JP2002053580A - Method for manufacturing tricyclic compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a manufacturing method capable of manufacturing a compound expressed by general formula (VIII) useful as a treating agent for anischuria easily in high yield and suitable for manufacturing it on an industrial scale, and to provide an intermediate to be used in the manufacturing method. SOLUTION: The method for manufacturing a compound expressed by general formula (VIII) comprises a process for manufacturing a compound expressed by general formula (IV) by subjecting a compound expressed by general formula (III) or a salt of the compound to Friedel-Crafts reaction. In the formulae, X is H or a lower alkyl group; Y is H, a lower alkyl group or the like; and R1 is a halogen atom or nitro.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a compound represented by the following general formula (VIII) useful as a therapeutic agent for urinary incontinence [hereinafter, a compound represented by the general formula (VIII) is converted to a compound (VIII)
Sometimes it is expressed. The same applies to compounds of other formula numbers.] And intermediates thereof.

[0002]

BACKGROUND OF THE INVENTION Compound (VIII)

[0003]

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[Wherein, X represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy or halogen atom, and Y represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted. Lower alkenyl, trifluoromethyl, substituted or unsubstituted lower alkoxy, amino, substituted or unsubstituted mono-lower alkyl-substituted amino, substituted or unsubstituted di-lower alkyl-substituted amino, substituted or unsubstituted aryl,
Substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkylamino, substituted or unsubstituted arylamino, substituted or unsubstituted alicyclic heterocyclic group or general formula (A)

[0005]

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Wherein n is 0 or 1, and P ¹ and P ²
Is the same or different and represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl or trifluoromethyl,
¹ and P ² may together form a cycloalkyl, and Q represents a group represented by hydroxy, substituted or unsubstituted lower alkoxy, amino or halogen atom). 46587 discloses its use as a therapeutic agent for urinary incontinence. The production method of compound (VIII) disclosed in WO98 / 46587 is as follows.

[0007]

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(Wherein X and Y have the same meanings as described above) The starting compound (X) can be prepared by a known method by converting 3-methylthiophene-2-carboxylic acid methyl ester to a radical initiator and a brominating agent. Produced by heating in the presence. Compound (XI) is compound (X) and commercially available compound (I
And X) in the presence of a base.

Compound (XII) is produced by reacting compound (XI) with an acetylating agent in the presence of a base. Compound (XIII) is obtained by hydrolyzing compound (XII) in the presence of a base, and then treating the carboxylic acid obtained with trifluoroacetic anhydride to form an acid anhydride, and then isolating the acid anhydride. The compound is produced by ring closure in the presence of a Lewis acid without performing the reaction.

Compound (VII) is produced by heating compound (XIII) in the presence of concentrated hydrochloric acid or the like. Further, compound (VIII) can be produced by reacting compound (VII) with compound (XXI) and then oxidizing the compound. However, in the above-mentioned production method, an intermediate having a methoxycarbonyl group on the thiophene ring [compound (XII)]
The compound (XIII) is produced by closing the ring, so that the positional isomer [compound (XIV)] is produced as a by-product, and the yields of the compound (XIII) are 28% and the compound (XIV) is 37%. %, Its regioselectivity is low, and there are many purification steps using silica gel chromatography, etc., so that this production method is not practically satisfactory as an industrial production method.

[0011]

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(Wherein, X is as defined above)

[0013]

DISCLOSURE OF THE INVENTION An object of the present invention is to provide a process suitable for industrial production, which can easily produce a compound (VIII) useful as a therapeutic agent for urinary incontinence in a high yield and the production process. It is to provide an intermediate used in the method.

[0014]

The present invention provides the following [1].
To [9] are provided. [1] General formula (VIII)

[0015]

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Wherein X and Y have the same meanings as defined above, respectively.

[0017]

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(Wherein R ¹ represents a halogen atom or nitro, and X has the same meaning as described above) or a salt thereof, which is subjected to a Friedel-Crafts reaction to obtain a compound represented by the general formula (IV)

[0019]

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(Wherein, R ¹ and X have the same meanings as described above), respectively. [2] General formula (I)

[0021]

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(Wherein R ^1a represents a halogen atom and X has the same meaning as described above) or a salt thereof and a compound of the general formula (II)

[0023]

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Wherein R ² represents a halogen atom, a lower alkylsulfonyloxy or a substituted or unsubstituted arylsulfonyloxy, and the compound represented by the general formula (IIIa)

[0025]

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(Wherein R ^1a and X are as defined above) or a salt thereof,
General formula (IVa) further obtained by a Friedel-Crafts reaction

[0027]

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Wherein R ^1a and X have the same ^{meanings as} defined above, respectively, and a compound represented by the general formula (V):

[0029]

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(Wherein R ³ and R ⁴ are the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, cycloalkyl, bicycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkanoyl) Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted benzocycloalkenyl, or substituted or unsubstituted cycloaliphatic hetero A compound represented by the general formula (VI)

[0031]

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(1) wherein R ³ , R ⁴ and X have the same meanings as defined above, respectively. [3] General formula (VIa)

[0033]

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Wherein R ^3a and R ^4a are each R ³ and
In the definition of R ⁴ , one of them represents a group that is not a hydrogen atom,
X has the same meaning as described above),
General formula (VII)

[0035]

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The method according to the above [2], comprising a step of producing a compound represented by the formula: wherein X is as defined above. [4] General formula (XVI)

[0037]

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(Wherein X is as defined above) or a salt thereof and a nitrite or a nitrite to obtain a diazonium derivative or a salt thereof, and the diazonium derivative or a salt thereof is obtained. Is reacted with (1) xanthogenic acid or a salt thereof to obtain a compound represented by the following general formula (XVII)
Wherein R ⁵ is C (S) OC ₂ H ₅ , or a salt thereof, which is further treated with a base,
(2) reacting with thiourea to obtain a compound represented by the following general formula (XVII), wherein R ⁵ is C (NH) NH ₂ , or a salt thereof, and treating this with a base, or (3) A) reacting with an alkali metal sulfide to obtain a compound represented by the following general formula (XVII), wherein R ⁵ is a hydrogen atom, or a salt thereof;

[0039]

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Wherein R ⁵ is C (S) OC ₂ H ₅ , C (N
H) NH ₂ or a hydrogen atom, and X has the same meaning as described above.]

[0041]

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(Wherein R ² has the same meaning as described above), and the compound represented by the general formula (IIIb)

[0043]

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(Wherein X is as defined above) or a salt thereof, and this compound is subjected to a Friedel-Crafts reaction to obtain a compound of the general formula (IVb)

[0045]

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Wherein X is as defined above, and this compound is reduced to give a compound of the general formula (VII)

[0047]

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[0048] The production method according to the above [1], comprising a step of producing a compound represented by the formula (wherein X has the same meaning as described above). [5] General formula (VII)

[0049]

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Wherein X is as defined above, the compound represented by the general formula (III)

[0051]

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Wherein R ¹ and X are as defined above, or a salt thereof,
Following the Friedel-Crafts reaction, the general formula (IV)

[0053]

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(Wherein, R ¹ and X have the same meanings as described above), respectively. [6] General formula (III)

[0055]

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Wherein R ¹ and X are as defined above, or a salt thereof,
General formula (IV) characterized by subjecting to a Friedel-Crafts reaction

[0057]

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(Wherein R ¹ and X are as defined above). [7] General formula (III)

[0059]

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(Wherein R ¹ and X are as defined above) or a salt thereof. [8] General formula (IV)

[0061]

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(Wherein R ¹ and X are as defined above).

[9] Formula (XVIIa)

Embedded image (Wherein, X has the same meaning as described above).

DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, the production method of the present invention will be described in detail. In the definition of each group of the general formula, lower alkyl, lower alkoxy, mono-lower alkyl-substituted amino,
Examples of the lower alkyl moiety of the di-lower alkyl-substituted amino and lower alkylsulfonyloxy include linear or branched C 1 to C 8, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, isopentyl, neopentyl, sec-pentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl, isooctyl and the like.

As the cycloalkyl, those having 3 to 8 carbon atoms,
For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like are included. Bicycloalkyl has 7 carbon atoms
~ 10, for example, bicyclo [2.2.1] heptyl, bicyclo [2.
2.2] octyl, bicyclo [3.3.1] nonyl and the like.

The lower alkenyl includes straight-chain or branched C2-C6, for example, vinyl, allyl, propenyl, methacryl, butenyl, crotyl, pentenyl, hexenyl and the like. As lower alkanoyl,
Having 1 to 8 carbon atoms, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl,
Hexanoyl, heptanoyl, octanoyl and the like are included.

The aryl moiety of aryl, arylamino and arylsulfonyloxy includes phenyl,
Naphthyl and the like. As the heteroaryl, a 5- or 6-membered monocyclic aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, a 3- or 8-membered fused two-ring or A tricyclic, condensed aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and the like;
More specifically, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnolinyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl,
Includes triazolyl, tetrazolyl, benzothienyl, benzofuryl, indolyl, indazolyl, benzimidazolyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, purinyl, and the like.

The aralkyl portion of aralkyl and aralkylamino includes, for example, benzyl, phenethyl, benzhydryl, naphthylmethyl and the like having 7 to 15 carbon atoms. The alkylene moiety in the heteroarylalkyl represents a group in which one hydrogen atom has been removed from the lower alkyl, and the heteroaryl moiety has the same meaning as the heteroaryl.

As benzocycloalkenyl, the number of carbon atoms
8-12, for example benzocyclobutenyl, indanyl,
Benzocyclohexenyl, benzocyclooctenyl and the like are included. As the alicyclic heterocyclic group, a 5- or 6-membered monocyclic alicyclic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, 3 to 8
A condensed alicyclic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, which is a condensed bicyclic or tricyclic fused ring, and more specifically, Pyrrolidinyl, piperidino, piperazinyl, piperidinyl, morpholino, thiomorpholino, homopiperidino,
Homopiperazinyl, tetrahydropyridinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl, tetrahydropyranyl, dihydrobenzofuranyl, morpholinyl, thiomorpholinyl and the like are included.

The halogen atom means each atom of fluorine, chlorine, bromine and iodine. As the substituents in the substituted lower alkyl, substituted lower alkoxy, substituted mono-lower alkyl-substituted amino, substituted di-lower alkyl-substituted amino, substituted cycloalkyl, substituted lower alkenyl and substituted lower alkanoyl, the same or different substituents 1 to 3, Examples include hydroxy, lower alkoxy, aryl, lower alkoxycarbonyl, lower alkanoyl and the like. The substitution position is not particularly limited. Here, the aryl and the lower alkanoyl are the same as those described above, respectively, and the lower alkyl portion of the lower alkoxy and the lower alkoxycarbonyl are the same as those described above for the lower alkyl.

The substituted aryl, substituted arylamino, substituted aralkyl, substituted aralkylamino, substituted heteroaryl, substituted heteroarylalkyl, substituted benzocycloalkenyl, substituted alicyclic heterocyclic group and substituted arylsulfonyloxy have the same substituents. Alternatively, there may be mentioned, for example, hydroxy, lower alkyl, lower alkoxy, aryl, aralkyl, lower alkoxycarbonyl, lower alkanoyl and the like having 1 to 3 substituents. The substitution position is not particularly limited. Here, as the lower alkyl, aryl, aralkyl and lower alkanoyl, the same as those described above can be mentioned, and as the lower alkyl part of the lower alkoxy and lower alkoxycarbonyl, the same as those described above for the lower alkyl can be mentioned. Can be

Examples of the alkali metal in the alkali metal sulfide include lithium, sodium, potassium and the like. Compound (I), compound (III), compound (XV
Examples of the diazonium derivative [I], the compound (XVII), the compound (XVI) [the compound (XIX) described below] or a salt of xanthogenic acid include, for example, lithium salt, sodium salt, potassium salt, magnesium salt, calcium salt, barium salt Alkali metal or alkaline earth metal salts, such as ammonium, etc.
Examples include ammonium salts such as tetramethylammonium, and organic amine addition salts such as morpholine salts and piperidine salts.

Examples of the nitrite include methyl nitrite, ethyl nitrite, propyl nitrite, isopropyl nitrite, butyl nitrite, isobutyl nitrite, isoamyl nitrite, and the like. For example, sodium nitrite, potassium nitrite and the like can be mentioned. Further, it is preferable that R ³ and R ⁴ are a combination of a substituted or unsubstituted aralkyl and a hydrogen atom.

In the production method of the present invention, compound (VII)
Can be produced by the following steps A-1 to B4 and steps B1 to B4. Further, compound (VIII) is compound (VI)
It can be produced by treating I) according to steps 5 and 6. Step A-1

[0074]

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(Wherein R ^1a , R ² , R ³ , R ⁴ and X have the same meanings as described above). The compound (IIIa) or a salt thereof is an equivalent to an excess amount of the compound (I) or a salt thereof. Compound (II) can be produced by reacting compound (II) without a solvent or in a solvent, if necessary, in the presence of a base. Usually, the reaction is at 0 ° C
It is preferably carried out at a temperature between the boiling point of the solvent used. Examples of the base include sodium hydroxide, potassium hydroxide and the like, and the use amount thereof is preferably 1 to 20 equivalents relative to compound (I) or a salt thereof.

The solvent is not particularly limited as long as it is inert in the reaction. Examples thereof include aliphatic hydrocarbon solvents such as hexane and cyclohexane, aromatic hydrocarbon solvents such as toluene, and non-aromatic solvents such as acetonitrile. Organic solvents, ether solvents such as dioxane, tetrahydrofuran, dimethoxyethane, and ethylene glycol dimethyl ether; halogenated hydrocarbon solvents such as dichloromethane, chloroform, and ethylene dichloride; and mixed solvents thereof can be used. The amount of use is preferably 1 to 100 times (volume) the compound (I) or a salt thereof.

Compound (I) or a salt thereof as a starting material is
It can be synthesized according to a known method (JP-A-3-255064, JP-A-3-173863, etc.). In addition, the compound represented by the general formula (XVa) which is a disulfide compound of the compound (I)

[0078]

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(Wherein R ^1a and X are the same as defined above) by a known method [Synthetic Co.
mmun., 16 , 819 (1986), etc.], and the reduced reaction solution may be used as it is as a raw material in Step 1 without purification. This reduction reaction is usually performed in a reaction solvent in the presence of a reducing agent at a temperature between 0 ° C. and the boiling point of the solvent used. Here, examples of the reducing agent include sodium borohydride and the like, and the amount of the reducing agent is preferably the compound (XVa)
1 to 10 equivalents, more preferably 1 to 4 equivalents.
The solvent is not particularly limited as long as it is inert in the reaction. For example, water, an alkaline aqueous solution such as lithium hydroxide, sodium hydroxide, or potassium hydroxide, or an aliphatic hydrocarbon solvent such as hexane or cyclohexane. , Aromatic hydrocarbon solvents such as toluene, non-aromatic organic solvents such as acetonitrile, hydrophilic solvents such as methanol, ethanol, dioxane, tetrahydrofuran, dimethoxyethane, and ethylene glycol dimethyl ether; halogens such as dichloromethane, chloroform, and ethylene dichloride. Or a mixed solvent thereof. The amount used is 1 to 100 relative to the compound (XVa).
It is preferable that the amount is twice (volume). Compound (XVa) is
Known methods [Farmaco. Ed. Sci., 22 (12), 989 (1967)
Etc.].

Compound (II) was prepared from 3-thiophene methanol by a known method [J. Am. Chem. Soc., 72 , 1655 (1950)].
Etc.]. 3-thiophene methanol can be obtained as a commercial product. Step A-2 Compound (IVa) is obtained by subjecting compound (IIIa) or a salt thereof to a Friedel-Crafts reaction according to a known method (JP-A-2-91040, etc.). , Can be manufactured. This reaction is carried out with the compound (III
The reaction can be carried out without solvent or in a solvent, if necessary, in the presence of a Lewis acid, using an equivalent or excess amount of an acid anhydride relative to a) or a salt thereof. Usually, the reaction is carried out at a temperature between -15 ° C and the boiling point of the solvent used. Examples of the acid anhydride include trifluoroacetic anhydride, acetic anhydride and the like. The amount of use is preferably 1 to 20 equivalents relative to compound (IIIa) or a salt thereof. Examples of the Lewis acid include boron trifluoride diethyl ether complex. The amount of use is preferably 0.1 to 1 equivalent relative to compound (IIIa) or a salt thereof. The solvent is not particularly limited as long as it is inert in the reaction,
For example, toluene, dichloromethane, ethylene dichloride, tetrachloroethane, tetrahydrofuran, dimethylformamide, dimethylsulfoxide and the like, or a mixed solvent thereof can be used. The amount used is 1 to 100 times (volume) the amount of compound (IIIa) or a salt thereof.
It is preferred that Step A-3 Compound (VI) can be prepared by subjecting compound (IVa) to a known method [Liebigs
Ann. Chem., 481 (1989), Chem. Abstr., 54 , 349 (196
0) etc.] to react with compound (V). This reaction is carried out using an equivalent to an excess amount of compound (V) with respect to compound (IVa), in the absence of a solvent or in a solvent, if necessary, in the presence of a catalyst. Examples of the catalyst include copper, copper powder, cuprous chloride, cupric chloride, cupric acetate and the like. The amount used depends on the type of solvent,
Although it is not particularly limited by conditions such as the reaction temperature, it is preferably 0.01 to 1 equivalent based on compound (IVa). Usually, the reaction is carried out at a temperature between 0 ° C. and the boiling point of the solvent to be used.
The solvent is not particularly limited as long as it is inert in the reaction, and examples thereof include toluene, dichloromethane, ethylene dichloride, tetrachloroethane, tetrahydrofuran, dimethylformamide, dimethylsulfoxide and the like, and a mixed solvent thereof. Its usage is
The amount is preferably 1 to 100 times (volume) the amount of the compound (IVa).

The compound (VI) can be precipitated by adding a hydrophilic solvent and water to the reaction solution after the reaction, so that the compound (VI) can be obtained in high yield and high quality without complicated operations such as extraction. Can be manufactured. As the hydrophilic solvent in this case, an alcohol solvent such as methanol, ethanol, and propanol, a ketone solvent such as acetone and ethyl methyl ketone, acetonitrile, and a mixed solvent thereof can be used. The amount of use is preferably 1 to 100 times (volume) the compound (VI).

When the compound (VIa) in which either R ³ or R ⁴ is not a hydrogen atom is obtained from the compound (VI), the compound (VII) is produced by further performing the step A-4. can do. When a compound [Compound (VII)] in which both R ³ and R ⁴ are hydrogen atoms in Compound (VI) is obtained, Step A-4 is not necessary, and the next step is Step 5. . Step A-4

[0083]

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(Wherein R ^3a , R ^4a and X have the same meanings as described above). Compound (VII) can be prepared by a known method [J. Che.
m. Soc., Perkin Trans. 1 , 2053 (1992), J. Org.
m., 60 , 6656 (1995), etc.]. This deprotection is achieved by the compound (VI
Using an equivalent or excess amount of acid or oxidizing agent relative to a),
The reaction is carried out without solvent or in a solvent, if necessary, in the presence of water. Usually, the reaction is carried out at a temperature between 0 ° C. and the boiling point of the solvent used. Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid,
Organic acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid, and trifluoromethanesulfonic acid. The amount of use is preferably 1 to 100 times (volume) the amount of the compound (VIa). As the oxidizing agent, 2,3-dichloro-5,6
-Dicyano-1,4-benzoquinone, ceric ammonium nitrate, manganese dioxide and the like can be used. The amount of use is preferably 1 to 50 equivalents to compound (VIa). The solvent is not particularly limited as long as it is inert in the reaction.For example, ethyl acetate, acetonitrile, methanol, ethanol, toluene, dichloromethane, ethylene dichloride, tetrachloroethane, tetrahydrofuran, dimethylformamide, dimethylsulfoxide and the like or a mixed solvent thereof are used. Etc. can be used. The amount of use is preferably 1 to 100 times (volume) the amount of the compound (VIa). When R ^3a or R ^4a is a substituted or unsubstituted aralkyl, catalytic reduction using Pd-C or the like may be performed according to a known method [Tetrahedron Lett., 28 , 515 (1987), etc.]. By doing so, deprotection can also be performed. When R ^3a or R ^4a is a substituted or unsubstituted lower alkanoyl, dehydration is performed by hydrazine treatment according to a known method [J. Org. Chem., 43 , 3711 (1978) and the like]. It can also be protected (provided that Pd- when R ^3a or R ^4a is formyl)
Deprotection is also possible by catalytic reduction using C or the like). Step B-1

[0085]

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Wherein R ^5a is C (S) OC ₂ H ₅ or C
(NH) NH ₂ , Z ⁻ represents an anionic species, and X has the same meaning as described above.] Examples of Z ⁻ include monovalent or polyvalent anionic species,
Preferably monovalent anionic species, such as chloride ions,
Bromide ion, iodide ion, tetrafluoroboron ion and the like can be mentioned.

The compound (XVI) or a salt thereof is reacted with a nitrite or a nitrite to obtain a diazonium derivative or a salt thereof, and the diazonium derivative or a salt thereof is reacted with (1) xanthogenic acid or a salt thereof to give a compound (XVIIb) or a salt thereof, which is further treated with a base or (2) reacted with thiourea to give a compound (XVIIb)
Compound (XVIIa) or a salt thereof can be produced by treating c) or a salt thereof and treating it with a base or (3) reacting with an alkali metal sulfide.

The starting compound (XVI) or a salt thereof can be produced according to a known method [J. Am. Chem. Soc., 27 , 649 (1905)]. The diazotization reaction of the compound (XVI) can be performed by a known method (Chemical Encyclopedia, Vol. 4, 16-17).
Page, Kyoritsu Shuppan, September 20, 1997, etc.) (Step B-1-1).

For example, compound (XIX) or a salt thereof can be prepared by reacting compound (XVI) or a salt thereof with a nitrite or a nitrite in a reaction solvent, if necessary, at -15 ° C.
It can be produced by reacting at a temperature between room temperature. The amount of the nitrite or nitrite to be used is preferably 1 to 10 equivalents, more preferably 1 to 2 equivalents, relative to compound (XVI) or a salt thereof. The solvent is not particularly limited as long as it is inert in the reaction.For example, hexane, an aliphatic hydrocarbon solvent such as cyclohexane, an aromatic hydrocarbon solvent such as toluene, a non-aromatic organic solvent such as acetonitrile, Examples thereof include ether solvents such as dioxane, tetrahydrofuran, dimethoxyethane, and ethylene glycol dimethyl ether; halogenated hydrocarbon solvents such as dichloromethane, chloroform, and ethylene dichloride; and mixed solvents thereof. The amount of the solvent to be used is 1 to 10 based on compound (XVI) or a salt thereof.
It is preferably 0 times (capacity).

Compound (XIX) obtained as described above
Or a salt thereof may not be isolated or purified, and the compound (XIX) or a reaction solution for producing the salt thereof may be used as it is.
It can be used for the next step. The reaction of compound (XIX) or a salt thereof with xanthogenic acid or a salt thereof, thiourea or an alkali metal sulfide can be carried out by a known method in a solvent.
[Tetrahedron Letters, 35 , 7549 (1994), etc.] (Step B-1-2). In this case, the response is 0
It is carried out at a temperature between ° C. and the boiling point of the solvent used. The amount of xanthic acid or a salt thereof, thiourea or alkali metal sulfide to be used is preferably 1 to 10 equivalents, more preferably 1 to 2 equivalents, relative to compound (XIX) or a salt thereof. As the solvent, those similar to those used in the above-mentioned Step B-1-1 can be mentioned, and the used amount thereof is 1 to 100 times (volume) based on the compound (XIX) or a salt thereof. Is preferred.

When the compound (XVIIb) or (XVIIc) or a salt thereof is obtained, the compound (XVIIb) or (XVIIb)
c) or their salts in the presence or absence of a solvent
The compound (XVIIa) or a salt thereof can be produced by treating with a base at a temperature between ℃ and the boiling point of the solvent used (Step B-1-3). Examples of the base include sodium hydroxide, potassium hydroxide, potassium carbonate and the like,
The amount used is preferably 1 to 20 equivalents relative to compound (XVIIb) or (XVIIc) or a salt thereof. As the solvent, those similar to the one used in the above-mentioned step B-1-1 can be mentioned. The amount of the compound (XVII
b) or (XVIIc) or a salt thereof, 1-1
It is preferably 00 times (capacity).

In the production of the compound (XVIIa) or a salt thereof, the compound represented by the general formula (XVb)

[0093]

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In some cases, a compound represented by the formula (wherein X has the same meaning as described above) is produced as a by-product, and this compound is subjected to a reduction reaction in the same manner as described in the above-mentioned step A-1. To give compound (XVIIa) or a salt thereof. Step B-2

[0095]

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(Wherein R ² and X have the same meanings as described above). Compound (IIIb) or a salt thereof can be produced by reacting compound (XVIIa) or a salt thereof with compound (II). it can. The reaction between compound (XVIIa) or a salt thereof and compound (II) can be carried out in the same manner as in the method described in the aforementioned step A-1. Step B-3

[0097]

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Wherein X is as defined above. Compound (IVb) can be produced by subjecting compound (IIIb) or a salt thereof to a Friedel-Crafts reaction. This Friedel-Crafts reaction can be performed in the same manner as in the method described in the above step A-2. Step B-4

[0099]

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(Wherein X is as defined above) Compound (VII) was prepared by a known method [Org.
n. Coll. Vol.II., 130, (1943) etc.]
It can be produced by treating with a reducing agent at a temperature between room temperature and the boiling point of the solvent used. As a reducing agent,
Stannous chloride dihydrate, iron and the like can be mentioned, and the use amount thereof is preferably 1 to 10 equivalents to compound (IVb). As the solvent, those similar to the one used in the above-mentioned step B-1-1 can be mentioned. The amount of use is preferably 1 to 100 times (volume) the amount of the compound (IVb). The reduction reaction can be performed by a known method [Org. Syn. C.
oll. Vol. V., 829, (1973) etc.], and catalytic reduction using Pd-C or the like can also be applied.

Using compound (VII) obtained in step A-4 or B-4 as a starting material, compound (VIII) useful as a therapeutic agent for urinary incontinence can be produced according to a known method (eg, WO98 / 46587). (Hereinafter, steps 5 and 6). Step 5

[0102]

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(Wherein X and Y are as defined above) Compound (XX) can be prepared by a known method [J. Med. Chem. 39 , 304 (1)
996) etc.], after introducing compound (XXI) into the corresponding carbonate with phenyl chloroformate or p-nitrophenyl chloroformate in an inert solvent such as tetrahydrofuran at a temperature between 0 and 25 ° C. Compound (VII) at the same temperature
Can be produced by reacting Also,
In the production method of the present invention, it is preferable that compound (XXI) is 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid.

Step 6 Compound (VIII) is prepared by converting compound (XX) into dichloromethane, chloroform, ethylene dichloride, in the presence of two or more equivalents of an oxidizing agent such as metachloroperbenzoic acid or magnesium monoperoxyphthalic acid hexahydrate. It can be prepared by treating in an inert solvent such as 1,1,2,2-tetrachloroethane at a temperature between 0 ° C. and a temperature between the boiling points of the solvents used for 1 to 24 hours.

In the production method of the present invention, the intermediate obtained in each step can be subjected to the next step without particular purification or isolation. Hereinafter, the present invention will be described more specifically with reference to Examples, but the present invention is not limited to these Examples.

[0106]

EXAMPLES The physicochemical data of each compound was measured by the following instruments. ¹ H-NMR: Nippon Bruker AC 300 (300 MHz) MS: Hitachi M-80B

Example 1 (1) 2-Fluoro-6- (3-thienylmethylthio) benzoic acid 3-thiophene methanol 69.3 g (607 mmol) was added to toluene 80
Dissolve in 0 mL, and under ice-cooling, 79.1 g (631 mmol) of thionyl chloride
Was added dropwise and stirred at room temperature for 1 hour. To this, a 2.27 mol / L aqueous solution of sodium hydroxide was added and washed to prepare a toluene solution of 3-chloromethylthiophene. Also, 2-fluoro
800 mL of water and 46.5 g (1160 mmol) of sodium hydroxide were added to and dissolved in 80.0 g (465 mmol) of -6-mercaptobenzoic acid, and the mixture was stirred at 40 ° C for 1 hour. To this solution, the previously prepared 3-
After adding a toluene solution of chloromethylthiophene and stirring for 2 hours, the reaction solution was separated and the toluene layer was removed. The aqueous layer was made acidic (pH 1) with 60 mL of concentrated hydrochloric acid, and extracted and separated with 800 mL of a mixed solvent of toluene / ethyl acetate = 2/1. The organic layer was concentrated under reduced pressure to 400 mL, 400 mL of toluene was added, and the mixture was again concentrated under reduced pressure to 400 mL, and then heated, cooled, and crystallized.
111 g (89% yield) of benzoic acid was obtained. ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 4.17 (2H,
s), 5.2-5.9 (1H, brs), 6.98 (1H, ddd, J = 8.2, 1.0
Hz, J _HF = 9.6 Hz), 7.07 (1H, dd, J = 5.0, 1.3 H
z), 7.10 (1H, d, J = 8.2 Hz), 7.11 (1H, dd, J = 3.
0, 1.3 Hz), 7.26 (1H, dd, J = 5.0, 3.0 Hz), 7.32
(1H, ddd, J = 8.2, 8.2 Hz, J _HF = 5.7 Hz) .MS (EI)
m / z = 268 (M ⁺ ).

(2) 9-fluoro-4,10-dihydrothieno
[3,2-c] [1] benzothiepin-10-one 150 g of 2-fluoro-6- (3-thienylmethylthio) benzoic acid (5
59 mmol) was dissolved in 870 mL of toluene, and 141 g (671 mmol) of trifluoroacetic anhydride was added dropwise under ice cooling, followed by stirring for 1 hour. Thereafter, the mixture was heated to 40 ° C. and stirred for 1 hour. The reaction solution was washed sequentially with water, a saturated aqueous solution of sodium hydrogen carbonate, and saturated saline. The organic layer was concentrated under reduced pressure to 300 mL, and after heating the obtained organic layer, 600 mL of isopropyl alcohol was added,
After cooling and crystallization, the precipitated solid is collected by filtration to give 9-fluoro-4,10-dihydrothieno [3,2-c] [1] benzothiepin.
121 g of -10-one (85% yield) was obtained. ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 3.98 (2H,
s), 6.95 (1H, d, J = 5.0Hz), 7.14 (1H, ddd, J = 7.
8, 1.2 Hz, J _HF = 10.0 Hz), 7.36 (1H, ddd, J = 7.8,
7.8 Hz, J _HF = 5.3 Hz), 7.44 (1H, dd, J = 7.8, 1.
2 Hz), 7.57 (1H, d, J = 5.0 Hz). MS (EI) m / z = 250 (M ⁺ ).

(3) 9-benzylamino-4,10-dihydrothieno [3,2-c] [1] benzothiepin-10-one 9-fluoro-4,10-dihydrothieno [3,2-c] [1] Benzoamine 1200 mL in 400 g (1600 mmol) of benzothiepin-10-one
Was added and the mixture was heated and stirred at 80 ° C. for 6 hours. The reaction solution was crystallized by dropwise addition of 4000 mL of ethanol and 4000 mL of water sequentially, and the precipitated solid was collected by filtration to obtain 9-benzylamino-4,10-.
518 g of dihydrothieno [3,2-c] [1] benzothiepin-10-one
(96% yield). ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 3.93 (2H,
s), 4.43 (2H, d, J = 5.5Hz), 6.68 (1H, dd, J = 8.
5, 1.1 Hz), 6.90 (1H, dd, J = 7.3, 1.1 Hz), 6.91
(1H, d, J = 5.1 Hz), 7.12 (1H, dd, J = 8.5, 7.3 H
z), 7.2-7.4 (5H, m), 7.50 (1H, d, J = 5.1 Hz), 8.33
(1H, brs) .MS (EI) m / z = 337 (M ⁺ ).

(4) 9-amino-4,10-dihydrothieno [3,2
-c] [1] benzothiepin-10-one 9-benzylamino-4,10-dihydrothieno [3,2-c] [1] benzothiepin-10-one 100 g (296 mmol) in ethyl acetate 2000m
L was added and the mixture was heated and stirred at 45 ° C. To this solution was added a solution of 69.3 g (296 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in ethyl acetate, and the mixture was heated and stirred at the same temperature for 2 hours. The reaction solution was washed sequentially with an aqueous sodium hydrogen sulfite solution and an aqueous sodium hydrogen carbonate solution. After decolorizing the organic layer with activated carbon, the solution was concentrated under reduced pressure to 500 mL, and ethanol 500
After adding and heating, the mixture was cooled and crystallized, and the precipitated solid was collected by filtration to give 9-amino-4,10-dihydrothieno [3,2-c] [1].
64 g of benzothiepin-10-one (87% yield) was obtained. ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 3.93 (2H,
s), 5.70 (2H, brs), 6.68 (1H, dd, J = 8.2, 1.3 Hz),
6.92 (1H, d, J = 5.1 Hz), 6.95 (1H, dd, J = 7.4,
1.3 Hz), 7.10 (1H, dd, J = 8.2, 7.4 Hz), 7.51 (1H,
d, J = 5.1 Hz) .MS (EI) m / z = 247 (M ⁺ ).

(5) (S)-(+)-9- (3,3,3-trifluoro-2-
(Hydroxy-2-methylpropanoylamino) -4,10-dihydrothieno [3,2-c] [1] benzothiepin-10-one (S)-(+)-3,3,3-trifluoro-2-hydroxy 2-Methylpropanoic acid (0.79 g, 5.0 mmol) was added to dimethylacetamide (10
dissolved in thionyl chloride (0.36 ml, 5.0 mm
ol), and the mixture was stirred at -15 to -5 ° C for 1 hour. To this reaction solution, 9-amino-4,10-dihydrothieno [3,2-c] [1] benzothiepin-10-one (0.62 g, 2.5 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, the resulting oily residue was dissolved in ethyl acetate (50 ml), and the organic layer was washed successively with a 5% aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous magnesium sulfate. . After filtering off the drying agent, the organic layer was concentrated under reduced pressure, and the obtained oily residue was purified by silica gel column chromatography (hexane / ethyl acetate = 5/1), and further triturated with hexane to obtain a residue.
(S)-(+)-9- (3,3,3-trifluoro-2-hydroxy-2-methylpropanoylamino) -4,10-dihydrothieno [3,2-c]
[1] Benzothiepin-10-one was obtained (0.60 g, 63%). ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 1.72 (s, 3H),
3.98 (s, 2H), 4.22 (br, 1H), 6.97 (d, 1H, J = 5.0
Hz), 7.43 (t, 1H, J = 8.0 Hz), 7.51 (d, 1H, J = 8.0
Hz), 7.62 (d, 1H, J = 5.0 Hz), 8.29 (d, 1H, J =
8.0 Hz), 10.62 (br, 1H).

(6) (S)-(+)-5,5-dioxo-9- (3,3,3-trifluoro-2-hydroxy-2-methylpropanoylamino) -4,10-dihydrothieno [ 3,2-c] [1] benzothiepin-10
-One (S)-(+)-9- (3,3,3-trifluoro-2-hydroxy-2-methylpropanoylamino) -4,10-dihydrothieno [3,2-c]
[1] Benzothiepin-10-one (0.3 g, 0.77 mmol) was dissolved in dichloromethane (30 ml), and meta-chloroperbenzoic acid (0.67 g, 3.5 equivalents) was added under ice-cooling, followed by stirring at room temperature for 3 hours. After the completion of the reaction, the reaction solution was 5% aqueous sodium sulfite,
The extract was washed sequentially with a 5% aqueous sodium hydrogen carbonate solution and saturated saline, and dried over anhydrous magnesium sulfate. After filtering off the drying agent, the organic layer was concentrated under reduced pressure, and the obtained oily residue was subjected to silica gel column chromatography (hexane / ethyl acetate).
= 3/1) and further triturated with isopropyl ether to give (S)-(+)-5,5-dioxo-9- (3,
3,3-trifluoro-2-hydroxy-2-methylpropanoylamino) -4,10-dihydrothieno [3,2-c] [1] benzothiepin-10-one was obtained (0.21 g, 64%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 1.74 (s, 3H), 4.
68 (s, 2H), 7.03 (d, 1H, J = 5.1 Hz), 7.74 (d, 1H,
J = 5.1 Hz), 7.76 (d, 1H, J = 8.3 Hz), 7.97-8.03
(m, 2H), 8.67 (d, 1H, J = 8.3 Hz), 10.80 (br, 1H).

Example 2 (1) 2- (ethoxythiocarbonylthio) -6-nitrobenzoic acid 6.46 g (30.0 mmol) of 6-nitroanthranilic acid was added to 27.3 m 2 of water.
L and a solution of 3.15 mL of a 10 mol / L aqueous sodium hydroxide solution were dissolved, and 2.24 g (31.5 mmol) of sodium nitrite was added thereto, followed by cooling with ice. This solution was ice-cooled with 5.0 mL of water and 12 mol / L hydrochloric acid 2.
The diazonium salt was prepared by slowly adding dropwise to 84 mL of the mixed solution while maintaining 0 to 5 ° C. In another container, 5.29 g (33.0 mmol) of potassium xanthate was dissolved in 15 mL of water, 60 mL of dichloromethane was added, and the prepared diazonium salt was added dropwise with stirring at room temperature. After the completion of dropping,
The pH was adjusted to 3 with 12 mol / L hydrochloric acid, and 60 mL of dichloromethane was added to carry out a liquid separation operation. The aqueous layer was extracted again with ethyl acetate, and the ethyl acetate layer was combined with the dichloromethane layer, dried over anhydrous magnesium sulfate, and concentrated. The concentrated residue is subjected to silica gel column chromatography (chloroform
/ Ethyl acetate = 1/1) to give 2.50 g (29% yield) of 2- (ethoxythiocarbonylthio) -6-nitrobenzoic acid. ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 1.33 (3H, t, J
= 7.1 Hz), 4.61 (2H, q, J = 7.1 Hz), 6.14 (1H, br
s), 7.70 (1H, dd, J = 8.4, 7.7 Hz), 7.95 (1H, dd,
J = 7.7, 1.1 Hz), 8.34 (1H, dd, J = 8.4, 1.1 Hz) MS (EI) m / z = 287 (M ⁺ )

(2) 2-mercapto-6-nitrobenzoic acid 2- (ethoxythiocarbonylthio) -6-nitrobenzoic acid 1
00 mg (0.35 mmol) was dissolved in ethanol, 91.9 mg (1.39 mmol) of potassium hydroxide was added, and the mixture was stirred at room temperature for 2 hours.
The reaction solution was acidified (pH 1) with 1 mol / L hydrochloric acid, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. After concentrating the ethyl acetate, the residue was dissolved in tetrahydrofuran (2 mL) and methanol (0.5 mL), and cooled with ice under sodium borohydride 15.
9 mg (0.42 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Thereafter, the mixture was made acidic (pH 1) with 1 mol / L hydrochloric acid, and ethyl acetate was added thereto to carry out liquid separation. The ethyl acetate layer was dried over anhydrous magnesium sulfate. The ethyl acetate layer was concentrated to give 2-mercapto-6-
31.3 mg (yield 45%) of nitrobenzoic acid were obtained. ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 4.16 (1H,
s), 6.13 (1H, brs), 6.73 (1H, dd, J = 8.0, 7.7 Hz),
7.70 (1H, dd, J = 7.7, 1.0 Hz), 7.92 (1H, dd, J =
8.0, 1.0 Hz) MS (EI) m / z = 199 (M ⁺ )

(3) 2-Nitro-6- (3-thienylmethylthio) benzoic acid 2- (ethoxythiocarbonylthio) -6-nitrobenzoic acid 3
00 mg (1.04 mmol) was dissolved in 3 mL of ethanol, 276 mg (4.06 mmol) of potassium hydroxide was added, and the mixture was stirred at room temperature for 1 hour. After the reaction solution was acidified (pH 1) with 1 mol / L hydrochloric acid, dichloromethane was added thereto for liquid separation, and the organic layer was concentrated. The concentrated residue was dissolved in 10 mL of tetrahydrofuran and 2.5 mL of methanol, 78.7 mg (2.08 mmol) of sodium borohydride was added, and the mixture was stirred for 1 hour. In another container, 143 mg (1.25 mmol) of 3-thiophene methanol was dissolved in 1.2 mL of dichloromethane, and 0.12 mL (1.56 mmol) of thionyl chloride was added dropwise under ice cooling, followed by stirring at room temperature for 30 minutes. After the reaction, water is added and the mixture is separated.
Further, the organic layer was sequentially washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride. This dichloromethane solution was added to the previous reaction solution, and the mixture was stirred for 1 hour. After that, the reaction solution was acidified (pH 1) with 6 mol / L hydrochloric acid, and further dichloromethane was added to separate the mixture. The organic layer was dried over anhydrous magnesium sulfate and concentrated, and the concentrated residue was purified by silica gel column chromatography (hexane / ethyl acetate = 7/3).
188 mg (61% yield) of 2-nitro-6- (3-thienylmethylthio) benzoic acid were obtained. ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 4.17 (2H,
s), 5.30 (1H, brs), 7.00 (1H, dd, J = 3.0, 1.3 Hz),
7.05 (1H, dd, J = 5.0, 1.3 Hz), 7.27 (1H, dd, J =
5.0, 3.0 Hz), 7.43 (1H, t, J = 8.0 Hz), 7.52 (1H,
dd, J = 8.0, 1.2Hz), 8.08 (1H, dd, J = 8.0, 1.2 H
z) MS (EI) m / z = 295 (M ⁺ )

(4) 9-nitro-4,10-dihydrothieno [3,2
-c] [1] Benzothiepin-10-one 2-nitro-6- (3-thienylmethylthio) benzoic acid 50.0mg
(0.174 mmol) was dissolved in 1 mL of dichloromethane,
0.041 mL (0.291 mmol) of trifluoroacetic anhydride was added and 3.
Stirred at room temperature for 5 hours. Under ice cooling again, trifluoroacetic anhydride (0.041 mL, 0.291 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Then, under ice cooling, boron trifluoride diethyl ether complex 2m
g was added and stirred for 10 minutes. Dichloromethane and a saturated aqueous solution of sodium hydrogen carbonate were added to the reaction solution, and the mixture was separated.The organic layer was dried over anhydrous magnesium sulfate and concentrated, and 9-nitro-4,1 was added.
0-dihydrothieno [3,2-c] [1] benzothiepin-10-one 4
2.4 mg (90% yield) were obtained. ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 4.08 (2H,
s), 7.00 (1H, d, J = 5.0Hz), 7.48 (1H, dd, J = 8.
2, 7.8 Hz), 7.65 (1H, d, J = 5.0 Hz), 7.81 (1H, d
d, J = 8.2, 1.2 Hz), 7.83 (1H, dd, J = 7.8, 1.2 H
z) MS (EI) m / z = 277 (M ⁺ )

(5) 9-nitro-4,10-dihydrothieno [3,2
-c] [1] benzothiepin-10-one 1.82 g (10.0 mmol) of 6-nitroanthranilic acid in 12.8 mL of water
And a solution of 12 mol / L hydrochloric acid (1.8 mL) dissolved in sodium nitrite aqueous solution [747 mg (10.5 mmol) of sodium nitrite / water
3.6 mL] was slowly added dropwise while maintaining 0 to 5 ° C., followed by stirring for 30 minutes to prepare a diazonium salt. In a separate container, 2.26 g (12.0 mmol) of potassium xanthate and 4.23 g (30.6 mmol) of potassium carbonate were dissolved in 9 mL of water, the temperature was raised to 50 ° C., and the diazonium salt prepared above was added dropwise. Thereafter, the temperature was further raised to 80 ° C., and after reacting for 2 hours, a 2-mercapto-6-nitrobenzoic acid solution was prepared. In another container, 1.41 mL (15.0 mmol) of 3-thiophene methanol was dissolved in 18 mL of toluene, and 1.38 mL of thionyl chloride (18.0 mm
oL) was added dropwise, followed by stirring for 30 minutes, followed by sequential washing with 18 mL of water and 18 mL of a saturated aqueous sodium hydrogen carbonate solution to prepare a toluene solution of 3-chloromethylthiophene. This toluene solution was added to the previously prepared 2-mercapto-6-nitrobenzoic acid solution and reacted at 40 ° C. for 3 hours. After liquid separation of the reaction solution, the aqueous layer was adjusted to pH 1 to 2 with 8 mL of 12 mol / L hydrochloric acid, and then extracted with 60 mL of ethyl acetate. The extract was concentrated to dryness, and 18 mL of toluene was added to the residue to prepare a suspension of 2-nitro-6- (3-thienylmethylthio) benzoic acid in toluene. To this suspension was added 1.95 mL (13.8 mmol) of trifluoroacetic anhydride,
The resulting solid was collected by filtration, dried, and 9-nitro-4,10-dihydrothieno [3,2-c] [1] benzothiepin-1.
1.59 g of 0-one [57% yield based on 6-nitroanthranilic acid] was obtained.

The 9-nitro-4,10-dihydrothieno [3,2-c] [1] benzothiepin-10-one obtained in the above (1) to (4) or (5) is replaced with the following (6) 9-amino-4,10-dihydrothieno [3,2-c] [1] benzothiepin-10-
Got on.

(6) 9-amino-4,10-dihydrothieno [3,2
-c] [1] Benzothiepin-10-one 16.3 mg (0.072 mmol) of stannous chloride dihydrate was dissolved in 0.5 mL of ethanol and 0.5 mL of 12 mol / L hydrochloric acid, and 9-nitro-
After adding 5 mg (0.018 mmol) of 4,10-dihydrothieno [3,2-c] [1] benzothiepin-10-one and stirring for 1 hour, the temperature was raised to 100 ° C., and the mixture was further stirred for 1 hour. After cooling to room temperature
The pH was adjusted to around 9 with a 0.5 mol / L aqueous sodium hydroxide solution, and ethyl acetate was added to carry out liquid separation. The organic layer was dried over anhydrous magnesium sulfate and concentrated, and 9-amino-4,10-dihydrothieno [3,2-c] [1] benzothiepin-10-one 4 mg (90% yield)
I got The obtained 9-amino-4,10-dihydrothieno [3,2-
c] [1] Benzothiepin-10-one was treated in the same manner as (5) and (6) of Example 1 to give (S)-(+)-5,5-dioxo-9- (3,3 , 3-Trifluoro-2-hydroxy-2-methylpropanoylamino) -4,10-dihydrothieno [3,2-c] [1]
Benzothiepin-10-one can be produced.

[0120]

INDUSTRIAL APPLICABILITY According to the present invention, a production method suitable for industrial production in which compound (VIII) useful as a therapeutic agent for urinary incontinence can be easily produced in good yield and an intermediate used in the production method A body is provided.

 ──────────────────────────────────────────────────続 き Continuing from the front page (72) Inventor Shinichiro Mohri 1-53-1, Takasu-cho, Sakai City, Osaka Prefecture Kyowa Hakko Kogyo Co., Ltd. Fermentation Industry Co., Ltd. Pharmaceutical Research Institute F term (reference) 4C071 AA01 AA07 BB01 CC22 EE13 FF26 HH08 JJ01 KK01 KK11 LL01 4H039 CA42 CA71 CG20 CG90

Claims (9)

[Claims] 1. A compound of the general formula (VIII) [In the formula, X represents a hydrogen atom, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkoxy or a halogen atom, and Y represents a hydrogen atom, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkenyl. ,
Trifluoromethyl, substituted or unsubstituted lower alkoxy, amino, substituted or unsubstituted mono-lower alkyl-substituted amino, substituted or unsubstituted di-lower alkyl-substituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl A substituted or unsubstituted aralkylamino, a substituted or unsubstituted arylamino, a substituted or unsubstituted alicyclic heterocyclic group, or a compound represented by the general formula (A): (In the formula, n is 0 or 1, P ¹ and P ² are the same or different and are a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted Or represents unsubstituted aralkyl or trifluoromethyl, or P ¹ and P ² may together form cycloalkyl, and Q represents hydroxy, substituted or unsubstituted lower alkoxy, amino or halogen atom Represents a group represented by formula (I)), wherein the compound represented by the general formula (III): Wherein R ¹ represents a halogen atom or nitro, and X has the same meaning as defined above, or a salt thereof, which is subjected to a Friedel-Crafts reaction to obtain a compound represented by the general formula (IV) Embedded image Wherein R ¹ and X have the same meanings as defined above, respectively. 2. A compound of the general formula (I) (Wherein R ^1a represents a halogen atom, and X has the same meaning as described above) or a salt thereof, and a compound represented by the general formula (II): Wherein R ² represents a halogen atom, a lower alkylsulfonyloxy or a substituted or unsubstituted arylsulfonyloxy, and reacted with a compound represented by the following general formula (IIIa): (Wherein R ^1a and X have the same meanings as described above) or a salt thereof, respectively, according to Friedel-Crafts (Fr.
iedel-Crafts) reaction, and the resulting general formula (IV
a) embedded image (Wherein R ^1a and X have the same meanings as described above), respectively, and a compound represented by the general formula (V): (Wherein, R ³ and R ⁴ are the same or different and each represents a hydrogen atom,
Substituted or unsubstituted lower alkyl, cycloalkyl,
Bicycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkanoyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroarylalkyl, (Represented by a substituted or unsubstituted benzocycloalkenyl or a substituted or unsubstituted alicyclic heterocyclic group), (Wherein, R ³ , R ⁴ and X are as defined above)
The method according to claim 1, comprising a step of producing a compound represented by the formula: 3. A compound of the general formula (VIa) (Wherein R ^3a and R ^4a are each defined as R ³ and R ⁴ ,
One of which represents a group which is not a hydrogen atom, X is as defined above, and the compound represented by the general formula (VI
I) The production method according to claim 2, comprising a step of producing a compound represented by the formula (wherein, X has the same meaning as described above). 4. A compound of the general formula (XVI) (Wherein X is as defined above) or a salt thereof and a nitrite or a nitrite to obtain a diazonium derivative or a salt thereof. ) Reacting with xanthogenic acid or a salt thereof to obtain a compound represented by the following general formula (XVII) wherein R ⁵ is C (S) OC ₂ H ₅ or a salt thereof, and further treating the compound with a base , (2) reacting with thiourea to obtain a compound represented by the following general formula (XVII), wherein R ⁵ is C (NH) NH ₂ , or a salt thereof, which is further treated with a base, or 3) reacting with an alkali metal sulfide to obtain a compound represented by the following formula (XVII), wherein R ⁵ is a hydrogen atom, or a salt thereof; [In the formula, R ⁵ represents C (S) OC ₂ H ₅ , C (NH) NH ₂ or a hydrogen atom, and X has the same meaning as described above.] This compound is represented by the general formula (II): (Wherein R ² has the same meaning as described above), and reacted with a compound represented by the general formula (IIIb): (Wherein X is as defined above) or a salt thereof, and this compound is subjected to a Friedel-Crafts reaction to obtain a compound represented by the general formula (IVb). ] Wherein X is as defined above, and this compound is reduced to give a compound of the general formula (VII) The production method according to claim 1, comprising a step of producing a compound represented by the formula (wherein, X has the same meaning as described above). 5. A compound of the formula (VII) (Wherein X has the same meaning as described above) in a process for producing a compound represented by the following general formula (III): (Wherein R ¹ and X have the same meanings as described above) or a salt thereof, respectively, by Friedel-Crafts (Fr.
iedel-Crafts) to give a compound of the general formula (IV) Wherein R ¹ and X have the same meanings as defined above, respectively. 6. A compound of the general formula (III) (Wherein R ¹ and X have the same meanings as described above) or a salt thereof, respectively, by Friedel-Crafts (Fr.
iedel-Crafts), characterized by the general formula (IV): (Wherein, R ¹ and X have the same meanings as described above), respectively. 7. A compound of the general formula (III) (Wherein, R ¹ and X have the same meanings as described above), or a salt thereof. 8. A compound of the general formula (IV) (Wherein R ¹ and X have the same meanings as described above). 9. A compound of the general formula (XVIIa) (Wherein, X has the same meaning as described above).