SU509227A3 - The method of producing pyrimido derivatives (5,4-) pyrimidine - Google Patents

Description

(54) METHOD FOR PRODUCING PYRMIDO (5,4-d) -PYRIMIDINE DERIVATIVES

or R4, is reacted with an amine of general formula III

H-A, where A have the above for

R R.

one

ix

g

NT

OR R value, at a temperature of 100-250 ° C, followed by isolation of the target product in free form or as a salt by a known technique.

The reaction is carried out depending on the reactivity of the radical to be replaced at temperatures between 100-250, preferably 150-200 ° C, if necessary in the presence of an acid binding agent and in a solvent such as glycol dimethyl ether or dimethyl sulfoxide, preferably in excess of the amine used . The interaction can be carried out without solvent. In addition, it is possible to conduct interaction in the presence of a reaction accelerator, for example, in the presence of a copper salt or a salt of the starting amine. Suitable acid binding agents are inorganic bases such as sodium carbonate or potassium carbonate and tertiary organic bases such as triethylamine or pyridine; the latter can also be used as a solvent. Halogen atoms, such as chlorine atoms, and sulfonyl groups, such as the chlorosulfonyl, methylsulfonyl, ethylsulfonyl or phenylsulfonyl groups, and Za-substituted mercapto groups, such as methylthio, phenylthio or benzylthiogroup, are suitable for the Zi radicals that can be substituted for Zi. For this, for example, hydrochloric, hydrobromic, sulfuric or phosphoric acids have proven suitable as acids. The starting materials of the general formula 11 used can be obtained from the corresponding halopyrimido - (5,4 - d) - pyrimidines by reaction with the corresponding amines and thus obtained thiopyrimido. (5,4 - d) - pyrimidines by oxidation, for example chlorine or hydrogen peroxide is converted to the corresponding sulfonyl compounds.

EXAMPLE 1: 2.6 - bis - (2 - hydroxyethyl - 2-methoxyethylamino) - 4.8 - dipiperidinopyrimido - (5.4 - d) - pyrimidine.

11.0 g (0.03 mol) of 2.6 - dichloro - 4.8 - dipiperidinopyrimido - (5.4 - d) - pyrimidine and 50 g of 2-oxyethyl - 2 - labels with ethylamine for 3 hours is heated to 200 ° C, the reaction mixture is poured into water, and 2,6 - bis - (2 -oxyethyl - 2 - methoxyethylamino) - 4,8-dipyperidinopyrimido- (d) - pyrimidine precipitates as a gummy precipitate. After decanting the aqueous phase, the material is re-precipitated from 0.2 N hydrochloric acid 2} 1. ammonia solution. After re-decanting, flushing with water and drying out

product is 13.6 g (85% of theory); yellow resin, R / - 0.5 TLC, silica gel, ethyl acetate.

.C26H44N804 (mol.v. 532.6). Bychieleno,%: C 58,, 33; N 21.04. , Found,%: C 58.60; H8.29; N21.41. The same compound is obtained in a similar way from 2-chloro-6-chlorosulfonyl-4.8-dipiperidinopyrimido- (5.4-d) -pyrimidine for 4-5 hours by heating with 2-hydroxyethyl-2-methoxyethylamine at 200 ° C. PRI mme R 2. 2.6 - bis - (2 - oxystil - 2-methoxyethylamino) - 4.8 - dipiperidinopyrimido - (5.4 - d) - pyrimidine.

2.3 g (0.005 mol) of 2.6 - bis - (2 - hydroxyethyl -2 methoxyethylamino) - 4.8 - bis (methylthio) nirimido. G .-; .-. (5.4., -, .d), .., - .. pyrimidine (mp. 126-128 ° C) and 50 ml of piperidine are heated to 200 ° C in the presence of piperidishydrochloride in a sealed tube for 4 hours . The reaction mixture is evaporated in vacuo, 100 ml of water are added to the residue, 2.6 - bis - (2 hydroxyethyl 2 - methoxyethylamino) - 4.8 - dipiperidinopyrimido - (5.4 d) - pyrimidine is isolated as a gummy mass and cleaned re-precipitation from a solution of 0.2 n. hydrochloric acid 2 n. ammonia solution. The yield of 1.8 tons (68%).

A similar substance is obtained in a similar way from 4,8 - bis - (benzylthio) - 2,6 - bis - (2-goxyethyl - 2 - methoxy thythylamino) pyrimido - (5,4-if) - pyrimidine (mp. 131- 133 ° C) or from 2,6-bis- (2-hydroxyethyl-2-methoxyethylamino) -4, 8, -bis- (fellthio) pyrimido- (5.4-d) -pyrimidine (m.p. 160-163 ° C) for 2-3 hours by heating

with piperidine to 200 ° C.

Example 3. 2.6 - bis - (2 - hydroxyethyl - 2-methoxyethylamino) - 4.8 diniperidinopyrimido - (5.4 - d) - pyrimidine.

1.0 g (0.002 mol) 2,6 - bis - (chlorosulfonyl) -4, 8 - dipiperidinopyrimido - (5,4 - d) -pyrimidine (mp. 207-209 ° С, decomposition) or

0.9 g (0.002 mol) 2,6 - bis - (metstsulfugshl) -4, 8 - dipiperidinopyrimido - (5,4 d) - pyrimidine (mp. 218-220 ° C) is heated with 5 g of 2 - hydroxyethyl -2 - methoxyethylamine for 5 hours to 200 ° C. The reaction mixture was poured into water, 2,6-bis- (2 -oxyethyl-2-methoxyethylamino) was separated, 8 - dipiperidinopyrimido - (5,4 - d) - pyrimidine in the form of a gummy sediment. After decanting the water, washing and drying, the yield is

0.6-0.7 g (56-66%). The purification is carried out on a column with silica gel (solvent benzene-acetone-α-ethanol 15: 3: 2), yellow resin.

A similar compound is obtained in a similar manner from 2,6 - bis - (ethylsulfonyl) - 4,8-dipiperidinopyrimido - (5,4 - d) - pyrimidine (mp, 159-160 ° C) or from 2,6 bis - ( phenylsulfonyl) - 4.8 - dipiperkdanopyrimido - (5.4 - d) pyrimidine (mp. 257-259 ° C) for 10-15 hours by heating with 2 - hydroxyethyl - 2 - methoxyethylamine to

200 s.

60

PRI me R 4. 4.8 - yis - (diethylamino) - 2.6 bis - (2 - hydroxyethyl - 2 - methoxyethylamino) pyrimido - (5.4 - d) - pyrimidine

17.2 g (0.05 mol), 2.6 - dichloro 4.8 - bis - (diethylamino) - pyrimido - (5.4 - d - pyrimidine (mp. 134-136 ° C) with 90 g 2 - Hydroxyethyl -2 methoxyethylamine is heated to 200 ° C for 4 hours. The reaction mixture is stirred at 400 mL of water, the substance is precipitated as a gummy precipitate, the reaction mixture is cooled, the precipitate is filtered, washed with water and dried. , 4 g (96%).

The substance is re-precipitated from 0.2 n. hydrochloric acid 2 n. ammonia solution (approximately to pH 5) and recrystallized from cyclohexane acetic ether (5: 1), to obtain 4.8 - bis - (diethylamino) -2.6 bis) (2 hydroxyethyl 2 - methoxy ethyl amine) pyrimido (5,4-d) is pyrimidine; mp.84-86 ° C. Yield 20.6 g (81%).

C24H44N8O4 (508.7).

, Calculated,%: C 56.67; H 8.72; N22.03.

Found,%: C 56.90; H 8.73; N 22.00. The substance is obtained in a similar way from 2 - chloro- "

- 4.8 - diethylamino - 6 - (2 - hydroxyethyl - 2 methoxyethylamino) - pyrimido (5.4 - d) - pyrimidine and 2 - hydroxyethyl - 2 - methoxyethylamine.

Example 5. 4.8 - bis - (diethylamino) - 2.6 bis - X2 - .oxyethyl - 2 - methoxyethylamino) pyrimido - (5.4 - d) - pyrimidine.

17.2 g (0.05 mol) 2.5 - dichloro - 4.8 - bis (diethylamino) - pyrimido - (5.4 - d) - pyrimidine and 90 g of 2 - hydroxyethyl - 2 - methoxyethylamine are heated in Te4ejme 56 hour to a temperature of 150 ° C or 32 hours to 170 ° C. Separation of the starting mixture and purification of the crude product is carried out analogously to example 4. After recrystallization From the mixture cyclohexanone-ethyl acetate (5: 1) yield 43 g (78%); m.p. 84-86 ° C.

EXAMPLE 6 4.8 - bis - (diethylamino) - 2.6 bis - (2 - hydroxyethyl - 2 - methoxyethylamino) pyrimido - (5.4 - d) - pyrimidine.

3.1 g (0.005 mol) 4.8 - bis - (benzylthio) - 2.6 bis - (2 - hydroxyethyl - 2 - methoxyethylamino) pyrimido - (5.4 - d) - pyrimidine (mp. 131- 133 ° C) and 60 ml of dethylamine are heated in the presence of diethylaminohydrochloride or a small amount of copper sulphate in a sealed tube to 200 ° C for 3 hours. The reaction mixture is evaporated, the residue is poured into 80 ml of water, while crude 4.8 - bis - (diethylamino) 2, 6 - bis - (2 - hydroxyethyl 2 - methoxyethylamino, but) pyrimido (5.4 - d) - pyrimidine in the form of a resinous mass. After replanting from. 0.2 n. hydrochloric acid 2 n. ammonia solution. Yield 1.3 g (51%).

After purification on a column with silica gel (benzene-acetone-ethanol system 15: 3: 2); m.p. 84 - 86 ° C.

PRI me R 7. 4.8 - bis - (diethylamino) - 2.6 bis (3 - hydroxypropyl - 2 - methoxyethylamino) pyrimido - (5,4-d) - pyrimidine.

Prepared from 2.6 - dichloro - 4.8 - bis - (diethylamino) - pyrimido - (5.4 - d) - pyrimidine and 3 yuxipropyl - 2 - methoxyethylamine as in Example 4. Yield 76%; m.p. 89-91 ° C.

PRI me R 8. 4.8 - bis - (diethylamino) - 2.6 bis - (2 - hydroxypropyl - 2 - methoxyethylamino) pyrimido - (5.4 - d) - pyrimidine.

Prepared from 2.6 - dichloro - 4.8 - (diethylamino) -pyrimido - (5.4 - d) - pyrimidine and 2 hydroxypropyl - 2 - methoxyethylamine

example 4. Output 78%; m.p. 85-87 ° C.:.

PRI me R 9. 4.8 - bis - (diethylamino) - 2.6 bis - (2 - hydroxy - 2.2 - dimethylethyl 2 methoxyethylamino) - pyrimido - (5.4 - d) - pyrimidine.

Prepared from 2,6 - dichloro - 4,8 - bis - (dketilamino) - pyrimido - (5,4 - d) - pyrimidine and 2 hydroxy - 2,2 - dimethylethyl - 2 - methoxyethylamine as in example 4 (reaction time 8 hours ). After purification on a column of silica gel (system acetone - benzene - 1: 5) and recrystallization from a mixture of cyclohexane - ethyl acetate (6: 1) yield 53%; m.p. 101 - 102 ° C.i

PRI me R 10. 4.8 - bis - (dipropylamino) - 2,6-bis - (2 - hydroxyethyl - 2 - methoxyethylaminopyrimido - (5,4-d) - pyrimidine.

Prepared from 2.6 - dichloro - 4.8 - bis - (dipro. Pilamino) - pyrimido - (5.4 - d) - pyrimidine (mp. 163-164 ° C) and 2 - hydroxyethyl - 2 - methoxyethylamine analogous to example 4. Yield 71%; mp 70-73 ° C,

Example. 4.8 - bis - (diisopropylamino) 2, 6 - bis - (2 - hydroxyethyl - 2 - methoxyethylamino) - pyrimido - (5.4 - d) - pyrimidine.

Prepared from 2.6 - dichloro - 4.8 - bis - (di: opropylamino) - pyrimido - (5.4 - d) - pyrimidine

(mp. 226-228 ° C) and 2 - hydroxyethyl - 2 - methoxyethylamine as in Example 4. Yield 82%;

tpl 165-167 ° C.

EXAMPLE 12 4.8 - bis - (ethylbutylamino) 2, 6 - bis - (2 - hydroxyethyl - 2 - methoxyethylamino) - HMpHNomo - (5.4 - d) - pyrimidine. Prepared from 4.8 - bis - (ethyl butylamino) - 2.6 dichloropyrimido - (5.4 - d) - pyrimidine (mp. 96-98 ° C) and 2 - hydroxy: ethyl - 2 - methoxyethylamine as in Example 4 .79% yield; m.p. 79-80 ° C .:

PRI me R 13. 4.8 - bis - (diallylamino) - 2.6 bis - (2 - hydroxyethyl - 2 - methoxyethylamino). Pyrimido - (5.4 - d) - pyrimidine.

Prepared from 2.6 - dichloro - 4.8 - bis - (diallylamino) - pyrimido - (5.4 - d) - pyrimidine (mp. LOO-IOl C and 2 - oisethyl - 2 - methoxyethylamine as in Example 4. After purification on a column of silica gel (acetic ether - petroleum ether 10: 1). Yield 56%; mp. 58-60 ° C. Example 14. 4.8 - bis - (di:) tilamino) - 2.6 Pease - (2, 3 - dioxypropyl - 2 - methoxyethylamino) - pyrimido (5.4 - d) - pyrimidine.

6.9 g (0.02 mol), 2.6 - dachloro - 4.8 - bis (iethylamino) - pyrimido - (5.4 - d) - pyrimidine, and 40 g of 2,3 - dioxypropyl - 2 - methoxyethylamine are heated in for 4 hours to 200 ° C. The reaction mixture is poured into 300 ml of water, the reaction product is isolated in the form of a resin. Replant from 0.1 n, sssic acid, 2 n. ammonia solution, washed with water and dried. After recrystallization of a mixture of benzene - petroleum ether (1: 1), 4.8 - bis - (diethylamino) - 2.6 - bis - (2, .3 dioxypropyl - 2 - methoxyethylamino) - pyrimido (5.4- d ) - pyrimidine; m.p. 101-103 ° C. The yield of 8.6 g (76%).

Ci6H48N8N06 (568.8). Calculated,%: C 54.91; H 8.51; N 19.70. Found,%: C 55.20; H 8.44; N 19.80. A similar substance is obtained in a similar way from 2,6 - bis (ethylsulfonyl) - 4,8 - bis (diethylamino) pyrimido - (5,4-d) - pyrimidine (1.PL, 126-128C) and 2,3-dioxypropyl 2 -methoxyethylamine with 16 hours of heating to 200 ° C, followed by purification on a column of silica gel.

PRI me R 15. 4.8 - bis - (diethylamino) - 2.6 bis - (2, 3 - dioxypropyl - 3 - methoxypropylamino) - pyrimido - (5.4 - d) - pyrimidine.

Prepared from 2.6 dichloro-4.8-bis (diethylamino) -pyrimido (5.4 d) pyrimidine and 2.3 dioxypropyl-3-methoxypropylamine in analogy to Example 14. Yield 67%; resin R / 0.7 - Oi, 8 (film for thin chromatography on silica gel F Macherey Nagel, acetone system).

Example 16. 4.8 - bis - (hexamethyleneimino) - 2.6 - bis - (2 - oxioxy - 2 - methoxyethylamino) - pyrimido - (5.4 - d) - pyrimidine.

Prepared from 2.6 - dichloro - 4.8 - bis - (hexamethylylmino) pyrimido - (5.4 - d) - pyrimidine (mp. 170-172 ° C) and 2 - hydroxyethyl - 2 - methoxyethylamine as in Example 1 After recrystallization from a mixture of benzene - petroleum ether (1: 1), yield 79%; t.pp. 99th south. ,

EXAMPLE 17 2 diethanolamino - 4.8 - bis - (diethylamino) 6 - (2 - hydroxyethyl - 2-methoxyethylamino) - pyrimido - (5.4 - d) - pyrimidine.

4.3 g (0.01 mol) of 2 - chloro and 4.8 - bis .- (diethylamino) - 6 - (2 - hydroxyethyl - 2 methoxyethylamino) - pyrimido - (5.4 - d) - pyrimido. the resin obtained from 2,6 - dichloro - 4,8 -bis - (diethylamino) - pyrimido - (5,4 - d -) -pyrimidine and 2 hydroxyethyl - 2 - methoxyethylamine 11grev1shm to 120 ° C and 15 g of diethanolamine for The mixture is poured into water for 2 hours, the reaction product is isolated as a viscous oil, and precipitated from 0.2N hydrochloric acid with 2N ammonia solution and recrystallized from ethyl acetate

petroleum ether (1: 3). Yield 3.4 g (73%); Т.1Ш. 112-114 ° C.,

C, 3H4jN804 (494.7). Calculated,%: C 55.85; .H8.56; N22.66. Found,%: C 56.00; H 8.82; N 22.70.

A similar compound is obtained in the same way as ns 2 - chloro - 6 diethanolamino - 4.8 - bis - diethylamino) - pyrimido (5.4 - d) - pyrimidine and 2. hydroxyethyl -2 - methoxyethylamine approximately by heating for 2-3 hours to 200 ° s

EXAMPLE 18 4.8 - bis - (diethylamino) - 2 (2, 3 - daoxypropyl - 2 - methoxyethylamino) - 6 - (2 hydroxyethyl - 2 - methoxyethylamino) pyrimido (5.4 d). pyrimidine. Prepared from chloro-4,8 - bis - (diethylamino) - 6 - (2 okshetil -2. - methoxyethylamino) pyrimido (5,4 d) - pyrimidine and 2,3 dioxypropyl 2 methoxyethylamine similarly to example 17. After purification with silica gel column (1: 1 acetone-benzene system) Yield 58%; m.p1.67.70 ° C .:

Example 19. 4.8 - bis - (diethylamino) - 2.6 bis (2 - hydroxyethyl 3 methoxypropylamino) - pyrimido (5.4 d) pyrimidane. It is obtained from 2.6 - dichloro 4.8 bis (diethylamino) - pyrimido - (5.4 - d) pyrimidine and 2 hydroxyethyl - 3 methoxypropylamine similarly to example 4. After recrystallization from a mixture of benzene - petroleum ether (1: 2). Yield 79%; T.SH1 .. ,,

PRI me R 20. 2,6 bis - (3 ethoxypropyl "S - hydroxyethylamino) 4,8 - bis (diethylamino) .. pyrimido - (5,4 - d) - pyrimidine.

Prepared from 2.6 - dichloro 4.8 - bis (diethylamino) - pyrimido - (5.4 d) - pyrimidine and 3-ethoxypropyl - 2 - hydroxyethylamine as in Example 4 (reaction time 6 hours). After recrystallization from a mixture cyclogxane - ethyl acetate (3: 1), yield 71%; t.m1.77-79 ° C.:, Example21. 4,8 - bis - (diethylamino) 2,6 bis - (2 - hydroxyethyl - 3 - isopropoxypropylamino) - pyrimido - (5,4 - d) - pyrimidine.

Prepared from 2.6 - dichloro - 4.8 - bis - (diethylamino) - pyrimido - (5.4 - d) - pyrimidine and 2 -oxyethyl - 3 ° - isopropoxypropylamine as in Example 20. After purification on a column of silica gel (system benzene-acetone 3: 1); yield 49%; resin; R / 0.6 (thin film on silica gel F, Macherey Nagel, systems. A benzene-acetone 3: 1).

PRI me R 22. 2,6 - bis - (2, 3 dioxypropyl - 2 - methoxyethylamino) - 4.8 bis - (dipropylamino) - pyrimido - (5.4 - d) pyrimidine.

Prepared from 2.6 - dichloro - 4.8 - bis - (dipropylamino) - pyrimido (5.4 - d) - pyrimidine and 2,3 - dioxypropyl - 2 - methoxyethylamino as in Example 14. 75% yield, mp. 88-9) ° C (from a mixture of ethyl acetate - petroleum ether 1: 4)

Claims (3)

Claim I. Investigation of pyrimido derivatives (5.4 d) - pyrimidine of general formula 1, in; in where RI means an alkoxy radical containing 1 to 3 carbon atoms, an alkyl radical having 2 or 3 carbon atoms; R2 is a hydroxyalkyl radical with 2-4 carbon atoms or a dioxyalkyl radical with 3 carbon atoms ;; РЗ - alkyl group substituted with alkoxy radical with 1-3 carbon atoms or hydroxy group with 2 or 3 carbon atoms; R4 - dialkylamino radical, where each alkyl radical has 2-4 carbon atoms, diallylamino group, piperidine or hexamethylenimine ring or salts thereof characterized in that the compound of the general formula 11 g where one or da of the radicals Zi or Z means interchangeable radacals; Zj chlorine, chlorosulfonyl, methylsulfonyl, ethylsulfonic or a phenylsulfonyl group Zj is methylthio, phenylthio, or benzylthio, and Zi and Zj cannot simultaneously mean a radical to be replaced, others from the radicals Zi and Zj mean i-nt - NV V or R, where RI, Rj, RS, R4 are as defined above, they are reacted with an amine of the general formula 111 nl ,. where A has the above for - - or R, value, at a temperature of 100-250 ° C, followed by isolation of the target product in free form or as a salt with a known technique. 2. A method according to claim 1, characterized in that the process is carried out at a temperature of 150-200 ° C. 3. Method pop. 1 and 2, characterized in that the process is carried out in a solution medium. NOTE: Temperature interval 100-250 ° specified in clause 1 on the basis of the application list of this application.