DE1618378B - Process for the preparation of acylaminoalkyl-benzenesulfonyl-ureas - Google Patents

Description

X-CO-NH-Y - / ^r ~ \ -SO ₂ -NH-CO-NH-R ¹

(I)

manufactures in which mean

X (a) a phenyl radical which can be substituted by fluorine, chlorine, bromine, low molecular weight alkyl, alkoxy, alkenoxy, alkoxyalkoxy, phenalkoxy or phenoxy, low molecular weight acyl, benzoyl, trifluoromethyl, low molecular weight acyloxy, —CN or —NO _{2, and if desired} can also carry fluorine, chlorine, bromine, low molecular weight alkyl, alkoxy or alkoxyalkoxy as a further substituent,

(b) a naphthyl radical, which is optionally substituted once or twice by chlorine, bromine, low molecular weight alkyl or alkoxy can be substituted,

(c) a tetrahydronaphthyl or indanyl radical,

(D) a thienyl radical, which is optionally one or two times by low molecular weight Alkyl, alkoxy, alkoxyalkoxy, allyloxy, benzyloxy, chlorine or bromine can be substituted,

(e) a tetramethylene phenyl radical,

Y is a hydrocarbon chain with 2 to 3 carbon atoms, preferably the group

" ¹

R ¹

_{2 2}

(a) alkyl of 3 to 6 carbon atoms,

(b) cycloalkyl with 5 to 8 carbon atoms,

(c) cyclohexenyl,

(d) Cyclohexyl substituted with one or two methyl groups, the methyl groups are preferably in the 4-position on the cyclohexyl radical,

(e) cyclohexylmethyl, cyclohexenylmethyl,

(f) endomethylene, cyclohexyl, endomethylene - cyclohexenyl, endomethylene - cyclohexylmethyl, endomethylene - cyclohexenylmethyl,

(g) nortricyclyl.

The process is characterized in that acylaminoalkylbenzenesulfinic acids are used with hydroxy ureas converts anhydrous phosphoric acid or sulfuric acid in the presence of polyphosphoric acids.

The reaction is expediently carried out in Gegenwan an inert diluent, e.g. B. a ^ aliphatic or aromatic hydrocarbon, an ether such as dioxane or a carboxylic acid carried out like glacial acetic acid. Indifferent solvents such as ureas are particularly suitable dissolve well and also a great dissolving power for the above-mentioned condensing agents used to have.

Instead of the sulfinic acid, its salts, in particular the alkali metal salts, can also be used.

The reaction is conveniently carried out with an excess of polyphosphoric acid at room temperature or carried out at a slightly elevated temperature by mixing the reaction components with one another stirred until a syrup is formed, which you can expediently take a few hours, e.g. B. overnight.

For work-up, water can be added, for example. When using with water miscible diluents, the precipitate is then suctioned off and dissolved in very dilute ammonia and acidification of the filtrate, the desired product in the raw state isolated.

The benzenesulfinic acids used as the starting material can be converted into corresponding ones by reduction Benzenesulfochlorides obtained by methods known per se, for example by reduction with Sodium sulfite.

They are sparingly soluble in water, but can be relatively easily, for example by treatment with Thionyl chloride, convert into the corresponding sulfinic acid chlorides.

In particular, the process is suitable for the preparation of such acylamine alkylbenzenesulfonylureas, which are characterized by the general formula I.

X-CO-NH-Y - / "" ^ - SO ₂ -NH-CO-NH-R ¹

and which are accordingly made up of benzenesulfonic acids of the general formula

50 X - CO - NH- Y-

SO ₂ H (II)

or their alkali salts and hydroxyureas of the general formula IV

60 HO

N —CO —NH-R ¹

(IV)

The invention relates to a process for the preparation of acylaminoalkyl-benzenesulfonyl-ureas.

can be produced.
In the formulas means

X (a) is a phenyl radical which is associated with a fluorine, chlorine, bromine, low molecular weight alkyl, Alkoxy, alkenoxy, alkoxy-alkoxy, phenalkoxy or phenoxy, low molecular weight

Acyl, benzoyl, trifluoromethyl, low molecular weight. Acyloxy, - CN or --NO ₂ can be substituted and, if desired, can also carry fluorine, chlorine, bromine, low molecular weight alkyl, alkoxy or alkoxyalkoxy as a further substituent,

(B) a naphthyl radical, which is optionally substituted once or twice by chlorine, bromine, low molecular weight Alkyl or alkoxy can be substituted,

(c) a tetrahydronaphthyl or indanyl radical,

(d) a thiophenyl radical, which is optionally substituted once or twice by low molecular weight alkyl, Alkoxy, alkoxyalkoxy, allyloxy, benzyloxy, chlorine or bromine may be substituted can,

(e) a tetramethylene phenyl radical.

The meaning of X mentioned under (a) is preferred. Of the disubstituted phenyl radicals standing for X those which carry the substituents in the 2- and 5-positions to the carbonamide group are preferred.

Y is a hydrocarbon chain with 2 to 3 carbon atoms, preferably the grouping -CH ₂ -CH ₂ -

R ¹ (a) alkyl with 3 to 6 carbon atoms,

(b) cycloalkyl with 5 to 8 carbon atoms,

(c) cyclohexenyl,

(d) with one to two methyl groups substituted - ⁵⁰ are cyclohexyl, where the methyl groups are preferably in 4 abutment condition on the cyclohexyl radical,

(e) cyclohexylmethyl, cyclohexenylmethyl,

(f) endomethylene cyclohexyl, endomethylene cyclohexenyl, Endomethylene-cyclohexylmethyl, endomethylene-cyclohexenylmethyl,

(g) nortricyclyl.

In the definitions above and below low molecular weight alkyl always stands for one with 1 to 4 carbon atoms in a straight line or branched chain. Low molecular weight acyl means an acyl residue (organic acid residue) with up to corresponding to 4 carbon atoms, preferably a straight-chain or branched alkanoyl radical Chain length.

Examples of the bridge member Y may be mentioned

- CH ₂ - CH ₂ - - CH ₂ - CH ₂ - CH ₂

-CH (CH ₃ ) -CH ₂ - -CH ₂ -CH (CH ₃ ) -O, N

35

whereby
- CH ₂ CH ₂

55

is preferred.

Possible ring systems as member X in the above formula are, for example, the following

OCH ₃

6-

OCH ₃

.65

OCH ₃

OCH ₃

OCH,

OCOCH ₃

CH,

OCH,

OCjH ₇ (n)

OC ₂ H ₅

OCH ₂ CH = CH ₂

OCH ₂ CH ₂ OCH ₃ OCOCH ₃

CH,

H ₃ C

OCH ₃

OQH ₃

9 "

CH ₃

Cl

OQH ₇ («)

Cl

1618 DCH ₃ IO 378
6th <> Q-. c * - I.
OCH ₃ 5 H ₃ C OCH ₃ C ₂ H ₅ CH ₃ $ - 20th OCH ₃ OCH ₃ CH ₃ (CH ₃ J ₂ CH OQH ₅
CH ₃ 30th OCH ₃
CH ₃ OCH ₂ CH = CH ₂ 35 \
OQH ₇ («) OCH ₃ CH ₃ OCH ₃ OCH ₂ CH ₂ OCH ₃ OCH ₃

OCH ₂ CH = CH ₂

40

OCH ₂ CH ₂ OCH ₃ OCH ₃

Br

CH ₃ O

OCH ₂ CH = CH ₂

OQH ₅

OCH ₃

Br

OQH ₅

CH ₃

55

60

• 65

Br

9-

Cl CH ₃

CH,

QH ₅

(CH ₃ ) CH ₂

OCH,

OC ₂ H

₂ H ₅

CH ₃

<^ VcO - NH-CH ₂ -CH ₂ OCH ₃

CF ₃

b-

CO-NH-CH ₇ -CH ₇

A production method for hydroxyureas of the formula IV is described in German patent _1131655 .

For example, the following hydroxyureas can be used for the implementation according to the invention Find:

QH ₉

CH ₃ O
OCH ₂ CH ₂ OCH ₃ .

OCH ₃

The following are examples of the sulfinic acids that can be used as starting materials:

- NH-CH ₂ -CH ₂

SO ₂ H

20th HN-
I. HN-CO -NH 40 OH OH 25th HN-CO -NH OH HN-CO -NH 30th OH HN-CO -NH 35 OH CO-NH-CH ₂

CO-NH-CH ₂ -CH ₂ -

-SO ₂ H

OCH ₃

CO-NH-CH ₇ -CH,

-SO ₂ H Other processes have already become known for the production of the process products. However, the condensation of acylaminoalkyl-benzenesulfinic acids with hydroxyureas has neither been described nor suggested.

Attempts, appropriately substituted benzenesulfonic acids with ureas to acylaminoalkyl-benzenesulfonyl-ureas to condense have so far failed. It was therefore surprising that the analogous reaction of benzenesulfinic acids with hydroxyureas produces the desired products in good Yield supplies. In particular, it was not to be expected that the very sensitive molecule of acylaminoalkyl-benzenesulfinic acid ^ the reaction is accessible without affecting the acylamino group is pulled.

The process products are used as pharmaceuticals to lower blood sugar levels.

example 1

3.78 g of benzamido-ethyl-benzenesulfinic acid (prepared by reducing the corresponding sulfochloride with Na ₂ SO ₃ , melting point 121 to 123 ° C. from methanol) and 3.2 g of N-cyclohexyl-N'-hydroxyurea are finely triturated. Then 50 ml of dioxane and 100 g of polyphosphoric acid are added and everything is rubbed into a viscous syrup. Staggered after standing overnight

309614/192

with water, rubbed in and vacuumed off. The product obtained is loaded with highly diluted ammonia acts. After the undissolved material has been filtered off with suction, a precipitate is obtained by acidifying the filtrate, which is washed with water and recrystallized from dilute methanol. The thus obtained N- [4 - (/? - Benzamido-ethyl) -benzenesulfonyl] -N'-cyclohexylurea melts at 198 to 200 ° C (yield 1.4 g).

B e i s ρ i e 1 2

3.53 g of 4 - [/ S- (2-methoxy-5-chlorobenzamido) -ethyl] -benzenesulfinic acid (prepared by reducing the corresponding sulfochloride with Na ₂ SO ₃ , melting point 106 to 108 ° C) are mixed with 1 , 6 g of N-cyclohexyl-N'-hydroxyurea, 50 ml of glacial acetic acid and 60 g of polyphosphoric acid ground in a mortar to form a syrup. After standing for 3 hours at room temperature, ice water is added, the precipitate formed is filtered off with suction and treated with weakly diluted ammonia. After suction, the filtrate is acidified and the semi-solid precipitate that has formed is again dissolved in dilute ammonia and precipitated again.

After recrystallization from methanol, the N- [4 - (/ 9- <2-methoxy-5-chlorobenzamido> ethyl) - benzenesulfonyl] - N '- cyclohexyl - urea vom M.p. 169-170 ° C (yield 1.1 g).

The experiment succeeded in the same way using only 30 g of polyphosphoric acid. .

Example 3

8.8 g of N-0 (2-methoxy-5-chlorobenzamido) ethyl] benzenesulfinic acid and 3.3 g of N-butyl-N'-hydroxyurea are triturated in the mortar with 50 ml of dioxane. After adding 100 g of polyphosphoric acid the result is a homogeneous assortment. After 3 hours it will mixed with ice water and the precipitate extracted with 0.5% ammonia. After acidification the ammoniacal solution and recrystallization from methanol gives N- [4 - (/ S- <2-methoxy - 5 - chlorobenzamido> - ethyl) - benzenesulfonyl] -N'-butyl-urea from m.p. 148 to 149 ° C (yield 2.3 g).

Example 4

7.1 g of 4 - [/ S- (2-methoxy-5-chlorobenzamido) ethyl] -benzenesulfinic acid and 3.5 g of N - (4 - methyl - cyclohexyl) - N'-hydroxy urea are in the mortar Triturated with 100 ml of glacial acetic acid. After adding 100 g of polyphosphoric acid, a homogeneous mass is formed, which is left to stand for 3 hours at room temperature. When water is added, a precipitate is formed from which is extracted with 0.5% ammonia. After acidifying the ammoniacal solution and recrystallization from methanol gives the N- [4 - (/? - <2-methoxy - 5 - chlorobenzamido > - ethyl) benzenesulfonyl] - N '- (4 - methylcyclohexyl) - urea. 189-190 ° C (yield 1.3g).

Claims (2)

20 claims: 1. Process for the preparation of acylaminoalkyl - Benzenesulfonyl - ureas, characterized in that one acylaminoalkyl-benzenesulfinic acids or their salts with hydroxyurea in the presence of polyphosphoric acids, anhydrous phosphoric acid or Converts sulfuric acid. 2. The method according to claim 1, characterized in that using accordingly substituted starting materials acylaminobenzenesulfonyl ureas of the general formula I.