DE1545900B1 - Process for the preparation of 1-H-Benzo-2,3-thiazinon-4-dioxyden- (2,2) - Google Patents

Description

The invention relates to a process for the preparation of 1-H-benzo-2,3-thiazinon-4-dioxyden- (2,2) of the general formula

Lower alcohols have proven to be particularly suitable solvents for the reaction. The reaction is carried out at 60 to 70 ⁰ C.

3. The benzylisothiuronium bromido-carboxylic acid ester obtained in this way is in a suitable solvent with ammonia and an oxidizing agent, preferably with hydrogen peroxide, in the appropriate Bis (o-carbamidobenzyl) disulfide converted.

wherein R _{1 can be} a hydrogen, chlorine, bromine or fluorine atom.

The ring structure of 2,3-benzothiazine on which these compounds are based has not been up until now known.

According to the invention, these l-H-benzo-2,3-thiazinon-4-dioxyde- (2,2) produced by the following four step synthesis:

1. An o-toluene carboxylic acid ester is converted into the corresponding a-Bromo-o-toluene carboxylic acid ester converted.

NH, »

Br-NH ₃ + H ₂ O ₂

IV

CH ₂ S CONH,

CH ₂ Br COOR,

In the above formulas II and III, R _{1 has} the meaning given in formula I and R ₂ can represent an alkyl, aryl, alkaryl or aralkyl group. Because of the simple production, the low price and the optimal conversion rate in step 3 of the synthesis _{according to the invention, R 1 is} preferably a low molecular weight alkyl group, such as the methyl, ethyl or propyl group; the methyl group is particularly preferred.

The conversion of the o-toluene carboxylic acid ester in the corresponding a-bromo-o-toluene carboxylic acid ester can by the action of elemental bromine in Presence of dibenzoyl peroxide in an organic solvent which is inert under the reaction conditions be performed. The reaction is preferably carried out in boiling carbon tetrachloride. It is also possible to replace the a-bromo group in the o-toluene carboxylic acid ester by means of N-bromo amides, such as Introduce N-bromosuccinimide.

2. The a-bromo-o-toluene carboxylic acid ester obtained in this way becomes with thiourea in a solvent to the corresponding benzylisothiuronium bromido-carboxylic acid ester implemented:

Lower alcohols are preferably used as solvents for this reaction step, especially methanol is preferred.

4. A suspension of the bis-o-carbamidobenzyl disulfide is in a solvent-water mixture with elemental chlorine in the 1-H-benzo-2,3-thiazinon-4-dioxide- (2,2) transferred:

Cl ₂

The one for the chlorination of a suspension of biso-carbamidobenzyl disulfide Suitable solvents mixed with water have the general formula

ίθ

CH ₂ Br
COOR,

H ₂ NC-NH ₂

H-C

VI

X ₁

NH ₂

Br® where R ₃ and R _{4 can be} identical or different and can be hydrogen atoms or low molecular weight alkyl groups. Such solvents are, for example, formamide and particularly preferably dimethylformamide. The ratio of water to this solvent has a great influence on the yield of 1-H-benzo-2,3-thiazinon-4-dioxyden- (2,2) of the general formula I. Thus, with the preferred use of

Dimethylformamide, a mixture of dimethylformamide and water in a ratio of 2: 3, has proven particularly advantageous. The chlorination can be carried out in the temperature range of 0 to 70 ¹ C, the preferred range is from 30 to 50 ° C.

The chlorination of bis-o-carbamidobenzyl disulfide can also be carried out in glacial acetic acid. Less good yields were obtained.

The 1 - H - benzo-2,3-thiazinon-4-dioxyde- (2,2) prepared according to the invention are valuable pharmaceuticals. They show hypoglycemic activity without causing any side effects, respectively therefore useful for treating diabetes; they are also anti-convulsive and anti-inflammatory effective.

example 1

1H-Benzo-2,3-thiazinon-4-dioxide- (2,2)
1. methyl a-bromo-o-toluene carboxylate

4.1-H-Benzo-2,3-thiazinon-4-dioxide- (2,2)

Through a suspension of 332.4 g (1 mol) of bis-

(o-carbamidobenzyl) disulfide in 4.41 40% dimethylformamide a moderate stream of chlorine is passed at 30 "C. for 5 hours. The temperature of the clear solution is 50'C at the end. The solution is removed from excess by bubbling in air Freed chlorine and left to stand at O'C overnight.

ίο The colorless, crystalline precipitate is analytically pure.

Mp. 220 ° C, yield 131 g (33 ° ' ₀ of theory).

Further quantities of less pure product can be obtained from the mother liquor by concentration will.

Claims (3)

Claim: Process for the preparation of 1-H-Benzo-2,3-thiazinon-4-dioxyden- (2,2) the general formula <O 100 g of dibenzoyl peroxide are added to the boiling solution of 3.0 kg (20 mol) of methyl o-toluene carboxylate in 20 1 of carbon tetrachloride, and about half of a solution of 3.2 kg (20 mol) of bromine in 4 1 of CCI _{4 is then added} fairly quickly run towards. Then another 100 g of dibenzoyl peroxide are added and the second half of the bromine solution is instilled. The mixture is refluxed for about 15 minutes and the CCl _{4 is} then distilled off, a slight vacuum being applied towards the end. Based on content determinations, the residue consists of 90 to 95% methyl α-bromo-o-toluene carboxylate. It is processed further directly. 35 2. o-Carbmethoxybenzylisothiuronium bromide 2.5 kg (10 mol + 10%) α - bromine - ο - toluocarboxylic acid methyl ester are dissolved in 5 1 of methanol and treated with 0.76 kg (mol) of thiourea while stirring. The mixture is refluxed for 8 hours, then the methanol is distilled off and the residue is slurried with acetonitrile. 2.49 kg (81% of theory) of o-carbmethoxybenzylisothiuronium bromide are obtained as a colorless crystal mass with a melting point of 160 to 164 ° C. An analytically pure product is obtained by recrystallization from acetonitrile. Mp. 167 to 168 ° C. 3. Bis (o-carbamidobenzyl) disulfide A suspension of 1.35 kg (5 mol) of o-carbmethoxybenzylisothiuronium bromide, suspended in 71% methanol, saturated with ammonia gas. Man 150 ml of 30% strength hydrogen peroxide are added dropwise with stirring and the mixture is left to stand overnight. The next day is again saturated with ammonia gas and the same amount of 30% hydrogen peroxide is added dropwise. After 24 hours, the precipitate is filtered off with suction, washed with methanol and then with ether. 0.54 kg (66% of theory) of colorless product are obtained, which after recrystallization from methanol and some dimethylformamide at 233 ° C melts. wherein R ₁ denotes a hydrogen, chlorine, bromine or fluorine atom, characterized in that an o-toluene carboxylic acid ester is obtained either by the action of elemental bromine in the presence of an organic peroxide, in particular dibenzoyl peroxide, in an organic solvent or in boiling carbon tetrachloride or brominated using N-bromoamides, such as N-bromosuccinimide, in α-position, the obtained a-bromo-o-toluolcarbonsäureester with thiourea in an organic solvent, in particular in a lower alcohol, at 60 to 70 ⁰ C, the thus obtained Benzylisothiuroniumbromid - ο - carboxylic acid ester in an organic solvent, in particular a lower alcohol, with ammonia and an oxidizing agent, preferably with hydrogen peroxide, can react, the bis (o-carbamidobenzyl) disulfide thus obtained in a solvent mixture, the water and a solvent of the general formula ,O H-C VI R * contains, where R ₃ and R ₄ . may be the same or different and are hydrogen atoms or low molecular weight alkyl groups, particularly at a mixing ratio of the solvent and of the water of 2: 3 and at a temperature of 0 to 70 ° C, preferably chlorinated at 30 to 5O ⁰ C, in suspension.