DE1793647C3 - 2-cyano-dihydrocinnamaldehyde dialkyl acetals - Google Patents

Description

CN

Sulfonamides, e.g. B. with sulfisoxazole, sulfamethoxazole, Sulfadimethoxin or Sulfachinoxaün can be combined. For oral administration to an adult there is such a combination z. B. from 0.5 g of sulfisoxazole and 100 mg of a compound of the formula II in a pharmaceutically customary administration form, such as. B. tablets, capsules or aqueous suspensions.

The compounds of formula 1 can after

■ ο the following reaction scheme, in which the symbols R <to R ^{4 have} the meanings already given and R is Ci-3-alkyl, preferably methyl, are obtained.

wherein

R O-i-alkyl,

R ^{1 is} hydrogen, chlorine, methyl or methoxy, R ^{2 is} hydrogen, chlorine or methoxy, R ^{3 is} Ci-7-alkoxy and

R ⁴ Ci-7-alkoxy

means.

The invention relates to 2-cyano-dihydrocinnamaldehyde dialkyl acetals the formula

R ²

R ¹

CH,

OR

CH

- ■ \ CH OR

CN

R C-j-alkyl,

R ^{1 is} hydrogen, chlorine, methyl or methoxy, R ^{2 is} hydrogen, chlorine or methoxy, R ^{3 is} Ci_7-alkoxy and

R ⁴ C 1-7 alkoxy

means.

The compounds of formula I can be used as intermediates for the preparation of compounds the formula

-NH,

(II)

wherein R ¹ to R ^{4 have} the meanings given above,

serve, into which they can be converted by condensation with guanidine. This condensation with Guanidine happens almost quantitatively. The compounds of formula II can accordingly in a much higher yield can be obtained than by known methods, e.g. Those of the U.S. patent 30 49 544, was possible.

The compounds of the formula II have an antibacterial effect and are particularly suitable for local applications suitable. You can use antibacterial agents

- 'f V CHO + NC CIKCH ₁ OR

R ⁴

(IV)

(V)

RAW

lower alkali alkoxide

CHOIR

C-N

(III)

RAW

lower alkali alkoxide

(anhydrous)

OR

\ / CH

R -'- <f V-CH ₁ -CH \) R

2 v- ri wi \ (I)

C-, N

According to this scheme, an aldehyde of the formula IV can first be reacted with an iS-alkoxy-propionitrile of the formula V in the presence of a lower alkali metal alkoxide, such as sodium methoxide or potassium ethoxide, and a Ci _ 3-alkanol of the formula ROH such as methanol, ethanol or propanol . The reaction temperature is not critical, but it is generally between 60 and 140 ^° C. This gives a compound of the formula III. It is converted to the compound of formula 1 by treatment with the alkanol ROH in the presence of a lower alkali alkoxide under anhydrous conditions. Here too, reaction temperatures of about 60 to about 140 ^° C. are suitable.

Most of the aldehydes of the formula IV are known or can be obtained according to known ones Methods, e.g. according to the Vilsmeyer reaction (H ouben-Weyl, methods of organic chemistry

[1954], Volume VU, Part 1, _ page 29) or according to Rosenmund (Organic Synthesis, Coll. Vol. 3, 551 [1955]).

example 1

The solution obtained from 6 g of sodium and 300 ml of methanol is mixed with 47.5 g of Ϊ-methoxypropionitrile and 98 g of 3,4,5-trimethoxybenzaldehyde. The reaction mixture is refluxed for 4 hours, then cooled, and 150 ml of water are added. The reaction mixture is left to crystallize for one hour with stirring at 5 to 10 ^° C., then filtered and washed with 60% strength ice-cold methanol. The air-dry raw material, which melts at 78 to 80 ^{° C., is used without further purification.} Yield 92g.

A solution of 19 g of sodium in 300 ml of methanol is treated with 106 g of SAS trimethoxy ^ '- methoxymethyl cinnamonitrile Boiled under reflux for 24 hours. The solution is poured into 1 liter of water and repeated extracted with benzene. The combined benzene extracts (500 to 700 ml) are 3 times with 500 ml Washed water and evaporated in vacuo. With vacuum distillation, the residue gives 83 g of 3,4,5-trimethoxy ^ '- cyano-dihydrocinnamaldehyde-dimethylacetal (Bp = 215 to 225 ° C / 11 mm; η = 1.5230) as a clear, viscous oil that crystallizes on standing. The end Preparation recrystallized from methanol melts at 69 to 70 ° C (n = 1.5190).

The product can be converted into 2,4-diamino-5- (3 ', 4', 5'-trimethoxybenzyl) pyrimidine as follows to be transferred:

31.5 g of SAS-trimethoxy ^ '- cyano-dihydrocinnamaldehyde-dimethylacetal are refluxed with 200 ml of a methanolic guanidine solution (0.250 mol of guanidine) for 2 hours. The methanol is completely distilled off with stirring, the residue solidifying to form a yellowish crystal mass. The residue is slurried in 100 rnl of water, after cooling, filtered off and dried, provides 28 g of 2,4-diamino-5- (3 ', 4', 5'-trimethoxybenzyl) pyrimidine (mp. = 199-200 ⁰ C) .

20 g of the above, yellowish discolored product are added to 30 ml of 3N sulfuric acid at 60 ° with stirring. The solution is cooled with stirring to 5 to 1O ⁰ C, the crystals filtered off and washed 2 times with 10 mL of cold 3 N sulfuric acid. 1.3 g of discolored material with a melting point of 195 ° to 196 ° C. are obtained from the filtrate and can be added to further cleaning batches. The crystallized sulfate is dissolved in 200 ml of hot water, the solution is treated while hot with charcoal and the product is precipitated by adding a solution of 20 g of sodium hydroxide in 40 ml of water with cooling. 17.5 g of white are obtained

2,4-diamino-5- (3 ', 4', 5 ', -trimethoxybenzyl) -pyrimidine, mp = 200 to 201 ° C.

Example 2

166 g of veratrumaldehyde and 95 g of methoxypropionitrile are refluxed for 4 hours with stirring in a methanolic sodium methylate solution (11 g of sodium in 400 μl of absolute methanol). The solution is crystallized by cooling to 0 ⁰ C and seeding. The crystals are filtered off and washed with ice-cold 60% methanol. 147 g of air-dry 3,4-dimethoxy-2'-methoxymethyl-cinnamonitrile are obtained. A second fraction of 35 g is obtained by diluting the filtrate with water, extracting with benzene and vacuum distillation. The product recrystallized from methanol melts at 75 ° C. (n; = 1.5862).

180 g of 3,4-dimethoxy-2'-methoxymethyl-cinnamonitrile are refluxed for 24 hours in a methanolic sodium methylate solution (37 g of sodium in 600 ml of absolute methanol). The reaction solution is poured into 1.5 liters of water and extracted with 500 ml of benzene. The benzene extracts are washed repeatedly with small amounts of acetic acid-containing water and evaporated in vacuo. Distillation of the residue at 205 to 210 ^° C. gives 152 g of 3,4-dimethoxy. 2'-cyano-dihydrocinnamaldehyde dimethylacetal as a colorless oil which crystallizes in the original. The preparation recrystallized from methanol for analysis purposes melts at 50 to 51 ° C. (n V = 1.5235).

The product can be converted into 2,4-diamino-5- (3 ', 4'-dimethoxybenzyl) pyrimidine as follows to be transferred:

26.5 g of 3,4-dimethoxy-2'-cyano-dihydrocinnamaldehyde dimethyl acetal are boiled with 250 ml of methanolic 1 N guanidine solution for 2 hours. The solvent is then completely distilled off within 2 hours. The crystalline residue is in 100 ml Slurried water, filtered and washed with a little alcohol and ether. 24.5 g of 2,4-diamino-5- (3 ', 4'-dimethoxybenzyl) pyrimidine are obtained of m.p. = 233 ° C.

Example 3

90 g of 4,5-dimethoxy-2-methylbenzaldehyde and 50 g of methoxypropionitrile are in a methanolic Sodium methylate solution (5.5 g of sodium in 150 ml of methanol) was refluxed with stirring for 4 hours. The solution is poured into 1 liter of water and extracted with benzene. The benzene solution is with Washed water, evaporated and the residue is distilled at 200 to 208 °. 103 g are obtained 4,5-Dimethoxy-2-methyl-2'-methoxymethyl-cinnamonitrile as a yellowish oil which crystallizes on standing. The Preparation recrystallized from methanol melts at 68 to 69 ° C (n; = 1.5823).

283 g of 4,5-dimethoxy-2-methyl-2-methoxymethylcinnamonitrile are refluxed with a methanolic sodium methylate solution (53 g of sodium in 800 ml of absolute methanol) for 24 hours. The reaction solution is poured into 1.5 liters of water and extracted with benzene. The benzene solution is repeatedly extracted with water containing small amounts of acetic acid and evaporated in vacuo. The residue is distilled at 205 to 211 ° C. and yields 250 g of 4,5-dimethoxy-2-methyl-2'-cyano-dihydrocinnamaldehyde-dimethylacetal, which crystallizes on standing. The recrystallized from methanol preparation melts at 60 to 6I ⁰ C (n = 1.5228).

The product can be converted into the 2,4-diamino-5- (4 ', 5'-dimethoxy-2'-methylbenzyl) -pyrimidine as follows To be transferred:

55.8 grams of 4,5-dimethoxy-2-methyl-2'-cyano-dihydrocinnamaldehyde dimethylacetal are with 250 ml of Imolar methanolic guanidine solution for 2 hours Heated to reflux. The solvent is then completely distilled off, the crystalline residue is in 100 ml Slurried water, filtered off and washed with a little ice-cold alcohol and ether. You get

(15 74 g of 2,4-diamino-5- (4 ', 5'-dimethoxy-2'-methylbenzyl) pyrimidine of m.p. = 233 ° C.

Claims (1)

Claim: 2-cyano-dihydrocinnamaldehyde dialkyl acetals formula OR CH CH, CH OR