SU376944A1 - METHOD OF OBTAINING 2-AMINO-ALKYLAMINOTHIENO- [3,2-a] -PYRIMIDINE DERIVATIVES - Google Patents

Description

one

The invention relates to a method for the preparation of new pyrimidine derivatives, which in terms of pharmacological action are superior to known compounds of a similar structure and can be used in medicine.

Based on the well-known in chemistry of heterocyclic compounds of the reaction of intramolecular cylization of diethanolamine in the presence of acid, the proposed method of obtaining derivatives of 2-aminoalkylaminothieno-3, 2-c-pyrimidine of the general formula

RI is hydrogen or Ci-Sb-alkyl with a straight or branched chain;

R2 is hydrogen or methyl in position 6 or 7;

Rs and R4 - hydrogen or one of the radicals can mean alkyl, and the other hydrogen.

A is an alkylene with a straight or branched chain, containing 2--10 carbon atoms, OR their salts, consisting in the fact that the compound of the general formula

RI

XHN-A-N-f

H

ten

N x

 CH-RS

1 c: H-R4

ngsno

he

in which X is a hydrogen or easily detachable protecting group, for example, acetyl, benzoyl or d-toluenesulfonyl, and A, Ri, R2, Rs and R4 are as described above, is subjected to intramolecular cyclization in the presence of an acidic condensation agent, is cleaved off a protecting group and the desired product is isolated by known methods in free form or in the form of a salt.

Cleavage of the protective radical X, for example acyl, is preferably carried out hydrolytically in the presence of acids or bases.

The exchange decomposition reaction is carried out in the presence of an acidic condensation agent, usually in a solvent at O-175 ° C. Acids, such as serva, phosphoric perchlorofluorine, saline, hydrobromic acid, toluene sulfono.va, anhydrous salts, can be used as a condensation agent. metals, such as zinc chloride, or cationoo: bmennik. From solvents, higher hydrocarbons such as tetralin, acids such as sulfuric or phosphoric may be used. The reaction can be carried out in the alloy. Cyclization is best carried out in an inert gas atmosphere.

Inorganic and organic acids, such as hydrochloric, sulfuric, phosphoric, tare, tartaric, citric, maleic and fumaric acids, can be used to obtain the acid addition salts.

The starting compounds can be obtained: by reacting 2,4-dichlorothieno-3,2-pyrimidine with an appropriate diethanolamino, m and subsequent treatment with an amine of the general formula

RI

XHN-A- I -H, N

where Rb X and A are as defined above. If X is a protective radical, then it can then be hydrolytically cleaved. Example.

; 2- (2-Amino-ethylamino) -4-diethanolamino7-methylthieno-3,2-l-lirimidine 1 - dihydrochloride.

2.87 g (0.01 mol) of 2-, chloro-4-diethanolamino7-methylthieno-3, 2nd-niri: midine (obtained from 2,4-dichloro-7-methylthieno-3,2-pyrimidine and diethanolamine) 10 ml of 1,2-diaminoethane is heated to 120 ° C for 4 hours, the excess amine is distilled off in vacuo and the residue is purified chloromographically on a colony using a silica gel for chromatography (particle size 0.2-0.5 mm, Merck) , eluted with methanol-concentrated ammonia (9; 1).

Homogeneous | cancer | evaporation is evaporated, the remaining non-crystalline 2- (2-aminoethylamino) -4-diethylamino-7-methylthieno - 3,2-b - | pyrimidine is dissolved in an excess of ethanolic hydrochloric acid solution, evaporated to dryness and the residue is recrystallized from mixtures of methanol - ethanol (3: 1). Yield 2.6 g (68%).

Polished,%: C 40.62; H 6.03; N 18.22.

CisHssCbNsOaS (384.34).

Found,%: C 40.45; H 6.18; N 18.11.

2- (2-Aminoethylamino) -7-methyl-4-morpholinothieno-3, 2-n-pyrimidine dihydrochloride.

3.84 g (0.01 mol) of 2 - (. 2-aminoethylamino) -4 diethanolamino-7-methylthieno-3, 2nd - pyrimide dihydrochloride is dissolved in 50 ml of concentrated | sulfuric acid, incubated for 3 DAYS at 20 ° С in a dry environment, poured ice water, strongly alkalinized

40% -HibiM sodium hydroxide and many times extracted with methylene chloride.

The combined extracts are washed with water, dried over sodium sulfate and diluted with hydrochloric acid solution. The precipitate is filtered off with suction, washed with ether and recrystallized from methanol. T. nl. 335 ° C (decomp.). The output of 1.98 g (54%).

Calculated,%: C, 42.70; H 5.77; N 19.10. CisHaiCl.NsOS (366.33). Found,%: C 42.50; H 5.88; N; 18.95. The following compounds are prepared analogously:

2 - (3-Aminopropyl) -ethylamino-4 - morpholinothieno-3, 2-ё - lirimidine dihydrochloride, t. 1 pl. 280 ° C (ethanol), from 2- (3-aminolO Peel) ethylamino - 4 - diethanolaminothieno - 3,2-d pyrimidine dihydrochloride;

2- (5-Ami110len1Tyl) -ethylamino-4-morpholinothieno-3, 2nd (-1pyrimidine-dihydrochloride, t.nl. 236-238 ° C (ethyl acetate - 3, 1), FROM 2 - ( 5-amino1 nentyl) - ethylamino-4 diethanolamino-thieno - 3,2-d - pyrimidine dihydrochloride;

2- (6-Aminohexyl) -methylamino-4 - morpholinothieno-3, 2nd (-lyry: midin. - dihydrochloride, mp 227-228 ° C (ethanol), from 2- (6-a1 Minohexyl) - methylamino - 4-diethanolaminotino 3, 2-a-lirimidine-dihydrochloride;

2- (4-Amipobutnl) - -: butylamino - 4-morpholinO | Thieno-3, 2-c - pyrimidine - dihydrochloride, so l. 280 ° C (ethanol), from 2- (4-aminobutyl) - "- butylamino-4-diethanolamino-thieno-3, 2nd (-lirimidine dihydrochloride;

2- (2-Aminoethyl) - isapropylamino-4-morpholino-thieno-3, 2-y -oirimidine - dihydrochloride, so on. 278-280 ° C (ethanol), from 2- 2-aminoethyl) -isolrolylamino-4-diethanol-amino-thien-3, 2-pyrimidine dihydrochloride1;

2- (2 - Amino-ethylamino) - 4-morpholinothia; HO-3, 2-ui-pyrimidine, t. Nl. 282-283 ° С (decomposed), from 2- (2-aminoethylamino) -4-diethanolamino-thieno-3, 2nd - pyrimidine - dihydrochloride (t. Pl. 194-195 ° С). Calculated,%: C 40.91; H 5.44; CI 20.13. CizHisCUNsOS (352.30). Found,%: C 40.98; H 5.51; C1 19.99. In the same manner, people get: 2- (2-Amino-ethylamino) -6-.methyl-4-morpholinothieno-3, 2 -1 -1Nirimidin1-dihydrochloride, t. Pl. 309-311 ° C (decomposed., Methanol), and the base from 2- (2-aminoethylamino) -4-diethavolamino-6-methylthieno - 3,2 - d - lirimidine dihydrochloride;

2- (2-Aminoethyl) -methylamino-4 - morpholinothieno-3, 2-a - pyrimidine - dihydrochloride, so pl. 275 ° С (decomposition, ethanol) and a base from 2- (2-aminoethyl) -methylamino-4-diethanolamino-thieno-3; 2-nd pyrimidine dihydrochloride;

2- (2-Aminoprolylamino) -4 - morpholinothieno-3, 2-nd α-pyrimidine dihydrochloride, t. Pl. 214-216 ° C (decomposition., This-nol), and the base