JPH11199574A - Production of dibenzothiazepine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To easily obtain at high yield the subject compound useful as an intermediate of antipsychotic agents from readily available raw materials by using a specified nitrobenzene derivative and a thiosalicylic acid derivative as starting materials. SOLUTION: This compound of formula III is obtained by reaction of (A) a compound of formula I [R<1> to R<4> are each H, a (substituted) alkyl(carbonyl), an alkoxy, an aryl(oxy) or an arylcarbonyl; X is a halogen] with (B) a compound of formula II (R<5> to R<8> are each the same as R<1> ) to obtain a 2-nitro-2'- carboxy-diphenylsulfide derivative, reduction of the resultant derivative to obtain the corresponding-2-amino-2'-carboxy-diphenylsulfide derivative and then dehydrocondensation of the resultant compound. The sulfidation reaction between the components A and B is preferably performed in an organic solvent in the presence of a base.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a method for producing a dibenzothiazepine derivative useful as an intermediate of a pharmaceutical.
The present invention is particularly useful as 11- [4-
The present invention relates to a method for producing a dibenzothiazepine derivative represented by the following general formula (5), which is useful as an intermediate of (2- (2-hydroxyethoxy) ethyl] -1-piperazinyldibenzothiazepine and a derivative thereof.

[0002]

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(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
R ⁶ , R ⁷ , and R ⁸ may be the same or different from each other, and may be a hydrogen atom, or an optionally substituted alkyl, alkoxy, alkylcarbonyl, aryl, aryloxy, or aryloxy group. Represents a carbonyl group).

[0004]

2. Description of the Related Art A dibenzothiazepine derivative represented by the above general formula (5) is described in EP-0282236-A1, and this dibenzothiazepine derivative is used as a raw material and is useful as an antipsychotic drug. (2- (2-
(Hydroxyethoxy) ethyl] -1-piperazinyl dibenzothiazepine derivatives. That is, dibenzo [b, f] [1,4] thiazepin-11-one, which is a representative compound of the diazepine derivative of the general formula (5), is reacted with phosphorus oxychloride to obtain an 11-chloro-dibenzothiazepine derivative. And then 11-
Piperazine is added to the chloro-dibenzothiazepine derivative to obtain an 11-piperazinyl-dibenzothiazepine derivative, and finally, the 11-piperazinyl-dibenzothiazepine derivative and 2-chloroethoxyethanol are added under basic conditions. After the reaction, the above 11- [4- (2- (2
-Hydroxyethoxy) ethyl] -1-piperazinyldibenzothiazepine derivative.

[0005] The above-mentioned EP-02282236-A1 discloses dibenzo [b, f] [1,4] thiazepine-11.
As a production method of ON, a method utilizing a cyclization reaction of phenyl 2- (phenylthio) phenylcarbamate or a similar compound thereof (in the presence of polyphosphoric acid) is described.

Helv. Chim. Acta. 42 volumes,
On page 1263 (1959), a methyl thiosalicylate derivative and a 2-halogenated-nitrobenzene derivative are described.
The mixture was reacted by heating in the presence of sodium to give 2-nitro-2 ′
Synthesizing a carboxy-diphenyl sulfide derivative,
This is reduced using Raney nickel to give 2-amino-
2′-carboxy-diphenyl sulfide derivative,
Finally, a method for producing a dibenzothiazepine derivative by reacting at a high temperature is described.

[0007] Org. Prep. Proced. In
t. , P. 287 (1974) discloses that a thiosalicylate derivative and a 2-iodo-nitrobenzene derivative are heated in the presence of sodium methylate and copper, and then treated with an alkali and an acid to give 2-nitro-2. '-Carboxy-diphenyl sulfide derivative was synthesized and reduced with an aqueous ammonia solution of ferrous sulfate to give 2-amino-
2′-carboxy-diphenyl sulfide derivative,
Finally, a method of producing a dibenzothiazepine derivative by reacting under heating and reduced pressure is described.

WO 92/19607 discloses that 2-aminothiophenol is reacted with 2-fluorobenzonitrile to obtain 2- (2-aminophenylthio) benzonitrile, which is then hydrolyzed. And 2-
A method for producing a dibenzothiazepine derivative of the general formula (5) by converting (2-carboxyphenylthio) aniline and finally subjecting this compound to a cyclization reaction is described.

As described above, several methods have already been known as methods for producing the dibenzothiazepine derivative of the general formula (5), but these methods have low yields and require high temperatures for the reaction. There are problems that require improvement as an industrial production method, such as the necessity of using a certain special raw material or the use of a compound that requires industrially complicated post-treatment.

[0010]

Accordingly, the present invention provides an industrially advantageous method for producing the dibenzothiazepine derivative of the general formula (5), that is, using a readily available starting compound, It is an object of the present invention to provide a method for producing a dibenzothiazepine derivative in high yield without complicated post-treatment.

[0011]

Means for Solving the Problems The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have been able to obtain a high yield and a simple method by using easily available nitrobenzene derivatives and thiosalicylic acid derivatives. The present invention has been completed by finding a novel method capable of producing a dibenzothiazepine derivative by operation.

The present invention provides a compound represented by the general formula (1):

[0013]

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Wherein R ¹ , R ² , R ³ and R ⁴
May be the same or different, and represent a hydrogen atom,
Or an alkyl group, an alkoxy group, an alkylcarbonyl group, an aryl group, an aryloxy group or an arylcarbonyl group which may have a substituent;
Represents a halogen atom) and a nitrobenzene derivative represented by the general formula (2):

[0015]

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Wherein R ⁵ , R ⁶ , R ⁷ and R ⁸
May be the same or different, and represent a hydrogen atom,
Or a thiosalicylic acid derivative represented by an alkyl group, an alkoxy group, an alkylcarbonyl group, an aryl group, an aryloxy group, or an arylcarbonyl group which may have a substituent; :

[0017]

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(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
R ⁶ , R ⁷ , and R ⁸ have the same meanings as described above), and then form the 2-nitro-2′-carboxy-diphenyl sulfide derivative.
Reducing the carboxy-diphenyl sulfide derivative,
General formula (4):

[0019]

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Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
R ⁶ , R ⁷ , and R ⁸ have the same meanings as described above), and then form the 2-amino-2′-carboxy-diphenyl sulfide derivative,
A carboxy-diphenyl sulfide derivative is dehydrated and condensed, characterized by the general formula (5):

[0021]

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(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
R ⁶ , R ⁷ , and R ⁸ have the same meanings as described above).

The present invention also provides a compound of the general formula (3):

[0024]

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Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
R ⁶ , R ⁷ , and R ⁸ may be the same or different from each other, and may be a hydrogen atom, or an optionally substituted alkyl, alkoxy, alkylcarbonyl, aryl, aryloxy, or aryloxy group. A 2-nitro-2′-carboxy-diphenyl sulfide derivative represented by the following formula (4):

[0026]

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(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
R ⁶ , R ⁷ , and R ⁸ have the same meanings as described above), and then form the 2-amino-2′-carboxy-diphenyl sulfide derivative,
A carboxy-diphenyl sulfide derivative is dehydrated and condensed, characterized by the general formula (5):

[0028]

Embedded image

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
R ⁶ , R ⁷ , and R ⁸ have the same meanings as described above). The present invention also provides a compound represented by the general formula (3):
There are also nitro-2'-carboxy-diphenyl sulfide derivatives.

The method for producing the dibenzothiazepine derivative of the general formula (5) of the present invention can be represented, for example, by the following reaction scheme.

[0031]

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[0032]

BEST MODE FOR CARRYING OUT THE INVENTION In the production method of the present invention, the “optionally substituted alkyl group” represented by R ^{1 to} R ⁸ is defined as (1) “an unsubstituted carbon atom having 1 to 10 carbon atoms. Or 2 linear or branched alkyl groups ”or (2)“ a linear or branched alkyl group having 1 to 10 carbon atoms having a substituent ”.

(1) "1 carbon atom having no substituent"
As the "10 to 10 linear or branched alkyl groups", a linear or branched alkyl group having 1 to 8 carbon atoms (particularly 1 to 5 carbon atoms) is preferable, and for example, a methyl group , Ethyl group, propyl group (including isomer), butyl group (including isomer), pentyl group (including isomer),
Hexyl groups (including isomers), heptyl groups (including isomers), octyl groups (including isomers), nonyl groups (including isomers), decyl groups (including isomers), and the like can be given. Preferably, methyl, ethyl, propyl (including isomers), butyl (including isomers), pentyl (including isomers), hexyl (including isomers),
A heptyl group (including an isomer), an octyl group (including an isomer), particularly preferably a methyl group, an ethyl group, a propyl group (including an isomer), a butyl group (including an isomer),
Pentyl group (including isomers).

(2) "1 carbon atom having a substituent"
Examples of the alkyl portion of the "10 to 10 linear or branched alkyl groups" include the alkyl groups described in the above (1).

"Substituents having 1 to 10 carbon atoms
Substituents on the “linear or branched alkyl group” may be substituted at any position of the alkyl moiety, (2-
1) For example, methoxy group, ethoxy group, propoxy group (including isomer), butoxy group (including isomer), pentyloxy group (including isomer), hexyloxy group (including isomer), heptyloxy group Linear or branched having 1 to 10 carbon atoms such as (including isomers), octyloxy group (including isomers), nonyloxy group (including isomers), and decyloxy group (including isomers) Linear or branched having 1 to 5 carbon atoms such as an alkoxy group, (2-2) acetyl group, propionyl group (including isomers), butanoyl group (including isomers), and pentanoyl group An alkylcarbonyl group having 2 to 6 carbon atoms having an alkyl group portion, (2-3) “optionally substituted phenylcarbonyl group”, or (2-4) “optionally substituted phenyl group” may be mentioned. Can.

Examples of the "phenylcarbonyl group which may be substituted" in (2-3) include a "phenylcarbonyl group having no substituent" or a "phenylcarbonyl group having a substituent". it can. Examples of the “phenyl group which may be substituted” in (2-4) include a “phenyl group having no substituent” or a “phenyl group having a substituent”. "Substituted phenylcarbonyl group" or "substituted phenyl group"
Examples of the substituent include a phenyl group, a phenylcarbonyl group, an alkyl group as described above, an alkoxy group as described above, and an alkylcarbonyl group as described above.

In the production method of the present invention, the “optionally substituted alkoxy group” represented by R ^{1 to} R ⁸ is represented by (3)
"A straight-chain or branched alkoxy group having 1 to 10 carbon atoms having no substituent and an alkoxy group having 1 to 10 carbon atoms having a substituent", or (4) "A carbon atom having a substituent and having no substituent" An alkoxy group having 1 to 10 carbon atoms having a linear or branched alkyl group portion of 1 to 10 "is meant.

The “(3) alkoxy group having 1 to 10 carbon atoms having no substituent and having 1 to 10 carbon atoms and having a linear or branched alkyl group portion” includes:
The alkoxy group described in the above (2-1) can be mentioned. (4) "1 to 1 carbon atoms having a substituent"
As a substituent of "an alkoxy group having 1 to 10 carbon atoms having 10 linear or branched alkyl moieties",
The alkyl group described in (1) above, the alkylcarbonyl group having 2 to 6 carbon atoms described in (2-2), (2-3)
Described in the "optionally substituted phenylcarbonyl group",
The "phenyl group which may be substituted" described in (2-4) can be mentioned.

In the production method of the present invention, "an optionally substituted alkylcarbonyl group" represented by R ^{1 to} R ⁸
Is (5) "unsubstituted carbon atoms having 1 to 10 carbon atoms."
Alkylcarbonyl groups having 2 to 11 carbon atoms having two linear or branched alkyl moieties ", (6)" linear or branched having 1 to 10 carbon atoms having substituents " An alkylcarbonyl group having from 2 to 11 carbon atoms having an alkyl-like moiety.

(5) Alkyl moiety of "alkylcarbonyl group having 2 to 11 carbon atoms having a linear or branched alkyl group moiety having 1 to 10 carbon atoms and having no substituent" Examples thereof include the alkyl groups described in the above (1). And, as the substituent of (6) an alkylcarbonyl group having 2 to 11 carbon atoms having a linear or branched alkyl moiety having 1 to 10 carbon atoms having a substituent, The substituent of the alkyl group described in the above (2) can be mentioned.

In the production method of the present invention, the “aryl group which may have a substituent” represented by R ^{1 to} R ⁸ is represented by (7)
"Aryl group having no substituent" or (8)
It means “aryl group having a substituent”.

Examples of (7) the "aryl group having no substituent" include a phenyl group, a naphthyl group and an anthryl group.
A naphthyl group, particularly preferably a phenyl group. (8)
Examples of the substituent of the “aryl group having a substituent” include the substituents of the alkyl group described in the above (2).

In the production method of the present invention, the “aryloxy group which may have a substituent” represented by R ^{1 to} R ⁸ is
(9) An "aryloxy group having an aryl moiety having no substituent" or (10) an "aryloxy group having an aryl moiety having a substituent".

As the aryl group of the "aryloxy group having an aryl group part having no substituent" of (9), the aryl group described in the above (7) can be mentioned. Examples of the substituent of the “aryloxy group having an aryl group part having a substituent” in (10) include the substituents of the alkyl group described in the above (2).

In the production method of the present invention, an “arylcarbonyl group which may have a substituent” represented by R ^{1 to} R ⁸
Means (11) “arylcarbonyl group having an aryl group part having no substituent” or (12) “arylcarbonyl group having an aryl group part having a substituent”.

As the aryl group of the “arylcarbonyl group having an aryl group part having no substituent” in (11), the aryl group described in the above (7) can be mentioned. As a substituent of the “arylcarbonyl group having an aryl group part having a substituent” in (12),
The substituent of the alkyl group described in the above (2) can be mentioned.

R ^{1 to} R ⁸ may be the same or different from each other, and are preferably a hydrogen atom, an alkyl group, an alkoxy group, an alkylcarbonyl group, an aryl group, an aryloxy group, or an arylcarbonyl group. , A hydrogen atom, an alkyl group, an alkoxy group or an alkylcarbonyl group.

In the production method of the present invention, examples of the halogen atom represented by X include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, preferably a fluorine atom, a chlorine atom and a bromine atom.

In the first step, the nitrobenzene derivative represented by the general formula (1) and the thiosalicylic acid derivative represented by the general formula (2) are reacted in a solvent, preferably in the presence of a base, to give 2- A nitro-2'-carboxy-diphenyl sulfide derivative is produced.

Specific examples of the nitrobenzene derivative represented by the general formula (1) used in the first step of the present invention include, for example, 2-chloronitrobenzene, 2-bromonitrobenzene, 2-fluoronitrobenzene, 2-yo-nitro-benzene. Donitrobenzene, 2-chloro-5-methoxy-nitrobenzene, 2-bromo-5-methoxy-nitrobenzene,
2-fluoro-5-methoxy-nitrobenzene, 2-iodo-5-methoxy-nitrobenzene, 2-chloro-5
-Methyl-nitrobenzene, 2-bromo-5-methyl-
Nitrobenzene, 2-fluoro-5-methyl-nitrobenzene, 2-iodo-5-methyl-nitrobenzene, 2
-Chloro-5-phenyl-nitrobenzene, 2-bromo-5-phenyl-nitrobenzene, 2-fluoro-5-
Phenyl-nitrobenzene, 2-iodo-5-phenyl-nitrobenzene, 2-chloro-5-acetyl-nitrobenzene, 2-bromo-5-acetyl-nitrobenzene, 2-fluoro-5-acetyl-nitrobenzene or 2-yo- De-5-acetyl-nitrobenzene can be mentioned, preferably 2-chloronitrobenzene or 2-bromonitrobenzene.

Specific examples of the thiosalicylic acid derivative represented by the general formula (2) used in the production method of the present invention include thiosalicylic acid, 5-methoxy-thiosalicylic acid,
-Methyl-thiosalicylic acid, 5-phenyl-thiosalicylic acid or 5-acetyl-thiosalicylic acid, preferably thiosalicylic acid or 5-methoxythiosalicylic acid.

The nitrobenzene derivative of the general formula (1) is
Usually 0.7 to 10 per mol of thiosalicylic acid derivative
It is preferably used in a molar amount, particularly 1.0 to 5 times the molar amount.

The solvent used in the first step is not particularly limited as long as it does not participate in the reaction. For example, water, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyridone, Amide-based organic solvents such as dimethylimidazolidone, methanol, ethanol, n-propanol, isopropanol, aliphatic alcohol-based organic solvents such as n-butanol, acetone, methyl ethyl ketone, ketone-based organic solvents such as methyl isobutyl ketone, acetonitrile, An amide-based organic solvent such as benzonitrile is preferable, and water, an amide-based organic solvent, and an aliphatic alcohol-based organic solvent are preferable.

The solvent in the first step is preferably used in such an amount that the total amount of the starting compounds with respect to the solvent is in the range of 0.05 to 0.8 times (total weight of starting compounds / volume of solvent). In particular, an amount in the range of 0.1 to 0.6 times (total weight of raw material compounds / volume of solvent) is preferable.

The reaction temperature in the first step may be a temperature up to the boiling point of a commonly used solvent, but is preferably 0.
To 150 ° C, particularly preferably 20 to 100 ° C.
It is in the range of ° C.

The reaction time in the production of the first step is significantly affected by the reaction temperature, but the reaction is usually completed within 20 hours.

The base preferably used in the first step includes, for example, potassium carbonate, sodium carbonate, lithium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide or sodium methylate.
Particularly preferred are potassium carbonate, sodium carbonate, sodium hydroxide, and potassium hydroxide. These bases are preferably used in an amount in a range of 1 to 10 moles based on the total amount of the raw material compounds, and particularly preferably 1.5 to 10 times.
It is preferable to use an amount that gives a 5-fold molar ratio.

In the first step, an additive for accelerating the reaction may be further added in addition to the base. Examples of such additives include potassium iodide, N, N-dimethylaminopyridine and the like. it can. At this time, the additive is used in an amount of 0.05 to
An amount having a ratio in the range of 10 mol% (mol number of the additive / mol number of the total amount of the raw material compounds) is preferable, and particularly 0.1 to 5%.
It is preferable that the amount is in the range of mol% mol (same as above).

The 2-nitro-2'-carboxy-diphenyl sulfide derivative represented by the general formula (3) obtained in the first step of the production method of the present invention is a nitrobenzene derivative represented by the aforementioned general formula (1) And a thiosalicylic acid derivative represented by the general formula (2). Examples of such a 2-nitro-2′-carboxy-diphenyl sulfide derivative include 2-nitro-2′-carboxy-diphenyl Sulfide, 2-nitro-4-methoxy-2′-carboxy-diphenyl sulfide, 2-nitro-4-methyl-2′-carboxy-diphenyl sulfide, 2-nitro-4-phenyl-2′-carboxy-diphenyl sulfide, 2-nitro-4-acetyl-
2'-carboxy-diphenyl sulfide, and 2-
Nitro-2'-carboxy-4'-methoxy-diphenyl sulfide can be mentioned, preferably 2-nitro-2'-carboxy-diphenyl sulfide, or 2
-Nitro-2'-carboxy-4'-methoxy-diphenyl sulfide.

In the first step, a 2-nitro-2'-carboxy-diphenyl sulfide derivative is obtained by combining ordinary washing and separation operations, for example, adding an acid to the reaction mixture to make it acidic, Is filtered to obtain a crude product, or water and an extraction solvent (organic solvent) are added to the reaction solution, and an acid is added thereto to make the pH of the aqueous layer acidic. The crude product is obtained by concentrating the organic layer under reduced pressure. In general, there is no problem if these conditions are used in the next step, but for further purification, purification may be carried out by column chromatography or recrystallization operation. The purification method may be appropriately selected for each compound. As the acid used in the above treatment, preferably hydrochloric acid, sulfuric acid, phosphoric acid,
Or acetic acid.

The second step in the production method of the present invention is to reduce the 2-nitro-2'-carboxy-diphenyl sulfide derivative represented by the general formula (3) and reduce the 2-amino-amino compound represented by the general formula (4). This is a method for producing a 2′-carboxy-diphenyl sulfide derivative.

The reducing agent used in the second step is not particularly limited as long as it is used for general reduction of a nitro group, but is preferably a Raney-nickel method (hereinafter referred to as reaction (A)) or The ferrous salt method (hereinafter referred to as reaction (B)).

Reaction (A): Raney nickel method The amount of Raney nickel used in this method is as follows.
The amount of nickel is usually from 1.0 to 80% by weight, and preferably from 5.0 to 40% by weight, based on the 2-nitro-2'-carboxy-diphenyl sulfide derivative. The type of Raney nickel is a 10-60% Ni-Al alloy, and a material containing Cr and Mo as an additive may be used. It is also possible to use stabilized nickel. Although the yield is not significantly affected by the method of developing Raney nickel, the method of W-6 (Matsuo Kubo, Komatsu
Shinichiro, "Raney-catalyst" (Kawaken Fine Chemical Co., Ltd.) (May 10, 1971), p. 55 gave the best results. Of course, other deployment methods have shown sufficient activity. When the reaction is carried out in the reaction (A), the reaction is usually carried out under an increased pressure of hydrogen, so that the reaction is carried out in an autoclave.
Higher hydrogen pressures give better results, but usually between 5 and 1
Perform at 00 atm. The reaction can be carried out at normal pressure, in which case the reaction is carried out while flowing hydrogen.

The solvent used in the reaction (A) is not particularly limited as long as it does not participate in the reaction. For example, methanol, ethanol, n-propanol, isopropanol or n-butanol Preferred are aliphatic alcohol-based organic solvents such as toluene. The solvent is 2-nitro-
The ratio of the 2′-carboxy-diphenyl sulfide derivative to the solvent is 0.05 to 0.6 times (2-nitro-
2'-carboxy-diphenyl sulfide derivative weight /
(Volume of the solvent).
An amount that results in a ratio in the range of 0.6 times (same as above) is preferable.

The reaction temperature in the reaction (A) may be any temperature up to the boiling point of the solvent usually used, but is preferably in the range of 20 to 200 ° C., particularly preferably 2 to 200 ° C.
It is in the range of 5-150C. The reaction time is significantly affected by the reaction temperature and the hydrogen pressure.
The reaction is completed within 0 hours.

The method for obtaining the 2-amino-2'-carboxy-diphenyl sulfide derivative in the reaction (A) is as follows.
By combining a usual washing operation and a separation operation, for example, filtering the reaction mixture and concentrating the obtained filtrate under reduced pressure, a crude product can be obtained. Normally, there is no problem in using it in this state in the next step, but for further purification, purification may be performed by column chromatography or recrystallization operation, and the purification method may be appropriately selected for each compound.

Reaction (B): Ferrous salt method As the ferrous salt used in this method, for example, ferrous sulfate or ferrous chloride can be mentioned, and these are hydrated or anhydrous. It may be used in any state of the compound, preferably ferrous sulfate heptahydrate, anhydrous ferrous chloride, ferrous chloride tetrahydrate or ferrous chloride n-hydrate is there. The amount of these used is an amount in the range of 0.1 to 30 times the weight of the 2-nitro-2'-carboxy-diphenyl sulfide derivative as the iron amount, preferably 0.5 to 10 times the weight. The amount is within the range.

As the solvent used in the reaction (B), a mixed solvent of water and aqueous ammonia is usually used. The ammonia water used is usually concentrated ammonia water (ammonia concentration 25
(About 28 wt%), but as long as the contained amount of ammonia is sufficient, a lower-concentration ammonia water may be used, or an ammonia gas blown into water may be used. Water is 2-nitro-2'-carboxy-
When the amount of the diphenyl sulfide derivative relative to water is 0.0
The amount is preferably in the range of 1 to 0.4 times equivalent (weight of 2-nitro-2'-carboxy-diphenyl sulfide derivative / volume of water), particularly preferably 0.02 to 0.
An amount that gives a ratio in the range of twice equivalent (the same) is preferable. As for the amount of ammonia, the amount of the 2-nitro-2'-carboxy-diphenyl sulfide derivative used for ammonia is 0.1%.
It is preferably used in such an amount that the ratio falls within the range of 005 to 0.5 equivalent (weight of 2-nitro-2'-carboxy-diphenyl sulfide derivative / weight of ammonia), and particularly preferably 0.01 to 0.5. An amount that gives a double equivalent (same as above) is preferable.

The reaction temperature in the reaction (B) may be a temperature up to the boiling point of a commonly used solvent, but is preferably in the range of 20 to 100 ° C., particularly preferably 4 to 100 ° C.
The range is 0 to 90 ° C. Although the reaction time is significantly affected by the reaction temperature, the reaction is usually completed within 2 hours.

A method for obtaining a 2-amino-2'-carboxy-diphenyl sulfide derivative in the reaction (B) is as follows.
By combining the usual washing operation and separation operation, for example, the reaction mixture is filtered, and an acid is added to the filtrate to make the pH of the aqueous layer acidic. The crude product is obtained by concentrating the organic layer under reduced pressure. Normally, there is no problem in using it in this state in the next step, but for further purification, purification may be performed by column chromatography or recrystallization operation, and the purification method may be appropriately selected for each compound. The acid is preferably hydrochloric acid, sulfuric acid, phosphoric acid or acetic acid.

The 2-amino-2'-carboxy-diphenyl sulfide derivative represented by the general formula (4) obtained in the second step of the production method of the present invention is a 2-amino-2'-carboxy-diphenyl sulfide derivative represented by the general formula (3). Defined by nitro-2'-carboxy-diphenyl sulfide derivatives;
Examples of the 2′-carboxy-diphenyl sulfide derivative include 2-amino-2′-carboxy-diphenyl sulfide, 2-amino-4-methoxy-2′-carboxy-diphenyl sulfide, and 2-amino-4-methyl-2 ′ -Carboxy-diphenyl sulfide, 2-amino-4-phenyl-2'-carboxy-diphenyl sulfide, 2-amino-4-acetyl-2'-carboxy-diphenyl sulfide, and 2-amino-2'-carboxy-4 ' -Methoxy-diphenyl sulfide, preferably 2-amino-2'-carboxy-diphenyl sulfide, or 2-amino-2'-
Carboxy-4'-methoxy-diphenyl sulfide.

The third step in the production method of the present invention comprises the step of dehydrating and condensing a 2-amino-2'-carboxy-diphenyl sulfide derivative represented by the general formula (4) to obtain a dibenzothiazepine represented by the general formula (5). This is a method for producing a derivative.

The reaction in the third step may be carried out without a solvent, but preferably a solvent which is hydrophobic and inert to the reaction is used. Examples of such a solvent include aromatic hydrocarbon solvents such as toluene, xylene and benzene, chlorobenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, 1,4-dichlorobenzene, bromobenzene,
Aromatic halide solvents such as 1,2-dibromobenzene, 1,3-dibromobenzene and 1,4-dibromobenzene, cyclic hydrocarbon solvents such as cyclohexane, cycloheptane and cyclooctane or ethyl acetate, butyl acetate; Examples thereof include aliphatic ester solvents such as methyl butyrate, ethyl butyrate, and butyl butyrate. Particularly preferred are toluene, xylene, and 1,2-dichlorobenzene.

The amount of the solvent used in the third step is not particularly limited, but may be 2-amino-2'-carboxy-.
The volume ratio (W / V%) of the solvent to the weight of the diphenyl sulfide derivative can be, for example, 3% or more, and is preferably in the range of 4% to 40%. In order to increase the reaction rate and the conversion, an azeotropic dehydration operation (refluxing while removing by-product water) may be performed using a Dean-Stark apparatus. The reaction temperature in the third step is not particularly limited as long as it is equal to or lower than the boiling point of the organic solvent described above, but is preferably about 100 ° C to 200 ° C.

The dibenzothiazepine derivative represented by the general formula (5) obtained in the third step is defined by the 2-amino-2′-carboxy-diphenyl sulfide derivative represented by the general formula (4). Examples of such a dibenzothiazepine derivative as a target substance include dibenzo [b, f] [1,4] thiazepin-11-one and 8-methyl-dibenzo [b, f] [1,4] thiazepine-11.
-One, 8-phenyl-dibenzo [b, f] [1,4]
Thiazepin-11-one, 8-methoxy-dibenzo [b, f] [1,4] thiazepin-11-one, or 2
-Methoxy-dibenzo [b, f] [1,4] thiazepin-11-one, preferably dibenzo [b, f] [1,4] thiazepin-11-one, or 2
-Methoxy-dibenzo [b, f] [1,4] thiazepin-11-one.

As a purification method in the third step, the dibenzothiazepine derivative is precipitated as crystals when the reaction mixture is cooled. Therefore, a high-purity dibenzothiazepine derivative can be obtained by filtering the crystals. If further purification is required, recrystallization or column chromatography may be used.

Preferred embodiments of the present invention are as follows. (1) A method for producing a dibenzothiazepine derivative according to the present invention, wherein the nitrobenzene derivative is 2-chloronitrobenzene or 2-bromonitrobenzene. (2) In the method for producing a dibenzothiazepine derivative of the present invention, the thiosalicylic acid derivative may be thiosalicylic acid or 5-
A method for producing a dibenzothiazepine derivative which is methoxythiosalicylic acid.

(3) A process for producing a dibenzothiazepine derivative according to the present invention, wherein the base is potassium carbonate. (4) In the method for producing a dibenzothiazepine derivative of the present invention, the 2-nitro-2'-carboxy-diphenyl sulfide derivative is converted to 2-nitro-2'-carboxy-diphenyl sulfide or 2-nitro-2'-carboxy-
A method for producing a dibenzothiazepine derivative which is 4'-methoxy-diphenyl sulfide. (5) A method for producing a dibenzothiazepine derivative according to the present invention, wherein the solvent in the first step is N, N-dimethylformamide.

(6) In the process for producing a dibenzothiazepine derivative of the present invention, the reducing agent used in the reaction (A) in the second step is a mixture of a dibenzothiazepine derivative in which raney-nickel or ferrous sulfate heptahydrate is used. Manufacturing method. (7) In the process for producing a dibenzothiazepine derivative of the present invention, the reducing agent used in the reaction (A) of the second step is Raney-nickel and the solvent is methanol or n-butanol. Manufacturing method. (8) In the method for producing a dibenzothiazepine derivative of the present invention, the reducing agent used in the reaction (B) of the second step is ferrous sulfate heptahydrate, and the solvent is a 28% aqueous ammonia solution. Recipe.

(9) In the process for producing a dibenzothiazepine derivative of the present invention, the 2-amino-2'-carboxy-diphenyl sulfide derivative is converted to 2-amino-2'-carboxy-diphenyl sulfide, 2-amino-2'- Carboxy-4'-methoxy-diphenyl sulfide or 2
A method for producing a dibenzothiazepine derivative which is -methoxy-dibenzo [b, f] [1,4] thiazepin-11-one. (10) In the process for producing a dibenzothiazepine derivative of the present invention, the dibenzothiazepine derivative is dibenzo [b, f]
[1,4] A method for producing a dibenzothiazepine derivative which is thiazepin-11-one or 2-methoxy-dibenzo [b, f] [1,4] thiazepin-11-one.

(11) In the method for producing a dibenzothiazepine derivative of the present invention, the nitrobenzene derivative is 2-chloronitrobenzene or 2-bromonitrobenzene, and the thiosalicylic acid derivative is thiosalicylic acid or 5-methoxythiosalicylic acid. The base is potassium carbonate, and the 2-nitro-2'-carboxy-diphenyl sulfide derivative is 2-nitro-2'-carboxy-diphenyl sulfide or 2-nitro-2 '
-Carboxy-4'-methoxy-diphenyl sulfide, the solvent in the first step is N, N-dimethylformamide, and the 2-amino-2'-carboxy-diphenyl sulfide derivative is 2-amino-2'-carboxy. −
Diphenyl sulfide or 2-amino-2'-carboxy-4'-methoxy-diphenyl sulfide, wherein the dibenzothiazepine derivative is dibenzo [b, f]
[1,4] thiazepin-11-one or 2-methoxy-dibenzo [b, f] [1,4] thiazepin-11-one, and the reducing agent used in the reaction (A) of the second step is Raney. Nickel, and the solvent is methanol or n-butano-
A dibenzothiazepine derivative in which the reducing agent used in the reaction (B) of the second step is ferrous sulfate heptahydrate and the solvent is a 28% aqueous ammonia solution.

[0082]

According to the process for producing dibenzothiazepine of the present invention, a nitrobenzene derivative and a thiosalicylic acid derivative are reacted in the presence of a base to give 2-nitro-2 '.
A carboxy-diphenyl sulfide derivative is produced, and then a 2-amino-2'-carboxy-diphenyl sulfide derivative obtained by reduction is produced, followed by dehydration condensation, thereby being useful as a pharmaceutical intermediate. The dibenzothiazepine derivative represented by the general formula (5) can be produced with high yield and simple operation.

[0083]

EXAMPLES Next, the production method of the present invention will be described in more detail with reference to Examples and Comparative Examples of the present invention, but the present invention is not limited to these Examples.

Example 1 2-chloronitrobenzene 9
4.5 g (0.60 mol) and 159.0 g of potassium carbonate
(1.15 mol) and N, N-dimethylformamide 1
The solution was added to 20 ml and dissolved to obtain an N, N-dimethylformamide solution. A solution obtained by dissolving 77.1 g (0.50 mol) of thiosalicylic acid in 120 ml of N, N-dimethylformamide was dropped into the obtained N, N-dimethylformamide solution, and the mixture was reacted by stirring at 70 ° C. for 6 hours. . 800 ml of water and 700 ml of ethyl acetate are added to the obtained reaction solution.
And added. 400 g of ice and 194 of concentrated hydrochloric acid were added to the separated aqueous layer.
The solution was stirred at room temperature for 1 hour after the pH of the aqueous layer was acidified by addition of water. The precipitated crystals were filtered and dried to obtain 134.0 g (0.49 mol) of 2-nitro-2'-carboxy-diphenyl sulfide as a yellow powder.
(Yield based on thiosalicylic acid = 98%) ¹ H-NMR (DMSO-d ₆ ); δ = 7.1 to 8.3
(M, 8), 13.1-13.5 (br, 1)

Example 2 2-chloronitrobenzene 9
4.5 g (0.60 mol) and 159.0 g of potassium carbonate
(1.15 mol) and N, N-dimethylformamide 1
The solution was added to 20 ml and dissolved to obtain an N, N-dimethylformamide solution. A solution obtained by dissolving 77.1 g (0.50 mol) of thiosalicylic acid in 120 ml of N, N-dimethylformamide was dropped into the obtained N, N-dimethylformamide solution, and the mixture was reacted by stirring at 70 ° C. for 6 hours. . To the obtained reaction solution, 200 ml of water and 194 ml of concentrated hydrochloric acid were added to make the pH of the aqueous layer acidic, and the solution was added at room temperature for 1 hour.
Stirred for hours. The precipitated crystals were filtered and dried to obtain 123.0 g (0.45 mol) of 2-nitro-2'-carboxy-diphenylsulfide as a yellow powder. (Yield based on thiosalicylic acid = 90%)

Example 3 Example 2 was the same as Example 1 except that 2-bromonitrobenzene was used instead of 2-chloronitrobenzene and the amount used was 121.2 g (0.60 mol). To perform 2-nitro-
13'-carboxy-diphenyl sulfide 134.0 g
(0.49 mol). (Yield based on thiosalicylic acid = 98%)

Example 4 The same procedure as in Example 1 was carried out except that 5-methoxythiosalicylic acid was used instead of thiosalicylic acid in Example 1, and the amount used was 93.8 g (0.50 mol). The operation was performed to obtain 2-nitro-2'-carboxy-4'-methoxy-diphenylsulfide.
3 g (0.45 mol) were obtained. (Yield based on 5-methoxythiosalicylic acid = 90%) Melting point: 185-187 ° C

Example 5 In a 300 ml autoclave, Raney nickel (Ni content 4 as a 50% alloy)
g), 2-nitro- obtained in the same manner as in Example 1.
13.8 g of 2'-carboxy-diphenyl sulfide
(0.05 mol) and 100 ml of methanol were added thereto, and the mixture was adjusted to a hydrogen pressure of 20 atm, and then reacted at room temperature with stirring for 5 hours. The obtained reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain 11.3 g (0.046 mol) of 2-amino-2'-carboxy-diphenylsulfide as a colorless powder. (2-
Nitro-2'-carboxy - diphenylsulfide Yield = 92% for ^{sulphide) 1 H-NMR (DMSO-} d 6); δ = 5.0~5.9
(Br, 2), 6.5 to 8.1 (m, 8), 12.8 to
13.5 (br, 1)

Example 6 Raney nickel (1 g of Ni as a 50% alloy) and 4.0 g (14.5 mmol) of 2-nitro-2'-carboxy-diphenyl sulfide obtained in the same manner as in Example 1 And n-butanol 5
The suspension was suspended in 0 ml to obtain an n-butanol suspension. 100 g while blowing hydrogen into the obtained n-butanol suspension.
The mixture was reacted by stirring at 15 ° C. for 15 hours. The resulting reaction suspension was filtered, and the filtrate was concentrated under reduced pressure to give 3.24 g of 2-amino-2'-carboxy-diphenyl sulfide as a colorless powder.
(13.2 mmol) were obtained. (Yield based on 2-nitro-2′-carboxy-diphenyl sulfide = 91
%)

Example 7 2.75 g (10.0 mmol) of 2-nitro-2'-carboxy-diphenyl sulfide obtained in the same manner as in Example 1 was added to a concentrated aqueous ammonia solution (ammonia concentration = 28% by weight). ) Dissolved in 40 ml to obtain an ammonia mixture. A solution prepared by dissolving 21.6 g (77.8 mmol) of ferrous sulfate heptahydrate in 70 ml of water was added dropwise to the obtained ammonia mixed solution.
The reaction was performed by heating for 0 minutes. The obtained reaction solution was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure to 30 ml, and 70 ml of ethyl acetate and 2 ml of acetic acid were added. The separated organic layer was dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure to give 2-amino-colorless powder.
2.33 g of 2'-carboxy-diphenyl sulfide
(9.50 mmol) was obtained. (Yield based on 2-nitro-2′-carboxy-diphenyl sulfide = 95
%)

Example 8 2-Nitro-2'-carboxy-4'-methoxy- obtained in the same manner as in Example 4.
Except that 15.2 g (0.05 mol) of diphenyl sulfide was used, the same operation as in Example 6 was carried out to give 2-amino-2'-carboxy-4'-methoxy- as a colorless powder.
12.7 g (0.46 mol) of diphenyl sulfide were obtained. (Yield based on 2-nitro-2'-carboxy-4'-methoxy-diphenylsulfide = 92%) Melting point: 150-151 ° C

Example 9 24.5 g (0.10 mol) of 2-amino-2'-carboxy-diphenyl sulfide obtained in the same manner as in Example 5 was mixed with 300 ml of toluene.
To give a toluene solution. The obtained toluene solution was refluxed for 20 hours to react. After cooling the obtained reaction solution to room temperature, the precipitated crystals were filtered. The obtained residue was dried to obtain 15.7 g of dibenzo [b, f] [1,4] thiazepin-11-one as colorless needle crystals.
(0.069 mol). (Yield based on 2-amino-2′-carboxy-diphenyl sulfide = 69%) Melting point: 259 to 260 ° C. ¹ H-NMR (DMSO-d ₆ ); δ = 7.05 to 7.
80 (m, 8), 10.7 (s, 1)

Example 10 24.5 g (0.10 mol) of 2-amino-2'-carboxy-diphenyl sulfide obtained in the same manner as in Example 5 was mixed with 300 ml of toluene.
to give a toluene solution. The obtained toluene solution was reacted by refluxing while azeotropically dehydrating (using a Dean-Stark apparatus) for 20 hours. After cooling the obtained reaction solution to room temperature, the precipitated crystals were filtered. The obtained residue was dried to obtain dibenzo [b, f] [1,
4] Thiazepin-11-one as colorless needle-like crystals
8.2 g (0.080 mol) were obtained. (2-amino-
(Yield based on 2′-carboxy-diphenyl sulfide = 80%)

Example 11 A reaction was carried out in the same manner as in Example 12, except that the reaction solvent in Example 10 was changed to xylene and the reaction time was changed to 15 hours, to obtain dibenzo [b, f] [1,
4] Thiazepin-11-one as colorless needle crystals
2.3 g were obtained. (0.098 mol) (2-amino-
(Yield based on 2'-carboxy-diphenyl sulfide = 98%)

Example 12 Example 11 was carried out using 27.5 g (0.10 mol) of 2-amino-2'-carboxy-4'-methoxy-diphenylsulfide obtained in the same manner as in Example 8. The reaction was carried out in the same manner as in
23.6 g (0.092 mol) of dibenzo [b, f] [1,4] thiazepin-11-one was obtained as colorless needle crystals. (Yield based on 2-amino-4-methoxy-2'-carboxy-diphenylsulfide = 92%) Melting point: 220-223 ° C

Claims (6)

[Claims] 1. General formula (1): (In the formula, R ¹ , R ² , R ³ , and R ⁴ may be the same or different from each other, and may be a hydrogen atom, or an optionally substituted alkyl group, alkoxy group, alkylcarbonyl group, aryl group A nitrobenzene derivative represented by the general formula (2): (Wherein, R ⁵ , R ⁶ , R ⁷ , and R ⁸ may be the same or different from each other, and may be a hydrogen atom, or an optionally substituted alkyl group, alkoxy group, alkylcarbonyl group, aryl group A thiosalicylic acid derivative represented by the formula (3), an aryloxy group or an arylcarbonyl group: (Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ ,
And R ⁸ have the same meaning as described above)
After producing the nitro-2'-carboxy-diphenyl sulfide derivative, the 2-nitro-2'-carboxy-
The diphenyl sulfide derivative is reduced to give a compound of the general formula (4): (Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ ,
And R ⁸ have the same meaning as described above)
After forming the amino-2'-carboxy-diphenyl sulfide derivative, the 2-amino-2'-carboxy-
A general formula (5), wherein a diphenyl sulfide derivative is subjected to dehydration condensation. (Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ ,
And R ⁸ have the same meanings as described above). 2. The dibenzothiazepine derivative according to claim 1, wherein the reaction between the nitrobenzene derivative of the general formula (1) and the thiosalicylic acid derivative of the general formula (2) is carried out in an organic solvent in the presence of a base. Production method. 3. The method for producing a dibenzothiazepine derivative according to claim 1, wherein the dehydration condensation of the 2-amino-2′-carboxy-diphenyl sulfide derivative of the general formula (4) is performed in an organic solvent. 4. General formula (3): (Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ ,
And R ⁸ may be the same or different from each other;
A hydrogen atom or an alkyl group, an alkoxy group, an alkylcarbonyl group, an aryl group, an aryloxy group or an arylcarbonyl group which may have a substituent)
The 2-nitro-2'-carboxy-diphenyl sulfide derivative represented by the formula is reduced to give a compound of the general formula (4): (Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ ,
And R ⁸ have the same meaning as described above)
After forming the amino-2'-carboxy-diphenyl sulfide derivative, the 2-amino-2'-carboxy-
General formula (5), characterized by dehydrating and condensing a diphenyl sulfide derivative: (Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ ,
And R ⁸ have the same meanings as described above). 5. The method for producing a dibenzothiazepine derivative according to claim 4, wherein the dehydration condensation of the 2-amino-2′-carboxy-diphenyl sulfide derivative of the general formula (4) is carried out in an organic solvent. 6. A compound of the general formula (3): (Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ ,
And R ⁸ may be the same or different from each other;
A hydrogen atom or an alkyl group, an alkoxy group, an alkylcarbonyl group, an aryl group, an aryloxy group or an arylcarbonyl group which may have a substituent)
A 2-nitro-2'-carboxy-diphenyl sulfide derivative represented by the formula: