JPS58118557A - Preparation of 5-acetyl-2-alkylbenzenesulfonamide - Google Patents

Abstract

PURPOSE:To prepare the titled compound useful as an intermediate raw material of a heart medicine, economically, in an industrial scale, by sulfonating easily available 4-alkylacetophenone with sulfur trioxide, etc. in concentrated sulfuric acid, chlorinating the product with thionyl chloride, and reacting with NH3. CONSTITUTION:The 5-acetyl-2-alkylbenzenesulfonamide of formula III is prepared from the 4-alkylacetophenone of formulaIthrough the 5-acetyl-2-alkylbenzenesulfonyl chloride of formula II. In the above process, the starting raw material of formulaIis sulfonated with sulfur trioxide or fuming sulfuric acid in concentrated sulfuric acid at a low temperature of 0-20 deg.C or below, the resultant 5-acetyl-2-alkylbenzenesulfonic acid or sulfonic acid salt is made to react with thionyl chloride to obtain the compound of formula II, and the product is made to react with NH3 to obtain the objective compound. The characteristic feature of the process is the selective sulfonation at the 3-position by the coordination of sulfuric acid in the sulfonation process.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for preparing 5-1 cetyl-2-alkylbenzenesulfonamides.

5-acetyl-2-7A by reacting the id with ammonia
This invention relates to a method for producing benzenesulfonamide.

5-1 cetyl-2-alkylbenzenesulfonamide is a compound useful as an intermediate raw material for the production of phenylethanolamine derivatives known as heart drugs.

The method for preparing 5-acetyl-2-alkylbenzenesulfonamide is well known to woodcutter.

For example, Indian, J. Chem, 18B 27
7-9 (1979), 4-methylacetophenone was thermally reacted with techlorsulfone f[m] in chloroform.
-Acetyl-2-methylbenzenesulfonyl chloride and reacted with ammonia [5-7cetyl-2
A method for obtaining -methylbenzenesulfonamide has been described, but the yield is as low as 309.

After diazotizing 4-methylacetophenone at low temperature, it is reacted with sulfur dioxide gas in the presence of copper chloride in glacial acid to form 5-7cetyl-2-methylbenzenesulfoniflechloride, which is then reacted with ammonia. A method for producing 5-anatyl-2-methylbenzene sulfonamide is described, but the raw material is expensive and the diazotization and reaction are carried out at a low degree, resulting in poor volumetric efficiency and low overall volumetric efficiency. [Due to the long reaction time, this reaction cannot be said to be industrially advantageous.]

In view of this situation, the present inventors reacted industrially available 4-1 lukyl acetophenone with raw material phenone in concentrated sulfuric acid with anhydrous IIIk #l or sulfuric acid.
Furthermore, 5-17tyl-2-1rubenzenosulfonyl chloride obtained by reaction with thionyl chloride is reacted with ammonia. 5-1 Yachiru with good yield commercially
The present invention was accomplished by learning that 2-alkylbenzenesulfonamides can be obtained.

That is, the object of the present invention is to obtain industrially advantageous 5-acetyl-2-
To provide a method for producing alkylbenzenesulfonamides, the gist of which is to react 4-alkylacetophenone with sulfuric anhydride or fuming sulfuric acid in concentrated sulfuric acid to sulfonate the resulting sulfonic acid or sulfonate. Thionyl is reacted to form 5-7cetyl-2-alkylbenzenesulfonyl chloride, which is then reacted with ammonia (JCI(3). In other words, the feature of the present invention is that as shown in the above reaction formula, 5-7cetyl-2-alkylbenzenesulfonyl chloride is reacted with iI acid to 4-alkylacetophenone. 5-acetyl-2-alkylbenzenesulfonic acid was selectively synthesized by the action of 803 at low temperature, and 5-acetyl-2-alkylbenzenesulfonic acid was then reacted with thionyl chloride to form a 5-7 cetyl-
2-Arylbenzene sulfonyl chloride
This is a method for producing 5-1 cetyl-2-alkylbenzenesulfonamide by further reacting with ammonia. Although its mechanism of action is not fully understood, the sulfonation reaction is an epoch-making method that can yield orange-benzene sulfonic acid in good yield. When a 4-alkyl acetophenone is reacted with anhydrous sulfuric acid or oleum without using concentrated sulfuric acid, the acetyl group is sulfonated and the 5-
1 Yathyl-2-methylbenzenesulfonic acid is hardly obtained.

The concentrated sulfuric acid used in the sulfonation of the present invention is about 98%, and 4-aA/I? 3 to 15 mol, preferably 4 to 8 mol, is mixed per 1 mol of ruacetophenone. If it is less than 3 moles, the yield will be IJtFL.

Even if 15 moles or more is used, there is no significant effect, so it is a bad idea.

SO3 in anhydrous sulfuric acid or fuming sulfuric acid added after mixing with concentrated sulfuric acid is 4-alkyl Vacetoph! / N1-
12-15 moV for T-Az, M*L<1!4-10
Moles are appropriate. If it is less than 2 moles, the yield will be low, and if it exceeds 15 moles, there will be no significant effect.

2 It is best to carry out the reaction at a low temperature of 20'C or lower,
Particularly, when it is carried out in the range of 0-10'c, good results are obtained but it is accompanied by difficulties. Since the sulfonic acid obtained by the reaction is stored in the water as it is, it is economically desirable to extract it in the form of a salt. It is better to take it out.

Next, for the chlorination reaction, catalysts such as dimethylformamide, pyridine, and N-methylpyrrolidone are used.

Although good results may sometimes be obtained in the presence of a base having a tertiary nitrogen such as dimethylacetamide, the reaction is sufficient even without a catalyst. The reaction is usually carried out in a jaA solvent. As the solvent, any organic solvent can be used as long as it does not have a live water injection hole, but it is convenient for use as a solvent such as tetrahydrofuran, dioxane, diethyl ether, anisole, and ethylene glycol.

The amount of thionyl chloride used in the reaction is preferably equal to or more than 1.0 molar based on the 5-7cetyl-2-alkylbenzenesulfone rice.
A range of 1-1.5 moles gives good results. The reaction temperature is preferably 10 to 100°C, preferably 40 to 80°C. If the ty is too low, the reaction rate will be 80%, but if it is too high, the yield may be low due to the #1 reaction, which is not preferable.

Next, in the amidation reaction, the 5-7cetyl-2-alkylbenzenesulfonyl chloride produced in the above reaction can be directly reacted with ammonia without isolating it.

Ammonia is usually best used in the form of aqueous ammonia.
Considering economy, it is preferable to use 28% ammonium water. The reaction temperature is generally low, and as in the case of sulfonation, it is desirable to carry out the reaction in the range of 0 to 20°C. If the temperature exceeds 20℃, the yield will be low (Fr), which is not preferable, and if the temperature exceeds 0℃
It is characterized by sulfonating industrial fruits to maintain the 5-7 cetyl-2-77 lekylbenzene sulfonate in high yield by using thionyl chloride as the chlorinating agent and ammonia as the amidating agent. This is an excellent method for obtaining bonamide, which has never been seen before.

The alkyl group applied to the method of the present invention is C1
-C5 lower alkyl groups are generally used, but other groups containing hydrogen oxide, such as alkoxy groups and aryl groups, can also be widely used.

The present invention will be explained in more detail below with reference to Examples, but the present invention is not limited thereto.

Example 1 98% MfI! 530g (5,3 Morn Kobanko, 4-
Continued stirring.

560 ml of acetic anhydride while cooling to 5-10°C.
After dropwise addition of 7.0 g (7,07 L), stirring was continued for 5 hours while maintaining the temperature at 5°C.

Shun, 45, added 214 ounces of water and the resulting reaction solution.
% sodium hydroxide aqueous solution 2,187 g (24,6
mol) was added to neutralize. This neutralized reaction solution was heated at 60°C.
After raising the temperature to 34° C., the resulting sodium 5-7 cetyl-2-methylbenzenesulfonate was crystallized and collected.

The amount was 228.5 g, the purity was 95.0%, and the yield was 92.0%. 205 g of sodium 5-acetyl A/-2-methylbenzenesulfonate (0,
825 morph was suspended in 257,950 g of tetrahydro and 6.0 g of dimethyV formamide (0,0
Then, 117.8 g (0,990 mol) of thionyl chloride was added dropwise to the mixture and the temperature was raised to 64°C.

Stirring was then continued at 64-65°C for 1 hour. The resulting reaction solution was analyzed by high performance liquid chromatography.

The yield was 92.7% and 85% based on 4-methylacetophenone.

To the above reaction mixture of 5-7 cetyl-2-methylbenzenesulfonyl chloride, 250 g (4.12 mol) of 28S ammonia aqueous solution was added dropwise at 10°C or below, and after stirring for 1 hour, tetrahydrofuran was added at 35°C or below. The residue was distilled off under reduced pressure to crystallize 5-acetyl-2-methylbenzenesulfonamide.

This was taken in an oven and dried to obtain 154.9 g (0,727 mol) of 5-acetyl-2-methylbenzenesulfonamide. The melting point is 150.5-151.5°C,
The yield was 95% based on 5-7 cetyl-2-methylbenzenesulfonyl chloride and 81.0% based on 4-methylacetophenone.

Example 2 Suspension was suspended in 80 g of toluene, 0.67 g (0,0085 mol) of pyridine was added as a catalyst, and 11.1 g of thionyl chloride was added using the same method as in Example 1.
g (0,094 mol) and 5-acetyl-2-methylbenzenesulfonylchloride F 16. sg (0
,072 attempts) I got it. The yield was 84.7%, 4
- 77.9% for methylacetophenone.

1/20 g of 1[[15-7 Yachi A/-2-methylbenzenesulfonyl chloride reaction solution.

Add 30 g of aqueous ammonia (0,494 morph) and prepare in the same manner as in Example 1, adding 13.5 g of C5-1 cetyl-2-methylbenzenesulfonamide (0,06
The combined yield was 88.1% for 5-1 cetyl-2-methylbenzenesulfonyl chloride and 68.6% for 4-methylacetophenone.

Examples 3-5 The following results were obtained in the same manner as in Example 1.

Table (al) 5-acetyl-2-methylbenzenesulfonyl chloride @2J 5-acenal-2-methylbenzenesulfonamide 3) Example 5 is for 60% oleum Performer Sasaki, Representative of Steel Chemical Industry Co., Ltd. Hiroshi

Claims (4)

[Claims] (1) Using 4-alkylacetophenone as a raw material, in producing 5-acetyl-2-11-kylbenzenesulfonamide through 5-acetyl-2-albenzenesulfonide, 4-alkylacetophenone is The resulting 5-7 cetyl-2-ankybenzene sulfonic acid or sulfonate was reacted with sulfuric acid anhydride or fuming sulfuric acid in concentrated sulfuric acid, and thionyl chloride was reacted with thionyl chloride. c s -7 An a-adic method of 5-7 cetyl-2-alkylbenzenesulfonamide, which is characterized by preparing benzenes-1-lephonyl chloride in 7-tyl-2-alum and reacting this with ammonia. (2) The method according to claim ( ), wherein the sulfonation reaction is carried out at a low temperature of 20°C or lower. (3) The method according to claim (1), wherein 5-1cetyl-2-1Vbenzenesulfonic acid is reacted with thionyl chloride isolated as a sodium salt. (4) The method according to claim 11, wherein the ammonia to be reacted with 5-acetyl-2-alkylbenzenesulfonyl chloride is aqueous ammonia. 1) The method described.