. to room temperature.

[7-7] In the method for producing a compound of the formula (TH-2a) according to the above aspect [7], preferably, the combination of R ^1a and R ^1b is (R ^1a , R ^1b ) = (hydrogen atom, hydrogen Atom), (hydrogen atom, bromine atom), (bromine atom, hydrogen atom), (methoxymethyl group, hydrogen atom), (fluorine atom, hydrogen atom), (hydrogen atom, fluorine atom), (fluorine atom, fluorine atom) R ^2a and / or R ^2b is a methyl group; the sulfonylating agent is p-toluenesulfonyl chloride, the basic solvent is pyridine, and the reaction temperature is from 0 ° C. to room temperature.

[7-8] In the method for producing a compound of the formula (TH-2a) according to the above aspect [7], preferably, R ^1a and R ^1b are hydrogen atoms; and R ^2a and / or R ^2b is a methyl group The sulfonylating agent is p-toluenesulfonyl chloride, the basic solvent is pyridine, and the reaction temperature is from 0 ° C. to room temperature.

[8] The eighth aspect of the present invention is a compound of the following formula (I):

[In the formula (I), p is an integer of 0 to 4;
Each R ¹ independently represents 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, a cyanated C _1-6 alkyl group, a halogenated C 1 _{~ 6} alkoxy group, C 1 _{~ 6} alkoxy C _{1 ~ 6} alkyl group, a mono / di C _{2 ~ 7} alkanoylamino group, carboxamido group, or a group selected from C _{1 ~ 6} alkoxycarbonyl group; R ^2a And R ^2b are each independently a C _1-6 alkyl group], and a method of producing a compound represented by the formula (TH-2):

[Wherein, in the formula (TH-2), p, R ¹ , R ^2a and R ^2b are the same as the groups defined in the above formula (I); E is a p-toluenesulfonyl group, a benzenesulfonyl group , A p-nitrobenzenesulfonyl group, a 2,4-dinitrobenzenesulfonyl group, a methanesulfonyl group, or a trifluoromethanesulfonyl group] and a base in a solvent not involved in the reaction In addition, a mixed solution containing the compound represented by the formula (TH-2) and the base is formed, and the mixed solution including the compound represented by the formula (TH-2) and the base from 0 ° C. The reaction is carried out at a reflux temperature to obtain a compound represented by the formula (I).

[8-1] In the method for producing the compound of the formula (I) according to the embodiment [8], p is preferably an integer of 0 to 3; more preferably an integer of 0 to 2; Preferably, it is an integer of 0.

[8-2] In the method for producing a compound of the formula (I) according to the aspect [8], R ¹ is preferably a halogen atom, a hydroxy C _1-6 alkyl group, a C _1-6 alkoxy C _1-6 It is an alkyl group, a carboxamido group, or a C _1-6 alkoxycarbonyl group; more preferably a halogen atom or a C _1-6 alkoxy C _1-6 alkyl group; still more preferably a fluorine atom, a bromine atom, or It is a methoxymethyl group. When there are multiple R ^{1 s} , R ^{1 s} may be the same or different.

[8-3] In the method for producing a compound of the formula (I) according to the embodiment [8], R ^2a and / or R ^2b is preferably a methyl group.

[8-4] In the method for producing a compound of the formula (I) according to the embodiment [8], E is preferably p-toluenesulfonyl group, benzenesulfonyl group or methanesulfonyl group; more preferably p-toluenesulfonyl group.

[8-5] In the method for producing a compound of the formula (I) according to the above aspect [8], preferably, the base is potassium tert-butoxide, sodium tert-butoxide, sodium ethoxide, sodium hydride or 1,1 8-diazabicyclo [5.4.0] -7-undecene (DBU); more preferably potassium tert-butoxide or sodium tert-butoxide; still more preferably potassium tert-butoxide.

[8-6] In the method for producing a compound of the formula (I) according to the above aspect [8], preferably, the solvent not involved in the reaction is tert-butyl alcohol, dimethyl sulfoxide (DMSO), or N-methylpyrrolidone ( NMP); more preferably tert-butyl alcohol.

[8-7] In the method for producing a compound of the formula (I) according to the above aspect [8], preferably, the reaction temperature is from room temperature to 80 ° C.

[8-8] In the method for producing a compound of the formula (I) according to the embodiment [8], preferably, p is an integer of 0 to 2; R ¹ is a fluorine atom, a bromine atom, or a methoxymethyl group R ^2a and / or R ^2b is a methyl group; the base is potassium tert-butoxide, the solvent is tert-butyl alcohol, and the reaction temperature is from room temperature to 80 ° C.

[8-9] In the method for producing a compound of the formula (I) according to the embodiment [8], preferably, p is an integer of 0; R ^2a or R ^2b is a methyl group; the base is potassium tert- It is a butoxide, the solvent is tert-butyl alcohol, and the reaction temperature is from room temperature to 80 ° C.

[9] A ninth aspect of the present invention relates to a compound represented by the following formula (Ia):

[In formula (I-a), R ^1a and R ^1b are each independently a hydrogen atom, 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, a halogenated C _{1 ~ 6} alkoxy group, C 1 _{~ 6} alkoxy C _{1 ~ 6} alkyl group, mono / di C _{2 ~ 7} alkanoylamino group, carboxamido group, or a C A method for producing a compound represented by the formula: TH wherein R ^2a and R ^2b are each independently a C _1-6 alkyl group, which is a group selected from _{1 to 6} alkoxycarbonyl groups; -2a):

[Wherein, in the formula (TH-2a), R ^1a , R ^1b , R ^2a and R ^2b are the same as the group defined in the formula (I-a); E is a p-toluenesulfonyl group, A solvent which does not take part in the reaction between the compound represented by the formula: benzenesulfonyl group, p-nitrobenzenesulfonyl group, 2,4-dinitrobenzenesulfonyl group, methanesulfonyl group, or trifluoromethanesulfonyl group] The reaction is carried out at a temperature at which the mixed solution containing a compound represented by the formula (TH-2a) and the base is refluxed from 0 ° C. to a compound represented by formula (Ia). It is a method.

[9-1] In the method for producing a compound of the formula (I-a) according to the above aspect [9], R ^1a and R ^{1 b} are preferably each independently a hydrogen atom, a halogen atom, a hydroxy C _{1 6} alkyl group, C 1 _{~ 6} alkoxy C _{1 ~ 6} alkyl group, a carboxamide group, or a C _{1 ~ 6} alkoxycarbonyl group; more preferably, R ^1a is a hydrogen atom, a halogen atom, or a C _{1 ~ 6} alkoxy A C _1-6 alkyl group, R ^1b is a hydrogen atom or a halogen atom; more preferably, R ^1a is a hydrogen atom, a fluorine atom, a bromine atom or a methoxymethyl group, and R ^1b is a hydrogen atom A combination of R ^1a and R ^1b which is an atom, a fluorine atom or a bromine atom, more specifically (R ^1a , R ^1b ) = (hydrogen atom, hydrogen atom), (hydrogen atom, bromine atom), Bromine atom, hydrogen atom), (methoxymethyl group, hydrogen) Child), it is a (fluorine atom, hydrogen atom), (hydrogen atom, a fluorine atom), (a fluorine atom, a fluorine atom); Particularly preferably, R ^1a and R ^1b is hydrogen atom.

[9-2] In the method of producing a compound of the formula (Ia) according to the aspect [9], R ^2a and / or R ^2b is preferably a methyl group.

[9-3] In the method for producing a compound of the formula (I-a) according to the above aspect [9], E is preferably p-toluenesulfonyl group, benzenesulfonyl group or methanesulfonyl group; more preferably Is a p-toluenesulfonyl group.

[9-4] In the method for producing a compound of the formula (I-a) according to the above aspect [9], preferably, the base is potassium tert-butoxide, sodium tert-butoxide, sodium ethoxide, sodium hydride or 1,8-diazabicyclo [5.4.0] -7-undecene (DBU); more preferably potassium tert-butoxide, sodium tert-butoxide or sodium ethoxide; still more preferably potassium tert- It is a butoxide.

[9-5] In the method for producing a compound of the formula (I-a) according to the above aspect [9], preferably, the solvent not involved in the reaction is tert-butyl alcohol, dimethyl sulfoxide (DMSO), or N-methyl Pyrrolidone (NMP); more preferably tert-butyl alcohol.

[9-6] In the method for producing a compound of the formula (Ia) according to the above aspect [9], preferably, the reaction temperature is from room temperature to 80 ° C.

[9-7] In the method for producing a compound of the formula (I-a) according to the above aspect [9], preferably, a combination of R ^1a and R ^1b is (R ^1a , R ^1b ) = (hydrogen atom, hydrogen Atom), (hydrogen atom, bromine atom), (bromine atom, hydrogen atom), (methoxymethyl group, hydrogen atom), (fluorine atom, hydrogen atom), (hydrogen atom, fluorine atom), (fluorine atom, fluorine atom) R ^2a and / or R ^2b is a methyl group; the base is potassium tert-butoxide, the solvent is tert-butyl alcohol, and the reaction temperature is from room temperature to 80 ° C.

[9-8] In the method for producing a compound of the formula (I-a) according to the above aspect [9], preferably, R ^1a and R ^1b are hydrogen atoms; and R ^2a and / or R ^2b are methyl groups The base is potassium tert-butoxide, the solvent is tert-butyl alcohol, and the reaction temperature is from room temperature to 80 ° C.

[10] A tenth aspect of the present invention relates to p, E, R ¹ , R ^2a and p in the formulas (TH-1), (TH-2) and (I) in the following (Scheme 6): R ^2b is the same group as defined in the above aspect [4]; the reaction conditions of step [1] -1 and step [1] -2 are the same as the reaction conditions in the above aspect [4] The same is applied to a process for producing a 1,1-dialkyl-1,2-dihydronaphthalene derivative represented by formula (I) and an intermediate of the process.

[11] The eleventh aspect of the present invention relates to E, R ^1a , R ^1b in formulas (TH-1a), (TH-2a) and (Ia) in the following (Scheme 7): R ^2a and R ^2b are the same groups as defined in the above aspect [5]; reaction conditions of step [2] -1 and step [2] -2 are those in the above aspect [5] And the reaction conditions are the same as in the reaction conditions, and a process for producing the 1,1-dialkyl-1,2-dihydronaphthalene derivative represented by the formula (Ia) and an intermediate of the process.

Hereinafter, each group in each formula of the above aspects [1] to [11] will be specifically described.
In the following, each group in the formulas (TH-1), (TH-2), (I) and formulas in the subgenus thereof in the present specification will be specifically described.
In the description of the compound of the present invention, for example, “C _1-6 ” indicates that the number of carbon atoms is 1 to 6, and unless otherwise specified, the total carbon of a linear, branched or cyclic group Represents the number of atoms. For a group containing a chain group and a cyclic group, it means "the total number of carbon atoms in the chain and ring".

In the present specification, unless otherwise specified, the "halogen atom" includes, for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
In the present specification, unless otherwise specified, “halogenated” in the “halogenated C _1-6 alkyl group” and the like means several, preferably 1 to 5 of the aforementioned “halogen atoms” as a substituent. It means that you may have.
In the present specification, unless otherwise specified, "cyanated" in "cyanated C _1-6 alkyl" and the like has several, preferably 1 to 5 "cyano groups" as a substituent. Means that it may be

In the present specification, unless otherwise specified, the "C _1-6 alkyl group" is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, Or a group such as hexyl.

In the present specification, unless otherwise specified, the “halogenated C _1-6 alkyl group” means that the “C _1-6 alkyl” is optionally substituted with several, preferably 1 to 5 halogen atoms. A group such as fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl or pentafluoroethyl. It can be mentioned.

In the present specification, unless otherwise specified, the "hydroxy C _1-6 alkyl group" means that the aforementioned "C _1-6 alkyl" is optionally substituted with several, preferably 1 to 5 hydroxyl groups. And groups such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl or 2,2-dimethyl-2-hydroxyethyl (= 2-hydroxy-2-methylpropyl).
In the present specification, unless otherwise specified, the “cyanated C _1-6 alkyl group” is an optionally substituted “C _1-6 alkyl” with several, preferably 1 to 5 cyano. Groups such as cyanomethyl, 1-cyanoethyl or 2-cyanoethyl.

In the present specification, unless otherwise specified, the "C _1-6 alkoxy group" represents an alkoxy in which the aforementioned "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 or hexyloxy can be mentioned.
In the present specification, unless otherwise specified, the “halogenated C _1-6 alkoxy group” refers to a halogenated alkoxy in which the aforementioned “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.

Herein, unless otherwise specified, the "C _{1 ~ 6} alkoxy C _{1 ~ 6} alkyl group" means a group wherein the above "C _{1 ~ 6} alkoxy" is substituted into the "C _{1 ~ 6} alkyl" Do. In the present specification, unless otherwise specified, the "C _1-6 alkoxy C _1-6 alkyl" is, for example, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, 1,1-dimethoxymethyl or 1, Examples include 1-diethoxyethyl and the like.

Herein, unless otherwise indicated, the term "mono / di C _{2 ~ 7} alkanoylamino group", one or two hydrogen atoms on the nitrogen atom of the "amino group", "C _{1 ~ 6} alkyl "Amino group substituted by -C (O)-group" means, for example, acetamide, propionamide, butyramide, isobutyramide, valeramide, isovaleramide, pivalamide, hexanamide, heptaneamide, cyclopropanecarboxamide, cyclobutanecarboxamide And groups such as cyclopentane carboxamide, cyclohexane carboxamide, 2-methylcyclopropane carboxamide, or diacetamide.

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 substituted with the above “C _1-6 alkyl group”, ie, The term "ester group" means, for example, groups such as methoxycarbonyl (methyl ester), ethoxycarbonyl (ethyl ester) or tert-butoxycarbonyl (tert-butyl ester).

In the above embodiments of the present specification, unless otherwise specified, the “sulfonyl group” is a methanesulfonyl group, p-toluenesulfonyl group, benzenesulfonyl group, p-nitrobenzenesulfonyl group, 2,4-dinitrobenzenesulfonyl group, methane Groups such as a sulfonyl group or a trifluoromethanesulfonyl group can be mentioned. However, the sulfonyl group described above is not necessarily limited.

In the above embodiment, unless otherwise specified, "sulfonylating agent" means one capable of replacing the hydroxy group of the target compound with a sulfonyl group, for example, p-toluene as a sulfonylating agent Examples thereof include sulfonyl chloride, p-toluenesulfonic acid anhydride, benzene sulfonyl chloride, p-nitrobenzene sulfonyl chloride, 2,4-dinitrobenzene sulfonyl chloride, methanesulfonyl chloride, trifluoromethanesulfonic acid anhydride and the like. However, it is not necessarily limited to the sulfonylating agent described above.

In the above embodiments, unless otherwise specified, as the "basic solvent", for example, pyridine, triethylamine, N, N-diisopropylethylamine, 2,6-lutidine, tributylamine, cyclohexyldimethylamine, or N-methyl Basic solvents which do not affect the reaction, such as morpholine, may be mentioned. However, it is not necessarily limited to the basic solvent described above. As these solvents, one type of solvent may be used alone, or two or more types of solvents may be appropriately selected and mixed and used at an appropriate ratio.

In the above specification, unless otherwise specified, the "base" is, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, unless otherwise specified. Sodium bicarbonate, tripotassium phosphate, sodium acetate, cesium fluoride, triethylamine, N, N-diisopropylethylamine, tributylamine, cyclohexyldimethylamine, pyridine, lutidine, 4-dimethylaminopyridine (DMAP), N, N- Dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo [4.3.0] -5-nonene, 1,4-diazabicyclo [2.2.2] octane, 1 , 8-Diazabicyclo [5.4.0] -7-c Decene (DBU), imidazole, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, sodium hydride, potassium hydride, sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, methyllithium, Bases such as n-butyllithium, sec-butyllithium, tert-butyllithium and the like can be mentioned. However, it is not necessarily limited to the bases described above.

In the above embodiments of the present specification, the “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), hexamethylphosphoryl triamide, 1,3-dimethyl-2-imidazolidinone, dimethylsulfoxide (DMSO), acetonitrile , Propionitrile, diethyl ether, diisopropyl ether, diphenyl ether, methyl tert-butyl ether (MTBE), tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane , Methyl acetate, ethyl acetate, butyl acetate, acetone, methyl ethyl ketone, dichloromethane, chloroform, carbon tetrachloride, and the solvent does not affect to the reaction selected from 1,2-dichloroethane and the like. However, it is not necessarily limited to the solvent described above. As these solvents, one type of solvent may be used alone, or two or more types of solvents may be appropriately selected and mixed and used at an appropriate ratio.

In the present specification, unless otherwise specified, when a cyclic group is substituted by a variable substituent, it means that the variable substituent is not bonded to a specific carbon atom of the cyclic group. For example, the variable substituent R ^x in the following formula A means that any of carbon atoms i, ii, iii or iv in the formula A can be substituted.

Optical isomers may exist in the hydroxyl group in the formula (TH-1) of the compound in the present specification. In the present specification, unless otherwise specified, it is meant that the formula (TH-1) includes isomers represented by (R) -isomer and (S) -isomer. Similarly, the formulas (TH-2), (TH-1a) and (TH-2a) also mean that isomers represented by (R) -isomer and (S) -isomer are included.

The compounds of the present invention may form an acid addition salt or form a salt with a base, depending on the type of substituent. Such salts are not particularly limited as long as they are pharmaceutically acceptable salts, and examples thereof include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, basicity, Or salts with acidic amino acids. Preferred examples of the metal salt include, for example, 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, aluminum salt and the like (For example, in addition to mono salts, disodium salts and dipotassium salts are also included). Preferred examples of the salts with organic bases include, for example, methylamine, ethylamine, t-butylamine, t-octylamine, diethylamine, trimethylamine, triethylamine, cyclohexylamine, dicyclohexylamine, dibenzylamine, ethanolamine, diethanolamine, triamine Ethanolamine, piperidine, morpholine, pyridine, picoline, lysine, arginine, ornithine, ethylenediamine, N-methylglucamine, glucosamine, phenylglycine alkyl ester, guanidine, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, N And salts with N, N'-dibenzylethylenediamine and the like. Preferred examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferred examples of salts with organic acids are, for example, formic acid, acetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, enanthate, capric acid, myristic acid, palmitic acid, stearic acid, lactic acid, sorbic acid, Salts with aliphatic monocarboxylic acids such as mandelic acid, salts with aliphatic dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, fumaric acid, fumaric acid, maleic acid, malic acid and tartaric acid, 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, pyruvic acid, oxylic acid, salicylic acid, N-acetylcysteine, etc. Salts with organic carboxylic acids, salts with organic sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc., aspartic acid, Acid addition salts with acidic amino acids such as phosphate and the like. Preferred 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. Among these, pharmaceutically acceptable salts are preferred. For example, when the compound has an acidic functional group, inorganic salts such as alkali metal salts (eg, sodium salt, potassium salt etc.), alkaline earth metal salts (eg, calcium salt, magnesium salt, barium salt etc.), Ammonium salts and the like, and when having a basic functional group in the compound, for example, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid, And salts with organic acids such as oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid and the like.

The salt is formed into a desired salt by, for example, mixing a solution containing the compound of the present invention and an appropriate amount of an acid or a base according to a conventional method, followed by fractional filtration, or the mixed solvent is distilled off. It can be obtained by In addition, the compound of the present invention or a salt thereof may form a solvate with a solvent such as water, ethanol, glycerol and the like.
As a review on salts, Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Stahl & Wermuth (Wiley-VCH, 2002) have been published, and a detailed description is made in this document.

The compounds herein may exist in unsolvated or solvated forms. As used herein, "solvate" refers to a molecular complex comprising the compound of the present invention 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 may be geometrical isomers (geometrical isomers), configurational isomers (configurational isomers), tautomers (tautomeric isomers), optical isomers (optical isomers), stereoisomers (diastereomers) In the case of having an isomer such as a mer), a regioisomer (regioisomer) or a rotamer (rotational isomer), either one isomer or a mixture is also encompassed in the compound of the present invention.

When geometric isomers, configurational isomers, stereoisomers, conformers and the like are present in the compound in the present specification, each can be isolated by known means.

When the compounds in the present specification contain optical isomers, stereoisomers, regioisomers, rotamers or tautomers, each isomer may be a single compound by a synthesis method known per se, a separation method. It can be obtained as one compound. For example, as the optical resolution method, a method known per se, such as (1) fractional recrystallization method, (2) diastereomer method, (3) chiral column method and the like can be mentioned.

(1) Fractional Recrystallization Method: A crystalline diastereomer is obtained by ionically binding an optical resolution agent to a racemate, and then separated by the fractional recrystallization method, if necessary, the neutralization step It is a method of obtaining free optically pure compounds. Optical resolution agents include, for example, (+)-mandelic acid, (-)-mandelic acid, (+)-tartaric acid, (-)-tartaric acid, (+)-1-phenethylamine, (-)-1-phenethylamine, Cinchonin, (-)-cinchonidin, brucine etc. may be mentioned.

(2) Diastereomer method: A mixture of racemates is covalently bonded (reacted) to an optical resolution agent to form a mixture of diastereomers, which is then subjected to ordinary separation means (eg, fractional recrystallization, silica gel column chromatography After separation into optically pure diastereomers via HPLC (high performance liquid chromatography) etc., and then optical purification by removing the optical resolution agent by chemical treatment such as hydrolysis reaction. Is a method of obtaining various optical isomers. For example, when a compound of the present invention has a hydroxyl group or a primary or secondary amino group in the molecule, the compound and an optically active organic acid (eg, MTPA [α-methoxy-α- (trifluoromethyl) phenylacetic acid], By subjecting (-)-menthoxyacetic acid etc. and the like to a condensation reaction, diastereomers of ester or amide form can be obtained, respectively. On the other hand, when the compound of the present invention has a carboxy group in the molecule, the compound and an optically active amine or alcohol reagent are subjected to a condensation reaction to obtain an amide form or an ester form of the diastereomer, respectively. Each of the above separated diastereomers is converted to an optical isomer of the original compound by acid hydrolysis or basic hydrolysis reaction.

(3) Chiral column method: A method of direct 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, water, various buffers (eg, phosphate buffer), The optical isomers can be separated by developing using an organic solvent (eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine) alone or as a mixed solution. Also, 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 Inc.).

The compounds herein may also be crystalline. In the case of crystals, single crystals or a mixture of crystals are included in the compounds of the present invention. In addition, when crystals of the compound in the present specification have crystal polymorphism, any crystal form is also included in the compound of the present invention.

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

Compounds herein include isotopes (eg, isotopes of hydrogen, isotopes of carbon such as ² H and ³ H, isotopes of chlorine such as ¹¹ C, ¹³ C, and ¹⁴ C, ³⁶ Cl, etc. , Fluorine isotopes, ¹⁸ F, iodine isotopes, ¹²³ I and ¹²⁵ I, nitrogen isotopes, ¹³ N and ¹⁵ N, oxygen isotopes, such as ¹⁵ O, ¹⁷ O, and ¹⁸ O Also included are compounds labeled or substituted with isotopes of phosphorus, such as ³² P, and isotopes of sulfur, such as ³⁵ S).

Compounds of the present invention that are 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) used in the above, and is useful in the field of medical diagnosis and the like.

Compounds of the present invention that are labeled or substituted with certain isotopic labels are useful in drug and / or substrate tissue distribution studies. For example, ³ H and ¹⁴ C are useful for the research purpose in that they are easy to label or replace and easy to detect.

Isotopically labeled compounds of the present invention may be obtained by conventional techniques known to those skilled in the art or by methods analogous to the synthetic methods described in the examples below. Also, instead of unlabeled compounds, the isotope labeled compounds obtained can be used for pharmacological experiments.

In the production method of the present invention, “the temperature at which the mixed solution containing the compound represented by the above formula (TH-1) and the sulfonylating agent is refluxed from 0 ° C.”, “from 0 ° C. to the above formula (TH-2) A temperature at which the mixed solution containing the compound represented by the above and the base refluxes, "from 0 ° C to the mixed solution containing the compound represented by the formula (TH-1a) and the sulfonylating agent, The meaning of “temperature” and “the temperature at which the mixed solution containing the compound represented by the above formula (TH-2a) and the base is refluxed from 0 ° C.” means each mixed solution (from 0 ° C.) The term "solvent" refers to any temperature within the range of the reflux temperature.
In the present specification, unless otherwise specified, "room temperature" means laboratory, laboratory temperature, etc., usually about 1 ° C. to about 30 ° C., preferably usually about 5 ° C. to about 30 ° C. More preferably, it exhibits a temperature of usually about 15 ° C. to about 25 ° C., more preferably 20 ± 3 ° C.

In the production method of the present invention, one type of solvent may be used alone, or two or more types of solvents may be mixed and used at an appropriate ratio, as appropriate selected according to the reaction conditions.
In the production method of the present invention, the steps of extraction, drying, purification and the like of the compound may be appropriately performed by a 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 sufficiently proceeds, unless otherwise specified.

[Method for producing compound represented by the formula (TH-1) in the present specification]
Hereinafter, the method for producing the compound represented by the formula (TH-1) in the present invention will be described in detail. The compound represented by the formula (TH-1) and a solvate thereof are generally known compounds which can be easily obtained from commercially available compounds or commercially available compounds by a production method known in the literature as a starting material or a synthetic intermediate. It can be easily produced by combining chemical production methods, and can be produced, for example, according to the representative production methods shown below.
In the formulas (SM-2) and (KT-1), the definitions of p, R ¹ , R ^2a and R ^2b are described in the embodiments [1] to [4] unless otherwise specified. Are identical to their respective definitions.

In the method for producing the compound of formula (TH-1), the compounds of formula (SM-2) and formula (KT-1) may form a salt, and such a salt is pharmaceutically acceptable. It is not particularly limited as long as it is a salt to be obtained, and examples thereof include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. Preferred examples of the metal salt include, for example, 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, aluminum salt and the like (For example, in addition to mono salts, disodium salts and dipotassium salts are also included). Preferred examples of the salts with organic bases include, for example, methylamine, ethylamine, t-butylamine, t-octylamine, diethylamine, trimethylamine, triethylamine, cyclohexylamine, dicyclohexylamine, dibenzylamine, ethanolamine, diethanolamine, triamine Ethanolamine, piperidine, morpholine, pyridine, picoline, lysine, arginine, ornithine, ethylenediamine, N-methylglucamine, glucosamine, phenylglycine alkyl ester, guanidine, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, N And salts with N, N'-dibenzylethylenediamine and the like. Preferred examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferred examples of salts with organic acids are, for example, formic acid, acetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, enanthate, capric acid, myristic acid, palmitic acid, stearic acid, lactic acid, sorbic acid, Salts with aliphatic monocarboxylic acids such as mandelic acid, salts with aliphatic dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, fumaric acid, fumaric acid, maleic acid, malic acid and tartaric acid, 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, pyruvic acid, oxylic acid, salicylic acid, N-acetylcysteine, etc. Salts with organic carboxylic acids, salts with organic sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc., aspartic acid, Acid addition salts with acidic amino acids such as phosphate and the like. Preferred 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. Among these, pharmaceutically acceptable salts are preferred. For example, when the compound has an acidic functional group, inorganic salts such as alkali metal salts (eg, sodium salt, potassium salt etc.), alkaline earth metal salts (eg, calcium salt, magnesium salt, barium salt etc.), Ammonium salts and the like, and when having a basic functional group in the compound, for example, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid, And salts with organic acids such as oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid and the like.

Further, in the method for producing the compound of the formula (TH-1), the compound of the formula (KT-1) can be used in the next reaction as the reaction liquid or as a crude product, but from the reaction mixture It can be separated and can be easily purified by a means known per se, such as extraction, concentration, neutralization, filtration, distillation, recrystallization, chromatography and the like.

In the method for producing the compound of the formula (TH-1), functional groups (for example, carboxy group, amino group, hydroxyl group, carbonyl group, mercapto group) to which the compounds of the formula (SM-2) and the formula (KT-1) can be converted , C 1 _{~ 6} alkoxycarbonyl group, C 6 _{~ 14} aryloxycarbonyl group, C 7 _{~ 20} aralkyloxycarbonyl group, a sulfo group (-SO ₂ OH), when containing a halogen atom, etc.), these functional groups, For example, in the book written by Richard C. Larock et al., Comprehensive Organic Transformations, Second Edition, October 1999, Wiley-VCH, Inc. It can be converted according to the method described.

Further, in the method for producing the compound of the formula (TH-1), the compound of the formula (SM-2) and the formula (KT-1) has a hydroxyl group (alcoholic hydroxyl group, phenolic hydroxyl group, heterocyclic hydroxyl group etc.) as a substituent When there are reactive groups such as an amino group, a carboxy group and a thiol group, these groups can be appropriately protected, and the protective groups can be removed at an appropriate stage. The method for introducing and removing such protective groups may be appropriately selected depending on the type of the protected group or the protective group. For example, Protective Groups in Organic Synthesis (Protective Groups in Organic) by Greene et al. Synthesis) The fourth edition, 2007, can be carried out by the method described in the book of John Wiley & Sons (John Wiley & Sons).

In the method for producing a compound of the formula (TH-1) described below, the reaction conditions in the production method are as follows unless otherwise specified. 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 term "range from -78 ° C to the temperature at which the solvent refluxes" at the above reaction temperature means a temperature within the range from -78 ° C to the temperature at which the solvent (or mixed solvent) used for the reaction is refluxed. . 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 of -78 ° C to a temperature at which methanol refluxes. Similarly, “at a temperature from −78 ° C. to reflux of the reaction solution” means any temperature within the range from −78 ° C. to a temperature at which the reaction solution refluxes.

In addition, each step in the process for producing a compound of the formula (TH-1) described below can be carried out without solvent, or by dissolving or suspending the starting compound in a solvent not involved in an appropriate reaction before the reaction. . Examples of the solvent not involved in the reaction include water, cyclohexane, hexane, benzene, chlorobenzene, toluene, xylene, methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, N, N-dimethylformamide (for example) DMF), N, N-dimethylacetamide, N-methylpyrrolidone (NMP), hexamethylphosphoric triamide, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, acetonitrile, propionitrile, diethyl ether, diisopropyl Ether, diphenyl ether, methyl tert-butyl ether (MTBE), tetrahydrofuran, 2-methyltetrahydrofuran, 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, acetic anhydride, formic acid, acetic acid, propionic acid, trifluoroacetic acid, methane sulfone Acids, hydrochloric acid, sulfuric acid and the like can be mentioned. These solvents may be used alone, or may be appropriately selected according to the reaction conditions, and two or more solvents may be mixed and used in an appropriate ratio. These solvents are suitably selected according to reaction conditions.
In the production method of the present specification, unless otherwise specified, when describing as “a solvent not involved in the reaction” or “a solvent inert to the reaction”, one type of solvent may be used alone. Alternatively, it means that two or more solvents may be mixed and used at an appropriate ratio, which is appropriately selected according to the reaction conditions.

Examples of the base (or deacidifying agent) used in each step in the method for producing a compound of the formula (TH-1) described below include, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, carbonate Lithium, 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-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo [4.3.0] -5-nonene, 1, 4-Diazabicyclo [2.2.2] octane, 1,8 Diazabicyclo [5.4.0] -7-undecene (DBU), imidazole, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, sodium hydride, potassium hydride, sodium amide, lithium diisopropylamide And lithium hexamethyldisilazide, methyllithium, n-butyllithium, sec-butyllithium, tert-butyllithium and the like. However, it is not necessarily limited to what was described above. These bases are suitably selected according to reaction conditions.

The acid or acid catalyst used in each step in the process for producing the compound of the formula (TH-1) described below is, for example, hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, Oxalic acid, phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, boron trifluoride ether complex, zinc iodide, anhydrous aluminum chloride And anhydrous zinc chloride, anhydrous iron chloride and the like. However, it is not necessarily limited to what was described above. These acids or acid catalysts are suitably selected according to reaction conditions.

[Production Method A] A method for producing a compound represented by the formula (TH-1):

<Step 1> Compound Represented by Formula (SM-2) and Compound Represented by Formula (RG-1) (In Formula (RG-1), X Represents a Halogen Atom) [Formula (SM-2) And a compound of the formula (RG-1) is a commercially available compound, or a compound which can be produced from the commercially available compound according to a known production method in the literature] using a method known in the literature, for example, Journal of the American Chemical Society (Journal · Potassium hydroxide, sodium hydroxide, sodium hydride, potassium tert-butoxide according to the method described in “The American Chemical Society”, 115 (23), p10628-36, 1993 ”and the like. Such as tetrabutylammonium hydrogen sulfate in the presence of a base such as sodium tert-butoxide In a solvent which does not participate in the reaction such as tert-butyl alcohol, tetrahydrofuran, toluene, dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP) or the like in the presence or absence of a sodium salt, from 0 ° C. to a temperature at which the solvent refluxes The reaction can be carried out to produce a compound represented by the formula (KT-1).

<Step 2> [Production Method A] Using a compound represented by the formula (KT-1) obtained in <Step 1>, known methods in the literature, for example, “Experimental Chemical Lecture 4th Edition 26 Organic Synthesis VIII Sodium borohydride, lithium borohydride, hydrogenated diisobutylaluminum hydride (DIBAH), hydrogenation according to the method described in “Analytical synthesis, reduction, sugar, labeling compound”, page 234-245, 1992, Maruzen ”, etc. Diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4 in the presence of reducing agents such as lithium aluminum (LAH), borane-tetrahydrofuran (BH ₃ · THF), borane-dimethyl sulfide (BH ₃ · Me ₂ S) -In a solvent not involved in the reaction, such as dioxane, methanol, ethanol, 2-propanol, or a mixed solvent thereof From the solvent to carry out the reaction at a temperature at which reflux can be produced a compound represented by the formula (TH-1).

The formula (TH-1a) corresponding to the lower formula of the formula (TH-1) can be produced according to the production method of the above formula (TH-1).

Preparation of 1-amino-2-hydroxy-4,4-dialkyl-1,2,3,4-tetrahydronaphthalene represented by formula (i) from the compound of formula (I) obtained in the present invention The method will be described in detail.
[Production Method B] [Method for Producing Compound Represented by Formula (i)]
The definitions of p, R ¹ , R ^2a and R ^{2b in} the formulas of the formula (EP-1) and the formula (i) are the respective ones described in the embodiments [1] to [4] unless otherwise specified. It is identical to the definition of

<Step 1> Using a compound represented by the formula (I), the method is known in the literature, for example, described in “Experimental Chemistry Lecture 4th Edition 20 Organic Synthesis V Oxidation Reaction, p.276-280, 1992, Maruzen” Hydrogen peroxide (H ₂ O ₂ ), m-chloroperbenzoic acid (MCPBA), trifluoroperacetic acid (CF ₃ COOOH), Oxone (registered trademark) (DuPont) or tert-butyl according to the method described In a solvent which does not participate in the reaction such as dichloromethane, chloroform, toluene, benzene, acetonitrile, acetone, water or the like in the presence of a peracid or peroxide such as hydroperoxide (TBHP) or a mixed solvent thereof from 0 ° C. The reaction can be carried out at a temperature at which the compound refluxes to produce a compound represented by the formula (EP-1).

<Step 2> [Production Method B] Using a compound represented by the formula (EP-1) obtained in <Step 1>, known methods in the literature, for example, “Journal of the Chemical Society, Perkin Transactions 1, p 2807 The solvent is refluxed from 0 ° C. using ammonia water, a mixed solution of ammonia water / ethanol, a mixed solution of ammonia water / 7 N ammonia-methanol solution, etc. according to the method described in “2810, 1983”. The reaction can be carried out at temperature to produce a compound of formula (i). The compound of the formula (i) thus obtained can be resolved into chiral compounds by the above-mentioned optical resolution method.

[Production Method C] [Method for Producing Compound Represented by Formula (i-a)]
The compound of the formula (ia) can be produced according to the above-mentioned [Production method B] using the formula (Ia) corresponding to the subformula of the formula (I). Further, the compound of the formula (ia) obtained can be resolved into a chiral compound by the above-mentioned optical resolution method.
In the formulas (EP-1-a) and (ia), the definitions of R ^1a , R ^1b , R ^2a and R ^2b are the above embodiments [1] to [5] unless otherwise specified. It is identical to each definition described in.

EXAMPLES The following examples are provided to further illustrate the present invention in detail, but these examples are merely examples, and do not limit the scope of the present invention, and do not limit the scope of the present invention. May be

JEOL JNM-ECX400 FT-NMR (Nippon Electron) was used for measurement of nuclear magnetic resonance spectrum (NMR). Liquid chromatography-mass spectrometry (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), acetonitrile: 0.05% aqueous trifluoroacetic acid solution 5: 95 (0 min) to 95: 5 Mobile phases and gradient conditions from (1.0 min) to 95: 5 (1.6 min) to 5:95 (2.0 min) were used.

^{In 1} H-NMR data, 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 Is heavy chloroform, DMSO-D ₆ is heavy dimethyl sulfoxide, and CD ₃ OD is heavy methanol. ^{In the 1} H-NMR data, signals that can not be identified because of broadband such as hydroxyl group (OH), amino group (NH ₂ ), proton of carboxyl group (COOH), etc. are not described in the data.

In LC-Mass data, M means molecular weight, RT means retention time, [M + H] ⁺ , [M + Na] ⁺ means molecular ion peak.

In the examples, "room temperature" usually refers to a temperature of about 1 ° C to about 30 ° C.

Example 1 Synthesis of 1,1-Dimethyl-1,2-dihydronaphthalene:
<Step 1> Synthesis of 1,1-Dimethyl-3,4-dihydronaphthalen-2 (1H) -one:
Commercially available 3,4-dihydronaphthalene-2 in a solution of tetrabutylammonium hydrogen sulfate (13.9 g) and 50% aqueous potassium hydroxide (75.0 g) in tetrahydrofuran (93.5 mL) under ice-water cooling A solution of (1H) -one (CAS number 530-93-8) (37.5 g) and iodomethane (40.1 mL) in tetrahydrofuran (93.5 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, extraction was performed twice with tert-butyl methyl ether, and the organic layer was washed with 1 N hydrochloric acid and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give a crude product of the title compound as a brown oil.
LCMS: m / z 175 [M + H] ⁺ , UPLC retention time: 1.02 minutes

<Step 2> Synthesis of 1,1-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol:
(Example 1) Sodium borohydride (9.7 g) was added in two portions to a solution of the crude product obtained in <Step 1> in methanol (223.5 mL) under ice-water cooling, Stir for 1 hour. After water (100 mL) was added to the reaction solution, methanol was distilled off under reduced pressure, and the obtained residue was treated twice with tert-butyl methyl ether with tert-butyl methyl ether / ethyl acetate = 1/1 mixed solution It extracted once. Heptane is added to the organic phase, and the mixture is concentrated under reduced pressure. A mixed solution of tert-butyl methyl ether / heptane = 1/2 (100 mL) is added to the obtained residue and stirred for 3 hours under ice water cooling. The title compound (37.2 g, 82%) was obtained as a white solid.
LCMS: m / z 175 [M + H] ⁺ , UPLC retention time: 0.94 minutes

<Step 3> Synthesis of 1,1-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl 4-methylbenzenesulfonate:
(Example 1) p-toluenesulfonyl chloride (32.5 g) was added to a solution of the compound (15 g) obtained in <Step 2> in pyridine (75 mL) under ice-water cooling, and stirred at room temperature for 40 hours did. To the reaction mixture was added 1N aqueous sodium hydroxide solution (100 mL) under ice-water cooling, and the mixture was stirred at room temperature for 30 minutes. Water was added to the mixture and extracted with tert-butyl methyl ether. The organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (24.5 g, 87%) as a white solid.
LCMS: m / z 331 [M + H] ⁺ , UPLC retention time: 1.27 minutes * (CDCl ₃ ) δ: 7.81 (2H, d, J = 8 Hz), 7.32 (2H, d, J = 8 Hz), 7.24 (1 H, d, J = 8 Hz), 7.16-7.06 (2 H, m), 7.02 (1 H, d, J = 8 Hz), 4.69 (1 H , Dd, J = 6, 5 Hz), 2. 94 (1 H, dt, J = 17, 7 Hz), 2. 78 (1 H, dt, J = 17, 7 Hz), 2. 44 (3 H, s) ), 2.12-2.07 (2H, m), 1.24 (3H, s), 1.20 (3H, s)

<Step 4> Synthesis of 1,1-dimethyl-1,2-dihydronaphthalene:
Example 1 To a solution of the compound (24 g) obtained in <Step 3> in tert-butyl alcohol (120 mL) was added potassium tert-butoxide (16.5 g) at room temperature, Heated for time. Water was added to the reaction solution, and extracted twice with tert-butyl methyl ether. The organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (11.0 g, 92%) as a yellow oil.
MS-ESI (m / z) [M + H] ⁺ = 159 (retention time 1.25 min): [UPLC] [Method A] Waters AQUITY UPLC system and CAPCELL Pak column (2.0 mm × 50 mm, 3 μm) (Shiseido) Methanol: 0.05% aqueous trifluoroacetic acid solution 5: 95 (0 minutes) to 95: 5 (1.0 minutes) to 95: 5 (1.6 minutes) to 5: 95 (2.0 minutes) Mobile phase and gradient conditions were used.
(CDCl ₃ ) δ: 7.30 (1 H, d, J = 7 Hz), 7.22-7.12 (2 H, m), 7.04 (1 H, dd, J = 7, 2 Hz), 6 .48-6.43 (1 H, m), 5.97-5.91 (1 H, m), 2.26 (2 H, dd, J = 4, 2 Hz), 1.28 (6 H, s).

According to the present invention, there is provided a process which is suitable for short-step and industrial production of a compound represented by formula (I). In addition, useful synthetic intermediates in the production method represented by formula (TH-2) are provided.

Claims (4)

1. Formula (TH-2):
   

   

   [In the formula (TH-2), p is 0 to 4;
   Each R ¹ independently represents 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, a cyanated C _1-6 alkyl group, a halogenated C 1 _{~ 6} alkoxy group, C 1 _{~ 6} alkoxy C _{1 ~ 6} alkyl group, a mono / di C _{2 ~ 7} alkanoylamino group, carboxamido group, or a group selected from C _{1 ~ 6} alkoxycarbonyl group; R ^2a And R ^2b is each independently a C _1-6 alkyl group;
   And E is a group selected from p-toluenesulfonyl group, benzenesulfonyl group, p-nitrobenzenesulfonyl group, 2,4-dinitrobenzenesulfonyl group, methanesulfonyl group, or trifluoromethanesulfonyl group. Or a salt thereof, or a solvate thereof.
2. Formula (TH-2a):
   

   

   [In the formula (TH-2a),
   R ^1a and R ^1b are each independently a hydrogen atom, 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, a cyanated C _{1- 6} alkyl group, a halogenated C _{1 ~ 6} alkoxy group, C 1 _{~ 6} alkoxy C _{1 ~ 6} alkyl group, and a mono- / di-C _{2 ~ 7} alkanoylamino group, carboxamido group, or a C _{1 ~ 6} alkoxycarbonyl group Is the basis;
   R ^2a and R ^2b are each independently a C _1-6 alkyl group;
   And E is a group selected from p-toluenesulfonyl group, benzenesulfonyl group, p-nitrobenzenesulfonyl group, 2,4-dinitrobenzenesulfonyl group, methanesulfonyl group, or trifluoromethanesulfonyl group, or a compound thereof A salt, or a solvate thereof.
3. The following formula (I):
   

   

   [In the formula (I), p is an integer of 0 to 4;
   Each R ¹ independently represents 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, a cyanated C _1-6 alkyl group, a halogenated C 1 _{~ 6} alkoxy group, C 1 _{~ 6} alkoxy C _{1 ~ 6} alkyl group, a mono / di C _{2 ~ 7} alkanoylamino group, carboxamido group, or a group selected from C _{1 ~ 6} alkoxycarbonyl group; R ^2a And R ^2b are each independently a C _1-6 alkyl group], a method of producing a compound represented by
   Following formula (TH-1):
   

   

   [Wherein, in the formula (TH-1), p, R ¹ , R ^2a and R ^2b are the same as the definition in the above-mentioned formula (I)] and a sulfonylating agent in a basic solvent To form a mixed solution containing the compound represented by the formula (TH-1) and the sulfonylating agent, and from 0.degree. C. to the compound represented by the formula (TH-1) and the sulfonylating agent. The reaction is carried out at a temperature at which the mixed solution containing
   

   

   [Wherein, in the formula (TH-2), p, R ¹ , R ^2a and R ^2b are as defined in the formula (I); E represents a p-toluenesulfonyl group, a benzenesulfonyl group, p-nitrobenzene A step of obtaining a compound represented by the formula (TH-2), which is a group selected from a sulfonyl group, a 2,4-dinitrobenzenesulfonyl group, a methanesulfonyl group, and a trifluoromethanesulfonyl group; And a base are added to a solvent not involved in the reaction to form a mixed solution containing the compound represented by the formula (TH-2) and the base, and from 0 ° C. to the formula (TH-2) A process comprising: reacting at a temperature at which the mixed solution containing the compound represented by the base and the base is refluxed to obtain the compound represented by the formula (I).
4. The following formula (I-a):
   

   

   [In formula (I-a), R ^1a and R ^1b are each independently a hydrogen atom, 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, a halogenated C _{1 ~ 6} alkoxy group, C 1 _{~ 6} alkoxy C _{1 ~ 6} alkyl group, mono / di C _{2 ~ 7} alkanoylamino group, carboxamido group, or a C A method of producing a compound represented by the formula: R ^2a and R ^2b each independently represents a C _{1 to 6} alkyl group, which is a group selected from _{1 to 6} alkoxycarbonyl groups;
   Following formula (TH-1a):
   

   

   [Wherein, in the formula (TH-1a), R ^1a , R ^1b , R ^2a and R ^2b are the same as the definition in the above formula (I-a)], a sulfonylating agent, a base Forming a mixed solution containing the compound represented by the formula (TH-1a) and the sulfonylating agent in an organic solvent, and the compound represented by the formula (TH-1a) and the sulfonyl from 0 ° C. The reaction is carried out at a temperature at which the mixture solution containing the agent is refluxed, and the formula (TH-2a):
   

   

   [Wherein, in the formula (TH-2a), R ^1a , R ^1b , R ^2a and R ^2b are the same as the definition in the formula (I-a); E is a p-toluenesulfonyl group, a benzenesulfonyl group, a step of obtaining a compound represented by the above formula (TH-2a), which is a group selected from p-nitrobenzenesulfonyl group, 2,4-dinitrobenzenesulfonyl group, methanesulfonyl group, and trifluoromethanesulfonyl group; Compound and a base are added to a solvent not involved in the reaction to form a mixed solution containing the compound represented by the formula (TH-2a) and the base; A production method comprising the step of reacting at a temperature at which the mixed solution containing the compound represented by 2a) and the base is refluxed to obtain a compound represented by the formula (Ia).