JPS6033425B2 - Method for producing 5-acetyl-2-alkylbenzenesulfonamide - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing 5-acetyl-2-alkylbenzenesulfonamides.

More specifically, it relates to a method for producing 5-acetyl-2-alkylbenzenesulfonamide by sulfonating 4-alkylacetophenone and reacting 5-acetyl-2-alkylbenzenesulfonyl chloride obtained by chlorinating the same with ammonia.

5-acetyl-2-alkylbenzenesulfonamide is a compound useful as an intermediate raw material for the production of phenylamine derivatives, which are known as heart drugs.

Conventionally, various methods for producing 5-acetyl-2-alkylbenzenesulfonamide are known.

For example, Indian. J. Chem. Group 1 277-9 (
(1979), 4-methylacetophenone was heated and reacted with chlorosulfonic acid in chloroform to form 5-acetyl-2-methylbenzenesulfonyl chloride, which was then reacted with ammonia to form 5-acetyl-2-methylbenzenesulfonyl chloride. A method to obtain an amide is described,
Its yield is as low as 30%. Also Gfr. Offen. 2
843016 (1979), 3-amino-4-methylacetophenone was diazotized at low temperature, and then reacted with sulfur dioxide gas in the presence of chlorinated steel in sulfurous acid in the presence of copper chloride to form 5-acetyl- A method is described in which 5-acetyl-2-methylbenzenesulfonamide is produced by producing 2-methylbenzenesulfonyl chloride and reacting this with ammonia, but the raw materials are expensive and the diazotization reaction is carried out at low concentrations. Therefore, the volumetric efficiency is poor and the overall process is long, so it cannot be said that the reaction is industrially advantageous. In view of this situation, the present inventors have conducted extensive studies on a method for producing 5-acetyl-2-alkylbenzenesulfonyl chloride using 4-alkylacetophenone, which is industrially easily available, as a raw material through 5-acetyl-2-alkylbenzenesulfonyl chloride. 4-alkylacetophenone was reacted with anhydrous sulfuric acid or fuming sulfuric acid in concentrated sulfuric acid, and then 5-acetyl-2-alkylbenzenesulfonyl chloride obtained by reacting with thionyl chloride was reacted with ammonia. If so, it can be produced with good industrial yield 5
It was discovered that -acetyl-2-alkylbenzenesulfonamide can be obtained, leading to the present invention.

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 sulfonate a 4-alkylacetophenone by reacting it with sulfuric anhydride or fuming sulfuric acid in concentrated sulfuric acid, and add thionyl chloride to the obtained sulfonic acid or sulfonate. This is a method for producing 5-acetyl-2-alkylbenzenesulfonamide, which is characterized by reacting 5-acetyl-2-alkylbenzenesulfonyl chloride with ammonia.

That is, the feature of the present invention is to coordinate 4-alkyl acetophenone with sulfuric acid to form a sulfuric acid complex as shown in the above reaction formula, and selectively synthesize 5-acetyl-2-alkylbenzene sulfonic acid by reacting with S03 at a low temperature. This is a method of reacting this with thionyl chloride to produce 5-acetyl-2-alkylbenzenesulfonyl chloride, and further reacting with ammonia to produce 5-acetyl-2-alkylbenzenesulfonamide. Although its mechanism of action is not fully understood, it is revolutionary that 5-acetyl-2-alkylbenzene sulfonic acid can be selectively obtained in good yield by coordinating sulfuric acid to 4-alkylacetophenone in the sulfonation reaction. This is an excellent method. When 4-alkylacetophenone is reacted with anhydrous sulfuric acid or oleum without using concentrated sulfuric acid, the acetyl group is sulfonated and 5-acetyl-2-methylbenzenesulfonic acid is hardly obtained.

The concentrated sulfuric acid used in the sulfonation of the present invention is about 98%, and 3 to 30%
Mix 15 moles, preferably 4 to 8 moles.

When the amount is less than 3 moles, the yield decreases, and even when 15 moles or more is used, there is no significant effect and it is uneconomical.

The appropriate amount of S03 in the anhydrous sulfuric acid or fuming sulfuric acid added after mixing with concentrated sulfuric acid is 2 to 15 mol, preferably 4 to 10 mol, per 1 mol of 4-alkylacetophenone.

If it is less than 2 moles, the yield will be low, and if it exceeds 15 moles, there will be no significant effect.

It is best to carry out the reaction at a low temperature of 20°C or lower.
In particular, good results can be obtained if the test is carried out within the range of 0 to 10:00.
If it exceeds 2000, the yield will decrease, so it is not preferable.
Furthermore, low temperatures below 0° C. are difficult to implement industrially.

Since it is difficult to separate the sulfonic acid obtained by the reaction as it is, it is desirable to extract it in the form of its salt. Economically, it is best to add an alkali, especially a necessary amount of sodium hydroxide, and extract it as sodium sulfonate. Next, for the chlorination reaction, use a catalyst such as dimethylformamide, pyridine,
Although good results may sometimes be obtained in the presence of a base having a tertiary nitrogen such as N-methylpyrrolidone or dimethylacetamide, the reaction is sufficient even without a catalyst.

The reaction is usually carried out in an organic solvent. Any organic solvent without active hydrogen can be used as the solvent, but for example, tetrahydrofuran, dioxane, diethyl ether, anisole, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, benzene, toluene, xylene, etc. are suitable for industrial use. It's convenient. Good results are obtained when the amount of thionyl chloride used in the reaction is equal to or more, preferably in the range of 1.1 to 1.5 moles, relative to 5-acetyl-2-alkylbenzenesulfonyl acid.

The reaction temperature is 10 to 100 oo, preferably 4 to 80 oo.
It is best to heat it to qo. If it is too low, the reaction rate will be slow, and if it is too high, the yield may decrease due to side reactions, which is not preferable. Next, in the amidation reaction, without isolating the 5-acetyl-2-alkylbenzenesulfonyl chloride produced by the reaction,
Ammonia can be added as it is to react. Ammonia is usually used in the form of aqueous ammonia, and in terms of economy, it is preferable to use 28% ammonium water. Generally speaking, the reaction temperature is preferably low, and as in the case of the sulfonation, it is desirable to carry out the reaction in the range of 0 to 20 o'clock. If the temperature exceeds 2.0°C, the yield will decrease, which is undesirable, and it will be difficult to maintain the temperature below 0°C in industrial implementation.

The reaction of the present invention is characterized in that the 3-position is selectively sulfonated by once coordinating sulfuric acid, and thionyl chloride is used as the chlorinating agent and ammonia is used as the amidating agent. This is an excellent method that has never been seen before, allowing 5-acetyl-2-alkylbenzenesulfonamide to be obtained in good yield.

The alkyl group applicable to the method of the present invention includes C,
-C5 lower alkyl groups are generally used, but other hydrocarbon-containing groups such as alkoxy groups and aryl groups can also be widely used.

The present invention will be explained in more detail with reference to Examples below.
This does not limit the invention.

Example In 198% sulfuric acid 530 ml (5.3 mol), 4
15% of monomethylacetophenone (1.0 mol)
The mixture was added dropwise while holding the o-saw, and the temperature was kept at the same temperature for 30 minutes to continue the process.

Then, sulfuric anhydride was added for 560 hours while cooling to 5-1000℃
7.0 mol) was added dropwise, and the rope was kept at 5°C for 5 hours.

After diluting the obtained reaction solution with 2 liters of water, 45%
2187 ml (24.6 mol) of an aqueous sodium hydroxide solution was added to neutralize the mixture.

This neutralized reaction solution was heated to 60° C. and then slowly cooled to 34° C., and the produced sodium 5-acetyl-2-methylbenzenesulfonate was crystallized and collected in a furnace. The yield is 22
Purity is 95.0% after 8.5 min, yield is 92.0%
Met.

205 ml (0.825 mol) of the obtained sodium 5-acetyl-2-methylbenzenesulfonate was suspended in 950 ml of tetrahydrofuran, and 6.0 ml (0.082 mol) of dimethylformamide was added as a catalyst. 6 quasi 0
After raising the temperature to
mol) was added dropwise. He then continued praying for an hour at 64-6,500. When the obtained reaction solution was analyzed by high performance liquid chromatography, 177.8 units (0.765 mol) of 5-acetyl-2-methylbenzenesulfonyl chloride were obtained. The yield was 92.7% and 853% based on 4-methylacetophenone. Add 250 ml of 28% ammonia aqueous solution to the reaction solution of 5-acetyl-2-methylbenzenesulfonyl chloride at 10 qC or less.
After dropping Yu (4.12 mol) and worshiping for 1 hour, 35
Tetrahydrofuran was removed under reduced pressure at q0 or less to crystallize 5-acetyl-2-methylbenzenesulfonamide.

This was taken out in an oven and dried to produce 5-acetyl-2-methylbenzenesulfonamide. 9 (0.727 mol) was obtained.

The melting point is 150.5-151.5q0, and the yield is 5-acetyl-2-methylbenzenesulfonyl chloride'
In contrast, it was 95%, and 81.0% with respect to 4-methylacetophenone. Example 2 21 (0.085 mol) of sodium 5-acetyl-2-methylsulfonate obtained in the same manner as in Example 1 was suspended in 80 t of toluene, and 0.6 mol of pyridine was added as a catalyst.
After adding 11.1 moles (0.0085 mol) of thionyl chloride in the same manner as in Example 1, 16.1 moles of 5-acetyl-2-methylbenzenesulfonyl chloride was added. 8 mol (0.072 mol) was obtained.

The yield was 84.7%, 77.9% based on 4-methylacetophenone. To the above reaction solution of 5-acetyl-2-methylbenzenesulfonyl chloride were added 20 g of dioxane and 30 g (0.494 mol) of 28% aqueous ammonia, and in the same manner as in Example 1, 5-acetyl-2-
Methylbenzenesulfonamide 13.5 min (0.063
4 mol) was obtained.

The yield was 88.1% for 5-acetyl-2-methylbenzenesulfonyl chloride and 88.1% for 4-methylacetophenone. It was 6%.

Claims (1)

[Claims] 1. In producing 5-acetyl-2-alkylbenzenesulfonamide using 4-alkylacetophenone as a raw material and 5-acetyl-2-alkylbenzenesulfonyl chloride, 4-alkylacetophenone is Sulfonation is performed by reacting with anhydrous sulfuric acid or fuming sulfuric acid in concentrated sulfuric acid, and the resulting 5-acetyl-2-alkylbenzenesulfonic acid or sulfonate is reacted with thionyl chloride to form 5-acetyl-2-alkylbenzenesulfonyl chloride. , a method for producing 5-acetyl-2-alkylbenzenesulfonamide, which is characterized by reacting this with ammonia. 2. The method according to claim 1, 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-acetyl-2-alkylbenzenesulfonic acid is isolated as a sodium salt and then reacted with thionyl chloride. 4. The method according to claim 1, wherein the ammonia to be reacted with 5-acetyl-2-alkylbenzenesulfonyl chloride is aqueous ammonia. 5. The method according to claim 1, wherein the alkyl group is a methyl group.