CN112409191A

CN112409191A - Process for preparing optically active aminoalcohols

Info

Publication number: CN112409191A
Application number: CN201910783254.8A
Authority: CN
Inventors: 孙宝权; 陈炎亮; 沙春波; 林金光; 葛永辉
Original assignee: Mochida Pharmaceutical Co Ltd
Current assignee: Mochida Pharmaceutical Co Ltd
Priority date: 2019-08-23
Filing date: 2019-08-23
Publication date: 2021-02-26
Also published as: WO2021038889A1

Abstract

According to the present invention, there is provided a method for producing a compound represented by the formula (B) (aminotetralol) and a salt thereof, using a compound represented by the formula (A), a compound represented by the formula (A-5), a compound represented by the formula (A-6), or a compound represented by the formula (A-7) as a starting material. Thus, a novel aminotetralol and a process for producing a salt thereof are 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 No.920332-28-1) as TRPV1 antagonist and are expected to be useful as 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, 8-amino-3, 4-dihydronaphthalen-2 (1H) -one (formula (IM-3)) obtained by alkylation of phenyl group, Birch reduction (Birch reduction), and deprotection of alkyl group using 8-aminonaphthalen-2-ol (formula (SM-1)) as a starting material is subjected to asymmetric reduction in the presence of Ru catalyst to produce a compound of formula (B) (scheme 1).

However, this production method is not suitable for mass synthesis or industrial production because Birch reduction is used in the process and a metal catalyst is used for asymmetric reduction (a process for reducing the residual ratio of metal in the resulting compound is necessary).

[ chemical formula 2]

(scheme 1)

In addition, 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 selective reduction of the naphthalene ring, followed by resolution using an optically active column to prepare a compound of formula (B) (scheme 2).

However, in this production method, other isomer (S form) obtained by column resolution is difficult to reuse, and therefore, it is not suitable for mass synthesis or industrial production.

[ chemical formula 3]

(scheme 2)

Further, a method for producing the compound of the formula (B) is also 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, in this production method, other isomers obtained by column resolution are also difficult to reuse, and are not suitable for mass synthesis or industrial production.

[ chemical formula 4]

(scheme 3)

The methods for producing the compound of formula (B) disclosed in the above-mentioned documents have a problem that, depending on the reaction type of the production process, the reagents used, and the necessity of column resolution of racemic modification or diastereomer, reuse of the other isomer after resolution is difficult, and an improved production method thereof has been desired in 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 the formula (B), it is required to find a novel production method which is 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.

A method for oxidizing a secondary alcohol to a ketone using TEMPO as an oxidizing agent is disclosed in U.S. patent No. 5136103 specification (patent document 9) and the like. However, a TEMPO oxidation reaction using 1,2,3, 4-tetrahydronaphthalene having a substituted amino group and a hydroxyl group in the molecule (e.g., tert-butyl- (7-hydroxy-5, 6,7, 8-tetrahydronaphthalen-1-yl) carbamate, etc.) as a raw material has not been known. In addition, a flow chemistry (flow reaction) -based TEMPO oxidation reaction using this compound for a raw material is also unknown.

The use of Lactobacillus kefir (Lactobacillus kefir) in the patent specification (patent document 10) or 5342767 (patent document 11) is disclosed in the patent specification (5225339)Lactobacillus kefir) But an enzyme suitable for the reduction of a ketone compound such as amino-3, 4-dihydronaphthalen-2 (1H) -one or β -tetralone with a protecting group has not been disclosed.

Enzymatic reduction of alpha-tetralone or beta-tetralone ketones (reductase: from Lactobacillus kefir) was disclosed in Advanced Synthesis & Catalysis, 350(14+15), 2322-2328, 2008 (non-patent document 1). However, in the case of using a reductase derived from lactobacillus kefir, the reduction of β -tetralone (ketone group at β -position of benzene ring) does not proceed.

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: specification of U.S. patent No. 5136103;

patent document 10: specification of U.S. patent No. 5225339;

patent document 11: specification of U.S. patent No. 5342767;

non-patent document

Non-patent document 1: advanced Synthesis & Catalysis, 350(14+15), pages 2322-2328, 2008.

Disclosure of Invention

Problems to be solved by the invention

Under such circumstances, a novel method for producing the compound represented by the above formula (B) has been 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 is provided a novel process for producing a compound represented by the above formula (B). 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). The production method of the preferred embodiment is an industrially advantageous production method with a good yield of the compound represented by the formula (B), and has high industrial applicability.

Drawings

FIG. 1 shows an example of a reaction apparatus used in flow chemistry.

Detailed Description

[ solution of the invention ]

Provided herein are methods for producing the compound represented by the formula (B) and salts thereof. Several embodiments are directed to a process for producing a compound represented by the formula (B) or a salt thereof, which comprises using a compound represented by the formula (A) 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 (A-5) 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 (A-6) 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 (A-7) as a starting material. In other embodiments, the compound represented by the formula (A-6) is prepared by using the compound represented by the formula (A-5) or the formula (A-7) as a starting material. In other embodiments, the compound represented by the formula (A-7) is prepared by using the compound represented by the formula (A-6) as a starting material.

Each of the schemes is described below in detail.

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

[ chemical formula 5]

The preparation method comprises the following steps:

a step for obtaining a compound represented by the formula (A-5) by t-butoxycarbonylating an amino group of the compound represented by the formula (A),

[ chemical formula 6]

[ chemical formula 7]

；

A step of subjecting the compound represented by the formula (A-5) to an oxidation reaction to obtain a compound represented by the formula (A-6),

[ chemical formula 8]

；

A step of subjecting the compound represented by the formula (A-6) to asymmetric reduction to obtain a compound represented by the formula (A-7),

[ chemical formula 9]

(ii) a And

deprotecting the t-butoxycarbonyl group of the compound represented by the formula (A-7) to obtain a compound represented by the formula (B) and a salt thereof.

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

[ chemical formula 10]

The preparation method comprises the following steps:

[ chemical formula 11]

[ chemical formula 12]

；

[ chemical formula 13]

(ii) a And

[3] The 3 rd embodiment is a process for producing a compound represented by the formula (B) and a salt thereof,

[ chemical formula 14]

The preparation method comprises the following steps:

[ chemical formula 15]

[ chemical formula 16]

(ii) a And

[4] The 4 th embodiment is a process for producing a compound represented by the formula (B) or a salt thereof,

[ chemical formula 17]

The preparation method comprises the following steps:

a step of deprotecting the tert-butoxycarbonyl group of the compound represented by the formula (A-7) to obtain a compound represented by the formula (B) and a salt thereof,

[ chemical formula 18]

。

[5] Scheme 5 is a process for preparing a compound represented by formula (A-6),

[ chemical formula 19]

The preparation method comprises the following steps:

[ chemical formula 20]

。

[6] Scheme 6 is a process for preparing a compound represented by formula (A-7),

[ chemical formula 21]

The preparation method comprises the following steps:

[ chemical formula 22]

。

< Process for producing the Compound represented by the formula (A-5) >

The compound represented by the formula (A-5) is obtained by subjecting an amino group of the compound represented by the formula (A) to tert-butoxycarbonylation.

Examples of the t-butoxycarbonylation agent include: di-tert-butyl dicarbonate (Boc)₂O), 2- (t-butyloxycarbonylimino) -2-phenylacetonitrile (Boc-ON), N-t-butyloxycarbonylimidazole, 2- (t-butyloxycarbonylthio) -4, 6-dimethylpyrimidine, 1-t-butyloxycarbonylthio-1, 2, 4-triazole, t-butyl carbonate, t-butyl carbazate, N- (t-butyloxycarbonyloxy) phthalimide, and the like. Di-tert-butyl dicarbonate (Boc) is preferred₂O), 2- (tert-Butoxycarbonyloxyimino) -2-phenylacetonitrile (Boc-ON), more preferably di-tert-butyl dicarbonate (Boc-ON)₂O)。

The amount of the tert-butoxycarbonylation agent used is usually 1.0 to 2.0 molar equivalents, preferably 1.1 to 1.8 molar equivalents, and more preferably 1.3 to 1.65 molar equivalents, relative to 1 molar equivalent of the compound represented by the formula (a).

The reaction may be carried out in the presence of a solvent. As solvents, for example, it is possible to use: solvents which do not participate in the reaction, such as methylene chloride, acetonitrile, diethyl ether, tetrahydrofuran, 1, 2-dimethoxyethane, 1, 4-dioxane, tert-butyl ether, toluene, and water, or a mixed solvent thereof, may be appropriately selected depending on the type of the tert-butoxycarbonylation agent used. Preferred are tetrahydrofuran, 1, 4-dioxane, a mixed solvent of tetrahydrofuran-water and a mixed solvent of 1, 4-dioxane-water, and more preferred are tetrahydrofuran, a mixed solvent of tetrahydrofuran-water and a mixed solvent of 1, 4-dioxane-water.

The reaction may be carried out in the presence of a base. As the base, there can be used: bases such as sodium hydrogen carbonate, potassium carbonate, sodium carbonate, triethylamine, N-diisopropylethylamine, and pyridine can be appropriately selected depending on the type of the t-butoxycarbonylating agent used. Sodium bicarbonate, triethylamine and pyridine are preferred, and sodium bicarbonate is more preferred.

The amount of the base used is, for example, 1.0 to 4.0 molar equivalents, preferably 1.0 to 3.5 molar equivalents, and more preferably 1.0 to 3.2 molar equivalents, relative to 1 molar equivalent of the compound represented by the formula (a).

The reaction temperature may be, for example, in the range of-78 ℃ to the temperature of refluxing the solvent, in the range of-78 ℃ to room temperature, in the range of 0 ℃ to the temperature of refluxing the solvent, or in the range of 0 ℃ to room temperature, and may be appropriately selected depending on the kind of the t-butoxycarbonylating agent used. Preferably in the range of 20 ℃ to 55 ℃.

< Process for producing the Compound represented by the formula (A-6) >

The compound represented by the formula (A-6) can be obtained by subjecting a compound represented by the formula (A-5) or a compound represented by the formula (A-7) to an oxidation reaction.

Examples of the oxidation reaction include: swern oxidation, PCC oxidation (chromate oxidation), Dess-Martin oxidation, TPAP oxidation, TEMPO oxidation, and the like. TEMPO oxidation is preferred.

In the oxidation reaction, for example, a batch method and flow chemistry (reaction based on a flow mode using a Continuous Stirred Tank Reactor (CSTR)) are employed.

The amount of the oxidizing agent used in the oxidation reaction is usually 1.0 to 2.2 molar equivalents, preferably 1.2 to 2.1 molar equivalents, and more preferably 1.4 to 2.0 molar equivalents, relative to 1 molar equivalent of the compound represented by the formula (a-5) or the compound represented by the formula (a-7).

The amount of TEMPO used in the TEMPO oxidation is usually 0.01 to 1.0 molar equivalent, preferably 0.05 to 0.7 molar equivalent, more preferably 0.5 molar equivalent, relative to 1 molar equivalent of the compound represented by the formula (A-5) or the compound represented by the formula (A-7).

The amount of sodium hypochlorite (NaClO) used in the TEMPO oxidation is usually 1.0 to 2.5 molar equivalents, preferably 1.1 to 2.2 molar equivalents, and more preferably 1.2 to 2.0 molar equivalents, relative to 1 molar equivalent of the compound represented by the formula (A-5) or the compound represented by the formula (A-7).

NaHCO in TEMPO oxidation with respect to 1 molar equivalent of the compound represented by the formula (A-5) or the compound represented by the formula (A-7)₃The amount of (B) is usually 1.0 to 5.0 molar equivalents, preferably 2.0 to 4.5 molar equivalents, and more preferably 4.0 molar equivalents.

The amount of KBr used in the TEMPO oxidation is usually 0.01 to 0.30 molar equivalents, preferably 0.02 to 0.25 molar equivalents, and more preferably 0.05 to 0.2 molar equivalents, relative to 1 molar equivalent of the compound represented by the formula (A-5) or the compound represented by the formula (A-7).

The reaction may be carried out in the presence of a solvent. As solvents, for example, it is possible to use: solvents that do not participate in the reaction, such as dichloromethane, 1, 2-dichloroethane, chloroform, acetonitrile, acetone, and water, or a mixed solvent thereof, may be appropriately selected depending on the type of oxidation reaction used. In the TEMPO oxidation, dichloromethane, acetonitrile, acetone, water or a mixed solvent thereof is preferable, and dichloromethane, water, or a dichloromethane-water mixed solvent is more preferable.

The reaction temperature may be, for example, in the range of-78 ℃ to the temperature of refluxing the solvent, in the range of-78 ℃ to room temperature, in the range of 0 ℃ to the temperature of refluxing the solvent, in the range of 0 ℃ to room temperature, or the like, and may be appropriately selected depending on the oxidation reaction to be used. In TEMPO oxidation, the temperature is preferably in the range of-2 ℃ to 5 ℃.

After the TEMPO oxidation reaction, Na may also be used in order to remove TEMPO₂S₂O₄(aqueous solution), etc.

< Process for producing the Compound represented by the formula (A-7) >

The compound represented by the formula (A-7) can be obtained by asymmetrically reducing a ketone compound represented by the formula (A-6).

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 microorganism derived from the genus Lactobacillus (L.) (Lactobacillus sp.) As an asymmetric reduction of the enzyme. Asymmetric reduction using ketoreductases is performed using ketoreductases, coenzymes, and coenzyme regeneration systems. Typical examples of coenzymes of ketoreductases include NADP. 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 the formula (a-6).

In the asymmetric reduction using an enzyme, the amount of the enzyme used is usually 1.0 to 25 times, preferably 5 to 20 times, and more preferably 10 times the amount of 1g of the compound represented by the formula (A-6).

In the use of a compound derived from the genus Lactobacillus (A)Lactobacillus sp.) In the asymmetric reduction of the ketoreductase (b), the amount of the enzyme to be used is usually 1.0 to 25 times, preferably 5 to 20 times, and more preferably 10 times the amount of 1g of the compound represented by the formula (A-6).

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 2.0 times the amount of 1g of the compound represented by the formula (A-6).

For asymmetric reduction using an enzyme, Glucose Dehydrogenase (GDH) can be used. When Glucose Dehydrogenase (GDH) is used, the amount of Glucose Dehydrogenase (GDH) used is usually 0.01 to 0.5 times, preferably 0.05 to 0.2 times, and more preferably 0.05 times or 0.2 times the amount of the compound represented by the formula (A-6) per 1g of the compound.

Nicotinamide adenine dinucleotide phosphate can be used for the asymmetric reduction using an enzyme. When nicotinamide adenine dinucleotide phosphate is used, the amount of nicotinamide adenine dinucleotide phosphate used is usually 0.01 to 0.5 times, preferably 0.025 to 0.1 times, and more preferably 0.025 times or 0.1 times the amount of 1g of the compound represented by the formula (A-6).

The asymmetric reduction may be carried out in the presence of a solvent. As solvents, for example, it is possible to use: 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 mixed solvent 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, and can be appropriately selected depending on the type of enzyme used.

In the use of a compound derived from the genus Lactobacillus (A)Lactobacillus sp.) In the asymmetric reduction of the ketoreductase of (2), the solvent is preferably dimethyl sulfoxide, toluene, water or a mixed solvent thereof, and more preferably toluene, water or a mixed solvent of toluene and water.

In the asymmetric reduction using an enzyme, the amount of the organic solvent used is usually 1.0 to 15 times, preferably 2 to 13 times, and more preferably 5.0 times the amount of 1g of the compound represented by the formula (A-6).

In the asymmetric reduction using an enzyme, the amount of the buffer used is usually 10 to 40 times, preferably 15 to 30 times, and more preferably 30 times the amount of 1g of the compound represented by the formula (A-6).

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

The reaction temperature for carrying out the asymmetric reduction may 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 temperature range in which the enzyme is not inactivated, preferably in a range of 20 to 60 ℃, more preferably in a range of 20 to 25 ℃ or in a range of 50 to 60 ℃, and still more preferably in a range of 20 to 25 ℃.

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

The compound represented by the formula (B) and a salt thereof can be obtained by deprotecting the tert-butoxycarbonyl group of the chiral alcohol compound represented by the formula (A-7) or desalinating the salt of the formula (B) obtained by deprotecting the tert-butoxycarbonyl group.

Examples of the reagent used for the deprotection of a t-butoxycarbonyl group include an acidic reagent, preferably hydrogen chloride (generated in a solvent system using hydrochloric acid or acetyl chloride and an alcohol-based solvent such as methanol, ethanol, or propanol), hydrogen bromide, and trifluoroacetic acid, more preferably hydrogen chloride (generated in a solvent system using hydrochloric acid or acetyl chloride and an alcohol-based solvent such as methanol, ethanol, or propanol), and trifluoroacetic acid, and particularly preferably hydrogen chloride (generated in a solvent system using hydrochloric acid or acetyl chloride and an alcohol-based solvent such as methanol, ethanol, or propanol).

Deprotection of the t-butoxycarbonyl group may be carried out in the presence of a solvent. Examples of the solvent for deprotecting the t-butoxycarbonyl group include: halogen-based solvents such as dichloromethane, chloroform, and 1, 2-dichloroethane; 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; a solvent which does not participate in the reaction, such as water, or a mixed solvent thereof, preferably a halogen-based solvent such as methylene chloride, chloroform, or 1, 2-dichloroethane; an alcohol solvent such as methanol, ethanol, propanol, or butanol, and more preferably propanol (n-propanol).

The reaction temperature for deprotecting the t-butoxycarbonyl group can be appropriately selected from the reaction temperatures, for example, in the range of-78 ℃ to the temperature of solvent reflux, in the range of-78 ℃ to room temperature, in the range of 0 ℃ to the temperature of solvent reflux, or in the range of 0 ℃ to room temperature. Preferably 0 to 55 ℃.

The salt of formula (B) may be desalted using a base. As the base for desalting the salt of formula (B), there can be used: bases such as sodium hydrogen carbonate, potassium carbonate, sodium carbonate, triethylamine, N-diisopropylethylamine, and pyridine, preferably sodium hydrogen carbonate, potassium carbonate, and sodium carbonate, and more preferably sodium hydrogen carbonate.

The desalting of the salt of formula (B) may be carried out in the presence of a solvent. Examples of the solvent for desalting the salt of formula (B) include: halogen-based solvents such as dichloromethane, chloroform, and 1, 2-dichloroethane; ether solvents such as tetrahydrofuran, 1, 4-dioxane, and butyl ether; polar solvents such as ethyl acetate, isopropyl acetate, acetonitrile, dimethyl sulfoxide, dimethylformamide and the like; the solvent or a mixed solvent thereof which does not participate in the reaction, such as water, is preferably ethyl acetate, isopropyl acetate, water, an ethyl acetate-water or an isopropyl acetate-water mixed solvent, and more preferably an ethyl acetate-water mixed solvent.

The 8-amino-1, 2,3, 4-tetrahydronaphthalen-2-ol [ CAS number 624729-66-4] of formula (A) in scheme [1] can be prepared by selective reduction of the naphthalene ring using 8-aminonaphthalen-2-ol (formula (SM-1)) as a starting material by a publicly known preparation method, for example, the following preparation method described in International publication No. 2009/050289 pamphlet (patent document 5).

[ chemical formula 23]

(diagram 4)

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. In addition, the reaction mixture can be isolated by a conventional method, and can be easily purified by a known method, 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 in proportion and then 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 each of 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, 72 hours, or 115 hours and a time having these as the ranges of the lower limit value and the upper limit value.

In the above reaction temperature, for example, "the range from-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 the mixed solvent) used in the reaction is refluxed. For example, in the case of using methanol in the solvent, "from-78 ℃ to the temperature at which the solvent is refluxed" means a temperature in the range from-78 ℃ to the temperature at which the methanol is refluxed.

The "temperature from 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. As described above, the lower limit of the temperature is, for example, -78 ℃ or 0 ℃, or 20 ℃, 23 ℃, 25 ℃, 40 ℃, 50 ℃, 70 ℃, 80 ℃, 90 ℃, or 100 ℃, and the temperatures of ± 1 ℃, ± 2 ℃, ± 3 ℃, ± 4 ℃ and ± 5 ℃ may be used.

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 ℃.

The compounds in the present specification may form acid addition salts depending on the kind of the substituent. 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 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, and mandelic acid; salts with aliphatic dibasic acids such as oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, malic acid, and tartaric acid; salts with aliphatic tricarboxylic acids such as citric acid; salts with aromatic monocarboxylic acids such as benzoic acid and salicylic acid; salts with aromatic dibasic 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. Among them, pharmaceutically acceptable salts are preferred. Examples thereof include: salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.; or salts with organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, and the like.

The salt can be obtained by a conventional method, for example, by mixing the compound in the present specification and a solution containing an appropriate amount of an acid to form a target salt, followed by collecting the salt by filtration stepwise or distilling off the mixed solvent. The compound or a salt thereof in the present specification can 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 5), the compound represented by the formula (B) and a salt thereof can be produced via the compounds of the formulae (a-5), (a-6) and (a-7) using the compound of the formula (a) as a starting material.

[ chemical formula 24]

Scheme 5

Further, as shown in the following (scheme 6), the compound represented by the formula (B) and a salt thereof can be prepared by changing the protecting group of the amino group of the compound of the formula (a) to a protecting group other than t-butoxycarbonyl group, for example, a carbamate-based protecting group such as methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, or allyloxycarbonyl; a sulfonyl-based protecting group such as methanesulfonyl, ethanesulfonyl, benzenesulfonyl, tolyl, or nitrobenzenesulfonyl; acetyl, BA protecting group P such as an alkylcarbonyl-based or arylcarbonyl-based protecting group such as alkylcarbonyl, trifluoroacetyl or benzoyl¹Prepared according to the method shown above (scheme 5).

[ chemical formula 25]

Scheme 6

Further, the protecting group P of the compound of the formula (A)¹Or a protecting group P of the compound of the formula (A-7P)¹Deprotection according to protecting group P¹The type (2) is a group known from the literature, for example, "Protective Groups in Organic Synthesis (4)^thEdition) 4 th Edition, 2007, John Wiley & Sons, Greene et al, published as .

In the present specification, the compounds represented by the formulae (A), (A-5) and (A-5p) as racemates include the (R) configuration and the (S) configuration. For example, it means that the formula (a-5S) and the formula (a-5R) (= the formula (a-7)) are included in the formula (a-5).

[ chemical formula 26]

[ 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), etc.) and then a ketone group is converted into a racemic alcohol group, followed by a fractional recrystallization method (ionic bonding of an optical resolving agent to a 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 No. 2009/055749)Pamphlet), chiral column method (see pamphlet of International publication No. 2009/050289), etc. to form a chiral alcohol group.

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

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, availability of an organic solvent and/or water as a reaction solvent, capability of performing a reaction under mild conditions (normal temperature and normal pressure), and cheapness 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 an effective reaction for easily obtaining a chiral compound.

In the asymmetric reduction reaction using an enzyme, 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), 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]

[ flow chemistry ]

The flow chemistry refers to a continuous synthesis method using a reaction apparatus in which a solution is fed from a container containing 2 or more different solutions (for example, a raw material + solvent, a reagent + solvent, and the like) through a tube at a constant flow rate by a pump, fed to the reaction container, and fed to a recovery drum (recovery ドラム).

An example of a reaction apparatus used in flow chemistry is shown in FIG. 1. The reaction device comprises: a nitrogen inlet (L1, L2, L3, L4); a vessel (M1) containing feedstock, TEMPO and dichloromethane; containing KBr and NaHCO₃And a container of water (M2); a vessel (M3) containing 5.0wt% NaClO; pumps (P1, P2, P3): pre-cooling tubes (T1, T2, T3); mixers (S1, S2, S3); and a reaction vessel (R1, R2, R3).

The reaction apparatus is used, for example, in the following manner. First, a vessel M1 was charged with raw materials (compound of formula (A5)), TEMPO and methylene chloride, a vessel M2 was charged with KBr, sodium bicarbonate and water, and a vessel M3 was charged with 5.0wt% NaClO. While flowing nitrogen gas from the nitrogen inlet ports L1, L2, L3 and L4, the reagents were flowed from the vessels M1, M2 and M3 at predetermined flow rates by the pumps P1, P2 and P3, passed through the precooling pipes T1, T2 and T3, passed through the reaction vessel R1, reaction vessel R2 and reaction vessel R3 in this order, and injected into the collection drum CD. Then, the target compound (the compound of formula (A-6)) was obtained from the recovered drum CD.

Flow Chemistry is also applicable to such reactions where it is difficult to ensure safety in typical batch syntheses (for a review of Flow Chemistry see ChemSusChem, 5(2), Special Issue; Flow Chemistry, p. 213-439, p. 2.13/2012).

The batch method is a general synthetic reaction, and means a method of purifying a product after a reaction is carried out using a reaction vessel. The batch process has the advantage that the compound can be synthesized in a number of steps.

The flow method (flow chemistry) is a reaction method using a Continuous Stirred Tank Reactor (CSTR) as a reaction apparatus and employing a flow mode. The flow method can be used in a small reaction vessel for the reaction, so that the reaction efficiency is high, and the reaction conditions can be precisely controlled, thereby stably supplying the target substance.

All publications cited in this specification, for example, other patent documents such as prior art documents, public publications, and patent publications, 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.

In the determination of the nuclear magnetic resonance spectra (NMR) of the compounds of the formula (A-5), of the formula (A-6), of the formula (A-7) and of the formula (B), a Bruker AVANCEIII 400MHz NMR spectrometer (Bruker 5mm PABBO Z-gradient probe, TOPSPIN 3.5 software) was used. In addition, JEOL JNM-LA300 FT-NMR (Japanese Electron) was used for the measurement of the nuclear magnetic resonance spectrum (NMR) of the bromate salt of the compound of the formula (B) and the compound of the formula (I).

The High Performance Liquid Chromatography (HPLC) of the formula (A-5), the formula (A-6), the formula (A-7) and the formula (B) was carried out in accordance with the following method.

[ Table 2]

[ measurement conditions of the Compounds of formula (A-5), formula (A-6) and formula (A-7) ]

[ Table 3]

[ Retention Time (RT) ]

[ Table 4]

[ measurement conditions of the Compound of formula (B) ]

[ Table 5]

[ Retention Time (RT) ]

[ Table 6]

[ chiral analysis method of Compound of formula (A-7) ]

[ Table 7]

[ Retention Time (RT) ]

In addition, the liquid chromatography-Mass spectrometry (LC-Mass) of the bromate salt of the compound of formula (B) and the compound of formula (I) was measured by the following method.

[UPLC]Using a Waters AQUITY UPLC system and a BEH C18 column (2.1 mm. times.50 mm, 1.7)μm) (Waters), with acetonitrile: 0.05% aqueous trifluoroacetic acid = 5: 95(0 min) to 95: 5(1.0 min.) to 95: 5(1.6 min.) to 5: 95(2.0 min) mobile phase and gradient conditions.

¹In the H-NMR data, in the pattern of the NMR signal, s is a singlet, d is a doublet, t is a triplet, q is a quartetMultiple peak, m is multiple peak, brs is broad peak, J is coupling constant, Hz is Hz, DMSO-d₆Is heavy dimethyl sulfoxide, CDCl₃Heavy chloroform. In that¹H-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.

Examples 1a to 1d Synthesis of tert-butyl (7-hydroxy-5, 6,7, 8-tetrahydronaphthalen-1-yl) carbamate (A-5)

[ chemical formula 27]

Example 1a

To a solution of 0.5g of the compound of formula A (prepared according to the preparation method described in the pamphlet of International publication No. 2009/050289) and 0.154g of sodium hydrogencarbonate in 5mL of 1, 4-dioxane-5 mL of water was added 0.74g of di-tert-butyl dicarbonate (Boc)₂O), stirring for 22 hours at the reaction temperature of 20-30 ℃. Then 0.104g of sodium bicarbonate is added, and the mixture is stirred for 18 hours at the reaction temperature of 20-30 ℃. Then 0.15g of di-tert-butyl dicarbonate is added and stirred for 5 hours at the reaction temperature of 20-30 ℃. Then 0.15g of di-tert-butyl dicarbonate is added and stirred for 16 hours at the reaction temperature of 20-30 ℃. Then 0.1g of di-tert-butyl dicarbonate is added and stirred for 1 hour at the reaction temperature of 20-30 ℃. Ethyl acetate was added to the reaction solution, and the organic layer was separated. The aqueous layer was washed with ethyl acetate, combined with the organic layer obtained above, and then washed with saturated brine. The organic layer was concentrated under reduced pressure, and the resulting residue was solidified with dichloromethane and n-heptane to obtain 0.46g of the labeled compound.

(example 1b)

To a solution of 1.0g of the compound of formula A (prepared by the preparation method described in the pamphlet of International publication No. 2009/050289) and 1.55g of sodium hydrogencarbonate in 10mL of tetrahydrofuran-10 mL of water was added 1.61g of di-tert-butyl dicarbonate (Boc)₂O), and stirring for 17 hours at the reaction temperature of 45-55 ℃. Then 0.13g of di-tert-butyl dicarbonate is added and stirred at the reaction temperature of 45-55 DEG CStirring for 2 hours. The reaction solution was cooled to room temperature, methyl tert-butyl ether (MTBE) was added thereto, the pH was adjusted to 5-6 with 10w/v% citric acid solution, and the organic layer was separated. The aqueous layer was extracted with methyl t-butyl ether, combined with the organic layer obtained previously, and then washed with water and saturated brine. The organic layer was concentrated under reduced pressure, and the resulting residue was solidified with methylene chloride and n-heptane to give 1.34g of the labeled compound.

Example 1c

To a solution of 10g of the compound of formula A (prepared according to the preparation method described in the pamphlet of International publication No. 2009/050289) and 15.5g of sodium hydrogencarbonate in 100mL of tetrahydrofuran-100 mL of water was added 17.4g of di-tert-butyl dicarbonate (Boc)₂O), and stirring for 17 hours at the reaction temperature of 45-55 ℃. Then, 1.3g of di-tert-butyl dicarbonate was added and stirred at a reaction temperature of 45 to 55 ℃ for 2 hours. 1.3g of di-tert-butyl dicarbonate is added and stirred for 1 hour at the reaction temperature of 45-55 ℃. The reaction solution was cooled to room temperature, methyl tert-butyl ether (MTBE) was added thereto, the pH was adjusted to 5-6 with a 10% citric acid solution, and the organic layer was separated. The aqueous layer was extracted with methyl t-butyl ether, combined with the organic layer obtained previously, and then washed with water and saturated brine. The organic layer was concentrated under reduced pressure, and the resulting residue was solidified with dichloromethane and n-heptane to give 15.1g of the labeled compound.

(example 1d)

A solution of 218.5g of the compound of formula A (prepared by the method described in WO 2009/050289) in 1.9L of tetrahydrofuran was adjusted to a temperature of 20 to 30 ℃ and an aqueous solution of sodium hydrogencarbonate (319g (3.2eq) of sodium carbonate and 1.9L of water) was added at a temperature of 20 to 30 ℃ over 10 minutes. The temperature of the mixed solution was adjusted to 0 to 10 ℃ and 413g of di-tert-butyl dicarbonate was added over 15 minutes while maintaining the same temperature. The reaction temperature is set to 45-55 ℃, and the mixture is stirred for 18 hours at the same temperature. Cooling the reaction temperature to 20-30 ℃, then adding 1.9L of methyl tert-butyl ether into the reaction solution, and stirring for 10 minutes at 20-30 ℃. Adding 2.5L 10% citric acid solution, and separating organic layer. The aqueous layer was extracted with methyl tert-butyl ether (1L X2 times), combined with the organic layer obtained before, and washed with water (1L X2 times). Concentrating under reduced pressure until the organic layer becomes about 500mL, then adding 1L of dichloromethane, concentrating under reduced pressure until the organic layer becomes about 500mL, performing the above operation 2 times, then adding 1L of n-heptane, concentrating under reduced pressure until the organic layer becomes about 500mL, adding 800mL of n-heptane, concentrating under reduced pressure until the organic layer becomes about 600mL, adding 300mL of dichloromethane and 600mL of n-heptane, concentrating under reduced pressure until the organic layer becomes about 600mL, adding 1L of dichloromethane, adding 21g of activated carbon, and stirring the mixed solution at 20-30 ℃ for 2 hours. Thereafter, the mixed solution was filtered, and the filtrate was concentrated under reduced pressure until about 500mL was reached, and 800mL of methylene chloride was added to conduct concentration under reduced pressure until the solution reached about 500 mL. 800mL of methylene chloride was added and filtered to obtain a solid. The resulting solid was dried at 35 ℃ for 15 hours to obtain 303.3g of the labeled compound as a gray black solid.

[ physical Property data of formula (A-5) ]

(1H NMR, 400MHz, manufacturer: Bruker, DMSO-d6,. delta.ppm);

8.36 (s、1H)、7.09 (d、1H、J=7Hz)、7.03 (t、1H、J=7Hz)、6.87 (d、1H、J=7Hz)、4.78 (d、1H、J=4Hz)、3.90-3.84 (m、1H)、2.89-2.81 (m、2H)、2.75-2.65 (m、1H)、2.42 (dd、1H、J=7,17Hz)、1.90-1.80 (m、1H)、1.62-1.53 (m、1H)、1.46 (s、9H)。

(examples 2a-2f) Synthesis of tert-butyl (7-oxo-5, 6,7, 8-tetrahydronaphthalen-1-yl) carbamate (A-6)

[ chemical formula 28]

(example 2a)

In the same manner as in examples 1a to 1d, 0.5g of tert-butyl (R) - (7-hydroxy-5, 6,7, 8-tetrahydronaphthalen-1-yl) carbamate (formula (a-7)) obtained from (R) -8-amino-1, 2,3, 4-tetrahydronaphthalen-2-ol was used, and oxidation was carried out in a solvent (12.5mL of dichloromethane-7.5 mL of water) at a reaction temperature (0 to 5 ℃) under the reagent conditions shown in the following table to confirm that the labeled compound was obtained (IPC purity by HPLC (IPC = process analysis)).

[ Table 8]

(example 2b)

In the same manner as in examples 1a to 1d, 0.5g of tert-butyl (R) - (7-hydroxy-5, 6,7, 8-tetrahydronaphthalen-1-yl) carbamate (formula (A-7)) obtained from (R) -8-amino-1, 2,3, 4-tetrahydronaphthalen-2-ol was used, and oxidation was carried out at a reaction temperature of 0 to 5 ℃ under the reagent conditions shown in the following Table to confirm that the labeled compound (IPC purity by HPLC) was obtained.

[ Table 9]

(example 2c)

In the same manner as in examples 1a to 1d, a solution of 10g of t-butyl (R) - (7-hydroxy-5, 6,7, 8-tetrahydronaphthalen-1-yl) carbamate (formula (A-7)) in 250mL (25-volume-fold) of methylene chloride and 150mL (15-volume-fold) of water was cooled to-2 to 2 ℃ and TEMPO (0.5eq), KBr (0.2eq), NaHCO (C-H) and 150mL (15-volume-fold) of water were added thereto at the same temperature₃(4.0eq) and NaClO ((8.1%), 1.4 eq.). Completion of the reaction was immediately confirmed at 95.5% purity where IPC purity was confirmed. The reaction solution was subjected to a post-treatment to obtain the labeled compound (1H-NMR yield 77.1%).

(example 2d)

TEMPO oxidation using a flow pattern of a Continuous Stirred Tank Reactor (CSTR) as shown in FIG. 1 was carried out. A container M1 was charged with 25g of tert-butyl- (7-hydroxy-5, 6,7, 8-tetrahydronaphthalen-1-yl) carbamate (formula (A-5)) obtained by the same procedure as in examples 1a to 1d and a 500mL dichloromethane solution of TEMPO (0.5eq), a container M2 was charged with KBr (0.05eq), sodium bicarbonate (4eq) and 375mL of water, and a container M3 was charged with 5.0wt% NaClO (1.3 eq). Nitrogen gas was introduced from each of the nitrogen inlets L1, L2, L3, L4, and simultaneously with the use of each of the pumps P1, P2, and P3, the reagents were introduced from each of the vessels M1, M2, and M3 at flow rates of 13.67 mL/min, 9.83 mL/min, and 4.27 mL/min, respectively, passed through the precoolers T1, T2, and T3 (temperature 0 to 5 ℃, tube length: 2M, tube diameter: 1/16SS), and then passed through the reactor R1, the reactor R2, and the reactor R3 in this order (the volumes of the

reactors

1,2, and 3 were 25mL, and the reactors were cooled to 0 to 5 ℃ C.), and were injected into the collection drum CD (the reaction time in each reactor was 0.9 min). The target product was obtained with IPC purity =96.5% of the reaction solution obtained in recovery drum CD.

(example 2e)

TEMPO oxidation using a flow mode of a Continuous Stirred Tank Reactor (CSTR) as shown in FIG. 1 was carried out. 35g of tert-butyl (R) - (7-hydroxy-5, 6,7, 8-tetrahydronaphthalen-1-yl) carbamate (formula (A-5)) obtained by the same procedure as in examples 1a to 1d and TEMPO (0.5eq) in 700mL of dichloromethane were charged into vessel M1, KBr (0.05eq), sodium bicarbonate (4eq) and 525mL of water were charged into vessel M2, and 5.0% by weight of NaClO (1.3eq) was charged into vessel M3. Nitrogen gas was introduced from each of the nitrogen inlets L1, L2, L3, L4, and simultaneously, each of the reagents was introduced from each of the vessels M1, M2, and M3 at a flow rate of 13.67 mL/min, 9.83 mL/min, and 4.27 mL/min by using each of the pumps P1, P2, and P3, respectively, passed through the precoolers T1, T2, and T3 (temperature 0 to 5 ℃, tube length: 2M, tube diameter: 1/16SS), and then injected into the collection drum CD sequentially through the reaction vessels R1, R2, and R3 (

reaction vessels

1,2, and 3 had a capacity of 25mL, and cooled to 0 to 5 ℃ respectively) (reaction time in each reaction vessel was 0.9 min, and flow completion required 47 min). The IPC purity of 850g of the reaction solution obtained in the recovery drum CD was 95.0%. Adding Na to the reaction solution₂S₂O₄Aqueous solution (Na)₂S₂O₄: 10g, water: 250mL) was stirred for 30 minutes. The organic layer was separated from the aqueous layer, after which the organic layer was washed with water (300 mL. times.2). The organic layer is concentrated under reduced pressure to a volume of 1.5 to 2.5v, then 30 to 50mL of n-heptane is added, and the mixture is stirred at room temperature for 1 hour, then 200mL of n-heptane is added, and the mixture is stirred at room temperature for 16 hours. FiltrationThe resulting solid was collected and washed with 70mL of n-heptane to give 25.2g of the title compound as an off-white solid.

(example 2f)

TEMPO oxidation using the flow mode of the Continuous Stirred Tank Reactor (CSTR) shown in FIG. 1 was carried out. Vessel M1 was charged with 276.6g of tert-butyl- (7-hydroxy-5, 6,7, 8-tetrahydronaphthalen-1-yl) carbamate (formula (A-5)) obtained by the same procedure as in (examples 1a to 1d) and 82.588g of TEMPO (0.5eq) in 5535mL of dichloromethane (20v), vessel M2 was charged with 6.251g of KBr, 352.943g of sodium bicarbonate and 4149mL of water, and vessel M3 was charged with 1.849L of 5.0wt% NaClO. Nitrogen gas was introduced from each of the nitrogen inlet ports L1, L2, L3 and L4, and simultaneously, each reagent was introduced from M1, M2 and M3 at flow rates of 13.67 mL/min, 9.83 mL/min and 4.27 mL/min by using pumps P1, P2 and P3, passed through precoolers T1, T2 and T3 (temperature 0 to 5 ℃, tube length: 2M and tube diameter: 1/16SS), and then injected into a recovery drum CD sequentially passing through reactor R1, reactor R2 and reactor R3 (

reaction vessels

1,2 and 3 had a capacity of 25mL, cooled to 0 to 5 ℃ respectively) (reaction time in each vessel in flow mode was 0.9 min, and flow completion required 410 min). 6845g of the resulting reaction mixture and 2597g of 3.7% Na were added₂S₂O₄The solution was stirred for 30 minutes. The organic layer was separated from the aqueous layer, after which the organic layer was washed with water (3 L.times.2 times). The organic layer was concentrated under reduced pressure to a volume of 2.5v, after which 205mL of n-heptane and 1 fragment of the compound of formula a6 which had been taken up were added and stirred at room temperature for 1 hour. 2.1L of n-heptane was further added, and the resultant solid was collected by filtration, washed with 800mL of n-heptane, and dried under reduced pressure for 13 hours to obtain 190g of the title compound as a tan solid.

[ physical Property data of formula (A-6) ]

(1H NMR, 400MHz, manufacturer: Bruker, CDCl3,. delta.ppm);

7.42 (d、1H、J=7Hz)、7.14 (t、1H、J=7Hz)、6.97 (d、1H、J=7Hz)、6.12 (s、1H)、3.41 (s、2H)、3.01 (t、2H、J=6Hz)、2.51 (dd、2H、J=6,7Hz)、1.44 (s、9H)。

example 3a-3g Synthesis of tert-butyl (R) - (7-hydroxy-5, 6,7, 8-tetrahydronaphthalen-1-yl) carbamate (A-7)

[ chemical formula 29]

(example 3a)

In a glass flask having a capacity of 8mL, 2.0g of KRED (ketoreductase derived from Lactoballius sp.), 0.2g D-glucose, 0.02g of Glucose Dehydrogenase (GDH), 0.01g of Nicotinamide Adenine Dinucleotide Phosphate (NADP), and 3.0mL of a phosphate buffer solution (21.25 g of K was added₂HPO₄10.62g KH₂PO₄Added to 1000mL of water) and stirred to prepare a mixed solution A. A mixed solution prepared by dissolving 0.1g of the compound of the formula (A-6) obtained by the same procedure as in (example 2a-2f) in 0.2mL of dimethyl sulfoxide (DMSO) was added to the mixed solution A prepared previously. The mixture was stirred at a reaction temperature of 23 ℃ C (20-25 ℃ C.) for 43 hours (shaking at 250rpm in a rotary shaker). A part of the reaction solution was taken out and analyzed by HPLC, confirming that the labeled compound was obtained.

It should be noted that KRED used in (examples 3a to 3g) was ketoreductase from Lactoballius sp (enzymeWorks, Inc., product No.: EW-KRED-172).

(example 3b)

In a reaction vessel, 20g KRED (ketoreductase from Lactoballius sp.), 2g D-glucose, 0.2g Glucose Dehydrogenase (GDH), 0.1g Nicotinamide Adenine Dinucleotide Phosphate (NADP) and a buffer (0.86 g K was added₂HPO₄·3H₂O, 0.3g KH₂PO₄Added to 30mL of water) was stirred to prepare a mixed solution B. A mixed solution prepared by dissolving 1g of the compound of the formula (A-6) obtained by the same procedure as in (examples 2a to 2f) in 13mL of toluene was added to the mixed solution B prepared above. Stirring for 15 hours at a reaction temperature of 23 ℃ (20-25 ℃). The reaction solution was subjected to celite filtration, and the aqueous layer and the organic layer were separated, and the aqueous layer was washed with 30mL of chloroformBenzene was extracted, and combined with the organic layer obtained before, followed by washing with water (30mL × 2 times), and then the organic layer was concentrated, thereby obtaining 0.5g (optical purity of 99.9% ee) of the title compound as a brown oil.

(example 3c)

Under the reaction conditions shown in the table below, a study of the amount of KRED was performed. The formula (A-6) is a compound obtained by carrying out the same operation as in the method of (example 2a-2 f). The buffer solution K was prepared in the same manner as in example 3b₂HPO₄・3H₂O、KH₂PO₄And (5) modulating.

[ Table 10]

(example 3d)

The solvent amount was investigated under the reaction conditions shown in the following table. The formula (A-6) is a compound obtained by carrying out the same operation as in the method of (example 2a-2 f). The buffer solution K was prepared in the same manner as in example 3b₂HPO₄・3H₂O、KH₂PO₄And (5) modulating.

[ Table 11]

(example 3e)

The amount of the buffer was investigated under the reaction conditions shown in the following table. The formula (A-6) is a compound obtained by carrying out the same operation as in the method of (example 2a-2 f). The buffer solution K was prepared in the same manner as in example 3b₂HPO₄・3H₂O、KH₂PO₄And (5) modulating.

[ Table 12]

(example 3f)

10g of the compound of the formula (A-6), 50mL of toluene, and 300mL of a buffer (K) obtained by the same procedure as in (examples 2a to 2f)₂HPO₄・3H₂O and KH₂PO₄The composition of (1) was the same as in the above example), 100g KRED, 20g D-glucose, 0.25g NADP and 0.5g GDH, were subjected to an enzymatic reaction at a reaction solution pH = 6.0-7.0 and a reaction temperature of 23 ℃ (20-25 ℃) for 23 hours, followed by an enzymatic reaction at 50-60 ℃ for 16 hours, and then post-treated according to the above post-treatment method, to obtain 11.75g of the labeled compound as a deep red oil.

Example 3g

At 108.4g K₂HPO₄・3H₂O and 37.82g KH₂PO₄1279g of KRED, 253g D-glucose, 12.61g of NADP, and 25.26g of GDH were added to 3780mL of buffer solution prepared by dissolving in 3780mL of water to form a mixed solution (MS-6-1), followed by stirring for 1 hour. 126.05g of the compound of formula (A-6) obtained by the same procedure as in (example 2a-2f) was dissolved in 630mL of toluene to obtain a mixed solution, which was added to the mixed solution (MS-6-1) prepared above. The reaction solution was kept at pH =6.0 to 7.0 at a reaction temperature of 23 ℃ (20 to 25 ℃) while stirring for 26 hours. 500mL of tert-amyl alcohol and 130mL of isoamyl alcohol were added to the reaction solution, and the mixture was stirred at a reaction temperature of 23 ℃ C (20 ℃ C. to 25 ℃ C.) for 16 hours. 1300mL of ethyl acetate and 126g of diatomaceous earth were added, and the mixture was heated to 60 ℃ and stirred at the same temperature for 1 hour. After cooling to 20 ℃ and filtration, the aqueous layer and the organic layer were separated, and the aqueous layer was extracted with 1300mL of ethyl acetate, combined with the organic layer obtained previously, and then washed with 1300mL of water to obtain an organic layer (OP-6-1). Further, 1300mL of ethyl acetate was added to the filtered diatomaceous earth, and the mixture was stirred at 20 to 30 ℃ for 10 hours and filtered to obtain an organic layer (OP-6-2), and 1300mL of ethyl acetate was added to the filtered diatomaceous earth, and the mixture was stirred at 20 to 30 ℃ for 2 hours and filtered to obtain an organic layer (OP-6-3). The organic layer (OP-6-1), the organic layer (OP-6-2) and the organic layer (OP-6-3) are combined to form an organic layer (OP-6A). Using 113g of the compound of the formula (A-6) obtained by the same procedure as in (example 2a-2f), the same procedure as described above was carried outThe same procedure was followed to carry out the reaction, thereby obtaining an organic layer (OP-6B). The organic layers (OP-6A) and (OP-6B) were combined and concentrated to give 331g of the title compound as a red-brown oil.

[ physical Property data of formula (A-7) ]

(1H NMR, 400MHz, manufacturer: Bruker, CDCl3,. delta.ppm);

7.51 (d、1H、J=7Hz)、7.05 (t、1H、J=7Hz)、6.80 (d、1H、J=7Hz)、6.19 (brs、1H)、4.10-4.05 (1H、m)、2.92-2.81 (2H、m)、2.80-2.69 (1H、m)、2.43 (dd、1H、J=7,16Hz)、2.03-1.88 (1H、m)、1.78-1.63 (1H、m)、1.45(9H、s)。

with respect to the absolute steric configuration of formula (A-7), after converting formula (A-7) into formula B, the absolute steric configuration of formula (A-7) is determined in accordance with the analytical value of formula B separately synthesized according to the method described in International publication No. 2003/095420 pamphlet or the like.

Example 4a hydrochloride Synthesis of (R) -8-amino-1, 2,3, 4-tetrahydronaphthalen-2-ol (formula B-HCl)

[ chemical formula 30]

2g of n-PrOH is filled into a reaction vessel and stirred at-5 ℃. 0.76g of acetyl chloride was added dropwise at the same temperature over 10 minutes. After the reaction temperature was raised to 50 to 55 ℃, a solution of 0.5g of the compound of formula (A-7) in 6g of n-PrOH, obtained by the same procedure as in (example 3a-g), was added over 45 minutes. Stirring for 45 minutes at the reaction temperature of 50-55 ℃, then standing and cooling to ensure that the reaction temperature is between 20-30 ℃, and stirring for 16 hours at the temperature of 20-30 ℃. The obtained solid was filtered, washed with n-PrOH (5 mL. times.2), and dried at 40 to 50 ℃ for 6.5 hours to obtain 0.23g of a labeled compound.

Example 4B Synthesis of (R) -8-amino-1, 2,3, 4-tetrahydronaphthalen-2-ol (formula B)

[ chemical formula 31]

1.81g of n-PrOH is filled into a reaction vessel and stirred at-5 to 5 ℃. 2.35g of acetyl chloride were added dropwise at the same temperature over 10 minutes. After the reaction temperature was raised to 33 to 37 ℃, a solution of 4.25g of the compound of the formula (A-7) in 12.75g of n-PrOH, which was obtained by the same procedure as in (example 3a-g), was added over 45 minutes. Stirring the mixture at a reaction temperature of 33 to 37 ℃ for 49.5 hours, and then stirring the mixture at a reaction temperature of 20 to 25 ℃ for 19 hours. The resulting solid was filtered, washed with i-PrOAc (10 mL. times.2) and dried at 30-40 ℃ for 4 hours to give the hydrochloride salt (2.04 g). The separately synthesized 0.07g of hydrochloride was combined to 2.11g, suspended in 12mL of ethyl acetate, and the pH of the aqueous layer was adjusted to 7-8 using an aqueous sodium bicarbonate solution. The aqueous layer and the organic layer were separated, and then the aqueous layer was extracted with ethyl acetate (12 mL. times.2 times), the organic layers were combined, washed with water (10 mL. times.2 times), and the organic layer was concentrated under reduced pressure to obtain 1.34g of the labeled compound.

Example 4c Synthesis of (R) -8-amino-1, 2,3, 4-tetrahydronaphthalen-2-ol (formula B)

138g of n-PrOH is put into a reaction vessel and stirred at-5 to 5 ℃. 180.1g of acetyl chloride were added dropwise at the same temperature over 1 hour. The reaction temperature was raised to 33 to 37 ℃ and then a solution of 331g of the crude compound of formula (A-7) in 750mL of n-PrOH, obtained by the same procedure as in (examples 3a-g), was added over 45 minutes. Stirring the mixture for 15 hours at a reaction temperature of 33 to 37 ℃, and then stirring the mixture for 2 hours and 10 minutes at a reaction temperature of 50 to 55 ℃. After the reaction temperature reached 33 to 37 ℃, a mixed solution obtained by adding 26g of HCl to 192g i-PrOAc was added at 33 to 37 ℃ for 30 minutes. The reaction temperature is increased to 50-55 ℃, and the mixture is stirred for 1.5 hours. The resulting solid was filtered, washed with i-PrOAc, and dried under reduced pressure at 20 to 30 ℃ for 36 hours to obtain 158g of hydrochloride. 158g of this hydrochloride salt were suspended in 1000mL of ethyl acetate and aqueous sodium bicarbonate (76g of sodium bicarbonate, 1000mL of water) was added over 30 minutes. The aqueous layer and the organic layer were separated, and then the aqueous layer was extracted with ethyl acetate (1000 mL. times.2 times), the organic layers were combined, washed with 1000mL of water, and the organic layer was concentrated under reduced pressure to obtain 136g of the labeled compound.

[ physical Property data of formula (B) ]

(¹H-NMR, 400MHz, manufacturer: bruker, CDCl₃、δppm)；

6.91 (1H、t、J=7Hz)、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=7,16Hz)、2.02-1.89 (1H、m)、1.85-1.65 (1H、m)。

Description of the symbols

L1, L2, L3, L4: a nitrogen inlet;

m1: a vessel containing feedstock + TEMPO + dichloromethane;

m2: containing KBr + NaHCO₃+ a container of water;

m3: a vessel containing NaClO;

p1, P2, P3: a pump;

t1, T2, T3: a pre-cooling tube;

s1, S2, S3: a blender;

r1, R2, R3: a reaction vessel;

CD: and (5) recovering the barrel.