CN113563209A

CN113563209A - Process for preparing optically active aminoalcohols

Info

Publication number: CN113563209A
Application number: CN202010355546.4A
Authority: CN
Inventors: 赵彬; 顾晓敏; 罗剑; 陈川; 蔡小飞; 叶家捷; 李�杰; 孙丰来
Original assignee: Mochida Pharmaceutical Co Ltd
Current assignee: Mochida Pharmaceutical Co Ltd
Priority date: 2020-04-29
Filing date: 2020-04-29
Publication date: 2021-10-29

Abstract

According to the present invention, there is provided a method for producing a compound (aminotetralol) represented by the formula (B) using a compound represented by the formula (SM8) or a compound represented by the formula (a8) as a starting material. Thus, a novel process for producing aminotetralol is provided.

Description

Process for preparing optically active aminoalcohols

Technical Field

The present invention relates to a novel process for producing (R) -8-amino-1, 2,3, 4-tetrahydronaphthalen-2-ol represented by the following formula (B) and a salt thereof.

Background

(R) -8-amino-1, 2,3, 4-tetrahydronaphthalen-2-ols of the following formula (B) correspond to partial structural formulae of, for example, (E) -2- (7-trifluoromethyl chroman-4-ylidene) -N- ((7R) -7-hydroxy-5, 6,7, 8-tetrahydronaphthalen-1-yl) acetamide (CAS number 920332-28-1) as TRPV1 antagonist and are expected to be useful intermediates in the preparation of the compounds.

[ chemical formula 1]

A method for producing the compound of formula (B) is disclosed in international publication No. 2003/095420 pamphlet (patent document 1), international publication No. 2005/040100 pamphlet (patent document 2), international publication No. 2005/040119 pamphlet (patent document 3), and international publication No. 2010/127855 pamphlet (patent document 4). In this document, an 8-amino-3, 4-dihydronaphthalen-2 (1H) -one (formula (IM-3)) obtained by a reaction of alkylation of a phenol group, Birch reduction, and deprotection of an alkyl group using 8-aminonaphthalen-2-ol (formula (SM-1)) as a starting material is subjected to asymmetric reduction in the presence of a Ru catalyst to prepare a compound of formula (B) (scheme 1).

However, this production method requires a step of using Birch reduction in its process and a metal catalyst in asymmetric reduction to reduce the metal residual rate in the resulting compound.

[ chemical formula 2]

(scheme 1)

Further, a method for producing the compound of formula (B) is also disclosed in international publication No. 2009/050289 pamphlet (patent document 5), international publication No. 2010/045401 pamphlet (patent document 6) and international publication No. 2010/045402 pamphlet (patent document 7). In this document, 8-aminonaphthalen-2-ol (formula (SM-1)) is used as a starting material, and 8-amino-1, 2,3, 4-tetrahydronaphthalen-2-ol (formula a) as a racemate is derived by ring-selectively reducing the naphthalene ring, followed by resolution using an optically active column, thereby preparing a compound of formula (B) (scheme 2).

However, this preparation method is difficult to reuse the other isomer (S form) obtained after column resolution.

[ chemical formula 3]

(scheme 2)

Further, a method for producing the compound of formula (B) is disclosed in international publication No. 2009/055749 pamphlet (patent document 8). In this document, a compound of formula (B) is prepared by introducing a chiral auxiliary group into a racemate of formula (a) and subjecting the diastereomer obtained after the diastereomer resolution to column resolution (scheme 3).

However, this preparation method is also difficult to reuse other isomers obtained after column resolution.

[ chemical formula 4]

(scheme 3)

The methods for producing the compound of formula (B) disclosed in the above-mentioned documents have problems that the resolution of racemic modification or diastereomer using a column is difficult due to the kind of reaction in the production process, reagents used, and the like, and that the other isomer after the resolution is difficult to reuse, and an improved production method thereof is required for mass synthesis or industrial production of the compound of formula (B). That is, in consideration of the mass synthesis or industrial production of the compound of formula (B), it is desired to find a novel production method different from the production methods described in the above-mentioned documents. Since a production method for synthesizing a large amount of the compound of the formula (B) in high yield and high optical purity is not known, it is considered that the above-mentioned problems can be solved if a production method for synthesizing a large amount of the compound of the formula (B) in high chemical yield and high optical purity in a short process can be found.

International publication No. 2018/205948 pamphlet (patent document 9) discloses 8-bromo-1, 2,3, 4-tetrahydronaphthalen-2-ol (non-patent document 2) and a method for producing the same, but (R) -8-bromo-1, 2,3, 4-tetrahydronaphthalen-2-ol, which is one of chiral bodies thereof, and a method for producing the same are unknown.

8-fluoro-1, 2,3, 4-tetrahydronaphthalen-2-ol is disclosed in CAS Registry (non-patent document 3), but (R) -8-fluoro-1, 2,3, 4-tetrahydronaphthalen-2-ol, which is one of its chiral bodies, and a method for producing the same are not known. In addition, 8-chloro-1, 2,3, 4-tetrahydronaphthalen-2-ol is disclosed in CAS Registry (non-patent document 4), but (R) -8-chloro-1, 2,3, 4-tetrahydronaphthalen-2-ol, which is one of its chiral bodies, and a method for producing the same are not known.

In Bioorganic&Medicinal Chemistry Letters, 18(6), page 1830-1834, 2008 (non-patent document 1) disclose: by using Pd catalyst (Pd) on 8-bromo-6-fluoro-1, 2,3, 4-tetrahydronaphthalen-2-ol₂(dba)₃) And tert-butyl carbamate followed by deprotection of the Boc group to produce 8-amino-6-fluoro-1, 2,3, 4-tetrahydronaphthalen-2-ol (yield 18%).

Documents of the prior art

Patent document

Patent document 1: international publication No. 2003/095420 pamphlet;

patent document 2: international publication No. 2005/040100 pamphlet;

patent document 3: international publication No. 2005/040119 pamphlet;

patent document 4: international publication No. 2010/127855 pamphlet;

patent document 5: international publication No. 2009/050289 pamphlet;

patent document 6: international publication No. 2010/045401 pamphlet;

patent document 7: international publication No. 2010/045402 pamphlet;

patent document 8: international publication No. 2009/055749 pamphlet;

patent document 9: international publication No. 2018/205948 pamphlet;

non-patent document

Non-patent document 1: bioorganic & Medicinal Chemistry Letters, 18(6), page 1830-1834, 2008;

non-patent document 2: CAS number 444619-84-5;

non-patent document 3: CAS number 1823867-35-1;

non-patent document 4: CAS number 1823929-47-0.

Disclosure of Invention

Problems to be solved by the invention

Based on this situation, a new method for producing the compound represented by the above formula (B) is desired.

Means for solving the problems

The present inventors have conducted intensive studies to solve the above problems. As a result, the present inventors have found a method for easily producing the compound represented by the formula (B) in a good yield, and have completed the present invention based on this finding.

Effects of the invention

According to the present invention, there are provided novel processes for producing the compound represented by the above formula (B) and a salt thereof. It is preferable to provide an efficient production method suitable for mass synthesis or industrial production of the compound represented by the above formula (B) and a salt thereof. The production method of the preferred embodiment is a method for producing the compound represented by the formula (B) or a salt thereof in a good yield and industrially advantageously, and is highly useful industrially. Further, there is provided a novel compound represented by the formula (A8) as a starting material for obtaining the compound represented by the formula (B) and a salt thereof.

Detailed Description

[ solution of the invention ]

Provided herein are methods for producing the compound represented by the formula (B) and salts thereof. Several schemes are methods for preparing compounds represented by formula (B) and salts thereof starting from compounds represented by formula (SM 8). In other embodiments, the compound represented by the formula (B) and a salt thereof are prepared by using the compound represented by the formula (SM8-BR) as a starting material. In other embodiments, the compound represented by the formula (B) and salts thereof are prepared by using the compound represented by the formula (A8) as a starting material. Further, the production methods of the compound represented by the formula (B) and a salt thereof using the compound represented by the formula (A8-BR) as a starting material are also described in other embodiments.

In another embodiment, there are provided a compound represented by the above formula (A8) and a method for producing the same. Several schemes are compounds represented by formula (A8-BR). In other embodiments, the compound represented by the formula (a8) is prepared using the compound represented by the formula (SM8) as a starting material. Further, the production methods of the compound represented by the formula (A8-BR) using the compound represented by the formula (SM8-BR) as a starting material are also described in other embodiments.

Each of the schemes is specifically described below.

[1] Scheme 1 is a process for preparing a compound represented by formula (B),

[ chemical formula 5]

The preparation method comprises the following steps:

a step of obtaining a compound represented by the formula (A8) by asymmetrically reducing a ketone group of the compound represented by the formula (SM8),

[ chemical formula 6]

[ in the formula (SM8), X represents a halogen atom ]

[ chemical formula 7]

[ in the formula (A8), X represents a halogen atom ]; and

a step of obtaining a compound represented by the formula (B) by reacting ammonia water with a compound represented by the formula (A8) in the presence of a catalyst.

[1-1] in the above scheme [1], X in the compounds represented by the formulae (SM8) and (A8) is preferably a fluorine atom, a chlorine atom, or a bromine atom; more preferably a bromine atom.

[1-2]Scheme [1] above]Among them, the catalyst is preferably a Pd catalyst or a Cu catalyst, more preferably a Cu catalyst, and still more preferably Cu₂O。

[1-3] the 1 st to 3 rd embodiments are a method for producing a salt of the compound represented by the formula (B) of the above-mentioned embodiment [1], which comprises the following steps: the salt of the compound represented by the formula (B) is obtained by adding an inorganic acid or an organic acid to the compound represented by the formula (B).

[2] Scheme 2 is a process for preparing a compound represented by formula (B),

[ chemical formula 8]

The preparation method comprises the following steps:

reacting a compound represented by the formula (A8) with ammonia in the presence of a catalyst to obtain a compound represented by the formula (B),

[ chemical formula 9]

[ in the formula (A8), X represents a halogen atom ].

[2-1] in the above-mentioned scheme [2], X in the compound represented by the formula (A8) is preferably a fluorine atom, a chlorine atom, or a bromine atom; more preferably a bromine atom.

[2-2]Scheme [2] above]Among them, the catalyst is preferably a Pd catalyst or a Cu catalyst, more preferably a Cu catalyst, and still more preferably Cu₂O。

[2-3] the 2-3 nd embodiments are methods for producing a salt of the compound represented by the formula (B) of the above scheme [2], which comprises: the salt of the compound represented by the formula (B) is obtained by adding an inorganic acid or an organic acid to the compound represented by the formula (B).

[3] Scheme 3 is a process for preparing a compound represented by formula (A8),

[ chemical formula 10]

[ in the formula (A8), X represents a halogen atom ]

The preparation method comprises the following steps:

the compound represented by the formula (A8) is obtained by asymmetrically reducing the ketone group of the compound represented by the formula (SM8),

[ chemical formula 11]

[ in the formula (SM8), X represents a halogen atom ].

[3-1] in the above-mentioned scheme [3], X in the compounds represented by the formulae (SM8) and (A8) is preferably a fluorine atom, a chlorine atom, or a bromine atom; more preferably a bromine atom.

[4] The 4 th scheme is a compound represented by the formula (A8),

[ chemical formula 12]

[ in the formula (A8), X represents a halogen atom ].

[4-1] in the above-mentioned scheme [4], X in the compound represented by the formula (A8) is preferably a fluorine atom, a chlorine atom, or a bromine atom; more preferably a bromine atom.

< Process for producing the Compound represented by the formula (A8) >

The compound represented by the formula (A8) is obtained by asymmetrically reducing a ketone compound represented by the formula (SM 8).

Examples of asymmetric reduction include: asymmetric reduction using a chemical catalyst or the like, asymmetric reduction using a biocatalyst (yeast, fungi, mold, enzyme, or the like), or the like. Preferably, the asymmetric reduction is carried out using an enzyme, more preferably using a ketoreductase (KRED: keto reductase) as the enzyme, and particularly preferably using a ketoreductase derived from Escherichia coli sp. Asymmetric reduction using ketoreductases is performed using ketoreductases, coenzymes, and coenzyme regeneration systems. NADP is included in a typical example of a coenzyme for ketoreductases. In addition, as a typical example of a coenzyme regeneration system for regenerating a coenzyme NADP, oxidation of glucose by Glucose Dehydrogenase (GDH) is known. The asymmetric reduction using the ketoreductase is preferably carried out in a solvent in the presence of a buffer.

For example, in the asymmetric reduction using a chemical catalyst or the like, the amount of the reducing agent used in the asymmetric reduction is usually 1.0 to 2.2 molar equivalents, preferably 1.2 to 2.0 molar equivalents, relative to 1 molar equivalent of the compound represented by formula (SM 8).

In the asymmetric reduction using an enzyme, the amount of the enzyme used is usually 0.01 to 0.1 times, preferably 0.02 to 0.07 times, and more preferably 0.047 to 0.05 times the amount of 1g of the compound represented by the formula (SM 8).

In the asymmetric reduction using Ketoreductase (KRED) derived from Escherichia coli sp, the amount of the enzyme used is 0.01 to 0.1 times, preferably 0.02 to 0.07 times, and more preferably 0.047 to 0.05 times the amount of 1g of the compound represented by the formula (SM 8).

D-glucose can be used for asymmetric reduction using an enzyme. When D-glucose is used, the amount of D-glucose used is usually 1.0 to 5.0 times, preferably 1.5 to 3.5 times, and more preferably 1.9 to 2.0 times the amount of 1g of the compound represented by the formula (SM 8).

Glucose Dehydrogenase (GDH) can be used for asymmetric reduction using an enzyme. When Glucose Dehydrogenase (GDH) is used, the amount of Glucose Dehydrogenase (GDH) used is usually 0.01 to 0.1 times, preferably 0.01 to 0.05 times, and more preferably 0.019 to 0.02 times the amount of 1g of the compound represented by the formula (SM 8).

Nicotinamide Adenine Dinucleotide Phosphate (NADP) can be used for the asymmetric reduction using an enzyme. When Nicotinamide Adenine Dinucleotide Phosphate (NADP) is used, the amount of Nicotinamide Adenine Dinucleotide Phosphate (NADP) used is usually 0.001 to 0.1 times, preferably 0.005 to 0.05 times, and more preferably 0.009 to 0.01 times the amount of the compound represented by formula (SM8) per 1g of the compound.

The asymmetric reduction may be carried out in the presence of a solvent. As the solvent, for example, there can be used: alcohol solvents such as methanol, ethanol, propanol, and butanol; hydrocarbon solvents such as heptane, hexane, octane, and toluene; ether solvents such as tetrahydrofuran, 1, 4-dioxane, and butyl ether; polar solvents such as acetone, acetonitrile, dimethyl sulfoxide, and dimethylformamide; the solvent such as water or a solvent mixture thereof which does not participate in the reaction can be appropriately selected depending on the kind of the enzyme to be used.

In the asymmetric reduction using an enzyme, as a buffer, for example, there can be used: phosphate buffer, potassium phosphate buffer (e.g., K is selected from₂HPO₄·3H₂O、KH₂PO₄Prepared with a reagent such as Tris/HCl buffer, sodium tetraborate/HCl buffer, or triethanolamine buffer, and the like, can be appropriately selected depending on the type of enzyme used.

In asymmetric reduction using Ketoreductase (KRED) derived from Escherichia coli sp, dimethyl sulfoxide, water, or a mixed solvent of dimethyl sulfoxide and water is preferable as the solvent.

In the asymmetric reduction using Ketoreductase (KRED) derived from Escherichia coli sp, the amount of the organic solvent used is usually 1.0 to 10 times, preferably 2 to 5 times, and more preferably 2.5 to 3.0 times the amount of 1g of the compound represented by the formula (SM 8).

In the asymmetric reduction using Ketoreductase (KRED) derived from Escherichia coli sp, the amount of the buffer used is usually 10 to 40 times, preferably 15 to 30 times, and more preferably 28 to 30 times the amount of 1g of the compound represented by formula (SM 8).

In the asymmetric reduction using an enzyme, the pH of the reaction solution is usually 6.0 to 7.5, preferably 6.5 to 7.0.

The reaction temperature for carrying out the asymmetric reduction can be appropriately selected from reaction temperatures such as a temperature range of-78 ℃ to the reflux temperature of the solvent, a temperature range of-78 ℃ to room temperature, a temperature range of 0 ℃ to the reflux temperature of the solvent, or a temperature range of 0 ℃ to room temperature. Preferably in the range of 0 ℃ to room temperature.

The reaction temperature in the asymmetric reduction using an enzyme is usually in a range of a temperature at which the enzyme is not inactivated, preferably in a range of 20 to 60 ℃, more preferably in a range of 20 to 35 ℃, and still more preferably in a range of 20 to 30 ℃.

In the present specification, unless otherwise specified, the expression (SM8) includes the following expressions (for example, expression (SM8-FL), expression (SM8-CL), expression (SM8-BR), expression (SM8-ID), and the like). Similarly, in the present specification, unless otherwise specified, the case where the expression (A8) is used refers to expressions including the lower order (for example, expression (A8-FL), expression (A8-CL), expression (A8-BR), expression (A8-ID), and the like).

Further, the formula (SM8-FL) is a compound represented by the formula (SM8) in which X is a fluorine atom. Formula (SM8-CL) is a compound represented by formula (SM8) wherein X is a chlorine atom. Formula (SM8-BR) is a compound represented by formula (SM8) wherein X is a bromine atom. Formula (SM8-ID) is a compound represented by formula (SM8) wherein X is an iodine atom.

Further, formula (A8-FL) is a compound represented by formula (A8) wherein X is a fluorine atom. Formula (A8-CL) is a compound represented by formula (A8) wherein X is a chlorine atom. Formula (A8-BR) is a compound represented by formula (A8) wherein X is a bromine atom. Formula (A8-ID) is a compound represented by formula (A8) wherein X is an iodine atom.

< Process for producing the Compound represented by the formula (B) >

The compound represented by formula (A8) is subjected to an amination reaction using ammonia (ammonia water (e.g., 25%, 28%, 30%, etc.)) in the presence of a metal catalyst to obtain a compound represented by formula (B). The concentration (%) of aqueous ammonia was w/w% or w/v%.

As a catalyst for the amination reaction of a compound represented by formula (A8) using ammonia as a nitrogen source, for example, there can be mentioned: pd catalyst, Cu catalyst, etc. Examples of the Pd catalyst include: pd₂(dba)₃ PdCl₂Josiphos complex, etc., and examples of the Cu catalyst include: CuI, Cu (OAc)₂、Cu₂O、CuO、CuBr、CuCl、CuSO₄、CuFe₂O₄Etc., preferably a Cu catalyst, more preferably Cu₂O。

Examples of the solvent for the amination reaction include: solvents such as dimethyl sulfoxide, N-dimethylformamide, N-methylpyrrolidone (NMP), 1, 4-dioxane, acetonitrile, toluene, and mixed solvents thereof, and N-methylpyrrolidone (NMP) is preferable.

A base may be present in the amination reaction, and examples of the base include: bases such as potassium carbonate, potassium phosphate, cesium carbonate, N-diisopropylethylamine, and triethylamine.

The amination reaction is carried out by heating a sealed tube using a sealed tube reaction vessel (for example, stainless steel, glass, or the like). In general, when the heating reaction is performed, the reaction is not heated to a temperature equal to or higher than the boiling point of the solvent or reagent to be used, and when the reaction is performed at a temperature equal to or higher than the boiling point of the solvent or reagent to be used, the reaction is performed in a closed system using a sealed tube reaction vessel or the like.

Examples of solvents which can be used for carrying out the amination reaction and their boiling points are: dimethylsulfoxide (boiling point 189 deg.c), N-dimethylformamide (boiling point 153 deg.c), N-methylpyrrolidone (NMP) (boiling point 202 deg.c), 1, 4-dioxane (boiling point 101 deg.c), acetonitrile (boiling point 82 deg.c), toluene (boiling point 110.6 deg.c). The boiling point of ammonia water was 37.7 ℃ for 25% ammonia water and 24.7 ℃ for 32% ammonia water.

The reaction temperature for the amination reaction can be appropriately selected from reaction temperatures in the range of 100 to 250 ℃, 100 to 200 ℃, 100 to 150 ℃ and the like, for example. Preferably in the range of 100 to 120 ℃.

In the amination reaction, Cu is used₂In the case of O, the amount of the metal catalyst used is usually 0.1 to 1.0 molar equivalent, preferably 0.2 to 0.8 molar equivalent, and more preferably 0.5 to 0.7 molar equivalent, relative to 1 molar equivalent of the compound represented by the formula (A8).

In the amination reaction, the amount of the organic solvent used is usually 0.1 to 30 times, preferably 0.5 to 20 times, the amount of the compound represented by the formula (A8) per 1g of the compound.

In the amination reaction, the amount of ammonia water used is usually 1.0 to 50 times, preferably 2.5 to 30 times, and more preferably 2.5 to 3.5 times the amount of 1g of the compound represented by the formula (A8).

Unless otherwise specified, the numerical ranges described in the present specification also include values of ± 10% of the value. For example, the term "0.1 to 1.0 molar equivalent" means 0.1. + -. 0.01 to 1.0. + -. 0.1 molar equivalent, and the term "0.1 to 30-fold amount" means 0.1. + -. 0.01 to 30. + -. 3-fold amount.

As the compound represented by the formula (SM8) in the above scheme [1], a commercially available compound can be used. Alternatively, commercially available compounds can be used and obtained by a preparation method known in the literature.

Among the compounds represented by formula (SM8), compounds having X ═ fluorine atom (formula (SM8-FL)) can be prepared, for example, by the preparation method of scheme 4 described in european patent publication No. 343830 pamphlet.

[ chemical formula 13]

Scheme 4

Among the compounds represented by the formula (SM8), compounds in which X is a chlorine atom (formula (SM8-CL)) can be produced, for example, by the production method of the following scheme 5 described in european patent publication No. 343830.

[ chemical formula 14]

Scheme 5

Among the compounds represented by the formula (SM8), compounds in which X is a bromine atom (formula (SM8-BR)) can be produced, for example, by the production method of the following scheme 6 described in Journal of Medicinal Chemistry, 36(17), pages 2485 to 93, 1993.

[ chemical formula 15]

Scheme 6

Note that, in formula (SM8), a compound having X ═ iodine atom (formula (SM8-ID)) can be prepared according to the preparation methods of formula (SM8-FL), formula (SM8-CL), and formula (SM8-BR) (scheme 7).

[ chemical formula 16]

Scheme 7

The starting compounds of the respective steps in the production method may be used in the next step as they are in the form of a reaction solution or as a crude product. Furthermore, it can be isolated from the reaction mixture according to a conventional method, and can be easily purified by a known means, for example, separation means such as extraction, concentration, neutralization, filtration, distillation, recrystallization, chromatography, and the like.

When a mixed solvent is used in the above reaction, two or more solvents may be mixed in an appropriate ratio, for example, in a volume ratio or a weight ratio of 1: 1-1: 10 was mixed and used.

The reaction time in each step of the production method is not particularly limited, and is not limited as long as the reaction is sufficiently performed. For example, the reaction time may be 0.1 hour, 0.5 hour, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 10 hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 hours, 60 hours, or 72 hours, and a time having these values as the lower limit and the upper limit.

In the above reaction temperature, the lower limit and the upper limit of the reaction temperature may be, for example, temperatures of. + -. 1 ℃,. + -. 2 ℃,. + -. 3 ℃,. + -. 4 ℃ and. + -. 5 ℃ of the respective temperatures.

In the above reaction temperature, the range of, for example, — 78 ℃ to the temperature at which the solvent is refluxed "means a temperature in the range from-78 ℃ to the temperature at which the solvent (or mixed solvent) used in the reaction is refluxed. For example, in the case of using methanol as the solvent, "the temperature from-78 ℃ to the reflux temperature of the solvent" means a temperature in the range from-78 ℃ to the reflux temperature of methanol. The "temperature of 0 ℃ to the reflux temperature of the solvent" also means a temperature ranging from 0 ℃ to the reflux temperature of the solvent (or the mixed solvent) used in the reaction.

In the production method of the present specification, "room temperature" refers to a temperature in a laboratory, a research laboratory or the like, and "room temperature" in examples of the present specification is a temperature showing usually about 1 ℃ to about 30 ℃ (defined in japanese pharmacopoeia). It shows a temperature of usually about 5 ℃ to about 30 ℃, more usually about 15 ℃ to about 25 ℃, and further preferably 20. + -. 3 ℃.

In the present specification, the compound represented by the formula (B) may form an acid addition salt. The salt is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include a salt with an inorganic acid, a salt with an organic acid, and the like. Suitable examples of the salt with an inorganic acid include: and salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Suitable examples of the salt with an organic acid include: salts with aliphatic monocarboxylic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, heptanoic acid, decanoic acid, myristic acid, palmitic acid, stearic acid, lactic acid, sorbic acid, mandelic acid and the like; salts with aliphatic dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, etc.; salts with aliphatic tricarboxylic acids such as citric acid; salts with aromatic monocarboxylic acids such as benzoic acid and salicylic acid; salts with aromatic dicarboxylic acids such as phthalic acid; salts with organic carboxylic acids such as cinnamic acid, glycolic acid, pyruvic acid, oxyacids (hydroxy acids), salicylic acid, and N-acetylcysteine; salts with organic sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like; acid addition salts with acidic amino acids such as aspartic acid and glutamic acid.

The salt can be obtained by a conventional method, for example, by mixing the compound represented by the formula (B) with a solution containing an appropriate amount of an acid to form a target salt, collecting the salt by filtration step by step, or distilling off the mixed solvent. The compound or a salt thereof in the present specification may form a solvate with a solvent such as water, ethanol, or glycerin. As an overview of Salts, Handbook of Pharmaceutical Salts is published: properties, Selection, and use, Stahl and Wermuth (Wiley-VCH, 2002), are described in detail herein.

As shown in the following (scheme 8), the compound represented by formula (B) can be produced via the compound represented by formula (a8) using the compound represented by formula (SM8) as a starting material.

[ chemical formula 17]

Scheme 8

Further, as shown in the following (scheme 9), the compound represented by the formula (B) can be produced via the compound represented by the formula (a8-BR) using the compound represented by the formula (SM8-BR) as a starting material.

[ chemical formula 18]

Scheme 9

[ asymmetric reduction of ketone ]

Various reactions are known as a method for converting a ketone group located in a molecule into a chiral alcohol group. For example, the following methods are available: using reducing agents (sodium borohydride, Lithium Aluminium Hydride (LAH), borane-tetrahydrofuran (BH)₃THF), and the like) and then converting the ketone group into a racemic alcohol group, followed by a fractional recrystallization method (ionic bonding of an optical resolving agent to the racemate to obtain a crystalline diastereomer. A method of separating the compound by recrystallization and, if necessary, neutralizing the compound to obtain a free chiral compound), a diastereomer method (see international publication)2009/055749 pamphlet), a chiral column method (see International publication No. 2009/050289), and the like.

Further, there have been known asymmetric reduction reactions using a transition metal catalyst (e.g., Ru, Rh, etc.) (WO 2009/050289, Organometallics 10, p 500, 1991, etc.), and the reaction of Al (CH)₃)₃Asymmetric reduction reaction in combination with BINOL as a ligand (angelw. chem. int. ed., 41, p. 1020, 2002), asymmetric reduction reaction using a chiral ru (binap) catalyst (j. Am. chem. soc. 110, p. 629, 1988), asymmetric reduction reaction using oxazaborolidine (j. Am. chem. soc. 109, p. 5551, 1987), asymmetric reduction reaction using a biocatalyst (yeast, fungi, mold, enzyme, etc.) (see table 1), and the like.

In several embodiments, the asymmetric reduction is preferably based on an asymmetric reduction of a biocatalyst. Asymmetric reduction by a biocatalyst has not only advantages of high stereoselectivity, use of an organic solvent and/or water as a reaction solvent, reaction under mild conditions (normal temperature and pressure), and low cost compared to a chemical catalyst, but also reduction of waste after the reaction, and environmental-friendly reaction, and therefore has recently been attracting attention as a reaction and is a useful reaction for easily obtaining a chiral compound.

In the asymmetric reduction reaction using an enzyme, generally, the chemical yield (%) and the optical activity yield (ee%) of the obtained chiral compound vary depending on the reaction specificity (selectivity for the reaction species peculiar to the enzyme), the substrate specificity (selectivity for the substrate species), and the reaction conditions (reaction temperature, pH, solvent, reaction time, and the like). For many enzymes, the reaction specificity is very high, and the reaction catalyzed by one enzyme is limited, but there are various enzymes with high substrate specificity to those with low substrate specificity. Therefore, for example, in the case of asymmetrically reducing a ketone group to a chiral alcohol group, even if an enzyme is selected to perform an enzymatic reaction under the same conditions, which can give a good chemical yield and optical activity yield in a compound having a structure similar to that of the substrate (ketone compound) used, the desired chiral alcohol compound cannot necessarily be obtained in the same chemical yield and optical activity yield.

For example, various substances shown in table 1 are known as biocatalysts capable of selectively reducing a ketone group of β -tetralone to a chiral alcohol.

[ Table 1]

[ amination reaction ]

The method of converting a halogen atom of a halogenated aryl group into an amino group (amination reaction) may be carried out using NHR as a nitrogen source in the presence of a metal catalyst, in the presence or absence of a Ligand (Ligand)^AR^B(R^AAnd R^BEach independently represents a hydrogen atom, a substituent such as methyl, ethyl, or benzyl), R^CCONH₂(R^CIndependently represents a substituent such as methyl, ethyl, benzyl, methoxy, ethoxy, tert-butoxy or benzyloxy).

For the amination of halogenated aryl groups using ammonia as a nitrogen source, for example, the following metal catalysts are known as literature methods, but the methods are not limited thereto. Pd₂(dba)₃(J. Am. chem. Soc., 129(34), pages 10354-10355, 2007) PdCl₂Josiphos complex (J. Am. chem. Soc., 128(31), pp.10028-10029, 2006), CuI (chem. Commun., 26, pp.3052-3054, 2008; J.Org. chem., 74(12), pp.4542-4546, 2009), Cu (OAc)₂(Angew. chem. int. Ed., 48(2), p. 337-339, 2009), Cu₂O (Ukrainskii Khimiche ski Zhurnal (Russian Edition), 53(12), p.1299-302, 1987).

For example, amination of 8-halo-1, 2,3, 4-tetrahydronaphthalen-2-ol in which a secondary alcohol is present in the molecule is known using Pd₂(dba)₃As the metal catalyst and amination reaction using tert-butyl carbamate as a nitrogen source, but examples using other metal catalysts are not known.

In several embodiments, the amination reaction is preferably one in which ammonia is directly introduced into the amino group. In addition, for example in using NHR^A1R^B1(R^A1Is a hydrogen atom, R^B1A protecting group for an amino group such as benzyl or 4-methoxybenzyl), R^CCONH₂(R^CIndependently represents a substituent such as methyl, ethyl, benzyl, methoxy, ethoxy, tert-butoxy or benzyloxy) and the like, and then an amino group can be introduced by deprotecting the protecting group. However, the amination reaction using a protected amino compound requires a deprotection step of a protecting group, and therefore, in consideration of mass synthesis or industrial production, a reaction in which an amino group is directly introduced with ammonia is preferably used.

All publications cited in this specification, such as prior art documents and publications, patent publications, and other patent documents, are incorporated herein by reference in their entirety.

Examples

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

Bruker AV400 was used for the determination of the nuclear magnetic resonance spectra (NMR) of the compounds of the formulae (A8-BR) and (B).

The High Performance Liquid Chromatography (HPLC) of the formula (A8-BR) and the formula (B) was carried out according to the following method.

[ Table 2]

[ Table 3]

[ Table 4]

[ Table 5]

[ Table 6]

[ Table 7]

[ Table 8]

[ Table 9]

¹In the H-NMR data, in the pattern of the NMR signal, s is singlet, d is doublet, t is triplet, q is quartet, m is multiplet, brs is broad, J is coupling constant, Hz is Hz, DMSO-d₆Is deuterated dimethyl sulfoxide (heavy dimethyl sulfoxide), CDCl₃Tritiated chloroform (heavy chloroform).¹H-NMR data for hydroxyl (OH), amino (NH)₂) Signals that cannot be confirmed because of their broad band, protons in amide groups (CONH), and the like are not recorded in the data.

(example 1A) to example 1D Synthesis of (R) -8-bromo-1, 2,3, 4-tetrahydronaphthalen-2-ol (formula (A8-BR))

[ chemical formula 19]

Scheme 9-1

(example 1A)

KRED (ketoreductase from Escherichia coli sp, 5mg), D-glucose (200mg), Glucose Dehydrogenase (GDH) (2mg), Nicotinamide Adenine Dinucleotide Phosphate (NADP) (1mg) and phosphate buffer (3mL, 10.62g KH) were mixed in a flask equipped with an Orbital shaker (Orbital shaker) (model: NRY-200, manufactured by Shanghai Rongnan laboratory instruments Co., Ltd.)₂PO₄21.25g of K₂HPO₄Added to 1000mL of water and stirred to prepare a mixed solution. Next, a mixed solution prepared by dissolving 8-bromo-3, 4-dihydronaphthalen-2 (1H) -one (formula (SM8-BR)) (100mg) in dimethyl sulfoxide (DMSO) (0.3mL) was added to the previously prepared mixed solution, and the mixture was stirred at a reaction temperature of 30 ℃ for 20 hours (rotation speed of 250rpm on an orbital shaker). A part of the reaction solution was taken out and analyzed by HPLC, and it was confirmed that the labeled compound was obtained at an IPC yield (IPC — step analysis) of 97.8% and an optical purity of 99.7%.

(example 1B)

KRED (ketoreductase from Escherichia coli sp., 0.25g), D-glucose (10g), Glucose Dehydrogenase (GDH) (0.1g), Nicotinamide Adenine Dinucleotide Phosphate (NADP) (0.05g) and a buffer (1.55 g of KH) were mixed in a reaction vessel₂PO₄4.06g of K₂HPO₄・3H₂O in 145mL of water) was added to the mixture, and the mixture was stirred at 20 to 25 ℃. Next, a mixed solution prepared by dissolving 8-bromo-3, 4-dihydronaphthalen-2 (1H) -one (formula (SM8-BR)) (5g) in dimethyl sulfoxide (DMSO) (15mL) was added dropwise to the mixed solution prepared previously. Stirring the mixture at a reaction temperature of 20 to 25 ℃ for 1 hour, and then adjusting the pH of the reaction solution to a range of 6.5 to 7.0 using a 2M aqueous solution of sodium carbonate. Then, the reaction mixture was stirred at a reaction temperature of 20 to 25 ℃ for 1 hour, and then the pH of the reaction mixture was adjusted to 6.5 to 7.0 using a 2M aqueous sodium carbonate solution. Further stirring the mixture at a reaction temperature of 20 to 25 ℃ for 1 hour, and then adjusting the pH of the reaction solution to a range of 6.5 to 7.0 using a 2M aqueous solution of sodium carbonate. Then, the reaction mixture was stirred at a reaction temperature of 20 to 25 ℃ for 16 hours (a part of the reaction mixture was taken out and analyzed by HPLC, whereby the IPC yield of the labeled compound was confirmed99.6%).

Methyl tert-butyl ether (MTBE) (50mL) was added to the reaction solution, and further, Diatomite (5g) containing water (5g) was added thereto, and the temperature of the mixed solution was set to 50 to 60 ℃ and stirred for 30 minutes. The temperature of the mixed solution is cooled to 20-25 ℃, and further stirred for 1 hour at the same temperature. The above mixed solution was filtered, and the filtrate (wet cake ) was washed with MTBE (5mL) to give filtrate A. The wet filter cake is put into a reaction vessel, added with MTBE (40mL) and stirred for 2 hours at 20-25 ℃. The suspension containing the wet cake was filtered and the wet cake was washed with MTBE (5mL) to give filtrate B. Filtrate a and filtrate B were mixed, stirred at 20 to 30 ℃ for 5 minutes, and then the aqueous layer and the organic layer were separated, the aqueous layer was extracted with MTBE (45mL), and after combining with the previously obtained organic layer, the organic layer was washed with water (30mL), and the organic layer was concentrated, whereby a crude labeled compound (4.61g) was obtained. The obtained crude labeled compound was subjected to silica gel column chromatography (n-heptane: ethyl acetate: 1) to obtain a labeled compound (4.15g, optical purity 99.9%).

(example 1C)

KRED (ketoreductase from Escherichia coli sp., 0.83g), D-glucose (33.28g), Glucose Dehydrogenase (GDH) (0.33g), Nicotinamide Adenine Dinucleotide Phosphate (NADP) (0.17g) and buffer (5.31 g of KH) were mixed in a reaction vessel₂PO₄13.89g of K₂HPO₄・3H₂O was added to 499mL of water) to prepare a mixed solution, and the mixed solution was stirred at 20 to 25 ℃. Next, a mixed solution prepared by dissolving 8-bromo-3, 4-dihydronaphthalen-2 (1H) -one (formula (SM8-BR)) (17.3g) in dimethyl sulfoxide (DMSO) (50mL) was added dropwise to the mixed solution prepared previously. Stirring the mixture at a reaction temperature of 20 to 25 ℃ for 1 hour, and then adjusting the pH of the reaction solution to a range of 6.5 to 7.0 using a 2M aqueous sodium carbonate solution. Then, the reaction mixture was stirred at a reaction temperature of 20 to 25 ℃ for 1 hour, and then the pH of the reaction mixture was adjusted to 6.5 to 7.0 using a 2M aqueous sodium carbonate solution. Further stirring the mixture at a reaction temperature of 20 to 25 ℃ for 1 hour, and then adjusting the pH of the reaction solution to a range of 6.5 to 7.0 using a 2M aqueous solution of sodium carbonate. Thereafter, in the reactionStirring for 16 hours at the temperature of 20-25 ℃. A part of the reaction solution was taken out and analyzed by HPLC, whereby the IPC yield of the labeled compound was 97.4%. The same post-treatment as in (example 1B) was performed to obtain a title compound (17.12g, 99.9% optical purity).

(example 1D)

KRED (ketoreductase from Escherichia coli sp. 5.55g), D-glucose (220g), Glucose Dehydrogenase (GDH) (2.20g), Nicotinamide Adenine Dinucleotide Phosphate (NADP) (1.12g) and buffer (35.12 g of KH) were mixed in a reaction vessel₂PO₄91.80g of K₂HPO₄・3H₂Adding O into 3300mL of water), preparing a mixed solution, and stirring at 20-25 ℃. Next, a mixed solution prepared by dissolving 8-bromo-3, 4-dihydronaphthalen-2 (1H) -one (formula (SM8-BR)) (110.31g) in dimethyl sulfoxide (DMSO) (330mL) was added dropwise to the mixed solution prepared previously. Stirring the mixture at a reaction temperature of 20 to 25 ℃ for 1 hour, and then adjusting the pH of the reaction solution to a range of 6.5 to 7.0 using a 2M aqueous sodium carbonate solution. Then, the reaction mixture was stirred at a reaction temperature of 20 to 25 ℃ for 1 hour, and then the pH of the reaction mixture was adjusted to 6.5 to 7.0 using a 2M aqueous sodium carbonate solution. Further stirring the mixture at a reaction temperature of 20 to 25 ℃ for 2 hours, and then adjusting the pH of the reaction solution to a range of 6.5 to 7.0 using a 2M aqueous solution of sodium carbonate. Then, the mixture was stirred at a reaction temperature of 20 to 25 ℃ for 16 hours. A part of the reaction solution was taken out and analyzed by HPLC, whereby the IPC yield of the labeled compound was 97.4%.

MTBE (1100mL) was added to the reaction solution, followed by Diatomite (110g) containing water (110g), and the mixture was stirred at 50-60 ℃ for 30 minutes. And cooling the mixed solution to 20-25 ℃, and further stirring for 2 hours at the same temperature. The above mixed solution was filtered, and the filtrate (wet cake) was washed with MTBE (110mL) to obtain filtrate C. The wet filter cake is put into a reaction vessel, added with MTBE (900mL) and stirred for 12 hours at 20-25 ℃. The suspension containing the wet cake was filtered and the wet cake was washed with MTBE (110mL) to give filtrate D. Filtrate C and filtrate D were mixed, and the aqueous layer and the organic layer were separated, and the aqueous layer was extracted with MTBE (1000mL), and after combining with the previously obtained organic layer, the organic layer was washed with water (675mL), and the organic layer was concentrated, whereby a crude labeled compound (108.03g, 99.8% optical purity) was obtained.

[ physical Property data of formula (A8) ]

( ¹H-NMR, 400 MHz, manufacturer: bruker, DMSO-d6, δ ppm) 7.40 (d, 1H, J ═ 8 Hz), 7.10 (d, 1H, J ═ 8 Hz), 7.04 (t, 1H, J ═ 8 Hz), 4.89 (d, 1H, J ═ 4 Hz), 3.99 to 3.95 (m, 1H), 2.92 to 2.86 (m, 2H), 2.70 to 2.60 (m, 1H), 1.83 to 1.75 (m, 1H), 1.65 to 1.55 (m, 1H)).

KRED (ketoreductase derived from Escherichia coli sp.) used in examples 1A to 1D was an enzyme manufactured by EnzymeWorks corporation (product No.: HQ-K-105).

The absolute configuration of the compound of formula (A8-BR) obtained in (example 1A) to (example 1D) was determined by converting the compound of formula (A8-BR) into formula (B), and then matching the analysis value of the compound of formula (B) separately synthesized by the method described in international publication No. 2003/095420 pamphlet or the like.

Reference example 1 Synthesis of 8-bromo-1, 2,3, 4-tetrahydronaphthalen-2-ol (formula (A8-BR-Rac))

[ chemical formula 20]

Scheme 9-2

Adding 8-bromo-3, 4-dihydronaphthalene-2 (1H) -one (formula (SM8-BR)) (20.0g) and methanol (200mL) into a reaction vessel, and adding NaBH at an internal temperature of 0-5 DEG C₄(8.28g) and stirred at the same temperature for 1 hour (a part of the reaction solution was taken out and analyzed by HPLC, and the yield of IPC was 98.5%). A10% sodium hydrogencarbonate aqueous solution (1.5L) was added dropwise to the reaction solution at a temperature of 5 ℃ or lower, and the mixture was stirred at a temperature of 0 to 5 ℃ for 0.2 hour. Ethyl acetate (1.5L) was added, the aqueous layer and the organic layer were separated, the aqueous layer was extracted with ethyl acetate (1.5L), and after combining with the organic layer obtained previously, it was washed with 25 wt% aqueous sodium chloride (1.5L)The organic layer was concentrated, whereby the crude labeled compound (21.53g) was obtained. The obtained crude labeled compound was subjected to silica gel column chromatography (n-heptane: ethyl acetate: 1), whereby a labeled compound (21.29g) was obtained. The obtained compound of the formula (A8-BR-Rac) was confirmed to be consistent with the known physical property data in the literature.

(example 2A) to example 2G Synthesis of (R) -8-amino-1, 2,3, 4-tetrahydronaphthalen-2-ol (formula (B))

[ chemical formula 21]

Schemes 9-3

(example 2A)

(R) -8-bromo-1, 2,3, 4-tetrahydronaphthalen-2-ol (formula (A8-BR)) (100mg) obtained in the enzymatic reduction and Cu were reacted in the same manner as in examples 1A to 1D₂O (40mg), N-methylpyrrolidone (NMP) (2mL), and ammonia water (3mL) were mixed in a sealed tube reaction vessel, and a sealed tube reaction was carried out at 105 to 115 ℃ for 20 hours. After dilution with water, extraction with ethyl acetate was carried out, the organic layer was washed with a 25 wt% aqueous solution of sodium chloride, and the organic layer was washed with Na₂SO₄After drying and filtration, the organic layer was concentrated to obtain a crude labeled compound (106 mg). Thin layer chromatography (n-heptane: ethyl acetate ═ 1: 1) was performed, and fractional distillation was performed, whereby the title compound (10mg) (optical purity 96.8%) was obtained.

(example 2B)

(R) -8-bromo-1, 2,3, 4-tetrahydronaphthalen-2-ol (formula (A8-BR)) (2.2g) obtained in the enzymatic reduction and Cu were reacted in the same manner as in examples 1A to 1D₂O (700mg), NMP (3.5mL, 1.6v), and ammonia (5.5mL) were mixed in a sealed tube reaction vessel, and a sealed tube reaction was carried out at 105 to 115 ℃ for 37 hours (the IPC yield was 83.75% after 16 hours, 88.91% after 21 hours, and 93.12% after 37 hours). After diluting with water (17mL) and ethyl acetate (11mL), the mixture was filtered, the filtrate was washed with ethyl acetate (4mL, 3 times), and the aqueous layer and the organic layer were separated. Then, the user can use the device to perform the operation,the aqueous layer was extracted with ethyl acetate (11mL, 5 times), combined with the organic layer obtained previously, washed with water (20mL, 2 times), and the organic layer was washed with 10% Na₂SO₄The organic layer was concentrated by washing with an aqueous solution, whereby a crude labeled compound (1.25g, 61.27%, optical purity 95.6%) was obtained.

(example 2C)

The reaction solvent was verified by conducting a sealed tube reaction under the conditions shown in the following table.

[ Table 10]

In example 2C-2, (R) -8-amino-1, 2,3, 4-tetrahydronaphthalen-2-ol was obtained in 0.74g (yield 50%), and in example 2C-3, (R) -8-amino-1, 2,3, 4-tetrahydronaphthalen-2-ol was obtained in 0.5g (36.6%).

(example 2D)

The closed-tube reaction was carried out under the conditions shown in the following table, and the amount of ammonia water was verified.

[ Table 11]

(example 2E)

(R) -8-bromo-1, 2,3, 4-tetrahydronaphthalen-2-ol (formula (A8-BR)) (3.00g) obtained in the enzymatic reduction and Cu were reacted in the same manner as in examples 1A to 1D₂O (0.96g, 0.51eq), NMP (3mL, 1v) and ammonia (10.5mL, 3.5v) were mixed in a sealed tube reaction vessel, and a sealed tube reaction was carried out at 105 to 115 ℃ for 21 hours (a part of the reaction solution was taken out and analyzed by HPLC, and the IPC yield was confirmed to be 92.93%). After the reaction solution was cooled, a 25 wt% aqueous solution of sodium chloride (23mL) and 2-methyltetrahydrofuran (2-MeTHF) (15mL) were added to the reaction solution, followed by filtration, and the filtrate was washed with 2-MeTHF (15 mL). Separating the aqueous layer and the organic layer, extracting the aqueous layer with 2-MeTHF (15mL, 4 times), combining with the previously obtained organic layer, and then adding 10 wt%Na₂SO₄The organic layer was washed with an aqueous solution (15mL) and decolorized by passing through a CUNO (trademark) chamber (filter) over 1 hour. The CUNO-chambers were washed with 2-MeTHF (15mL), the solvent was concentrated, isopropyl acetate (6mL) was added, n-heptane (1.5mL) was added dropwise at 30-40 ℃ and the mixture was stirred at the same temperature for 0.5 hour. N-heptane (10.5mL) was further added dropwise thereto, and the mixture was stirred at 30 to 40 ℃ for 0.5 hour. N-heptane (3.0mL) was further added dropwise thereto, and the mixture was stirred at 30 to 40 ℃ for 0.5 hour. N-heptane (3.0mL) was further added dropwise thereto, and the mixture was stirred at 30 to 40 ℃ for 0.5 hour. And cooling the mixed solution at 20 ℃ for 30 minutes, and stirring at 15-25 ℃ for 1 hour. The mixed solution was filtered, and the filtrate was washed with n-heptane (3mL) and dried, whereby the title compound (1.375g, 60.1%) was obtained.

(example 2F)

The same procedures as in examples 1A to 1D were carried out to reduce (R) -8-bromo-1, 2,3, 4-tetrahydronaphthalen-2-ol (formula (A8-BR)) (16.32g, NMP solution, content 61.1%), Cu₂O (3.18g, 0.51eq), NMP (5mL, 0.5v) and ammonia (35mL, 3.5v) were mixed in a sealed tube reaction vessel, and a sealed tube reaction was carried out at 105 to 115 ℃ for 40 hours (IPC yield was 90.16% at 40 hours). After the reaction solution was cooled, a 25 wt% aqueous solution of sodium chloride (75mL) and 2-MeTHF (50mL) were added to the reaction solution, and the mixture was filtered using Diatomite (20.00g), and the filtrate (cake) was washed with 2-MeTHF (50 mL). The aqueous and organic layers were separated, the aqueous layer was extracted with 2-MeTHF (50mL, 2 times), combined with the previously obtained organic layer, and then treated with 8 wt% Na₂SO₄The organic layer (92.5% of the total amount) was taken out, and 0.5M aqueous hydrochloric acid (111mL) was added dropwise at 5 to 15 ℃. The aqueous and organic layers were separated, and the aqueous layer was extracted with 2-MeTHF (30 mL). To the aqueous layer was added 10% aqueous sodium hydroxide (22mL), and the mixture was extracted with 2-MeTHF (100mL, 50 mL). The organic layer was combined with the organic layer obtained previously, concentrated at 40 ℃ or lower, and n-heptane (80mL) was added dropwise at 35 to 45 ℃ and then cooled to 5 ℃. Then, stirring the mixture at 0 to 10 ℃ for 24 hoursThe residue was collected by filtration, and the filtrate was washed with n-heptane (10mL) and dried, whereby the title compound (4.50g, 67.8%, optical purity 99.9%) was obtained.

(example 2G)

The sealed tube reaction was performed under the conditions shown in the following table.

[ Table 12]

(post-treatment 2G-1)

The reaction of example 2G-1 was terminated, and after the reaction solution was cooled, a 25 wt% aqueous solution of sodium chloride (345mL) and 2-MeTHF (250mL) were added to the reaction solution, and filtration was performed using Diatomite, and the filtrate (cake) was washed with 2-MeTHF (230 mL). The aqueous and organic layers were separated and the aqueous layer was extracted with 2-MeTHF (230mL, 2X) to give an organic phase (2G-1) that was combined with the previously obtained organic layer.

(post-treatment 2G-2)

The reaction of example 2G-2 was terminated, and after the reaction solution was cooled, a 25 wt% aqueous sodium chloride solution (375mL) and 2-MeTHF (250mL) were added to the reaction solution, and filtration was performed using Diatomite, and the filtrate (cake) was washed with 2-MeTHF (250 mL). The aqueous and organic layers were separated and the aqueous layer was extracted with 2-MeTHF (250mL, 2X) to give an organic phase (2G-2) that was combined with the previously obtained organic layer.

(post-treatment 2G-3)

After mixing the organic phase (2G-1) and the organic phase (2G-2) obtained previously, 8 wt% Na was added₂SO₄After washing with an aqueous solution (480mL, 2 times), a 0.5M aqueous hydrochloric acid solution (1156mL) was added dropwise to adjust the pH to 0.88. The aqueous and organic layers were separated, and the aqueous layer was extracted with 2-MeTHF (290 mL). To the aqueous layer was added 10% aqueous sodium hydroxide (230mL), and the mixture was extracted with 2-MeTHF (1000mL, 500mL, 3 times). Combining with the organic layer obtained previously, concentrating the organic layer at 40 deg.C or lower, adding n-heptane (576mL) dropwise at 35-45 deg.C, cooling to 0-10 deg.C, stirring at the same temperature, filtering, collecting filtrate with n-heptaneThe residue was washed with an alkane (96mL) and dried to obtain the title compound (53.55g, 70.8%, 99.9% optical purity).

[ physical Property data of formula (B) ]

( ¹H-NMR, 400 MHz, manufacturer: bruker, CDCl₃、δ ppm) 6.91 (1H、t、J = 7 Hz)、6.52-6.46 (2H、m)、4.19-4.04 (2H、m)、3.51 (1H、brs)、2.93-2.65 (3H、m)、2.31 (1H、dd、J = 7, 16 Hz)、2.02-1.89 (1H、m)、1.85-1.65 (1H、m).

The ammonia water used in the examples 2A to 2G is 25 to 28% ammonia water.

Claims

1. A process for producing a compound represented by the formula (B),

[ chemical formula 22]

The preparation method comprises the following steps:

[ chemical formula 23]

In the formula (SM8), X is a halogen atom,

[ chemical formula 24]

In the formula (A8), X is a halogen atom; and

2. A process for producing a compound represented by the formula (B),

[ chemical formula 25]

The preparation method comprises the following steps:

reacting ammonia water with a compound represented by the formula (A8) in the presence of a catalyst to obtain a compound represented by the formula (B),

[ chemical formula 26]

In the formula (A8), X is a halogen atom.

3. A process for producing a compound represented by the formula (A8),

[ chemical formula 27]

In the formula (A8), X is a halogen atom,

the preparation method comprises the following steps:

[ chemical formula 28]

In the formula (SM8), X is a halogen atom.

4. A compound represented by the formula (A8),

[ chemical formula 29]

In the formula (A8), X is a halogen atom.