DE1618378C - Process for the preparation of acylaminoalkyl benzenesulfonyl urea - Google Patents

Description

X-CO-NH-Y

(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 substituted can be,

(e) a tetramethylene phenyl radical,

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

40 The method is characterized in that Acylaminoalkylbenzolsulfinsäuren hydroxyureas reacted with in the presence of polyphosphoric acid, anhydrous phosphoric acid or sulfuric acid.

The reaction is expediently carried out in the presence of an inert diluent, e.g. B. one 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 benzenesulfonic acids used as starting material can be obtained by reducing corresponding benzenesulfochlorides by methods known per se obtained, for example by reduction with sodium sulfate.

They are sparingly soluble in water, but can be removed relatively easily, for example by treating 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

_{2 2}

R ¹ (a) alkyl with 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 group being h are preferably in the 4-position on the cyclohexyl radical,

(e) cyclohexylmethyl, cyclohexenylmethyl,

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

(g) nortricyclyl.

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

X-CO-NH-Y

y ν

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 mono- or twofold by chlorine, bromine, low molecular weight Alkyl or alkoxy may be substituted ω,

(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) Cyclohexyl substituted with one or two methyl groups, the methyl groups being preferred are in the 4-position 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 those with 1 to 4 carbon atoms in a straight or branched chain. Means low molecular weight acyl an acyl radical (organic acid radical) with up to 4 carbon atoms, preferably a straight chain or branched alkanoyl radical of the corresponding 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 ) -

whereby

-CH ₂ -CH ₂ -

is preferred.

Possible ring systems as member X in the above formula are, for example, the following O ₇ N

35

40

45

OCH

OCH

.65

OCH,

OCH ₃

OCH ₃

OCOCH ₃

CH,

OCH ₃

OC ₃ H ₇ (H)

OC ₂ H ₅

OCH ₂ CH =

OCH ₂ CH ₂ OCH ₃ OCOCH ₃

CH,

OCH ₁

CH ₃

H ₃ CH ₃ C 5 H ₃ C OCH ₃

PQH ₃ OCH ₂ CH ₂ OCH ₃ CH ₃

OCH,

IO

CH ₃
Cl

q-

OCOCH ₃

Cl

OCH,

Cl

y ν

Cl

Cl
Cl

OCH ₃

Cl

OCH ₂ CH = CH ₂ OCH ₃

OQH

OQH ₇ (»)

Cl

OCH ₂ CH = CH ₂

35

40

45

OCH ₂ CH ₂ OCH ₃ OCH ₃

F Br

OCH ₂ CH ₂ OCH ₃ OCH ₃

OCH ₃

CH ₃ O

OCH ₂ CH = CH ₂

OQH ₅

OCH ₃

Br

Cl

55

60

/ χ

Cl
■ / ~ \

CH ₃

CH ₃ -

OQH ₅

OCOCH ₃

CH ₃

C ₂ H ₅

(CH ₃ ) CH ₂

CH, OCH,

OQH ₅

OCH ₂ CH (CH ₃ ) ₂ CH ₃
/ "A-CO-NH-CH ₂ -CH ₂ - / V-SO ₂ H

OCH ₂ CH = CH ₂ OCH ₂ OCH ₃

SO, H

OCH ₂ CH ₂ OCH ₃ OCH ₂ CH ₂ OC ₂ H ₅

A production method for hydroxyureas of the formula IV is in the German patent 1 131 655.

/, —Χ a - \ For the implementation according to the invention can

<? y- - \ _ J> - for example, use the following hydroxyureas

\ = / | ^{= /} ^ find dung:

^{0CH3 OC2H5} 20 HN-CO-NH-C ₄ H ₉

OH

HN-CO-NH-OH

HN - CO - NH - ^ H V-CH ₃
OH

HN - CO - NH - ^ ΗΛ
OH

CH ₃ O OCH ₂ CH ₂ OCH ₃ .

OCH,

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

HN-CO-NH-CH ₂
OH

-CO-NH-CH ₇ -CH ₂

CO-NH-CH ₂

CO-NH-CH ₂ -CH ₂ -

-SO ₂ H

cO-NH-CH ₂ -CH ₂

OCH ₃

CO-NH-CH ₂ -CH ₂ -For the preparation of the process products, other processes have already become known. However, the condensation of acylaminoalkyl-benzenesulfinic acids with hydroxyureas has neither been described nor suggested.

Attempts to use appropriately substituted benzenesulfonic acids with ureas to give acylaminoalkyl-benzenesulfonylureas 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 the acylamino-SO H 55 alkyl-benzenesulfinic acid accessible for the reaction is without the acylamino group. is affected.

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

-SO, H

; with water, rubbed in and vacuumed off. The ί product obtained is treated with very dilute ¹ ammonia. 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 - (/ S-benzamido-ethyl) -benzenesulfonyl] -N'-cyclohexyl-urea melt (Yield 1.4 g) at 198-200 ⁰ C.

Example2

3.53 g of 4 - [/? - (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 to obtain the N- [4 - (/ - <2-methoxy-5-chloro-benzamido> ethyl) - benzenesulfonyl] - N '- cyclohexyl - urea, melting at 169-170 ⁰ 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 - [/ 9- (2-methoxy-5-chlorobenzamido) -ethyl] -benzenesulfinic acid and 3.3 g of N-butyl-N'-hydroxyurea are rubbed in the mortar with 50 ml of dioxane. After adding 100 g of polyphosphoric acid, a homogeneous liquid is formed. After 3 hours, ice water is added and the precipitate is extracted with 0.5% ammonia. Acidification of the ammoniacal solution and recrystallization from methanol gives Ν- [4 - (/? - < 2-methoxy - 5 - chlorobenzamido> - ethyl) - benzenesulfonyl] -N'-butyl-urea with a melting point of 148 to 149 ° C (yield 2.3 g).

B e i s ρ i e 1 4

7.1 g of 4 - [/ 9- (2-methoxy-5-chlorobenzamido) -ethyl] -benzenesulfinic acid and 3.5 g of N - (4 - methyl - cyclohexyl) - N'-hydroxyurea are in the Mortar rubbed 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 separates out and is extracted with 0.5% ammonia. After acidification of the ammoniacal solution and recrystallization from methanol, N- [4 - (/ J- <2-methoxy-5-chlorobenzamido> -ethyl) -benzenesulfonyl] - N '- (4 - methylcyclohexyl) - urea is obtained. F. 189 to 190 ⁰ C (yield 1.3 g).

Claims (2)

Patent 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 acylamino- 'benzenesulforiyl ureas of the general formula I.