CN1872846B - Preparation method of dibenzothiazepine* derivatives - Google Patents

Abstract

The present invention provides a kind of 2-amino- Dehydration condensation of 2'-hydroxyl-phenylene sulfide derivatives can be used to prepare 11-[4-(2-(2-hydroxyethoxy)ethyl)]-1-piperazinyl useful as antipsychotics Dibenzothiazepine derivatives represented by dibenzo[b,f][1,4]thiazepine-11-one as starting materials of dibenzothiazepine derivatives.

Description

The preparation method of dibenzothiazepine derivative

This application is the application number CN200610006965.7 (application date is July 9, 1999), the invention name is "dibenzothiazepine The divisional application of the Chinese application of "Preparation Method of Derivatives", the Chinese application is the application number CN99816885.8 (the international filing date is July 9, 1999), and the invention name is "Dibenzothiazepine A divisional application of the PCT application that entered the national phase.

technical field

The present invention relates to dibenzothiazepine useful as an intermediate of medicines Methods for the preparation of derivatives. In particular, the present invention relates to 11-[4-(2-(2-hydroxyethoxy)ethyl]-1-piperazinyldibenzothiazepines useful in the preparation of antipsychotics. Dibenzothiazepine shown in the following general formula (5) useful for intermediates of derivatives thereof Methods for the preparation of derivatives.

In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ may be the same or different, and represent a hydrogen atom or an alkyl, alkoxy, or alkylcarbonyl group that may have substituents , aryl, aryloxy or arylcarbonyl.

Background technique

衍生物，在EP-0282236-A1公报中有记载，阐明以这种二苯并硫氮衍生物为原料，能够衍生得到作为抗精神病药有用的11-〔4-(2-(2-羟基乙氧基)乙基〕-1-哌嗪基二苯并硫氮

衍生物。也就是说，阐明使通式(5)的二苯并硫氮衍生物的代表化合物二苯并〔b，f〕〔1，4〕硫氮-11酮与氧氯化磷反应，得到11-氯-二苯并硫氮

衍生物，接着使哌嗪加成到该11-氯-二苯并硫氮

衍生物上，得到11-哌嗪基-二苯并硫氮

衍生物，最后使该11-哌嗪基-二苯并硫氮衍生物与2-氯乙氧基乙醇在碱性条件下反应，能够衍生得到上述11-〔4-(2-(2-羟基乙氧基)乙基〕-1-哌嗪基二苯并硫氮

衍生物。For the dibenzothiazepine of the above general formula (5)

Derivatives are documented in the EP-0282236-A1 bulletin, illustrating that dibenzothiazepine Derivatives are used as raw materials to obtain 11-[4-(2-(2-hydroxyethoxy)ethyl]-1-piperazinyldibenzothiazepine, which is useful as an antipsychotic

derivative. That is to say, clarification makes the dibenzothiazepine of general formula (5) The representative compound of derivatives is dibenzo[b,f][1,4]sulfur -11 ketone reacts with phosphorus oxychloride to give 11-chloro-dibenzothiazepine

derivative, followed by the addition of piperazine to the 11-chloro-dibenzothiazepine

Derivatives, get 11-piperazinyl-dibenzothiazepine

derivatives, finally making the 11-piperazinyl-dibenzothiazepine Derivatives react with 2-chloroethoxyethanol under alkaline conditions to obtain the above-mentioned 11-[4-(2-(2-hydroxyethoxy)ethyl]-1-piperazinyldibenzothio nitrogen

derivative.

-11-酮的制备方法，还记载了利用2-(苯硫基)苯基氨基甲酸苯酯或其类似化合物的环化反应(多磷酸存在下)的方法。In the above-mentioned EP-0282236-A1 communique, as dibenzo [b, f] [1,4] sulfur nitrogen

- The production method of 11-one also describes a method using a cyclization reaction (in the presence of polyphosphoric acid) of phenyl 2-(phenylthio)phenylcarbamate or its analogues.

衍生物的方法。Helv.Chim.Acta, volume 42, page 1263 (1959) records that methyl thiosalicylate derivatives and 2-halogenated nitrobenzene derivatives are heated in the presence of sodium to synthesize 2-nitro -2'-Carboxyl-phenylene sulfide derivatives, which are reduced using Raney nickel to produce 2-amino-2'-carboxy-phenylene sulfide derivatives, which are finally reacted at high temperature to prepare dibenzosulfide nitrogen

Derivative method.

Org.Prep.Proced.Int., page 287 (1974) describes base and acid treatments after heating thiosalicylate derivatives and 2-iodonitrobenzene derivatives in the presence of sodium methoxide and copper , synthesize 2-nitro-2'-carboxy-phenylene sulfide derivatives, use ferrous sulfate ammonia solution to reduce it to make 2-amino-2'-carboxy-phenylene sulfide derivatives, and finally reduce Make it react under pressure condition, prepare dibenzothiazepine Derivative method.

衍生物的方法。In the WO92/19607 bulletin, it is described that after 2-aminothiophenol and 2-fluorobenzonitrile are reacted to obtain 2-(2-aminophenylthio) benzonitrile, the compound is hydrolyzed to prepare 2-(2 -carboxyphenylthio) aniline, finally make this compound carry out cyclization reaction, prepare the dibenzothiazepine of general formula (5)

Derivative method.

As mentioned above, as dibenzothiazepine of general formula (5) Although several methods are known for the preparation of derivatives, these methods have problems such as low yield, high-temperature reaction, special raw materials, or use of compounds that are troublesome for industrial post-processing, etc., which must be improved as industrial preparation methods.

invention disclosure

Therefore, the object of the present invention is to provide a kind of dibenzothiazepine that effectively prepares above-mentioned general formula (5) industrially Derivatives, that is, using readily available starting compounds, without complicated workup, and obtaining the desired dibenzothiazepines in high yields Methods for the preparation of derivatives.

衍生物的新型方法，从而完成了本发明。The inventors of the present invention have conducted intensive research in order to solve the above-mentioned problems, and as a result, have found that the diphenylene compound of the general formula (5) can be prepared in high yield and by simple operation using readily available nitrobenzene derivatives and thiosalicylic acid derivatives. And sulfur nitrogen

A novel method of derivatives, thus completing the present invention.

衍生物的制备方法，其特征在于使通式(1)表示的硝基苯衍生物与下述通式(2)表示的硫代水杨酸衍生物反应，生成下述通式(3)表示的2-硝基-2’-羧基-苯硫醚衍生物后，将该2-硝基-2’-羧基-苯硫醚衍生物还原，生成下述通式(4)表示的2-氨基-2’-羧基-苯硫醚衍生物后，使该2-氨基-2’-羧基-苯硫醚衍生物脱水缩合。The present invention relates to dibenzothiazepine represented by the following general formula (5)

The preparation method of the derivative is characterized in that the nitrobenzene derivative represented by the general formula (1) is reacted with the thiosalicylic acid derivative represented by the following general formula (2) to generate the compound represented by the following general formula (3). After the 2-nitro-2'-carboxy-phenylene sulfide derivatives, the 2-nitro-2'-carboxy-phenylene sulfide derivatives are reduced to generate the 2-amino group represented by the following general formula (4): -2'-carboxy-phenylene sulfide derivative, the 2-amino-2'-carboxy-phenylene sulfide derivative is dehydrated and condensed.

(In the formula, R ¹ , R ² , R ³ and R ⁴ may be the same or different, and represent a hydrogen atom or an alkyl, alkoxy, alkylcarbonyl, aryl, aryloxy or arylcarbonyl group that may have a substituent , and X represents a halogen atom)

(In the formula, R ⁵ , R ⁶ , R ⁷ and R ⁸ may be the same or different, and represent a hydrogen atom or an alkyl, alkoxy, alkylcarbonyl, aryl, aryloxy or arylcarbonyl group that may have a substituent )

(In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ represent the same meanings as above)

(In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ represent the same meanings as above)

(In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ represent the same meanings as above)

衍生物的制备方法，其特征在于使下述通式(3)表示的2-硝基-2’-羧基-苯硫醚衍生物还原，生成下述通式(4)表示的2-氨基-2’-羧基-苯硫醚衍生物后，使该2-氨基-2’-羧基-苯硫醚衍生物脱水缩合。The present invention also relates to dibenzothiazepine represented by the following general formula (5)

The preparation method of the derivative is characterized in that the 2-nitro-2'-carboxy-phenylene sulfide derivative represented by the following general formula (3) is reduced to generate the 2-amino-sulfide derivative represented by the following general formula (4). After the 2'-carboxy-phenylene sulfide derivative is prepared, the 2-amino-2'-carboxy-phenylene sulfide derivative is dehydrated and condensed.

(In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ may be the same or different, and represent a hydrogen atom or an alkyl group, an alkoxy group, an alkyl group that may have a substituent carbonyl, aryl, aryloxy or arylcarbonyl)

(In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ represent the same meanings as above)

(In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ represent the same meanings as above)

The present invention also relates to 2-nitro-2'-carboxy-phenylene sulfide derivatives represented by the above general formula (3).

衍生物的制备方法的各步骤可以用下述反应方案表示。The dibenzothiazepine of general formula (5) of the present invention

Each step of the preparation method of the derivative can be represented by the following reaction scheme.

BEST MODE FOR CARRYING OUT THE INVENTION

Dibenzothiazepine of the present invention In each of the general formulas involved in the preparation method of the derivative, the "alkyl group that may have a substituent" represented by ^R1 to ^R8 refers to a straight-chain or branched group having 1 to 10 carbon atoms without a substituent. An alkyl group, or a straight-chain or branched-chain alkyl group having 1 to 10 carbon atoms having a substituent.

As the above-mentioned "straight-chain or branched alkyl group having 1 to 10 carbon atoms having no substituent", a straight-chain alkyl group having 1 to 8 carbon atoms (particularly 1 to 5 carbon atoms) is preferable. Or branched chain alkyl, such as methyl, ethyl, propyl (including isomers), butyl (including isomers), pentyl (including isomers), hexyl (including isomers), heptyl (including isomers), octyl (including isomers), nonyl (including isomers), decyl (including isomers), etc., preferably methyl, ethyl, propyl (including isomers ), butyl (including isomers), pentyl (including isomers), hexyl (including isomers), heptyl (including isomers), octyl (including isomers), particularly preferably methyl , ethyl, propyl (including isomers), butyl (including isomers), pentyl (including isomers).

In addition, the alkyl moiety of "a linear or branched alkyl group having 1 to 10 carbon atoms having a substituent" includes, for example, the alkyl group described in (1) above.

The substituent of the above-mentioned "linear or branched alkyl group having 1 to 10 carbon atoms having a substituent" may be located at any position of the alkyl moiety. As examples of such substituents, for example, methoxy, ethoxy, propoxy (including isomers), butoxy (including isomers), pentyloxy (including isomers), hexyloxy (including isomers), heptyloxy (including isomers), octyloxy (including isomers), nonyloxy (including isomers), decyloxy (including isomers) and other carbon atoms 1 to 10 straight-chain or branched alkoxy groups, acetyl, propionyl (including isomers), butyryl (including isomers), pentanoyl, etc. have straight chains with 1 to 5 carbon atoms An alkylcarbonyl group having 2 to 6 carbon atoms in a straight or branched alkyl moiety, an optionally substituted phenylcarbonyl group, or an optionally substituted phenyl group.

The above-mentioned "phenylcarbonyl group which may be substituted" refers to a phenylcarbonyl group which does not have a substituent or a phenylcarbonyl group which has a substituent. "A phenyl group which may be substituted" means a phenyl group which does not have a substituent, or a phenyl group which has a substituent. As an alternative substituent of "phenylcarbonyl having a substituent" or "phenyl carbon having a substituent", for example, phenyl, phenylcarbonyl, the above-mentioned alkyl, the above-mentioned alkoxy or the above-mentioned alkylcarbonyl.

In the present invention, the "alkoxy group that may have a substituent" represented by ^R1 to ^R8 of the above general formulas (2), (3), (4) and (5) means a carbon atom having no substituent An alkoxy group with 1 to 10 carbon atoms in a linear or branched alkyl moiety having 1 to 10 carbon atoms, or a linear or branched chain with 1 to 10 carbon atoms having a substituent An alkoxy group having 1 to 10 carbon atoms in the alkyl moiety.

Examples of the "alkoxy group having 1 to 10 carbon atoms having a linear or branched alkyl moiety having 1 to 10 carbon atoms without a substituent" include the aforementioned alkoxy groups. In addition, examples of the substituent of "an alkoxy group having 1 to 10 carbon atoms having a linear or branched chain alkyl group having a substituent having 1 to 10 carbon atoms" include the above-mentioned alkyl groups , an alkylcarbonyl group having 2 to 6 carbon atoms, an optionally substituted phenylcarbonyl group and an optionally substituted phenyl group.

衍生物的制备方法涉及的各个通式中，R¹至R⁸表示的“可以具有取代基的烷基羰基”是指具有不带取代基的碳原子数1～10个的直链状或支链状烷基部分的碳原子数2～11个的烷基羰基，或者具有带取代基的碳原子数1～10个的直链状或支链状烷基部分的碳原子数2～11个的烷基羰基。Dibenzothiazepine of the present invention

In each of the general formulas involved in the preparation method of the derivative, the "alkylcarbonyl group that may have a substituent" represented by ^R1 to ^R8 refers to a straight-chain or branched carbon group with 1 to 10 carbon atoms without substituents. An alkylcarbonyl group with 2 to 11 carbon atoms in the chain alkyl part, or a straight-chain or branched chain alkyl part with 2 to 11 carbon atoms in the substituent the alkylcarbonyl.

Examples of the alkyl moiety of the "alkylcarbonyl group having 2 to 11 carbon atoms having a linear or branched chain alkyl moiety having 1 to 10 carbon atoms without substituents" include the above-mentioned alkyl groups. Examples of the substituent of the "alkylcarbonyl group having 2 to 11 carbon atoms having a linear or branched chain alkyl moiety having 1 to 10 carbon atoms with a substituent" include the above-mentioned alkyl substituents.

Dibenzothiazepine of the present invention In each general formula involved in the preparation method of the derivative, the "aryl group that may have a substituent" represented by ^R1 to ^R8 means an aryl group without a substituent or an aryl group with a substituent.

Examples of the above-mentioned "aryl group having no substituent" include phenyl, naphthyl, anthracenyl, etc., preferably phenyl and naphthyl, particularly preferably phenyl. As a substituent of "the aryl group which has a substituent", the substituent of the said alkyl group is mentioned, for example.

Dibenzothiazepine of the present invention In each general formula involved in the preparation method of the derivative, the "aryloxy group that may have a substituent" represented by ^R1 to ^R8 refers to an aryloxy group having an aryl moiety without a substituent, or an aryloxy group having a substituent The aryloxy group of the aryl moiety.

As the aryl group of the above-mentioned "aryloxy group having an aryl moiety having no substituent", there may be exemplified the above-mentioned aryl group. Moreover, as a substituent of "aryloxy group which has a substituent aryl moiety", the substituent of the above-mentioned alkyl group is mentioned, for example.

Dibenzothiazepine of the present invention In each general formula involved in the preparation method of the derivative, the "arylcarbonyl group that may have a substituent" represented by ^R1 to ^R8 refers to an arylcarbonyl group having an aryl moiety without a substituent, or an arylcarbonyl group having a substituent The arylcarbonyl of the aryl moiety.

The aryl group as the above-mentioned "arylcarbonyl group having an aryl moiety having no substituent" includes, for example, the above-mentioned aryl group. As the substituent of the "arylcarbonyl group having a substituted aryl moiety", there may be exemplified the substituents of the above-mentioned alkyl groups.

^R1 to ^R8 can be the same or different, preferably hydrogen atom, alkyl, alkoxy, alkylcarbonyl, aryl, aryloxy or arylcarbonyl, particularly preferably hydrogen atom, alkyl, alkoxy or alkyl carbonyl.

The halogen atom represented by X in the general formula (1) is, for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom, a chlorine atom or a bromine atom.

Secondly, to dibenzothiazepine of the present invention Each step of the preparation method of the derivative is described in detail.

Dibenzothiazepine in the present invention In the first step of the preparation method of the derivative, preferably in the presence of a base, in a solvent, the nitrobenzene derivative represented by the general formula (1) is reacted with the thiosalicylic acid derivative represented by the general formula (2) , to prepare a 2-nitro-2'-carboxy-phenylene sulfide derivative represented by the general formula (3).

As specific examples of nitrobenzene derivatives of the general formula (1) used in the first step above, for example, 2-chloronitrobenzene, 2-bromonitrobenzene, 2-fluoronitrobenzene, 2-iodonitrobenzene Benzene, 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 and 2-iodo-5-acetyl-nitrobenzene, preferably 2-chloronitrobenzene and 2-bromonitrobenzene.

As specific examples of thiosalicylic acid derivatives of the general formula (2) used in the first step, for example, thiosalicylic acid, 5-methoxy-thiosalicylic acid, 5-methyl-thiosalicylic acid Salicylic acid, 5-phenyl-thiosalicylic acid and 5-acetyl-thiosalicylic acid, preferably thiosalicylic acid and 5-methoxythiosalicylic acid.

The nitrobenzene derivative of the general formula (1) is usually used in an amount ranging from 0.7 to 10 moles relative to 1 mole of the thiosalicylic acid derivative of the general formula (2), and is particularly preferably used in a molar ratio of 1.0 to 5 times. Dosage use.

The first step above is usually carried out in the presence of a solvent. The solvent used in the first step is not particularly limited as long as it has nothing to do with the reaction, for example, water, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone can be used , dimethyl imidazolinone and other amide organic solvents, methanol, ethanol, n-propanol, isopropanol, n-butanol and other aliphatic alcohol organic solvents, acetone, methyl ethyl ketone, methyl isobutyl ketone Ketone organic solvents such as ketones, nitrile organic solvents such as acetonitrile and benzonitrile. Water, amide-based organic solvents, and aliphatic alcohol-based organic solvents are preferred.

The solvent in the first step is preferably used in such an amount that the ratio of the weight of the nitrobenzene derivative of the general formula (1) relative to the weight of the solvent "weight of the nitrobenzene derivative/weight of the solvent" reaches a range of 0.05 to 1.0, particularly preferably 0.1 The amount in the range of ~0.8 is used.

The reaction temperature in the first step may be a temperature lower than the boiling point of the solvent usually used, and is preferably in the range of 0 to 150°C, particularly preferably in the range of 20 to 100°C. The reaction time of the first step is significantly affected by the reaction temperature, and the reaction is usually completed within 20 hours.

The reaction in the first step is usually carried out in the presence of a base. As the base preferably used in this first step, for example, potassium carbonate, sodium carbonate, lithium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide and sodium methoxide, potassium carbonate, sodium carbonate, sodium hydroxide, hydroxide Potassium and sodium methoxide. These bases are preferably used in an amount of 1 to 10 times the molar ratio of the total amount of the starting material compounds, and particularly preferably used in an amount of 1.5 to 5 times the molar ratio.

When carrying out the reaction in the first step, in addition to the base, an additive for promoting the reaction may be further added. Examples of such additive include potassium iodide, N,N-dimethylaminopyridine, and the like. At this time, the amount of the additive is preferably an amount that reaches a ratio of 0.0005 to 0.5 (the number of moles of the additive/the number of moles of the nitrobenzene derivative) by molar ratio relative to the nitrobenzene derivative of the general formula (1), particularly preferably The amount to achieve a ratio of 0.001 to 0.1 (same).

The chemical structure of the 2-nitro-2'-carboxy-phenylene sulfide derivative of the general formula (3) obtained in the first step of the preparation method of the present invention is composed of the chemical structure of the nitrobenzene derivative of the general formula (1) and The chemical structure of the thiosalicylic acid derivatives of general formula (2) is determined, but as 2-nitro-2'-carboxy-phenylene sulfide derivatives, such as 2-nitro-2'-carboxy-phenylene sulfide , 2-nitro-4-methoxy-2'-carboxy-phenylene sulfide, 2-nitro-4-methyl-2'-carboxy-phenylene sulfide, 2-nitro-4-phenyl- 2'-Carboxy-phenylene sulfide, 2-nitro-4-acetyl-2'-carboxy-phenylene sulfide, and 2-nitro-2'-carboxy-4'-methoxy-phenylene sulfide. Preference is given to 2-nitro-2'-carboxy-phenylene sulfide and 2-nitro-2'-carboxy-4'-methoxy-phenylene sulfide.

When reclaiming the 2-nitro-2'-carboxy-phenylene sulfide derivative of the general formula (3) generated in the first step, conventional washing operations and separation operations can be combined, such as by adding an acid to the reaction mixture to make it It becomes acidic, and the precipitated crystal is filtered to obtain a crude product, or water and an extraction solvent (organic solvent) are added to the reaction liquid, and an acid is added thereto to adjust the pH of the aqueous layer to acidic. Alternatively, the crude product can also be obtained by concentrating the organic layer under reduced pressure. Usually, there is no problem even if it is used in the following steps in such a state, and what is necessary is just to refine|purify by column chromatography or recrystallization operation at the time of further purification. As for the specific purification method, it is preferable to select appropriately for each compound. As the acid used in the above treatment, hydrochloric acid, sulfuric acid, phosphoric acid and acetic acid are preferable.

The second step in the preparation method of the present invention is to prepare the 2-amino-2'-carboxyl of the general formula (4) by reducing the 2-nitro-2'-carboxy-phenylene sulfide derivatives of the general formula (3). - The phenylene sulfide method.

The reduction operation adopted in the 2nd step is not particularly limited as long as it is the operation adopted in the general reduction of nitro, preferably adopting Raney nickel method (hereinafter referred to as reaction (A)), ferrous salt method (hereinafter referred to as Reaction (B)) or a method using palladium or platinum or their compounds (hereinafter referred to as reaction (C)). As a supply source of hydrogen in the reduction reaction, hydrogen gas is generally used.

Reaction (A): Raney nickel method

The amount of Raney nickel used in this method is generally 1.0 to 80% by weight, preferably 5.0 to 40% by weight relative to the 2-nitro-2'-carboxy-phenylene sulfide derivative of general formula (3) as the nickel amount. weight%. The type of Raney nickel that can be used is, for example, a 10 to 60% Ni—Al alloy. In addition, an alloy to which Cr and Mo are added as additives may also be used. Stabilized nickel may also be used. Even if the development method of Raney nickel is changed, the yield will not be greatly affected, but the known method of W-6 (referring to Kubo Matsuo, Komatsu Shinichiro, "Raney catalyst", Kawaken Fine Chemical Co., Ltd. Club, May 10, Showa 46, page 55) obtained the best results. Of course, sufficient activity was exhibited even with other unfolding methods. When the reaction is carried out by the Raney nickel method, it is usually carried out under hydrogen pressurized conditions, so it is carried out in an autoclave. The higher the hydrogen pressure, the better the results obtained, usually at 5 to 100 atmospheres. The reaction can also be carried out under normal pressure, and in this case, the reaction is carried out while circulating hydrogen gas.

The solvent used in the reaction (A) is not particularly limited as long as it is irrelevant to the reaction, and is preferably an aliphatic alcohol organic solvent such as methanol, ethanol, n-propanol, isopropanol or n-butanol. The ratio of these solvents preferably reaches 0.05～0.6 times amount with respect to the solvent of the 2-nitro-2'-carboxy-phenylene sulfide derivative of general formula (3) (2-nitro-2'-carboxy-phenylene sulfide Derivative weight/capacity of solvent) is particularly preferably in a ratio of 0.1 to 0.6 times the amount (the same).

The reaction temperature in the reaction (A) may be any temperature below the boiling point of the commonly used solvent, and is preferably in the range of 20 to 200°C, particularly preferably in the range of 25 to 150°C. The reaction time is significantly affected by the reaction temperature and hydrogen pressure, and the reaction is usually completed within 20 hours.

After carrying out the reduction treatment by reaction (A), the recovery of the 2-amino-2'-carboxy-phenylene sulfide derivative of the general formula (4) generated can combine conventional washing operations and separation operations, such as filtering the reaction mixture, The obtained filtrate was concentrated under reduced pressure to obtain a crude product. Usually, there is no problem even if it is used in the following steps in this state, and it is sufficient to perform purification by column chromatography or recrystallization operation for further purification, and it is preferable to select an appropriate purification method 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 used in any state of hydrate or anhydrate. Preferred are ferrous sulfate heptahydrate, anhydrous ferrous chloride, ferrous chloride tetrahydrate, and ferrous chloride n-hydrate. The amount of these compounds used as the amount of iron atoms relative to the 2-nitro-2'-carboxy-phenylene sulfide derivatives of general formula (3) is the amount within the range of 0.1 to 30 times by weight, preferably 0.5 to 10 times by weight amount within.

As the solvent used in the reaction (B), a mixed solvent of water and ammonia water is usually used. The ammonia water used is usually carried out with strong ammonia water (the ammonia concentration is 25-28% by weight), as long as the amount of ammonia contained is sufficient, it is also possible to use lower concentration ammonia water, or feed ammonia gas into the water. Regarding water, the amount of 2-nitro-2'-carboxy-phenylene sulfide derivatives of preferred general formula (3) reaches 0.01～0.4 times equivalent (2-nitro-2'-carboxy-phenylene sulfide) relative to water The ratio in the range of derivative weight/water capacity) is particularly preferably in the range of 0.02 to 0.2 times equivalent (same). Regarding ammonia, the amount of 2-nitro-2'-carboxy-phenylene sulfide derivatives relative to ammonia preferably reaches 0.005 to 0.5 times the equivalent (2-nitro-2'-carboxy-phenylene sulfide derivatives weight/ammonia The ratio in the range of weight) is particularly preferably a ratio of 0.01 to 0.5 times the equivalent (the same).

The reaction temperature in reaction (B) should just be the temperature below the boiling point of the solvent normally used, Preferably it is the temperature in the range of 20-100 degreeC, Especially preferably, it is the temperature in the range of 40-90 degreeC. The reaction time is significantly affected by the reaction temperature, and the reaction is usually completed within 2 hours.

After the reduction treatment by reaction (B), the recovery of the 2-amino-2'-carboxy-phenylene sulfide derivatives of the general formula (4) generated can combine conventional washing operations and separation operations, for example, filtration can be used The reaction mixture is carried out by adding an acid (for example, hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid) to the filtrate to adjust the pH to an acidic side, or the like. Alternatively, the obtained filtrate can be concentrated under reduced pressure to obtain the target compound as a crude product. Usually, there is no problem even if such a crude product is used in the following steps. For further purification, it may be purified by column chromatography or recrystallization operation, and it is preferable to select an appropriate purification method for each compound.

Reaction (C): method using palladium or platinum (or their compounds)

In this method, palladium (Pd) or platinum (Pt) is used as a reduction catalyst (hydrogenation catalyst). The palladium or platinum used may be palladium or platinum alone or a compound thereof. In addition, palladium or platinum alone or compound is usually used in a state supported on the surface of a carrier such as carbon (C) or barium sulfate. Preference is given to Pd/C, Pd/barium sulfate and platinum oxide, with Pd/C being particularly preferred.

The amount of the catalyst containing palladium or platinum is preferably 0.01 to 30% by weight in terms of the weight of the palladium or platinum monomer relative to the amount of the 2-nitro-2'-carboxy-phenylene sulfide derivative of the general formula (3). The amount in the range of 0.05 to 10% by weight is particularly preferable. In addition, the supported amount of palladium or platinum on the catalyst carrier (in the case of a compound of palladium or platinum, in terms of the weight of each metal alone) is preferably in the range of 1 to 10% by weight. In addition, when Pd/C is used, it is generally possible to use a dry product with a moisture content of 5% or less called a dry product, or a water-containing product called a wet product with a moisture content of 5% or more. Examples of water-containing products include those having a water content of 10 to 70% by weight (ratio of the water content to the total amount of the catalyst).

In reaction (C), when using platinum oxide as a reduction catalyst, the consumption of platinum oxide relative to the 2-nitro-2'-carboxy-phenylene sulfide derivative of general formula (3) preferably reaches 0.1～50% by weight. The amount is particularly preferably in the range of 1 to 30% by weight.

Reaction (C) is usually carried out under hydrogen pressure. Therefore, the reaction is usually carried out in an autoclave. The higher the hydrogen pressure, the better the results obtained, typically using hydrogen pressurization conditions of 2 to 100 atmospheres. The reaction can also be carried out under normal pressure. In this case, the hydrogen gas is circulated to carry out the reduction reaction (hydrogenation reaction).

Reaction (C) is usually carried out in the presence of a solvent. The solvent used in the reaction (C) is not particularly limited as long as it is irrelevant to the reaction. For example, aliphatic alcohol organic solvents such as methanol, ethanol, n-propanol, isopropanol, or n-butanol can be used. , N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone or dimethylimidazolinone and other amide organic solvents. Among them, aliphatic alcohol organic solvents are preferred. These solvents are preferably used in an amount in the range of 2 to 70% by weight, particularly preferably in an amount in the range of 5 to 50% by weight, based on the 2-nitro-2'-carboxy-phenylene sulfide derivative of the general formula (3).

The reaction (C) is usually carried out at a temperature in the range of 10 to 200°C, and it is particularly preferable to use a reaction temperature in the range of 20 to 150°C. In addition, the reaction time is greatly affected by the reaction temperature and hydrogen pressure, and the reaction time within 30 hours is usually used.

After the reduction treatment (hydroprocessing) of reaction (C), the recovery of the 2-amino-2'-carboxy-phenylene sulfide derivative of the general formula (4) generated can combine conventional washing operations and separation operations, For example, it can be carried out by a method of filtering the reaction mixture, concentrating the obtained filtrate under reduced pressure to obtain a crude product, and the like. Usually, there is no problem even if it is used in the following steps in this state, and it is sufficient to perform purification by column chromatography or recrystallization operation for further purification, and it is preferable to select an appropriate purification method for each compound.

The chemical structure of the 2-amino-2'-carboxy-phenylene sulfide derivative of the general formula (4) obtained in the 2nd step (reduction step) of the preparation method of the present invention is obtained from the general formula used as the reaction raw material in the 2nd step The chemical structure of the 2-nitro-2'-carboxy-phenylene sulfide derivative of (3) was determined. As examples of 2-amino-2'-carboxy-phenylene sulfide derivatives of the general formula (4), such as 2-amino-2'-carboxy-phenylene sulfide, 2-amino-4-methoxy-2' -Carboxyl-phenylene sulfide, 2-amino-4-methyl-2'-carboxy-phenylene sulfide, 2-amino-4-phenyl-2'-carboxy-phenylene sulfide, 2-amino-4-acetyl Base-2'-carboxy-phenylene sulfide and 2-amino-2'-carboxy-4'-methoxy-phenylene sulfide. Preference is given to 2-amino-2'-carboxy-phenylene sulfide and 2-amino-2'-carboxy-4'-methoxy-phenylene sulfide.

衍生物的方法。The third step of the preparation method of the present invention is to dehydrate and condense the 2-amino-2'-carboxy-phenylene sulfide derivatives of the general formula (4) to prepare the dibenzothiazepine represented by the general formula (5)

Derivative method.

The reaction in the third step can be performed without a solvent, but it is preferably performed using a hydrophobic organic solvent inert to the reaction. Examples of such organic solvents include aromatic hydrocarbon solvents such as toluene, xylene, cumene, and benzene, chlorobenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, 1,4- Dichlorobenzene, bromobenzene, 1,2-dibromobenzene, 1,3-dibromobenzene, 1,4-dibromobenzene and other aromatic halide solvents, cyclohexane, cycloheptane, cyclooctane, etc. Cyclic hydrocarbon solvents or aliphatic ester solvents such as ethyl acetate, butyl acetate, methyl butyrate, ethyl butyrate, and butyl butyrate, etc. Particular preference is given to toluene, xylene, cumene and 1,2-dichlorobenzene.

For the consumption of the solvent used in the 3rd step is not particularly limited, the volume of solvent is relative to the ratio (W/V%) of the weight of the 2-amino-2'-carboxy-phenylene sulfide derivative of general formula (4) It is preferably 3% or more, particularly preferably in the range of 4 to 40%. In addition, in order to increase the reaction rate and conversion rate in the third step, an azeotropic dehydration operation (operation in which reflux is performed while removing generated water) can also be performed using a Dean-Stark apparatus. The reaction temperature in the third step is not particularly limited as long as it is not higher than the boiling point of the organic solvent used, but a temperature in the range of 100°C to 200°C is preferable.

衍生物的化学结构由通式(4)的2-氨基-2’-羧基-苯硫醚衍生物的化学结构确定。作为通式(5)的二苯并硫氮衍生物，例如二苯并〔b，f〕〔1，4〕硫氮-11-酮、8-甲基-二苯并〔b，f〕〔1，4〕硫氮-11-酮、8-苯基-二苯并〔b，f〕〔1，4〕硫氮

-11-酮、8-甲氧基-二苯并〔b，f〕〔1，4〕硫氮-11-酮和2-甲氧基-二苯并〔b，f〕〔1，4〕硫氮-

11-酮。优选二苯并〔b，f〕〔1，4〕硫氮

-11-酮以及2-甲氧基-二苯并〔b，f〕〔1，4〕硫氮-11-酮。The dibenzothiazepine of general formula (5) obtained in the 3rd step

The chemical structure of the derivative is determined by the chemical structure of the 2-amino-2'-carboxy-phenylene sulfide derivative of the general formula (4). Dibenzothiazepine as general formula (5) Derivatives such as dibenzo[b,f][1,4]thiazepine -11-one, 8-methyl-dibenzo[b,f][1,4]sulfur -11-one, 8-phenyl-dibenzo[b,f][1,4]sulfur

-11-one, 8-methoxy-dibenzo[b,f][1,4]sulfur -11-one and 2-methoxy-dibenzo[b,f][1,4]sulfur-

11-keto. Preferably dibenzo[b,f][1,4]sulfur

-11-one and 2-methoxy-dibenzo[b,f][1,4]sulfur -11-one.

衍生物的回收可以利用冷却反应混合物使二苯并硫氮

衍生物的晶体析出的方法容易地实施。因此，通过过滤该晶体可以得到高纯度的二苯并硫氮

衍生物。有必要进一步精制时，可以进行重结晶，或采用柱色谱法。或者也可以利用在使反应混合物析出晶体之前，加入碱性水溶液，分离水层后，进行冷却，使二苯并硫氮

衍生物结晶的方法。作为配制该操作中使用的碱性水溶液时使用的碱性化合物的实例，例如碳酸氢钠、碳酸钠、碳酸钾、氢氧化钠和氢氧化钾。碱性水溶液中碱性化合物的浓度优选为0.5～30重量％的范围。另外，碱性水溶液的用量没有特别的限定，优选相对于第3步骤的产物(通式(5)的二苯并硫氮

衍生物)以0.05～0.4重量倍左右的量使用。The dibenzothiazepine of the general formula (5) that the 3rd step generates

Derivatives can be recovered by cooling the reaction mixture to make dibenzothiazepine

The method of crystallization of the derivative is easily carried out. Therefore, high-purity dibenzothiazepine can be obtained by filtering the crystal

derivative. When further purification is necessary, recrystallization or column chromatography can be used. Or it can also be used to add an alkaline aqueous solution before the reaction mixture is crystallized, and after the water layer is separated, it is cooled to make dibenzothiazepine

Method of Derivative Crystallization. As examples of the basic compound used when preparing the basic aqueous solution used in this operation, there are, for example, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide. The concentration of the basic compound in the alkaline aqueous solution is preferably in the range of 0.5 to 30% by weight. In addition, the amount of alkaline aqueous solution is not particularly limited, preferably with respect to the product of the 3rd step (dibenzothiazepine of general formula (5)

Derivatives) are used in an amount of about 0.05 to 0.4 times by weight.

Preferred embodiments of the present invention are as follows.

(1) The nitrobenzene derivative of the general formula (1) is 2-chloronitrobenzene or 2-bromonitrobenzene.

(2) The thiosalicylic acid derivative of the general formula (2) is thiosalicylic acid or 5-methoxythiosalicylic acid.

(3) dibenzothiazepine of the present invention In the first step of the production method of the derivative, a base selected from potassium carbonate, sodium hydroxide and sodium methoxide is used.

(4) The 2-nitro-2'-carboxy-phenylene sulfide derivative of the general formula (3) is 2-nitro-2'-carboxy-phenylene sulfide or 2-nitro-2'-carboxy-4 '-methoxy-phenylene sulfide.

(5) Dibenzothiazepine of the present invention In the first step of the preparation method of the derivative, N,N-dimethylformamide or methanol is used as a reaction solvent.

(6) Dibenzothiazepine of the present invention In the reduction reaction in the second step of the production method of the derivative, Raney nickel is used as a reducing agent, and methanol or n-butanol is used as a solvent.

(7) Dibenzothiazepine of the present invention In the reduction reaction in the second step of the production method of the derivative, ferrous sulfate heptahydrate is used as a reducing agent, and an aqueous ammonia solution is used as a solvent.

衍生物的制备方法的第2步骤的还原反应在Pd/C、Pd/硫酸钡或氧化铂中任意一种还原催化剂存在下，使用甲醇或乙醇作为溶剂进行。(8) Dibenzothiazepine of the present invention

The reduction reaction in the second step of the preparation method of the derivative is carried out in the presence of any reduction catalyst selected from Pd/C, Pd/barium sulfate or platinum oxide, using methanol or ethanol as a solvent.

-11-酮。(9) 2-amino-2'-carboxy-phenylene sulfide derivatives of general formula (4) are 2-amino-2'-carboxy-phenylene sulfide, 2-amino-2'-carboxy-4'-methanol Oxy-phenylene sulfide or 2-methoxy-dibenzo[b,f][1,4]sulfur

-11-one.

衍生物为二苯并〔b，f〕〔1，4〕硫氮

-11-酮或2-甲氧基-二苯并〔b，f〕〔1，4〕硫氮

-11-酮。(10) Dibenzothiazepine represented by general formula (5)

Derivatives are dibenzo[b,f][1,4]sulfur

-11-one or 2-methoxy-dibenzo[b,f][1,4]sulfur

-11-one.

(11) As the nitrobenzene derivative of the general formula (1) as the first step reaction raw material, use 2-chloronitrobenzene or 2-bromonitrobenzene; in addition, as the thiosalicylate of the general formula (2) Acid derivative, use thiosalicylic acid or 5-methoxy thiosalicylic acid; As base, use potassium carbonate; As solvent, use N,N-dimethylformamide; Prepare as general formula (3) 2-nitro-2'-carboxyphenylene sulfide or 2-nitro-2'-carboxy-4'-methoxyphenylene sulfide derivatives.

(12) As the reaction raw material of the second step, use 2-nitro-2'-carboxy-phenylene sulfide or 2-nitro-2'-carboxy-4'-methoxy-phenylene sulfide in platinum, In the presence of palladium or their compounds, it is reduced with hydrogen to prepare 2-amino-2'-carboxy-phenylene sulfide or 2-amino-2'-carboxy-phenylene sulfide derivatives as general formula (4). -amino-2'-carboxy-4'-methoxy-phenylene sulfide.

-11-酮或2-甲氧基-二苯并〔b，f〕〔1，4〕硫氮-11-酮。(13) As the reaction raw material of the 3rd step, use 2-amino-2'-carboxy-phenylene sulfide or 2-amino-2'-carboxy-4'-methoxyl-phenylene sulfide to prepare as general formula ( 5) Dibenzothiazepine Derivatives of dibenzo[b,f][1,4]thiazepine

-11-one or 2-methoxy-dibenzo[b,f][1,4]sulfur -11-one.

Hereinafter, the preparation method of the present invention will be described in more detail with reference to the examples and comparative examples of the present invention, but the present invention is not limited by these examples.

[Example 1]

94.5 g (0.60 mol) of 2-chloronitrobenzene and 159.0 g (1.15 mol) of potassium carbonate were dissolved in 120 mL of N,N-dimethylformamide. To the obtained 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 added dropwise, and stirred at 70°C Allow to react for 6 hours. To the obtained reaction liquid were added 800 mL of water and 700 mL of ethyl acetate. 400 g of ice and 194 mL of concentrated hydrochloric acid were added to the separated aqueous layer to adjust the pH of the aqueous layer to acidic, and the solution was stirred at room temperature for 1 hour. The precipitated crystals were filtered and dried to obtain 134.0 g (0.49 mol) of 2-nitro-2'-carboxy-phenylene sulfide as a yellow powder. (yield relative to thiosalicylic acid: 98%)

¹ H-NMR (DMSO-d ₆ ): δ

7.1～8.3(m, 8H), 13.1～13.5(br, 1H)

[Example 2]

94.5 g (0.60 mol) of 2-chloronitrobenzene and 159.0 g (1.15 mol) of potassium carbonate were dissolved in 120 mL of N,N-dimethylformamide. To the obtained 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 added dropwise, and stirred at 70°C Allow to react for 6 hours. 200 mL of water and 194 mL of concentrated hydrochloric acid were added to the obtained reaction liquid to adjust the pH of the aqueous layer to acidic, and the solution was stirred at room temperature for 1 hour. The precipitated crystals were filtered and dried to obtain 123.0 g (0.45 mol) of 2-nitro-2'-carboxy-phenylene sulfide as a yellow powder. (yield relative to thiosalicylic acid: 90%)

[Example 3]

Except that 2-bromonitrobenzene is used to replace 2-chloronitrobenzene, and its amount is changed to 121.2g (0.60 moles), the same operation as in Example 1 is carried out to obtain 2-nitro-2'-carboxy-benzene Thioether 134.0 g (0.49 mol). (yield relative to thiosalicylic acid: 98%)

[Example 4]

Except that thiosalicylic acid is replaced with 5-methoxythiosalicylic acid, and its dosage is changed to 93.8g (0.50 moles), the same operation as in Example 1 is carried out to obtain 2-nitro-2'- Carboxy-4'-methoxy-phenylene sulfide 137.3 g (0.45 mol). (Yield relative to 5-methoxythiosalicylic acid: 90%). Melting point: 185～187℃

[Example 5]

Except that the solvent was changed from N,N-dimethylformamide to methanol, and the reaction temperature and time were changed to 64°C and 2 hours, the same operation as in Example 1 was carried out to obtain 2-nitro-2'- Carboxy-phenylene sulfide 131.3 g (0.48 mol). (yield relative to thiosalicylic acid: 96%)

[Example 6]

Except that potassium carbonate is changed into sodium hydroxide, and its consumption is changed to 46.0g (1.15 mole), carry out the same operation with embodiment 5, obtain 2-nitro-2'-carboxy-phenylene sulfide 130.0g (0.47 Moore). (yield relative to thiosalicylic acid: 94%)

[Example 7]

Except that potassium carbonate is changed to sodium methylate, its consumption is changed to 62.1g (1.15 moles), and the reaction time is changed to 5 hours, the same operation as in Example 5 is carried out to obtain 2-nitro-2'-carboxyl - Phenylsulfide 131.8 g (0.48 mol). (yield relative to thiosalicylic acid: 96%)

[Example 8]

Except having previously added 3.9 g (0.02 mol) of potassium iodide to the reaction solution, the same operation as in Example 7 was carried out to obtain 133.8 g (0.49 mol) of 2-nitro-2'-carboxy-phenylene sulfide. (yield relative to thiosalicylic acid: 97%)

[Example 9]

In the autoclave of 300mL, add Raney nickel (as 50% alloy, Ni amount is 4g), 13.8g (0.05 mole) of 2-nitro-2'-carboxy-phenylene sulfide obtained according to the method for embodiment 1 and Methanol 100mL was adjusted to a hydrogen pressure of 20 atmospheres, and stirred at room temperature for 5 hours to react. The resulting 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-phenylene sulfide as a colorless powder. (yield relative to 2-nitro-2'-carboxy-phenylene sulfide: 92%)

¹ H-NMR (DMSO-d ₆ ): δ

5.0～5.9(br, 2H), 6.5～8.1(m, 8H), 12.8～13.5(br, 1H)

[Example 10]

Suspend 4.0 g (14.5 mmoles) of Raney nickel (as a 50% alloy, the amount of Ni is 1 g) and 2-nitro-2'-carboxy-phenylene sulfide obtained by the method of Example 1 in n-butanol 50mL. While bubbling hydrogen into the obtained n-butanol suspension, stirring was carried out at 100° C. for 15 hours to allow a reaction. The resulting reaction suspension was filtered, and the filtrate was concentrated under reduced pressure to obtain 3.24 g (13.2 mmol) of 2-amino-2'-carboxy-phenylene sulfide as a colorless powder. (yield relative to 2-nitro-2'-carboxy-phenylene sulfide: 91%)

[Example 11]

2.75 g (10.0 mmol) of 2-nitro-2'-carboxy-phenylene sulfide obtained in Example 1 was dissolved in 40 mL of concentrated ammonia solution (ammonia concentration = 28% by weight). A solution obtained by dissolving 21.6 g (77.8 mmol) of ferrous sulfate heptahydrate in 70 mL of water was added dropwise to the obtained ammonia mixture, followed by heating at 80° C. for 10 minutes to allow a reaction. After cooling the obtained reaction solution to room temperature, it was filtered, and the filtrate was concentrated to 30 mL under reduced pressure, and 70 mL of ethyl acetate and 2 mL of acetic acid were added. The separated organic layer was dried over anhydrous magnesium sulfate, and the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 2.33 g (9.50 mmol) of 2-amino-2'-carboxy-phenylene sulfide as a colorless powder. (yield relative to 2-nitro-2'-carboxy-phenylene sulfide: 95%)

[Example 12]

Except using 15.2 g (0.05 mol) of 2-nitro-2'-carboxy-4'-methoxy-phenylene sulfide obtained according to the method of Example 4, the same operation as in Example 10 was performed to obtain a colorless 12.7 g (0.046 mol) of powdery 2-amino-2'-carboxy-4'-methoxy-phenylene sulfide. (yield relative to 2-nitro-2'-carboxy-4'-methoxy-phenylene sulfide: 92%)

Melting point: 150～151℃

[Example 13]

Fill 1.37g of Pd (5wt%)/C, 13.7g (0.05 moles) of 2-nitro-2'-carboxy-phenylene sulfide obtained according to the method of Example 1 and 95mL of methanol in a 300mL autoclave, After the hydrogen pressure was adjusted to 10 atmospheres, the mixture was stirred at 25°C for 6 hours to carry out hydrogenation reaction. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 11.7 g (0.048 mol) of 2-amino-2'-carboxy-phenylene sulfide as a colorless powder. (yield relative to 2-nitro-2'-carboxy-phenylene sulfide: 95%)

Melting point: 150～151℃

[Example 14]

Except that the reaction temperature was changed to 50°C and the reaction time was changed to 4 hours, the same operation as in Example 13 was carried out to obtain 12.0 g (0.049 mol) of 2-amino-2'-carboxy-phenylene sulfide. (yield relative to 2-nitro-2'-carboxy-phenylene sulfide: 98%)

[Example 15]

Except that 1.37g of Pd(5wt%)/C was changed to 2.91g of Pd(5wt%)/C (water content: 52.9wt%), the same operation as in Example 14 was carried out to obtain 2-amino-2' -Carboxy-phenylene sulfide 11.9 g (0.049 mol). (yield relative to 2-nitro-2'-carboxy-phenylene sulfide: 97%)

[Example 16]

Except that the amount of methanol used was changed to 50 mL and the reaction time was changed to 6 hours, the same operation as in Example 14 was carried out to obtain 11.9 g (0.049 mol) of 2-amino-2'-carboxy-phenylene sulfide. (yield relative to 2-nitro-2'-carboxy-phenylene sulfide: 97%)

[Example 17]

Except that the amount of methanol used was changed to 180 mL and the reaction time was changed to 6 hours, the same operation as in Example 14 was carried out to obtain 11.2 g (0.046 mol) of 2-amino-2'-carboxy-phenylene sulfide. (yield relative to 2-nitro-2'-carboxy-phenylene sulfide: 91%)

[Example 18]

Except for changing methanol to ethanol, the same operation as in Example 14 was carried out to obtain 11.2 g (0.046 mol) of 2-amino-2'-carboxy-phenylene sulfide. (yield relative to 2-nitro-2'-carboxy-phenylene sulfide: 92%)

[Example 19]

Except that 1.37g of Pd (5wt%)/C was changed to 640mg of platinum oxide (PtO ₂ ), the same operation as in Example 14 was performed to obtain 10.8g of 2-amino-2'-carboxy-phenylene sulfide (0.044 Moore). (yield relative to 2-nitro-2'-carboxy-phenylene sulfide: 88%)

[Example 20]

Except using 15.2 g (0.05 moles) of 2-nitro-2'-carboxy-4'-methoxy-phenylene sulfide obtained according to the method of Example 4, the same operation as in Example 14 was carried out to obtain 2- Amino-2'-carboxy-4'-methoxy-phenylene sulfide 12.7 g (0.046 mol). (yield relative to 2-nitro-2'-carboxy-4'-methoxyl-phenylene sulfide: 92%)

[Example 21]

24.5 g (0.10 mol) of 2-amino-2'-carboxy-phenylene sulfide obtained by the method of Example 9 was dissolved in 300 mL of toluene. The obtained toluene solution was refluxed for 20 hours to perform a reaction. After cooling the obtained reaction solution to room temperature, the precipitated crystals were filtered. The resulting filtrate was dried to give dibenzo[b,f][1,4]sulfur 15.7 g (0.069 mol) of colorless needle crystals of -11-one. (Yield relative to 2-amino-2'-carboxy-phenylene sulfide: 69%). Melting point: 259～260℃

¹ H-NMR (DMSO-d ₆ ): δ

7.05～7.80(m, 8H), 10.7(s, 1H)

[Example 22]

-11-酮的无色针状晶体18.2g(0.080摩尔)。(相对于2-氨基-2’-羧基-苯硫醚的收率：80％)。24.5 g (0.10 mol) of 2-amino-2'-carboxy-phenylene sulfide obtained by the method of Example 9 was dissolved in 300 mL of toluene. The obtained toluene solution was subjected to azeotropic dehydration (using a Dean-Stark apparatus) for 20 hours while being refluxed for reaction. After cooling the obtained reaction solution to room temperature, the precipitated crystals were collected by filtration. Next, the resulting filtrate was dried to obtain dibenzo[b,f][1,4]sulfur

18.2 g (0.080 mol) of colorless needle-like crystals of -11-one. (Yield relative to 2-amino-2'-carboxy-phenylene sulfide: 80%).

[Example 23]

-11-酮的无色针状晶体22.3g(0.098摩尔)。(相对于2-氨基-2’-羧基-苯硫醚的收率：98％)。Except that the reaction solvent is changed to xylene and the reaction time is changed to 15 hours, the same reaction as in Example 22 is carried out to obtain dibenzo[b,f][1,4]sulfur nitrogen

22.3 g (0.098 mol) of colorless needle crystals of -11-one. (Yield relative to 2-amino-2'-carboxy-phenylene sulfide: 98%).

[Example 24]

-11-酮的无色针状晶体22.3g(0.098摩尔)。(相对于2-氨基-2’-羧基-苯硫醚的收率：98％)。Except that the reaction solvent is changed to cumene, and the reaction time is changed to 10 hours, the same reaction as in Example 22 is carried out to obtain dibenzo[b, f][1,4] sulfur nitrogen

22.3 g (0.098 mol) of colorless needle crystals of -11-one. (Yield relative to 2-amino-2'-carboxy-phenylene sulfide: 98%).

[Example 25]

-11-酮的无色针状晶体21.5g(0.095摩尔)。(相对于2-氨基-2’-羧基-苯硫醚的收率：95％)。24.5 g (0.10 mol) of 2-amino-2'-carboxy-phenylene sulfide obtained by the method of Example 14 was dissolved in 300 mL of xylene. The resulting xylene solution was subjected to azeotropic dehydration (using a Dean-Stark apparatus) for 15 hours while being refluxed for reaction. After cooling the obtained reaction solution to 75° C., 240 mL of a saturated aqueous sodium bicarbonate solution was added thereto, followed by stirring at 75° C. for 30 minutes. Next, the precipitated crystals were collected by filtration. The resulting filtrate was dried to give dibenzo[b,f][1,4]sulfur

21.5 g (0.095 mol) of colorless needle crystals of -11-one. (Yield relative to 2-amino-2'-carboxy-phenylene sulfide: 95%).

[Example 26]

Except that the saturated sodium bicarbonate aqueous solution is changed to 1N sodium hydroxide aqueous solution, and its dosage is changed to 200mL, the same reaction as in Example 25 is carried out to obtain dibenzo[b,f][1,4]sulfur nitrogen 21.1 g (0.093 mol) of colorless needle crystals of -11-one. (Yield relative to 2-amino-2'-carboxy-phenylene sulfide: 93%).

[Example 27]

-11-酮的无色针状晶体22.0g(0.097摩尔)。(相对于2-氨基-2’-羧基-苯硫醚的收率：97％)。Except that the reaction solvent is changed to cumene, and the reaction time is changed to 10 hours, the same reaction as in Example 25 is carried out to obtain dibenzo[b, f][1,4] sulfur nitrogen

22.0 g (0.097 mol) of colorless needle crystals of -11-one. (Yield relative to 2-amino-2'-carboxy-phenylene sulfide: 97%).

[Example 28]

-11-酮的无色针状晶体23.6g(0.092摩尔)。(相对于2-氨基-4-甲氧基-2’-羧基-苯硫醚的收率：92％)。熔点：220～223℃Using 27.5 g (0.10 moles) of 2-amino-2'-carboxy-4'-methoxy-phenylene sulfide obtained according to the method of Example 12, the same reaction as in Example 23 was carried out to obtain 2-methoxy -Dibenzo[b,f][1,4]sulfur

23.6 g (0.092 mol) of colorless needle crystals of -11-one. (Yield relative to 2-amino-4-methoxy-2'-carboxy-phenylene sulfide: 92%). Melting point: 220～223℃

Industrial Applicability

衍生物。Dibenzothiazepine according to the present invention The preparation method of nitrobenzene derivatives is reacted with thiosalicylic acid derivatives to generate 2-nitro-2'-carboxy-phenylene sulfide derivatives, and then the product is reduced to generate 2-amino-2 '-Carboxyl-phenylene sulfide derivatives, followed by dehydration condensation of this product, can produce dibenzothiazepines represented by the general formula (5) with high practicability as intermediates of pharmaceuticals with high yield and simple operation

derivative.

Claims (4)

1. the dibenzo sulphur nitrogen of following general formula (5) expression

The preparation method of derivative,

In the formula, R ¹, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁷And R ⁸Identical or different, the expression hydrogen atom, or the straight chain shape or the branched-chain alkyl of 1～10 of carbonatoms, alkoxyl group with 1～10 of carbonatoms of the straight chain shape of 1～10 of carbonatoms or branched-chain alkyl part, alkyl-carbonyl with 2～11 of carbonatomss of the straight chain shape of 1～10 of carbonatoms or branched-chain alkyl part, phenyl, naphthyl, anthryl, has phenyl moiety, the aryloxy of naphthyl moiety or anthryl part, perhaps has phenyl moiety, the aryl carbonyl of naphthyl moiety or anthryl part

It is characterized in that, make the nitrobenzene derivative of following general formula (1) expression and the thio-salicylic acid derivative of following general formula (2) expression be selected from water, N, dinethylformamide, N, the N-N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, dimethyl-imidazolinone, aliphatics alcohols organic solvent, in the solvent of organic solvent of ketone and nitrile organic solvent, be selected from salt of wormwood, yellow soda ash, Quilonum Retard, sodium hydroxide, potassium hydroxide, react under the condition that the alkali of lithium hydroxide and sodium methylate exists, after generating the 2-nitro-2 '-carboxyl-diphenyl sulfide derivative of following general formula (3) expression, with this 2-nitro-2 '-carboxyl-diphenyl sulfide derivative reduction, after generating the 2-amino-2 '-carboxyl-diphenyl sulfide derivative of following general formula (4) expression, make this 2-amino-2 '-carboxyl-diphenyl sulfide derivative dehydrating condensation;

In the formula, R ¹, R ², R ³And R ⁴Represent implication same as described above, and X represents halogen atom;

In the formula, R ⁵, R ⁶, R ⁷And R ⁸Represent implication same as described above;

In the formula, R ¹, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁷And R ⁸Represent implication same as described above;

In the formula, R ¹, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁷And R ⁸Represent implication same as described above.

2. dibenzo sulphur nitrogen as claimed in claim 1

The preparation method of derivative is characterized in that described alkali is selected from salt of wormwood, yellow soda ash, sodium hydroxide, potassium hydroxide and sodium methylate.

3. dibenzo sulphur nitrogen as claimed in claim 1 The preparation method of derivative is characterized in that carrying out under the condition that the material in being selected from Raney Ni, ferrous salt, palladium, platinum, palladium compound and platinic compound exists the reduction of the 2-nitro-2 '-carboxyl-diphenyl sulfide derivative of above-mentioned general formula (3).

4. dibenzo sulphur nitrogen as claimed in claim 1 The preparation method of derivative is characterized in that carrying out the dehydrating condensation of the 2-amino-2 '-carboxyl-diphenyl sulfide derivative of above-mentioned general formula (4) in organic solvent.