SU1072807A3 - Process for preparing derivatives of pyrido-(1,2-a)-pyrimidine,or their acid additions salts,or their optical isomers - Google Patents

Abstract

Compounds of the general formula <IMAGE> [wherein R and R<1> are H or C1-4alkyl, or together form (CH=CH)-2, R<2> is H or C1-4alkyl R<3> is H, C1-4alkyl, phenyl, carboxy or salt thereof, alkoxycarbonyl, carbamoyl, cyano, -CO-NH-CO-SO2-C6H4-p-CH3 or -(CH2)s-COOR<14> (s is 1, 2 or 3 and R<14> is H or C1-4alkyl, n is 0 or 1, (a) if R<13> is H, and R<12->R<11> and R<9->R<10> form bonds then YR<7>R<8> represents oxygen or sulfur, or Y represents nitrogen, R<7> is C1-4alkyl, optionally substituted C6-10aryl or C7-12aralkyl, R<8> is a lone pair of electrons or C1-4 alkyl and in this latter case a salt is formed; and XR<4>R<5>R<6> represents halogen; or XR<5>R<6> represents oxygen or sulfur, and R<4> is H or C1-4alkyl, XR<6> represents nitrogen and R<4> is chloroacetyl, C1-4alkyl or optionally substituted C6-10aryl or heteroaryl and R<5> is H or alkyl or (b) if R<11> is H and R<9->R<10> and R<12->R<13> form bonds, then R<4>, R<5>, R<6>, R<7>, R<8>, X and Y are as defined in item (a) and (c) if R<10->R<11> and R<12->R<13> form bonds, then YR<7>R<8>R<9> represents an oxygen or sulfur anion or YR<8>R<9> represents oxygen or sulphur and R<7> is H or C1-4alkyl; or YR<9> represents nitrogen, R<7> is H, C1-4alkyl or optionally substituted C6-10aryl, and R<8> is C1-4alkyl, and XR<4>R<5>R<6> represents halogen or an oxygen or sulfur anion or XR<5>R<6> is O or S and R<4> is H or C1-4alkyl, or XR<6> represents nitrogen, R<4> is chloroacetyl, C1-4alkyl or optionally substituted C6-10aryl or heteroaryl and R<5> is H or C1-4alkyl, and if YR<8>R<9> and XR<5>R<6> each represent oxygen or or sulfur or if YR<9> and XR<6> each represent nitrogen (R<5> and R<8> each being H or C1-4alkyl), then R<4> and R<7> together form optionally substituted -(CH2)-s (s is 1, 2, 3 or 4)] and the tautomers and salts thereof. The compounds have physiological activity.

Description

This invention relates to a process for the preparation of new pyrido-l, 2-aJ-pyrimidine derivatives, which are used as initial products in the synthesis of medicinal substances. with phosgene in an organic solvent ij. The purpose of the invention is a method of producing new pyrido - {1 2-al-pyrimidine derivatives, the use of which as starting materials leads to the synthesis of pharmacologically active compounds. The goal is achieved by the fact that according to the method of producing pyrido-1,2-a derivatives, i-OD-R2 is pyrimide where R is hydrogen or} is alkyl; But is hydrogen or (C-C-a: dkoxy). „OOPl, CXIIli.Rr OR carbonyl; P - COOR4 -c (-WR4R5 6 7 4 C1-C4-alkyl; X - halogen; Rj hydrogen. C, -C alkyl, unsubstituted phenyl or substituted by halogen, C4-C,} - alkoxyC; -Sl-alkyl , C (-C5-alkoxycarbon, naphthyl; Rg, -C-C-alkyl or phenyl; R-C, -C-alkyl, or their acid addition salts, or their optical isomers, pyrnsch- l, 2-a pyrimidine of the general formula; i4 iO-Ri, where R and Rj have the indicated meanings, are reacted with a dihalogenimethiphenammonium halide of the general formula: where R (, RC and X have the indicated values, followed by isolation of the target product as a base and an acid additive salt, or optical isomer, or by reaction with aqueous ethanol, or by aminolysis and isolation of the target product as a base or acid addition salt. The method is carried out as follows. Pyrimidine, 2-a solution of pyrimidine in an inert solvent is added to a solution of dihalogenmethylammonium halide in an inert solvent and heated to complete the reaction.The hydrocarbons (benzene, toluene, xylene) and chlorinated hydrocarbons (chloroform, petylene chloride, chlorobenzene) are used as the inert solvent. The reaction is carried out at 110-120 ° C. The resulting compound of the formula I can be isolated without, for example by aminolysis, transferred to another center of the formula I. Compounds of the formula I can be used in the synthesis of pharmacologically active compounds. The interaction with aryl diazoni salts allows the preparation of 9-hydrazonopyrido 1, 2-p-pyrimidines, which in particular have antiallergic properties. Example 1. To a mixture of 16.3 g of phosgene-N, N-dimethyl 1-monochloride and 50 ml of dichloromethane, a solution of 23.5 g of 3-ethoxycarbonyl-6-methyl-4ox-6, 7.8.9 is added dropwise with stirring. -tetrahydro-4H-pyrido l, 2-a-pyrimidine in 30 ml of dichloromethane and stirred for 3 hours. The solvent is distilled off and the residue is crystallized. From ether, 35.2 g of highly hygroscopic 3-e. toxycarbonyl-b hydrochloride -methyl-9 (chlorine-N, N-dimethylamino) methyl: -4-, 7.8, 9-tetrahydro-4H-pyrido 1, 2, -a-pyrimidine is eluted in vacuo. The content of ionic chlorine. Calculated,%: 19.6. Found 2: 19.4 Example 2. 3-cyano-6-methyl-4-oxo-6,7,8,9 tetrahydro-4H-pyrido-1, 2-a-pyrimidine is reacted with phosgene-N, N -dimethylammonium onium chloride of Example 1. A highly hygroscopic hydrochloride of 3-cyano-6-methyl-9- (chlorine-H, N-dimethyl; mino) methylene-4-oxo-6,7,8,9 tetrahydro- 4H-pyrido-l, 2-aJ-pyrimidine. The content of ionic chlorine. Calculated,%: 10.70. , bN40Cl2 Found,%: 10.52. Example 3. 1.8 g of 3-ethoxycarbonyl-6-methyl-9 hydrochloride (chlorine-N, N-dimethylamino) methyl p-4oxo-6, 7,8,9-tetrahydro-4H-pyrio-LI, 2-aj- the pyrimidine prepared according to example 1 is suspended in 20 ml of ether. 0.55 g of triethylamine is added dropwise to the suspension with vigorous stirring. Triethylamine hydrochloride precipitated is filtered off. 1.33 g (82%) of 9-ethoxycarbonyl-6-methyl-9 (chlorine-N, N-dimethylamino) methyl | P-4oxo-6, 7,8,9-tetrahydro-4H-pyrylo-; 1, pyrimidine. M.p. 74-77 0.

Calculated,%: from 55.30; H 6.19; N 12.90.

 .

Found,%: C 55.25; H 6.10; N 12.98 ..

Example 4. 2.16 g of Z-cyano-6-methyl- {9-chloro-M I-dimethylamino) methylene-4-oxo6, 7,8,9-tetrahydro-4H-lirido-1 2-a-pyrimidine hydrochloride are suspended in 20 ml of dioxane. 1.01 g of triethylamine is added dropwise to the suspension. The triethylamine hydrochloride is filtered off. The crystals formed are also filtered. 1.41 g (79%) of 3-cyano-b-methyl UtnopN, N-dimethylamino-methylene} -4-oxo6, 7,8,9-tetrahydro-4H-pyrido-G1 2-aJ-pyrimidine are obtained. T. pl. 128-130C.

Calculated,% t e 56,02; H 5.42; N 20.10.

C ,, n, BYA40sg.

Found,%: C 55.85; H 5.51; N 20.14.

Example 5. 1.4 g of hydroglyrid 3-ethoxycarbonyl-6-methyl-9 (chloro-N-methyl-N-phenylamino) methylene 4-OXO-6, 7,8,9-tetrahydro-4H-pyrido-LI, 2- and the pyrimidine is suspended in 20 ml of ether. 0.55 g of triethylamine is added dropwise to the reaction mixture. The triethylamine hydrochloride is filtered off. The crystalline filtrates formed during cooling are filtered off. Obtain 0.89 g (42%) of 3-ethoxycarbonyl-6-methyl-9- (chlorine-H-netil-M-phenylgiino) methylene-4-OXO-6, 7,8,9-tetrahydro-4P-pyrido-Cl 2 and pyrimidine. M.p. 56-62 S.

Calculated,%: C, 61.9; H 5.71; N 10.83.

CrPyyy s-b - Found, i: C 62.02; H 5.80; N 10.75.

Example 6. Proceed as in the example. 1, but the optically active t-3-ethoxycarbonyl-6-methyl-4OKCO-G, 7,8,9-tetrahydro-4H-pyrido 1, 2-a-pyrimidine 1 (–111, methanol and get G- -3-ethoxycarbonyl-9-k, I dimethyl-n-methyldiamino (methylene) -6-methyl-4-oxo-6,7,8,9 tetrahydro-4H-pyrido-l, 2-aJ- pyrimidine, 72% yield, mp 240-242 ° C. after recrystallization from ethanol and sr-22 ° C, with 1 chloroform.

Calculated,%; C, 59.98; H 7.55; N 17.48.

Found,%: C 60,12; H 7.61; N 17.51.

Example 7. Proceed as -In example 1, but in the quality of the original product using + J-3-ethoxycarbonyl-6-methyl-4-oxo-6, 7,8,9 tetrahydro-4H-pyrido-1, 2-az-pyrimidine . (ei) about +110, with 1 methanol and get C- -T-3-ethoxycarbonyl-9-СН, H-dimethyl-H-methyl diamine (methylene) 6-methyl-4-oxo-6, 7,8,9 -tetrahydro4H-PIRIDO-1,2-aj-pyrimidine. Output D 75%, so pl. 240-241 C after the feather () f

crystallization from ethanol.

0

+327

1 chloroform.

C, 59.98; H 7.55;

Calculated N.48.

With bN24 "4 ° - &

C, 59.92; H 7.54; Found%

5 N

17.59.

Example 8. Proceed as in example 1, but in the quality of the original product using + -3-ethoxycarbonyl-6-methyl-4-oxo-6, 7,8,91L-o-methyl-h-oKt; o-o, / , o, dpo-4H-pyrido-tl, 2-az-pyri0 tetrahydroC (c6) +111, with 1 methanol midin

and get -1-3-ethoxycarbonyl-9N, m-dimethyl-n-ethyldiamino (methylene) 6-methyl-4-oxo-6 .7,8,9-tetrahydro4H-Pyrido-1, 2-a-pyrimidine. You move 80%, m. 233-240 ° С after recrystallization from ethanol and (o (,) jj

-362 °, with 1 chlorofor l.

Included,%: C 61.05; H 7.83; 16.75.

N

0

Found,%: C 60.97; And N 16.82.

Example 9. Proceed as in Example 1, but the optically active C + 3 ethoxycarbonyl-6-methyl-4oxo-6, 7,8,9-tetrahydro-4, 1-pyrido l, 2-aj-pyrimidine is used as the starting product. (oC), with 1 methanol, and get +} -3-ethoxycarbonyl-9-nH-d-4-methyl-m-ethyl0 diamino (methylene 3-6-methyl-4-oxo6, 7, .8,9-tetragudro-4H- pyrido l, 2-a-pyrimidine. Yield 82%, mp 238-240 o after recrystallized (L) "°

- -362, ethanol and ethium

5 chloroform I

Calculated,%: C 61.05; H 7.83; N 16.75.

C.

Nahtseno,%: C 61.27; H 7.80; N 16.77.

Example 10. Proceed as in example 1, but in the quality of the original product using optically active C-Z-ethoxycarbonyl-6-methyl 4-OXO-6, 7,8,9-tetrahydro-4H-pyrido up to 1, 2-a-pyrimidium t («t) with 1 petanol and get hydrochloride C + 3-3-ethoxycarbonyl-6-methyl 9-n-phenyl-n, m-DI1-methyl-formamidine 4-oxo-7, 8,9-tetrahydro-4H-pyridotl -, 2-a-pyrimidine. Yield 77%, so pl. 222-223 0 after necrisis allysis from ethanol and (ot) jj +191, with 1 chloroform. C, 60.21; H 6.49; Calculated N 13.37. Cj C 60.15; H 6.43; On the day,%: C N13,42. P i m i r 11. Proceed as in example 1, but as the original product using optically active fb -3-ethoxycarbonyl-6-methyl-4-ox-b, /, 8,9-tetrahydro-4Npyrido- 1, 2-a-pyripidine C (ot) j + 110®, methanol and get hydrochloride 1 C-Z-ethoxycarbonyl-6 methyl-9-1G-phenyl-and m-dimethylformamid) -4-o1sso-1,6 , 7,8-tetragi ro-4H-pyrido-{1, 2-a-pyrimidine. Yield 71%, mp. 221-223 ° C after recrystallization from ethanol and (o1) j -191 °, with 1 chloroform. Calculated,%: C 60.21; H 6.49; N 13.37. C2i: i27 4 3 l Found,%: C 60.54; H 6.45; N 13.42. Example 12. Proceed as in example 1, but the optically active -J-3-ethoxycarbonyl-6methyl-4-oxo-b, /, 8,9-tetragyro-4H pyridoyl, 2-a - is used as the starting product. pyrimidine (o) if -111 °, from 1 g of ethanol, C + H -3-ethoxycarbo 1yl-6 g1ethyl-9- and M-diietilaminocarbonyl 4-OXO-6,7,8,9-tetrahydro-hydrochloride are obtained. 4H-pyridine l, 2-a-pyrimidine. Yield 72%, mp. 1b6-168 ° C (With rasslohseniem) after recrystallization from ethanol and () - + 56 °, with 1 chloroform. Calculated,%: C, 52.40; H 6.45; N12.22. s, 5Hg7 CCPG Naado,%: C 52.28; N 6.51; N 12.30. Example 13. Proceed as in example 1, but the quality of the original product using optically active C + -3-ethoxycarbonyl-6methyl-4-oxo-6, 7,8,9-tetrahydro-4Npyrido-1, 2-d-pyrimidine { ct) j5 +110, c 1 1.; ethanol gives C-3-ethoxycarbonyl-6-methyl-9-ji hydrochloride, H-dipethyl 1 -lnonocarbonyl 4-OXO-6, 7,8,9-tetrahydro-4H-pyrido 1, 2-pyrimidine. Yield 70%, so pl. 166 - 168 ° C (with decomposition) after recrystallization from ethanol and (o) jf - 55.5 chloroform, Calculated,%: C 52.40; H 6.45; H 1 2, 2 2. . Found,%: C 52.44; H 6.28; N 12.21. Example 14. It is carried out as in Example 1, but dimethylamine hydrochloride is used as the amine, the reaction is carried out in diethyl ether and an oily product is obtained, which is converted into 3 ethoxycarbonyl-6-methyl-9-: 1, N, N, N perchlorate tetramethylformamidine) -4-oi: co-l, 6, 7,8-tetrahydro-4H-pyrido-l, 2-a pyrimidine. Yield 55%, mp. 225228 C after recrystallization from ethanol. Calculated,%: C 46,95; H 6.26; and 12.88. Found,%: C 47., 00; H 6.31; D) 12.71.

Claims (2)

The method of obtaining derivatives of pyrido [1,2-AZ-pyrimidine total form · X is halogen; K ₅ is hydrogen, C ₄ -C ₄ alkyl, unsubstituted phenyl or substituted by halogen, C ₄ -C ₄ -alkoxy, -C ₄ ~ alkyl, C ₂ -C ^ -alkoxycarbonyl, naphthyl; - C ₄ -C ₄ -alkyl or phenyl, K? - C ₄ -C ₄ -alkyl, or their acid additive salts, or their optical isomers, distinguished by the fact that pyrido [1,2-a] pyrimidine of the general formula. - t ,, .. where and K ₂ have the indicated meanings,, are reacted with dihalomethylene ammonium halide of the general formula l / @ / ⁿ 4 C = Ν. .Θ III ABOUT where is hydrogen, or C, -Cz-alkyl; Р η is hydrogen OR (С ₄ -С ₄ -alkoxy) -caronyl; ГЦ - СООК ₄ , СХЯН ₊ К ₅ or ~ С (ННдП5) 11¾ К ·,; I4 ~ C (~ C4-alkyl, where K ₄ , H $ and X have the indicated values, followed by isolation of the target product as a base or acid addition salt, or optical isomer, or reaction with aqueous ethanol, or aminolysis and isolation of the target product as a base or acid addition salt or optical isomer. _t ί 072,807 one 1072807 2