SU428607A3 - - Google Patents

Description

(54) METHOD FOR OBTAINING 2-AMINO-ALO-1-AMINOTHENO-3,2-a -PYRIMIDINE DERIVATIVES

12

aqueous carboxylic acid. The reaction takes place at a temperature of between 20 and 200 ° C, preferably in the presence of an organic solvent. A. ammonia is used in excess and the reaction is carried out in a closed vessel.

The derivative of the carboxylic acid formed on the basis of the amide or the imide of a carboxylic acid is split with an acid or with a new one, for example, with hydrazo-1M and hydroxylamine.

Compounds of general formula I, if necessary, could be converted into acid addition salts with physiologically tolerable inorganic or organic acids — hydrochloric, sulfuric, phosphoric, succinic, tartaric, citric, maleic, or fumaric.

The starting compounds of general formula II are obtained by reacting a 2-hydroxyalkyl-4-aminothieno-3, 2-d-pyrimidine of general formula III

 N

-A-y-f

Г Г1Ху х

N4 RJ R

where the radicals Ri, R2, Hz, R4 and A have the given meanings,

with halogenating agents, for example thionyl chloride. The reaction may be carried out in an inert solvent. Compounds of formula III are known.

Example A. 2- (5-Oxypentylamino) -4-morpholino-eeno-3, 2-d-pyrimidine.

5.1 g (0.02 mol) of 2-chloro-4-morpholinothieno-3, 2-e - | Pirimidine and 15 ml of 5-amino-1-pentanol are heated by IB for 4 hours to 120 ° C. After cooling the clear solution is poured into water. Oil is released, which after some time is discharged. The reaction product is filtered off with suction, washed with water and recrystallized from 7% strength methanol.

Output .3,6 g (57% of theory). Melting point 118-119 ° C.

Calculated,%: C 55.87; H 6.88; N 17.38.

C, FH, N4O2S (322.44).

Found,%: C 55.79; H 6.81; N 17.50.

The following compounds were obtained in the same way.

2- (3-Oxyethylamino) - 4-morpholinothieno 3, 2-y-pyrimidine

From 2-chloro-4-morpholinothieno, 3,2-e-1-pyrimidine and 2-aminoethanol. Melting point: 122-123 ° C (acetone).

2- (2-Hydroxyethyl) -methylimino-4-morpholinothieno-3, 2-d pyrimidine

From 2-chlorop-4-morpolipothieno-3,2-d-pyrphenmidine and 2-methylaminoethanol. Melting point 90-92 ° C (ether-metapol).

2- (3-Oxypropylamino) -4-morpholinothieno 3,2-d -nHpHMHAHH

From 2-chloro-4-morpholinothieno-3,2-e-pyrimidine and 3-amino-1-propanol. Melting point

hydrochloride 238-239 ° C (ethanol-ethyl acetate).

2 - (4 - Oxybutylamino) -4-morpholinothieno 3, 2-d-pyrimidine From 2-chloro-4-morpholinothieno - 3,2-d - pyrimidine and 4-amino-1-butanol). The melting point of hydrochloride is 212 ° C (ethanol).

2 - (2-hydroxypropylamino) -4-morpholinothieno 3, 2-d-pyrimidine From 2-chloro-4-morpholinothieno - 3,2-d - pyrimidine and 3-amino-2-nropanol). Melting point, hydrochloride 243-244 ° C (ethanol).

2- (5-hydroxypentyl) -methylamino - 4-morpholinothieno-3, 2-d-pyrimidine From 2-chloro-4-morpholinothieno - 3,2-d - pyrimidine and 5-methylamino-1-pentanol. The melting point of hydrochloride is 208-209 ° C (ethanol).

2- (3-hydroxypropyl) -methylamino-4-morpholinotheno-3, 2-d-pyrimidine From 2-chloro-4-morpholinothio-3,2-d-pyrimidine and 3-methylamino-1-propanol). The melting point of hydrochloride is 203 ° C (ethanol-acetone 2: 1).

2- (3-hydroxypropyl) -ethylamino-4-morpholinothieno-3, 2-d-pyrimidine

From chloro-4-morpholinothieno - 3,2-d - pyrimidine and 3-ethylamino-1-propanol. The melting point of hydro.chloride is 235 ° C (ethanol-acetone 2: 1).

2- (4-Oxybutyl) -methylamino-4 - morpholinothieno- 3, 2-d-pyrimidine

From 2-chloro-4-morpholinothieno - 3,2-d - pyrimidine and 4-methylamino-1-butanol. The melting point of hydrochloride is 207 ° C (ethanol-acetone 2: 1).

2- (4-Oxybutyl) -ethylamino-4 - morpholino-eeno-3, 2-d-pyrimidine

From 2-chloro-4-morpholinothieno - 3,2-d - pyrimidine and 4-ethylamino-1-butanol. The melting point of hydrochloride is 226-227 ° C (ethanol-acetone 2: 1).

2- (4-Oxybutyl) -n-propylamino-4 - morpholino-thieno- 3,2-d-pyrimidine From 2-chloro-4-morpholinothieno - 3,2-d - pyrimidine and 4-n-propylamino-1-butanol. The melting point of hydrochloride is 160-163 ° C (ethanol-acetone 2: 1).

2 (4-Oxybutyl) -n-butylamino-4 - morpholothiene-3, 2-d-pyrimidine

From 2-chloro-4-morpholinothieno - 3,2-d - pyrimidine and 4-n-butylamino-1-butanol. The melting point of hydrochloride is 162-165 ° C (ethanol-acetone 2: 1).

2 (5-Oxypentyl) -ethylamino-4 - morpholinothieno- 3, 2-d-pyrimidine

From 2-chloro-4-morpholinothieno - 3,2-d - pyrimidine and 5-ethylamino-1-pentanol. The melting point of hydrochloride is 115-120 ° C (ethanol). 2- (6-Oxyhexyl) -methylamino-4 - morpholinothieno- 3, 2-d-pyrimidine

From 2-chloro-4-morpholinothieno - 3,2-d - pyrimidine and 6-methylamino-1-hexaiol. The hydrochloride melting point is 115 ° C (ethanol).

2- (6-Oxyhexyl) -ethylamino-4 - morpholinothieno-3, 2-d-pyrimidine

From 2-chloro-4-morpholinothiepo - 3,2-d - pyrimidine and 6-ethylamino-1-hexanol. Rf 0.5; silica gel G firm Merck (petroleum ether - ethyl acetate 1: 1).

2- (5-Oxypentyl) -n-butylamino-4 - morpholinothieno- 3, 2-d-pyrimidine From 2-chloro-4-morpholinothieno - 3,2-d - pyrimidine and 5-n-butyl-1-1-pentanol. The melting point of hydrochloride is 90 ° C (isopropaiol is petroleum ether).

Example B. 2- (5-Chloropentylamino) -4-morpho-lino-thieno-3, 2-d-pyrimidine hydrochloride

To 18 g (0.05 mol) of 2- (5-hydroxypeptilamino) 4-morpholinothieno-3, 2nd pyrimidine 30 ml of thionyl chloride are added and left overnight at room temperature. Excess thionyl chloride is then removed in vacuo, and acetone or ester is added to the residue. Colorless cr; the precipitate is sucked off and dried. Melting point 151 -. The output of 12.5 g (66.3% of theory).

Calculated,%: C, 47.80; H 5.88; N 14.87. CisHzaCIgNgO (377.29).

Found,%: C 48.00; H 6.01; N 14.75.

In the same way, the following compounds were obtained.

2- (5-Chloropentyl) -methylamino-4 - morpholinothieno- 3, 2-d-pyrimidine-hydrochloride

From 2- (5-oxinentne) -methyl amino-4-morphol inio-3, 2-d-pyrimidine and thionyl chloride. Melting point 173-175 ° C (ethanol - acetone 1:).

2- (3-Chloropropyl) -methylamino-4 - morpholinothieno- 3, 2-d-pyrimidine-hydrochloride

From 2- (3-hydroxypropyl) -methylamino-4 - morpholinothieno- 3, 2-d-pyrimidila and thionyl chloride. Melting point 180 ° C (ethanol - acetone 1: 1).

2- (4-Chlorobutyl) -methylamino-4 - morpholinotheno-3, 2-d-pyrimidine hydrochloride From 2- (4-hydroxybutyl) -methylamino-4 - morpholinothieno-3, 2-d-pyrimidine and thionyl chloride. Melting point 205-208 0 (ethanol - acetone 1: 1).

2- (4-Chlorobutyl) -ethylamino-4 - morpholinotheno-3, 2-d-pyrimidine-hydrochloride From 2- (4-hydroxybutyl) -ethylamino-4 - morpholiHOTHeHO-r3, 2-d - pyrimidine and thionyl chloride. Melting point (ethanol - acetone 1: 1).

2- (4-Chlorobutyl) -n-propylamino-4 - morpholinothieno-3, 2-c-pyrimidine hydrochloride From 2- (hydroxybutyl) -n-propylamino-4 - morpholinothieno-3, 2-y-pyrimidine and thioiyl chloride. Melting point 195 ° C (ethanol-acetone 1: 1).

2- (4-Chlorobutyl) -n-butylamino-4 - morpholi yoetheno-3, 2-d -primidine-hydrochloride

From 2- (4-hydroxybutyl) -n-butylamino-4 - morpholinothieno-3, 2-d-pyrimidine and thionyl chloride.

Melting point 187-188 ° C (ethanol - acetone 1: 1).

2- {5-Chloropentyl) -ethylamino-4 - morpholinothieno 3, 2-d-pyrimidine hydrochloride From 2- (5-hydroxypentyl) -ethylamino-4 - morpholinothieno-3, 2-d-pyrimidine and thionyl chloride. Melting point 183-185 ° C (ethanol - acetone 1: 1).

2- (5-Chloropentyl) -n-butylamino-4-morpholinothieno-3, 2-d-pyrimidine

From 2- (5-hydroxypentyl) -n-butylamino-4 - morpho-oliothio-3, 2-d-pyrimidine and thionyl chloride. Oil, Rf 0.8, silica gel G, Merck (petroleum ether acetic ester 1: 1). 2- (6 - Chlorhexyl) -methylamino-4 - morpholinothieno- 3, 2-d-pyrimidine

From 2- (6-hydroxyhexyl) -methylamino-4 - morpholino-thieno-3, 2-e-nirimidine and thionyl chloride Oil, Rf 0.8, silica gel G, Merck company (netrol ether acetic ester 1: 1).

2- (6-Chlorhexyl) -ethylamino-4 - morpholinothieno- 3, 2-d-pyrimidine

From 2- (oxyhexyl) -ethylamino-4 - morpholinothieno- 3, 2-d-neyridine and thionyl chloride. Oil, Rf 0.8, Silica gel G, Merck

(petroleum ether acetic ester 1: 1).

Examples of the final product

Irimer 1. 2- (5 - Aminopentylamino) -4 morpholicotheno - 3,2-d-pyrimidine - dihydrochloride

16 g (0.0424 lolb) of 2- (5-chloropentilamino) 4-moprofol-phenyl-3,2-d-pyridimidine-hydrochloride together with 17.5 g (0.094 lul) of phthalimidcali is heated in 100 ml of dimethylformamide for 14 hours to temperatures of 145 ° C. After cooling, the reaction mixture was diluted with water and extracted with chloroform. The chloroform phase is dried with sodium sulfate and the solvent is recovered. The residue is triturated with a mixture of complex lsuster ether and petrolainoto ether and sucked off. Melting point 122 124 ° C (methanol / acetone 1: 1). Yield 10 g (52.35% of theory).

2.15 g (0.033 mol) of hydroxylamine hydrochloride is dissolved in 30 ml of ethanol and diluted with 15 ml of 4N. methanol solution of sodium methoxide (0.06 mol). After filtering out the precipitated sodium chloride, 3.82 g (0.00845 stranded) of phthalimmonium compound in 20 ml of ethanol and stir the mixture for 2 hours at (Room temperature. After suction of the gel-like salt) (sodium salt M-hydroxyphthalate, imide) the filtrate is diluted with methanolic hydrochloric acid and the impression is concentrated.The recovered crystalline product is filtered off with suction and recrystallized from a mixture of acetone and mganol. The melting point is 254-256 ° C. The yield is 1.94 g (58.1% of theory). 70; H 6.40; N 17.79; S 8.12. CisHjsCbNsOS (394.29). Found: C 45.50; H 6.56; N 17.60; S 8.24. In the same way, the following compounds were obtained. 2- (5-Aminopentyl) -methylamino-4 - morpholinothieno-3, 2-d-pyrimidine dihydrochloride From 2- (5-chloropentyl) methylamino-4 - morpholinothieno - 3,2- d - pyrimidine hydrochloride, phthalidine and hydroxylamine. Melting point 255-257 ° C (ethanol - acetone 1: 2). 2- (4-Aminobutyl) -methylamino-4 - morpholinothieno- 3, 2-d-pyrimidine-dihydrochloride From (4-chloro-rbutyl) -methyls, - morpholino-eeno-3, 2-d-pyrimidine, phtalimidkali and hydroxylamine. Melting point 260 ° C (ethanol - acetone). 2- (4-Aminobutyl) ethylamino-4 - morpholinothieno-3, 12-e-pyrimidine dihydrochloride From 2- (4-chlorobutyl) ethylamino-4 - morpholinothieno-3, 2-d-pyrimidine, phthalimidali and hydroxylamine. Melting point 259-261 ° C (ethanol - acetone). 2- (4-Aminobutyl) -n-propylamino-4-morpholothieno-3, 2-d-pyrimidine-dihydrochloride From 2- (4-chlorobutyl) -n-propylamino-4-morpholinothieno-3, 2-6-pyrimidine, phthalimide and hydroxylamine. Melting point 185 ° C (ethanol - acetone). 2- (4 - Aminobutyl) -n-butylamino-4 - mor flolinothieno-3,2-d-pyrimidine dihydrochloride From 2- (4-chlorobutyl) -c-butylamino-4 - morpholinothieno- 3, 2-d-pyrimidine , phthalimidcal and hydroxylamine. Melting point 280 ° C (ethanol - acetone). 2- (5-Aminopentyl) -ethylamino-4 - morpholinothieno-3, 2-d-pyrimidine dihydrochloride From 2- (5-chloro: rpentyl) - ethylamino-morpholinothieno-3, 2-d-pyrimidine, phthalimidal and hydroxylamine; Melting point 236-238 ° C (ethyl acetate-methanol 3: 1). 2- (6-Aminohexyl) -methylamino-4 - morpholino-thieno-3, 2-d-pyrimidine-dihydrochloride From 2- (6-chlorohexyl) -methylamino-4 - morpholinothieno-3, 2-d-pyrimidine, phthalimidkal and cate and 3-2-pyrimidine-3, 2-d-pyrimidine-3, 2-d-pyroimidino-3 Melting point 227-228 ° C (ethanol). 2- (6 - Aminohexyl) -ethylamino-4 - morpholinothieno- 3, 2-d-pyrimidine From 2- (6-chlorohexyl) -ethylamino-4 - morpholinothieno- 3, 2-d-pyrimidine, phthalimidro-hydroxylamine. Yellow 1 oil (R.f 0.5, silica gel, metabolic ammonia 9: 1). Example 2. 2- (5-Aminopentylamino) -4-morpholinotheno-3,2-d-pyridine-dihydrochloride 3.77 g (0.01 mol) 2- (5-chloro 1-pentoyl u) -4-morpholyl-nthieno-3, 2-d-pyr-imidine - hydrochloride together with 50 ml of liquid ammonia is heated for 16 hours in a bomb to a temperature of 00 ° C. After cooling, the excess ammonia is evaporated and the product is isolated from the residue by olonne chromatography (silica gel, methanol-ammonia 6: 1). After separation of the eluent, the residue is taken up with a large amount of methanol, diluted with a methanolic solution with hydrochloric acid, and crystalline dihydrochloride is precipitated to add acetone. Melting point 254-256 ° C (acetone-methanol). Output 1.1 g (27.9% of theoie). In the same way, the following connection is obtained. 2- (5-Aminopentyl) -methylamino-4 - morpholino-thieno-3, 2-d-pyrimidine-dihydrochloride s 2- (5-Chloro-pentyl) -methyl, - lurfolinothieno-3, 2-d-pyrimidine - hydrochloride and ammiac. Melting point 255-257 ° C (ethanol - acetone 1: 2). Subject of the acquisition 1. Method for the preparation of 2-aminoalkyl-amino-thieno-3,2-d-pyrimidine derivatives of the general formula IIN H7N-ANj where Ri and R2, which may be the same or different, denote hydrogen atoms or straight or branched alkyl radicals with 1 -6 carbon atoms, with R and Ra together with the nitrogen atom between them, can also form a saturated 5-7-membered monocyclic heterocyclic ring, which can also be interrupted by an oxygen atom or a nitrogen atom and / or substituted by an alkyl radical or a hydroxyl group sing, RS is a hydrogen atom or a straight or branched alkyl group with 1-6 carbon atoms, R4 is a hydrogen atom or a methyl group in the 6th or 7th position, A is a straight or branched alkylene chain containing 2-10 carbon atoms, or their salts, characterized in that the compound of the general formula II where RI, R2, H3, R4 and A have the values ordered. 910

Z is a halogen atom, a product by known methods in a free form. It is reacted with amm a - or in the form of its salt, lump, or amide or imide of carboxylic acid, or with their metal salts, followed by 2. Method according to l. 1, characterized in that by hydrolysis of the intermediate derivative of car-5, the reaction is carried out in a solvent and with tembonic acid and separation of the desired temperature between 20 and 200 ° C.

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