DE1066575B - Process for the preparation of sulfonylureas - Google Patents

Description

7 * 6

For the manufacture of sulfonylureas, in particular of benzenesulfonylureas, various processes are known. For example, benzenesulf react amide with allyl or phenyl cyanates, where it is advantageous to start from the sodium salts of the sulfonic acid amides (cf. French patent specification 993 465) Several other methods are described in Chemical Reviews, 50 (1952), Vol IV, S 1 ff These known methods are recently also used Manufacture of sulfonylureas with blood sugar lowering agents Effectiveness has been used

It was now em new, technically advantageous and surprising compared to the known prior art Process for the preparation of sulfonylureas of the general formula

R-SO ₂ -NH-CO-NH-R ₁

worm R is a phenyl or naphthyl radical optionally substituted one or more times by alkyl, alkoxy groups or halogen atoms, a diphenyl, phenoxyphenyl, phenylalkyl or tetrahydronaphthalene radical or an aliphatic or cycloahiphatic or mixed cycloahiphatic-ahphatic radical with up to 12 carbon atoms and. R ₁ denotes a saturated _or unsaturated alkyl, cycloalkyl, cycloalkylalkyl, phenylalkyl or phenyl radical, where the aliphatic radical can also be interrupted by oxygen Manufacturing
of sulfonylureas

Applicant:

Farbwerke Hoechst! Aktiengesellschaft

formerly Master Lucius & Brüning,

Frankfurt / M., Örunmgstr. 45

I.

Dr Walter Aumuller, Franfyfurt / M.-Unterhederbach,

and Heinz Herr, Franttfurt / M.-Smdhngen,

have been named as inventors

found by making alkali of sulfonic acid chlorao amides with formamides of the formula

H-CO-NH-R ₁

worm R ₁ the specified cond

The procedure according to the
the use of isobutylfi
benzenesulfonic acid j-chloramidn:
according to the following

has iutung, implements. Invention takes place in the event rmamid and N- (4-methyl-.tnum as starting materials Reaction equation

H., C-

o-n;

Xl

N / A

+ H-CO-NH-CH ₂ -CH

XH,

CH,

-SO ₂ -NH-CO-NH-CH ₂ -Ch:

XH,

CH ₃

+ NaCl

The formula scheme should not only show the representation of the N- (4-methylbenzenesulfonyl) -N'-isobutylurea, but to demonstrate in general the course of the multifaceted reaction

Apart from the surprising reaction rate there is a particular advantage of the method according to Invention darm that the required output materials are accessible in a simple manner. For example, sulfonic acid chloramide sodium salts can be obtained from sulfamides by implementing only chlorinated lime m waßngem medium and precipitation with table salt according to the in the German Patent 390 658 specified method are obtained The crude products thus obtained can be used directly for further implementation The formamides used according to the invention can in a simple way m excellent yield from formic acid esters, for example methyl formate, and primary aliphatic, cycloahphatic, aromatic and aromatic, delightful wet nurses by heating You will get places that are easy to use Connections represent 1

The process according to the invention is carried out at moderately elevated temperatures, preferably at steam bath temperature. However, they can also do something higher or lower temperatures are used Temperatures between 90 and 130 ° C are particularly suitable generally about 1 hour, however, the reactions can also with a reaction time of 15 to 120 minutes will be carried out; 1

in a particularly advantageous way,

The reaction occurs when you add the mixture

adding salts to the reaction components, e.g. "B. Na-

9 (IS 637/413

3 4

|, Potassium carbonate or, in particular, Na-knurls the reaction product with 1 ° / ₀ water

Triurnic bicarbonate and sodium carbonate, too, with the addition of ammonia. One clarifies with charcoal, sucks off and receives

of chlorinated lime has proven to be favorable. The amount becomes crystalline by acidification with dilute hydrochloric acid

of the added salts can contain up to 2 mol with molar precipitation of N- (4-methyl-benzenesulfonyl) -N'-n-butyl-urine-

Approaches amount. Instead of alkali salts you can use 5 fabric that is sucked off and dried in one

the reaction components also tertiary nurse, with a yield of 8.8 g (65% of theory) obtained crude

for example Tnbutylairun, add the product used, which has a melting point of 117 to 119 g, results in after

Sulfonsaurechloramidsalze are expediently m recrystallization from ethyl acetate 7.2 g (53% of

their water-containing crystals or in weak theory) N- (4-methyl-benzenesulfonyl) -N'-n-butyl-urine-

Used when moist. A deflagration of this io substance with a melting point of 125 to 127 g
Connection is under the specified conditions

(Dilution with salts, water content, relative to example 3

low reaction temperature) not to be feared N- (4-methyl-benzenesulfonyl) -N'-cyclohexyl-hamstofi

As reaction components for the process according to 22.7 g of 4-methylbenzenesulfonic acid chloramidnum

Chloramidalkah-, 15 and 12.7 g of N-cyclohexylformamide are mixed well according to the invention

especially -natnumsalze ahphatic and cyclo- and heated on the steam bath, after a few minutes

Ahphatic sulfonic acids, such as heptane, a thin liquid solution is created, with gases

sulfonsaure-chloramidnatnum, Cyclohexansulfonsaure- develop pungent odor after a total

Chloramidnatnum, also those aromatic sulfon- 8 minutes are left to cool, the reaction mixture is added

acid as Benzolsulf onsaure-chloramidnatnum, p-To-so with l ° / ₀ waßngem ammonia, filtered by .ungelösten

luolsulfonsaure-chloramidnatrium, 2-methyl-ö -chlor- substances and acidifies the filtrate with acetic acid

Benzolsulfonsaure- chloramidnatnum, Naphthahn-2-sul- After repeated transfer and precipitation of the reaction

fonsaure-chloramidnatnum, 5,6 / 7,8 -Tetrahydronaphtha- good with ammonia or acetic acid one dries the

hn-2-sulfonic acid-chloramidnatnum and ω-benzyl- obtained N - ^ - methyl-benzoteulfonylJ-N'-cyclohexyl-

sulfonic acid chloranndnatnum 25 urea The yield is 6.3 g (21% of the Theone).

The formyl compounds are suitable as formamides

fertilize ahphatic and cycloahphatic pnmarer N- ^ methyl-benzokulfonyty-N'-cyclo-hexyl-

Wet nurse, for example N-butyl- and N-isobutylformamide, urea melts at 170 to 172 ° C
N-Cyclohexylformamide, N-AUylformamide, also the

Formyl compounds of aromatic and aromatic-ah- 30 · Example 4

phatic wet nurse, for example N- (β-phenylethyl) - _XT _,,,. "

formamide and N-phenylformamide and N-benzenesulfonyl-N'-isobutylurea

The process products are particularly valuable - 13.3 g Benzolsulfonsaure-chloramidnatnum 3H ₂ O,

full remedies that are suitable for oral administration - 5.0 g of N-isobutyliormamide and 3.5 g of potassium carbonate

bare antidiabetic drugs are already known or are mixed well beforehand. The mixture is heated for about

Was beaten "30 minutes on the steam bath After about 10 minutes

Example 1 results in a vigorous evolution of gas.

XT IA iv / r _λ ι u ι iü ~ -η vr / i, 4th 11, 4th α cold and dissolve the reaction mixture in water, filtered

N- (4-Methylbenzenesulfonyl) -N'-Isobutylurea ^ _{acidifies the precipitate with dilute hydrochloric} acid

144.0 g of 4-methylbenzenesulfonic acid chloramidnate 40 The crystalline precipitate obtained is filtered off with suction and kneaded from 3 H ₂ O, 50.5 g of isobutylformamide and 71.0 g of sodium-diluted ethanol. 6.3 g of carbonate with about 2 are obtained H ₂ O are mixed well (50% of the Theone) N-benzenesulfonyl-N'-isobutyl-urine in a bowl and heated on the steam bath for 1 hour
slight bubble formation occurs. The reaction cake formed is heated in 750 ecm. Example 5
Dissolved water, add a drop of formaldehyde- ._ .... ^ ₁ ,, ,,,. ,, _1V · ν _Τ > «1 τ. λ. *
natnumsltfoxyktlosung for reducing the environmentally not N- (2-Meth _y l-6-chlorben olsulfonyl _{Z) -N'-all-y} l urine _S toff

Sodium 4-methylbenzenesulfonic acid chloramide added 15.8 g of 2-methyl-6-cMorbenzenesulfonic acid-cHoramαd, let the alkaline solution cool down and filtered. The natural, 7.0 g of sodium carbonate with about 2H ₂ O and the filtrate is acidified with dilute hydrochloric acid. The 50 4.3 g of N-allylformamide are mixed well and the formed balls are suctioned off and heated with 1% strength in the steam bath for 30 minutes. An ammonia is formed with acetic acid and bubbles appear. After cooling, the reaction mixture is well dissolved in warm water without precipitation of N- (4-methylbenzenesulfonyl) Formaldehyde sodium sulfoxylate solution, the drying is crystallized from about 450 ecm of methanol, excess benzenesulfonic acid-chloramidnataum is obtained after working up the mother liquor, 76 g are reduced and by adding dilute hydrochloric acid N- (4-methyl) -benzenesulfonyl) -N'-isobutylurea (56% a precipitate obtained, which is filtered off with suction. The substance of the Theone) from melting point 169 to 171 ° C. is treated with 1% ammonia

^{6 <} > undissolved and acidifies the filtrate with diluted

Example 2 hydrochloric acid. A precipitate of 4 g of N- (2-

.. ,, ",,,. ,,,. , _{T /} , ..., _ Methyl-o-chlorobenzene stdfonylJ-N'-allyl urea vom

'N- (4-methyl-benzolsulfonvl) -N'-n-but _y l-urea m.p. 184 to 187 ⁰ C, according to the Umknstallisieren

Analogously to Example 1, ethyl acetate melts at 192 to 194 ° C. for 30 minutes

Heat 14 g of 4-methylbenzenesulfonic acid chloramide-65

natnum, 5.0 g Nn-butylformamide and 7.0 g Natnum example 6
carbonate with about 2 H ₂ O forms a crystal cake, which in ._, ". ^ _x,. ...,. , ",," Warm water is dissolved by addition of forming N- (3,4-benzenesulfonic _Dmxethoxy-y l) -N'-isobutyl-urinary _S toff

Aldehyde sodium sulfoxylate is acidified with dilute 16.5 g of 3,4-dimethoxy-benzenesulfonic acid chloramide hydrochloric acid, the precipitated substance is suctioned off and 7.0 g sodium carbonate are added with about 2H ₂ O and

5.0g NI sobutylformamide are mixed well and heated for 45 minutes on the steam bath.After cooling, the reaction mixture is dissolved in warm water, the unreacted N-3,4-dimethoxybenzenesulfonic acid chloramidnate is reduced by adding a few drops of formaldehyde sulfoxylate solution, filtered and clean the filtrate with dilute hydrochloric acid. The resulting N- (3,4-dimethoxy-benzenesulfonyl) -N'-isobutyl-urinary substance is umknstallisiert from dilute ethanol and melts at 195-196 ⁰ C

Example 7
N-Cyclohexanesulfonyl-N'-DO-phenyl-athy ^ -urea

4.4 g of cyclohexanesulfonic acid chloramidnatnum, 2.4 g of N-jS-phenylethylamide and 2.2 g of sodium carbonate with about H ₂ O are mixed well and heated on the steam bath for 15 minutes, with evolution of gas. After cooling, the reaction mixture is dissolved verdunntem l% ammonia, filtered from the undissolved material and the filtrate is acidified with dilute hydrochloric acid to the obtained crystals are filtered off with suction and recrystallizing from Essigester at 128 melts on clay to 13O ⁰ C

Claims (1)

Claim Process for the preparation of sulfonylureas of the general formula R-SO ₂ -NH-CO-NH-R ₁ worm R is a phenyl- or naphthyliest, a diphenyl, phenoxyphene, phenylalkyl or tetrahydronaphthalene radical, or an aliphatic or cycloahiphatic or mixed cycloahphatic aliphatic radical with bjis cycloahphatic aliphatic radical Carbon atoms and R ₁ denotes a saturated or unsaturated alkyl, cycloalkyl, cycloalkyl-alkyl, phenylalkyl or phenyl radical, where the aliphatic radical can also be interrupted by oxygen, characterized in that alkali salts of sulfonic acid chloramides are used as formamides of the formula H-CO-VNH-R _x dried 2 g (40% of theory) N-cyclo- hexanesulfonyl-N '- (/ 3-phenyl-ethyl) -urea, which according to 25 worm R _{1 has} the meaning given, converts © 909 637/413 9