KR20080006001A - Method for producing indole derivative having piperidine ring - Google Patents

Abstract

It is possible to commercially advantageously produce 1-{1-[2-(7-methoxy-2,2-dimethyl-4-oxochroman-8-yl)ethyl] piperidin-4-yl}-N-methyl-1H-indole-6-carboxamide by coupling (7-methoxy-2,2-dimethyl-4-oxochroman-8-yl)acetaldehyde, which is obtained by oxidizing 8-(2-hydroxyethyl)-7-methoxy-2,2-dimethylchroman-4-one, with N-methyl-1-(piperidin-4-yl)-1H-indole-6-carboxamide.

Description

Method for producing indole derivatives having a piperidine ring {METHOD FOR PRODUCING INDOLE DERIVATIVE HAVING PIPERIDINE RING}

The present invention has 5-HT _1A antagonism and binding action and is useful as a prophylactic or therapeutic agent for lower urinary tract symptom, especially urinary storage symptom. -Methoxy-2,2-dimethyl-4-oxochroman-8-yl) ethyl] piperidin-4-yl} -N-methyl-1H-indole-6-carboxamide .

As one of the serotonin receptors, there is a 5-HT _1A receptor, and a compound having a 5-HT _1A antagonistic action or a binding action is expected to be used as a prophylactic or therapeutic agent for depression, anxiety, cognitive disorders, urination disorders and the like. In the prior art, various compounds having a piperidine ring have been reported as such compounds (Patent Document 1: WO 99/06384 Pamphlet, Patent Document 2: Japanese Patent Application Laid-Open No. 2002-114684, Patent Document 3: WO 98/43956). Issue pamphlet).

MEANS TO SOLVE THE PROBLEM The present inventors discovered the compound represented by the following general formula (I) as a novel piperidine ring containing indole derivative which has 5-HT _1A antagonism and binding effect, and has already applied for the patent (PCT / JP2005). / 008632 and US patent application Ser. No. 11/126209):

[In general formula (I),

R ¹ and R ² are substituents adjacent to each other, and two carbon atoms to which each of these substituents are bonded and these substituents may be integrated to be substituted with 1 to 4 substituents selected from the substituent group B1,

 (1) 5- to 7-membered non-aromatic hydrocarbon ring groups,

 (2) a 5 to 7 membered cyclic non-aromatic heterocyclic group,

 (3) 6-membered cyclic aromatic hydrocarbon ring group or

 (4) forming a 5 to 6 membered cyclic aromatic heterocyclic group,

 Here, substituent group B1 is (1) hydrogen atom, (2) halogen atom, (3) cyano group, (4) hydroxyl group, (5) nitro group, (6) oxo group, (7) carboxy group, (8) C3-8 cycloalkyl group, (9) C2-6 alkenyl group, (10) C2-6 alkynyl group, (11) C1-6 alkylthio group, (12) C1-6 alkoxycarbonyl group, (13) C1-6 alkyl Sulfonyl group, (14) C1-6 alkyl group (The C1-6 alkyl group may be substituted with halogen atom, hydroxyl group and C1-6 alkoxy group), (15) C1-6 alkoxy group (The C1-6 alkoxy group is 1 May be substituted with 3 to 3 halogen atoms), (16) an amino group (where the amino group is a substituent selected from the group consisting of C1-6 alkyl group, formyl group, C1-6 alkanoyl group and C1-6 alkylsulfonyl group) May be substituted), (17) carbamoyl groups (the carbamoyl groups may be substituted with one or two C1-6 alkyl groups), (18) C1-6 alkoxyimino groups, (19) identical carbon atoms Two C1-3 alkyl groups bonded to each other form A C5-6 cycloalkyl group to be formed, and (20) two C1-3 alkyl groups bonded to the same carbon atom are an oxygen atom and a tetrahydropyranyl group formed integrally with the carbon atom,

R ³ represents a hydrogen atom or a methyl group,

R ⁶ represents a substituent selected from substituent group A1,

 Here, substituent group A1 is a (1) hydrogen atom, (2) halogen atom, (3) cyano group, (4) hydroxyl group, (5) nitro group, (6) carboxy group, (7) C3-8 cycloalkyl group, (8) C2-6 alkenyl group, (9) C2-6 alkynyl group, (10) C1-6 alkylthio group, (11) C1-6 alkoxycarbonyl group, (12) C1-6 alkylsulfonyl group, (13) C1-6 alkyl group (The C1-6 alkyl group may be substituted with one to three substituents selected from the group consisting of a halogen atom, a hydroxyl group and C1-6 alkoxy), (14) C1-6 alkoxy group (above C1-6 alkoxy group may be substituted with 1 to 3 halogen atoms), (15) amino group (wherein the amino group is composed of C1-6 alkyl group, formyl group, C1-6 alkanoyl group and C1-6 alkylsulfonyl group) May be substituted with a substituent selected from the group) and (16) a carbamoyl group (wherein the carbamoyl group may be substituted with one or two C 1-6 alkyl groups).

The compound of general formula (I) exhibits 5-HT _1A antagonism and binding action and is useful as a prophylactic or therapeutic agent for lower urinary tract symptoms, especially urinary tract symptoms.

In particular, 1- {1- [2- (7-methoxy-2,2-dimethyl-4-oxochromen-8- which is a compound represented by the following formula (i) contained in the said General formula (I) Yl) ethyl] piperidin-4-yl} -N-methyl-1H-indole-6-carboxamide is expected to exhibit good action:

.

.

And an object of this invention is to provide the manufacturing method of compound (i) represented by said Formula (i), and its intermediate compound.

As a result of careful study, the present inventors found a method for producing compound (i) and completed the present invention.

That is, the present invention,

(1) 8- (2-hydroxyethyl) -7-methoxy-2,2-dimethylchroman-4-one represented by the following formula (a-6):

을 산화함으로써 얻어지는 하기 식 (a):

The following formula (a) obtained by oxidizing:

로 표시되는 (7-메톡시-2,2-디메틸-4-옥소크로만-8-일)아세트알데하이드와, 하기 식 (b):

(7-methoxy-2,2-dimethyl-4-oxochromen-8-yl) acetaldehyde represented by the following formula (b):

로 표시되는 N-메틸-1-(피페리딘-4-일)-1H-인돌-6-카르복사미드를 커플링하는 단계를 포함하는, 하기 식 (i):

Coupling N-methyl-1- (piperidin-4-yl) -1H-indole-6-carboxamide represented by the following formula (i):

로 표시되는 1-{1-[2-(7-메톡시-2,2-디메틸-4-옥소크로만-8-일)에틸]피페리딘-4-일}-N-메틸-1H-인돌-6-카르복사미드의 제조 방법,

1- {1- [2- (7-methoxy-2,2-dimethyl-4-oxochroman-8-yl) ethyl] piperidin-4-yl} -N-methyl-1H- represented by Process for preparing indole-6-carboxamide,

(2) In (1), formula (a-6):

으로 표시되는 8-(2-하이드록시에틸)-7-메톡시-2,2-디메틸크로만-4-온은, 하기 식 (a-5):

8- (2-hydroxyethyl) -7-methoxy-2,2-dimethylchroman-4-one represented by the following formula (a-5):

로 표시되는 화합물[식 (a-5)에서, X는 수산기의 보호기를 나타냄]의 보호기를 제거하여 얻어지는 것을 특징으로 하는 제조 방법,

In the compound represented by the following formula (a-5), X represents a protecting group of a hydroxyl group, which is obtained by removing a protecting group,

(3) In (1) or (2), formula (a-6):

으로 표시되는 8-(2-하이드록시에틸)-7-메톡시-2,2-디메틸크로만-4-온은, 하기 식 (a-4):

8- (2-hydroxyethyl) -7-methoxy-2,2-dimethylchroman-4-one represented by the following formula (a-4):

로 표시되는 화합물[식 (a-4)에서, X는 수산기의 보호기를 나타냄]과 메틸크로톤산을 반응시켜, 하기 식 (a-5):

In the compound represented by the formula (a (4), X represents a protecting group of a hydroxyl group) and methyl crotonic acid, the following formula (a-5):

로 표시되는 화합물[식 (a-5)에서, X는 위에서와 동일하게 정의됨]을 얻은 다음, 얻어진 화합물 (a-5)의 보호기를 제거함으로써 얻어지는 것을 특징으로 하는 제조 방법,

A process for producing a compound represented by the following formula (a-5), wherein X is defined in the same manner as above, and then removing the protecting group of the obtained compound (a-5).

(4) The formula (a-6) in any one of (1) to (3):

으로 표시되는 8-(2-하이드록시에틸)-7-메톡시-2,2-디메틸크로만-4-온은, 하기 식 (a-3):

8- (2-hydroxyethyl) -7-methoxy-2,2-dimethylchroman-4-one represented by the following formula (a-3):

으로 표시되는 화합물[식 (a-3)에서, X는 수산기의 보호기를 나타냄]과 산을 반응시켜, 하기 식 (a-4):

In the compound represented by the following formula (a-3), X represents a protecting group of a hydroxyl group, an acid is reacted with the following formula (a-4):

로 표시되는 화합물[식 (a-4)에서, X는 위에서와 동일하게 정의됨]을 얻은 다음, 얻어진 화합물 (a-4)와 메틸크로톤산을 반응시켜, 하기 식 (a-5):

To obtain a compound represented by the formula (a-4), X is the same as defined above, and then reacting the obtained compound (a-4) and methyl crotonic acid, the following formula (a-5):

로 표시되는 화합물[식 (a-5)에서, X는 위에서와 동일하게 정의됨]을 얻고, 얻어진 화합물 (a-5)의 보호기를 제거함으로써 얻어지는 것을 특징으로 하는 제조 방법,

A process for producing a compound represented by the formula (a-5), wherein X is defined in the same manner as above) and removing the protecting group of the obtained compound (a-5);

(5) The formula (a-6) in any one of (1) to (4):

으로 표시되는 8-(2-하이드록시에틸)-7-메톡시-2,2-디메틸크로만-4-온은, 하기 식 (a-2):

8- (2-hydroxyethyl) -7-methoxy-2,2-dimethylchroman-4-one represented by the following formula (a-2):

로 표시되는 2-[2-(1-에톡시에톡시)-6-메톡시페닐]에탄올의 수산기를 보호하여, 하기 식 (a-3):

Protecting the hydroxyl group of 2- [2- (1-ethoxyethoxy) -6-methoxyphenyl] ethanol represented by the following formula (a-3):

으로 표시되는 화합물[식 (a-3)에서, X는 수산기의 보호기를 나타냄]을 얻은 다음, 얻어진 화합물 (a-3)과 산을 반응시켜, 하기 식 (a-4):

After obtaining the compound represented by Formula (a-3), X represents a protecting group of a hydroxyl group, and then reacting the obtained compound (a-3) with an acid, the following formula (a-4):

로 표시되는 화합물[식 (a-4)에서, X는 위에서와 동일하게 정의됨]을 얻고, 얻어진 화합물 (a-4)와 메틸크로톤산을 반응시켜, 하기 식 (a-5):

To obtain a compound represented by the formula (a-4), X is the same as defined above, by reacting the obtained compound (a-4) and methyl crotonic acid, the following formula (a-5):

로 표시되는 화합물[식 (a-5)에서, X는 위에서와 동일하게 정의됨]을 얻은 후, 얻어진 화합물 (a-5)의 보호기를 제거함으로써 얻어지는 것을 특징으로 하는 제조 방법,

A process for producing a compound represented by the following formula (a-5), wherein X is defined in the same manner as above, and then removing the protecting group of the obtained compound (a-5).

(6) The formula (a-6) in any one of (1) to (5):

으로 표시되는 8-(2-하이드록시에틸)-7-메톡시-2,2-디메틸크로만-4-온은, 하기 식 (a-1):

8- (2-hydroxyethyl) -7-methoxy-2,2-dimethylchroman-4-one represented by the following formula (a-1):

로 표시되는 [2-(1-에톡시에톡시)-6-메톡시페닐]아세트산 에틸을 환원하여, 하기 식 (a-2):

Ethyl acetate of [2- (1-ethoxyethoxy) -6-methoxyphenyl] acetic acid is reduced to formula (a-2):

로 표시되는 2-[2-(1-에톡시에톡시)-6-메톡시페닐]에탄올을 얻고, 얻어진 화합물의 수산기를 보호하여, 하기 식 (a-3):

2- [2- (1-ethoxyethoxy) -6-methoxyphenyl] ethanol represented by the above was obtained, and the hydroxyl group of the obtained compound was protected to give the following formula (a-3):

으로 표시되는 화합물[식 (a-3)에서, X는 수산기의 보호기를 나타냄]을 얻은 다음, 얻어진 화합물 (a-3)과 산을 반응시켜, 하기 식 (a-4):

After obtaining the compound represented by Formula (a-3), X represents a protecting group of a hydroxyl group, and then reacting the obtained compound (a-3) with an acid, the following formula (a-4):

로 표시되는 화합물[식 (a-4)에서, X는 위에서와 동일하게 정의됨]을 얻고, 얻어진 화합물 (a-4)와 메틸크로톤산을 반응시켜, 하기 식 (a-5):

To obtain a compound represented by the formula (a-4), X is the same as defined above, by reacting the obtained compound (a-4) and methyl crotonic acid, the following formula (a-5):

로 표시되는 화합물[식 (a-5)에서, X는 위에서와 동일하게 정의됨]을 얻은 후, 얻어진 화합물 (a-5)의 보호기를 제거함으로써 얻어지는 것을 특징으로 하는 제조 방법,

A process for producing a compound represented by the following formula (a-5), wherein X is defined in the same manner as above, and then removing the protecting group of the obtained compound (a-5).

(7) The formula (a-6) in any one of (1) to (6):

으로 표시되는 8-(2-하이드록시에틸)-7-메톡시-2,2-디메틸크로만-4-온은, 하기 식:

8- (2-hydroxyethyl) -7-methoxy-2,2-dimethylchroman-4-one represented by the following formula:

1- (1-ethoxyethoxy) -3-methoxybenzene and ethyl bromoacetate are reacted with the following formula (a-1):

로 표시되는 [2-(1-에톡시에톡시)-6-메톡시페닐]아세트산 에틸을 얻고, 얻어진 화합물 (a-1)을 환원하여, 하기 식 (a-2):

[2- (1-Ethoxyethoxy) -6-methoxyphenyl] ethyl acetate represented by: was obtained, and the obtained compound (a-1) was reduced to give the following formula (a-2):

로 표시되는 2-[2-(1-에톡시에톡시)-6-메톡시페닐]에탄올을 얻고, 얻어진 화합물 (a-2)의 수산기를 보호하여, 하기 식 (a-3):

2- [2- (1-ethoxyethoxy) -6-methoxyphenyl] ethanol represented by the above was obtained, and the hydroxyl group of the obtained compound (a-2) was protected to give the following formula (a-3):

으로 표시되는 화합물[식 (a-3)에서, X는 수산기의 보호기를 나타냄]을 얻은 다음, 얻어진 화합물 (a-3)과 산을 반응시켜, 하기 식 (a-4):

After obtaining the compound represented by Formula (a-3), X represents a protecting group of a hydroxyl group, and then reacting the obtained compound (a-3) with an acid, the following formula (a-4):

로 표시되는 화합물[식 (a-4)에서, X는 위에서와 동일하게 정의됨]을 얻고, 얻어진 화합물 (a-4)와 메틸크로톤산을 반응시켜, 하기 식 (a-5):

To obtain a compound represented by the formula (a-4), X is the same as defined above, by reacting the obtained compound (a-4) and methyl crotonic acid, the following formula (a-5):

로 표시되는 화합물[식 (a-5)에서, X는 위에서와 동일하게 정의됨]을 얻은 후, 얻어진 화합물 (a-5)의 보호기를 제거함으로써 얻어지는 것을 특징으로 하는 제조 방법,

A process for producing a compound represented by the following formula (a-5), wherein X is defined in the same manner as above, and then removing the protecting group of the obtained compound (a-5).

(8) The production method according to any one of (2) to (7), wherein X is a benzoyl group,

(9) a compound represented by the following formula (II):

[In Formula (II), X ¹ represents a hydrogen atom or a protecting group of a hydroxyl group.],

(10) The compound according to (9), wherein the protecting group of the hydroxyl group is a benzoyl group,

(11) Benzoic acid 2- (7-methoxy-2,2-dimethyl-4-oxochromen-8-yl) ethyl or 8- (2-hydroxyethyl) -7-methoxy-2,2-dimethyl Croman-4-one,

(12) the following formula (c-3):

으로 표시되는 화합물과 메틸아민을 반응시키는 단계를 포함하는, 하기 식 (i):

Reaction of the compound and methylamine represented by the following formula (i):

로 표시되는 1-{1-[2-(7-메톡시-2,2-디메틸-4-옥소크로만-8-일)에틸]피페리딘-4-일}-N-메틸-1H-인돌-6-카르복사미드의 제조 방법,

1- {1- [2- (7-methoxy-2,2-dimethyl-4-oxochroman-8-yl) ethyl] piperidin-4-yl} -N-methyl-1H- represented by Process for preparing indole-6-carboxamide,

(13) In the formula (12), the formula (c-3):

으로 표시되는 화합물은, 하기 식 (c-2):

The compound represented by the following formula (c-2):

로 표시되는 화합물을 가수분해함으로써 얻어지는 것을 특징으로 하는 제조 방법,

It is obtained by hydrolyzing the compound represented by the manufacturing method,

(14) In the formula (12), the formula (c-3):

으로 표시되는 화합물은, 하기 식 (a):

The compound represented by the following formula (a):

로 표시되는 화합물과, 하기 식 (c-1):

The compound represented by following formula (c-1):

로 표시되는 화합물 또는 그의 염을 반응시켜, 하기 식 (c-2):

By reacting the compound or its salt represented by following formula (c-2):

로 표시되는 화합물을 얻은 다음, 얻어진 화합물을 가수분해함으로써 얻어지는 것을 특징으로 하는 제조 방법,

A method for producing the compound, which is obtained by hydrolyzing the obtained compound after obtaining the compound represented by

(15) In the formula (12), the formula (c-3):

으로 표시되는 화합물은, 하기 식 (a):

The compound represented by the following formula (a):

로 표시되는 화합물과, 하기 식 (b'-4):

The compound represented by following formula (b'-4):

로 표시되는 화합물[식 (b'-4)에서, Y는 2급 아민의 보호기를 나타냄]의 보호기를 제거해서 얻어지는 하기 식 (c-1):

The following formula (c-1) obtained by removing the protecting group of the compound represented by the formula [wherein Y represents a protecting group of a secondary amine] in the formula (b'-4):

로 표시되는 화합물 또는 그의 염을 반응시켜, 하기 식 (c-2):

By reacting the compound or its salt represented by following formula (c-2):

로 표시되는 화합물을 얻은 다음, 얻어진 화합물 (c-2)를 가수분해함으로써 얻어지는 것을 특징으로 하는 제조 방법,

Obtaining the compound represented by the following, The manufacturing method characterized by obtaining by hydrolyzing the obtained compound (c-2),

(16) The method according to (15), wherein Y is benzyloxycarbonyl.

(Effects of the Invention)

According to the invention, 1- {1- [2- (7-methoxy-2,2-dimethyl-4-oxochroman-8-yl) ethyl] piperidin-4-yl} -N-methyl- 1H-indole-6-carboxamide can be produced industrially advantageously. Furthermore, according to the present invention, it is possible to provide a production intermediate which is advantageously used for such production.

Best Mode for Carrying Out the Invention

Hereinafter, the manufacturing method of the compound represented by following formula (i) which concerns on this invention is demonstrated.

Process (1)

Step (1) is a step of coupling-reacting a compound represented by the following formula (a) and a compound represented by the following formula (b) to obtain a compound represented by the following formula (i):

The coupling reaction in step (1) may preferably be carried out under reductive amination reaction conditions, i.e. under the same conditions as are commonly used for reductive amination reactions of carbonyl and amine compounds. . Although the reduction reaction in this process is not specifically limited, For example, the reductive amination reaction by reducing agents, such as a borane and a borohydride complex compound, a catalytic reduction reaction in hydrogen atmosphere using a metal catalyst, etc. Can be mentioned.

Illustrative reductive amination reactions using the boron hydride complex compounds include WS Emerson, Organic Reactions, 4. 174 (1948), CF Lane, Synthesis, 135 (1975), JC Ctowell and SJ Pedegimas, Synthesis, 127 ( 1974) and AF Abdel-Magid, KG Carson, BD Harris, CA Marryanoff and RD Shah, Journal of Organic Chemistry, 61, 3849 (1996) and the like. Examples of the boron hydride complex compound used in the present step include sodium borohydride, sodium hydrogen borohydride, sodium triacetoxy borohydride and the like. When the boron hydride complex compound is used as the reducing agent, the solvent that can be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but specifically exemplifies methanol, ethanol and tetrahydrofuran. ), N, N-dimethylformamide, methylene chloride, 1,2-dichloroethane and the like.

The compound (b) is used in an amount of 0.8 to 2.5 equivalents, preferably 1 to 1.5 equivalents based on the compound (a). In this step, the boron hydride complex compound is used in an amount of 1 to 3 equivalents, preferably 1 to 1.5 equivalents based on the compound (a). Although the said reaction time is not specifically limited, Usually, it is 0.5 to 48 hours, Preferably it is 0.5 to 12 hours. Although the said reaction temperature is not specifically limited, Usually, it is -78 degreeC-reflux temperature of the said solvent, Preferably it is ice-cooling temperature-room temperature.

The solvent used in the case of using a catalytic reduction reaction under a hydrogen atmosphere is not particularly limited as long as it does not inhibit the reaction. Examples of the solvent that can be used include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like. Can be mentioned. Palladium, platinum oxide, Raney nickel, etc. are mentioned as a metal catalyst used for the said reaction. Although the said reaction time is not specifically limited, Usually, it is 1 to 48 hours, Preferably it is 1 to 24 hours. The reaction conditions are not particularly limited, but the reaction can be carried out at room temperature to the reflux temperature of the solvent, and conditions at normal pressure to 15 MPa, preferably at room temperature to 60 ° C, and at normal pressure to 0.5 MPa. .

The compound (a) is obtained through the following steps (A-1) to (A-6) and step (A).

Process (A-1)

Step (A-1) is a step of reacting 1- (1-ethoxyethoxy) -3-methoxybenzene with ethyl bromoacetate to obtain a compound represented by the formula (a-1).

This process can be carried out if necessary in the presence of a strong base such as n-butyllithium. The reaction solvent used in this step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Specific examples of the reaction solvent include tetrahydrofuran, heptane, hexane, toluene, 1 , 2-dimethoxyethane, diethyl ether, 1,2-dichloroethane and the like. The reaction temperature is usually -78 ° C to reflux temperature of the solvent, preferably -78 ° C to 0 ° C. Although the said reaction time is not specifically limited, Usually, it is 1 to 48 hours, Preferably it is 1 to 24 hours.

Process (A-2)

Step (A-2) is a step of reducing the compound represented by the formula (a-1) to obtain a compound represented by the formula (a-2).

The reduction reaction of the ester in the step (A-2) can be carried out under the conditions generally used in the reduction reaction described in, for example, the fourth edition of Experimental Chemistry Lecture 26 (pages 159 to 266), or the like. have. Examples of the reducing agent used in the reaction include lithium aluminum hydride, lithium borohydride, diisobutylaluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride and the like. The reaction solvent is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the above reaction. Specific examples of preferred reaction solvents for use include tetrahydrofuran, diethyl ether, dimethoxyethane, Ether solvents such as cyclopentylmethyl ether; Aromatic hydrocarbon solvents such as toluene and xylene; Or methylene chloride. Although the reaction temperature in this process is not specifically limited, Usually, it is -78 degreeC-reflux temperature of the said solvent, Preferably it is -78 degreeC-room temperature. The reducing agent is used in an amount of 1 to 3 equivalents, preferably 1 to 1.5 equivalents based on the compound (a-1).

Process (A-3)

(Wherein X represents a protecting group of a hydroxyl group).

Step (A-3) is a step of introducing a protecting group into the hydroxyl group of the compound represented by the formula (a-2) to obtain a compound represented by the formula (a-3).

As a protecting group of the hydroxyl group represented by X, the protecting group of well-known hydroxyl groups, such as an acetyl group or a benzoyl group, is mentioned, A benzoyl group is preferable. In the present step, for example, when protecting with a benzoyl group, benzoyl chloride is used in the presence of a base such as triethylamine, for example, an aromatic hydrocarbon solvent such as toluene, xylene, ester solvent such as ethyl acetate, dimeth The target object can be obtained by making it react with ether solvents, such as methoxyethane and cyclopentyl methyl ether. Benzoyl chloride can be used in the amount of 1 equivalent to excess based on the compound (a-2). In the present reaction, for example, when N, N, N ', N'-tetramethylethylenediamine, diisopropylethylamine, N, N-dimethylaniline and the like coexist, the yield is improved and the reaction time is shortened. The same preferable result may be obtained. The reaction temperature in the said process is 0-10 degreeC, Preferably it is 0 degreeC-room temperature. Although the reaction time in this process is not specifically limited, Usually, it is 0.5 to 48 hours, Preferably it is 0.5 to 4 hours.

Process (A-4)

Wherein X is defined the same as above.

Step (A-4) is a step of reacting the compound represented by the formula (a-3) with an acid to obtain a compound represented by the formula (a-4).

As the acid used in this step, any acid can be used as long as it is normally used, but it is preferable to use hydrochloric acid. The acid is used in the amount of 1 equivalent to large excess based on the compound (a-3). The reaction solvent used in this step is not particularly limited as long as it does not inhibit the above reaction and dissolves the starting material to some extent. Specific examples of the reaction solvent that can be used include toluene, dimethoxyethane, tetrahydrofuran, Water or a mixed solvent thereof; The reaction temperature in this process is 0-100 degreeC, Preferably it is 0 degreeC-room temperature. The reaction time is usually 0.5 to 48 hours, preferably 1 to 4 hours.

Process (A-5)

Wherein X is defined the same as above.

Step (A-5) is a step of reacting the compound represented by the formula (a-4) with methyl crotonic acid to obtain the compound represented by the formula (a-5).

This process is described, for example, in T. Timar et al., “Synthesis of 2,2-Dimethyl-4-Chroma nones”, J. Heterocyclic Chem., 37, 1389 (2000); J. C. Jaszberenyi et al., “On the Synthesis of Substituted 2,2-Dimethyl-4-Chromanones and Related Compounds”, Tetrahedron Letters, 33 (20), 2791-2794, 1992; The reaction can be carried out under conditions equivalent to those described in J. C. Jaszberenyi et al., Heterocycles, 38 (9), 2099, 1994, and the like. As another method, the compound (a-5) can be obtained by reacting the compound (a-4) and methyl crotonic acid in the presence of mesylic acid. In this step, the methyl crotonic acid is used in the amount of 1 equivalent to large excess based on the compound (a-4). In this reaction, if necessary, a dehydrating agent such as diphosphorus pentaoxide may be added. The reaction solvent used in the present step is not particularly limited as long as the starting material is dissolved to some extent without inhibiting the above reaction. Specific examples of the reaction solvent used include methanesulfonic acid. The reaction temperature in this process is room temperature to 100 degreeC, Preferably it is 40-60 degreeC. Although the said reaction time is not specifically limited, Usually, it is 0.5 to 48 hours, Preferably it is 1 to 4 hours.

Process (A-6)

Wherein X is defined the same as above.

Process (A-6) is a process of deprotecting the protecting group of the hydroxyl group of the compound represented by said formula (a-5), and obtaining a compound represented by said formula (a-6).

The reaction of this process is carried out under conditions generally used in the method of deprotecting the protecting group of an alcoholic hydroxyl group, for example, TW Greene, PGM Wuts, "Protective Groups in Organic Synthesis, Second Edition", John Wiley & Sons, Inc. It may be carried out under the same conditions as described in. For example, a target object can be obtained by making alcoholic hydroxyl group protected by the benzoyl group etc. react with sodium hydroxide water etc. in organic solvents, such as tetrahydrofuran, methanol, ethanol, or these mixed solvents, for example. Sodium hydroxide is used in the amount of 1 equivalent to large excess based on the compound (a-5). The reaction temperature in this process is 0-100 degreeC, Preferably it is room temperature-50 degreeC. Although reaction time is not specifically limited, Usually, it is 0.5 to 48 hours, Preferably it is 1 to 5 hours.

Process (A)

Step (A) is a step of oxidizing the compound represented by the formula (a-6) to obtain a compound represented by the formula (a).

According to methods known to those skilled in the art, aldehyde compounds can be obtained from alcohol compounds. Examples of known oxidation methods include Swern oxidation, Corey-Kim oxidation, Moffatt oxidation, PCC oxidation, PDC oxidation, Dess-Martin oxidation, SO ₃ -pyridine oxidation, TEMPO oxidation, and the like. The reaction solvent used in this step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Examples of the reaction solvent used include dimethyl sulfoxide, tetrahydrofuran, toluene and methylene chloride. , Chloroform, ethyl acetate, water or a mixed solvent thereof. The oxidizing agent is used in a catalytic amount to a large excess with respect to the compound (a-6). Although the reaction temperature in this process is not specifically limited, Usually, it is -78 degreeC-reflux temperature of the said solvent, Preferably it is -5 degreeC-room temperature. Although reaction time is not specifically limited, Usually, it is 1 to 10 hours, Preferably it is 1 to 5 hours. For example, in the case of TEMPO oxidation, it can be carried out according to the method described in the fourth edition of Experimental Chemistry Lecture 23 organic synthesis V oxidation reaction, Maruzen Co., Ltd. (p. 369 to 403). The reaction solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, dimethyl sulfoxide, tetrahydrofuran, toluene, methylene chloride, chloroform, ethyl acetate, water or these Mixed solvents; and the like. Further, in the presence of 2,2,6,6-tetramethylpiperidine oxide-sodium bromide, an oxidizing agent, for example, sodium hypochlorite in an aqueous sodium hydrogen carbonate solution, etc. Use more than equivalent. Although the said oxidation reaction temperature is not specifically limited, Usually, it is -20 degreeC-room temperature, Preferably it is -5 degreeC-room temperature. Although the said reaction time is not specifically limited, Usually, it is 1 to 10 hours, Preferably it is 1 to 5 hours.

For example, in the case of Swern oxidation, it can be carried out according to the method described in the fourth edition of Experimental Chemistry Lecture 23 organic synthesis V oxidation reaction, Maruzen Co., Ltd. (p. 298 to 346). In this case, the reaction solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, dimethyl sulfoxide, tetrahydrofuran, toluene, methylene chloride, chloroform, ethyl acetate, water Or a mixed solvent thereof. Examples of the oxidizing agent include oxalyl chloride, trifluoroacetic anhydride, acetic anhydride, cyclohexylimide, dioxide, or the like, as an activator of dimethyl sulfoxide, with respect to the compound (a-6). It is used in double molar amount or excess amount. Although the said reaction temperature is not specifically limited, Usually, they are -70 degreeC-room temperature. Although the said reaction time is not specifically limited, Usually, it is 3 to 10 hours, Preferably it is 3 to 5 hours. On the other hand, aldehyde compounds are described in D. P. Kjell et al., "A Nobel, Non aqueous Method for Regeneration of Aldehydes from Bisulfite Adducts". J. 0rganic. Chemistry. According to the method described in 64, 5722-5724 (1999), by converting to sodium bisulfite adduct, it can be purified simply and can be easily regenerated. The sodium hydrogen sulfite adduct can be obtained by reacting the aldehyde compound with an aqueous sodium hydrogen sulfite solution, for example, in an organic solvent such as ethanol, ethyl acetate, methanol, or a mixed solvent thereof. Sodium hydrogen sulfite used at this time is used in the amount of 1 equivalent to large excess with respect to the aldehyde compound. Although the said reaction temperature is not specifically limited, Usually, it is 10-40 degreeC, Preferably it is room temperature.

Although the said reaction time is not specifically limited, Usually, it is 1 to 48 hours, Preferably it is 12 to 24 hours.

The sodium hydrogen sulfite adduct thus obtained is treated with a base (aqueous solution) such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, or the like in an organic solvent such as ethanol, ethyl acetate, methanol, or a mixed solvent thereof. By this, an aldehyde compound can be obtained. At this time, the base is used in the amount of 1 equivalent to excess based on the sodium bisulfite adduct. Although the said reaction temperature is not specifically limited, Usually, it is 10-40 degreeC, Preferably it is room temperature.

Although the said reaction time is not specifically limited, Usually, it is 1 to 48 hours, Preferably it is 12 to 24 hours. The compound (a) can be used in the preparation of the compound (i), either purified or unpurified.

In addition, the compound (b) used at the said process (1) is obtained by the following process (B-1)-(B-6), for example.

Process (B-1)

Step (B-1) is a step of condensing 3-nitro-4-methylbenzoic acid and methylamine to obtain a compound represented by the formula (b-1).

The present reaction can be carried out under the same conditions as commonly used conditions described in the literature. Illustrating known methods, Rosowsky, A .; Forsch, R. A .; Moran, R. G .; Freisheim, J. H .; J. Med. Chem., 34 (1), 227-234 (1991), Brzostwska, M .; Brossi, A .; Flippen-Anders on, J. L .; Heterocycles, 32 (10), 1969-1972 (1991), Romero, D. L .; Morge, R. A .; Biles, C .; Berrios-Pena, N .; May, P. D .; Palmer, J. R .; Johnson, P. D .; Smith, H. W .; Busso, M .; Tan, C.-K .; Vorman, R. L .; Reusser, F .; ALthaus, I. W .; Downey, K. M; So, A. G .; Resnick, L .; Tarpley, W. G., Aristoff, P. A .; J. Med. Chem., 37 (7), 999-1014 (1994), etc. are mentioned.

Illustrative condensing agents usable in this process include CDI (N, N'-carbonyldiimidazole), Bop (1H-1,2,3-benzotriazol-1-yloxy (tri (dimethylamino)) Phosphonium hexafluorophosphate), WSC (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride), DCC (N, N-dicyclohexylcarbodiimide), diethylphosphoryl cyanide Etc. can be mentioned. In addition, if necessary, an organic base such as triethylamine, etc. may be added in an amount of 1 equivalent to excessive amount based on the 3-nitro-4-methylbenzoic acid. The reaction solvent used in this step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Specific examples thereof include tetrahydrofuran, 1,4-dioxane, ethyl acetate, and acetic acid. Methyl, dichloromethane, chloroform, N, N-dimethylformamide, toluene, xylene, etc. are mentioned. The reaction temperature varies depending on the raw materials, solvents, and the like used, and is not particularly limited, but is preferably ice temperature to reflux temperature of the solvent. Although reaction time is not specifically limited, Usually, it is 0.5 to 48 hours, Preferably it is 0.5 to 24 hours. The compound (b-1) obtained in this step can be purified in a conventional manner or used in subsequent steps without being purified.

Process (B-2)

Step (B-2) is a step of obtaining compound (b-2) by reacting the compound represented by the formula (b-1) with dimethylformaldehyde dimethylacetal.

This process is a synthesis method known to those skilled in the art, such as Coe, J. W .; Vetelino, M. G .; Bradlee, M. J .; The reaction can be carried out under the same conditions as described in Tetrahedron Lett., 37 (34), 6045-6048 (1996) and the like. The reaction solvent used in this step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, methanol, ethanol, tetrahydrofuran, N, N-dimethylformamide, and methylene chloride are used. , 1,2-dichloroethane and the like can be used. The reaction temperature is usually from room temperature to the reflux temperature of the solvent, preferably from room temperature to 100 캜. Although the said reaction time is not specifically limited, Usually, it is 1 to 72 hours, Preferably it is 1 to 48 hours. The compound (b-2) obtained in this step can be purified in a conventional manner or used in subsequent steps without being purified.

Process (B-3)

Step (B-3) is a step of obtaining the compound represented by the formula (b-3) by acetalizing the compound represented by the formula (b-2).

Acetalization in this process can be performed according to methods known to those skilled in the art, but are described, for example, in Coe, J. W .; Vetelino, M. G .; Bradlee, M. J .; And the conditions described in Tetrahedron Lett., 37 (34), 6045-6048 (1996), and the like. The acetylation reaction temperature is usually from room temperature to the reflux temperature of the solvent, preferably from room temperature to 100 캜. Although reaction time is not specifically limited, Usually, it is 1 to 72 hours, Preferably it is 1 to 48 hours. The compound of (b-3) obtained in this step can be purified according to a conventional method or used in subsequent steps without purification.

Process (B-4)

Step (B-4) is a step of reducing the compound represented by the formula (b-3) to obtain a compound represented by the formula (b-4).

The reduction reaction in this process can be carried out according to a known method, for example, a reduction reaction by catalytic hydrogenation using a noble metal catalyst such as Raney nickel, palladium, ruthenium, rhodium or platinum. Preferable examples in this case include a method of using palladium, palladium hydroxide or the like. As another example, the reduction reaction with iron in neutral conditions using ammonium chloride, etc. are mentioned. The solvent used in this step is not particularly limited as long as it does not inhibit the above reaction and dissolves the starting material to some extent, but is not particularly limited. For example, methanol, ethanol, tetrahydrofuran, N, N-dimethylformamide, methylene chloride, 1,2-dichloroethane and the like can be used. Although the reaction conditions in this process are not specifically limited, It is performed in the conditions of room temperature to the reflux temperature of the said solvent, and normal pressure-15 Mpa, Preferably it is performed in the conditions of room temperature-60 degreeC, and normal pressure-0.5 Mpa. . Although the said reaction time is not specifically limited, Usually, it is 1 to 48 hours, Preferably it is 1 to 24 hours. The compound of (b-4) obtained in this step can be purified according to a conventional method or used in subsequent steps without being purified.

Process (B-5)

(Wherein Y represents a protecting group of a secondary amine).

Step (B-5) is performed by reductive amination reaction between the compound represented by the formula (b-4) and the compound represented by the formula (b-4 '), followed by a ring-opening reaction, whereby It is a process of obtaining the compound represented by b-5).

As a protecting group of the secondary amine represented by Y, a well-known protecting group is mentioned, Specifically, a benzyloxycarbonyl group, tert- butyloxy carbonyl group, etc. are mentioned. The reductive amination reaction in the present process can be carried out under the same conditions as are commonly used, exemplifying such a reduction amination reaction, reductive amination reaction by a reducing agent such as borane, boron hydride complex compound, etc. And a catalytic reduction reaction in a hydrogen atmosphere using a metal catalyst. Examples of reductive amination reactions using the boron hydride complex compounds include WS Emerson, Organic Reactions, 4, 174 (1948), CF Lane, Syntheisis, 127 (1974), AF Abdel-Magid, KG Carson, BD Harris, The method described in the literature of CA Maryanoff and RD Shah, Journal of Organic Chemistry, 61, 3849 (1996) etc. is mentioned.

Examples of the boron hydride complex compound include sodium borohydride, sodium borohydride cyanide, sodium triacetoxy borohydride and the like. When the boron hydride complex compound is used as the reducing agent, the solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, methanol, ethanol, tetrahydrofuran, N, N -Dimethylformamide, methylene chloride, 1,2-dichloroethane and the like can be used. By carrying out this reaction in the presence of an acid, more preferable results, such as a yield improvement, can be obtained. The acid used in the reaction is not particularly limited, but examples thereof include mineral acids such as hydrochloric acid and organic acids such as acetic acid, such as zinc chloride and boron trifluoride diethyl ether complex, and titanium (IV) tetra. Lewis acids, such as isopropoxide, etc. are mentioned. The acid can also be used as a solvent.

The compound (b-4 ') is used in an amount of 0.8 to 2.5 equivalents, preferably 1 to 1.5 equivalents based on the compound (b-4). The boron hydride complex compound is used in an amount of 1 to 3 equivalents, preferably 1 to 1.5 equivalents based on the compound (b-4). The reaction temperature varies depending on the raw materials, solvents, and the like used, and is not particularly limited, but is usually -78 ° C to reflux temperature of the solvent, preferably ice temperature to room temperature. Although the said reaction time is not specifically limited, Usually, it is 0.5 to 48 hours, Preferably it is 0.5 to 12 hours.

The solvent used when using the catalytic reduction reaction under hydrogen atmosphere is not particularly limited as long as it does not inhibit the reaction. Examples thereof include methanol, ethanol, tetrahydrofuran, 1,4-dioxane and the like. Palladium, platinum oxide, Raney nickel, etc. are mentioned as a metal catalyst used for this reaction. The reaction conditions are not particularly limited, but may be carried out at room temperature to the reflux temperature of the solvent, and conditions of normal pressure to 15 MPa, preferably at a temperature of room temperature to 60 ° C., and normal pressure to 0.5 MPa. do. Although the said reaction time is not specifically limited, Usually, it is 1 to 48 hours, Preferably it is 1 to 24 hours.

The ring-opening reaction in this step is, for example, Coe, J. W .; Vetelino, M. G .; Bradlee, M. J .; Tetrahedron Lett., 37 (34), 6045-6048 (1996), Arai, E .; Tokuyama, H .; Linsell, M. S .; Fukuyama, T .; Tetrahedron Lett., 39 (1), 71-74 (1998), Tishler, A. N, Lanza, T. J .; Tetrahedron Lett., 27 (15), 1653 (1986), Sakamoto Takao, Kondo Yoshinori, Yamanaka Hiroshi, Chem. Pharm. Bull., Vol. 14, 2362 (1986) and the like can be carried out under the same conditions.

The reaction solvent used for the ring-opening reaction is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Specific examples thereof include water or water and methanol, ethanol and tetrahydro. In organic solvents, such as furan, 1, 4- dioxane, benzene, toluene, a suitable acid can be used in 1 equivalent-excess. Examples of the acid used in the reaction include acetic acid, hydrogen chloride, hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, p-toluenesulfonic acid pyridinium salt, camphorsulfonic acid ), And the like. Although the said reaction time is not specifically limited, Usually, it is 1 to 24 hours, Preferably it is 1 to 24 hours. The compound of (b-5) obtained in this step can be purified according to a conventional method or used in subsequent steps without purification.

Process (B-6)

(Wherein Y is defined the same as above).

Step (B-6) is a step of deprotecting the protecting group of the secondary amine of the compound represented by the formula (b-5) to obtain the compound represented by the formula (b).

The reaction of this process is carried out under conditions that are generally used to desorb the protecting groups of amino compounds, for example, TW Greene, PGM Wuts, "Protective Groups in Organic Chemistry, Second Edition", John Wiley & Sons (1991), It may be carried out under the same conditions as those described in 304 to 405. For example, when Y is protected by a benzyloxycarbonyl group, for example, compound (b) can be obtained by deprotection by hydrogenation using palladium-carbon as a catalyst in a solvent such as alcohol or tetrahydrofuran. have.

The compound (b) obtained in this step can be purified according to a conventional method or used in a subsequent step without purification.

The said compound (b) can be obtained also by the following process (B'-1)-a process (B'-6), and the said process (B-6) besides the manufacturing method mentioned above.

Process (B'-1)

Step (B'-1) is a step of obtaining compound (b'-1) by reacting 3-nitro-4-methylbenzoic acid with dimethylformaldehyde dimethylacetal. This step can be carried out under the same conditions as the above step (B-2).

Process (B'-2)

Step (B'-2) is a step of acetalizing compound (b'-1) to obtain compound (b'-2). This step can be carried out under the same conditions as the above step (B-3).

Process (B'-3)

Step (B'-3) is a step of obtaining compound (b'-3) by reducing compound (b'-2). This step can be carried out under the same conditions as the above step (B-4).

Process (B'-4)

Step (B'-4) is a step of obtaining compound (b'-4) by reacting compound (b'-3) with compound (b-4 '). The present step can be carried out under the same conditions as the above step (B-5).

Process (B'-5)

Step (B'-5) is a step of obtaining compound (b'-5) by hydrolyzing compound (b'-4).

This process is, for example, Mattasa. V. G .; Brown, F. J .; Bernstein, P. R .; Shapiro, H. S .; Maduskuie, T. P. J .; Cronk, L. A .; Vacek, E. P .; Yee, Y. K .; Snyder, D. W .; Krell, R. D .; Lerman, C. L .; Maloney, J. J .; J. Med. The reaction can be carried out under the same conditions as described in Chem., 33 (9), 2621-2629 (1990). Specifically, for example, a base (aqueous solution) such as sodium hydroxide is added to a solution of the compound (b'-4), stirred for several hours to 1 day, and then treated with an acid such as, for example, a tartaric acid solution. And compound (b'-5) can be obtained. The reaction solvent used in this step is not particularly limited as long as it does not inhibit the above reaction and dissolves the starting material to some extent. For example, methanol, ethanol, 2-propanol, tetrahydrofuran, 1,4-dioxane , Water and the like. Although it does not specifically limit as a base used for this process, For example, it is preferable to use sodium hydroxide, potassium hydroxide, lithium hydroxide, etc. The usage-amount of the said base is 1 equivalent-excess quantity with respect to the said compound (b'-4), Preferably it is 1-20 equivalent. Although the reaction time in this process is not specifically limited, Usually, it is 1 to 24 hours, Preferably it is 1 to 6 hours. The reaction temperature varies depending on the raw materials to be used, the solvent, and the like, and is not particularly limited, but is usually -78 ° C to the reflux temperature of the solvent, preferably ice temperature to room temperature.

The compound of (b'-5) obtained in this step may be purified by a conventional method or used in a subsequent step without purification.

Process (B'-6)

Step (B'-6) is a step of obtaining a compound (b-5) by condensing the compound (b'-5) and methylamine. This step can be carried out under the same conditions as in step (B-1).

In addition, the said compound (i) can also be obtained by following process (C-1)-(C-4).

Process (C-1)

Step (C-1) is to deprotect the protecting group of the secondary amine of the compound represented by the formula (b'-4), wherein in the formula (b'-4), Y represents a protecting group of secondary min. It is a process of obtaining the compound or its salt represented by said formula (c-1). Salts of the compounds are known pharmacologically acceptable salts, preferably hydrochloride salts.

The present step can be carried out under the same conditions as the above step (B-6).

Process (C-2)

Step (C-2) is a step of coupling the compound represented by the formula (c-1) and the compound represented by the formula (a) to obtain a compound represented by the formula (c-2).

This step can be carried out under the same conditions as in step (1).

Process (C-3)

Step (C-3) is a step of obtaining a compound represented by the formula (c-3) by hydrolyzing the compound represented by the formula (c-2).

This process can be carried out under the same conditions as the above process (B'-5).

Process (C-4)

Step (C-4) is a step of condensing the compound represented by the formula (c-3) and methylamine to obtain a compound represented by the formula (i).

This step can be carried out under the same conditions as in step (B-1).

Hereinafter, although an Example is given and this invention is demonstrated concretely, this invention is not limited to a following example. In this specification, "room temperature" means the temperature of the range of 20-30 degreeC, Preferably 25 degreeC.

(Manufacture example 1)

Synthesis of 4- (2-dimethylamino) vinyl-3-nitrobenzoate methyl

Under a nitrogen atmosphere, 570.0 g (3.15 mol) of 4-methyl-3-nitrobenzoic acid and 3420 mL of dimethylformamide (hereinafter referred to as "DMF") were added to a 10 L four-neck flask and stirred. Then, 1334 mL (1197 g, 9.44 mol) of N, N-dimethylformamide dimethylacetal was added to the reaction mixture in three portions. The reaction solution was stirred at room temperature for about 1 hour, and then the reaction vessel was heated in an oil bath (83 ° C.). After about 15 hours, the progress of the reaction was confirmed by HPLC, and then heating was stopped, and the vessel was cooled to an internal temperature of 28 ° C. in an ice-water bath.

9120 mL of water was added to a 15 L four-necked flask, and the flask was cooled and stirred on an ice bath to prepare cold water. The reaction solution was poured into the cold water for 6 minutes. The remaining reaction solution was washed with 100 mL of DMF, then removed, and the ice water bath was removed and stirred at room temperature for 76 minutes. The precipitated solid was collected by filtration, and the remaining solid was removed by washing with 1.5 L of water, and then the solid was washed with 1.5 L of water again. The crude crystal thus obtained was introduced into a 20 L stainless steel vessel, 6840 mL of methanol was added, and the reaction solution was stirred at room temperature for 65 minutes with a mechanical stirrer. The crystals were collected by filtration and then washed with 1140 mL of methanol. The washed crystals were dried at 40 ° C. under reduced pressure to obtain 668.7 g of the title compound as a red solid.

Yield 84.9%

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.99 (s, 6H), 3.90 (s, 3H), 5.92 (d, J = 13.3 Hz, 1H), 7.16 (d, J = 13.3 Hz, 1H), 7.47 (d, J = 8.6 Hz, 1H), 7.90 (dd, J = 8.6, 1.8 Hz, 1H), 8.49 (d, J = 1.8 Hz, 1H).

(Manufacture example 2)

Synthesis of 4- (2,2-dimethoxyethyl) -3-nitrobenzoate methyl

Under a nitrogen atmosphere, 522 g (2.09 mol) of methyl 4- (2-dimethylamino) vinyl-3-nitrobenzoate were added to a 10 L four-necked flask, followed by addition of 350O mL of methanol. Then, sulfuric acid / methanol mixture (concentrated sulfuric acid: 266 g, methanol: 676 mL) was added to the obtained solution at room temperature for 13 minutes. The reaction vessel was heated in a 55 ° C oil bath, and after the internal temperature exceeded 40 ° C, the reaction solution was heated and stirred, and then the reaction vessel was cooled in an ice bath. After 193.5 mL of triethylamine was added to the reaction solution, the obtained solution was concentrated under reduced pressure, and 600O mL of toluene and 2620 mL of water were added to the concentrated residue. The reaction solution was filtered by passing through a Hyflo Super-Cel equipped with a Buchner funnel, and then the Buchner funnel was washed with 525 mL of toluene to remove insoluble matters. The filtrate was transferred to a 20 L separator and the aqueous layer was separated and discarded. The organic layer was washed with 1305 mL of water, and then concentrated under reduced pressure (bath temperature of 40 ° C) to give 625.7 g of a brown oily substance containing the title compound.

¹ H-NMR (CDCl ₃ ) δ (ppm): 3.28 (d, J = 5.3 Hz, 2H), 3.45 (s, 6H), 3.96 (s, 3H), 4.57 (t, J = 5.3 Hz, 1H) , 7.51 (d, J = 8.1 Hz, 1H), 8.16 (dd, J = 8.1, 1.8 Hz, 1H), 8.53 (d, J = 1.8 Hz, 1H).

( Production Example  3)

3-amino-4- (2,2- Dimethoxyethyl Benzoic acid Methyl  synthesis

In a 7 L autoclave, 4- (2,2-dimethoxyethyl) -3-nitrobenzoate (assuming 100% yield of the previous process: 562 g, 2.09 mol) Washed with 300OmL of methanol. To this solution was added 56.2 g (10% (50% hydrous)) of palladium-carbon, followed by the addition of 2055 mL of methanol. The cold water was circulated through the jacket of the reactor and the hydrogen pressure was 0.1-0.3 MPa. The reaction was initiated under controlled control (at 14 to 23 ° C. internal temperature), and the reaction solution was stirred for 2.5 hours, after which the reaction solution was removed from the reactor and washed with 320 mL of methanol. The catalyst was filtered off, and the catalyst was washed with 1080 mL of methanol, and the filtrate was concentrated (bath temperature 40 ° C.) to precipitate the crystallized title compound. 265 mL) was added, heated to 40 ° C. to dissolve, and then concentrated to obtain a brown oily substance containing the title compound.

Yield: 572.4 g

¹ H-NMR (CDCl ₃ ) δ (ppm): 2.91 (d, J = 5.3 Hz, 2H), 3.38 (s, 6H), 3.88 (s, 3H), 4.17 (br, 2H), 4.50 (t, J = 5.3 Hz, 1H), 7.11 (d, J = 7.6 Hz, 1H), 7.3-7.45 (m, 2H).

( Production Example  4)

1- (1- Benzyloxycarbonylpiperidine -4-yl) -1H-indole-6-carboxylic acid Methyl  synthesis

Under a nitrogen atmosphere, 475 g (1.99 mol) of methyl 3-amino-4- (2,2-dimethoxyethyl) benzoic acid were added to a 15 L four-necked round bottom flask, followed by washing with 300 mL of acetic acid. . While stirring the solution obtained, 695 g (2.98 mol) of benzyl 4-oxo-1-piperidine carboxylic acid was added to the solution, followed by washing with 80 mL of acetic acid. Then, the reaction solution was stirred at room temperature for 1 hour and then cooled on an ice water bath. 631.1 g (2.98 mol) of sodium triacetoxy borohydride was added to the cooled reaction solution while maintaining the internal temperature at 15 ° C. or lower, and then divided into 8 portions, and the ice water bath was changed to a water bath. Stir for 3 hours. The stirred reaction solution was cooled again in an ice water bath, and then 380 mL of water was added thereto. The reaction solution was heated in an oil bath previously heated to 100 ° C., and then heating was stopped 6 hours after the internal temperature reached 80 ° C.

The reaction solution was transferred to a 20 L separator, 5938 mL of toluene and 2969 mL of water were added, stirred, and the aqueous layer was discarded. The organic layer was washed with 4453 mL and 2969 mL of 0.5N aqueous sodium hydroxide solution, twice with 2969 mL of 5% brine and then with 2969 mL of water.

The organic layer was concentrated (bath temperature 40 ° C.) to give 1025.1 g of a brown oily substance containing the title compound.

1017 mL of methanol was added to 1017.1 g of this oily substance to dissolve it, and 80 mg of seed crystals of the title compound were added at room temperature. After the solution was stirred for about 17 hours, the crystals were collected by filtration and washed with 50OmL of methanol. The washed crystals were concentrated under reduced pressure at 40 ° C. for about 2.5 hours to give 622.2 g of the title compound as pale yellow crystals.

Yield: 79.3%

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.80-2.05 (m, 2H), 2.05-2.23 (m, 2H), 2.92-3.15 (m, 2H), 3.96 (s, 3H), 4.30-4.60 (m, 3H), 5.18 (s, 2H), 6.58 (dd, J = 0.4, 2.8 Hz, 1H), 7.30-7.45 (m, 6H), 7.64 (dd, J = 0.4, 8.4 Hz, 1H), 7.80 (dd, J = 1.6, 8.4 Hz, 1H), 8.14 (s, 1H).

( Production Example  5)

1- (1- Benzyloxycarbonylpiperidine Synthesis of -4-yl) -1H-indole-6-carboxylic acid

In a 20 L four-necked round bottom flask, 617.0 g (1.57 mol) of 1- (1-benzyloxycarbonylpiperidin-4-yl) -1H-indole-6-carboxylic acid, 2036 mL of DME, and dimethyl sulfide 4072 mL of the slide side was added sequentially, and the obtained material was stirred while cooling in an ice water bath. When the internal temperature reached 10 ° C, 864.7 g (1.10 molar equivalents; 74.4 g of sodium hydroxide dissolved in 790 mL of tap water) of 8% aqueous sodium hydroxide solution was added dropwise to the solution for 7 minutes. After completion of the dropwise addition, the ice water bath was replaced with a water bath (24.5 ° C to 22.3 ° C), and the reaction solution was continuously stirred for 4 hours and 10 minutes in an internal temperature range of 20 ° C to 22 ° C.

Then, the reaction solution was divided equally into two parts (3.62 L × 2), and each was worked up in the same manner. 3.62 L of the reaction solution was cooled in an ice water bath, 2314 mL of tap water was added for 17 minutes, and then 1543 mL of ethyl acetate was added. When internal temperature became 10 degrees C or less, 420 mL of 2N hydrochloric acid was added to the said reaction liquid, and the pH of the aqueous layer was adjusted to 7. The solution was transferred to a 20 L separator, and then 2314 mL of tap water and 1543 mL of ethyl acetate were added and the aqueous layer was discarded.

The organic layer treated by dividing was collected, washed sequentially with 3085 g of 5% saline and 3085 mL of tap water. When the organic layer was concentrated under reduced pressure, since crystals precipitated, the concentration was stopped, 200 mL of tetrahydrofuran was added to form a solution, and the yield was calculated by quantifying the solution by HPLC. The organic layer was concentrated under reduced pressure, and then subjected to two azeotropic operations under reduced pressure using 2468 mL of toluene (total amount used for two azeotropic operations) to obtain 1333.6 g of a mixture of an off-white solid and a liquid.

Marked compound content: 566.1 g, yield: 95.2%

¹ H-NMR (CDCCl ₃ ) δ (ppm): 1.80-2.04 (m, 2H), 2.06-2.21 (m, 2H), 2.94-3.16 (m, 2H), 4.30-4.58 (m, 3H), 5.19 (s, 2H), 6.60 (dd, J = 0.8, 3.6 Hz, 1H), 7.30-7.44 (m, 6H), 7.68 (dd, J = 0.8, 8.4 Hz, 1H), 7.88 (dd, J = 1.6 , 8.4 Hz, 1H), 8.22 (s, 1H).

(Manufacture example 6)

Synthesis of 1- (1-benzyloxycarbonylpiperidin-4-yl) -N-methyl-1H-indole-6-carboxamide

1333.6 g of 1- (1-benzyloxycarbonylpiperidin-4-yl) -1H-indole-6-carboxylic acid (content: 566.1 g, 1.50 mmol) in a 15 L four-neck round bottom flask under nitrogen stream 5950 mL of tetrahydrofuran was added thereto, followed by stirring at room temperature. 339.5 g of N, N'-carbonyldiimidazole (hereinafter referred to as "CDI") was added to the obtained solution, and about 1 hour, 17.4 g of CDI was further added. After about 1 hour, the reaction solution was cooled in an ice water bath, 407 mL of a 40% aqueous methylamine solution was added dropwise for 12 minutes when the internal temperature became 10 ° C or lower, and the reaction solution was stirred at the same temperature for about 1.5 hours. It was.

Then, the reaction solution was divided equally into two parts (organic layer = 3740 mL × 2, aqueous layer = 92 mL × 2), and each was worked up in the same manner. One reaction solution (organic layer = 3740 mL, aqueous layer = 92 mL) was transferred to a 20 L separator, and then 5950 mL of ethyl acetate and 2975 mL of tap water were added sequentially, followed by separating. 540 mL of 2N hydrochloric acid was added to the organic layer, the pH of the aqueous layer was adjusted to 3, and the solution was separated. The organic layer was washed sequentially with 2975 g of 10% saline, 2975 g of 5% saline and 1488 mL of tap water.

The organic layer treated by dividing into 2 was collected, and the amount of the title compound in 14921.6 g of the organic layer was quantified.

HPLC quantitation content: 561.2 g, yield: 95.9%

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.93 (brs, 2H), 2.04-2.18 (m, 2H), 3.02 (brs, 2H), 4.26-4.60 (m, 3H), 5.18 (s, 2H ), 6.58 (dd, J = 0.8, 3.2 Hz, 1H), 7.28-7.44 (m, 7H), 7.65 (dd, J = 0.4, 8.4 Hz, 1H), 8.10 (s, 1H).

1270 mL of toluene was added to 12774.0 g of the organic layer, followed by concentration under reduced pressure (bath temperature of 40 ° C.), and 1270 mL of toluene was further added to the obtained concentrate, followed by concentration, to give 986.5 g of a tan oily substance. The obtained material was used in Preparation Example 7 below.

(Manufacture example 7)

Synthesis of N-methyl-1- (piperidin-4-yl) -1H-indole-6-carboxamide

Tetrahydrofuran in 985.5 g (content: 489.3 g, 1.25 mmol) of toluene solution of 1- (1-benzyloxycarbonylpiperidin-4-yl) -N-methyl-1H-indole-6-carboxamide 2447 mL was added to dissolve and the resulting solution was placed in a 7 L autoclave. Then, 2447 mL of methanol and 49 g of 10% palladium-carbon (50% hydrous) were sequentially added to the reaction vessel. The inside of the reaction vessel was replaced with nitrogen twice, and then twice with hydrogen. The reaction solution was stirred for about 2 hours while controlling the hydrogen pressure to 0.1 MPa to 0.2 MPa. Then, the pressure was released, the interior of the autoclave was nitrogen-substituted, the autoclave was opened, and the reaction solution was discharged from the bottom of the reaction vessel. After washing the inside of the autoclave with a mixed solution of methanol / tetrahydrofuran (1/1), combining the reaction solution and the washing solution, collecting the catalyst by filtration, and filtering the filtration cake with methanol / tetra. Washed with hydrofuran (1/1). The filtrate was concentrated under reduced pressure to obtain 830.5 g of a brown solution.

Content: 345.6 g, Yield: 98.0% (calculated yield from 1- (1-benzyloxycarbonylpiperidin-4-yl) -1H-indole-6-methyl carboxylate)

1468 mL of DME was added to 799.7 g (content: 332.8 g) of the brown solution, concentrated (bath temperature 40 ° C.), and then 1468 mL of DME was added and concentrated to give 677.0 g of a mixture of a pale yellow solid and a brown solution. Got it.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.88-2.02 (m, 2H), 2.06-2.16 (m, 2H), 2.80-2.92 (m, 2H), 3.22-3.32 (m, 2H), 4.46 (tt, J = 4.0, 12.0 Hz, 1H), 6.58 (dd, J = 0.8, 3.2 Hz, 1H), 7.36-7.44 (m, 2H), 7.65 (d, J = 8.4 Hz, 1H), 8.11 ( s, 1 H).

(Manufacture example 8)

Synthesis of N-methyl-4-methyl-3-nitrobenzamide

1.83 g (10 mmol) of 3-nitro-4-methylbenzoic acid were dissolved in 18.3 mL of tetrahydrofuran, and then 2.43 g (15 mmol) of CDI was added to this solution at room temperature under a nitrogen atmosphere. The reaction solution thus obtained was stirred at room temperature for 1.5 hours, and then cooled in an ice water bath, followed by dropping 2.33 g (30 mmol) of 40% aqueous methylamine solution. The reaction solution was stirred with cooling in an ice water bath for 15 minutes and stirred at room temperature for 2.5 hours.

Then, the reaction solution was diluted with ethyl acetate, poured into a 5% aqueous NaHCO ₃ solution, and extracted with ethyl acetate. The organic layer was washed successively with 0.1 N hydrochloric acid, 5% aqueous sodium hydrogen carbonate solution, 5% aqueous sodium chloride solution and water, dried over anhydrous magnesium sulfate, separated by filtration, and then concentrated under reduced pressure to give 1.75 g of the title compound as white crystals. Obtained as.

Yield: 90.1%

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.66 (s, 3H), 3.05 (d, J = 4.8 Hz, 3H), 6.20 (brs, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.95 (dd, J = 2.0, 8.4 Hz, 1H), 8.34 (d, J = 2.0 Hz, 1H)

ESI-MS: m / z 217 (M + Na) ⁺

(Manufacture example 9)

Synthesis of 4- (2-dimethylaminovinyl) -N-methyl-3-nitrobenzamide

1.65 g (8.49 mmol) of N-methyl-4-methyl-3-nitrobenzamide was dissolved in 9.9 mL of DMF, and then 6.49 g (50.90) of N, N-dimethylformamide dimethylacetal in this solution at room temperature under a nitrogen atmosphere. mmol) was added dropwise, and the obtained reaction solution was heated and stirred at 80 ° C for 46 hours.

Then, the reaction solution was concentrated under reduced pressure, and the residue was then purified by flash column chromatography (Merck, Silica Gel 60, 230 to 400 mesh; ethyl acetate: heptane, 1: 1 → 2: 1). ) Fractions containing the desired product were collected, concentrated under reduced pressure, and the residue was purified by flash column chromatography (Fuji silysia, NH-Silica Gel; ethyl acetate: heptane = 1: 1). Then, the fractions containing the target product were collected and concentrated under reduced pressure to obtain 800.2 mg of the title compound as dark red crystals.

Yield: 37.8%

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.97 (s, 6H), 3.01 (d, J = 4.8 Hz, 3H), 5.94 (d, J = 13.2 Hz, 1H), 6.18 (brs, 1H), 7.12 (d, J = 13.2 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.78 (dd, J = 2.0, 8.4 Hz, 1H), 8.22 (d, J = 2.0 Hz, 1H)

ESI-MS: m / z 272 (M + Na) ⁺

(Manufacture example 10)

Synthesis of 4- (2,2-dimethoxyethyl) -N-methyl-3-nitrobenzamide

100.0 mg (0.40 mmol) of 4- (2-dimethylaminovinyl) -N-methyl-3-nitrobenzamide obtained in Preparation Example 9 was dissolved in 0.5 mL of methanol, and then 53.8 mg / methanol 0.5 sulfuric acid was added to this solution at room temperature. After adding mL, it was heated and stirred at 55 ° C. for 5 hours.

Then, the obtained reaction solution was cooled in an ice water bath, and then, 243 mg (2.40 mmol) of triethylamine was added to the reaction solution, and the resultant was concentrated under reduced pressure. Water and toluene were added to the residue, and extracted with toluene. The resulting organic layer was dried over anhydrous sodium sulfate, separated by filtration, and then concentrated under reduced pressure to obtain 93.5 mg of the title compound as an orange-red oily substance.

Yield: 86.9%

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 3.04 (d, J = 4.8 Hz, 3H), 3.27 (d, J = 5.2 Hz, 2H), 3.35 (s, 6H), 4.56 (t, J = 5.2 Hz, 1H), 6.26 (brs, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.93 (dd, J = 2.0, 8.0 Hz, 1H), 8.26 (d, J = 2.0 Hz, 1H)

ESI-MS: m / z 291 (M + Na) ⁺

(Manufacture example 11)

Synthesis of 3-amino-4- (2,2-dimethoxyethyl) -N-methylbenzamide

10 mg of palladium-carbon 10 mg was added to a solution of 93.5 mg (0.35 mmol) of 4- (2,2-dimethoxyethyl) -N-methyl-3-nitrobenzamide obtained in Preparation Example 10, Hydrogenation was performed at room temperature and atmospheric pressure.

After completion of the reaction, the catalyst was separated by filtration using Hyflo Super-Cel, and then the filtrate was concentrated under reduced pressure to obtain 83.4 mg of the title compound as a pale brown oily substance.

Yield: 100%

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.88 (d, J = 5.2 Hz, 2H), 2.98 (d, J = 4.8 Hz, 3H), 3.37 (s, 6H), 4.18 (brs, 2H), 4.49 (t, J = 5.2 Hz, 1H), 6.09 (brs, 1H), 7.00 (dd, J = 1.6, 8.0 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 7.14 ( d, J = 1.6 Hz, 1H)

ESI-MS: m / z 261 (M + Na) ⁺

(Manufacture example 12)

Synthesis of 1- (1-benzyloxycarbonylpiperidin-4-yl) -N-methyl-1H-indole-6-carboxamide

83.4 mg (0.35 mmol) of 3-amino-4- (2,2-dimethoxyethyl) -N-methylbenzamide obtained in Preparation Example 11 was dissolved in 1.7 mL of acetic acid, and then 4-oxo- was added to the solution at room temperature. 123 mg (0.52 mmol) of 1-piperidinecarboxylic acid benzyl was added, and the obtained reaction solution was stirred at room temperature under a nitrogen atmosphere. After 1 hour, the reaction solution was cooled in a cold water bath, and then 117 mg (0.52 mmol) of STAB (sodium triacetoxyborohydride) was added to the reaction solution, and the reaction solution was stirred at room temperature for 1 hour and 20 minutes. Then, after cooling the reaction solution in a cold water bath, 1.7 mL of water was added dropwise to the reaction solution, and then heated and stirred at 100 ° C for 5 hours.

Toluene was added to the reaction solution and extracted. Here, since 1- (1-benzyloxycarbonylpiperidin-4-yl) -N-methyl-1H-indole-6-carboxamide was precipitated, ethyl acetate was added to the aqueous layer and 1- (1- Benzyloxycarbonylpiperidin-4-yl) -N-methyl-1H-indole-6-carboxamide was dissolved, neutralized with 5N sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, separated by filtration, concentrated under reduced pressure, and the residue was purified by flash column chromatography (Merck, Silica Gel 60, 230-400 mesh; ethyl acetate: heptane = 2: 1). 114.9 mg of 1- (1-benzyloxycarbonylpiperidin-4-yl) -N-methyl-1H-indole-6-carboxamide was obtained as a colorless oily substance.

The oily substance thus obtained was dissolved in 0.12 mL of toluene, and then 0.96 mL of cyclopentyl methyl ether was added dropwise to the solution while stirring at room temperature. The obtained solution was heated and stirred at 50 ° C., and seed crystals of 1- (1-benzyloxycarbonylpiperidin-4-yl) -N-methyl-1H-indole-6-carboxamide were added. Then, while heating and stirring the reaction solution at 50 ° C, 0.24 mL of heptane was added dropwise to the reaction solution, and then heated and stirred at 50 ° C for 10 minutes. The obtained reaction solution was slowly cooled to room temperature at a rate of 10 ° C./15 minutes, and then stirred at 10 ° C. for 1 hour. The precipitated crystals were collected by filtration, thereby yielding 99.3 mg of 1- (1-benzyloxycarbonylpiperidin-4-yl) -N-methyl-1H-indole-6-carboxamide as white crystals. Got it.

Yield: 72.7%

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.83-2.02 (br, 2H), 2.04-2.16 (br, 2H), 2.94-3.10 (br, 2H), 3.06 (d, J = 4.8 Hz , 3H), 4.30-4.58 (m, 3H), 5.17 (s, 2H), 6.24 (brs, 1H), 6.56 (d, J = 3.2 Hz, 1H), 7.28 (d, J = 3.2 Hz, 1H) , 7.31-7.41 (m, 6H), 7.62 (d, J = 8.4 Hz, 1H), 8.05 (s, 1H)

ESI-MS: m / z 414 (M + Na) ⁺

(Manufacture example 13)

Synthesis of 1- (1-ethoxyethoxy) -3-methoxybenzene

To a 15 L four-necked round bottom flask under nitrogen atmosphere was added 260 mL of tetrahydrofuran and 650.4 g (5.24 mol) of 3-methoxyphenol. Then, 65.8 g (0.26 mol) of pyridinium p-toluenesulfonate was added to this tetrahydrofuran solution, and stirring was started. The resulting mixture was cooled in a thermostat set at a temperature of 8 ° C. and then 760.1 g (10.54 mol) of ethyl vinyl ether was added dropwise for about 1.5 hours. Then, after the obtained reaction solution was stirred at the same temperature for 2.7 hours, the temperature of the thermostat was set to 15 ℃. It stirred about 2 hours from the time when internal temperature exceeded 14 degreeC. The temperature of the thermostat was set to 8 ° C., and 715.2 g of an aqueous 8% sodium bicarbonate solution was prepared by dissolving 57.2 g of sodium bicarbonate in 658 mL of tap water at the time when the internal temperature reached almost 10 ° C. Was added dropwise for 10 minutes. The reaction solution was transferred to a 20 L separatory funnel, 1040 mL of tap water was added, 4550 mL of toluene was added and extracted, and the organic layer was washed twice with 130 mL of tap water and 650 mL. The washed organic layer was concentrated under reduced pressure at 40 ° C. to obtain a pale yellow oily substance containing the title compound.

Yield: 1213.5 g, Content: 1019.3 g, Yield: 99.1%

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.21 (t, J = 6.8 Hz, 3H), 1.50 (d, J = 5.2 Hz, 3H), 3.50-3.60 (m, 2H), 3.79 ( s, 3H), 5.38 (q, J = 5.2 Hz, 1H), 6.50-6.66 (m, 3H), 7.13-7.20 (m, 1H).

(Example 1)

Synthesis of [2- (1-ethoxyethoxy) -6-methoxyphenyl] ethyl acetate

In a nitrogen atmosphere, 854.0 g (content: 717.4 g, 3.656 mol) of 1- (1-ethoxyethoxy) -3-methoxybenzene was added to a 20-L reactor and washed with 7174 mL of tetrahydrofuran. Then, the obtained solution was stirred. After circulating a coolant set at a temperature of 4 ° C. in the jacket of the reactor, 1156 g (4.414 mol) [2.71 M, n-hexane solution] of n-butyllithium was added dropwise to the reaction solution for 41 minutes, and then the reaction solution was added. Was stirred at the same temperature for about 1.5 hours. When the coolant temperature was set to -20 ° C and the internal temperature was found to be -10 ° C or lower, 417.8 g (2.19 mol) of copper (I) iodide was added to the reaction solution in three portions, and then the reaction solution was added. It stirred about 14 hours at the same temperature. The coolant set temperature was changed to −90 ° C., and 702.1 g (4.20 mol) of ethyl bromoacetate was added dropwise to the reaction solution for 26 minutes, followed by washing with 10 mL of tetrahydrofuran. After completion of the dropwise addition, the obtained reaction solution was stirred for 44 minutes, the coolant temperature setting was changed to -35 ° C, and the reaction solution was further stirred for about 1.8 hours. The coolant temperature setting was changed to −20 ° C., and when the internal temperature exceeded −20 ° C., the solution was stirred for 1 hour, and then the progress of the reaction was confirmed by HPLC. At the same temperature, 1435 mL of 28% aqueous ammonia was added to the reaction solution for about 30 minutes, and the coolant temperature was changed to 25 ° C. 7174 mL of toluene was added to the reaction solution, and the organic layer was washed with 1440 mL of 28% ammonia water and tap water (1435 mL × 3). 127 mL (0.73 mol) of N, N-diisopropylethylamine was added to the obtained organic layer, and it concentrated under reduced pressure, and the pale orange oily substance containing the title compound was obtained.

Yield: 1122.3 g, content: 990.7 g, yield: 96.0%

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.19 (t, J = 7.2 Hz, 3H), 1.24 (d, J = 7.2 Hz, 3H), 1.47 (d, J = 5.2 Hz, 3H) , 3.46-3.56 (m, 1H), 3.66-3.82 (m, 3H), 3.80 (s, 3H), 4.14 (q, J = 7.2 Hz, 2H), 5.39 (q, J = 5.2 Hz, 1H), 6.57 (d, J = 8.4 Hz, 1H), 6.70 (d, J = 8.8 Hz, 1H), 7.17 (dd, J = 8.8, 8.4 Hz, 1H).

(Example 2)

Synthesis of 2- [1-ethoxyethoxy] -6-methoxyphenyl] ethanol

Under a nitrogen atmosphere, 248.8 g of [2- (1-ethoxyethoxy) -6-methoxyphenyl] ethyl acetate (content: 213.0 g, 0.754 mol) and the same compound 561.6 were placed in a 15 L four-neck round bottom flask. g (content: 495.7 g, 1.756 mol), toluene (8504 mL) and DME (2126 mL) were added in sequence, then stirring was initiated and the reaction vessel was ice cooled. 1403.7 g (65% toluene solution, 1.8 molar equivalents) of sodium hydrogenated bis (2-methoxyethoxy) aluminum was dripped at this solution for 50 minutes. Immediately after completion of the dropping, the ice water bath was changed to a water bath, and the reaction solution was stirred for 2.5 hours. Then, the water bath was changed to an ice water bath, and about 1.5 L of 8% (w / w) aqueous sodium hydroxide solution (prepared by adding 4570 mL of water to 430 g of 93.0% sodium hydroxide) was added dropwise to the reaction solution for 47 minutes. It was. The resulting reaction solution was transferred to a 20 L separatory funnel, and then the total amount of the rest of the aqueous sodium hydroxide solution prepared above was added, and the aqueous layer was discarded. The organic layer was washed three times with tap water (1417 mL × 2 times, 709 mL × 1 times), and then concentrated under reduced pressure at 40 ° C. to quantify the title compound contained in the concentrated residue.

Concentrated residue weight: 1042.0 g, Content: 563.3 g

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.20 (t, J = 7.2 Hz, 3H), 1.50 (d, J = 5.6 Hz, 3H), 3.00 (t, J = 6.8 Hz, 2H) , 3.48-3.58 (m, 1H), 3.68-3.90 (m, 3H), 3.82 (s, 3H), 5.42 (q, J = 5.6 Hz, 1H), 6.58 (d, J = 8.0 Hz, 1H), 6.70 (d, J = 8.4 Hz, 1 H), 7.13 (dd, J = 8.4, 8.0 Hz, 1 H).

(Example 3)

Synthesis of Benzoic Acid 2- [2- (1-ethoxyethoxy) -6-methoxyphenyl] ethyl

1042.0 g of the organic layer residue obtained in Example 2 was transferred to a 15 L four-necked round bottom flask under nitrogen atmosphere, and then 8102 mL of toluene, 2025 mL of DME, 304.8 g of triethylamine and N, N, N, N-tetra 29.2 g of methylethylenediamine were added sequentially. Then, 388.1 g (2.761 mol) of benzoyl chloride was added dropwise to the solution over 40 minutes while the obtained solution was stirred under ice cooling. The reaction solution was stirred at the same temperature for 10 minutes, and then the ice bath was changed to a water bath, followed by further stirring for 2.8 hours. The reaction solution was transferred to a 20 L separatory funnel and washed twice with 3544 mL and 709 mL of tap water, respectively. The title compound in 10.84 L of the obtained organic layer was quantified.

Content: 745.0 g

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.18 (t, J = 7.2 Hz, 3H), 1.48 (d, J = 5.2 Hz, 3H), 3.17 (t, J = 7.2 Hz, 2H) , 3.45-3.56 (m, 1H), 3.66-3.80 (m, 1H), 3.76 (s, 3H), 4.45 (t, J = 7.2 Hz, 2H), 5.41 (q, J = 5.2 Hz, 1H), 6.55 (d, J = 8.4 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H), 7.13 (dd, J = 8.4, 8.0 Hz, 1H), 7.36-7.44 (m, 2H), 7.50-7.56 (m, 1 H), 7.98-8.06 (m, 2 H).

(Example 4)

Synthesis of Benzoic Acid 2- (2-hydroxy-6-methoxyphenyl) ethyl

The organic layer obtained in Example 3 was transferred to a 15 L four-necked round bottom flask, then 2126 mL of tetrahydrofuran was added, and the resulting solution was stirred while cooling in an ice water bath. Then, 1417 mL of 5N hydrochloric acid was added dropwise for 23 minutes, and the reaction solution was stirred at the same temperature for about 1 hour, and then the cold water of the bath was removed, followed by stirring for 2.5 hours. The reaction solution thus obtained was transferred to a 20 L separatory funnel, and the aqueous layer was discarded. The organic layer was washed twice with an aqueous 8% sodium bicarbonate solution (adjusted by adding 1956 mL of water to 170 g of sodium bicarbonate) and tap water (709 mL × 2). The washed organic layer was concentrated under reduced pressure at a bath temperature of 40 ° C. to obtain 1463.0 g of a slurry.

The resulting slurry was washed with 709 mL of tetrahydrofuran in a 10 L four-necked round bottom flask. Then, while stirring, 5670 mL of the toluene-heptane mixture (1: 8) was added dropwise for about 2.5 hours, followed by stirring at room temperature for about 14 hours. The precipitated crystals were collected by filtration, and then the collected crystals were washed with 708 mL of toluene-heptane mixture (1: 8). Then, at a bath temperature of 40 ° C., it was dried for about 4.5 hours under reduced pressure to obtain the title compound as white crystals.

Yield: 535.9 g, yield: 78.4%

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 3.15 (t, J = 7.2 Hz, 2H), 3.79 (s, 3H), 4.45 (t, J = 7.2 Hz, 2H), 5.86 (s, 1H), 6.48 (d, J = 8.4 Hz, 1H), 6.53 (d, J = 8.4 Hz, 1H), 7.09 (dd, J = 8.4, 8.4 Hz, 1H), 7.44 (dd, J = 7.6, 7.6 Hz, 2H), 7.56 (dd, J = 7.6, 7.6 Hz, 1H), 8.04 (d, J = 7.6 Hz, 1H).

(Example 5)

Synthesis of Benzoic Acid 2- (7-methoxy-2,2-dimethyl-4-oxochroman-8-yl) ethyl

To a 10 L four-necked round bottom flask, 202.2 g (2.020 mol) of 3-methylcrotonic acid and 2 L of methanesulfonic acid were added, followed by stirring on a water bath at 50 ° C. under a stream of nitrogen. 500.0 g (1.836 mol) of the benzoic acid 2- (2-hydroxy-6-methoxyphenyl) ethyl obtained in Example 4 were added to the obtained solution. Then, the reaction mixture was stirred at the same temperature for 1.8 hours and then ice-cooled. 2.5 L of toluene was injected into the reaction solution, and then 5 L of tap water was added dropwise for about 1 hour. The contents were transferred to a 20 L separator, and separated to discard the aqueous layer. The organic layer was washed three times with tap water (5 L × 3), and then concentrated under reduced pressure at a bath temperature of 40 ° C. to obtain 846.1 g of the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.39 (s, 6H), 2.62 (s, 2H), 3.13 (t, J = 6.8 Hz, 2H), 3.82 (s, 3H), 4.45 ( t, J = 6.8 Hz, 2H), 6.57 (d, J = 8.8 Hz, 1H), 7.38-7.45 (m, 2H), 7.51-7.57 (m, 1H), 7.82 (d, J = 8.8 Hz, 1H ), 7.98-8.04 (m, 2 H).

(Example 6)

Synthesis of 8- (2-hydroxyethyl) -7-methoxy-2,2-dimethylchroman-4-one

844.9 g of the oily material obtained in Example 5 was dissolved in 2.5 L of tetrahydrofuran and transferred to a 20 L four-neck round bottom flask. 2.5 L of methanol was added to this tetrahydrofuran solution, and the resulting solution was cooled with water (water temperature: 22 ° C), followed by stirring 158 g of an aqueous 8% (w / w) sodium hydroxide solution [sodium hydroxide (93.0%)]. Was prepared by adding 1678 mL of water to the mixture for 18 minutes. After completion of the dropwise addition, the water bath was removed, and the reaction solution was stirred at room temperature for about 3.5 hours. Then, 10 L of tap water was added dropwise to the reaction solution for about 1 hour. After the reaction vessel was ice-cooled, the reaction solution was stirred at about 100 ° C. or lower for about 1 hour. The precipitated crystals were collected by filtration and washed sequentially with 2 L of tap water and methanol-tap water mixture (1: 4, 400 mL / 1600 mL). Then, the crystals were dried under reduced pressure at 40 ° C. until the weight of the crystals became constant, to obtain 374.7 g of the crude title compound as a pale yellow-white solid.

Yield: 374.7 g, content: 305.8 g, yield: 66.6%

To a 15 L four-necked round bottom flask, 374.7 g (content: 305.8 g) of the crude titled compound and 2 L of ethyl acetate were added thereto, and then the stirring was started in a water bath heated to 80 ° C. 4.116 L of ethyl acetate was added to the obtained suspension, and the bath temperature setting was changed to 75 ° C. After confirming that the crystals were dissolved, the temperature of the water bath was gradually lowered, and seed crystals were added at an internal temperature of 45.3 ° C. Precipitation of crystals was observed 6 minutes after seed crystal addition. After lowering the temperature of the water bath, 6.116 L of heptane was added to the suspension at an internal temperature of 30 ° C. or lower for about 1 hour, and the reaction solution was stirred for about 13 hours at the same temperature. The suspension was cooled on ice, stirred for about 4 hours, filtered through a Buchner funnel to collect crystals, and the collected crystals were then washed with 918 mL of an ethyl-heptane (1: 2) mixture. The crystals were then dried under reduced pressure for about 3 hours on a 40 ° C. water bath and dried under reduced pressure for about 14 hours at room temperature to give the title compound as an off-white solid.

Yield: 294.5 g, Content: 275.4 g, Yield: 90.1%

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.45 (s, 6H), 2.68 (s, 2H), 2.96 (t, J = 6.8 Hz, 2H), 3.73-3.80 (m, 2H), 3.89 (s, 3H), 6.59 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H).

(Example 7)

Synthesis (Recrystallization) of 8- (2-hydroxyethyl) -7-methoxy-2,2-dimethylchroman4-one

To a 100 mL four-necked round bottom flask, 3.71 g (content: 3.0 g) of crude title compound and 45 mL of methyl isobutyl ketone were added, followed by heating and stirring in an oil bath heated to 82 ° C. to form a solution. It was. The solution was slowly cooled, and seed crystals were added at an inner temperature of 59 ° C. Every 30 minutes, the temperature setting of the oil bath was lowered by 5 ° C., and 30 mL of heptane was added dropwise for about 1 hour at an internal temperature of 26.7 ° C. After 18 minutes, the suspension was cooled with cold water and crystals were obtained by filtration after 1 hour and 50 minutes. The obtained crystals were washed with 3 mL of methyl isobutyl ketone-heptane mixed solution (3: 2), and then dried under reduced pressure for about 1 hour on a 40 DEG C water bath to obtain the title compound as a white solid.

Yield: 2.72 g, content: 2.64 g, yield: 87.8%

(Example 8)

Synthesis of (7-methoxy-2,2-dimethyl-4-oxochromen-8-yl) acetaldehyde

248.3 g (content: 232.7 g, 0.930 mol) of 8- (2-hydroxyethyl) -7-methoxy-2,2-dimethylchroman-4-one in a 15 L four-necked round bottom flask 294.0 g (content: 274.9 g, 1.098 mol) and 7614 mL of ethyl acetate were added and stirred. The cooling of this suspension was then initiated using a cold bath set at −4 ° C., followed by 161.9 g (1.574 moles) of sodium bromide, 508 mL of tap water and 2,2,6,6-tetramethylpiperidine oxide 3.17 g (20.28 mmol) were added sequentially. After the internal temperature reached 0 ° C., a mixture of 5.536 mol of sodium hypochlorite solution and 2538 g of a 7% (w / w) sodium hydrogen carbonate solution was added dropwise into the flask for about 2 hours. After completion of the dropwise addition, the temperature of the cooling bath was changed to 0 ° C, and the reaction solution was continuously stirred for 45 minutes. The reaction solution was transferred to a 20 L separatory funnel and the aqueous layer was discarded. The organic layer was washed sequentially with 2030 g of 10% aqueous sodium chloride solution and 2030 mL of tap water. The washed organic layer was concentrated under reduced pressure (40 ° C) to give 743.7 g of a slurry. 500 mL of DME was added to the slurry to form a solution. The resulting solution was concentrated under reduced pressure (40 ° C.), and 500 mL of DME was further added to the precipitated crystals to dissolve it. The solution was transferred to a 5 L four-necked round bottom flask and heated in a 40 ° C. water bath. After adding 515 mL of DME to the reaction solution, the mixture was stirred at 183 rpm, about 50 mL of tap water was added thereto, and 4 minutes later, cooling was started in an ice water bath. After adding seed crystals to the reaction solution, the mixture was stirred for about 1 hour, and then about 515 mL of tap water was added for about 30 minutes. Then, the reaction solution was further stirred for 1.3 hours, 1523 mL of heptane was added for about 1 hour, and the resulting solution was stirred for about 1 hour or more at the same temperature. The precipitated crystals were collected by filtration, washed with a mixed solution of DME / tap water / heptane (about 600 mL, mixed at a ratio of DME / tap water / heptane = 1/1 / 1.5), and then the crystals It dried under reduced pressure (bath temperature 40 degreeC) until the weight of nearly became a fixed amount, and the title compound was obtained as an off-white solid.

Yield: 478.0 g, Content: 413.9 g, Yield: 82.2%

¹ H-NMR (600 MHz, DMSO-d ₆ ) δ (ppm): 1.34 (s, 6H), 2.70 (s, 2H), 3.63 (s, 2H), 3.83 (s, 3H), 6.80 (d, J = 9.0 Hz, 1H), 7.72 (d, J = 9.0 Hz, 1H), 9.58 (s, 1H).

(Example 9)

Synthesis of (7-methoxy-2,2-dimethyl-4-oxochromen-8-yl) acetaldehyde

In a 20-neck, four-necked round-bottom flask (7-methoxy-2,2-dimethyl-4-oxochromen-8-yl), 6.54 g acetaldehyde (6.0 g), 54 mL ethanol and 6 ethyl acetate mL was added and the resulting reaction solution was stirred at room temperature. An aqueous sodium hydrogen sulfite solution (2.51 g dissolved in 6 mL of water) was added dropwise to the stirred reaction solution for 20 minutes. Then, 60 mL of ethyl acetate was added dropwise for 1.5 hours, and the reaction solution was stirred overnight at room temperature. The precipitated crystals were collected by filtration, and then the collected crystals were washed with an ethanol / ethyl acetate (1/1) mixture (12 mL) to obtain 8.14 g of sodium hydrogen sulfite adduct of the title compound.

Sodium hydrogen sulfite adduct of the title compound

¹ H-NMR (600 MHz, DMSO-d ₆ ) δ (ppm): 1.35 (s, 3H), 1.36 (s, 3H), 2.66 (s, 2H), 2.88 (dd, J = 13.0, 3.0 Hz, 1H ), 3.00 (dd, J = 13.0, 11.0 Hz, 1H), 3.81 (s, 3H), 4.18 (ddd, J = 11.0, 6.0, 3.0 Hz, 1H), 4.35 (d, J = 6.0 Hz, 1H) , 6.69 (d, J = 9.0 Hz, 1H), 7.60 (d, J = 9.0 Hz, 1H)

To a 30-necked four-necked round bottom flask, 6.0 g of sodium bisulfite adduct of the title compound and 120 mL of ethyl acetate were added and stirred. After adding 30 g of 10% aqueous potassium carbonate solution to the suspension, the obtained reaction solution was stirred at room temperature for 2 hours or more. The organic layer was separated and the organic layer was washed sequentially with 10% saline and tap water (twice). Toluene 12 mL was added to the washed organic layer, concentrated under reduced pressure, and dried under reduced pressure to obtain 3.49 g of the title compound as a pale yellow solid.

(Example 10)

1- {1- [2- (7-methoxy-2,2-dimethyl-4-oxochromen-8-yl) ethyl] piperidin-4-yl} -N-methyl-1H-indole-6 Synthesis of Carboxamide

677.0 g of N-methyl-1- (piperidin-4-yl) -1H-indole-6-carboxamide synthesized in Production Example 7 in a four-necked round bottom flask having a capacity of 15 L under nitrogen stream : 332.8 g, 1.293 mmol) and 2,00 mL of tetrahydrofuran were added. Furthermore, to this suspension, 426.4 g of (7-methoxy-2,2-dimethyl-4-oxochromen-8-yl) acetaldehyde obtained in Example 8 (content: 369.2 g, 1.15 equiv) and tetrahydrofuran 1328 mL and acetic acid 148 mL (2.0 molar equivalents) were added sequentially, and the reaction solution was stirred for 1 hour from the time point when dissolution of the raw material was confirmed at room temperature. Then, the reaction solution was cooled to 10 ° C. or lower in an ice water bath, and sodium triacetoxy borohydride (356.3 g, 1.3 molar equivalents) was added to the reaction solution in 4 portions. After about 10 minutes from the end of the total amount addition, the ice water bath was replaced with a water bath (21.9 ° C.) and stirred under temperature control. After about 1 hour, the reaction solution was sampled to confirm the end of the reaction by HPLC analysis. The reaction vessel was cooled in an ice water bath, and then 4500 mL of ethyl acetate was added to the reaction solution at about 10 ° C. Then, 5200 mL of 1N aqueous sodium hydroxide solution was added to the reaction solution for 36 minutes.

The reaction solution was transferred to a 20 L separator, washed with 2156 mL of ethyl acetate, and the organic layer was separated. The obtained organic layer was washed with 1000 g of 7% aqueous sodium hydrogen carbonate solution, 5% brine (3328 g and 1000 g twice) and 3328 mL of tap water.

The organic layer was concentrated under reduced pressure, 1664 mL of ethanol was added, concentrated, and 1902.6 g of the resulting solution was quantified. The content of the title compound was 581.1 g, the yield was 91.8%, and the HPLC purity was 92.5%.

1664 mL of ethanol was added to the concentrate to dissolve it, and 57.0 g of activated carbon was added thereto, followed by stirring for about 1 hour. The activated carbon was removed by filtration using Hyflo Super-Cel, and then washed with 400 mL of ethanol. The filtrate was concentrated under reduced pressure (internal temperature 40 ° C) to obtain 1461.8 g of the titled compound as a brown oily substance. Content: 552.5 g, HPLC Purity: 92.5%

(Example 11)

Synthesis of 1-piperidin-4-yl-1H-indole-6-carboxylic acid methyl hydrochloride

27.5 g of 1- (1-benzyloxycarbonylpiperidin-4-yl) -1H-indole-6-carboxylic acid methyl are dissolved in 68.75 mL of methanol and 68.75 mL of tetrahydrofuran and 10% palladium-carbon (about 50 % Water) agitation was performed for about 7.5 hours in a hydrogen atmosphere of 0.3 MPa in the presence of 1.1 g. The catalyst was removed by filtration and then the solvent was removed by distillation to give 16.69 g of the mixture. Using 6.96 g of this mixture, it was dissolved in 77 mL of 2-propanol and then slowly added 2.73 mL of concentrated hydrochloric acid under ice-cooling. The precipitated crystals were collected by filtration, and the collected crystals were washed with 2-propanol. After drying the crystals under reduced pressure, 5.89 g of the title compound were obtained.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 2.00-2.30 (m, 4H), 3.05-3.25 (m, 2H), 3.30-3.50 (m, 2H), 3.85 (s, 3H) , 4.80-5.00 (m, 1H), 6.61 (d, J = 3.1 Hz, 1H), 7.61 (d, J = 3.1 Hz, 1H), 7.60-7.70 (m, 2H), 8.26 (s, 1H).

(Example 12)

Of 1- {1- [2- (7-methoxy-2,2-dimethyl-4-oxochroman-8-yl) ethyl] piperidin-4-yl} -1H-indole-6-carboxylic acid methyl synthesis

2.92 g of 1-piperidin-4-yl-1H-indole-6-carboxylic acid methyl hydrochloride and 2.92 g of (7-methoxy-2,2-dimethyl-4-oxochromen-8-yl) acetaldehyde, 58.4 mL of tetrahydrofuran and 14.6 mL of acetic acid were added, then heated to 40 ° C., and the reaction solution was stirred for about 3 hours. After cooling the reaction solution in an ice water bath, 2.52 g of sodium triacetoxy borohydride was added to the reaction solution in three portions. The obtained reaction liquid was returned to room temperature, and progress of reaction was confirmed after 30 minutes. The reaction solution was again cooled in an ice water bath, then 87 mL of toluene and 29 mL of water were added, and the aqueous layer was discarded. The organic layer was washed sequentially with 49 mL, 69 mL, and 30 mL of 1N aqueous sodium hydroxide solution, followed by 29 mL of 5% saline solution, 14 mL, and 14 mL of water. By removing the solvent by distillation, 4.80 g of crude title compound was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.47 (s, 6H), 2.10-2.20 (m, 4H), 2.25-2.40 (m, 2H), 2.50-2.60 (m, 2H), 2.69 (s, 2H), 2.85-2.95 (m, 2H), 3.20-3.35 (m, 2H), 3.90 (s, 3H), 3.96 (s, 3H), 4.30-4.45 (m, 1H), 6.50-6.60 (m, 1H), 6.59 (d, J = 8.8 Hz, 1H), 7.42 (d, J = 3.1 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.79 (dd, J = 8.40, 1.50 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 8.16 (s, 1H).

(Example 13)

Synthesis of 1- {1- [2- (7-methoxy-2,2-dimethyl-4-oxochromen-8-yl) ethyl] piperidin-4-yl} -1H-indole-6-carboxylic acid

Of 1- {1- [2- (7-methoxy-2,2-dimethyl-4-oxochroman-8-yl) ethyl] piperidin-4-yl} -1H-indole-6-carboxylic acid methyl 3.5 g of the crude product was dissolved in 28.0 mL of tetrahydrofuran, and 14 mL of 1N aqueous sodium hydroxide solution was added to the resulting solution. To the obtained reaction solution, 14 mL of methanol was added, heated to 40 ° C., and stirred for 30 minutes. Then, 7 mL of tetrahydrofuran and 3.5 mL of methanol were added, followed by stirring for 2 hours, and further stirring at the same temperature for about 16 hours. The reaction solution was cooled in an ice water bath, and then 12.2 mL of 1N hydrochloric acid and 0.5 mL of 1N sodium hydroxide were added to adjust the pH to 7 to precipitate crystals. To the slurry was further added 10 mL of water, and then the crystals were collected by filtration, and the collected crystals were washed with 21 mL of a mixture of 2-propanol and water (5: 1). The washed crystals were dried under a reduced pressure to obtain 2.45 g of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.39 (s, 6H), 1.90-2.10 (m, 4H), 2.20-2.35 (m, 2H), 2.40-2.50 (m, 2H) , 2.70 (s, 2H), 2.70-2.80 (m, 2H), 3.05-3.15 (m, 2H), 3.85 (s, 3H), 4.40-4.55 (m, 1H), 6.53 (dJ = 3.4Hz, 1H ), 6.73 (d, J = 8.8 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.61 (dd, J = 8.0, 1.2 Hz, 1H), 7.63 (d, J = 8.8 Hz, 1H ), 7.72 (d, J = 3.4 Hz, 1 H), 8.15 (s, 1 H).

(Example 14)

Of 1- {1- [2- (7-methoxy-2,2-dimethyl-4-oxochroman-8-yl) ethyl] piperidin-4-yl} -1H-indole-6-carboxylic acid methyl synthesis

2.80 g of 1-piperidin-4-yl-1H-indol-6-carboxylic acid and 3.16 g of (7-methoxy-2,2-dimethyl-4-oxochromen-8-yl) acetaldehyde, DME 28 mL, tetrahydrofuran 14 mL and acetic acid 1.24 mL were added. Crystals precipitated, but the reaction solution was stirred for 1 hour. Then, the reaction solution was cooled in an ice water bath, and then 2.75 g of sodium triacetoxyborohydride was added to the reaction solution in three portions. After returning the reaction solution to room temperature, 3 mL of tetrahydrofuran was added, and the progress of the reaction was observed after about 1.5 hours. The reaction solution was cooled again in an ice-water bath, and then 68 mL of toluene and 29 mL of water were added, and after clarification filtration, 30 mL of toluene was added, and the aqueous layer was discarded. The organic layer was washed with 29 mL of 1N aqueous sodium hydroxide solution, 29 mL of 5% saline solution, and 29 mL of water. The solvent was removed by distillation to give 5.62 g of crude title compound.

(Example 15)

Synthesis of 1- {1- [2- (7-methoxy-2,2-dimethyl-4-oxochromen-8-yl) ethyl] piperidin-4-yl} -1H-indole-6-carboxylic acid

Of 1- {1- [2- (7-methoxy-2,2-dimethyl-4-oxochroman-8-yl) ethyl] piperidin-4-yl} -1H-indole-6-carboxylic acid methyl 4.0 g of crude product was dissolved in 40.0 mL of tetrahydrofuran, and then 16 mL of 1N aqueous sodium hydroxide solution was added to the resulting solution. Then, 20 mL of methanol was added to remove the partition of the reaction solution, and the reaction solution was stirred at 40 ° C. for about 20.5 hours. The stirred reaction solution was cooled in an ice-water bath, and then 15 mL of 1N hydrochloric acid was added to adjust the pH to 7 to precipitate crystals. 100 mL of water was added to this slurry, and the crystals were collected by filtration, and then the collected crystals were washed with 2-propanol / water (1/5, 24 mL). The washed crystals were dried under a reduced pressure to obtain 3.34 g of the title compound.

(Example 16)

1- {1- [2- (7-methoxy-2,2-dimethyl-4-oxochromen-8-yl) ethyl] piperidin-4-yl} -N-methyl-1H-indole-6 Synthesis of Carboxamide

1.0 g of 1- {1- [2- (7-methoxy-2,2-dimethyl-4-oxochromen-8-yl) ethyl] piperidin-4-yl} -1H-indole-6-carboxylic acid Was dissolved in 25 mL of ethanol, and 851 mg of 1,1'-carbonyldiimidazole was added to the resulting solution, and the reaction solution was stirred at 40 ° C for 2 hours. Then, the reaction solution was cooled in an ice water bath, and then 1.81 mL of 40% aqueous methylamine solution was added to the reaction solution, followed by stirring for 50 minutes. 40 mL of ethyl acetate and 20 mL of water were added to the stirred reaction solution, and the organic layer was separated. 20 mL of 10% saline was added to the obtained organic layer, followed by washing. Then, 8.5 mL of 1N hydrochloric acid was added to adjust pH to 7. The aqueous layer was discarded, and the organic layer was washed with 10 mL of water. The obtained organic layer was concentrated under reduced pressure, and then 3 mL of 1-propanol was added and then concentrated again to obtain the title compound.

The compound of Example 6 may also be prepared according to the following reference example.

(Reference Example 1)

Synthesis of 2,6-diacetoxytoluene

15.0 mL (16.3 g, 160 mmol) of acetic anhydride was added to a 62 mL suspension of 6.2 g (50 mmol) of 2,6-dihydroxytoluene and 27.6 g (20O mmol) of acetonitrile, which was stirred on an ice water bath. 3 minutes was dripped. After 27 minutes, stirring was stopped, and the reaction solution was allowed to stand at room temperature overnight, and then filtered, and then, 10 mL of toluene and 50 mL of water were added to the filtrate, followed by stirring and standing in a separating funnel. The aqueous layer was discarded, the organic layer was washed twice with 25 mL of water, and then the solvent was removed by distillation to give 10.3 g of the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.00 (s, 3H), 2.33 (s, 6H), 6.95 (d, J = 8.1 Hz, 2H), 7.24 (t, J = 8.3 Hz, 1H)

(Reference Example 2)

Synthesis of 2-acetoxy-6-hydroxytoluene

After dissolving 8.22 g (39.5 mmol) of 2,6-diacetoxytoluene in 82 mL of ethylene glycol dimethyl ether, 14.9 g (395 mmol) of sodium borohydride was added to the obtained solution, and the mixture was heated for 9 hours and 44 minutes in a 60 ° C water bath. Heated and stirred. After leaving the reaction solution at room temperature overnight, the reaction solution was added to a mixed solution of 100 mL of toluene and 100 mL of water stirred on an ice water bath, stirred for 5 minutes, then transferred to a separatory funnel and left to stand. The separated aqueous layer was extracted with 50 mL of toluene, the collected organic layer was washed twice with 50 mL of water, and then the solvent was removed by distillation to obtain 5.01 g of the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.04 (s, 3H), 2.34 (s, 3H), 6.63 (d, J = 8.8 Hz, 1H), 6.65 (d, J = 8.3 Hz, 1H), 7.05 (t, J = 8.3 Hz, 1H).

(Reference Example 3)

Synthesis of 2-acetoxy-6-methoxytoluene

To a 50 mL solution of 5.01 g (30.0 mmol) of acetonitrile of 2-acetoxy-6-hydroxytoluene, 12.44 g (90.0 mmol) of potassium carbonate and 12.77 g (90.0 mmol) of methyl iodide were added, followed by an oil bath at 90 ° C. Heated and stirred for 96 min. The reaction solution was allowed to stand at room temperature for about 3 hours, and then the reaction solution was added to a mixed solution of 100 mL of toluene and 10 mL of water stirred on an ice water bath, stirred for 2 minutes, then transferred to a separatory funnel, and left standing. It was. The aqueous layer was separated and discarded, and the organic layer was washed three times with 20 mL of a prescribed aqueous potassium hydroxide solution and 20 mL of water, and then the solvent was removed by distillation to obtain 4.69 g of the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.03 (s, 3H), 2.32 (s, 3H), 3.84 (s, 3H), 6.65 (d, J = 8.0 Hz, 1H), 6.74 ( d, J = 8.1 Hz, 1H), 7.16 (t, J = 8.3 Hz, 1H).

(Reference Example 4)

Synthesis of 2-hydroxy-6-methoxytoluene

To a 360 mL solution of 4.69 g (26.0 mmol) of 2-acetoxy-6-methoxytoluene, a 90 mL solution of 18.0 mL of concentrated sulfuric acid was added, followed by heating and stirring for 36 minutes on a 120 ° C. oil bath. The reaction solution was left at room temperature overnight, then transferred to a separatory funnel, extracted with 50 mL and 20 mL of toluene, the organic layers were collected, 30 mL of water, 30 mL of 5% aqueous sodium bicarbonate solution, and then water After washing twice with 30 mL, the solvent was removed by distillation to obtain 3.15 g of the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.12 (s, 3H), 3.82 (s, 3H), 4.71 (s, 1H), 6.45 (d, J = 8.3 Hz, 1H), 6.48 ( d, J = 8.8 Hz, 1H), 7.03 (t, J = 8.3 Hz, 1H).

(Reference Example 5)

Synthesis of 2- (N, N-diethylcarbamoyloxy) -6-methoxytoluene

To a 16 mL solution of 3.15 g (22.8 mmol) of acetonitrile of 2-hydroxy-6-methoxytoluene, 3.50 g (25.1 mmol) of potassium carbonate and 3.4 g (25.1 mmol) of diethylcarbamoyl chloride were added, The obtained reaction liquid was heated and stirred for 59 minutes on a 100 degreeC oil bath. Then, 0.6 g (4.4 mmol) of diethylcarbamoyl chloride was added, and the obtained reaction solution was further heated for 38 minutes, and then 30 mL of toluene and 30 mL of water were added while stirring the reaction solution in an ice water bath. After stirring for 20 minutes, the mixture was transferred to a separating funnel and allowed to stand. The aqueous layer was separated and discarded, and the organic layer was washed twice with 10 mL of aqueous potassium hydroxide aqueous solution followed by 10 mL of water, and then the solvent was removed by distillation to obtain 5.58 g of the crude title compound. Since the compound was solidified, some of this was obtained as seed crystals.

5.58 g of the crude title compound were heated and stirred in a water bath at 50 ° C., dissolved in 14.5 mL of ethanol and 8.9 mL of water, and then natural cooling was initiated at room temperature. Seed crystals were added until the temperature of the solution reached 35 ° C, and the start of precipitation was confirmed and cooled in a water bath and an ice water bath. The mixture was stirred for about 1 hour on an ice water bath and when the crystallization mixture temperature was 2.2 ° C., crystals were collected by filtration and then washed with 8 mL of 50% hydrous ethanol. The washed crystals were dried under reduced pressure (30 ° C., 90 minutes) to obtain 3.89 g of the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.24 (m, 6H), 2.05 (s, 3H), 3.43 (m, 4H), 3.85 (s, 3H), 6.71 (d, J = 8.3 Hz, 1H), 6.71 (d, J = 8.1 Hz, 1H), 7.13 (t, J = 8.3 Hz, 1H).

(Reference Example 6)

Synthesis of N, N-diethyl- (2-hydroxy-6-methoxyphenyl) acetamide

5.0 mL of lithium diisopropylamide (2M / tetrahydrofuran-ethylbenzene, 10 mmol) was stirred and cooled over a dry ice-ethanol refrigerant, followed by 2- (N, N-diethylcarbamoyloxy) -6- A solution of 8.0 mL of 0.95 g (4.0 mmol) tetrahydrofuran of methoxytoluene was added dropwise for 16 minutes. After 1 minute, warming was started at room temperature, and the mixture was stirred for 47 minutes, and then allowed to stand overnight. Then, 10 mL of toluene and 10 mL of water were added and stirred for 4 minutes, after which the resulting mixture was transferred to a separating funnel and allowed to stand. The aqueous layer was separated, and the collected aqueous layer was combined with the aqueous layer extracted twice (5.0 mL each) with 2 nd aqueous potassium hydroxide solution from the organic layer. After wash | cleaning this aqueous layer with 10 mL of toluene, 10 mL of toluene was thrown in, and the obtained mixture was stirred, adding 20 mL of 2N hydrochloric acid aqueous solution, it was transferred to the separatory funnel, and it left still. The organic layer was separated, and the collected organic layer was combined with the organic layer extracted with 5 mL of toluene from the aqueous layer. The organic layer was washed twice with 5 mL of water, and then concentrated under reduced pressure to obtain 0.81 g of the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.29 (m, 6H), 3.49 (m, 4H), 3.80 (s, 2H), 3.82 (s, 3H), 6.43 (d, J = 8.3 Hz, 1H), 6.64 (d, J = 8.3 Hz, 1H), 7.11 (t, J = 8.3 Hz, 1H).

(Reference Example 7)

Synthesis of 4-methoxy-3H-benzofuran-2-one

To a 5.0 mL solution of 0.47 g (2.0 mmol) of N, N-diethyl- (2-hydroxy-6-methoxyphenyl) acetamide, add 0.92 mL (1.36 g, 12 mmol) of trifluoroacetic acid, And heated and stirred for 71 minutes on an oil bath at 125 ° C. After cooling the obtained mixture at room temperature, 24 mL of 0.5 N sodium hydroxide aqueous solution was added with stirring, and the obtained mixture was transferred to the separating funnel, and it left still. The aqueous layer was separated and discarded, and the organic layer was washed twice with 5 mL of water, and then the solvent was removed by distillation to obtain 0.27 g of the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 3.66 (s, 2H), 3.86 (s, 3H), 6.67 (d, J = 8.3 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 7.26 (t, J = 8.3 Hz, 1H).

(Reference Example 8)

Synthesis of 2- (2-hydroxy-6-methoxyphenyl) ethanol

To a 150 mL solution of 10.76 g (65.5 mmol) of ethyleneglycol dimethyl ether of 4-methoxy-3H-benzofuran-2-one was added by stirring 7.18 g (189 mmol) of sodium borohydride, and the resulting mixture was stirred on an ice water bath. While cooling, a solution of 21 mL of 5.25 mL (9.66 g, 94.5 mmol) of ethylene glycol dimethyl ether in concentrated sulfuric acid was added dropwise for 30 minutes. The mixture thus obtained was heated and stirred for 49 minutes on a 50 ° C. water bath, and then 32 mL (25.3 g, 790 mmol) of methanol was added dropwise for 6 minutes while stirring on an ice water bath. The mixture was heated and stirred for 53 minutes on a 50 ° C. water bath, and then allowed to stand overnight at room temperature. Then, 30O mL of isopropyl acetate and 20OmL of water were added thereto, stirred for 5 minutes, then transferred to a separatory funnel and left to stand. . The aqueous layer was separated and discarded, and the organic layer was washed twice with 100 mL of water, and then the solvent was removed by distillation. The residue was crystallized from ethyl acetate-hexane, and the obtained crystals were dried under reduced pressure at 30 ° C. to obtain 3.12 g of the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.98 (t, J = 5.1 Hz, 2H), 3.79 (s, 3H), 3.93 (t, J = 5.1 Hz, 2H), 6.48 (d, J = 8.1 Hz, 1H), 6.59 (d, J = 8.0 Hz, 1H), 7.09 (t, J = 8.0 Hz, 1H).

(Reference Example 9)

Synthesis of 2- (2-hydroxy-6-methoxyphenyl) ethyl acetate

While cooling on an ice water bath, 1.0 mL (1.8 g, 18 mmol) of concentrated sulfuric acid was added dropwise to a 5.0 mL solution of 0.27 g (1.6 mmol) of acetic acid of 2- (2-hydroxy-6-methoxyphenyl) ethanol. The mixture was stirred at room temperature for 5 minutes, and then 6.0 mL (4.7 g, 102 mmol) of ethanol was added dropwise. Then, 20 mL of toluene and 20 mL of water were added to this mixed solution, and after stirring for 5 minutes, the mixture was transferred to a separating funnel and allowed to stand. The aqueous layer was separated and discarded, and the organic layer was washed twice with 10 mL of water, and then the solvent was removed by distillation to obtain 0.16 g of the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.09 (s, 3H), 3.02 (t, J = 7.1 Hz, 2H), 3.81 (s, 3H), 4.21 (t, J = 7.1 Hz, 2H), 6.48 (d, J = 8.3 Hz, 1H), 6.53 (d, J = 7.8 Hz, 1H), 7.10 (t, J = 8.3 Hz, 1H).

(Reference Example 10)

Synthesis of 8- (2-acetoxyethyl) -7-methoxy-2,2-dimethylchroman-4-one

5.79 g (27.5 mmol) of acetic acid 2- (2-hydroxy-6-methoxyphenyl) ethyl, 3.03 g (30.3 mmol) of 2-methylcrotonic acid and 3.26 g (16.9 mmol) of methanesulfuric acid diphosphorus pentaoxide The 29.0 mL solution of phonic acid was heated and stirred at 70 ° C. for 75 minutes. Then, 50 mL of toluene and 50 mL of water were added at room temperature, stirred for 5 minutes, and then the obtained mixture was transferred to a separating funnel and allowed to stand. The aqueous layer was separated and discarded, and the organic layer was washed with 25 mL of 5% aqueous sodium hydrogen carbonate solution and 25 mL of water, and then the solvent was removed by distillation to obtain 7.85 g of crude title compound. The obtained material was purified by silica gel chromatography (eluent composition: 10% ethyl acetate-hexane (volume ratio), Rf value: 0.4) to obtain 2.96 g of the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.46 (s, 6H), 2.04 (s, 3H), 2.67 (s, 2H), 2.99 (t, J = 7.3 Hz, 2H), 3.88 ( s, 3H), 4.18 (t, J = 7.3 Hz, 2H), 6.58 (d, J = 9.0 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H).

(Reference Example 11)

Synthesis of 8- (2-hydroxyethyl) -7-methoxy-2,2-dimethylchroman-4-one

To a 18.0 mL solution of 2.80 g (9.58 mmol) of ethanol in 8- (2-acetoxyethyl) -7-methoxy-2,2-dimethylchroman-4-one, 1.80 mL (3.31 g) of concentrated sulfuric acid with stirring at room temperature , 32 mL of a 9.0 mL solution of water was added, and the resulting mixture was heated and stirred for 43 minutes on a 100 ° C. oil bath. Then, after cooling the mixture at room temperature, 90 mL of toluene and 18 mL of water were added, and white crystals were precipitated, whereby the crystals were obtained by filtration (crystal 1), and the filtrate was cooled by ice and precipitated. The obtained crystals were again obtained by filtration (crystal 2). The filtrate obtained here was transferred to a separating funnel and allowed to stand. The aqueous layer was separated, and the organic layer was washed twice with 40 mL of a prescribed potassium hydroxide aqueous solution and again with 20 mL of water. Then, 2 mL of DME and 5 mL of water were added to the concentrate obtained by distillation. The crystal thus deposited was obtained by filtration (crystal 3). Crystals 1-3 were combined, washed with 10 mL of water, and dried under reduced pressure at 40 ° C. for 1 hour to obtain 2.44 g of the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.45 (s, 6H), 2.68 (s, 2H), 2.96 (t, J = 6.8 Hz, 2H), 3.77 (t, J = 6.8 Hz, 2H), 3.89 (s, 3H), 6.59 (d, J = 9.0 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H).

1- {1- [2- (7-methoxy-2,2-dimethyl-4-oxochroman-8-yl) ethyl] piperidin-4-yl} -N-methyl- It has become possible to industrially produce 1H-indole-6-carboxamide.

Claims (16)

8- (2-hydroxyethyl) -7-methoxy-2,2-dimethylchroman-4-one represented by the following formula (a-6):

The following formula (a) obtained by oxidizing:

(7-methoxy-2,2-dimethyl-4-oxochromen-8-yl) acetaldehyde represented by the following formula (b):

Coupling N-methyl-1- (piperidin-4-yl) -1H-indole-6-carboxamide represented by the following formula (i):

1- {1- [2- (7-methoxy-2,2-dimethyl-4-oxochroman-8-yl) ethyl] piperidin-4-yl} -N-methyl-1H- represented by Process for the preparation of indole-6-carboxamide. The method of claim 1, Formula (a-6):

8- (2-hydroxyethyl) -7-methoxy-2,2-dimethylchroman-4-one represented by the following formula (a-5):

The manufacturing method characterized by removing the protecting group of the compound represented by the following formula (a (X), X represents a protecting group of a hydroxyl group). The method according to claim 1 or 2, Formula (a-6):

8- (2-hydroxyethyl) -7-methoxy-2,2-dimethylchroman-4-one represented by the following formula (a-4):

In the compound represented by the formula (a (4), X represents a protecting group of a hydroxyl group) and methyl crotonic acid, the following formula (a-5):

A compound obtained by obtaining a compound represented by the formula (A-5), wherein X is defined in the same manner as above, and then removing the protecting group of the obtained compound (a-5). The method according to any one of claims 1 to 3, Formula (a-6):

8- (2-hydroxyethyl) -7-methoxy-2,2-dimethylchroman-4-one represented by the following formula (a-3):

In the compound represented by the following formula (a-3), X represents a protecting group of a hydroxyl group, an acid is reacted with the following formula (a-4):

To obtain a compound represented by the formula (a-4), X is the same as defined above, and then reacting the obtained compound (a-4) and methyl crotonic acid, the following formula (a-5):

It is obtained by obtaining the compound represented by the formula (wherein X is defined similarly to the above in formula (a-5)) and removing the protecting group of the obtained compound (a-5). The method according to any one of claims 1 to 4, Formula (a-6):

8- (2-hydroxyethyl) -7-methoxy-2,2-dimethylchroman-4-one represented by the following formula (a-2):

Protecting the hydroxyl group of 2- [2- (1-ethoxyethoxy) -6-methoxyphenyl] ethanol represented by the following formula (a-3):

After obtaining the compound represented by Formula (a-3), X represents a protecting group of a hydroxyl group, and then reacting the obtained compound (a-3) with an acid, the following formula (a-4):

To obtain a compound represented by the formula (a-4), X is the same as defined above, by reacting the obtained compound (a-4) and methyl crotonic acid, the formula (a-5):

It is obtained by removing the protecting group of the obtained compound (a-5) after obtaining the compound represented by the formula (In formula (a-5), X is defined similarly to the above.). The method according to any one of claims 1 to 5, Formula (a-6):

8- (2-hydroxyethyl) -7-methoxy-2,2-dimethylchroman-4-one represented by the following formula (a-1):

Ethyl acetate of [2- (1-ethoxyethoxy) -6-methoxyphenyl] acetic acid is reduced to formula (a-2):

2- [2- (1-ethoxyethoxy) -6-methoxyphenyl] ethanol represented by the above was obtained, and the hydroxyl group of the obtained compound was protected to give the following formula (a-3):

After obtaining the compound represented by Formula (a-3), X represents a protecting group of a hydroxyl group, and then reacting the obtained compound (a-3) with an acid, the following formula (a-4):

To obtain a compound represented by the formula (a-4), X is the same as defined above, by reacting the obtained compound (a-4) and methyl crotonic acid, the following formula (a-5):

It is obtained by removing the protecting group of the obtained compound (a-5) after obtaining the compound represented by the formula (In formula (a-5), X is defined similarly to the above.). The method according to any one of claims 1 to 6, Formula (a-6):

8- (2-hydroxyethyl) -7-methoxy-2,2-dimethylchroman-4-one represented by the following formula:

1- (1-ethoxyethoxy) -3-methoxybenzene and ethyl bromoacetate are reacted with the following formula (a-1):

[2- (1-Ethoxyethoxy) -6-methoxyphenyl] ethyl acetate represented by: was obtained, and the obtained compound (a-1) was reduced to give the following formula (a-2):

2- [2- (1-ethoxyethoxy) -6-methoxyphenyl] ethanol represented by the above was obtained, and the hydroxyl group of the obtained compound (a-2) was protected to give the following formula (a-3):

After obtaining the compound represented by Formula (a-3), X represents a protecting group of a hydroxyl group, and then reacting the obtained compound (a-3) with an acid, the following formula (a-4):

To obtain a compound represented by the formula (a-4), X is the same as defined above, by reacting the obtained compound (a-4) and methyl crotonic acid, the following formula (a-5):

It is obtained by removing the protecting group of the obtained compound (a-5) after obtaining the compound represented by the formula (In formula (a-5), X is defined similarly to the above.). The method according to any one of claims 2 to 7, X is a benzoyl group, The manufacturing method characterized by the above-mentioned. Compound represented by the following formula (II):

[In formula (II), X <^1> represents the protecting group of a hydrogen atom or a hydroxyl group. The method of claim 9, A compound wherein the protecting group of the hydroxyl group is a benzoyl group. Benzoic acid 2- (7-methoxy-2,2-dimethyl-4-oxochroman-8-yl) ethyl or 8- (2-hydroxyethyl) -7-methoxy-2,2-dimethylchroman- 4-on. Formula (c-3) below:

Reaction of the compound and methylamine represented by the following formula (i):

1- {1- [2- (7-methoxy-2,2-dimethyl-4-oxochroman-8-yl) ethyl] piperidin-4-yl} -N-methyl-1H- represented by Process for the preparation of indole-6-carboxamide. The method of claim 12, Formula (c-3):

The compound represented by the following formula (c-2):

It is obtained by hydrolyzing the compound represented by the manufacturing method characterized by the above-mentioned. The method of claim 12, Formula (c-3):

The compound represented by the following formula (a):

The compound represented by following formula (c-1):

By reacting the compound or its salt represented by following formula (c-2):

Obtaining the compound represented by the following, The manufacturing method characterized by obtaining by hydrolyzing the obtained compound. The method of claim 12, Formula (c-3):

The compound represented by the following formula (a):

The compound represented by following formula (b'-4):

The following formula (c-1) obtained by removing the protecting group of the compound represented by the formula [wherein Y represents a protecting group of a secondary amine] in the formula (b'-4):

By reacting the compound or its salt represented by following formula (c-2):

The compound represented by the above is obtained, and then obtained by hydrolyzing the obtained compound (c-2). The method of claim 15, Y is benzyloxycarbonyl.