DE1795489B - Process for the preparation of derivatives of 1-H-benzo-2,3-thiazinon- (4> dioxyds- (2,2). Excreted from: 1545900 - Google Patents

Description

wherein R is an alkyl group having 1 to 4 carbon atoms or a ^ -dialkylaminoethyl group and R] is 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 five step synthesis:

1. An o-toluene carboxylic acid ester is in itself known way either by the action of elemental bromine in the presence of an organic peroxide, preferably dibenzoyl peroxide, in an inert organic solvent, preferably in boiling carbon tetrachloride, or by means of N-bromamides, such as N-bromosuccinimide, brominated:

CH ₃

COOR ₂
CH ₂ Br

COOR,

In the above formulas II and III, R _{1 has} the meaning given above, and R ₂ can represent an alkyl, aryl, alkaryl, 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 2 is} preferably a low molecular weight alkyl group, such as the methyl, ethyl or propyl group; the methyl group is particularly preferred.

2. The thus obtained a-bromo-o-toluolcarbonsäureester is reacted in known manner with thiourea in a solvent at 60 to 7O ⁰ C:

55

60

CH ₂ Br

COOR,

III

H, N — C — NH,

^s nh;

NH,

COOR,

IV

Lower alcohols have proven to be particularly suitable solvents for the reaction.

3. The benzylisothiurium bromido-carboxylic acid ester thus obtained is left in a lower alcohol react with ammonia and hydrogen peroxide:

CH ₂ -SC

COOR ₂

NH,

IV

NH ₃ + H ₂ O ₂

; ■

CH ₂ -S

CONH ₂

25th

Methanol is preferably used as the solvent for this reaction step.

4. The bis-o-carbamidobenzyl disulfide obtained is in a solvent mixture, the water and a solvent of the general formula

H-C

R ₃

R ₄

VI

35

contains, in which R ₃ and R _{4 are} identical or different and are hydrogen atoms or low molecular weight alkyl groups, at a temperature of 0 to 70 ⁰ C in suspension, with elemental chlorine in the 1 - H - benzo - 2,3 - thiazinone - (4) - Dioxide - (2.2) converted: '_ R ₁ CH ₂ -S- ¹

CONH ₂

Cl ₂

50

55

60

Suitable solvents are, for example, formamide and especially dimethylformamide. The relationship Water in this solvent has a great influence on the yield of 1 -H-benzo-2,3-lhiazinop .- (4) -dioxyden- (2.2) of the general formula I. Thus, with the preferred use of dimethylformamide a dimethylformamide-water mixture in a ratio of 2: 3 is particularly favorable proven. The chlorination is preferably carried out in the temperature range from 30.degree. To 50.degree.

5. The 1-H-benzo-2,3-thiazinon- (4) -dioxide- (2,2) thus prepared is in a known manner in a solvent in the presence of a basic substance, preferably an alkali metal carbonate, with an alkylating agent or a / Ϊ-dialkylaminoethylating agent implemented at 80 to 100 ° C. Are alkylating agents or / f-dialkylamino ethylating agents for example alkyl halides or / Ϊ-dialkylaminoethyl halides or dialkyl sulfates. Particularly suitable solvents for this reaction are dimethyl sulfoxide or dimethylformamide.

The N-alkyl and N-dialkylaminoethyl derivatives of 1-H-benzo-2,3-thiazinon- (4) -dioxide prepared according to the invention <:-( 2 ,?} are valuable pharmaceuticals. They show hypoglycemic activity without any Producing side effects are therefore useful in treating diabetes; Besides that are they anti-convulsive and anti-inflammatory.

These compounds can be converted into their pharmaceutically acceptable acid addition salts will. Acids which can be used for the preparation of acid addition salts are, for example, maleic, Fumaric, benzoin, amber, methylsulphone, lemon, wine, salicylic, apple, cinnamon, hydrogen chloride, Hydrobromic, phosphoric and sulfonic acids. The acid addition salts can be added in a customary manner be prepared, for example by treating a solution or suspension of the free bases in an organic solvent with the desired acid and recovery of the salt formed by Crystallization process.

The substances prepared according to the invention also give starting products that are more valuable for synthesis Medicines such as antidiabetics and diuretics.

example 1

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

To the boiling solution of 3.0 kg (20 mol) of methyl o-toluene carboxylate in 20 l of carbon tetrachloride 100 g of dibenzoyl peroxide are added and about half of a solution of 3.2 kg is then left (20 moles) of bromine in 4 liters of carbon tetrachloride run in fairly rapidly. Then you give again 100 g of dibenzoyl peroxide are added and the second half of the bromine solution is added dropwise. One stops about 15 minutes under reflux and then distilled off the carbon tetrachloride, with one towards the end apply a slight vacuum. The residue is 90 to 95% due to content determinations from methyl a-bromo-o-toluene carboxylate. He will further processed directly.

b) o-Carbmethoxy-benzyl-isothiuronium bromide

2.5 kg (10 mol + 10%) methyl α-bromo-o-toluene carboxylate are dissolved in 5 l of methanol and treated with 0.76 kg (10 mol) of thiourea while stirring offset. The mixture is refluxed for 8 hours, then the methanol is distilled off and the slurry is carried out Residue with acetonitrile. 2.49 kg are obtained

1 79548S

(81% of theory) of o-carbomethoxybenzylisothiuronium bromide as a colorless crystal mass with a melting point of 160 to 164 ° C. Analytically pure product is obtained through Recrystallize from acetonitrile. Mp. 267 to 168 ° C.

c) bis (o-carbamidobenzyl) disulfide

A suspension of 1.35 kg (5 mol) of o-carbmethoxy-benzylisothiuronium bromide suspended in methanol is saturated with ammonia gas. 150 ml of 30% strength hydrogen peroxide are added dropwise with stirring and the mixture is left to stand overnight. The next day it is again saturated with ammonia 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 melts ^{at 233 ° C. after recrystallization from methanol and some dimethylformamide}

d) l-H-Benzo-2,3-thiazinon- (4) -dioxyd- (2,2)

Through a suspension of 332.4 g (1 mole) of bis (o-earbaniidcjbeiizy'O disulfide in 4.41 40% igeni dimethylformamide C for 5 hours passed, a moderate chlorine stream 30 at ^{the 0th} The temperature of the clear solution is at The end of 50 ° C. The solution is freed from excess chlorine by passing in air and left to stand overnight at 0 ° C. The colorless, crystalline precipitate is analytically pure By concentrating the mother liquor, further quantities of less pure product can be obtained.

e) 3-Methyl-1-H-benzo-2,3-thiazinon- (4) -dioxyd- (2,2)

19.7 g (0.1 mol) of 1-H-benzo-2,3-thiazinon- (4) -dioxide- (2.2) are dissolved in 170 ml of dimethylformamide, with 16 g (0.11 mol) of potassium carbonate and 12.6 g (0.1 mol) of dimethyl sulfate are added and the mixture is heated ^{to 100 ° C. for 14 hours.} After cooling, it is poured into 1 l of water and the precipitate is filtered off with suction. It is recrystallized from ethanol. Yield 14 g (66% of theory), melting point 145 ° C.

Example 2
3-ethyl-1-H-benzo-2,3-thiazinon- (4) -dioxyd- (2,2)

19.7 g (0.1 mol) 1 -H-benzo-2,3-thiazinon- (4) -dioxide- (2.2), prepared according to steps a) to d) of Example 1, with diethyl sulfate in the presence of calcium carbonate as in Example 1 implemented. The product is recrystallized from ethanol. Yield 14.5 g (65% of theory), melting point 160 ° C.

Example 3
3-n-Butyl-1H-benzo-2,3-thiazinon- (4) -dioxyd- (2,2)

19.7g (0.1 mol) 1-H-Benzo-2,3-thiazinon- (4) -dioxide- (2.2), prepared according to steps a) to d) of Example 1, are correspondingly with n-butyl iodide the procedure of Example 2 implemented. The product is recrystallized from isopropanol. yield 12 g (48% of theory), melting point 85 to 86 ° C.

Example 4

3 - (/? - Dimethylaminoethyl) -l-H-benzo-2,3-thiazinon- (4) -dioxide- (2,2) -hydrochloride

19.7 g (0.1 mol) 1- H-Benzo- 2,3-thiazinon- (4) -dioxyd- (2.2), prepared according to steps a) to d) of Example 1, are in 150 ml of dimethylformamide dissolved, with 16 g (0.11 mol) of potassium carbonate and 14.3 g (0.1 mol) / i-dimethylaminoethyl chloride hydrochloride added and heated to 100 ° C. for 6 hours with stirring. After cooling, it is poured into 1 l of water and separates from the precipitated oil after standing for a while at 0 ° C. The base is diluted in ice cold HCl dissolved and the crystalline hydrochloride filtered off with suction after the addition of ethanol. The product crystallizes to convert from ethanol. Mp. 250 ° C. (decomp.), Yield: 15.2 g (50% of theory).

Example 5

3 - (/ * - diethyiaminoethyl) -l-H-benzo-2,3-thiazinon- (4) -dioxide- (2,2) -hydrochloride

19.7 g (0.1 mol) 1-H-benzo-2,3-thiazinon- (4) -dioxyd- (2.2), prepared according to steps a) to d) of Example 1, are with / i-diethylaminoethyl chloride hydrochloride implemented analogously to Example 4. Here, however, the base is obtained in crystalline form. yield 21 g (70% of theory), melting point 70 ° C. It is converted into the hydrochloride analogously to Example 4. yield 16 g, melting point 218 ° C. (after recrystallization from ethanol).

Claims (2)

Patent claims: 1. Process for the preparation of 1-H-Benzo-2,3-thiazinon- (4) -dioxyden- (2,2) the general formula / VN R ₁ - IO ■ 5 wherein R is an alkyl group having 1 to 4 carbon atoms or a / J-Dialkyiaminoäthylgruppe and R is a hydrogen, chlorine, bromine or fluorine atom, characterized in that an o-toluene carboxylic acid ester in a known manner either by the action of elemental Bromine brominated in the presence of an organic peroxide in an inert organic solvent or by means of N-bromamides, the resulting α-bromotoluene carboxylic acid ester is reacted in a manner known per se with thiourea in an organic solvent at 60 to 70 ⁰ C, the benzylisothiuronium bromide obtained in this way -carboxylic acid ester can react in a lower alcohol with ammonia and hydrogen peroxide, the bis- (o-carbamidobenzyl) disulfide thus obtained in a solvent mixture, the water and a solvent of the general formula contains, where R ₃ and R _{4 are} identical or different and are hydrogen atoms or low molecular weight alkyl groups, ^{treated at a temperature of 0 to 70 0} C in suspension with elemental chlorine and the 1-H-benzo-2,3-thiazinone ( 4) -dioxyd- (2,2) in a manner known per se in a solvent in the presence of a basic substance with an alkylating agent or a / I-dialkylaminoethylating agent at 80 to 100 ^° C. 2. The method according to claim 1, characterized in that the bis (o-carbamido-benzyl) disulfide is treated at a temperature of 30 to 50 ⁰ C in a mixture of 2 parts of solvent and 3 parts of water with elemental chlorine. The invention relates to a process for the preparation of 1 - H - benzo - 2,3 - thiazinon - (4) - dioxyden - (2,2) of the general formula / VN / f \ N
O O
R.