JPH1045706A - Mew disulfide compound, production thereof and production of thiazepine derivative by using the same compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new diformyldiphenyldisulfide compound useful as a medicine, an agrochemical agent, a functional material and a synthetic intermediate of 2,3,4,5-tetrahydro-1,4-benzothiazepine useful as a medicine, an agrochmical agent and a function material. SOLUTION: This new disulfide compound is a diformyldiphenyldisulfide compound of formula I (R<1> is H, a halogen, a 1-4C linear or branched chain alkyl, a 1-4C alkoxy or cyano), e.g. 2,2'-diformyl-4,4'-dimethoxydiphenyldisulfide of formula II. The compound of the formula II is obtained by chlorinating a 2-alkylthiobenzaldehyde of formula III and then hydrolyzing the chlorinated compound by using a lower alcohol. A 2,3,4,5-tetrahydro-1,4-benzothiazepine of formula IV is obtained industrially advantageously, in good efficiency and economically by reacting the diformyldiphenyldisulfide compound of the formula I with 2-chloroethylamine or a mineral acid salt thereof in the presence of a base, and then cyclizing the reaction product by using a reducing agent.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a novel disulfide compound, a method for producing the same, and a method for producing a thiazepine derivative using the compound. More specifically, a novel diformyldiphenyl disulfide compound, a method for producing the same, and 2,3,4, using the compound as an intermediate
The present invention relates to a novel method for producing 5-tetrahydro-1,4-benzothiazepines.

[0002] 2,3,4,5-tetrahydro-1,4-
Benzothiazepines are useful compounds used for various uses such as medicines, pesticides, and functional materials, and the diformyl diphenyl disulfide compound itself is useful for various uses such as medicines, pesticides, and functional materials. Compound.

[0003]

2. Description of the Related Art Conventionally, 2,3,4,5-tetrahydro-
As a method for producing 1,4-benzothiazepines,
Although some are known, these manufacturing methods are classified as follows.

(1) Using thiosalicylic acid as a raw material JP-A-4-230681

[0005]

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(2) 2-[(2-aminoethyl) thio]-
Inorgan.Chem.Acta., 99 (1), L5, 1985; Inorg.Chem., 26 (1
8), 2963,1987

[0007]

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(3) Using a Grignard reagent as a raw material R. Hebd. Seans Acad. Sc
i. , Ser. C, 284 (4), 249, 1976.

[0009]

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[0010]

These known methods are:
In each case, expensive raw materials are used, and obtaining raw materials is not easy. Further, since the yield is low, the economic efficiency is not justified, and it is hard to say that this method is advantageous for industrial implementation. Thus, conventionally, it has been difficult to produce 2,3,4,5-tetrahydro-1,4-benzothiazepines industrially and advantageously.

The object of the present invention is to provide a variety of uses such as pharmaceuticals, agricultural chemicals and functional materials, and useful as intermediates of 2,3,4,5-tetrahydro-1,4-benzothiazepines. It is an object of the present invention to provide a novel diformyl diphenyl disulfide compound and a method for producing the same.

Another object of the present invention is to produce 2,3,4,5-tetrahydro-1,4-benzothiazepines industrially and efficiently by using the diformyldiphenyl disulfide compound. It is to provide a method for manufacturing economically.

[0013]

SUMMARY OF THE INVENTION In view of the above situation, the present inventors have found that 2,3,4,5- is advantageous industrially and easily and economically without using expensive raw materials. The present inventors have made intensive studies to provide a method for producing tetrahydro-1,4-benzothiazepines. As a result, the present inventors have found that a novel diformyl diphenyl disulfide compound represented by the following general formula (1) is important for producing 2,3,4,5-tetrahydro-1,4-benzothiazepines. It was found that it could be an intermediate.

That is, the diformyl diphenyl disulfide compound is reacted with 2-chloroethylamine or a mineral acid salt thereof in the presence of a base and then cyclized with a reducing agent to give 2,3,4, 5-tetrahydro-
They have found that 1,4-benzothiazepines can be easily obtained, and have completed the present invention.

The novel diformyldiphenyl disulfide compound of the present invention is represented by the following general formula (1).

[0016]

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(Wherein R ¹ is a hydrogen atom, a halogen atom,
It represents a linear or branched alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms or a cyano group. The method for producing the diformyldiphenyl disulfide compound represented by the general formula (1) is based on
It is characterized in that alkylthiobenzaldehydes are chlorinated using a chlorinating agent and then hydrolyzed using water or a lower alcohol.

That is, 2-alkylthiobenzaldehydes represented by the general formula (4) are chlorinated by a chlorinating agent, and a compound in which the alkyl portion of the alkylthio group is substituted by a chlorine atom or a part of the hydrogen atom of the alkylthio group Alternatively, a compound or the like entirely substituted with chlorine atoms is produced. A mixture of these chlorination reaction products is subsequently hydrolyzed to form a disulfide to obtain a compound represented by the general formula (1):
The diformyl diphenyl disulfide compound represented by

[0019]

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(Wherein R ¹ is a hydrogen atom, a halogen atom,
A linear or branched alkyl group having 1 to 4 carbon atoms, an alkoxy group or a cyano group having 1 to 4 carbon atoms is shown, and R ² is a linear or branched alkyl group having 1 to 4 carbon atoms. By reacting a diformyl diphenyl disulfide compound represented by the general formula (1) with 2-chloroethylamine or a mineral acid salt thereof in the presence of a base, and then cyclizing with a reducing agent, 2,3 represented by equation (5)
4,5-Tetrahydro-1,4-benzothiazepines can be produced.

[0021]

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(Wherein R ¹ is a hydrogen atom, a halogen atom,
It represents a linear or branched alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms or a cyano group. Also, after chlorinating a 2-alkylthiobenzaldehyde represented by the general formula (4) using a chlorinating agent, hydrolyzing it with water or a lower alcohol to give a dimer represented by the general formula (1) By reacting with a formyl diphenyl disulfide compound and subsequently reacting with 2-chloroethylamine or a salt thereof in the presence of a base, and then cyclizing with a reducing agent, the compound represented by the general formula (5) is obtained. , 3,
4,5-Tetrahydro-1,4-benzothiazepines can be produced.

[0023]

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(Wherein R ¹ is a hydrogen atom, a halogen atom,
A linear or branched alkyl group having 1 to 4 carbon atoms, an alkoxy group or a cyano group having 1 to 4 carbon atoms is shown, and R ² is a linear or branched alkyl group having 1 to 4 carbon atoms. )

[0025]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.

The novel disulfide compound of the present invention is a diformyl diphenyl disulfide compound represented by the above general formula (1).

R ^{1 in the} general formula (1) is preferably a hydrogen atom, a halogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, and a cyano group.

Among the diformyl diphenyl disulfide compounds represented by the above general formula (1), 2,2'-diformyl-4,4'-dimethoxydiphenyl disulfide represented by the formula (2) and the formula (3) 5,5'-
Dichloro-6,6'-diformyldiphenyl disulfide is preferred.

[0029]

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[0030]

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The novel disulfide compound of the present invention can be suitably produced by the production method of the present invention described below, but is not limited to those obtained by these production methods.

The diformyl diphenyl disulfide compound represented by the general formula (1) is a compound of the formula (4)
-Can be produced by chlorinating alkylthiobenzaldehydes with a chlorinating agent and then hydrolyzing with water or a lower alcohol.

Here, 2-alkylthiobenzaldehydes represented by the general formula (4) can be easily obtained, for example, according to the method described in JP-A-6-56760 by the present inventors. That is, by reacting a 2-halobenzaldehyde and an alkyl mercaptide alkali metal salt in the presence of a phase transfer catalyst, a 2-alkylthiobenzaldehyde represented by the general formula (4) can be easily produced from a known raw material. it can.

In the 2-alkylthiobenzaldehydes represented by the general formula (4), R ¹ represents a hydrogen atom, a halogen atom such as fluorine, chlorine, bromine or iodine, methyl, ethyl, n-propyl, isopropyl, n -Butyl, t-
A straight-chain or branched-chain alkyl group having 1 to 4 carbon atoms such as butyl, a straight-chain or branched-chain alkoxy group having 1 to 4 carbon atoms such as methoxy, ethoxy, n-propoxy, n-butoxy and t-butoxy; Or a cyano group, and R ² represents a linear or branched alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl and t-butyl. Specific examples of the compound represented by the general formula (4) include 2-methylthiobenzaldehyde and 2-methylthiobenzaldehyde.
Isopropylthiobenzaldehyde, 2- (n-butyl) thiobenzaldehyde, 2-chloro-6-methylthiobenzaldehyde, 4-chloro-6-methylthiobenzaldehyde, 4-bromo-6- (n-propyl) thiobenzaldehyde, 2-methylthio- 4-methoxybenzaldehyde, 2-methylthio-5-methoxybenzaldehyde, 2- (t-butyl) thio-4-methoxybenzaldehyde, 5-cyano-2-methylthiobenzaldehyde, 2- (t-butyl) thio-3-cyanobenzaldehyde And the like. Preferably, 2-methylthio-5-methoxybenzaldehyde, 2-chloro-6-methylthiobenzaldehyde, 2-methylthiobenzaldehyde, 4-bromo-6- (n-propyl) thiobenzaldehyde, 2- (t-butyl) thio-3 -Cyanobenzaldehyde.

Examples of the chlorinating agent used in the reaction include chlorine, sulfuryl chloride, thionyl chloride, N-chlorosuccinimide and the like. Chlorine and sulfuryl chloride are preferred from an economic viewpoint. The amount of the chlorinating agent varies depending on the type of the compound represented by the general formula (4), but is usually in a range of 0.5 to 7 moles, preferably 0.5 to 7 times the mol of the compound represented by the general formula (4). Is in the range of 0.8 to 3 times mol.

The reaction temperature of the chlorination varies depending on the compound represented by the general formula (4) and the chlorinating agent used, but is usually in the range of about -10 to 160 ° C, preferably about -5 to 100 ° C. . If the reaction temperature is too low, the reaction rate will be slow, and if it is too high, a side reaction will occur, causing a reduction in yield.

The reaction time varies depending on the compound represented by the general formula (4) and the chlorinating agent, and cannot be specified unconditionally, but is usually in the range of 1 to 24 hours, preferably 3 to 10 hours.

With respect to the solvent used for chlorination, chlorination can be carried out without a solvent depending on the compound represented by the general formula (4).
There is no particular limitation, for example, hexane, cyclohexane, hydrocarbons such as heptane, dichloroethane,
Halogenated hydrocarbons such as dichloromethane and chloroform, benzene, toluene, xylene, chlorobenzene,
Examples thereof include aromatic hydrocarbons such as dichlorobenzene and trichlorobenzene, and polar solvents such as N, N-dimethylformamide and dimethylsulfoxide. Preferred are chlorobenzene and dichloroethane.
When a solvent is used, its use amount is not particularly limited, but is usually 0.1 to 10 times the weight of the compound represented by the general formula (4).

By the present chlorination reaction, the various chlorination reaction products described above are obtained.

For the hydrolysis, water or a lower alcohol is used. As the lower alcohol, one having 1 to 6 carbon atoms is used, and examples thereof include methanol, ethanol, and isopropanol. Water or methanol is preferred from an economic standpoint. The amount of water or lower alcohol used for the hydrolysis varies depending on the compound represented by the general formula (4), and cannot be specified unconditionally. ~ 20 times weight, preferably 1
It is in the range of 10 to 10 times the weight.

The reaction temperature of the hydrolysis depends on the compound represented by the general formula (4) and the water or lower alcohol used for the hydrolysis, and cannot be specified unconditionally.
It is in the range of about -10 to 200C, preferably about 20 to 120C. If the reaction temperature is too low, the reaction rate will be slow, and if it is too high, a side reaction will occur, causing a reduction in yield.

The reaction time of the hydrolysis depends on the compound represented by the general formula (4) and the water or lower alcohol used for the hydrolysis, and cannot be specified unconditionally.
It ranges from about 0.5 to 20 hours, preferably from about 1 to 10 hours.

The hydrolysis is carried out by subjecting various chlorination reaction products of the compound represented by the general formula (4) to water or a lower alcohol, and the solvent is not particularly limited. Hydrocarbons such as hexane, cyclohexane and heptane, halogenated hydrocarbons such as dichloroethane, dichloromethane and chloroform; aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene, dichlorobenzene and trichlorobenzene;
And polar solvents such as N, N-dimethylformamide and dimethylsulfoxide. When using a solvent, the amount used is not particularly limited,
Usually, 0.1 to the compound represented by the general formula (4)
It is 10 to 10 times the weight.

The diformyl diphenyl disulfide compound represented by the general formula (1) thus obtained can be isolated by a conventional method such as distillation and crystallization. This reaction solution can be used in the next step without isolation.

The thus obtained diformyldiphenyl disulfide compound represented by the general formula (1) is reacted with 2-chloroethylamine or a salt thereof in the presence of a base, and then reacted with a reducing agent. By cyclizing, 2,3,4,5-tetrahydro-1,4-benzothiazepines represented by the general formula (5) can be produced.

Although the reaction mechanism is not clear, as shown in the following reaction formula, the diformyl diphenyl disulfide compound represented by the general formula (1) reacts with 2-chloroethylamine and is represented by the general formula (6). And the disulfide bond and the imine bond are reduced by the reducing agent,
It is considered that the elimination of hydrochloric acid produces twice-mole 2,3,4,5-tetrahydro-1,4-benzothiazepines represented by the general formula (5).

[0047]

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The amount of 2-chloroethylamine or a salt thereof used in the reaction varies depending on the compound represented by the general formula (1), and cannot be specified unconditionally. The amount is usually 0.1 to 10 times the molar amount,
Preferably it is in the range of 1 to 5 times the molar amount. Mineral salts are not particularly limited, and include hydrochlorides, sulfates, and the like. Preferred mineral salts are the hydrochlorides.

A base is added to make the reaction system alkaline. The base to be added is not particularly limited, and examples thereof include hydroxides such as sodium hydroxide and potassium hydroxide, triethylamine, and triethylamine. Examples thereof include tertiary amines such as butylamine, aromatic heterocyclic compounds such as pyridine and pyrazine, and aqueous solutions and alcohol solutions thereof. Sodium hydroxide is preferred from an economic standpoint. The amount of the base used is not particularly limited,
The amount is usually 0.1 to 10 times, preferably 1 to 5 times the molar amount of 2-chloroethylamine or a mineral acid salt thereof. The preferred pH in the reaction system is 8.0 to 11.0.
It is.

The reaction temperature of the reaction of the diformyldiphenyl disulfide compound represented by the general formula (1) with 2-chloroethylamine or a salt thereof in the presence of a base is represented by the general formula (1). Although it depends on the compound, it cannot be said unconditionally, but is usually in the range of about -10 to 200C, preferably about 0 to 100C. If the reaction temperature is too low, the reaction rate will be slow, and if it is too high, a side reaction will occur, causing a reduction in yield.

The reaction time is not particularly limited, but is usually about 0.5 to 24 hours, preferably about 1 to 10 hours.
Time range.

The reaction can be carried out without solvent or in a solvent, and the solvent is not particularly limited. Examples thereof include alcohols such as methanol, ethanol and isopropanol, and hydrocarbons such as hexane, cyclohexane and heptane. Halogenated hydrocarbons such as dichloroethane, dichloromethane, chloroform, etc., aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene, dichlorobenzene, trichlorobenzene, polar solvents such as N, N-dimethylformamide, dimethyl sulfoxide, and These aqueous solutions can be exemplified. When a solvent is used, its use amount is not particularly limited, but is usually 0.1 to 10 times the weight of the compound represented by the general formula (1).

The reducing agent used in the cyclization reaction is not particularly limited, and examples thereof include metal hydride complex compounds such as sodium borohydride and lithium aluminum hydride, and metal compounds such as isobutylaluminum hydride and tributyltin hydride. And hydrogen compounds. Preferred reducing agents are sodium borohydride and lithium aluminum hydride. In addition, a combination of a catalyst such as Raney nickel and palladium carbon with hydrogen (catalytic hydrogenation) is also preferably used for the cyclization reaction. The amount of the reducing agent used depends on the compound represented by the general formula (1) or the reducing agent to be used, and cannot be specified unconditionally.
With respect to the compound represented by, usually 0.5 to 10 times molar amount,
Preferably it is in the range of 1 to 6 times the molar amount.

The reaction temperature of the reaction depends on the compound represented by the general formula (1) and the reducing agent used, and cannot be specified unconditionally, but is usually about -10 to 200 ° C, preferably about 0 to 100 ° C. In the range of ° C. If the reaction temperature is too low, the reaction rate will be slow, and if it is too high, side reactions will occur,
This causes a decrease in yield.

The reaction time varies depending on the compound represented by the general formula (1) and the reducing agent used, and cannot be specified unconditionally, but is usually about 0.5 to 20 hours, preferably about 1 to 20 hours.
The range is 10 hours.

The solvent is not particularly restricted but includes, for example, alcohols such as methanol, ethanol and isopropanol, ethers such as ether, tetrahydrofuran and dioxane, hydrocarbons such as hexane, cyclohexane and heptane, dichloroethane, dichloromethane and the like.
Halogenated hydrocarbons such as chloroform, aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene, dichlorobenzene, and trichlorobenzene; N, N
Polar solvents such as dimethylformamide and dimethylsulfoxide, and aqueous solutions thereof. When a solvent is used, its use amount is not particularly limited, but is usually 0.1 to 10 times the weight of the compound represented by the general formula (1).

The 2,3,4,5-tetrahydro-1,4-benzothiazepines represented by the general formula (5) thus obtained are separated from the reaction mixture by a conventional method such as distillation and crystallization. Can be isolated and purified.

Further, 2,3 represented by the general formula (5)
4,5-tetrahydro-1,4-benzothiazepines are obtained by reacting a 2-alkylthiobenzaldehyde represented by the general formula (4) with a diformyl diphenyl disulfide compound represented by the general formula (1), The reaction for obtaining 2,3,4,5-tetrahydro-1,4-benzothiazepines represented by the general formula (5) from the diformyldiphenyl disulfide compound represented by the general formula (1) is continuously performed. It can also be manufactured by a method performed in the following manner. That is, a 2-alkylthiobenzaldehyde represented by the general formula (4) is chlorinated using a chlorinating agent, and then hydrolyzed using water or a lower alcohol to give diformyl represented by the general formula (1). The compound can be produced by reacting with a diphenyl disulfide compound, followed by reacting with 2-chloroethylamine or a salt thereof in the presence of a base, and then cyclizing with a reducing agent. When performing this method, it can be performed in the same manner as described above for each reaction.

The obtained 2,3 represented by the general formula (5)
Specific examples of 4,5-tetrahydro-1,4-benzothiazepines include 2,3,4,5-tetrahydro-1,
4-benzothiazepine, 7-methoxy-2,3,4,5
-Tetrahydro-1,4-benzothiazepine, 6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine, 9-cyano-2,3,4,5-tetrahydro-1,4 -Benzothiazepine and the like.

The 2,3,4,5-tetrahydro-1,4-benzothiazepines represented by the general formula (5) obtained in the present invention are not limited to the above examples. .

[0061]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

Production Example 1 2-methylthio-5-methoxybenzaldehyde used as a raw material was produced according to the method described in JP-A-6-56760. That is, in a 2 liter four-necked flask equipped with a stirrer, thermometer, cooler, and dropping funnel,
308.0 2-bromo-5-methoxybenzaldehyde
g (1.32 mol), 500 g of chlorobenzene, and 17.8 g (0.055 mol) of tetra-n-butylammonium bromide as a phase transfer catalyst, and 30% by weight.
Sodium aqueous solution of methyl thiol adjusted to a concentration 33
8.8 g (1.45 mol) was added dropwise at 90 ° C. over 3 hours, and the mixture was further stirred for 3 hours. After completion of the reaction, the aqueous layer was removed by liquid separation, chlorobenzene was distilled off, and then 192.2 g of 2-methylthio-5-methoxybenzaldehyde was obtained by distillation under reduced pressure.

Example 1 182.0 g (1.00 mol) of 2-methylthio-5-methoxybenzaldehyde obtained in Production Example 1 was added to four 1-liter units equipped with a stirrer, thermometer, cooling tube and gas inlet tube. 500 g of chlorobenzene was added to the flask, and 142 g of chlorine (2.00 g) was added at 50 ° C. for about 4 hours.
Mol) was blown into the chlorination reaction. Subsequently, 300 g of water was added, and the mixture was stirred at 100 ° C. for 4 hours to perform a hydrolysis reaction. The aqueous layer was removed by liquid separation, and cyclohexane was added for recrystallization, whereby yellow crystals 142.
6 g were obtained. According to the following data,
It was identified as 2'-diformyl-4,4'-dimethoxydiphenyl disulfide. The yield based on 2-methylthio-5-methoxybenzaldehyde was 85.4%.

Physical property value 2,2'-diformyl-4,4'-dimethoxydiphenyl disulfide Property: yellow crystal Melting point: 87-89 ° C ¹ H-NMR: δ (ppm) 3.85 (s), 6.96- 7.6
0 (m), 10.16 (s) IR: (CCl ₄ , cm ⁻¹ ) 3068, 2729, 16
55, 1352, 1130, 918 Elemental analysis: Calculated C: 57.47; H: 4.22; O: 19.13; S: 19.18 Found C: 57.41; H: 4.24; O : 19.07; S: 19.21.

Example 2 186.5 g (1.00 mol) of 2-chloro-6-methylthiobenzaldehyde was charged into a 1-liter four-necked flask equipped with a stirrer, a thermometer, a condenser tube and a gas inlet tube, and 500 g of chlorobenzene was added. Was added thereto, and 106.5 g (1.50 mol) of chlorine was blown in at 60 ° C. for about 4 hours to perform a chlorination reaction. Subsequently, 300 g of water was added and 1
The hydrolysis reaction was performed by stirring at 00 ° C. for 4 hours. The aqueous layer was removed by liquid separation, and the solvent was distilled off to obtain a crude crystal. Dissolve this in chlorobenzene, add cyclohexane,
After recrystallization, 139.3 g of yellow crystals were obtained. According to the following data, 5,5'-dichloro-6,
It was identified as 6'-diformyldiphenyl disulfide.
The yield based on 2-chloro-6-methylthiobenzaldehyde was 81.2%.

Physical properties 5,5'-dichloro-6,6'-diformyldiphenyl disulfide Property: yellow crystal Melting point: 232 to 233 ° C. ¹ H-NMR: δ (ppm) 7.25 to 7.62 (m) , 10.
68 (s) IR: (KBr, cm ^-1 ) 1680, 1662, 143
3,1413,1281,1080,706 Elemental analysis: calculated C: 48.99; H: 2.35; O: 9.32; S: 18.68 Found C: 49.01; H: 2.38 O: 9.32; S: 18.71.

Examples 3 to 6 The corresponding operations were performed in the same manner as in Example 2 except that the 2-alkylthiobenzaldehydes used as starting materials were changed to the compounds shown in Table 1, to obtain corresponding diformyldiphenyl disulfide compounds.

[0068]

[Table 1]

Example 7 Into a 1-liter four-necked flask equipped with a stirrer, thermometer, condenser and dropping funnel, 152.0 g (1.00 mol) of 2-methylthiobenzaldehyde was charged, and 500 g of chlorobenzene was added. Then, 202.5 g (1.50 mol) of sulfuryl chloride was added dropwise over about 4 hours to carry out a chlorination reaction. Subsequently, 250 g of methanol was added, and the mixture was stirred at 80 ° C. for 4 hours to perform a hydrolysis reaction. After the completion of the reaction, water was added, the mixture was cooled, and the crystallized crystals were collected by filtration to obtain 116.5 g of 2,2'-diformyldiphenyldisulfide. The yield based on 2-methylthiobenzaldehyde was 85.0%.

Example 8 109.6 g (0.40 mol) of 2,2'-diformyldiphenyl disulfide and 2-chloroethylamine were placed in a 1-liter four-necked flask equipped with a stirrer, a thermometer, a condenser and a dropping funnel. 92.8 g (0.80 mol) of the hydrochloride were charged, and 400 g of chlorobenzene and 100 parts of water were added.
Then, 117.3 g (0.88 mol) of a 30% aqueous sodium hydroxide solution was added dropwise at 30 ° C. over 2 hours.
After stirring at 3 ° C. for 3 hours, the aqueous layer was removed by liquid separation to obtain an organic layer. Next, 33.4 g (0.88 mol) of sodium borohydride and 200 g of isopropanol were charged into a two-liter four-necked flask equipped with a stirrer, a thermometer, a condenser, and a dropping funnel.
The mixture was added dropwise at 3 ° C over 3 hours, and further stirred at 50 ° C for 1 hour. This was cooled to room temperature, 500 g of water was added, and the mixture was separated to remove an aqueous layer. After evaporating the solvent of the obtained organic layer, 2,3,4,5-tetrahydro-
85.8 g of 1,4-benzothiazepine were obtained. 2,2 '
-The yield based on diformyl diphenyl disulfide is
It was 65.0%.

Example 9 In a 1-liter four-necked flask equipped with a stirrer, a thermometer, a cooling tube and a dropping funnel, 2,2'-diformyl-4,
133.6 g of 4'-dimethoxydiphenyl disulfide
(0.40 mol) and 92.8 g (0.80 mol) of 2-chloroethylamine hydrochloride, 400 g of chlorobenzene and 100 g of water were added, and 117.3 g of a 30% aqueous sodium hydroxide solution was added at 30 ° C. for 2 hours ( 0.8
8 mol), and the mixture was stirred at 30 ° C. for 3 hours, and then the aqueous layer was removed by liquid separation to obtain an organic layer. 33.4 g (0.88 mol) of sodium borohydride and 200 g of isopropanol were charged into a 2 liter four-necked flask equipped with a stirrer, a thermometer, a condenser tube and a dropping funnel. Drop it over time, and add 50 ° C
For 1 hour. This is cooled to room temperature and 500 g of water
Was added, and the mixture was separated to remove an aqueous layer. Cyclohexane was added to the obtained organic layer, and recrystallization was performed.
2,4.8 g of 2,3,4,5-tetrahydro-1,4-benzothiazepine were obtained. 2,2'-diformyl-4,
The yield based on 4'-dimethoxydiphenyl disulfide was 67.2%.

Examples 10 to 14 The same operation as in Example 9 was carried out except that the diformyl diphenyl disulfide compound and the reducing agent used as starting materials were changed to those shown in Table 2, and the corresponding 2,3,3
4,5-Tetrahydro-1,4-benzothiazepines were obtained. Incidentally, in the reducing agent in the Table, NaBH ₄ is sodium borohydride, H ₂ / Pd-C is a combination of hydrogen and palladium on carbon, the H ₂ / R-Ni shows a combination of hydrogen and Raney nickel.

[0073]

[Table 2]

Example 15 182.0 g (1.00 mol) of 2-methylthio-5-methoxybenzaldehyde was charged into a 1-liter four-necked flask equipped with a stirrer, a thermometer, a condenser tube and a gas inlet tube, and 500 g of chlorobenzene was added. Was added, and 142 g (2.00 mol) of chlorine was blown at 50 ° C. over about 4 hours. Then, 300 g of water was added, and the mixture was stirred at 100 ° C. for 4 hours. The aqueous layer was removed by liquid separation, and subsequently, 116.0 g (1.00 mol) of 2-chloroethylamine hydrochloride and water 10
After adding 0.0 g, 146.7 g (1.10 mol) of a 30% aqueous sodium hydroxide solution was added dropwise at 30 ° C. over 2 hours, and the mixture was stirred at 30 ° C. for 3 hours. An organic layer was obtained. Then, into a 2 liter four-necked flask equipped with a stirrer, thermometer, cooling tube and dropping funnel,
41.8 g (1.10 mol) of sodium borohydride and 200 g of isopropanol were charged, and the obtained organic layer was added dropwise at 50 ° C. over 3 hours, and further stirred at 50 ° C. for 1 hour. This was cooled to room temperature, 500 g of water was added, and the mixture was separated to remove an aqueous layer. Cyclohexane was added to the obtained organic layer, followed by recrystallization to obtain 7-methoxy-2,
113.1 g of 3,4,5-tetrahydro-1,4-benzothiazepine were obtained. The yield based on 2-methylthio-5-methoxybenzaldehyde was 58.0%.

Example 16 186.5 g (1.00 mol) of 2-chloro-6-methylthiobenzaldehyde was charged into a 1-liter four-necked flask equipped with a stirrer, a thermometer, a condenser and a dropping funnel, and 500 g of chlorobenzene was added. In addition, sulfuryl chloride 270.0 g (2.00 mol) was added dropwise at 50 ° C. over about 4 hours, and the mixture was further stirred for 1 hour. Next, 300 g of water was added, and the mixture was stirred at 100 ° C. for 4 hours. The aqueous layer was removed by liquid separation, followed by 2-chloroethylamine hydrochloride.
0 g (1.00 mol) and 100.0 g of water were added.
30% aqueous sodium hydroxide solution 14 at 0 ° C. for 2 hours
6.7 g (1.10 mol) was added dropwise, and the mixture was stirred at 30 ° C. for 3 hours. Then, the aqueous layer was removed by liquid separation to obtain an organic layer. Then, 41.8 g (1.10 mol) of lithium aluminum hydride and dioxane 2 were placed in a 2-liter four-necked flask equipped with a stirrer, a thermometer, a condenser, and a dropping funnel.
The resulting organic layer was added dropwise over 3 hours at 50 ° C., and further stirred at 50 ° C. for 1 hour. This was cooled to room temperature, 500 g of water was added, and the mixture was separated to remove an aqueous layer. Cyclohexane was added to the obtained organic layer, followed by recrystallization to give 6-chloro-2,3,4,5-tetrahydro-.
109.3 g of 1,4-benzothiazepine were obtained. The yield based on 2-chloro-6-methylthiobenzaldehyde was 54.8%.

[0076]

As described above, the present invention provides a novel diformyl diphenyl disulfide compound and a method for producing the same, and uses the compound for various uses such as medicines, agricultural chemicals, and functional materials. 2,
It is intended to provide a method for producing 3,4,5-tetrahydro-1,4-benzothiazepines. According to the present invention, a diformyl diphenyl disulfide compound and 2,3,
4,5-Tetrahydro-1,4-benzothiazepines can be produced industrially advantageously, efficiently and economically.

 ────────────────────────────────────────────────── ─── Continued on the front page (72) Inventor Hiroshi Gota 346 Miyanishi, Harima-cho, Kako-gun, Hyogo Pref.

Claims (15)

[Claims] 1. A diformyl diphenyl disulfide compound represented by the general formula (1). Embedded image (Wherein, R ¹ is a hydrogen atom, a halogen atom, a carbon number of 1 to 4)
A linear or branched alkyl group, an alkoxy group having 1 to 4 carbon atoms or a cyano group. ) 2. A diformyl diphenyl disulfide compound represented by the formula (2): 2,2'-diformyl-4,
The compound according to claim 1, which is 4'-dimethoxydiphenyl disulfide. Embedded image 3. A diformyl diphenyl disulfide compound represented by the formula (3): 5,5'-dichloro-6,6 '
The compound according to claim 1, which is -diformyldiphenyl disulfide. Embedded image 4. A compound of the general formula (1) characterized in that a 2-alkylthiobenzaldehyde represented by the general formula (4) is chlorinated using a chlorinating agent and then hydrolyzed using water or a lower alcohol. A method for producing a diformyldiphenyl disulfide compound represented by the formula: Embedded image (Wherein, R ¹ is a hydrogen atom, a halogen atom, a carbon number of 1 to 4)
Represents a linear or branched alkyl group, an alkoxy group having 1 to 4 carbon atoms or a cyano group, and R ² represents 1 to 4 carbon atoms.
Represents a linear or branched alkyl group. ) 5. The method according to claim 4, wherein the 2-alkylthiobenzaldehyde is 2-methylthio-5-methoxybenzaldehyde. 6. The method according to claim 4, wherein the 2-alkylthiobenzaldehyde is 2-chloro-6-methylthiobenzaldehyde. 7. The method according to claim 4, wherein the chlorinating agent is chlorine. 8. The method according to claim 4, wherein the chlorinating agent is sulfuryl chloride. 9. The method according to claim 4, wherein the lower alcohol is methanol. 10. After reacting a diformyl diphenyl disulfide compound represented by the general formula (1) with 2-chloroethylamine or a mineral acid salt thereof in the presence of a base,
2,3,4,5-tetrahydro-1,2 represented by the general formula (5), characterized by being cyclized using a reducing agent.
A method for producing 4-benzothiazepines. Embedded image (Wherein, R ¹ is a hydrogen atom, a halogen atom, a carbon number of 1 to 4)
A linear or branched alkyl group, an alkoxy group having 1 to 4 carbon atoms or a cyano group. ) 11. The mineral salt of 2-chloroethylamine is 2
The method according to claim 10, which is -chloroethylamine hydrochloride. 12. The method according to claim 10, wherein the reducing agent is sodium borohydride. 13. A 2-alkylthiobenzaldehyde represented by the general formula (4) is chlorinated using a chlorinating agent, and then hydrolyzed using water or a lower alcohol to obtain a compound represented by the general formula (1). A diformyl diphenyl disulfide compound, followed by a reaction with 2-chloroethylamine or a mineral acid salt thereof in the presence of a base, followed by cyclization using a reducing agent. A method for producing the represented 2,3,4,5-tetrahydro-1,4-benzothiazepines. Embedded image (Wherein, R ¹ is a hydrogen atom, a halogen atom, a carbon number of 1 to 4)
Represents a linear or branched alkyl group, an alkoxy group having 1 to 4 carbon atoms or a cyano group, and R ² represents 1 to 4 carbon atoms.
Represents a linear or branched alkyl group. ) 14. The method of claim 2, wherein the 2,3,4,5-tetrahydro-1,
4-benzothiazepines are 7-methoxy-2,3,4
The method according to any one of claims 10 to 13, which is 5-tetrahydro-1,4-benzothiazepine. 15. The method of claim 2, wherein 2,3,4,5-tetrahydro-1,
4-benzothiazepines are 6-chloro-2,3,4,5
The method according to any one of claims 10 to 13, which is -tetrahydro-1,4-benzothiazepine.