JPS58194881A - Improved method for preparing 7-sulfonamidothiochroman-1,1-dione - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as medicines, e.g. a hypotensive and diuretic agent, etc. and other industrial chemicals in high purity and yield by easy operations, by reacting a thiochroman-1,1-dione with chlorosulfonic acid and further ammonia. CONSTITUTION:A thiochroman-1,1-dione of formula I (R1 is H or lower alkyl; R2 is H, halogen or lower alkyl) is reacted with chlorosulfonic acid in the presence of dichloromethane to give a solution of 7-chlorosulfonylthiochroman- 1,1-dione of formula II in the dichloromethane. The resultant 7-chlorosulfonylthiochroman-1,1-dione is then reacted with liquid ammonia gas or liquid ammonia to afford the aimed substance of formula III. The volume of the dichloromethane to be used is 0.5-1.5 times of that of the compound of formula I , and the molar amount of the chlorosulfonic acid to be used is 8-12 times of that of the compound of formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 7-sulfonamidothiochroman-1, 1-
This invention relates to an improved method for upgrading diones on an industrial scale.

That is, the present invention provides a method for reacting thiochroman-1,1-diones represented by the general formula (I): 020 (in which R1 and R2 have the meanings specified below) and chlorosulfonic acid in the presence of dichloromethane. , the resulting general formula (2): (wherein R1 and R2 have the meanings given below)
'L7-chlorosulfonylthiochroman-1,1-,
, a general formula characterized by reacting a dichloromethane solution of diones with ammonia gas or liquid ammonia (
■): In the formula 2C, R1 represents a hydrogen atom or a lower alkyl group,
R2 represents a hydrogen atom, a halodane atom, or a lower alkyl group) 7-sulfonamidothiochroman-
An improved method for producing 1,1-diones is provided.

According to the method of the present invention, shearsulfonamide thiochroman-1,1-diones can be obtained with high purity and high yield through simple operations. 7 obtained by the present invention
-Sulfonamidothiochroman-1,1-diones are extremely useful as pharmaceuticals and other industrial chemicals, especially 6
-Methyl-7-sulfonated tothiochroman-1,I-
Diones are compounds useful as antihypertensive diuretics.

+1 Below, the advantages of the method of the present invention will be clarified in comparison with the conventional method. The method of the present invention and the conventional method can be expressed as follows.

■ Method of the present invention (1) (If)2 (III) ■ Conventional method (Friedel-Krach reaction) ■ Conventional method 2 (7'j, where R1 represents a hydrogen atom or a lower alkyl group, and R2 represents (Represents a hydrogen atom, a halogen atom, or a lower alkyl group.) Conventionally, as a method for producing 7-sulfonamide thiochroman-1,1-dione from thiochroman-1,1-diones, as shown in the above reaction formula, (1) A method of reacting thiochroman-1,1-diones with sulfuryl chloride by a Friedel-Crauff reaction and reacting the obtained 7-chlorosulfonylthiochroman-1,1-dione with liquid ammonia; and (2) a method of reacting thiochroman-1,1-dione with liquid ammonia. 7-1 obtained by reacting 1-diones with chlorosulfonic acid
A method of reacting 0rosulfonylthiochroman-1,1-diones with liquid ammonia is known. Among these methods, in production on an industrial scale, the method using lorsulfonic acid as a raw material is considered to be advantageous because it is inexpensive.

However, this method has the following drawbacks.

That is, in the first step, the raw material thiochroman-1,1-diones is treated as a solid, so the thiochroman-1,1-diones float on the liquid surface of chlorosulfonic acid in the reaction vessel and react. The system is difficult to become homogeneous. Second, large amounts of chlorosulfonic acid must be used to dissolve the raw materials and products. Then, in order to obtain 7-chlorosulfonylthiochroman-1,1-diones after the reaction is completed, the reaction solution is added to water to precipitate 7-chlorosulfonylthiochroman-1,1-diones. However, the generated 7-chlorosulfonylthiochroman-1,1-diones undergo thermal decomposition due to the heat generated by the hydrolysis of hachlorosulfonic acid, so the target 7-sulfonamidothiochroman-1.I-diones also undergo thermal decomposition. cannot be obtained in high yield. On the other hand, if we try to prevent thermal decomposition, 7
- It takes a long time to introduce a chlorosulfonic acid solution of -chlorosulfonylthiochroman-1,1-diones into water. Thirdly, in order to obtain the 7-chlorosulfonylthiochloroene-1,1-diones which are precipitated by adding the reaction solution to water, it must be extracted with an organic solvent. Moreover, in the second step, it is necessary to react the solid o'y-prolosulfonylthiochroman-1,I-diones with liquid ammonia, so the reaction takes a long time. Furthermore, in the first step, thiochroman-1,1-diones are added to the reaction system, and in the second step, 7-chlorosulfonylthiochroman-1,1-diones are added to the reaction system as solids, so that the sulfonation reaction and The amidation reaction must be carried out in an open system, and there are health and safety problems such as scattering of chlorosulfonic acid and inhalation of ammonia gas.

In view of these circumstances, the present inventors conducted studies to improve the yield, safety and health, and operational aspects. As a result, although chloroform and dichloroethane do not improve the reaction production rate of 7-10 rosulfonylthiochroman-1,1-diones at all, when dichloromethane, which is very similar to these, is used as a reaction solvent, Limited to 7-chlorosulfonylthiochroman-1,1
- A completely unexpected result was obtained in which diones were obtained in high yields. Furthermore, since dichloromethane can be used as a solvent in the next reaction, dichloromethane is used as a solvent in the first step, and the 7-chlorosulfonylthiochroman-1,1-dione in the dichloromethane solution is also used in the second step. The present invention was made based on the knowledge that the reaction between 7-sulfonate thiochroman-1,l-diones and ammonia gas or liquid ammonia can be carried out smoothly and the target 7-sulfonate thiochroman-1,l-diones can be obtained in high yield and purity. 9.

According to the manufacturing method of the present invention, the following advantages can be obtained. That is, (1) When a dichloromethane solution of thiochroman-1,1-diones is dropped into chlorosulfonic acid, the dichloromethane solution is dissolved in the chlorosulfonic acid and homogenized. As a result, thiochroman-1 in dichloromethane solution
, 1-diones and chlorosulfonic acid, the sulfonation reaction proceeds smoothly and the reaction time can be significantly shortened. ■ Even in the heat generated when adding the sulfonation reaction solution to water, the presence of dichloromethane with a low boiling point allows the dichloromethane to reflux and keep the system temperature constant, resulting in the production of 7-chlorosulfonylthiochroman-1, Thermal decomposition of I-diones can be prevented. Therefore, due to these effects, the production rate of 7-dirosulfonylthiochroman-1,1-diones is unexpectedly significantly improved. In addition, (2) Since the contact between thiochroman-1,1-diones and chlorosulfonic acid is improved, the amount of chlorosulfonic acid used can be significantly reduced compared to the conventional method in which a large amount of chlorosulfonic acid is used as a solvent. and (2) thiochroman-1.1-diones as raw materials or 7-chlorosulfonylnaochroman-1,1-diones as intermediates are not added in solid form to the reaction system. therefore,
It also improves operability.

The method of the present invention is significantly improved over conventional methods and is extremely useful as a method for producing 7-sulfonamidothiochroman-1,1-diones on an industrial scale.

7-sulfonamidothiochroman-1,1 according to the invention
-The improved method for producing diones will be explained in detail as follows. Immediately, the raw material thiochroman-1,1-diones is dissolved in dichloromethane. The amount of dichloromethane used at this time is the O of thiochroman-1,1-diones.
-5 to 1.5 times the capacity is appropriate. Then, chlorosulfonic acid may be added dropwise to this solution at room temperature. The dropped chlorosulfonic acid is immediately dissolved and homogenized in the dichloromethane solution of thiochroman-1,1-diones. If necessary, thiochroman-1, chlorosulfonic acid,
A solution of 1-dione in dichloromethane may be added dropwise to cause the reaction. Regardless of which method is used, the reaction is completed by a boost reaction after the dropwise addition is completed. The chlorosulfonic acid used is the raw material thiochroman-1,1-
8 to 12 times the molar amount of diones, or half of the conventional amount
One to one third of the amount is sufficient. And for boosting reaction 2~
The sulfonation reaction is sufficiently completed in 4 hours. After the sulfonation reaction is completed, the chlorosulfonic acid in the reaction solution is decomposed into sulfuric acid and hydrochloric acid with water, but the heat generated by this decomposition is caused by the presence of dichloromethane. Even if 7-chlorosulfonylthiochroman-1,1-diones are added, thermal decomposition of 7-chlorosulfonylthiochroman-1,1-diones does not occur because the heat generation is controlled. In addition, after adding water to the reaction solution, 7-chlorosulfonylthiochroman- was separated from the aqueous layer.
Separate the dichloromethane layer of 1,1-diones, but if you add a small amount of dichloromethane to the water added in advance, it will be easier to control the temperature. It is possible to increase the extraction efficiency of ons. When ammonia gas is blown into the dichloromethane layer thus separated or liquid ammonia is added, 7-sulfonamide thiochroman-1,1
-Dione crystals begin to precipitate. The amount of ammonia used is determined by the amount of 7-chlorosulfonylthiochroman-1,1-
The amount may be 1.2 to 2.0 times the molar amount of the dione. After the amidation reaction is completed, water is added to the system to dissolve the by-produced ammonium chloride and the mixture is heated to obtain 7-sulfonamide thiochroman-1,1-diones in high yield and purity.

Therefore, the method of the present invention significantly improves operability, reaction time, yield, etc. compared to conventional methods.

The method of the present invention will be specifically explained below with reference to Examples.

Example 1 98 g (0-5 mol) of 6-methylthiochroman-1,1-dione and 100 d of dichloromethane are placed in a quadrupole flask with a volume of 25,000 f to form a homogeneous solution. 466 g (4 mol) of chlorosulfonic acid was added dropwise to this at 30°C. After the completion of the dropwise addition, a boost reaction is carried out for 3 hours to complete the reaction. In addition, 600 d of water and 200 d of dichloromethane are placed in another quadrupole flask with a capacity of 2, and the above chlorosulfonation reaction solution is added dropwise thereto while cooling with water. The separated dichloromethane layer was fractionated. According to alkaline titration, 6-methyl-7-chlorosulfonylthiochroman-1,
1-dione was produced in a yield of 96 or more.

Add 10.2 l of ammonia gas to this dichloromethane solution.
Blow in i+ (0.6 mol) and add 500 ml of water.
In addition, F was separated and the residual liquid was dried to obtain 6-methyl-7-sulfonamidothiochroman-1,l-dione 133.2
I got g. (Yield 94t, purity 97t, m=p-236
~237°C0) Example 2 2 5 g of chlorsulfonic acid in a 500 d capacity bore flask
．． 5, li' (5 mol) and 2-methyl-6 previously dissolved in 120 d of dichloromethane.
-Chlorothiochroman-+, I-diFon 115g (0.
5 mol) was added dropwise at room temperature. After the dropwise addition, boost reaction is performed for 4 hours to complete the reaction. Add another 2 mL of water and 200 mL of dichloromethane to a 2-capacity flask.
1 is charged, and the previous reaction solution is added dropwise thereto at a temperature below 40'C. The separated dichloromethane layer was collected. According to alkaline titration, the yield of 2-methyl-6-chloro-7-chlorosulfonylthiochroman-1,1-dionga was 94.
It was generated at 5%. Add 2-8 g (0.75 mol) of liquid ammonia to this dichloromethane solution to cause a reaction, then add 500 g of water and distribute separately. The resulting residue is dried to produce 2-methyl-6-chloro-7-sulfone. Amidothiochroman-1,1-dione 149.4, f was obtained. (Yield 93%, purity 96.4%, m-p, 202-2
04°C0) Example 3 2 2-ethyl-6-methylthiochroman-1,1-sion 112g (0.5 mol), chlorsulfone 11699#
2-ethyl-6-methyl-
7-Sulfonamide thiochroman-1,1-dione 14
7g was obtained. (Yield: 93%, purity: 96%, m, p, 2
24-225°c0) In addition, the intermediate 2-ethyl-6-
Methyl-7-chlorosulfonylthiochroman-1,1-
The production rate of 1'one was 95 yen according to alkaline titration.

Example 4 2 6-chlorothiochroman-1,1-dione + og, 4g
(0.5 mol), chlorsulfonic acid 466g (4 mol)
and liquid ammonia I+.91 (0.7 mol) in the same manner as in Example 2 to obtain 6-chloro-7-sulfonamidothiochroman-1,1-dione 145y. (Yield 94.5 excellent, purity 96.4 m, m, p, 2
16-21g°C0) In addition, the intermediate 6-chloro-7-
The production rate ti of chlorosulfonylthiochroman-1,1-dione was found to be 97 excellent by alkaline titration.

Example 5 2 30 g (0.2 mol) of thiochroman-1,1-dione,
Example 1 using chlorosulfonic acid +16.5.9 (1 mol) and hyammonia gas 6.8,9 (0.4 mol)
The reaction was carried out in the same manner as above to obtain 50.6 g of 7-sulfonate thiochroman-1,1-dione.

(Yield 92 Excellent, Purity 95g6, m, p, 236-237
°C0) In addition, 7-chlorosulfonylthiochroman-1
, the production rate of l-dione was 94% according to alkaline titration.
Met.

Comparative Example 1 Chlorsulfonic acid 11 was added to a '1710 four diameter flask.
65.9 (10 mol) was charged, and 6-methylthiochroman-1,1-dionia 9 Bi2 (0.5 mol) was gradually added thereto at room temperature. After the addition was completed, the system was heated to 7,000 ℃ and it took 3 hours for the 6-methylthiochroman-1,1-dione added to the chlorosulfonic acid to dissolve. After dissolving 6-methylthiochroman-1.1-dione, a boost reaction was carried out for 5 hours. In addition, 3 liters of ice water was placed in another 5-volume quadrupole flask, and the above reaction solution was poured into it, and 600 ml of chloroform was added to extract the precipitated crystals, and the separated chloroform layer was collected. The chloroform was distilled off to give 6-methyl-7-chlorosulfonylthiochroman-1+I-dio7121.3.
I got Ii. (Yield 75%, purity 85q6, m-p・l
sg ~161'c,) This 6-methyl-7-chlorosulfonylthiochroman-1,1-dione was added to liquid ammonia 5009 (29 mol) and allowed to stand for 12 hours, then water 600- was added and filtered to obtain a residue. When dried, 6
-Me5-7-sulfonamidothiochroman-1,1
-Dione 98.3gt- was obtained. (yield 60%, purity 84
%, m, p, 236-2376C,) Comparative Example 2 6-Methylthiochroman-1,1-dione qsg (o·5 mol) and benzene 1 were added to a 500-capacity quadrupole flask.
Prepare ooag to make a homogeneous solution.

Add to this chlorsulfone e4661 (4 mol) 30'
Drop at C. After the completion of the dropwise addition, a boost reaction is carried out for 5 hours. In addition, 600 d of water and 200 ml of benzene were placed in another quadrupole flask having a capacity of 2, and the previous chlorosulfonation reaction solution was added dropwise thereto under water cooling. The separated benzene layer was collected. According to alkaline titration, 6-methyl-7-chlorosulfonylthiochroman-1,1-dione was produced in a yield of 65%. Ammonia gas +7 to this benzene solution
Blow in p (1 mol), add 600 ml of water and make p
The mixture was separated and the remaining liquid was dried to obtain 6-methyl-7-sulfonamide thiochromanto 1-dione 103-31.

(Yield: 60, purity: go, m-p, 236-237°
co) Comparative Example 3 2 6-Methylthiochroman-1,1-dione 9gF (0.
5 mol), 699 g (6 mol) of chlorosulfonic acid and ammonia gas +71 (1 mol) were reacted in the same manner as in Comparative Example 2 to obtain 6-methyl-7-sulfonamidothiochroman-1,1-dione 103. I got 21. (Yield 30
Sorry, purity 40, m, p, 236-237°co
) The production rate a of the intermediate 6-methyl-7-chlorosulfonylthiochroman-1,1-dione was 65% by alkaline titration.

Comparative Example 4 2 6-mer f-ochroman-1,1-dione 96.9 (
0.5 kol), chlorosulfonic acid 5δ2.5 II (5
mol) and ammonia gas (1 mol) in the same manner as in Comparative Example 2 to obtain 110.1# of 6-methyl-7-sulfonamide thiochromanole 1-dione. (Yield 32 buns, purity 401m, p.236-237
°c, ) The production rate of the thio intermediate 6-methyl-7-chlorosulfonylthiochroman-1,1-dione was 46 or more according to alkaline titration.

Claims (1)

[Claims] General formula: (In the formula, R1 and R2 have the meanings given below) The general formula obtained by reacting thiochroman-11-diones with tochlorosulfonic acid in the presence of dichloromethane It is characterized by reacting a dichloromethane solution of 7-chlorosulfonylthiochroman-1,1-diones represented by the following formula with ammonia gas or liquid ammonia. General formula: 0 In the formula, R1 represents a hydrogen atom or a lower alkyl group,
R2 represents a hydrogen atom, a halogen atom, or a lower alkyl group)
Improved production method for 1,1-diones.