RU2813203C2 - Method of producing heterocyclidene acetamide derivative - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to a new method of producing (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide, represented by Formula (I), which is a heterocyclidene acetamide derivative. The method includes carrying out a condensation reaction of a compound represented by Formula (B), or a salt thereof, and a compound represented by Formula (CA-1), using DMT-MM as a condensing reagent, obtaining a compound represented by Formula (I)

Formula (I):

[C118]

Formula (B):

[C119]

Formula (CA-1):

[C120]

EFFECT: new method of more easily obtaining the compound represented by formula (I) with high yield.

1 cl, 3 dwg, 30 tbl, 12 ex

Description

[Field of technology to which the invention relates]

[0001] The present invention relates to a new process for the preparation of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl )acetamide represented by formula (I), which is a heterocyclidene acetamide derivative. Moreover, the present invention relates to a new method for preparing (R)-8-amino-1,2,3,4-tetrahydronaphthalene-2-ol represented by formula (B), or a salt thereof, which is an intermediate useful in the preparation the compound represented by formula (I).

[Technique level]

[0002] (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide represented by formula (I ), is a transient receptor potential vannilloid channel-1 (TRPV1) antagonist, and is proposed as a prophylactic and/or therapeutic agent for TRPV1 receptor-associated diseases (e.g., pain (e.g., neuropathic pain, diabetic neuralgia, postoperative pain, osteoarthritis, rheumatoid arthritis pain, inflammatory pain, cancer pain, migraine and the like), nervous disorders, nerve damage, neurodegeneration, chronic obstructive pulmonary disease, asthma, rhinitis, inflammation of the mucous membranes, e.g. in the eyes, nervous skin disease, inflammatory skin disease, allergic disease, urinary incontinence, urge incontinence, overactive bladder, cystitis, itching and the like) (Patent Literature 1).

[C1]

[0003] WO 2007/010383 (Patent Literature 1) describes a method for producing the compound represented by formula (I). Herein, the compound represented by formula (I) is prepared by the steps <Step 1>-<Step 3> shown below (Scheme A).

<Step 1> The compound represented by formula (IM-k) is prepared by carrying out a condensation reaction using 8-amino-3,4-dihydronaphthalene-2(1H)-one (formula (IM-3)) prepared according to a method known in the art from this document (for example, WO 2005/040100 (Patent Literature 2) and the like) and (E)-2-(7-(trifluoromethyl)chroman-4-ylidene)acetic acid (formula (CA-1) in CAS No. 920334-15-2, non-patent literature 1) and a condensing agent hydrochloride (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI·HCl)).

<Step 2> The compound represented by the formula (IM-k) is reduced with sodium borohydride to obtain the compound represented by the formula (I-Rac).

<Step 3> The compound represented by formula (I-Rac) is optically separated on an optically active column to obtain the compound represented by formula (I) and the compound represented by formula (I-C), which is an isomer thereof.

[0004] However, in this production method, the compound represented by formula (I) is obtained by performing column separation in the final step, and it is difficult to reuse the compound represented by formula (I-C) obtained after column separation.

[0005]

[C2]

(Scheme A)

[0006] Meanwhile, WO 2005/040100 (Patent Literature 2), WO 2003/095420 (Patent Literature 3), WO 2005/040119 (Patent Literature 4), and WO 2010/127855 (Patent Literature 5) describe methods for preparing the compound represented by formula (B), which corresponds to the partial structural formula of formula (I).

[C3]

In this literature, 8-amino-3,4-dihydronaphthalene-2(1H)-one (formula (IM-3)) is prepared by alkylation of the phenolic group, Burch reduction, and deblocking of the alkyl group using 8-aminonaphthalene-2- ol (formula (SM-1)) as the starting compound, and thereby, the compound represented by formula (B) is prepared by its asymmetric reduction in the presence of a Ru catalyst (Scheme 1).

[0007] However, in these production methods, Birch reduction is used in one step, and a metal (Ru) catalyst is used in asymmetric reduction in the final step, therefore, a step for reducing the residual metal (Ru) content in the resulting compound is required.

[0008]

[C4]

(Scheme 1)

[0009] In addition, WO 2009/050289 (Patent Literature 6), WO 2010/045401 (Patent Literature 7) and WO 2010/045402 (Patent Literature 8) also describe methods for preparing the compound represented by formula (B). In this literature, the compound represented by formula (B) is obtained by resolution using an optically active column after obtaining racemic 8-amino-1,2,3,4-tetrahydronaphthalene-2-ol (formula A) by selective reduction of the naphthalene ring using 8 -aminonaphthalene-2-ol (formula (SM-1)) as the starting compound (Scheme 2).

[0010] However, in this production method, it is difficult to reuse other isomers (S-forms) obtained after column separation.

[0011]

[C5]

(Scheme 2)

[0012] In addition, WO 2009/055749 (Patent Literature 9) also describes a method for producing the compound represented by formula (B). In this literature, the compound represented by formula (B) is obtained by column separation of the diastereomer obtained after diastereomeric resolution of the racemate with the introduced chiral auxiliary represented by formula (A) (Scheme 3).

[0013] However, it is also difficult to reuse other isomers (S-forms) obtained after column separation in this production method.

[0014]

[C6]

(Scheme 3)

[0015] Methods for preparing the compound represented by formula (B) described in the relevant literature have problems such as types of reactions in the production method, reagents to be used, difficulties in reusing other isomers obtained after separation of the racemate or diastereoisomer on a column . Therefore, an improved production method is required for large-scale synthesis or industrial production of the compound represented by formula (B). That is, when considering large-scale synthesis or industrial production of the compound represented by formula (B), it is necessary to find a new production method different from the production methods described in the relevant literature. Since a method for large-scale synthesis of the compound represented by formula (B) in high yield and high optical purity has not yet been found, it is believed that the above-mentioned problems of producing the compound represented by formula (B) can be solved if a method for large-scale synthesis of the compound is found. represented by formula (B), in fewer steps, with high chemical yield and high optical purity.

[0016] US Patent Application No. 5,136,103 (Patent Literature 10) and the like describes a method for oxidizing a secondary alcohol to a ketone using 2,2,6,6-tetramethylpiperidine-1-oxyl radical (TEMPO) as an oxidizing agent. However, the TEMPO oxidation reaction in which 1,2,3,4-tetrahydronaphthalene (for example, tert-butyl-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)carbamate and the like) which contains a substituted amino group and hydroxyl group in the molecule, used as the starting compound, unknown. In addition, the oxidation reaction of TEMPO by on-line chemistry (on-line reaction) in which the compound is used as a starting compound is also unknown.

[0017] US Patent Application No. 5,225,339 (Patent Literature 11) and US Patent Application No. 5,342,767 (Patent Literature 12) describes the reduction of ketones by a reductase derived from Lactobacillus-derived kefir, but an enzymatic reaction tailored to keto compounds such as those protected by amino-3,4-dihydronaphthalene-2(1H)-one or β -tetralone, not described.

[0018] Advanced Synthesis & Catalysis, 350 (14+15), p2322-2328, 2008 (Non-Patent Literature 2) describes the enzymatic reaction of α- or β-tetralone ketones (reductase: derived from kefir derived from Lactobacillus). However, it is clearly stated that the reduction reaction of β-tetralone ketones does not occur when reductase derived from Lactobacillus-derived kefir is used.

[0019] WO 2018/205948 (patent literature 13) describes 8-bromo-1,2,3,4-tetrahydronaphthalene-2-ol (CAS No. 444619-84-5, non-patent literature 3) and a method for its preparation, but (R)-8-bromo-1,2,3,4-tetrahydronaphthalene-2-ol, which is its chiral form, and its preparation method are unknown.

[0020] CAS Registry describes 8-fluoro-1,2,3,4-tetrahydronaphthalene-2-ol (CAS No. 1823867-35-1, non-patent literature 4), but (R)-8-fluoro-1,2 ,3,4-tetrahydronaphthalene-2-ol, which is its chiral form, and the method for its preparation are unknown. Additionally, the CAS Registry describes 8-chloro-1,2,3,4-tetrahydronaphthalene-2-ol (CAS No. 1823929-47-0, non-patent literature 5), but (R)-8-chloro-1,2 ,3,4-tetrahydronaphthalene-2-ol, which is its chiral form, and the method for its preparation are unknown.

[0021] Bioorganic & Medicinal Chemistry Letters, 18(6), p1830-1834, 2008 (Non-Patent Literature 6) describes a process for preparing 8-amino-6-fluoro-1,2,3,4-tetrahydronaphthalene-2-ol (yield 18%) by reductive amination of 8-bromo-6-fluoro-1,2,3,4-tetrahydronaphthalene-2-ol with Pd catalyst (Pd ₂ (dba) ₃ ) and tert-butylcarbamate, and subsequent removal of the Boc group.

[List of citations]

[Patent Literature]

[0022]

[Patent Literature 1] WO 2007/010383

[Patent Literature 2] WO 2005/040100

[Patent Literature 3] WO 2003/095420

[Patent Literature 4] WO 2005/040119

[Patent Literature 5] WO 2010/127855

[Patent Literature 6] WO 2009/050289

[Patent Literature 7] WO 2010/045401

[Patent Literature 8] WO 2010/045402

[Patent Literature 9] WO 2009/055749

[Patent Literature 10] US Patent Application No. 5136103

[Patent Literature 11] US Patent Application No. 5225339

[Patent Literature 12] US Patent Application No. 5342767

[Patent Literature 13] WO 2018/205948

[0023]

[Non-patent literature]

[Non-Patent Literature 1] CAS No. 920334-15-2

[Non-Patent Literature 2] Advanced Synthesis & Catalysis, 350 (14+15), p2322-2328, 2008

[Non-Patent Literature 3] CAS No. 444619-84-5

[Non-Patent Literature 4] CAS No. 1823867-35-1

[Non-Patent Literature 5] CAS No. 1823929-47-0

[Non-Patent Literature 6] Bioorganic & Medicinal Chemistry Letters, 18(6), p1830-1834, 2008

[Summary of the present invention]

[Technical problem]

[0024] Under these circumstances, a new method for producing the above-mentioned compound represented by formula (I) is required.

[Solution to the problem]

[0025] The inventors of the present invention have repeatedly carried out extensive research to solve the above-described problems. As a result, the inventors have discovered a new method for more easily preparing the compound represented by formula (I) in high yield, and have completed the present invention based on this finding. That is, the inventors have discovered a new method for preparing the compound represented by formula (I) by the condensation reaction of a carboxylic acid represented by formula (CA-1) and an amino alcohol represented by formula (B) or a salt thereof using DMT-MM (4-( 4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride) (CAS No: 3945-69-5) as the condensing reagent (Scheme B).

[0026]

[C7]

(Diagram B)

[0027] The inventors have further discovered a new method for preparing the compound represented by formula (B) or a salt thereof, which is an intermediate useful in the preparation of the compound represented by formula (I), and have completed the present invention based on this finding (Scheme C- 1).

[C8]

(Diagram C-1)

[0028] The inventors have further discovered a new method for preparing the compound represented by formula (B) or a salt thereof, which is an intermediate useful in the preparation of the compound represented by formula (I), and have completed the present invention based on this finding (Scheme C- 2).

[C9]

(Diagram C-2)

[Effect of the present invention]

[0029] The present invention provides a new method for producing a compound represented by formula (I) or a compound represented by formula (B) or a salt thereof. The present invention preferably provides an efficient production method suitable for large-scale synthesis or industrial production of the compound represented by formula (I) or the compound represented by formula (B) or a salt thereof. Preparation methods according to some aspects of the present invention are methods that provide a compound represented by formula (I) or a compound represented by formula (B), or a salt thereof, in high yield and industrially advantageous, and, therefore, these methods are very useful in industry. In addition, certain other aspects provide new compounds represented by formulas (A-7) and (A8), which are starting compounds in the preparation of the compound represented by formula (B) and a salt thereof.

[Brief description of drawings]

[0030]

[Figure 1] FIGURE 1 is an example of a reaction apparatus used for flow chemistry;

[Figure 2] FIGURE 2 is a figure showing the crystal structure of the HBr salt of the compound represented by formula (B); And

[Figure 3] FIGURE 3 is a figure showing the crystal structure of the compound represented by formula (I).

[Description of embodiments]

[0031] [Aspects of the present invention]

A method for producing the compound represented by formula (I) is provided. In some aspects, there is a method for producing a compound represented by formula (I) by using a compound represented by formula (A) as a starting compound. Some other aspects are a method for producing the compound represented by formula (I) by using the compound represented by formula (A-5) as a starting compound. Still other aspects include a method for producing the compound represented by formula (I) by using the compound represented by formula (A-6) as a raw material. Still other aspects are a method of producing a compound represented by formula (I) by using a compound represented by formula (A-7) as a raw material.

[0032] Still other aspects are a method for producing the compound represented by formula (I) by using the compound represented by formula (SM8) as a starting compound. Still other aspects include a method for producing the compound represented by formula (I) by using the compound represented by formula (SM8-BR) as a raw material. Still other aspects include a method for producing the compound represented by formula (I) by using the compound represented by formula (A8) as a raw material. Still other aspects include a method for producing the compound represented by formula (I) by using the compound represented by formula (A8-BR) as a starting compound. Still other aspects include a method for producing a compound represented by formula (I) by using a compound represented by formula (B) as a starting compound.

[0033] In addition, a method for producing the compound represented by formula (B) or a salt thereof is also provided. In some aspects, there is a method for preparing a compound represented by formula (B) or a salt thereof using a compound represented by formula (A) as a starting compound. Some other aspects are a method of producing the compound represented by formula (B) or a salt thereof by using the compound represented by formula (A-5) as a raw material. In still other aspects, there is a method for preparing the compound represented by formula (B) or a salt thereof by using the compound represented by formula (A-6) as a raw material. In still other aspects, there is a method for preparing the compound represented by formula (B) or a salt thereof by using the compound represented by formula (A-7) as a raw material.

[0034] Still other aspects are a method of producing the compound represented by formula (B) or a salt thereof by using the compound represented by formula (SM8) as a raw material. Still other aspects include a method for preparing the compound represented by formula (B) or a salt thereof by using the compound represented by formula (SM8-BR) as a raw material. In still other aspects, there is a method for preparing the compound represented by formula (B) or a salt thereof by using the compound represented by formula (A8) as a raw material. In still other aspects, there is a method for preparing the compound represented by formula (B) or a salt thereof by using the compound represented by formula (A8-BR) as a raw material.

[0035] Still other aspects are a method of producing a compound represented by formula (A-6) by using a compound represented by formula (A-5) or formula (A-7) as a raw material. Still other aspects are a method of producing a compound represented by formula (A-7) by using a compound represented by formula (A-6) as a raw material. Still other aspects are the compound represented by formula (A-7).

[0036] Still other aspects are a method of producing the compound represented by formula (A8) by using the compound represented by formula (SM8) as a starting compound. Still other aspects are a method of producing a compound represented by formula (A8-BR) by using a compound represented by formula (SM8-BR) as a raw material. Still other aspects are the compound represented by formula (A8) and the compound represented by formula (A8-BR).

Hereinafter, in the present invention, each of the aspects will be described specifically.

[0037] [1] The first aspect is a method for producing a compound represented by formula (B) or a salt thereof, the method comprising: tert-butoxycarbonylation of an amino group of a compound represented by formula (A), obtaining a compound represented by formula (A-5) ; carrying out an oxidation reaction of the compound represented by formula (A-5) to obtain the compound represented by formula (A-6); asymmetrically reducing the compound represented by formula (A-6) to obtain the compound represented by formula (A-7); and deblocking a tert-butoxycarbonyl group of the compound represented by formula (A-7), obtaining the compound represented by formula (B) or a salt thereof.

Formula (B):

[C10]

Formula (A):

[C11]

Formula (A-5):

[C12]

Formula (A-6):

[C13]

Formula (A-7):

[C14]

[0038] [2] The second aspect is a method for producing a compound represented by formula (B) or a salt thereof, the method comprising: carrying out an oxidation reaction of the compound represented by formula (A-5) to obtain a compound represented by formula (A-6 ); asymmetrically reducing the compound represented by formula (A-6) to obtain the compound represented by formula (A-7); and deblocking the tert-butoxycarbonyl group of the compound represented by formula (A-7), obtaining the compound represented by formula (B) or a salt thereof.

Formula (B):

[C15]

Formula (A-5):

[C16]

Formula (A-6):

[C17]

Formula (A-7):

[C18]

[0039] [3] The third aspect is a method for producing a compound represented by formula (B) or a salt thereof, the method comprising: asymmetrically reducing a compound represented by formula (A-6) to obtain a compound represented by formula (A-7) ; and deblocking the tert-butoxycarbonyl group of the compound represented by formula (A-7), obtaining the compound represented by formula (B) or a salt thereof.

Formula (B):

[C19]

Formula (A-6):

[C20]

Formula (A-7):

[C21]

[0040] [4] The fourth aspect is a method for producing a compound represented by formula (B) or a salt thereof, the method comprising: deblocking a tert-butoxycarbonyl group of a compound represented by formula (A-7), obtaining a compound represented by formula (B ), or its salt.

Formula (B):

[C22]

Formula (A-7):

[C23]

[0041] [4B] The 4B-th aspect is a method for producing a salt of a compound represented by formula (B), the method including: adding an acid to a compound represented by formula (B), obtaining a salt of a compound represented by formula (B).

Formula (B):

[C24]

[0042] [4B-1] In the aspect above [4B], the acid used in preparing the salt of the compound represented by formula (B) is preferably an inorganic acid or an organic acid, more preferably is an inorganic acid, and even more preferably is is hydrobromic acid.

[0043] [5] The fifth aspect is a method for producing a compound represented by formula (A-6), the method comprising: carrying out an oxidation reaction of a compound represented by formula (A-5) to obtain a compound represented by formula (A-6).

Formula (A-6):

[C25]

Formula (A-5):

[C26]

[0044] [6] The sixth is a method for producing a compound represented by formula (A-7), the method comprising: asymmetrically reducing a compound represented by formula (A-6) to obtain a compound represented by formula (A-7).

Formula (A-7):

[C27]

Formula (A-6):

[C28]

[0045] [7] The seventh aspect is a method for producing a compound represented by formula (I), the method comprising: conducting a condensation reaction of a compound represented by formula (B) or a salt thereof and a compound represented by formula (CA-1) using DMT-MM as a condensing reagent, obtaining the compound represented by formula (I).

Formula (I):

[C29]

Formula (B):

[C30]

Formula (CA-1):

[C31]

[0046] [8] The eighth aspect is a method for producing a compound represented by formula (I), the method comprising: tert-butoxycarbonylation of an amino group of a compound represented by formula (A), obtaining a compound represented by formula (A-5); carrying out an oxidation reaction of the compound represented by formula (A-5) to obtain the compound represented by formula (A-6); asymmetrically reducing the compound represented by formula (A-6) to obtain the compound represented by formula (A-7); deblocking the tert-butoxycarbonyl group of the compound represented by formula (A-7), obtaining the compound represented by formula (B) or a salt thereof; and conducting a condensation reaction of the compound represented by formula (B) or a salt thereof and the compound represented by formula (CA-1), using DMT-MM as a condensing reagent, to obtain the compound represented by formula (I).

Formula (I):

[C32]

Formula (A):

[C33]

Formula (A-5):

[C34]

Formula (A-6):

[C35]

Formula (A-7):

[C36]

Formula (B):

[C37]

Formula (CA-1):

[C38]

[0047] [9] The ninth aspect is a method for producing a compound represented by formula (I), the method comprising: carrying out an oxidation reaction of a compound represented by formula (A-5) to obtain a compound represented by formula (A-6); asymmetrically reducing the compound represented by formula (A-6) to obtain the compound represented by formula (A-7); deblocking the tert-butoxycarbonyl group of the compound represented by formula (A-7) to obtain the compound represented by formula (B) or a salt thereof; and conducting a condensation reaction of the compound represented by formula (B) or a salt thereof and the compound represented by formula (CA-1), using DMT-MM as a condensing reagent, to obtain the compound represented by formula (I).

Formula (I):

[C39]

Formula (A-5):

[C40]

Formula (A-6):

[C41]

Formula (A-7):

[C42]

Formula (B):

[C43]

Formula (CA-1):

[C44]

[0048] [10] The tenth aspect is a method for producing a compound represented by formula (I), the method comprising: asymmetrically reducing a compound represented by formula (A-6) to obtain a compound represented by formula (A-7); deblocking the tert-butoxycarbonyl group of the compound represented by formula (A-7) to obtain the compound represented by formula (B) or a salt thereof; and conducting a condensation reaction of the compound represented by formula (B) or a salt thereof and the compound represented by formula (CA-1), using DMT-MM as a condensing reagent, to obtain the compound represented by formula (I).

Formula (I):

[C45]

Formula (A-6):

[C46]

Formula (A-7):

[C47]

Formula (B):

[C48]

Formula (CA-1):

[C49]

[0049] [11] The eleventh aspect is a method for producing a compound represented by formula (I), the method comprising: deblocking a tert-butoxycarbonyl group of a compound represented by formula (A-7), obtaining a compound represented by formula (B) or salt; and conducting a condensation reaction of the compound represented by formula (B) or a salt thereof and the compound represented by formula (CA-1), using DMT-MM as a condensing reagent, to obtain the compound represented by formula (I).

Formula (I):

[C50]

Formula (A-7):

[C51]

Formula (B):

[C52]

Formula (CA-1):

[C53]

[0050] [12] The twelfth aspect is the compound represented by formula (A-7).

[C54]

[0051] In each of the aspects above, “deblocking the tert-butoxycarbonyl group of the compound represented by formula (A-7) to obtain the compound represented by formula (B) or a salt thereof” may further include:

Desalting a salt of the compound represented by formula (B), which is obtained by deblocking the tert-butoxycarbonyl group of the compound represented by formula (A-7), obtaining the compound represented by formula (B); or

converting the compound represented by formula (B) which is obtained by deblocking the tert-butoxycarbonyl group of the compound represented by formula (A-7) into a salt thereof, obtaining a salt of the compound represented by formula (B).

[0052] [13] The thirteenth aspect is a method for producing a compound represented by formula (B), the method comprising: asymmetrically reducing a keto group of a compound represented by formula (SM8), obtaining a compound represented by formula (A8); and reacting the compound represented by formula (A8) with aqueous ammonia in the presence of a catalyst to obtain the compound represented by formula (B).

Formula (B):

[C55]

Formula (SM8):

[C56]

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

Formula (A8):

[C57]

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

[0053] [13-1] In the aspect above [13], each X in the compound represented by formula (SM8) and the compound represented by formula (A8) is preferably a fluorine atom, a chlorine atom, or a bromine atom, and more preferably is a bromine atom.

[0054] [13-2] In the aspect above [13], the catalyst is preferably a Pd catalyst or a Cu catalyst, more preferably a Cu catalyst, and even more preferably a Cu ₂ O.

[0055] [13-3] The 13-3rd aspect is a method for producing a salt of the compound represented by formula (B) in the aspect above [13], the method comprising: adding an inorganic acid or an organic acid to the compound represented by formula ( B), obtaining a salt of the compound represented by formula (B). The inorganic acid or organic acid used to prepare a salt of the compound represented by formula (B) is preferably an inorganic acid, more preferably is hydrochloric acid or hydrobromic acid, and even more preferably is hydrobromic acid.

[0056] In the present invention, unless otherwise specified, “halogen atom” refers to, for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.

[0057] [14] The fourteenth aspect is a method for producing a compound represented by formula (B), the method comprising: reacting a compound represented by formula (A8) with aqueous ammonia in the presence of a catalyst to obtain a compound represented by formula (B).

Formula (B):

[C58]

Formula (A8):

[C59]

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

[0058] [14-1] In the aspect above [14], X in the compound represented by formula (A8) is preferably a fluorine atom, a chlorine atom or a bromine atom, and more preferably is a bromine atom.

[0059] [14-2] In the aspect above [14], the catalyst is preferably a Pd catalyst or a Cu catalyst, more preferably a Cu catalyst, and even more preferably a Cu ₂ O.

[0060] [14-3] The 14-3rd aspect is a method for producing a salt of the compound represented by formula (B) in the aspect above [14], the method comprising: adding an inorganic acid or an organic acid to the compound represented by formula ( B), obtaining a salt of the compound represented by formula (B). The inorganic acid or organic acid used in preparing the salt of the compound represented by formula (B) is preferably an inorganic acid, more preferably is hydrochloric acid or hydrobromic acid, and even more preferably is hydrobromic acid.

[0061] [15] The fifteenth aspect is a method for producing a compound represented by formula (A8), the method comprising: asymmetrically reducing a keto group of a compound represented by formula (SM8), obtaining a compound represented by formula (A8).

Formula (A8):

[C60]

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

Formula (SM8):

[C61]

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

[0062] [15-1] In the aspect above [15], each X in the compound represented by formula (SM8) and the compound represented by formula (A8) is preferably a fluorine atom, a chlorine atom, or a bromine atom, and more preferably is a bromine atom.

[0063] [16] The sixteenth aspect is a compound represented by formula (A8).

[C62]

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

[0064] [16-1] In the aspect above [16], X in the compound represented by formula (A8) is preferably a fluorine atom, a chlorine atom or a bromine atom, and more preferably is a bromine atom.

[0065] [17] The seventeenth aspect is a method for producing a compound represented by formula (I), the method comprising: asymmetrically reducing the keto group of a compound represented by formula (SM8), obtaining a compound represented by formula (A8); reacting the compound represented by formula (A8) with aqueous ammonia in the presence of a catalyst to obtain the compound represented by formula (B); and conducting a condensation reaction of the compound represented by formula (B) and the compound represented by formula (CA-1), using DMT-MM as a condensing reagent, to obtain the compound represented by formula (I).

Formula (I):

[C63]

Formula (SM8):

[C64]

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

Formula (A8):

[C65]

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

Formula (B):

[C66]

Formula (CA-1):

[C67]

[0066] [17-1] In the aspect above [17], each X in the compound represented by formula (SM8) and the compound represented by formula (A8) is preferably a fluorine atom, a chlorine atom or a bromine atom, and more preferably represents a bromine atom.

[0067] [17-2] In the aspect above [17], the catalyst is preferably a Pd catalyst or a Cu catalyst, more preferably a Cu catalyst, and even more preferably a Cu ₂ O.

[0068] [18] The eighteenth aspect is a method for producing a compound represented by formula (I), the method comprising: asymmetrically reducing the keto group of a compound represented by formula (SM8), obtaining a compound represented by formula (A8); reacting the compound represented by formula (A8) with aqueous ammonia in the presence of a catalyst to obtain the compound represented by formula (B); adding an acid to the compound represented by formula (B), obtaining a salt of the compound represented by formula (B); and conducting a condensation reaction of a salt of the compound represented by formula (B) and the compound represented by formula (CA-1), using DMT-MM as a condensing reagent, to obtain the compound represented by formula (I).

Formula (I):

[C68]

Formula (SM8):

[C69]

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

Formula (A8):

[C70]

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

Formula (B):

[C71]

Formula (CA-1):

[C72]

[0069] [18-1] In the aspect above [18], each X in the compound represented by formula (SM8) and the compound represented by formula (A8) is preferably a fluorine atom, a chlorine atom or a bromine atom, and more preferably represents a bromine atom.

[0070] [18-2] In the aspect above [18], the catalyst is preferably a Pd catalyst or a Cu catalyst, more preferably a Cu catalyst, and even more preferably a Cu ₂ O.

[0071] [18-3] In the aspect above [18], the acid used in preparing the salt of the compound represented by formula (B) is preferably an inorganic acid or an organic acid, more preferably is an inorganic acid, even more preferably is hydrochloric acid or hydrobromic acid, and is particularly preferably hydrobromic acid.

[0072] [19] The nineteenth aspect is a method for producing a compound represented by formula (I), the method comprising: reacting a compound represented by formula (A8) with aqueous ammonia in the presence of a catalyst to obtain a compound represented by formula (B); and conducting a condensation reaction of the compound represented by formula (B) and the compound represented by formula (CA-1), using DMT-MM as a condensing reagent, to obtain the compound represented by formula (I).

Formula (I):

[C73]

Formula (A8):

[C74]

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

Formula (B):

[C75]

Formula (CA-1):

[C76]

[0073] [19-1] In the aspect above [19], each X in the compound represented by formula (SM8) and the compound represented by formula (A8) is preferably a fluorine atom, a chlorine atom or a bromine atom, and more preferably represents a bromine atom.

[0074] [19-2] In the aspect above [19], the catalyst is preferably a Pd catalyst or a Cu catalyst, more preferably a Cu catalyst, and even more preferably a Cu ₂ O.

[0075] [20] The twentieth aspect is a method for producing a compound represented by formula (I), the method comprising: reacting a compound represented by formula (A8) with aqueous ammonia in the presence of a catalyst to obtain a compound represented by formula (B); adding an acid to the compound represented by formula (B), obtaining a salt of the compound represented by formula (B); and conducting a condensation reaction of a salt of the compound represented by formula (B) and the compound represented by formula (CA-1), using DMT-MM as a condensing reagent, to obtain the compound represented by formula (I).

Formula (I):

[C77]

Formula (A8):

[C78]

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

Formula (B):

[C79]

Formula (CA-1):

[C80]

[0076] [20-1] In the aspect above [20], each X in the compound represented by formula (SM8) and the compound represented by formula (A8) is preferably a fluorine atom, a chlorine atom or a bromine atom, and more preferably represents a bromine atom.

[0077] [20-2] In the aspect above [20], the catalyst is preferably a Pd catalyst or a Cu catalyst, more preferably a Cu catalyst, and even more preferably a Cu ₂ O.

[0078] [20-3] In the aspect above [20], the acid used in preparing the salt of the compound represented by formula (B) is preferably an inorganic acid or an organic acid, more preferably is an inorganic acid, even more preferably is hydrochloric acid or hydrobromic acid, and is particularly preferably hydrobromic acid.

[0079] In the present invention, hereinafter, each of the reactions in the above-described aspects will be described in detail.

[0080] <Step of producing the compound represented by formula (A-5)>

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

[0081] Examples of tert-butoxycarbonylation agents include di-tert-butyl dicarbonate (Boc ₂ O), 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (Boc-ON), N-tert-butoxycarbonylimidazole, 2-(tert-butoxycarbonylthio )-4,6-dimethylpyrimidine, 1-tert-butoxycarbonyl-1,2,4-triazole, tert-butylphenylcarbonate, tert-butylcarbazate, N-(tert-butoxycarbonyloxy)phthalimide and the like. Di-tert-butyl dicarbonate (Boc ₂ O) and 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (Boc-ON) are preferred, and di-tert-butyl dicarbonate (Boc ₂ O) is more preferred. The amount of tert-butoxycarbonylation agent used is typically 1.0-2.0 molar equivalents, preferably 1.1-1.8 molar equivalents, and more preferably 1.3-1.65 molar equivalents, based on 1 molar equivalent of compound, represented by formula (A).

[0082] The reaction can be carried out in the presence of a solvent. As the solvent, for example, a non-reaction solvent such as dichloromethane, acetonitrile, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, tert-butyl ether, toluene, water and the like can be used. or a mixed solvent thereof. The solvent may be suitably selected depending on the type of tert-butoxycarbonylation agent to be used. Tetrahydrofuran, 1,4-dioxane, tetrahydrofuran-water mixed solvent, and 1,4-dioxane-water mixed solvent are preferred, and tetrahydrofuran, tetrahydrofuran-water mixed solvent, and 1,4-dioxane-water mixed solvent are more preferred.

[0083] The reaction can be carried out in the presence of a base. As the base, bases such as sodium hydrogen carbonate, potassium carbonate, sodium carbonate, triethylamine, N,N-diisopropylethylamine, pyridine and the like can be used. The base can be suitably selected depending on the type of tert-butoxycarbonylation agent to be used. Sodium hydrogen carbonate, triethylamine and pyridine are preferred, and sodium hydrogen carbonate is more preferred.

[0084] The amount of base used is, for example, 1.0-4.0 molar equivalents, preferably 1.0-3.5 molar equivalents, and more preferably 1.0-3.2 molar equivalents, relative to 1 molar equivalent the compound represented by formula (A).

[0085] As for the reaction temperature, the reaction can be carried out, for example, in the range of -78°C to the temperature at which the solvent boils, in the range of -78°C to room temperature, in the range of 0°C to the temperature at where the solvent boils, or in the range from 0°C to room temperature. The reaction temperature can be suitably selected depending on the type of tert-butoxycarbonylation agent to be used. The reaction temperature is preferably in the range of 20°C-55°C.

[0086] <Step of producing the compound represented by formula (A-6)>

The compound represented by formula (A-6) is obtained by carrying out an oxidation reaction of the compound represented by formula (A-5) or the compound represented by formula (A-7).

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

[0087] TEMPO oxidation is generally a reaction in which TEMPO and a reoxidant are mixed as an oxidizing agent to oxidize a substrate, such as an alcohol. In addition, TEMPO oxidation can also be carried out in the presence of a base.

[0088] In the oxidation reaction, for example, batch method and flow chemistry are used (flow reaction using a chemical stirred flow reactor (CSTR)).

[0089] The amount of oxidant used in the oxidation reaction is typically 1.0-2.2 molar equivalents, preferably 1.2-2.1 molar equivalents, and more preferably 1.4-2.0 molar equivalents, relative to 1 molar equivalent of the compound represented by formula (A-5) or the compound represented by formula (A-7).

[0090] The amount of TEMPO used in TEMPO oxidation is typically 0.01-1.0 molar equivalents, preferably 0.05-0.7 molar equivalents, and more preferably 0.5 molar equivalents, relative to 1 molar equivalent of the compound represented formula (A-5) or the Compound represented by formula (A-7).

[0091] Examples of reoxidants in TEMPO oxidation include sodium hypochlorite (NaClO), iodobenzene diacetate and the like. The amount of sodium hypochlorite used in TEMPO oxidation is typically 1.0-2.5 molar equivalents, preferably 1.1-2.2 molar equivalents, and more preferably 1.2-2.0 molar equivalents, relative to 1 molar equivalent of compound represented by formula (A-5), or a compound represented by formula (A-7).

[0092] TEMPO oxidation can be carried out in the presence of a base, and, for example, the amount of NaHCO ₃ used as base is usually 1.0-5.0 molar equivalents, preferably 2.0-4.5 molar equivalents, and more preferably 4.0 molar equivalents, relative to 1 molar equivalent of the compound represented by formula (A-5) or the Compound represented by formula (A-7).

[0093] The amount of KBr used in TEMPO oxidation is typically 0.01-0.30 molar equivalents, preferably 0.02-0.25 molar equivalents, and more preferably 0.05-0.2 molar equivalents, relative to 1 molar equivalent of the compound represented by formula (A-5) or the compound represented by formula (A-7).

[0094] The oxidation reaction (eg, TEMPO oxidation) can be carried out in the presence of a solvent. As the solvent, for example, a non-reaction solvent such as dichloromethane, 1,2-dichloroethane, chloroform, acetonitrile, acetone, water and the like, or a mixed solvent thereof, can be used. The solvent can be suitably selected depending on the type of oxidation reaction to be used. In TEMPO oxidation, dichloromethane, acetonitrile, acetone, water or a mixed solvent thereof is preferred; dichloromethane, acetonitrile, acetone, water, dichloromethane-water, acetonitrile-water or acetone-water is more preferred; and dichloromethane, water or dichloromethane-water is even more preferred.

[0095] Regarding the oxidation reaction (for example, the reaction temperature in TEMPO oxidation), the reaction can be carried out, for example, in the range of -78°C to the temperature at which the solvent boils, in the range of -78°C to room temperature, in range from 0°C to the temperature at which the solvent boils, or from 0°C to room temperature. The reaction temperature can be suitably selected depending on the type of oxidation reaction to be used. In TEMPO oxidation, the reaction temperature is preferably in the range of -2°C to 5°C.

[0096] A reducing agent such as Na ₂ S ₂ O ₄ (aqueous solution) can also be used to remove TEMPO after the TEMPO oxidation reaction.

[0097] <Step of producing the compound represented by formula (A-7)>

The compound represented by formula (A-7) is obtained by asymmetric reduction of the ketone compound represented by formula (A-6).

[0098] Examples of asymmetric reduction include asymmetric reduction using a chemical catalyst or the like, asymmetric reduction using a biocatalyst (yeast, fungi, mold, enzyme and the like), and the like. Asymmetric reduction using an enzyme is preferred, asymmetric reduction using ketone reductase (ketoreductase: KRED) as an enzyme is more preferable, and asymmetric reduction using ketone reductase derived from Lactobacillus sp. as an enzyme is particularly preferred. An asymmetric reaction using ketone reductase is carried out using ketone reductase, a coenzyme and a coenzyme regeneration system. Typical examples of coenzymes for ketone reductases include NADP. Moreover, as a typical example of a coenzyme regeneration system that regenerates NADP, which is a coenzyme, glucose oxidation by glucose dehydrogenase (GDH) is known. Moreover, the asymmetric reaction using ketone reductase is preferably carried out in a solvent in the presence of a buffer solution.

[0099] The amount of reducing agent used in an asymmetric reaction, for example, in an asymmetric reaction using a chemical catalyst or the like, is generally 1.0-2.2 molar equivalents, and is preferably 1.2-2.0 molar equivalents, relative to 1 molar equivalent of the compound represented by formula (A-6).

[0100] In an asymmetric reaction using an enzyme, the amount of enzyme used is usually 1.0-25 times, preferably 5-20 times, and more preferably 10 times the amount of 1 g of the compound represented by formula (A-6).

[0101] In an asymmetric reaction using ketone reductase derived from Lactobacillus sp., the amount of enzyme used is usually 1.0-25 times, preferably 5-20 times, and more preferably 10 times the amount of 1 g of the compound represented by the formula ( A-6).

[0102] D-glucose can be used in an asymmetric reaction using an enzyme. When D-glucose is used, the amount of D-glucose used is generally 1.0 to 5.0 times, preferably 1.5 to 3.5 times, and more preferably 2.0 times the amount of 1 g of the compound represented by the formula ( A-6).

[0103] In an asymmetric reaction 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 1 g of the compound represented by formula (A-6).

[0104] In an asymmetric reaction using an enzyme, a coenzyme can be used, and, for example, nicotinamide adenine dinucleotide phosphate (NADP) can be used. When nicotinamide adenine dinucleotide phosphate (NADP) is used, the amount of nicotinamide adenine dinucleotide phosphate (NADP) 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 1 g of the compound, represented by formula (A-6).

[0105] The asymmetric reaction can be carried out in the presence of a solvent. As the solvent, for example, a non-reaction solvent such as alcohol solvents such as methanol, ethanol, propanol, butanol and the like can be used; hydrocarbon solvents such as heptane, hexane, octane, toluene and the like; ethereal solvents such as tetrahydrofuran, 1,4-dioxane, butyl ether and the like; polar solvents such as acetonitrile, dimethyl sulfoxide, dimethylformamide and the like; and water, or a mixed solvent thereof. The solvent may be suitably selected depending on the type of enzyme to be used.

In an asymmetric reaction using an enzyme, for example, buffer solutions such as phosphate buffer solution, potassium phosphate buffer solution (which can be prepared, for example, from reagents such as K ₂ HPO ₄ 3H ₂ O, KH ₂ PO ₄ and the like), Tris/HCl buffer solution, sodium tetraborate-hydrochloric acid buffer solution, triethanolamine buffer solution and the like. The buffer solution can be suitably selected depending on the type of enzyme to be used.

[0106] In the asymmetric reaction using ketone reductase derived from Lactobacillus sp., the solvent is preferably dimethyl sulfoxide, toluene, water or a mixed solvent thereof, and more preferably is toluene, water or a mixed solvent of toluene-water.

[0107] In an asymmetric reaction using an enzyme, the amount of organic solvent used is usually 1.0-15 times, preferably 2-13 times, and more preferably 5.0 times the amount of 1 g of the compound represented by formula (A-6 ).

[0108] In an asymmetric reaction using an enzyme, the amount of buffer solution used is usually 10-40 times, preferably 15-30 times, and more preferably 30 times the amount of 1 g of the compound represented by formula (A-6).

[0109] In an asymmetric reaction using an enzyme, the pH of the reaction solution is usually 6.0-7.5, preferably 6.0-6.5, 6.5-7.0 or 6.0-7.0, and more preferably it is 6.0-7.0.

[0110] The reaction temperature for carrying out the asymmetric reaction can be suitably selected from a reaction temperature, for example, in the range of -78°C to the temperature at which the solvent boils, in the range of -78°C to room temperature, in the range of 0° C to the temperature at which the solvent boils, in the range from 0°C to room temperature, and the like. The reaction temperature is preferably in the range from 0°C to room temperature.

[0111] The reaction temperature when carrying out an asymmetric reaction using an enzyme is usually in the temperature range at which the enzyme is not deactivated, and it is preferably in the range of 20°C-60°C, more preferably in the range of 20°C-25° C or in the range of 50°C-60°C, and even more preferably in the range of 20°C-25°C.

[0112] <Step of producing the compound represented by formula (B) or a salt thereof of formula (A-7)>

The compound represented by formula (B) or a salt thereof is obtained by deprotecting the tert-butoxycarbonyl group of the chiral alcohol compound represented by formula (A-7), desalting the salt of the compound represented by formula (B) obtained by deprotecting the tert-butoxycarbonyl group, or converting the compound represented by formula (B), obtained by deblocking the tert-butoxycarbonyl group into its salt.

[0113] Examples of reagents used to deblock the tert-butoxycarbonyl group generally include acidic reagents, and the reagent is preferably hydrogen chloride (which is hydrochloric acid, or which is generated in a solvent system using acetyl chloride and an alcohol solvent such as methanol, ethanol , propanol and the like), hydrogen bromide, and trifluoroacetic acid; more preferably, it is hydrogen chloride (which is hydrochloric acid, or which is generated in a solvent system using acetyl chloride and an alcohol solvent such as methanol, ethanol, propanol and the like) and trifluoroacetic acid; and is particularly preferably hydrogen chloride (which is hydrochloric acid, or which is generated in a solvent system using acetyl chloride and an alcohol solvent such as methanol, ethanol, propanol and the like).

[0114] Deprotection of the tert-butoxycarbonyl group can be carried out in the presence of a solvent. Examples of solvents for deblocking the tert-butoxycarbonyl group include non-reactive solvents such as halogen solvents such as dichloromethane, chloroform, 1,2-dichloroethane and the like; alcohol solvents such as methanol, ethanol, propanol, butanol and the like; hydrocarbon solvents such as heptane, hexane, octane, toluene and the like; ether solvents such as tetrahydrofuran, 1,4-dioxane, butyl ether and the like; polar solvents such as acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide and the like; and water, or a mixed solvent thereof, and halogen solvents such as dichloromethane, chloroform, 1,2-dichloroethane and the like, and alcohol solvents such as methanol, ethanol, propanol, butanol and the like are preferred, and propanol (n- propanol) is more preferred.

[0115] The reaction temperature for deblocking the tert-butoxycarbonyl group can be suitably selected from a reaction temperature, for example, in the range of -78°C to the temperature at which the solvent boils, in the range of -78°C to room temperature, in the range of 0°C to the temperature at which the solvent boils, in the range from 0°C to room temperature, and the like. The reaction temperature is preferably in the range of 0°C-55°C.

[0116] It is possible to desalt the compound represented by formula (B) by using a base. As the base for desalting the salt of the compound represented by formula (B), bases such as sodium hydrogen carbonate, potassium carbonate, sodium carbonate, triethylamine, N,N-diisopropylethylamine, pyridine and the like, and sodium hydrogencarbonate, potassium carbonate and sodium carbonate can be used. are preferred, and sodium bicarbonate is more preferred.

[0117] Desalting the salt of the compound represented by formula (B) can be carried out in the presence of a solvent. Examples of solvents for desalting the salt of the compound represented by formula (B) include non-reaction solvents such as halogen solvents such as dichloromethane, chloroform, 1,2-dichloroethane and the like; ether solvents such as tetrahydrofuran, 1,4-dioxane, butyl ether and the like; polar solvents such as ethyl acetate, isopropyl acetate, acetonitrile, dimethyl sulfoxide, dimethylformamide and the like; and water, or a mixed solvent thereof, and ethyl acetate, isopropyl acetate, water, and a mixed solvent of ethyl acetate-water or isopropyl acetate-water are preferred, and a mixed solvent of ethyl acetate-water is more preferred.

[0118] <Step of producing a salt from the compound represented by formula (B)>

The compound represented by formula (B) can be converted into a salt by using an organic acid or an inorganic acid. As the acid for converting the compound represented by formula (B) into its salt, acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, enanthic acid, capric acid, myristic acid, palmitic acid, stearic acid, lactic acid, sorbic acid, mandelic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid , malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid, phthalic acid, cinnamic acid, glycolic acid, pyruvic acid, hydroxylic acid, salicylic acid, N-acetylcysteine, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid acid, glutamic acid and the like, and hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid and others β-toluenesulfonic acid is preferred, hydrochloric acid and hydrobromic acid are more preferred, and hydrobromic acid is even more preferred.

[0119] Conversion of the compound represented by formula (B) into a salt thereof can be carried out in the presence of a solvent. Examples of solvents for converting the compound represented by formula (B) into a salt thereof include non-reaction solvents such as halogen solvents such as dichloromethane, chloroform, 1,2-dichloroethane and the like; ether solvents such as tetrahydrofuran, 1,4-dioxane, butyl ether and the like; alcohol solvents such as methanol, ethanol and the like; polar solvents such as ethyl acetate, isopropyl acetate, acetonitrile, dimethyl sulfoxide, dimethylformamide and the like; and water, or a mixed solvent thereof, and a non-reacting solvent such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, ethyl acetate and water, or a mixed solvent thereof is preferred , and ethyl acetate, water, or ethyl acetate-water is more preferred.

[0120] <Step of producing the compound represented by formula (A8)>

The compound represented by formula (A8) is obtained by asymmetric reduction of the ketone compound represented by formula (SM8).

[0121] Examples of asymmetric reduction include asymmetric reduction using a chemical catalyst or the like, asymmetric reduction using a biocatalyst (yeast, fungi, mold, enzyme and the like), and the like. Asymmetric reduction using an enzyme is preferred, asymmetric reduction using ketone reductase (KRED: ketoreductase) as an enzyme is more preferable, and asymmetric reduction using ketone reductase derived from Escherichia coli sp. as an enzyme is particularly preferred. The asymmetric reaction using ketone reductase is carried out using ketone reductase, coenzyme and coenzyme regeneration system. Typical examples of coenzymes for ketone reductases include NADP. Moreover, as a typical example of a coenzyme regeneration system that regenerates NADP, which is a coenzyme, glucose oxidation by glucose dehydrogenase (GDH) is known. Moreover, the asymmetric reaction using ketone reductase is preferably carried out in a solvent in the presence of a buffer solution.

[0122] The amount of reducing agent used in the asymmetric reaction, for example, in an asymmetric reaction using a chemical catalyst or the like, is generally 1.0-2.2 molar equivalents, and is preferably 1.2-2.0 molar equivalents relative to 1 molar equivalent the compound represented by formula (SM8).

[0123] In an asymmetric reaction using an enzyme, the amount of enzyme used is usually 0.01-0.1 times, preferably 0.02-0.07 times, and more preferably 0.047-0.05 times the amount of 1 g of compound , represented by formula (SM8).

[0124] In an asymmetric reaction using ketone reductase (KRED) derived from Escherichia coli sp., the amount of enzyme used is 0.01-0.1 fold, preferably 0.02-0.07 fold, and more preferably 0.047-fold 0.05 times the amount of 1 g of the compound represented by formula (SM8).

[0125] D-glucose can be used in an asymmetric reaction using an enzyme. When D-glucose is used, the amount of D-glucose used is usually 1.0-5.0 times, preferably 1.5-3.5 times, and more preferably 1.9-2.0 times the amount of 1 g of compound , represented by formula (SM8).

[0126] In an asymmetric reaction using an enzyme, glucose dehydrogenase (GDH) can be used. When glucose dehydrogenase (GDH) is used, the amount of glucose dehydrogenase (GDH) used is usually 0.01-0.1 times, preferably 0.01-0.05 times, and more preferably 0.019-0.02 times the amount of 1 g of compound , represented by formula (SM8).

[0127] In an asymmetric reaction using an enzyme, nicotinamide adenine dinucleotide phosphate (NADP) can be used. When nicotinamide adenine dinucleotide phosphate (NADP) is used, the amount of nicotinamide adenine dinucleotide phosphate (NADP) used is usually 0.00-0.1 times, preferably 0.005-0.05 times, and more preferably 0.009-0.01 times the amount of 1 g of the compound. represented by formula (SM8).

[0128] The asymmetric reaction can be carried out in the presence of a solvent. As the solvent, for example, a non-reaction solvent such as alcohol solvents such as methanol, ethanol, propanol, butanol and the like can be used; hydrocarbon solvents such as heptane, hexane, octane, toluene and the like; ether solvents such as tetrahydrofuran, 1,4-dioxane, butyl ether and the like; polar solvents such as acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide and the like; and water or a mixed solvent thereof, and the solvent may be suitably selected depending on the type of enzyme to be used.

In an asymmetric reaction using an enzyme, the buffer solution can be, for example, buffer solutions such as phosphate buffer solution, potassium phosphate buffer solution (which can be prepared, for example, from reagents such as K ₂ HPO ₄ 3H ₂ O and KH ₂ PO ₄ ), Tris/HCl buffer solution, sodium tetraborate hydrochloric acid buffer solution, triethanolamine buffer solution and the like, and the buffer solution can be suitably selected depending on the type of enzyme to be used.

[0129] In the asymmetric reaction using ketone reductase (KRED) derived from Escherichia coli sp., the solvent is preferably dimethyl sulfoxide, water or a mixed dimethyl sulfoxide-water solvent.

[0130] In the asymmetric reaction using ketone reductase (KRED) obtained from Escherichia coli sp., the amount of organic solvent used is usually 1.0-10 times, preferably 2-5 times, and more preferably 2.5-3 times. 0 multiple of the amount of 1 g of the compound represented by formula (SM8).

[0131] In an asymmetric reaction using ketone reductase (KRED) derived from Escherichia coli sp., the amount of buffer solution used is usually 10-40 times, preferably 15-30 times, and more preferably 28-30 times the amount of 1 g the compound represented by formula (SM8).

[0132] In an asymmetric reaction using an enzyme, the pH of the reaction solution is usually 6.0-7.5, and preferably 6.5-7.0.

[0133] The reaction temperature for carrying out the asymmetric reaction can be suitably selected from a reaction temperature, for example, in the range of -78°C to the temperature at which the solvent boils, in the range of -78°C to room temperature, in the range of 0° C to the temperature at which the solvent boils, in the range from 0°C to room temperature, and the like. The reaction temperature is preferably in the range from 0°C to room temperature.

[0134] The reaction temperature when carrying out an asymmetric reaction using an enzyme is usually in the temperature range at which the enzyme is not deactivated, and it is preferably in the range of 20°C-60°C, more preferably in the range of 20°C-35° C, and even more preferably is in the range of 20°C-30°C.

[0135] Unless otherwise indicated in the present invention, when Formula (SM8) is referred to, it includes its minor formulas (e.g., Formula (SM8-FL), Formula (SM8-CL), Formula (SM8-BR), Formula (SM8-ID) and similar). Likewise, unless otherwise stated in the present invention, when formula (A8) is referred to, it includes its subordinate formulas (eg, formula (A8-FL), formula (A8-CL), formula (A8-BR), formula ( A8-ID) and similar).

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

Moreover, Formula (A8-FL) represents a compound in which X=fluorine atom in the compound represented by Formula (A8). Formula (A8-CL) represents a compound in which X=chlorine atom in the compound represented by formula (A8). Formula (A8-BR) represents a compound in which X=bromine atom in the compound represented by formula (A8). Formula (A8-ID) is a compound in which X=iodine atom in the compound represented by formula (A8).

[0136] <Step of preparing the compound represented by formula (B) from formula (A8)>

The compound represented by formula (B) is prepared by carrying out an amination reaction of the compound represented by formula (A8) in the presence of a metal catalyst using ammonia (aqueous ammonia (eg, 25%, 28%, 30%, and the like)). The concentration (%) of aqueous ammonia is w/w% or w/v%.

[0137] Examples of catalysts for the amination reaction of the compound represented by formula (A8) using ammonia as a nitrogen source include Pd catalyst, Cu catalyst and the like. Examples of Pd catalysts include Pd ₂ (dba) ₃ PdCl ₂ -Josiphos complex and the like, and examples of Cu catalysts include CuI, Cu(OAc) ₂ , Cu ₂ O, CuO, CuBr, CuCl, CuSO ₄ , CuFe ₂ O ₄ and the like , and a Cu catalyst is preferred, and Cu ₂ O is more preferred.

[0138] Examples of solvents for the amination reaction include solvents such as dimethyl sulfoxide, N,N-dimethylformamide, N-methylpyrrolidone (NMP), 1,4-dioxane, acetonitrile, toluene, a mixed solvent thereof, and the like, wherein N-methylpyrrolidone (NMP ) is preferred.

[0139] A base may be present in the amination reaction, and examples of bases include bases such as potassium carbonate, potassium phosphate, cesium carbonate, N,N-diisopropylethylamine, triethylamine and the like.

[0140] The amination reaction is carried out by heating a sealed tube using a sealed tube reactor (made, for example, of stainless steel, glass or the like). When a heating reaction is carried out, heating is generally not carried out above the boiling point of the solvent or reagent used, and heating is carried out in a closed system using a sealed tube reactor or the like when the reaction is carried out at a temperature above the boiling point of the solvent or reagent used.

[0141] Examples of solvents that can be used in the amination reaction and their boiling points are as follows: dimethyl sulfoxide (boiling point 189°C), N,N-dimethylformamide (boiling point 153°C), N-methylpyrrolidone (NMP) (temperature boiling point 202°C), 1,4-dioxane (boiling point 101°C), acetonitrile (boiling point 82°C) and toluene (boiling point 110.6°C). Additionally, the boiling point of aqueous ammonia is 37.7°C for 25% aqueous ammonia and 24.7°C for 32% aqueous ammonia.

[0142] The reaction temperature for carrying out the amination reaction can be suitably selected from, for example, a reaction temperature in the range of 100°C-250°C, in the range of 100°C-200°C, in the range of 100°C-150°C and the like. The reaction temperature is preferably in the range of 100°C-120°C.

[0143] In the amination reaction where Cu ₂ O is used, the amount of metal catalyst used is generally 0.1-1.0 molar equivalents, preferably 0.2-0.8 molar equivalents, and more preferably 0.5-0 .7 molar equivalents, relative to 1 molar equivalent of the compound represented by formula (A8).

[0144] In the amination reaction, the amount of organic solvent used is usually 0.1 to 30 times, and preferably 0.5 to 20 times the amount of 1 g of the compound represented by formula (A8).

[0145] In the amination reaction, the amount of aqueous ammonia used is generally 1.0 to 50 times, preferably 2.5 to 30 times, and more preferably 2.5 to 3.5 times the amount of 1 g of the compound represented by the formula ( A8).

[0146] Unless otherwise indicated, the range of numerical values described in the present invention also includes values ±10% of these values. For example, when the phrase "0.1-1.0 molar equivalents" is mentioned, it means 0.1 ± 0.01 to 1.0 ± 0.1 molar equivalents, and when the phrase "0.1-30 times" is used quantity...", this means from 0.1±0.01 to 30±3 times.

[0147] <Step of producing the compound represented by formula (I)>

The compound represented by formula (I) is prepared by a condensation reaction of the compound represented by formula (B) or a salt thereof and the compound represented by formula (CA-1), using DMT-MM as the condensing reagent.

[0148] Condensation reactions can be carried out in the presence of a solvent. Examples of solvents include non-reaction solvents such as alcohol solvents such as methanol, ethanol, propanol, isopropanol, butanol and the like; ether solvents such as tetrahydrofuran, 1,4-dioxane, butyl ether and the like; and water or a mixed solvent thereof, and alcohol solvents, water or a mixed solvent thereof is preferred; methanol, ethanol, isopropanol, water, or a mixed solvent thereof is more preferred; methanol, ethanol or isopropanol is even more preferred; and methanol or isopropanol are particularly preferred.

[0149] In the condensation reaction, the applied amount of the carboxylic acid-containing compound represented by formula (CA-1) is generally 0.5 to 2.0 molar equivalents, preferably 0.5 to 1.5 molar equivalents, and more preferably 0.7-1.25 molar equivalents, relative to 1 molar equivalent of the compound represented by formula (B) or a salt thereof. As will be described below, the inventors of the present invention have discovered that the use of DMT-MM as a condensing agent provides a selective condensation reaction of the carboxyl group of the compound represented by formula (CA-1) and the amino group of the compound represented by formula (B), and that, therefore, it is not necessary to protect the hydroxyl groups of the compound represented by formula (B) in the condensation reaction.

[0150] In the condensation reaction, the salt of the compound represented by formula (B) is preferably an HCl salt or an HBr salt.

[0151] In the condensation reaction, the amount of DMT-MM used as the condensing reagent is generally 1.0-2.0 molar equivalents, preferably 1.1-1.8 molar equivalents, and more preferably 1.2-1.5 molar equivalents relative to 1 molar equivalent of the compound represented by formula (B) or a salt thereof.

[0152] When the salt of the compound represented by formula (B) is used in the condensation reaction, a base can be added. Examples of bases include organic bases such as triethylamine, N,N-diisopropylethylamine, pyridine and the like; and inorganic bases such as lithium hydroxide (lithium hydroxide monohydrate), sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate and the like. Triethylamine, N,N-diisopropylethylamine, pyridine, sodium carbonate or potassium carbonate is preferred, and triethylamine is more preferred.

[0153] The amount of base that can be added when the salt of the compound represented by formula (B) is used in the condensation reaction is usually 1.0-2.5 molar equivalents, preferably 1.05-2.3 molar equivalents or more preferably is 1.05 to 2.1 molar equivalents, relative to 1 molar equivalent of the salt of the compound represented by formula (B).

[0154] In the condensation reaction, the amount of solvent used is generally 5.0 to 100 times, preferably 5 to 40 times, and more preferably 5 to 30 times the amount of 1 g of the compound represented by formula (B) or a salt thereof.

[0155] The reaction temperature when carrying out the condensation reaction can be suitably selected from a reaction temperature, for example, in the range of -78°C to the temperature at which the solvent boils, in the range of -78°C to room temperature, in the range of 0° C to the temperature at which the solvent boils, in the range from 0°C to room temperature, and the like. The reaction temperature is preferably in the range from 0°C to room temperature.

[0156] 8-Amino-1,2,3,4-tetrahydronaphthalene-2-ol [CAS No. 624729-66-4] represented by formula (A) in the above-described aspect [1], can be obtained by selective reduction of the naphthalene ring using 8-aminonaphthalene-2-ol (formula (SM-1)) as a starting compound according to the production method , known from the literature, for example, the production method below, which is described in WO 2009/050289 (patent literature 6).

[0157]

[C81]

(Diagram 4-1)

[0158] (E)-2-(7-(trifluoromethyl)chroman-4-ylidene)acetic acid [CAS No. 920334-15-2] represented by formula (CA-1), in the above-described aspects [7]-[11] and the above-described aspects [17]-[20], can be prepared by performing several steps using 3-hydroxybenzotrifluoride (formula (CA-SM)) as a starting compound according to a production method known from the literature, for example, the production method below, which is described in WO 2007/010383 (Patent Literature 1).

[0159]

[C82]

(Diagram 4-2)

[0160] For the compound represented by formula (SM8), in the above-described aspects [13], [15], [17] and [18], a commercially available compound can be used. Alternatively, it can be prepared according to a preparation method known in the literature using a commercially available compound.

[0161] In the compound represented by formula (SM8), the compound in which X=fluorine atom (formula (SM8-FL)) can be prepared according to, for example, the preparation method (Scheme 4-3) below, which is described in the publication of the European patent application no. 343830.

[C83]

(Diagram 4-3)

[0162] In the compound represented by formula (SM8), the compound in which X=chlorine atom (formula (SM8-CL)) can be prepared according to, for example, the preparation method (Scheme 4-4) below, which is described in the European publication patent application no. 343830.

[C84]

(Diagram 4-4)

[0163] In the compound represented by formula (SM8), the compound in which X=bromine atom (formula (SM8-BR)) can be prepared according to, for example, the preparation method (Scheme 4-5) below, which is described in the Journal of Medicinal Chemistry, 36(17), pp. 2485-93, 1993 and European Journal of Medicinal Chemistry (1993), 28(9), pp. 693-701.

[C85]

(Scheme 4-5)

[0164] In formula (SM8), the compound in which X=iodine atom (formula (SM8-ID)) can be obtained according to the production methods for formula (SM8-FL), formula (SM8-CL) and formula (SM8- BR) (diagram 4-6).

[C86]

(Scheme 4-6)

[0165] The starting compound of each of the production process steps can be used in the next step as the reaction solution itself or as a crude product. In addition, the starting compound can also be isolated from the reaction mixture according to a conventional method, and can be easily purified by a known method, for example, by separation methods such as extraction, concentration, neutralization, filtration, distillation, recrystallization, chromatography and the like.

[0166] When the mixed solvent is used in the above reactions, it can be used by mixing two or more kinds of solvents in a suitable ratio, for example, in a ratio of 1:1 to 1:10 as a volume ratio or mass ratio.

[0167] Unless otherwise specified, the reaction time for each of the steps in the production method is not limited as long as it is a length of time that allows the reaction to sufficiently react, for example, the reaction time can be any of 0.1 hour , 0.5 hours, 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 it may be a duration within the lower limit and upper limit of these durations.

[0168] With regard to the reaction temperature, the temperature when referring to the phrase “in the range of -78°C to the boiling temperature of the solvent” means a temperature in the range of -78°C to the boiling temperature of the solvent (or mixed solvent) used in the reaction, for example, when methanol is used as a solvent, the phrase “from -78°C to the temperature at which the solvent boils” means that the temperature is in the range from -78°C to the temperature at which Methanol boils.

[0169] The same applies when the phrase “from 0°C to the boiling point of the solvent” is referred to, and it means a temperature in the range from 0°C to the boiling temperature of the solvent (or mixed solvent) used for reaction. The lower limit temperature is, for example, -78°C or 0°C as described above, but it may also be other temperatures such as 20°C, 23°C, 25°C, 40°C, 50° C, 70°C, 80°C, 90°C, 100°C, 150°C and the like.

[0170] As for the reaction temperature, the lower limit value and the upper limit value of the reaction temperature may be, for example, ±1°C, ±2°C, ±3°C, ±4°C and ±5°C of the respective temperatures.

[0171] Unless otherwise indicated, in the production method of the present invention, “room temperature” means the temperature of a laboratory, experimental laboratory or the like, and “room temperature” in examples of the present invention generally means a temperature of from about 1°C to about 30°C ( defined by the Japanese Pharmacopoeia). It preferably indicates a temperature typically from about 5°C to about 30°C, more preferably indicates a temperature typically from about 15°C to about 25°C, and even more preferably indicates a temperature of 20°C ± 3°C.

[0172] The compounds of the present invention may form an acid addition salt depending on the type of substituent. The salt is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include an inorganic acid salt, an organic acid salt and the like. Preferable examples of inorganic acid salts include salts of hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of organic acid salts include salts of aliphatic monocarboxylic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, enanthic acid, capric acid, myristic acid, palmitic acid, stearic acid, lactic acid, sorbic acid acid, mandelic acid and the like; salts of aliphatic dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid and the like; salts of aliphatic tricarboxylic acids such as citric acid and the like; salts of aromatic monocarboxylic acids such as benzoic acid, salicylic acid and the like; salts of aromatic dicarboxylic acids such as phthalic acid and the like; salts of organic carboxylic acids such as cinnamic acid, glycolic acid, pyruvic acid, hydroxylic acid, salicylic acid, N-acetylcysteine and the like; organic sulfonic acid salts such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like; and an acid addition salt of acidic amino acids such as aspartic acid, glutamic acid and the like.

[0173] The salt described above can be prepared according to a conventional method, for example, by mixing a solution containing a suitable amount of acid with a compound described in the present invention to obtain the required salts, and then fractionating the salts and collecting them by filtration; or by distilling off the mixed solvent. In addition, the compound of the present invention or a salt thereof can form a solvate with a solvent such as water, ethanol, glycerol and the like. “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” was published as a review article on salts. Stahl & Wermuth (Wiley-VCH, 2002), and this book includes a detailed description.

[0174] As shown in (Scheme 5) below, using the compound represented by formula (A) as a starting compound, the compound represented by formula (B) or a salt thereof can be obtained through compounds of formulas (A-5), (A -6) and (A-7).

[0175]

[C87]

(Scheme 5)

[0176] In addition, as shown in (Scheme 6) below, the compound represented by formula (B) or a salt thereof can be prepared by the method according to (Scheme 5) described above by replacing the protecting group of the amino group of the compound represented by formula (A), to a protecting group that is different from the tert-butoxycarbonyl group, for example, a P ¹ protecting group such as carbamate protecting groups such as a dimethoxycarbonyl group, an ethoxycarbonyl group, a benzyloxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, a 9-fluorenylmethyloxycarbonyl group , allyloxycarbonyl group and the like; sulfonyl protecting groups such as methanesulfonyl group, ethanesulfonyl group, benzenesulfonyl group, tosyl group, nitrobenzenesulfonyl group and the like; and alkylcarbonyl or arylcarbonyl protecting groups such as an acetyl group, an ethylcarbonyl group, a trifluoroacetyl group, a benzoyl group and the like.

[0177]

[C88]

(Scheme 6)

P ¹ =methoxycarbonyl group, ethoxycarbonyl group, benzyloxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, 9-fluorenylmethyloxycarbonyl group, allyloxycarbonyl group, methanesulfonyl group, ethanesulfonyl group, benzenesulfonyl group, tosyl group, nitrobenzenesulfonyl group, acetyl group, ethylcarbonyl naya group, trifluoroacetyl group, benzoyl group, etc.

[0178] The conditions for protecting the compound represented by formula (A) with a protecting group P ¹ or removing the protecting group P ¹ of the compound represented by formula (A-7p) can be selected depending on the type of protecting group P ¹ in a manner known in the literature, for example , a method of protection and removal described in the book, “Protective Groups in Organic Synthesis, 4th Edition, 2007, John Wiley & Sons, Greene et al.”

[0179] As shown in (Scheme 7) below, using the compound represented by formula (SM8) as a starting compound, the compound represented by formula (B) can be produced through the compound represented by formula (A8).

[0180]

[C89]

(Scheme 7)

[0181] In addition, as shown in (Scheme 8) below, using the compound represented by formula (SM8-BR) as a starting compound, the compound represented by formula (B) can be obtained through the compound represented by formula (A8-BR ).

[C90]

(Scheme 8)

[0182] As shown in (Scheme 9) below, using the compound represented by formula (A) as a starting compound, the compound represented by formula (I) can be produced through the compound represented by formula (B). In (Scheme 9), the compound represented by formula (B-HA) is the acid salt HA of the compound represented by formula (B), where HA is an acid.

[C91]

(Scheme 9)

[0183] In addition, as shown in (Scheme 10) below, using the compound represented by formula (A) as a starting compound, the compound represented by formula (I) can be obtained through the compound represented by formula (B). The definition of the P ¹ substituent in (Scheme 10) is the same as the definition in (Scheme 6) described above. In (Scheme 10), the compound represented by formula (B-HA) is the acid salt HA of the compound represented by formula (B), where HA is an acid.

[C92]

(Scheme 10)

[0184] In addition, as shown in (Scheme 11) below, using the compound represented by formula (SM8) as a starting compound, the compound represented by formula (I) can be obtained through the compound represented by formula (B). In (Scheme 11), the compound represented by formula (B-HA) is the acid salt HA of the compound represented by formula (B), where HA is an acid.

[C93]

(Diagram 11)

[0185] In addition, as shown in (Scheme 12) below, using the compound represented by formula (SM8-BR) as a starting compound, the compound represented by formula (I) can be obtained through the compound represented by formula (B). In (Scheme 12), the compound represented by formula (B-HA) is the acid salt HA of the compound represented by formula (B), where HA is an acid.

[C94]

(Scheme 12)

[0186] In the present invention, compounds of formula (A), formula (A-5) and formula (A-5p), which are racemates, include (R) form and (S) form. This means that, for example, formula (A-5) includes formula (A-5S) and formula (A-5R) (=formula (A-7)).

[C95]

[0187] [Asymmetric Ketone Reduction]

Various reactions are known to convert a keto group on a molecule to a chiral alcohol group. For example, there is a method in which a keto group is converted into a racemic alcohol group by using a reducing agent (sodium borohydride, lithium aluminum hydride (LAH), borane-tetrahydrofuran (BH3-THF) and the like), and then a chiral alcohol group is obtained in a manner such that as a fractional recrystallization method (a method in which a crystalline diastereomer is obtained by ionic coupling of an optical separation agent with a racemate, and this crystalline diastereomer is fractionated by recrystallization and neutralized, if necessary, to obtain a free chiral compound), a diastereomeric method (see WO 2009/055749) and a method with a chiral column (see WO 2009/050289).

[0188] In addition, the following reactions are known: asymmetric reduction reaction using a transition metal catalyst (eg, Ru, Rh and the like) (WO 2009/050289; Organometallics 10, p500-, 1991; and the like), asymmetric reduction reaction in which Al(CH ₃ ) ₃ and BINOL are mixed as a ligand (Angew. Chem. Int. Ed., 41, p1020-, 2002), an asymmetric reduction reaction using a chiral Ru (BINAP) catalyst (J. Am. Chem. Soc. 110, p629-, 1988), asymmetric reduction reaction using oxazaborolidine (J. Am. Chem. Soc. 109, p5551-1987), asymmetric reduction reaction using a biocatalyst (yeast, fungi, mold, enzyme and the like ) (see table 1) and the like.

[0189] In some aspects, the asymmetric reaction is preferably carried out using a biocatalyst. The asymmetric reaction using a biocatalyst has the advantages not only that it has high stereoselectivity, organic solvent and/or water can be used as the reaction solvent, the reaction occurs under mild conditions (normal temperature, normal pressure), and it is cheaper, than chemical catalyst and the like, but it is also a reaction that has attracted attention in recent years as an environmentally friendly reaction because the amount of waste after the reaction can be reduced, and is also a suitable reaction for easily producing a chiral compound.

[0190] Typically, in an asymmetric reduction reaction using an enzyme, the chemical yield (%) and optically active yield (ee%) of the chiral compound that is produced varies depending on the reaction specificity (selectivity for the type of enzyme-specific reaction), substrate specificity (selectivity for substrate type) and reaction conditions (reaction temperature, pH, solvent, reaction time and the like). Many enzymes have very high reaction specificity and the reactions catalyzed by a single enzyme are limited, but there are different enzymes, that is, enzymes with higher substrate specificity or enzymes with lower substrate specificity. Accordingly, for example, when a keto group is asymmetrically reduced to a chiral alcohol group, even if an enzyme is selected for which a favorable chemical yield and optically active yield is obtained from compounds having a structure similar to that of the substrate (ketone compound) to be used and the enzymatic reaction carried out under the same conditions, the desired chiral alcohol compound cannot be obtained with the same chemical yield and optically active yield.

[0191] For example, biocatalysts that can selectively reduce the keto group of β-tetralone [CAS number: 530-93-8] to a chiral alcohol shown in Table 1 are known.

[0192]

[Table 1]

Biocatalyst Source Document with description enzyme Magnaporthe grisea expressed in Escherichia coli BL21 Angewandte Chemie, International Edition, 51(11), p2643-2646, 2012 Whole cells of Kluyveromyces marxianus CBS 6556 Tetrahedron Asymmetry, 22(23), p1985-1993, 2011 Thermoanaerobacter ethanolicus (TeSADH) Practical Methods for Biocatalysis and Biotransformations, p284-287, 2010 Didymosphaeria igniaria whole cells KCH6670 Journal of Industrial Microbiology & Biotechnology, 37(11), p1121-1130, 2010 Paracoccus pantotrophus DSM 11072, overexpressed in E. coli ChemSusChem, 1(5), p431-436, 2008 Ralstonia sp. DSM 6428 (RasADH) Journal of Organic Chemistry, 73(15), p6003-6005, 2008 Sphingobium yanoikuyae Organic Letters, 10(11), p2155-2158, 2008 Thermoanaerobacter ethanolicus expressed in Escherichia coli WO 2008/013949 Thermoanaerobacter ethanolicus W110A Angewandte Chemie, International Edition, 46(17), p3091-3094, 2007 Rhodococcus ruber DSM 44541 Organic Letters, 9(11), p2163-2166, 2007 W110A TESADH. Journal of Organic Chemistry, 72(1), p30-34, 2007 Lactobacillus kefir.sp Advanced Synthesis & Catalysis, 350(14+15), p2322-2328, 2008 yeast Candida viswanathii Biocatalysis and Biotransformation, 31(3), p123-131, 2013 mushrooms Absidia cylindrospora KCh 336 Current Microbiology, 65(2), p189-194, 2012 Lyophilized cells of Comamonas sp. Tetrahedron: Asymmetry, 19(16), p1954-1958, 2008 Rhodococcus ruber DSM 44541 Journal of Organic Chemistry, 68(2), p402-406, 2003 Saccharomyces montanus cbs 6771 Tetrahedron: Asymmetry, 7(10), p2983-2996, 1996 mold Aspergillus ochraceus atcc 1009. Tetrahedron: Asymmetry, 7(10), p2983-2996, 1996 Mucor racemosus rhizopus arrhizus atcc 11145 Cell culture solution Lycoperiscumesculentum (tomato) International Journal of ChemTech Research, 4(1), p203-207, 2012 plant Daucas Carota root ext US Patent Application Publication No. 2004-0082043 Coryneum betulinum KCh 6534 Current Microbiology, 65(2), p189-194, 2012 Fusarium culmorum Biocatalysis and Biotransformation, 27(3), p179-185, 2009

[0193] [Chemistry in the flow]

For synthetic reactions, there is usually an on-line method (on-line chemistry) and a batch method. Flow chemistry is a continuous synthesis process using a reaction device that directs liquid from a vessel containing two or more different kinds of solutions (e.g., raw material+solvent, reagent+solvent, and the like) through a pipe into a reactor, and then into a recovery tank at a constant flow rate using a pump.

[0194] On-line chemistry can be used in converting the compound represented by formula (A-5) into the compound represented by formula (A-6) by an oxidation reaction. Figure 1 shows an example of a reaction device used in flow chemistry. The reaction device shown in Figure 1 has nitrogen inlets (L1, L2, L3, L4); vessel (M1) containing raw material, TEMPO and dichloromethane; vessel (M2) containing KBr, NaHCO ₃ and water; vessel (M3) containing 5.0% by weight NaClO; pumps (P1, P2, P3); pre-cooling pipes (T1, T2, T3); mixers (S1, S2, S3); and reactor (R1, R2, R3).

[0195] The reaction device of Figure 1 is used, for example, as follows. First, the raw material (the compound represented by formula (A-5)), TEMPO and dichloromethane are supplied to vessel M1, KBr, sodium hydrogen carbonate and water are supplied to vessel M2, and 5.0% by weight NaClO is supplied to vessel M3. With nitrogen gas flowing from the respective nitrogen inlets L1, L2, L3, L4, the reactants are pumped from the respective vessels M1, M2, M3 at a predetermined flow rate using the respective pumps P1, P2, P3, then passed through the respective pre-cooling pipes T1, T2, T3 are then sequentially passed through reactor R1, reactor R2 and reactor R3, and thus poured into the CD recovery tank. Then, the target product (the compound represented by formula (A-6)) is obtained from the CD recovery tank.

Flow chemistry can also be applied to reactions that are difficult to maintain safely in a normal batch manner (see review article on flow chemistry ChemSusChem, 5(2), Special Issue; Flow Chemistry, pp. 213-439, February 13, 2012).

[0196] The batch method is a conventional synthetic reaction and is a method of purifying the product obtained after a reaction using a reactor. The batch process has the advantage that the compound can be prepared in several steps.

In the flow-through method (in-line chemistry), the reaction is carried out in an on-line basis using, for example, a chemical stirred flow reactor (CSTR) as the reaction device. In the flow method, since the reaction can be carried out in a small reactor, the reaction efficiency is high and the reaction conditions can be accurately controlled so that the target product can be stably supplied.

[0197] [Amination reaction]

The process (amination reaction) for converting a halogen atom of a halogenated aryl to an amino group can be carried out in the presence of a metal catalyst and in the presence or absence of a ligand, using as a nitrogen source a compound represented by NHR ^A R ^B (wherein each R ^A and R ^B independently represents an atom hydrogen or a substituent such as a methyl group, ethyl group, benzyl group and the like), R ^C CONH ₂ (wherein R ^C independently represents a substituent such as a methyl group, ethyl group, benzyl group, dimethoxy group, ethoxy group, a tert -butoxy group, benzyloxy group and the like), or the like.

[0198] Regarding the amination reaction of halogenated aryl using ammonia as a nitrogen source, for example, the following method using a metal catalyst is known as a method known in the literature, but the method is not limited to it. Pd ₂ (dba) ₃ (J. Am. Chem. Soc., 129(34), p10354-10355, 2007), PdCl ₂ -Josiphos complex (J. Am. Chem. Soc., 128(31), p10028- 10029, 2006), CuI (Chem. Commun., 26, p3052-3054, 2008; J. Org. Chem., 74(12), p4542-4546, 2009), Cu(OAc) ₂ (Angew. Chem. Int. Ed., 48(2), p337-339, 2009), Cu ₂ O (Ukrainian Khimiche skii Zhurnal (Russian Edition), 53(12), P1299-302, 1987).

[0199] For example, for the amination reaction of 8-halo-1,2,3,4-tetrahydronaphthalen-2-ol, in which a secondary alcohol is present in the molecule, it is known to have an amination reaction using Pd ₂ (dba) ₃ as a metal catalyst and tert-butylcarbamate as a nitrogen source, but examples using other metal catalysts are unknown.

[0200] In some aspects, the amination reaction is preferably a reaction that directly introduces an amino group with ammonia. Alternatively, an amino group can be introduced by deprotecting the protecting group after substitution, for example with a protected amino compound such as NHR ^A1 R ^B1 (wherein R ^A1 represents a hydrogen atom and R ^B1 represents an amino protecting group such as a benzyl group, 4-dimethoxybenzyl and the like), and R ^C CONH ₂ (wherein R ^C independently represents a substituent such as a methyl group, ethyl group, benzyl group, dimethoxy group, ethoxy group, t-butoxy group, benzyloxy group and the like). However, since the amination reaction using a protected amino compound requires a deprotection step, a reaction that directly introduces the amino group with ammonia is preferred when considering large-scale synthesis or industrial production.

[0201] [Condensation reactions]

In general, regarding the condensation reaction of a compound containing a carboxyl group and a compound containing an amino group, an amide bond can be obtained by carrying out a condensation reaction using, for example, a condensing agent such as 1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-hydrochloride 3-(3'-dimethylaminopropyl)carbodiimide (WSC HCl), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent), bis(2-oxo-3-oxazolidinyl)phosphine chloride (BOP-Cl), 2- hexafluorophosphate chloro-1,3-dimethylimidazolinium (CIP) and the like (see, for example, Experimental Chemistry Course 22, 4th Edition, Organic Synthesis IV: Acids, Amino Acids, Peptides, pp. 193-309, 1992, Maruzen; and the like).

[0202] As a result of the example of a condensing agent, the inventors of the present invention have discovered that the compound represented by formula (I) can be easily obtained in high yield by using, in particular, DMT-MM as a condensing reagent in the condensation reaction of the compound represented by formula (B) , which contains both a hydroxyl group and an aniline amino group, and heterocyclideneacetic acid, represented by formula (CA-1), which contains a carboxyl group.

[0203] All publications cited in the present invention, such as prior art documents, unexamined patent publications, patent publications and other patent documents, are incorporated by reference in their entirety. The present invention includes the scope of the claims, specifications and drawings of Chinese Patent Application No. 201910783254.8 (filed on August 23, 2019), International Patent Application No. PCT/JP2019/036451 (filed on September 18, 2019) and Chinese Patent Application No. 202010355546.4 (filed on April 29 2020), which are the basis for asking the priority of this application.

Examples

[0204] In the following, the present invention will be specifically described with reference to examples, but the present invention is not limited to them.

[0205] A Bruker AVANCE III 400 MHz NMR spectrometer (equipped with a 5 mm Bruker PABBO Z-gradient probe and TOPSPIN 3.5 software) was used to obtain nuclear magnetic resonance (NMR) spectra of compounds represented by formula (A-5), formula (A- 6), formula (A-7) and formula (B). In addition, JEOL JNM-LA300 FT-NMR (JEOL Ltd.) was used to obtain nuclear magnetic resonance (NMR) spectra of the bromate salt of the compound represented by formula (B) and the compound represented by formula (I).

The compounds represented by Formula (A-5), Formula (A-6), Formula (A-7) and Formula (B) were tested by high performance liquid chromatography (HPLC) under the following conditions.

[0206]

[Table 2]

[HPLC analysis conditions for the compound represented by Formula (A-5), Formula (A-6) and Formula (A-7)]

Measuring device Agilent 1260 HPLC with UV detector or equivalent column Waters Xbridge C18, (150mm×4.6mm, 3.5µm) (PN: 186003034) Measurement wavelength 210 nm Column temperature 40°C Flow rate 1.0 ml/min Injection volume 5 µl Sample concentration The compound represented by formula (A-5) or formula (A-7): 0.2 mg/ml,
Compound represented by formula (A-6): 0.25 mg/ml Duration of work 20 minutes Duration of data collection 20 minutes Thinning agent CH ₃ CN Mobile phase A Aqueous solution 5 mM NH ₄ Ac
(preparation method: 770 mg NH ₄ Ac is accurately weighed and thoroughly mixed with 2000 ml of pure water, and the mixture is degassed by ultrasonic waves) Mobile phase B CH ₃ CN Gradient program Rebalancing duration: 5 minutes

[Table 3]

[Retention time (RT) of each connection]

Compound RT (min) Relative retention time (RRT) Ethyl acetate 5.8 0.62 The compound represented by formula (A) 6.2 0.67 Dichloromethane 7.0 0.75 Compound represented by Formula (A-5) or Formula (A-7) 9.3 1.00 TEMPO 9.5 1.02 The compound represented by formula (A-6) 9.8 1.05 Toluene 11.0 1.18

[Table 4]

[HPLC analysis conditions for the compound represented by formula (B)]

Measuring device Shimadzu LC-20A HPLC with UV detector column ACE 3 C18 (150 mm×4.6 mm, 3 µm) Measurement wavelength 213 nm Column temperature 35°C Flow rate 1.0 ml/min Sample concentration Compound represented by formula B: 0.1 mg/ml,
Hydrochloride salt of the compound represented by formula B: 0.12 mg/ml Injection volume 5 µl Mobile phase Mobile phase A: aqueous solution of 5 mM NH ₄ Ac Mobile phase B: CH ₃ CN Gradient program Duration of work 16 minutes Thinning agent MeOH

[Table 5]

[Retention time (RT) for each connection]

Compound RT (min) Relative retention time (RRT) Formula (B) 7.0 1.00 Formula (A-7) 9.6 1.36 Toluene 11.0 1.57

[Table 6]

[HPLC chiral analysis conditions for the compound represented by formula (A-7)]

Measuring device Shimadzu LC-20A HPLC with UV detector or equivalent column Daicel Chiralpak AD-H (250×4.6 mm, 5.0 µm) column, PN:19325 Measurement wavelength 230 nm Column temperature 35°C Flow rate 1.0 ml/min Injection volume 5 µl Sample concentration 2.5 mg/ml Duration of data collection 20 minutes Duration of work 20 minutes Thinning agent EtOH Mobile phase Mixed solution of 0.1% diethylamine n-hexane/ethanol (9/1, v/v)
(Preparation method: 900 ml of n-hexane and 100 ml of ethanol were mixed thoroughly, and then 1 ml of diethylamine was added and mixed with the mixed solution of n-hexane and ethanol) Isocratic program

[Table 7]

[Retention time (RT) for each connection]

Compound RT (min) Relative retention time (RRT) The compound represented by formula (A-7) 8.1 1.00 Enantiomer of the compound represented by formula (A-7) 9.9 1.22

[0207] In addition, the liquid chromatography-mass spectrometry (LC-Mass) spectrum of the bromate salt of the compound represented by formula (B) and the compound represented by formula (I) was obtained by the following method.

[UPLC] A Waters AQUITY UPLC system and BEH C18 column (2.1 mm×50 mm, 1.7 µm) (Waters) were used, and the mobile phase and gradient conditions were acetonitrile:aqueous 0.05% trifluoroacetic acid=5: 95 (0 minutes)-95:5 (1.0 minutes)-95:5 (1.6 minutes)-5:95 (2.0 minutes).

[0208] In ¹ H-NMR data, c denotes singlet, d denotes doublet, t denotes triplet, kv denotes quartet, m denotes multiplet, uss denotes pattern-broadened NMR signals, J denotes coupling constant, Hz denotes Hertz, DMSO- d ₆ is deuterated dimethyl sulfoxide, and CDCl ₃ is deuterated chloroform. In ¹ H-NMR data, signals that cannot be confirmed due to broadband signals, such as hydroxyl group (OH), amino group (NH ₂ ) and amide group (CONH) protons, are not reported in the data.

[0209] In LC-Mass data, M denotes molecular weight, RT denotes retention time, and [M+H] ⁺ denotes molecular ion peak.

[0210] (Examples 1a-1d) Preparation of tert-butyl (7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)carbamate (A-5)

[0211]

[C96]

[0212] (example 1a)

Di-tert-butyl dicarbonate (Boc ₂ O) (0.74 g) was added to a solution of the compound represented by formula A (obtained according to the preparation method described in WO 2009/050289) (0.5 g) and sodium hydrogen carbonate (0.154 g) in 1,4-dioxane (5 ml)-water (5 ml), and the mixture was stirred at a reaction temperature of 20°C-30°C for 22 hours. Sodium hydrogen carbonate (0.104 g) was further added to the mixture, and the mixture was stirred at a reaction temperature of 20°C-30°C for 18 hours. Di-tert-butyl dicarbonate (0.15 g) was further added to the mixture, and the mixture was stirred at a reaction temperature of 20°C-30°C for 5 hours. Di-tert-butyl dicarbonate (0.15 g) was further added to the mixture, and the mixture was stirred at a reaction temperature of 20°C-30°C for 16 hours. Di-tert-butyl dicarbonate (0.1 g) was further added to the mixture, and the mixture was further stirred at a reaction temperature of 20°C-30°C for 1 hour. Ethyl acetate was added to the reaction solution, and the organic layer was fractionated. The aqueous layer was washed with ethyl acetate, and the organic layer was combined with the previously obtained organic layer, and then washed with brine. The organic layer was concentrated under reduced pressure, and the resulting residue was solidified with dichloromethane and n-heptane to give the title compound (0.46 g).

[0213] (example 1b)

Di-tert-butyl dicarbonate (Boc ₂ O) (1.61 g) was added to a solution of the compound represented by formula A (WO 2009/050289) (1.0 g) and sodium hydrogen carbonate (1.55 g) in tetrahydrofuran (10 ml)-water (10 ml), and the mixture was stirred at a reaction temperature of 45°C-55°C for 17 hours. Di-tert-butyl dicarbonate (0.13 g) was further added to the mixture, and the mixture was stirred at a reaction temperature of 45°C-55°C for 2 hours. After cooling the reaction solution to room temperature, methyl tert-butyl ether (MTBE) was added to the reaction solution, and the pH was adjusted to 5-6 with 10 w/v% citric acid solution, then the organic layer was fractionated. The aqueous layer was extracted with methyl tert-butyl ether, and the organic layer was combined with the previously obtained organic layer, and then washed with water and brine. The organic layer was concentrated under reduced pressure, and the resulting residue was solidified with dichloromethane and n-heptane to give the title compound (1.34 g).

[0214] (example 1c)

Di-tert-butyl dicarbonate (Boc ₂ O) (17.4 g) was added to a solution of the compound represented by formula A (obtained according to the preparation method described in WO 2009/050289) (10 g) and sodium hydrogen carbonate (15.5 g ) into tetrahydrofuran (100 ml)-water (100 ml), and the mixture was stirred at a reaction temperature of 45°C-55°C for 17 hours. Di-tert-butyl dicarbonate (1.3 g) was further added to the mixture, and the mixture was stirred at a reaction temperature of 45°C-55°C for 2 hours. Di-tert-butyl dicarbonate (1.3 g) was further added to the mixture, and the mixture was further stirred at a reaction temperature of 45°C-55°C for 1 hour. After cooling the reaction solution to room temperature, methyl tert-butyl ether (MTBE) was added to the reaction solution, and the pH was adjusted to 5-6 with 10% citric acid solution, then the organic layer was fractionated. The aqueous layer was extracted with methyl tert-butyl ether, and the organic layer was combined with the previously obtained organic layer, and then washed with water and brine. The organic layer was concentrated under reduced pressure, and the resulting residue was solidified with dichloromethane and n-heptane to give the title compound (15.1 g).

[0215] (example 1d)

A solution of the compound represented by formula A (obtained according to the preparation method described in WO 2009/050289) (218.5 g) in tetrahydrofuran (1.9 L) was brought to a temperature of 20°C-30°C, and an aqueous solution of sodium hydrogen carbonate (319 g, (3.2 eq. sodium carbonate and 1.9 L water) was added to the solution over 10 minutes at a temperature of 20°C-30°C. The temperature of the mixed solution above was set to 0°C-10°C, and di-tert-butyl dicarbonate (413 g) was added to the mixed solution over 15 minutes while maintaining the same temperature. The reaction temperature was set to 45°C-55°C, and the mixed solution was stirred at the same temperature for 18 hours. After cooling the reaction temperature to 20°C-30°C, methyl tert-butyl ether (1.9 L) was added to the reaction solution, and the mixed solution was stirred at 20°C-30°C for 10 minutes.10% citric acid solution (2.5 L) was added to the mixed solution, and the organic layer was fractionated.The aqueous layer was extracted with methyl tert-butyl ether (1 L×2 times), and the organic layer was combined with the previously obtained organic layer, and then washed with water (1 L× 2 times). After concentrating the organic layer under reduced pressure until it was 500 ml, the operation of adding dichloromethane (1 L) and concentrating the organic layer under reduced pressure until the organic layer was approximately 500 ml was carried out twice, then adding n-heptane (1 l), and the organic layer was concentrated under reduced pressure until the organic layer was approximately 500 mL, n-heptane (800 L) was added and the organic layer was concentrated under reduced pressure until the organic layer was approximately 600 mL, and dichloromethane (300 ml) and n-heptane (600 ml) were added and the organic layer was concentrated under reduced pressure until the organic layer was approximately 600 ml, then dichloromethane (1 L) was added and activated carbon (21 g) was added to her, and the mixed solution was stirred at 20°C-30°C for 2 hours. Next, the mixed solution was filtered, and the filtrate was concentrated under reduced pressure until it was approximately 500 ml, then dichloromethane (800 ml) was added thereto, and the solution was concentrated under reduced pressure until it was approximately 500 ml. Dichloromethane (800 ml) was added and the solution was filtered to leave a solid residue. The resulting solid was dried at 35°C for 15 hours to obtain the title compound (303.3 g) as a greyish-black solid.

[0216] [Physical property data of the compound represented by formula (A-5)]

( ^1H NMR, 400 MHz, manufacturer: Bruker, DMSO-d ₆ , δ ppm)

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

[0217] (Examples 2a-2f) Preparation of tert-butyl (7-oxo-5,6,7,8-tetrahydronaphthalene-1-yl)carbamate (A-6)

[0218]

[C97]

[0219] (example 2a)

Using tert-butyl (R)-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)carbamate (formula (A-7)) (0.5 g) derived from (R)-8 -amino-1,2,3,4-tetrahydronaphthalene-2-ol in the same way as in the methods (examples 1a-1d), the oxidation reaction was carried out under the reagent conditions shown in the following table, in a solvent (dichloromethane (12.5 ml)-water (7.5 ml)) at the reaction temperature (0°C-5°C), and it was confirmed that the title compound was obtained (IPC purity using HPLC (IPC=as received control)).

[0220]

[Table 8]

No. Reagent IPC purity A6 (%) Reaction duration TEMPO
(eq.) _NaHCO3
(eq.) KBr
(eq.) 10% NaClO
(eq.) 10
(min) thirty
(min) 60
(min) 18
(h) 1 0.05 4 0.05 2 35.6 50.6 55.7 61.4 2 0.275 3 0.125 1.7 87.0 87.9 88.9 78.9 3 0.5 2 0.05 2 78.0 89.2 88.9 77.5 4 0.05 2 0.2 2 30.5 47.0 55.9 58.3 5 0.05 4 0.2 1.4 27.6 36.6 38.1 37.2 6 0.5 4 0.2 2 87.2 91.1 91.5 88.4 7 0.5 4 0.05 1.4 68.8 72.7 72.5 69.9 8 0.275 3 0.125 1.7 78.3 79.0 79.7 81.4 9 0.05 2 0.05 1.4 25.7 42.4 34.3 56.5 10 0.5 2 0.2 1.4 64.7 69.9 49.8 66.8

[0221] (example 2b)

Using tert-butyl (R)-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)carbamate (formula (A-7)) (0.5 g) derived from (R)-8 -amino-1,2,3,4-tetrahydronaphthalene-2-ol in the same way as in the methods (examples 1a-1d), the oxidation reaction was carried out under the reagent conditions shown in the following table, at the reaction temperature (0°C- 5°C), yielding the title compound (IPC purity using HPLC).

[0222]

[Table 9]

No. Reagent Solvent
water: 15 times its volume
Solvent: 10 times its volume IPC purity A6 (%) Reaction time (min) TEMPO
(eq.) _NaHCO3
(eq.) KBr
(eq.) 10% NaClO
(eq.) 10 thirty 60 eleven 0.5 4 0.05 2 water
7.5 ml Acetone
5 ml 0 0 0.8 12 0.5 4 0.05 2 water
7.5 ml CH ₃ CN
5 ml 14.9 13.6 10.6

[0223] (example 2c)

A solution of tert-butyl (R)-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)carbamate (Formula (A-7)) (10 g), which was prepared in the same manner as in Methods (examples 1a-1d) in dichloromethane (250 ml, 25 times its volume) - water (150 ml, 15 times its volume) cooled to -2°C-2°C, and TEMPO (0.5 eq.), KBr (0.2 eq.), NaHCO ₃ (4.0 eq.) and NaClO ((8.1%), 1.4 eq.) were added to the solution at the same temperature. When the IPC purity was then confirmed, the reaction was confirmed to be completed with a purity of 95.5%. The reaction solution was treated and thereby the title compound was obtained ( ^1H -NMR yield 77.1%).

[0224] (example 2d)

TEMPO oxidation was carried out in on-line mode using the chemical stirred flow reactor (CSTR) shown in Figure 1. A solution (500 ml) of tert-butyl-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl) carbamate (Formula (A-5)) (25 g) prepared in the same manner as in methods (Examples 1a-1d) and TEMPO (0.5 eq.) in dichloromethane was added to vessel M1, and KBr (0.05 eq.), sodium bicarbonate (4 eq.) and water (375 ml) were added to vessel M2, and 5.0 wt.% NaClO (1.3 eq.) was added to vessel M3. With nitrogen gas flowing from the respective nitrogen inlets L1, L2, L3, and L4, reagents were supplied from the respective vessels M1, M2, and M3 at each flow rate of 13.67 mL/min, 9.83 mL/min, and 4. 27 ml/min using the corresponding pumps P1, P2, and P3, then passed through the corresponding pre-cooling pipes T1, T2 and T3 (temperature 0°C-5°C, pipe length: 2 m, pipe diameter: 1/16 SC), then passed successively through reactor R1, reactor R2 and reactor R3 (where each of reactors 1, 2, and 3 had a capacity of 25 ml, and the corresponding reactors were cooled to 0°C-5°C), and thereby poured into CD recovery tank (where the reaction time in each of the reactors was 0.9 minutes). The target product was obtained with an IPC purity of 96.5% of the reaction solution obtained from the CD recovery tank.

[0225] (example 2e)

TEMPO oxidation was carried out in on-line mode using the chemical stirred tank flow reactor (CSTR) shown in Figure 1. Tert-butyl (R)-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)carbamate ( formula (A-5)) (35 g) prepared in the same way as in methods (Examples 1a-1d), TEMPO (0.5 eq.) and dichloromethane (700 ml) were added to vessel M1, and KBr (0 .05 eq), sodium bicarbonate (4 eq) and water (525 ml) were added to vessel M2, and 5.0 wt% NaClO (1.3 eq) was added to vessel M3. With nitrogen gas flowing from the respective nitrogen inlets L1, L2, L3, and L4, reagents were supplied from the respective vessels M1, M2, and M3 at each flow rate of 13.67 mL/min, 9.83 mL/min, and 4. 27 ml/min using the corresponding pumps P1, P2, and P3, then passed through the corresponding pre-cooling pipes T1, T2, and T3 (temperature 0°C-5°C, pipe length: 2 m, pipe diameter: 1/ 16 SC), then sequentially passed through reactor R1, reactor R2 and reactor R3 (where each of reactors 1, 2 and 3 had a capacity of 25 ml, and the corresponding reactors were cooled to 0°C-5°C), and then poured into the tank for CD recovery (where the reaction time in each of the reactors was 0.9 minutes and it required 47 minutes to complete the flow). The IPC purity of the reaction solution (850 g) obtained from the CD recovery tank was 95.0%. An aqueous solution of Na ₂ S ₂ O ₄ (Na ₂ S ₂ O ₄ : 10 g, water: 250 ml) was added to the reaction solution, and the mixed solution was stirred for 30 minutes. After separating the organic layer and the aqueous layer, the organic layer was washed with water (300 ml×2 times). After concentrating the organic layer under reduced pressure to a volume of 1.5-2.5 volume, n-heptane (30-50 ml) was added thereto, and the mixture was stirred at room temperature for 1 hour, and n-heptane ( 200 ml), and the mixture was stirred at room temperature for 16 hours. The resulting solid was collected by filtration and washed with n-heptane (70 ml), thereby obtaining the title compound (25.2 g) as an off-white solid.

[0226] (example 2f)

TEMPO oxidation was carried out in on-line mode using a chemical stirred flow reactor (CSTR) shown in Figure 1. Tert-butyl-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)carbamate (formula (A -5)) (276.6 g) obtained in the same way as in methods (examples 1a-1d), TEMPO (82.588 g, 0.5 eq.) and dichloromethane (5.535 ml, 20 vol) were added to vessel M1 , and KBr (6.251 g), sodium bicarbonate (352.943 g) and water (4.149 ml) were added to vessel M2, and 5.0 wt% NaClO (1.849 L) was added to vessel M3. With nitrogen gas flowing from the respective nitrogen inlets L1, L2, L3, and L4, reagents were supplied from M1, M2, and M3 at each flow rate of 13.67 mL/min, 9.83 mL/min, and 4.27 mL/min. min using the corresponding pumps P1, P2, and P3, then passed through the corresponding pre-cooling pipes T1, T2, and T3 (temperature 0°C-5°C, pipe length: 2 m, pipe diameter: 1/16 SC) , then sequentially passed through reactor R1, reactor R2 and reactor R3 (where each of reactors 1, 2, and 3 had a capacity of 25 ml, and the corresponding reactors were cooled to 0°C-5°C), and then poured into the recovery tank CD (where the reaction time in each of the reactors in flow mode was 0.9 minutes and it required 410 minutes to complete the flow). A 3.7% Na ₂ S ₂ O ₄ solution (2.597 g) was added to 6.845 g of the resulting reaction mixed solution, and the mixed solution was stirred for 30 minutes. After separating the organic layer and the aqueous layer, the organic layer was washed with water (3 L×2 times). After concentrating the organic layer under reduced pressure to a volume of 2.5 vol, n-heptane (205 ml) and one fragment of the already obtained compound represented by Formula A-6 were added thereto, and the mixture was stirred at room temperature for 1 hour. In addition, n-heptane (2.1 L) was added thereto, and the resulting solid was collected by filtration, washed with n-heptane (800 ml) and dried under reduced pressure for 13 hours to obtain the title compound (190 d) in the form of a brown solid residue.

[0227] Physical property data of the compound represented by formula (A-6)]

( ^1H NMR, 400 MHz, manufacturer: Bruker, CDCl ₃ , δ ppm)

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

[0228] (Examples 3a-3g) Preparation of tert-butyl (R)-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)carbamate (A-7)

[0229]

[C98]

[0230] (example 3a)

KRED (ketone reductase derived from Lactobalius sp., 2.0 g), D-glucose (0.2 g), glucose dehydrogenase (GDH) (0.02 g), nicotinamide adenine dinucleotide phosphate (NADP) (0.01 g) and phosphate buffer solution (3.0 ml prepared by adding 21.25 g K ₂ HPO ₄ and 10.62 g KH ₂ PO ₄ to 1000 ml water) was mixed in a glass test tube (8 ml capacity) and stirred to obtain mixed solution A. Mixed solution obtained by dissolving the compound (0.1 g) of formula (A-6) obtained in the same way as in methods (Examples 2a-2f) in dimethyl sulfoxide (DMSO) (0.2 ml) was added to the previously prepared mixed solution A The mixture was stirred at a reaction temperature of 23°C (20°C-25°C) for 43 hours (at 250 rpm on a circular shaker). A portion of the reaction solution was collected and subjected to HPLC analysis, and the title compound was confirmed to be obtained.

KRED used in Examples 3a-3g is a ketone reductase derived from Lactobacillus sp. (EnzymeWorks, Inc., Product Number: EW-KRED-172).

[0231] (example 3b)

KRED (ketone reductase derived from Lactobalius sp., 20 g), D-glucose (2 g), glucose dehydrogenase (GDH) (0.2 g), nicotinamide adenine dinucleotide phosphate (NADP) (0.1 g) and buffer solution (prepared by adding 0 .86 g K ₂ HPO ₄ 3H ₂ O and 0.3 g KH ₂ PO ₄ to 30 ml water) were mixed in a reactor and stirred to obtain mixed solution B. Mixed solution obtained by dissolving compound (1 g) of formula (A- 6), obtained in the same way as in methods (examples 2a-2f), in toluene (13 ml) was added to the previously obtained mixed solution B. The mixture was stirred at a reaction temperature of 23°C (20°C-25°C) in within 15 hours. The reaction solution was filtered using celite, and the aqueous layer and the organic layer were separated, then the aqueous layer was extracted with toluene (30 ml), and the organic layer was combined with the previously obtained organic layer, and then washed with water (30 ml x 2 times), then concentrated, yielding the title compound (0.5 g, optical purity 99.9% ee) as a brown oil.

[0232] (example 3c)

The study of KRED amount and pH was carried out under the reaction conditions shown in the table below. The compound represented by formula (A-6) was prepared in the same manner as in the methods (Examples 2a-2f). The buffer solution was prepared from K ₂ HPO ₄ ·3H ₂ O and KH ₂ PO ₄ in the same way as in example 3b.

[0233]

[Table 10]

No. Conditions Reaction stage IPC purity A-6
(g) pH Enzyme
(multiple = multiple of its weight) D-glucose Solvent
(multiple = multiple of its volume) Pace.
(°C) Duration
(h) A7
(%) 1 0.5 6.5-7.0 KRED 5x
GDH 0.2 multiple
NADP 0.1x 2.0 multiple Toluene 13 times
Buffer solution 30x 20-25 112 93.8 2 0.5 6.5-7.0 KRED 10x
GDH 0.2 multiple
NADP 0.1x 2.0 multiple Toluene 13 times
Buffer solution 30x 20-25 112 97.3 3 0.5 6.0-6.5 KRED 5x
GDH 0.2 multiple
NADP 0.1x 2.0 multiple Toluene 13 times
Buffer solution 30x 20-25 40 83.1 4 0.5 6.5-7.0 KRED 5x
GDH 0.2 multiple
NADP 0.1x 2.0 multiple Toluene 13 times
Buffer solution 30x 20-25 40 90.1 5 0.5 7.0-7.5 KRED 5x
GDH 0.2 multiple
NADP 0.1x 2.0 multiple Toluene 13 times
Buffer solution 30x 20-25 40 84.5

[0234] (example 3d)

Solvent amount testing was carried out under the reaction conditions shown in the table below. The compound represented by formula (A-6) was prepared in the same manner as in the methods (Examples 2a-2f). The buffer solution was prepared from K ₂ HPO ₄ ·3H ₂ O and KH ₂ PO ₄ in the same way as in example 3b.

[0235]

[Table 11]

No. Conditions Reaction stage IPC purity A-6
(g) pH Enzyme
(multiple = multiple of its weight) D-glucose Solvent
(multiple = multiple of its volume) Pace.
(°C) Duration
(h) A7
(%) 1 0.5 6.5-7.0 KRED 10x
GDH 0.2 multiple
NADP 0.1x 2.0 multiple Toluene 5 times
Buffer solution 30x 20-25 18 95.6 2 0.5 6.5-7.0 KRED 10x
GDH 0.2 multiple
NADP 0.1x 2.0 multiple Toluene 10 times
Buffer solution 30x 20-25 18 93.3

[0236] (example 3e)

The study of the amount of buffer solution, the amount of starting material and the amount of KRDE was carried out under the reaction conditions shown in the table below. The compound represented by formula (A-6) was prepared in the same manner as in the methods (Examples 2a-2f). The buffer solution was prepared from K ₂ HPO ₄ ·3H ₂ O and KH ₂ PO ₄ in the same way as in example 3b.

[0237]

[Table 12]

No. Conditions Reaction stage IPC purity A-6
(g) pH Enzyme
(multiple = multiple of its weight) D-glucose Solvent
(multiple = multiple of its volume) Pace.
(°C) Duration
(h) A7
(%) 1 5 6.5-7.0 KRED 10x
GDH 0.2 multiple
NADP 0.1x 2.0 multiple Toluene 5 times
Buffer solution 30x 20-25 4 67.0 23 95.5 87 95.3 2 0.5 6.5-7.0 KRED 5x
GDH 0.2 multiple
NADP 0.1x 2.0 multiple Toluene 5 times
Buffer solution 30x 20-25 16 84.7 26 93.2 46 95.7 72 95.9 3 0.5 6.5-7.0 KRED 10x
GDH 0.2 multiple
NADP 0.1x 2.0 multiple Toluene 5 times
Buffer solution 15x 20-25 18 89.0 28 94.2 48 96.2 74 95.8

[0238] (example 3f)

The enzymatic reaction was carried out for 23 hours with the pH of the reaction solution=6.0-7.0 and at a reaction temperature of 23°C (20°C-25°C), and then for 16 hours at 50°C-60°C , using the compound (10 g) of formula (A-6), obtained in the same way as in methods (examples 2a-2f), toluene (50 ml), buffer solution (300 ml, composition K ₂ HPO ₄ 3H ₂ O and KH ₂ PO ₄ was the same as in the above examples), KRED (100 g), D-glucose (20 g), NADP (0.25 g) and GDH (0.5 g), then the treatment was carried out as mentioned the above processing method, thereby obtaining the title compound (11.75 g) as a dark red oil.

[0239] (example 3g)

KRED (1.279 g), D-glucose (253 g), NADP (12.61 g) and GDH (25.26 g) were added to the buffer solution (3.780 ml) obtained by dissolving K ₂ HPO ₄ 3H ₂ O (108 .4 g) and KH ₂ PO ₄ (37.82 g) in water (3.780 ml) to obtain a mixed solution (MS-6-1), and then the mixed solution was stirred for 1 hour. The mixed solution obtained by dissolving the compound (126.05 g) of formula (A-6) obtained in the same way as in the methods (Examples 2a-2f) in toluene (630 ml) was added to the previously obtained mixed solution (MS-6 -1). The reaction solution was stirred at a reaction temperature of 23°C (20°C-25°C) for 26 hours, maintaining the pH of the reaction solution at pH=6.0-7.0. Tert-amyl alcohol (500 ml) and isoamyl alcohol (130 ml) were added to the reaction solution, and the mixed solution was stirred at a reaction temperature of 23°C (20°C-25°C) for 16 hours. Ethyl acetate (1300 ml) and celite (126 g) were added thereto, the temperature was raised to 60°C, and the mixture was stirred at the same temperature for 1 hour. After cooling to 20°C, filtration was carried out, and the aqueous layer and the organic layer were separated, and the aqueous layer was extracted with ethyl acetate (1300 ml), then the organic layer was combined with the previously obtained organic layer, and then washed with water (1300 ml) to obtain an organic layer (OP-6-1). In addition, ethyl acetate (1300 ml) was added to the filtered celite, and the mixture was stirred at 20°C-30°C for 10 hours and filtered to obtain an organic layer (OP-6-2), and again ethyl acetate (1,300 ml) was added to the filtered celite, and the mixture was stirred at 20°C-30°C 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) were combined to form an organic layer (OP-6A). Moreover, the reaction was carried out in the same way as in the method described above using the compound (113 g) of formula (A-6) obtained in the same way as in the methods (Examples 2a-2f), and thereby an organic layer ( OP-6B). The organic layer (OP-6A) and the organic layer (OP-6B) were combined and then concentrated, thereby obtaining the title compound (331 g) as a reddish-brown oil.

[0240] [Physical property data of the compound represented by formula (A-7)]

( ^1H NMR, 400 MHz, manufacturer: Bruker, CDCl ₃ , δ ppm)

7.51 (d, 1H, J=7 Hz), 7.05 (t, 1H, J=7 Hz), 6.80 (d, 1H, J=7 Hz), 6.19 (us s, 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 Hz, 16 Hz), 2.03-1.88 (1H, m), 1.78-1.63 (1H, m), 1.45 (9H, s)

[0241] The absolute configuration of the compound represented by formula (A-7) was determined by converting the compound represented by formula (A-7) into the compound represented by formula (B), then comparing its analytical data with that of the compound represented by formula (B), obtained separately by the method described in WO 2003/095420 and the like, and confirming whether the analytical data matches. In addition, whether the hydroxyl groups in the compound represented by formula (B) have the (R) configuration was determined by converting the compound represented by formula (B) into its hydrobromide and analyzing the hydrobromide by X-ray crystal structure (see (Example 5) and Figure 2 ).

[0242] (Example 4a) Preparation of (R)-8-amino-1,2,3,4-tetrahydronaphthalene-2-ol hydrochloride (formula B-HCl)

[0243]

[C99]

[0244] n-PrOH (2 g) was added to the reactor and stirred at -5°C to 5°C. Acetyl chloride (0.76 g) was added dropwise at the same temperature over 10 minutes. After raising the reaction temperature to 50°C-55°C, a solution of the compound (0.5 g) of formula (A-7) obtained in the same way as in methods (Example 3a-g) in n-PrOH (6 g ) was added to the mixture over 45 minutes. After stirring at a reaction temperature of 50°C-55°C for 45 minutes, the mixture was cooled so that the reaction temperature reached 20°C-30°C, and the mixture was stirred at 20°C-30°C for 16 hours. The resulting solid was filtered, washed with n-PrOH (5 ml×2x) and dried at 40°C-50°C for 6.5 hours to obtain the title compound (0.23 g).

[0245] (Example 4b) Preparation of (R)-8-amino-1,2,3,4-tetrahydronaphthalene-2-ol (Formula B)

[0246]

[C100]

[0247] n-PrOH (1.81 g) was added to the reactor and stirred at -5°C to 5°C. Acetyl chloride (2.35 g) was added dropwise at the same temperature over 10 minutes. After raising the reaction temperature to 33°C-37°C, a solution of the compound (4.25 g) of formula (A-7), obtained in the same way as in the methods (Example 3a-g), in n-PrOH (12, 75 g) was added to the mixture over 45 minutes. After stirring at a reaction temperature of 33°C-37°C for 49.5 hours, the mixture was stirred at a reaction temperature of 20°C-25°C for 19 hours. The generated solid was filtered, washed with i-PrOAc (10 ml×2x) and dried at 30°C-40°C for 4 hours to obtain the hydrochloride (2.04 g). After mixing the separately obtained hydrochloride (0.07 g) to obtain 2.11 g, the combined product was suspended in ethyl acetate (12 ml) and the pH of the aqueous layer was adjusted to 7-8 using aqueous sodium hydrogen carbonate solution. After separating the aqueous layer and the organic layer, the aqueous layer was extracted with ethyl acetate (12 ml×2×), and the organic layers were combined, washed with water (10 ml×2×), then concentrated under reduced pressure to obtain the title compound (1.34 G).

[0248] (Example 4c) Preparation of (R)-8-amino-1,2,3,4-tetrahydronaphthalene-2-ol (Formula B)

[0249] n-PrOH (138 g) was added to the reactor and stirred at -5°C to 5°C. Acetyl chloride (180.1 g) was added dropwise at the same temperature over 1 hour. After raising the reaction temperature to 33°C-37°C, a solution of the crude compound (331 g) of formula (A-7) obtained in the same manner as in methods (Example 3a-g) in n-PrOH (750 ml) added to the mixture over 45 minutes. After stirring at a reaction temperature of 33°C-37°C for 15 hours, the mixture was stirred at a reaction temperature of 50°C-55°C for 2 hours and 10 minutes. After the reaction temperature was adjusted to 33°C-37°C, a mixed solution prepared by adding HCl (gas) (26 g) to iso-PrOAc (192 g) was added to the mixture at 33°C-37°C for 30 minutes. The reaction temperature was raised to 50°C-55°C and the mixture was stirred for 1.5 hours. The resulting solid was filtered, washed with iso-PrOAc and dried under reduced pressure at 20°C-30°C for 36 hours to obtain the hydrochloride (158 g). Hydrochloride (158 g) was suspended in ethyl acetate (1,000 ml), and an aqueous solution of sodium hydrogen carbonate (76 g sodium hydrogen carbonate, 1000 ml water) was added to it over 30 minutes. After separating the aqueous layer and the organic layer, the aqueous layer was extracted with ethyl acetate (1,000 ml×2x), and the organic layers were combined, washed with water (1000 ml) and concentrated under reduced pressure to obtain the title compound (136 g).

[0250] [Physical property data of the compound represented by formula (B)]

( ¹ H-NMR, 400 MHz, manufacturer: Bruker, CDCl ₃ , δ ppm)

6.91 (1H, t, J=7 Hz), 6.52-6.46 (2H, m), 4.19-4.04 (2H, m), 3.51 (1H, br s), 2.93-2.65 (3H, m), 2.31 (1H, dd, J=7 Hz, 16 Hz), 2.02-1.89 (1H, m), 1.85-1.65 (1H, m)

[0251] (Example 5) Preparation of (R)-8-amino-1,2,3,4-tetrahydronaphthalene-2-ol hydrobromide (formula (B-HBr)):

[0252]

[C101]

[0253] Crude compound (99.9 g) (R)-8-amino-1,2,3,4-tetrahydronaphthalene-2-ol, prepared by the same method as in (Example 4b) or (Example 4c), was dissolved in ethyl acetate (1 L), and an aqueous solution of 48% hydrobromic acid (80 ml) was added to the mixture while cooling with ice water. The precipitated solid was collected by filtration and washed successively with isopropanol (300-400 ml) and ethyl acetate (500 ml). The resulting purified hydrobromide (123.9 g, 98.3% ee) was dissolved in hot water (250 ml) and activated carbon (20 g) was added to it. The activated carbon was filtered using Celite when it was hot and washed with water. The filtrate was concentrated under reduced pressure, and the resulting residue was recrystallized from water. The resulting crystals were collected by filtration and washed with isopropanol and ethyl acetate to give the title compound (34.2 g, 98.4% ee). The filtrate was collected, concentrated under reduced pressure, and recrystallized twice from water to give the title compound (29.1 g, 98.9% ee).

[0254] The optical purity of the hydrobromide of the compound represented by formula (B) was measured using an LC-10 HPLC system of Shimadzu Corporation under the following conditions.

[0255]

[Table 13]

Column CHIRALCEL OJ-H ID 4.6×250 mm (Daicel) Elution solvent n-hexane/ethanol/diethylamine=50/50/0.1 (v/v/v) Flow rate 0.5 ml/min Column temperature 20°C Measurement wavelength 254 nm Elution duration R shape - 11.2 minutes, S shape - 12.5 minutes

[0256] In addition, the X-ray crystal structure of one crystal of the resulting hydrobromide of the compound represented by formula (B), ((R)-8-amino-1,2,3,4-tetrahydronaphthalene-2-ol) was analyzed using AFC-7 Rigaku, and obtained the following results (see figure 2).

[0257]

[Table 14]

Crystal system Monoclinic Space group P21 (#4) Unit cell parameters a=7.7320 (19) Å, α=90.02 (3)°,
b=8.681 (3) Å, β=103.47°,
c=8.017 (2) Å, γ=90.00 (2)° volume 523.3 (3) Å3 Clarification method Full matrix least squares data/limitations/parameters 1549/1/121 Approximation accuracy at F2 1,430 finite R coefficients [I>2sigma(I)] R1=0.0590, wR2=0.1710 R coefficients (all data) R1=0.1033, wR2=0.2584 Absolute structural parameter -0.06 (5) Largest difference, peak and hole 0.296 and -0.384 e.Å-3

[0258] (Example 6) Preparation of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-[(7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]acetamide (formula (I)):

[0259]

[C102]

[0260] Triethylamine (0.27 ml, 1.0 eq.) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) (0 .80 g, 1.5 eq.) was added to a suspension of (R)-8-amino-1,2,3,4-tetrahydronaphthalene-2-ol hydrobromide (formula (B-HBr)) (0.47 g), prepared in (Example 5) and (E)-2-(7-(trifluoromethyl)chroman-4-ylidene)acetic acid (formula (CA-1)) (0.50 g, 1.0 eq.) prepared by the method preparation described in WO 2007/010383 in methanol (5.00 ml: approximately 10 times its volume relative to 1 g of the compound represented by the formula (B-HBr)), and the mixture was stirred at room temperature for 3 hours. After cooling the reaction solution on ice, the precipitated crystals were collected by filtration and washed with cold methanol. The resulting solid was dissolved in ethanol (6 ml) by heating, and then water (6 ml) was added while heating. After cooling the mixture, the precipitated solid was filtered, washed successively with 50% water-ethanol and water, and then dried under reduced pressure to obtain the title compound (0.56 g) as a solid residue.

[0261] [Physical property data of the compound represented by formula (I)]

( ^1H -NMR data ( _CDCl3 ) (δ: ppm)):

7.80-7.58 (m, 1H), 7.24-6.92 (m, 5H), 6.45 (s, 1H), 4.29 (t, 2H, J=6 Hz), 4 .28-4.15 (m, 1H), 3.51 (t, 2H, J=5 Hz), 3.10-2.78 (m, 3H), 2.69-2.53 (m, 1H ), 2.14-2.00 (m, 1H), 1.90-1.67 (m, 2H)

(LC-MS):

RT=4.73 (minutes), [M+H] ⁺ =404

Optical purity: 97.9%ee

[0262] The optical purity of the compound represented by formula (I) was determined using a Shimadzu Corporation LC-VP HPLC system under the following conditions.

[Table 15]

Column CHIRALCEL AD-H ID 4.6×250 mm (Daicel) Elution solvent Ethanol Flow rate 0.5 ml/min Column temperature 40°C Measurement wavelength 254 nm Elution duration The compound represented by formula (I) - 10.5 minutes,
Enantiomer of the compound represented by formula (I) - 18.6 minutes

[0263] The crystal structure of the compound represented by formula (I) was analyzed with SPring-8 beamline BL32B2 using R-AXIS V Rigaku detector (see Figure 3).

[0264]

[Table 16]

Crystal system Monoclinic Space group P21 (#4) Unit cell parameters a=16.344 Å, α=90°,
b=7.272 Å, β=113.80°,
c=19.088 Å, γ=90° volume 2075.6 Å3 Z 4 density (calculated) 1.291 mg/ ^m3 Clarification method Full matrix least squares date/restrictions/parameters 5861/1/581 Approximation accuracy at F2 1.123 finite R coefficients [I>2sigma(I)] R1=0.0590, wR2=0.1710 R coefficients (all data) R1=0.0653, wR2=0.1795 Largest difference, peak and hole 0.408 and -0.323 e.Å-3

[0265] (Example 7) Preparation of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-[(7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]acetamide : (Example (1) conditions for a condensation reaction)

[0266]

[C103]

[0267] <Example 1> Triethylamine (120 μL, 1.05 eq.) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) (339 mg, 1.5 eq.) was added to a suspension of (R)-8-amino-1,2,3,4-tetrahydronaphthalene-2-ol hydrobromide (200 mg) obtained in (Example 5), and (E )-2-(7-(trifluoromethyl)chroman-4-ylidene)acetic acid (212 mg, 1.0 eq.), prepared by the preparation method described in WO 2007/010383, in methanol (3.15 ml: 15. 75 times its volume relative to 1 g of the compound represented by the formula (B-HBr)), and the mixture was stirred at room temperature for 3 hours. Water was added thereto, and the precipitated solid was filtered, washed with water and dried, to obtain the title compound (291 mg) as a solid.

[0268] <Example 2> Triethylamine (240 µl, 2.1 eq.) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) (339 mg, 1.5 eq.) was added to a suspension of (R)-8-amino-1,2,3,4-tetrahydronaphthalene-2-ol hydrobromide (200 mg) obtained in (Example 5), and (E )-2-(7-(trifluoromethyl)chroman-4-ylidene)acetic acid (212 mg, 1.0 eq.) prepared by the preparation method described in WO 2007/010383 in methanol (3.15 ml: 15.75 a multiple of its volume relative to 1 g of the compound represented by the formula (B-HBr)), and the mixture was stirred at room temperature for 3 hours. Water was added thereto, and the precipitated solid was filtered, washed with water and dried, to obtain the title compound (273 mg) as a solid.

[0269] <Example 3> Triethylamine (120 µl, 1.05 eq.) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) (339 mg, 1.5 eq.) was added to the suspension of (R)-8-amino-1,2,3,4-tetrahydronaphthalene-2-ol hydrobromide (200 mg) obtained in (Example 5), and (E )-2-(7-(trifluoromethyl)chroman-4-ylidene)acetic acid (212 mg, 1.0 eq.), prepared by the preparation method described in WO 2007/010383 in methanol (1.60 ml: 8 times its volume relative to 1 g of the compound represented by the formula (B-HBr)), and the mixture was stirred at room temperature for 3 hours. Water was added thereto, and the precipitated solid was filtered, washed with water and dried, to obtain the title compound (298 mg) as a solid.

[0270] <Example 4> Triethylamine (120 µl, 1.05 eq.) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) (339 mg, 1.5 eq.) was added to a suspension of (R)-8-amino-1,2,3,4-tetrahydronaphthalene-2-ol hydrobromide (200 mg) obtained in (Example 5), and (E )-2-(7-(trifluoromethyl)chroman-4-ylidene)acetic acid (212 mg, 1.0 eq.), prepared by the preparation method described in WO 2007/010383, in methanol (3.15 ml: 15. 75 times its volume relative to 1 g of the compound represented by the formula (B-HBr)), and the mixture was stirred at boiling for 3 hours. After cooling the mixture, water was added thereto, and the precipitated solid was filtered, washed with water and dried to obtain the title compound (291 mg) as a solid.

[0271] In <Example 1> to <Example 4> (Example 7) described above, the generation of endo product of the compound represented by formula (I) ((R)-N-(7-hydroxy-5,6,7, 8-tetrahydronaphthalene-1-yl)-2-(7-(trifluoromethyl)-2H-chromen-4-yl)acetamide).

[0272] The chemical purity of the compound represented by formula (I) was measured using a Shimadzu Corporation LC-VP HPLC system under the following conditions.

[Table 17]

Column Develosil ODS-HG-5 ID 4.6×150 mm (NOMURA CHEMICAL CO., LTD.) Elution solvent Acetonitrile/water=50/50 (v/v) Flow rate 1.0 ml/min Column temperature 40°C Measurement wavelength 273 nm Elution duration Endo product of the compound represented by formula (I) - 5.9 minutes,
Compound represented by formula (I) - 9.1 minutes

[0273] (Example 8) Preparation of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-[(7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]acetamide : (Example (2) conditions for a condensation reaction)

[0274]

[C104]

[0275] <Example 1> 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) (257 mg, 1.5 eq.) was added to a suspension of (R)-8-amino-1,2,3,4-tetrahydronaphthalene-2-ol (101 mg) prepared in the same manner as in (Example 4b) or (Example 4c), and (E)-2 -(7-(trifluoromethyl)chroman-4-ylidene)acetic acid (200 mg, 1.25 eq.), prepared by the preparation described in WO 2007/010383, in isopropanol (3.0 ml: approximately 30 times its volume relative to 1 g of the compound represented by formula (B)), and the mixture was stirred at room temperature for 6 hours. (3 ml) was added thereto, and the precipitated solid was filtered, washed with water and dried, to obtain the title compound (209 mg) as a solid residue.

[0276] <Example 2> 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) (257 mg, 1.5 eq.) was added to a suspension of (R)-8-amino-1,2,3,4-tetrahydronaphthalene-2-ol (126 mg) prepared in the same manner as in (Example 4b) or (Example 4c), and (E)-2 -(7-(trifluoromethyl)chroman-4-ylidene)acetic acid (200 mg, 1.0 eq.), prepared by the preparation described in WO 2007/010383, in isopropanol (3.00 ml: approximately 24 times its volume relative to 1 g of formula (B)), and the mixture was stirred at room temperature for 6 hours. Water (3 ml) was added thereto, and the precipitated solid was filtered, washed with water and dried, to obtain the title compound (238 mg) as a solid.

[0277] <Example 3> 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) (257 mg, 1.5 eq.) was added to a suspension of (R)-8-amino-1,2,3,4-tetrahydronaphthalene-2-ol (152 mg) prepared in the same manner as in (Example 4b) or (Example 4c), and (E)-2 -(7-(trifluoromethyl)chroman-4-ylidene)acetic acid (200 mg, 0.83 eq.), prepared by the preparation method described in WO 2007/010383, in isopropanol (3.00 ml: approximately 20 times its volume relative to 1 g of the compound represented by formula (B)), and the mixture was stirred at room temperature for 6 hours. Water (3 ml) was added thereto, and the precipitated solid was filtered, washed with water and dried, to obtain the title compound (243 mg) as a solid.

[0278] <Example 4> 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) (257 mg, 1.5 eq.) was added to a suspension of (R)-8-amino-1,2,3,4-tetrahydronaphthalene-2-ol (177 mg) prepared in the same manner as in (Example 4b) or (Example 4c), and (E)-2 -(7-(trifluoromethyl)chroman-4-ylidene)acetic acid (200 mg, 0.71 eq.), prepared by the preparation method described in WO 2007/010383, in isopropanol (3.00 ml: approximately 20 times its volume relative to 1 g of the compound represented by formula (B)), and the mixture was stirred at room temperature for 6 hours. Water (3 ml) was added thereto, and the precipitated solid was filtered, washed with water and dried, to obtain the title compound (238 mg) as a solid.

[0279] (Example 9a) Preparation of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-[(7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl]acetamide :

After carrying out the condensation reaction (reaction conditions: 20°C-25°C, stirring for 22 hours), using (R)-8-amino-1,2,3,4-tetrahydronaphthalene-2-ol (1.04 g , purity 99.35%), prepared in the same manner as in (Example 4b) or (Example 4c), (E)-2-(7-(trifluoromethyl)chroman-4-ylidene)acetic acid (1.05 eq. .) obtained by the preparation method described in WO 2007/010383, isopropanol (25 times its volume relative to the compound represented by formula (B)), and 4-(4,6-dimethoxy-1,3,5-triazine-2 chloride -yl)-4-methylmorpholinium (DMT-MM) (1.3 eq.), work-up was carried out according to (Example 8), thereby obtaining the title compound (1.87 g) as a solid residue.

[0280] (Example 9b) Preparation of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-[(7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl]acetamide (scaling):

After carrying out the condensation reaction (reaction conditions: 20°C-25°C, stirring for 22 hours), using (R)-8-amino-1,2,3,4-tetrahydronaphthalene-2-ol (110 g), prepared in the same manner as in (Example 4b) or (Example 4c), (E)-2-(7-(trifluoromethyl)chroman-4-ylidene)acetic acid (173.9 g, 1.05 eq.), obtained by the preparation method described in WO 2007/010383, isopropanol (2,600 ml: 25 times its volume relative to the compound represented by formula (B)), and 4-(4,6-dimethoxy-1,3,5-triazine-2 chloride -yl)-4-methylmorpholinium (DMT-MM) (243.7 g, 1.3 eq.), work-up was carried out according to (Example 8), thereby obtaining the title compound (183.3 g) as a grayish -white solid residue.

[0281] The optical purity of the compound represented by formula (I) was measured using a Shimadzu Corporation LC-VP HPLC system under the following conditions.

[Table 18]

Column CHIRALCEL AD-H ID 4.6×250 mm (Daicel) Elution solvent Ethanol Flow rate 0.5 ml/min Column temperature 40°C Measurement wavelength 254 nm Elution duration The compound represented by formula (I) - 10.5 minutes,
Enantiomer of the compound represented by formula (I) - 18.6 minutes

[0282] Bruker AV 400 was used to obtain nuclear magnetic resonance (NMR) spectra of the compounds represented by formula (A8-BR) and formula (B).

High performance liquid chromatography (HPLC) of the compounds represented by formula (A8-BR) and formula (B) was carried out in the following manner.

[Table 19]

Measurement conditions for the compound represented by formula (A8-BR)

Measuring device Thermo U-3000 with UV detector or equivalent column Waters Xbridge C18 (4.6mm×150mm, 3.5µm) Measurement wavelength 220 nm Column temperature 35°C Flow rate 1.0 ml/min Injection volume 5 µl Sample concentration 0.5 mg/ml Duration of work 21 min Duration of data collection 21 min Thinning agent ACN:H ₂ O=50:50 (v/v) Mobile phase A 10 mM NH ₄ Ac in H ₂ 0 Mobile phase B ACN Gradient program Rebalancing duration: 21 minutes

[Table 20]

Retention time (RT)

Compound RT (min) Relative retention time (RRT) Formula (SM8-BR) 10.6 1.1 Formula (A8-BR) 9.7 1.0

[Table 21]

Measurement conditions for the compound represented by formula (B)

Measuring device Thermo U-3000 with UV detector or equivalent column ACE 3 C18 (150 mm×4.6 mm, 3 µm) Measurement wavelength 213 nm Column temperature 35 ^o C Flow rate 1.0 ml/min Injection volume 5 µl Sample concentration 0.12 mg/ml Duration of work 16 min Duration of data collection 16 min Thinning agent MeOH Mobile phase A 5 mm NH ₄ Ac in H2O Mobile phase B ACN Gradient program Rebalancing duration: 16 minutes

[Table 22]

Retention time (RT)

Compound RT (min) Relative retention time (RRT) Formula (B) 6.9 1.0 Formula (A8-BR) 9.7 1.4

[Table 23]

Chiral analysis method for the compound represented by formula (A8-BR)

Measuring device Shimadzu LC-20A HPLC with PDA detector or equivalent column Daicel Chiralpak IB (250 mm×4.6 mm, 5 µm) Measurement wavelength 273 nm Column temperature 35°C Flow rate 1.0 ml/min Injection volume 5 µl Sample concentration 0.6 mg/ml Duration of data collection 15 minutes Duration of work 15 minutes Thinning agent EtOH Mobile phase Hexanes: 0.1% ethanolamine in EtOH=95:5 (v/v) Isocratic program

[Table 24]

Retention time (RT)

Compound RT (min) Relative retention time (RRT) Formula (A8-BR) 7.9 1.00 Enantiomer formula (A8-BR) 7.0 0.89

[Table 25]

Chiral analysis method for the compound represented by formula (B)

Measuring device Agilent 1260 HPLC with UV detector or equivalent Column Daicel Chiralcel OJ-H (250×4.6 mm, 5.0 µm) Measurement wavelength 237 nm Column temperature 25°C Flow rate 0.5 ml/min Injection volume 5 µl Sample concentration 0.6 mg/ml Duration of data collection 11.0 min Duration of work 25 min Thinning agent EtOH Mobile phase n-Hexane:ethanol:DEA (50:50:0.1, v/v/v) Isocratic program

[Table 26]

Retention time (RT)

Compound RT (min) Relative retention time (RRT) Formula (B) 11.0 1.00 Enantiomer of formula (B) 12.1 1.10

[0283] (Example 10A)-(Example 10D) Preparation of (R)-8-bromo-1,2,3,4-tetrahydronaphthalene-2-ol (A8-BR)

[0284]

[C105]

[0285] (example 10A)

KRED (ketone reductase derived from Escherichia coli sp., 5 mg), D-glucose (200 mg), glucose dehydrogenase (GDH) (2 mg), nicotinamide adenine dinucleotide phosphate (NADP) (1 mg) and phosphate buffer solution (3 ml, prepared by adding 10.62 g KH ₂ PO ₄ and 21.25 g K ₂ HPO ₄ to 1000 ml water) were mixed in a flask equipped with an orbital shaker (manufactured by Shanghai Nanrong Laboratory Equipment Co., Ltd., model number: NRY-200) and stirred , obtaining a mixed solution. Then, a mixed solution prepared by dissolving 8-bromo-3,4-dihydronaphthalene-2(1H)-one (formula (SM8-BR)) (100 mg) in dimethyl sulfoxide (DMSO) (0.3 ml) was added to the pre the resulting mixed solution, and the mixture was stirred at a reaction temperature of 30°C for 20 hours (where a rotation speed of the orbital shaker was 250 rpm). A portion of the reaction solution was collected and subjected to HPLC analysis, and it was confirmed that the title compound was obtained with an IPC yield of 97.8% and an optical purity of 99.7%.

[0286] (example 10B)

KRED (ketone reductase derived from Escherichia coli sp., 0.25 g), D-glucose (10 g), glucose dehydrogenase (GDH) (0.1 g), nicotinamide adenine dinucleotide phosphate (NADP) (0.05 g) and buffer solution ( 1.55 g of KH ₂ PO ₄ and 4.06 g of K ₂ HPO ₄ ·3H ₂ O were added to 145 ml of water) were mixed in a reactor to obtain a mixed solution, and it was stirred at 20°C-25°C. Then, a mixed solution prepared by dissolving 8-bromo-3,4-dihydronaphthalene-2(1H)-one (formula (SM8-BR)) (5 g) in dimethyl sulfoxide (DMSO) (15 ml) was added dropwise to the pre the resulting mixed solution. After stirring at a reaction temperature of 20°C-25°C for 1 hour, the pH of the reaction solution was adjusted to the range of pH=6.5-7.0 using a 2M sodium carbonate aqueous solution. Then, after stirring at a reaction temperature of 20°C-25°C for 1 hour, the pH of the reaction solution was adjusted to the range of pH=6.5-7.0 using a 2M sodium carbonate aqueous solution. In addition, after stirring at a reaction temperature of 20°C-25°C for 1 hour, the pH of the reaction solution was adjusted to the range of pH=6.5-7.0 using a 2M sodium carbonate aqueous solution. Then, the reaction solution was stirred at a reaction temperature of 20°C-25°C for 16 hours (some of the reaction solution was collected and subjected to HPLC analysis, and the IPC yield of the title compound was confirmed to be 99.6%).

Methyl tert-butyl ether (MTBE) (50 ml) was added to the reaction solution, and diatomaceous earth (5 g) containing water (5 g) was further added thereto, then the mixed solution was stirred at a temperature of 50°C-60 °C for 30 minutes. The temperature of the mixed solution was lowered to 20°C-25°C, and the mixed solution was further stirred at the same temperature for 1 hour. The mixed solution described above was filtered, and the filtered material (wet filter cake) was washed with MTBE (5 ml) to obtain filtrate A. The wet filter cake described above was placed in a reactor, and MTBE (40 ml) was added thereto. then the mixture was stirred at 20°C-25°C for 2 hours. The suspension containing the wet filter cake was filtered, and the wet filter cake was washed with MTBE (5 ml) to obtain filtrate B. After mixing filtrate A and filtrate B and stirring the mixture at 20°C-30°C for 5 minutes, aqueous layer and the organic layer were separated, and the aqueous layer was extracted with MTBE (45 ml), then the organic layer was combined with the previously prepared organic layer, washed with water (30 ml) and concentrated to give the crude title compound (4.61 g). The resulting crude title compound was subjected to silica gel column chromatography (n-heptane:ethyl acetate=1:1) to obtain the title compound (4.15 g, optical purity 99.9%).

[0287] (example 10C)

KRED (ketone reductase derived from Escherichia coli sp., 0.83 g), D-glucose (33.28 g), glucose dehydrogenase (GDH) (0.33 g), nicotinamide adenine dinucleotide phosphate (NADP) (0.17 g) and buffer a solution (5.31 g of KH ₂ PO ₄ and 13.89 g of K ₂ HPO ₄ ·3H ₂ O were added to 499 ml of water) was mixed in a reactor to obtain a mixed solution, and it was stirred at 20°C-25°C. Then, a mixed solution prepared by dissolving 8-bromo-3,4-dihydronaphthalene-2(1H)-one (formula (SM8-BR)) (17.3 g) in dimethyl sulfoxide (DMSO) (50 ml) was added dropwise to the previously obtained mixed solution. After stirring at a reaction temperature of 20°C-25°C for 1 hour, the pH of the reaction solution was adjusted to the range of pH=6.5-7.0 using a 2M sodium carbonate aqueous solution. Then, after stirring at a reaction temperature of 20°C-25°C for 1 hour, the pH of the reaction solution was adjusted to the range of pH=6.5-7.0 using a 2M sodium carbonate aqueous solution. In addition, after stirring at a reaction temperature of 20°C-25°C for 1 hour, the pH of the reaction solution was adjusted to the range of pH=6.5-7.0 using a 2M sodium carbonate aqueous solution. Then, the mixture was stirred at a reaction temperature of 20°C-25°C for 16 hours. Some of the reaction solution was collected and subjected to HPLC analysis, and the IPC yield of the title compound was confirmed to be 97.4%. The same processing as in (Example 1B) was carried out to obtain the title compound (17.12 g, optical purity 99.9%).

[0288] (example 10D)

KRED (ketone reductase derived from Escherichia coli sp., 5.55 g), D-glucose (220 g), glucose dehydrogenase (GDH) (2.20 g), nicotinamide adenine dinucleotide phosphate (NADP) (1.12 g) and buffer solution ( 35.12 g of KH ₂ PO ₄ and 91.80 g of K ₂ HPO ₄ ·3H ₂ O were added to 3300 ml of water) were mixed in a reactor to obtain a mixed solution, and it was stirred at 20°C-25°C. Then, a mixed solution prepared by dissolving 8-bromo-3,4-dihydronaphthalene-2(1H)-one (formula (SM8-BR)) (110.31 g) in dimethyl sulfoxide (DMSO) (330 ml) was added dropwise to the previously obtained mixed solution. After stirring at a reaction temperature of 20°C-25°C for 1 hour, the pH of the reaction solution was adjusted to the range of pH=6.5-7.0 using a 2M sodium carbonate aqueous solution. Then, after stirring at a reaction temperature of 20°C-25°C for 1 hour, the pH of the reaction solution was adjusted to the range of pH=6.5-7.0 using a 2M sodium carbonate aqueous solution. In addition, after stirring at a reaction temperature of 20°C-25°C for 2 hours, the pH of the reaction solution was adjusted to the range of pH=6.5-7.0 using a 2M sodium carbonate aqueous solution. Then, the mixture was stirred at a reaction temperature of 20°C-25°C for 16 hours. A portion of the reaction solution was collected and subjected to HPLC analysis, and the IPC yield of the title compound was confirmed to be 97.4%.

MTBE (1.100 ml) was added to the reaction solution, and diatomaceous earth (110 g) containing water (110 g) was further added thereto, and the mixed solution was stirred at a temperature of 50°C-60°C for 30 minutes. The temperature of the mixed solution was lowered to 20°C-25°C, and the mixed solution was further stirred at the same temperature for 2 hours. The mixed solution described above was filtered, and the filtered material (wet filter cake) was washed with MTBE (110 ml) to obtain filtrate C. The wet filter cake described above was placed in a reactor, and MTBE (900 ml) was added thereto. then the mixture was stirred at 20°C-25°C for 12 hours. The suspension containing the wet filter cake was filtered, and the wet filter cake was washed with MTBE (110 ml) to obtain filtrate D. Filtrate C and filtrate D were mixed, and the aqueous layer and organic layer were separated, and the aqueous layer was extracted with MTBE (1000 ml) then the organic layer was combined with the previously prepared organic layer, washed with water (675 ml) and concentrated to give the crude title compound (108.03 g, optical purity 99.8%).

[0289] [Physical properties data of formula (A8)]

( ^1H NMR, 400 MHz, manufacturer: Bruker, DMSO-d ₆ , 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), 3.99-3.95 (m, 1H), 2.92-2.86 (m, 2H), 2.70-2.60 (m, 1H), 1.83-1 .75 (m, 1H), 1.65-1.55 (m, 1H))

[0290] KRED (ketone reductase derived from Escherichia coli sp.) used in (Example 10A)-(Example 10D) is an enzyme manufactured by EnzymeWorks, Inc. (Product Number: HQ-K-105).

[0291] The absolute configuration of the compound represented by formula (A8-BR) obtained in (Example 10A) to (Example 10D) was determined by converting formula (A8-BR) to formula (B), and then confirmed whether its analytical data was consistent with the analytical data data of the compound represented by formula (B), obtained separately by the method described in WO 2003/095420, and the like.

[0292] (Reference Example 1) Preparation of 8-bromo-1,2,3,4-tetrahydronaphthalene-2-ol (formula (A8-BR-Rac))

[C106]

8-Bromo-3,4-dihydronaphthalene-2(1H)-one (formula (SM8-BR)) (20.0 g) and methanol (200 ml) were added to the reactor, and NaBH ₄ (8.28 g) was added at the reactor temperature of 0°C-5°C, and the mixture was stirred at the same temperature for 1 hour (some of the reaction solution was collected and subjected to HPLC analysis, and the IPC yield was confirmed to be 98.5%). An aqueous solution of 10% sodium hydrogen carbonate (1.5 L) was added dropwise when the temperature of the reaction solution was 5°C or lower, and the mixed solution was stirred for 0.2 hours at a mixed solution temperature of 0°C-5°C. Ethyl acetate (1.5 L) was added, and the aqueous layer and the organic layer were separated, then the aqueous layer was extracted with ethyl acetate (1.5 L), and the organic layer was combined with the previously obtained organic layer, washed with an aqueous solution of 25 wt% sodium chloride (1.5 L). 5 L) and concentrated to give the crude title compound (21.53 g). The resulting crude title compound was subjected to silica gel column chromatography (n-heptane:ethyl acetate=1:1) to obtain the title compound (21.29 g). The resulting compound represented by the formula (A8-BR-Rac) was confirmed to be consistent with the physical property data known from the literature.

[0293] (Example 11A)-(Example 11G) Preparation of (R)-8-amino-1,2,3,4-tetrahydronaphthalene-2-ol (Formula (B))

[0294]

[C107]

(example 11A)

(R)-8-bromo-1,2,3,4-tetrahydronaphthalene-2-ol (formula (A8-BR)) (100 mg), prepared by enzymatic reaction in the same way as in the methods of Example 10A-Example 10D, Cu ₂ O (40 mg), N-methylpyrrolidone (NMP) (2 ml) and aqueous ammonia (3 ml) were mixed in a sealed reactor, and the sealed reactor was reacted at a temperature of 105°C-115°C for 20 hours . After diluting the mixture with water, the mixture was extracted with ethyl acetate, and the organic layer was washed with an aqueous solution of 25 wt% sodium chloride, dried with Na ₂ SO _4, filtered and concentrated to obtain the crude title compound (106 mg). Thin layer chromatography (n-heptane:ethyl acetate=1:1) was performed for separation, thereby obtaining the title compound (10 mg) (optical purity 96.8%).

[0295] (example 11B)

(R)-8-bromo-1,2,3,4-tetrahydronaphthalene-2-ol (formula (A8-BR)) (2.2 g) prepared by enzymatic reaction in the same way as in the methods of Example 10A-Example 10D, Cu ₂ O (700 mg), NMP (3.5 ml, 1.6 vol) and aqueous ammonia (5.5 ml) were mixed in a sealed reactor, and the reaction in the sealed reactor was carried out at a temperature of 105°C- 115°C for 37 hours (IPC yield was confirmed to be 83.75% after 16 hours, 88.91% after 21 hours and 93.12% after 37 hours). After diluting the mixture with water (17 ml) and ethyl acetate (11 ml), the mixture was filtered and the filtered material was washed with ethyl acetate (4 ml, 3 times), then the aqueous layer and the organic layer were separated. Then, the aqueous layer was extracted with ethyl acetate (11 ml, 5x), and the organic layer was combined with the previously prepared organic layer, washed with water (20 ml, 2x), aqueous 10% Na ₂ SO ₄ and concentrated to give the crude title compound (1.25 g, 61.27%, optical purity 95.6%).

[0296] (example 11C)

The reaction in a sealed reactor was carried out under the conditions shown in the table below, and the reaction solvent was checked.

[Table 27]

Example No. Reagent (eq.) Reaction conditions IPC (%)
@6.91 min A8-BR _{Cu2O NH3} ^. _H2O NMP Temp./Duration B 11C-1 1.90 g
(1.0 eq.) 0.60 g
(0.50 eq.) 4.8 ml
(2.5 rev) 1 ml
(0.5 rev) 105-115°C/13 h 63.97 105-115°C/37 h 82.32 11C-2 2.07 g
(1.0 eq.) 0.66 g
(0.51 eq.) 5.2 ml
(2.5 rev) 2 ml
(1 rev) 105-115°C/13 h 66.46 105-115°C/37 h 93.75 11C-3 1.90 g
(1.0 eq.) 0.60 g
(0.50 eq.) 4.8 ml
(2.5 rev) 2.9 ml
(1.5 rev) 105-115°C/13 h 70.34 105-115°C/37 h 93.10

[0297] Example 11C-2 yielded 0.74 g (50%) of (R)-8-amino-1,2,3,4-tetrahydronaphthalene-2-ol, and Example 11C-3 yielded 0.5 g (36.6%) (R)-8-amino-1,2,3,4-tetrahydronaphthalene-2-ol.

[0298] (example 11D)

The reaction in a sealed reactor was carried out under the conditions shown in the table below, and the amount of aqueous ammonia was checked.

[Table 28]

Example No. Reagent (eq.) Reaction conditions IPC (%)
@6.83 min (A8-BR-Rac) _{Cu2O NH3} ^. _H2O NMP Temp./Duration (B)-Rac 11D-1 3.00g 0.96 g
(0.51 eq.) 7.5 ml
(2.5 rev) 3 ml
(1 rev) 105-115°C/21 h 91.85 11D-2 3.00g 0.96 g
(0.51 eq.) 10.5 ml
(3.5 rev) 3 ml
(1 rev) 105-115°C/21 h 92.93

In the table, (B)-Rac denotes the racemic compound represented by formula (B).

[0299] (example 11E)

(R)-8-bromo-1,2,3,4-tetrahydronaphthalene-2-ol (formula (A8-BR)) (3.00 g) prepared by enzymatic reaction in the same way as in the methods of Example 10A-Example 10D, Cu ₂ O (0.96 g, 0.51 eq.), NMP (3 ml, 1 vol) and aqueous ammonia (10.5 ml, 3.5 vol) were mixed in a sealed reactor, and the reaction was sealed closed reactor was carried out at a temperature of 105°C-115°C for 21 hours (some of the reaction solution was collected and subjected to HPLC analysis, and the IPC yield was confirmed to be 92.93%). After cooling the reaction solution, an aqueous solution of 25 wt% sodium chloride (23 ml) and 2-methyltetrahydrofuran (2-MeTHF) (15 ml) were added to the reaction solution, and the mixed solution was filtered, then the filtered material was washed with 2-MeTHF (15 ml) . The aqueous layer and the organic layer were separated, and the aqueous layer was extracted with 2-MeTHF (15 ml, 4x), then the organic layer was combined with the previously prepared organic layer, washed with an aqueous solution of 10 wt% Na ₂ SO ₄ (15 ml), then decolorized with CUNO (trade name) (filter) for 1 hour. CUNO was washed with 2-MeTHF (15 ml) and the solvent was concentrated, then isopropyl acetate (6 ml) was added, and n-heptane (1.5 ml) was added dropwise at 30°C-40°C, and the mixture was stirred at that same temperature for 0.5 hours. In addition, n-heptane (10.5 ml) was added dropwise, and the mixture was stirred at 30°C-40°C for 0.5 hour. In addition, n-heptane (3.0 ml) was added dropwise, and the mixture was stirred at 30°C-40°C for 0.5 hour. In addition, n-heptane (3.0 ml) was added dropwise, and the mixture was stirred at 30°C-40°C for 0.5 hour. The mixed solution described above was cooled at 20°C for 30 minutes and stirred at a temperature of 15°C-25°C for 1 hour. The mixed solution was filtered and the filtered material was washed with n-heptane (3 ml) and dried to give the title compound (1.375 g, 60.1%).

[0300] (example 11F)

(R)-8-bromo-1,2,3,4-tetrahydronaphthalene-2-ol (formula (A8-BR)) (16.32 g, NMP solution, content 61.1%), obtained by enzymatic reaction of the same In a manner similar to those of Example 10A-Example 10D, Cu ₂ O (3.18 g, 0.51 eq.), NMP (5 mL, 0.5 vol) and aqueous ammonia (35 ml, 3.5 vol) were mixed in a sealed reactor, and the reaction in the sealed reactor was carried out at a temperature of 105°C-115°C for 40 hours (it was confirmed that the IPC yield in 40 hours was 90.16%). After cooling the reaction solution, an aqueous solution of 25 wt% sodium chloride (75 ml) and 2-MeTHF (50 ml) was added to the reaction solution, and the mixed solution was filtered using diatomite (diatomaceous earth) (20.00 g), then the filtered material (filter residue) was washed with 2-MeTHF (50 ml). The aqueous layer and the organic layer were separated, and the aqueous layer was extracted with 2-MeTHF (50 ml, 2x), then the organic layer was combined with the previously obtained organic layer, washed with an aqueous solution of 8 wt% Na ₂ SO ₄ (50 ml, 2x), and the organic layer (92.5% of the total amount) was collected, then an aqueous solution of 0.5 M hydrochloric acid (111 ml) was added dropwise at 5°C-15°C (in this case, pH=1.2). The aqueous layer and the organic layer were separated, and the aqueous layer was extracted with 2-MeTHF (30 ml). An aqueous solution of 10% sodium hydroxide (22 ml) was added to the aqueous layer, and the aqueous layer was extracted with 2-MeTHF (100 ml, 50 ml, 50 ml). After mixing with the previously obtained organic layer, the organic layer was concentrated at 40°C or lower, and n-heptane (80 ml) was added dropwise at 35°C-45°C, then the mixture was cooled to 5°C. Then, the mixture was stirred at 0°C-10°C for 24 hours and collected by filtration, and the filtered material was washed with n-heptane (10 ml) and dried to obtain the title compound (4.50 g, 67.8%, optical purity 99.9%).

[0301] (example 11G)

The reaction in a sealed reactor was carried out under the conditions shown in the table below.

[Table 29]

Example Reagent (eq.) Reaction conditions IPC (%)
@7.34 min (A8-BR) _{Cu2O NH3} ^. _H2O NMP Temp./Duration (B) 11G-1 72.44 g
(NMP solution, content 63.8%) 14.56 g
(0.50 eq.) 162 ml
(3.5 rev) 23 ml
(0.5 rev) 105-115°C/20 h 90.87 11G-2 78.39 g
(NMP solution, content 63.8%) 15.78 g
(0.50 eq.) 175 ml
(3.5 rev) 25 ml
(0.5 rev) 105-115°C/20 h 89.60

[0302] (Processing 11G-1)

After the reaction of Example 11G-1 was completed and the reaction solution was cooled, an aqueous solution of 25 wt% sodium chloride (345 ml) and 2-MeTHF (250 ml) was added to the reaction solution, and the mixed solution was filtered using diatomaceous earth, then the filtered material (residue filter) were washed with 2-MeTHF (230 ml). The aqueous layer and the organic layer were separated, and the aqueous layer was extracted with 2-MeTHF (230 ml, 2x), then the organic layer was combined with the previously obtained organic layer to obtain the organic phase (11G-1).

[0303] (Processing 11G-2)

After the reaction of Example 11G-2 was completed and the reaction solution was cooled, an aqueous solution of 25 wt% sodium chloride (375 ml) and 2-MeTHF (250 ml) was added to the reaction solution, and the mixed solution was filtered using diatomaceous earth, then the filtered material (residue filter) were washed with 2-MeTHF (250 ml). The aqueous layer and the organic layer were separated, and the aqueous layer was extracted with 2-MeTHF (250 ml, 2x), then the organic layer was combined with the previously obtained organic layer to obtain the organic phase (11G-2).

[0304] (Work up 11G-3)

After mixing the previously obtained organic phase (11G-1) and the organic phase (11G-2), the mixture was washed with an aqueous solution of 8 wt% Na ₂ SO ₄ (480 ml, 2 times), then an aqueous solution of 0.5 M hydrochloric acid was added dropwise acid (1.156 ml), and the pH was adjusted to 0.88. The aqueous layer and the organic layer were separated, and the aqueous layer was extracted with 2-MeTHF (290 ml). An aqueous solution of 10% sodium hydroxide (230 ml) was added to the aqueous layer, and the aqueous layer was extracted with 2-MeTHF (1000 mo, 500 mo, 500 mo, 3 times). After combining with the previously obtained organic layer, the organic layer was concentrated at 40°C or lower, and n-heptane (576 ml) was added dropwise at 35°C-45°C, and then the mixture was cooled to 0°C-10°C , stirred at the same temperature, collected by filtration, and the filtered material was washed with n-heptane (96 ml) and dried to give the title compound (53.55 g, 70.8%, optical purity 99.9%).

[0305] [Physical properties data of formula (B)]

( ¹ H-NMR, 400 MHz, manufacturer: Bruker, CDCl ₃ , δ ppm)

6.91 (1H, t, J=7 Hz), 6.52-6.46 (2H, m), 4.19-4.04 (2H, m), 3.51 (1H, uss), 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)

[0306] The aqueous ammonia used in (Example 11A)-(Example 11G) is 25%-28% aqueous ammonia.

[0307] (Example 12A)-(Example 12B) Preparation of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-[(7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalene- 1-yl]acetamide

[C108]

[0308] (example 12A)

The condensation reaction (reaction conditions: 20°C-25°C, stirring for 17 hours) was carried out using (R)-8-amino-1,2,3,4-tetrahydronaphthalene-2-ol (3 g) obtained in the same manner as in (Example 11G), (E)-2-(7-(trifluoromethyl)chroman-4-ylidene)acetic acid (4.83 g, 1.0 eq.) prepared by the preparation method described in WO 2007/010383, isopropanol (60.01 g: 20 times its weight relative to the compound represented by formula (B)), and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-chloride 4-methylmorpholinium (DMT-MM) (6.67 g, 1.3 eq.). After adding water (75 ml) to the reaction solution, the mixed solution was cooled to 10°C-15°C, stirred at the same temperature for 1 hour, filtered, and the filtered material was washed with water and dried at 36°C for 16 hours . 2-MeTHF (90 g) was added to the resulting filter material, and the mixture was stirred at 70°C-80°C for 0.5 hours, then the solution was concentrated under reduced pressure at 40°C or below until the volume of the solution was 6 ml. Then, after stirring the concentrated solution at 70°C-80°C for 1 hour, it was cooled to 0°C-5°C, and 60 g of n-heptane was added dropwise at the same temperature, then the mixture was further stirred at that same temperature for 30 minutes. The mixture was collected by filtration and the filtered material was washed with n-heptane (9 g) and dried to give the title compound (5.96 g, optical purity 99.9%).

[0309] (example 12B) [scaling]:

The condensation reaction (reaction conditions: 20°C-25°C, stirring for 13 hours) was carried out using (R)-8-amino-1,2,3,4-tetrahydronaphthalene-2-ol (44.5 g) prepared by the same method as in (Example 11G), (E)-2-(7-(trifluoromethyl)chroman-4-ylidene)acetic acid (72.5 g, 1.0 eq.) obtained by the preparation method, described in WO 2007/010383, isopropanol (900 g: 18 times its weight relative to the compound represented by formula (B)) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4 chloride -methylmorpholinium (DMT-MM) (100.05 g, 1.3 eq.). Workup was carried out as in (Example 12a) to give the title compound (95.7 g, 100% optical purity).

[0310] [Physical property data of the compound represented by formula (I)]

( ^1H -NMR data ( _CDCl3 ) (δ: ppm)):

7.80-7.58 (m, 1H), 7.24-6.92 (m, 5H), 6.45 (s, 1H), 4.29 (t, 2H, J=6 Hz), 4 .28-4.15 (m, 1H), 3.51 (t, 2H, J=5 Hz), 3.10-2.78 (m, 3H), 2.69-2.53 (m, 1H ), 2.14-2.00 (m, 1H), 1.90-1.67 (m, 2H)

(LC-MS):

RT=4.73 (minutes), [M+H] ⁺ =404

[0311] The optical purity of the compound represented by formula (I) was measured using a Shimadzu Corporation LC-VP HPLC system under the following conditions.

[Table 30]

Column CHIRALCEL AD-H ID 4.6×250 mm (Daicel) Elution solvent Ethanol Flow rate 0.5 ml/min Column temperature 40°C Measurement wavelength 254 nm Elution duration The connection represented by (I) is 10.5 minutes,
The enantiomer of the compound represented by (I) is 18.6 minutes

[Explanation of footnotes]

[0312] L1, L2, L3, L4: nitrogen inlet

M1: Container containing raw materials, TEMPO and dichloromethane

M2: Container containing KBr, NaHCO ₃ and water

M3: Container containing NaClO

P1, P2, P3: pump

T1, T2, T3: pre-cooling pipe

S1, S2, S3: stirrer

R1, R2, R3: reactor

CD: Retrieval tank

Claims (11)

A method for producing a compound represented by formula (I), the method comprising: carrying out a condensation reaction of the compound represented by Formula (B) or a salt thereof and the compound represented by Formula (CA-1), using DMT-MM as a condensing reagent, obtaining the compound represented by Formula (I) Formula (I): [C118] Formula (B): [C119] Formula (CA-1): [C120]