DE1670233A1 - Process for the preparation of substituted pyrimidinecarboxylic acids - Google Patents

Description

Process for the preparation of substituted pyrimidinoarboxylic acids From US Pat. No. 3,254,086 s-ind esters of pyrimidinecarboxylic acids are known which are substituted by a dimethylanilino group. Pyrimidinecarboxylic acids, which carry a trifluoromethylanilino group in the nucleus are disclosed in US Pat 3,254,087.

The present invention relates to a process for the preparation of substituted pyrimidinoarboxylic acids of the formez- @ where R1, R2 and R3 can be identical or different and represent hydrogen, halogen, alkyl or alkenyl up to 5 carbon atoms, the trifluoromethyl, nitro, methoxy or sulfonamido group.

It, It @ was found as # 1 Mole Malons. acid dinitrile with 2 moles of dime ethylformamide chloride expediently in an inert solvent such as a chlorinated hydrocarbon, Benzene, toluene at temperatures of 10-110 ° C under Bilqun @ of 1-dimethylamino-3-chloro-4-cyano-2-aza-pentadiene-5-cimethyliminium chloride (I) (see formula below) reacts. This connection can be made by reaction with sodium perchlorate in the form of their perchlorate easily in pure form and good Yield can be obtained. @Instead of malononitrile can easily also the Diruethylaminoaminomethylenaalodinitril can be used.

In the compound obtained, the 3-position chlorine atom is without difficulty exchangeable for amines. @ o reacts e.g. m-aminobenzotrifluoride with this compound, advantageously in one of the solvents mentioned, with formation of 1- (m-trifluoromethyl) anilino-1-dimethylaminomethylene-amino-3-dimethylimonio-2-cyanopropene (1) perchlorate corresponding to compound II in the formula. But also other amines such as 2,3-dimethylaniline, dimethylamine, aniline and N-methylaniline react with of the compound I with formation of the correspondingly substituted compound II.

This is subject to when treating @ ammonia, preferably when heating, a ring closure with the formation of appropriately substituted 5-cyanopyrimidines (formula III), which are then saponified to give the carboxylic acids (formula IV).

This chemically peculiar process has compared to those in the. quoted US-ratentsQhriften. The manufacturing methods described have the advantage of eibnfach structured and technically easily accessible materials. The procedural opening can also be carried out easily and without considerable effort and consistently deliver veg good yields, the process according to the registration provides so @ it a considerable technical progress and an enrichment of technology in the field of synthesis of pyrimidine compounds.

F orr n-elc, c.rena (£ i (a » 91 + I 3 P- 0t3 t'j f tJ ' . llH ~ ç C., t>: 3, rus t CH ~ '' H 'ciss, "- / ! C y. e c; ., , "33 -it) r L iL-iOa t oini Off .

Examples are 1. 4- (m-Trifluoromethylanilino) -5-carboxy-pyrimidine liai) 1-Dimethylamino-5-dimethylimonio-3-chloro-2-cyano-4-aza-pentadiene- (1,3) -perchlorate: For a formulation mixture a @ s: 7.5 @ dimethylicrmamid and 51.3 ml of oxalyloloride in 1 @ 0 ml of chloroform er en 13, @ g of malonic acid dinitrile, dissolved in 20 ml of chlorofort, dripped in. The Liscchun2 will be 20 i-Aa o @ ea @ tion da Anf @ nalich @ same Realtions, enisch himself .c '.- loroi'orLii. <(- zo-eii, derLrejifeuc'stand ias @loroform i. @. ab @ e withdrawn, the mushy back stood .. <. te- "Lreuu.nc.ilun.it'inerjj-J-su.-von25ß ; s-m .. "m:.? rc: a: lunFr.: i;: i ~ mer1;. ;; uvo: c Rtem @Lren and Rüalung with iner Disung 25 g of sodium perchlorate in 200 ml of water are added. Hierhei ce., Eiden s @ ci, yellow Bristalle from which nac @ dem Ab-Til eyes from @ cetonitrile / ether (1: 1) recrystallized Nerden and the empirical formula C9H14N4C1] C104.

Yield 51 g (sus 1% of theory); M.p. 171 ° C.

The same product is obtained if instead of halononitrile the dimethylaminomethylene malodinitrile used @ @ird: From 2.4 g of dimethylaminomethylene malodinitrile, 2.5 ml of dimethylformamia and 2 ml of oxalyl chloride in 30 ml of Chlorofom @ercen after previously described procedure 4.55 g (72.5 @ d.Th.) yellow crystals of mp. 171 ° C obtained. b) 4- (m-iriflaormethylanilino) -5-cyano-pyrimidine: * vin in mixture also 31.25 g of the previously obtained Percloras, 4Q, O g of m-Aminobenzo criflaoria and 100 ml Chloroform is refluxed for 30 ml. Then distilled the chloroform & bundle shake the residue to remove unchanged m-aminobenzotrifluoride 2 times with 7 0 Ml of ether. 200 ml of 25% ammonia are added to the residue and cooked for 20 min. After cooling, the product crystallizes out, which out Ethanol is recrystallized.

Yield 19.1 g (72.3% of theory); M.p. 164-165 ° C. o) 2.1 of these Compound with 42.0 g of 75% sulfuric acid for 8 hours on the boiling water bath warmed up and then poured onto about 80 g of ice, the white crystalline precipitate is sucked off, washed neutral with water, dissolved in Sn-NaOH and this lusang with 2N-HC1 adjusted to pH 6.3, the compound crystallizes out, yield 1.73 g (76.5% of theory); M.p. 231-232 ° C.

2. 4- (2,3-Dimethylanilino) 5-cyano-pyrimidine 3.1 g of the example la obtained perchlorate are with 12.1 g of 2,3-dimethylaniline and 20 ml of chloroform 20 min, heated to reflux. The reaction mixture is then used on a rotary evaporator concentrated, the residue digested 3 times with 30 ml of ether, then with 50 sl conc.

Ammonia is added and the mixture is heated on a boiling water bath for 20 minutes. The aqueous phase is then poured off and the residue initially st from a Mixture of 20 ml rethanol and 5 ml water, then recrystallized twice from methanol, the 4- (2,3-dimethylanilino) -5-cyano-nyrimidine is obtained in pure form.

Yield 1.8 g (80% of theory); M.p. 202-203.5 ° C.

1.5 g of this compound are mixed with 20 ml of 75% sulfuric acid Heated for 2 1/4 hours on the boiling water bath and then to approx. 60 g Poured ice. Of the precipitate is filtered off with suction, in 40 ml of 2N NaOh dissolved, filtered and the dilute acidified with 2N HO1 to pH 6.3. Of the precipitate is filtered off with suction. washed with a little water and made from dimethylformamide / water (1: 1) recrystallized, the compound being obtained in pure form with 1/2 mol of water of crystallization is, yield 1.1 g (68% of theory); M.p. 231-252 ° C.

3.4imethylamino - oyanö-pimdi 6.3 g of the obtained according to Example la Perchlorate with 50 ml of saturated ammonium chloride solution and with 1 ml of conc.

Atamonia 10 min, on the boiling bath tubHa $ ia cooling down that falls 4-Dimethylamino-5-cyano-pyrimidine in pors from colorless needles, after suctioning off is recrystallized from isopropanol or a little water.

Yield 1.7 g (58% of theory, melting point 114 ° C.

4. 4- (N-methylanilino) -5-cyano-pyrimidine 3.13 g of the example la obtained perchlorate are mixed with 3.2 g of methyl aniline in 20 ml of chloroform 15 Minutes at reflux. The reaction mixture is mixed with ether and the precipitated 1- (N-methylanilino) -1-dimethylamino-methylane -amino-3-dimethyliminium-2-oyanopropen- (1) -perohlorat and methylaniline hydrochloride is sucked off. After recrystallization the perchlorate melts from a mixture of acetonitrile and ethyl acetate 190 ° C. The recrystallized perchlorate is concentrated with 20 ml. Treated with ammonia and the reaction mixture worked up according to example b. The product is made from it a mixture of ethanol and water recrystallized.

Yield 1.7 g (81% of theory), melting point 92.degree.

5. 4-Anillino-5-cyano-pyrimidine The peroxide obtained according to Example 1a. vird is reacted as in Example 4 with 3 g of aniline instead of methyl aniline. The emerging 4-anilino-5-eyano-pyrimidine is used in Fora colorless needles from Schmp. 168 ° C obtained ~ <4 (o-Shloranilino) -5-canq-imide with the one obtained according to Example la perchlorate are heated to 60 ° C for 8.5 hours with 51go-chloroaniline in 200 ml chloroform. The precipitated o-chloroanilino hydrochloride is filtered off with suction and the filtrate is evaporated in vacuo The viscous residue is mixed with isopropanol and the colors that have precipitated out are read out Sucked off crystals.

Yield 69.7 8 (85%% h.); M.p. 117-120 ° C.

The compound obtained in accordance with the above is consoled with 470 ml of saturated aaunonium chloride without mouth 115 ml.

Ammonia 15 Now at room temperature, the precipitated crystals are agitated and sucked off and about 270 ml of isopropanol recrystallized.

Yield 28.4 g (61.93% of theory) of colorless crystals; Sohmp. 138-140 ° C.

7 * 4- (o-chloroanilino) -5-carboxy-pyrimidine 25.2 g of the example 6 obtained cyano-pyrimidines are in 160 ml of 50% sulfuric acid for 35 hours. The reaction mixture is heated to 90 -5 ° 8 and the colorless precipitate is cooled suctioned off and recrystallized from 300 ml of dimethylformamide.

Extensions 14, e g (58 d. Th.); M.p. 2? 5-276 ° C dec.

8 * En 84 (a-chloroaniline65-cyano-pyrimidine 31st g of the example Ra obtained perchlorate are mixed with 25sus g of m-chloroaniline in 100 ml of Chlorotorm Heated to 60 ° C. for 1 hour, the solvent removed in vacuo and the residue with t 150 ml conc. Ammonia heated on a boiling water bath for 30 minutes. The reaction mixture is cooled to 10 ° C, filtered off the precipitated colorless crystals and removed Ethylace that recrystallized.

Yield 15.8 g (68.5% of theory); M.p. 186-187 ° C.

9. 4- (m-chloroanilino) -5-arboxy-pyrimidine 4.4 g of the example 8 cyanopyrimidine obtained are 8 hours with 15 ml of 75% sulfuric acid 95 ° 0 heated.

The reaction mixture is poured onto 50 ml of ice water, the precipitated Sucked off precipitate and from a mixture of 80 ml of dimethylformamide with 15 ml Recrystallized water.

Yield 2.6 g (55% of theory; melting point 282-283 ° C.

10. 4- (p-Chloroanilino) -5-cyano-pyrimidine 31.5 g of the example The perchlorates obtained are mixed with 25w5 g of p-chloroaniline according to the example 8 implemented.

The further reaction with 130 ml of conc. Ammonia is used accordingly Example 8 carried out, and the reaction product recrystallized from ethanol.

Yield 17.8 g (76.5% of theory) of yellow crystals; M.p. 183-184 ° C.

11.. 4- (p-Chloroanilino) -5-carboxy-pyrimidine 50 g of the example 10 received. Cyano-pyrimidins are 8 hours with 25 ml of 55% sulfuric acid. heated to 95 ° C. and the reaction mixture poured onto 50 ml of ice water. The unusual one The reaction product is filtered off with suction and washed out with water and then with methanol and dried. The crude product is made from a mixture of dimethylformamide and water recrystallized.

Yield 326 g (66.5% of theory); Scnmp. 281-283 ° C.

-Patent claims-

Claims (3)

Claims 1. Process for the preparation of substituted pyrimidine carboxylic acids of r F. ormel 1 r (-x R1 Rx wherein R1, R2 and R3 can be identically different and represent hydrogen, halogen, alkyl or alkenyl up to 5 carbon atoms, the trifluoromethyl, nitro, methoxy ode sulfonamido group, characterized in that 1 mol of malononitrile with -2 mol Dimethylformamide chloride, preferably in an inert solvent such as a chlorohydrocarbon, benzene or toluene, at temperatures from 10-11 to 1-dimethylmino-3-chloro-4-cyano-2-azapentadiene-5-dimethyliminium chloride and reacted with sodium peroxide is converted into the corresponding perchlorate, this is then reacted with an amine, preferably in one of the solvents mentioned, to give the corresponding 1-amino-1-dinethylaminomethylene-amino-3-dimethylimonio-2-cyanopropene (l) perchlorate, which is treated with ammonia is converted into the corresponding 4-amino-5-cyano-pyrimidine and then saponified. 2. The method according to claim 1, characterized in that the amine 2,3-dimethylaniline or m-trifulormethylaniline is used. 3. The method according to claim 1, characterized in that # instead of Malonsäuredinitril the Dimethylaminomethylenmalonsäuredinitril is used.