SU791240A3 - Method of preparing pyridopyrimidine derivatives or their salts - Google Patents

Description

; 54) METHOD FOR PRODUCING PYRIDOPYRIMIDIN DERIVATIVES The invention relates to a process for the preparation of pyrimidine derivatives of the general formula: alkoxy, alkenyloxy, alkynyloxy (aralkoxy, alkylthio C-Cf, alkoxycarbonyl, cyano, acyloxy, trifluoromethyl, nitro; hydrogen, halogen, alkyl puncture line - group - (CH-CH) -substituted or substituted by R and R groups where R is the same or different and significant water genus, halo, alkyl, alkoxy, aralkoxy, alkylthio

OR THEIR SALTS, apkylsulfinyl, apkylsulfonyl C ,, - Cg, alkoxycarbonyl or R together with two adjacent carbon atoms form an alkylenedioxy group containing 1-2 carbon atoms; or their salts. A known method for the preparation of pyridopyrimidine derivatives of general formula (T) or their salts by cyclization of 2-aminopyridine derivatives of general formula COOI where R, R is a dotted line, R and R have the above values, R is alkyl containing 2-4 carbon atoms, og t heating to 150-260 C 1 However, carrying out the process at high temperatures contributes to the decarboxylation of the resulting product. The purpose of the invention is to increase the selectivity of the process.

The goal is achieved by the cyclization of 2-aminopyridine derivatives of the general formula

have the values previously indicated, in the presence of an acid condensing agent, then the resulting reaction mixture is treated with water or an alcohol of the general formula

R-OH (v)

where R-is as defined above, followed by transesterification of the obtained desired product. or / and by free-flowing or as a salt.

The process is carried out at a temperature of 50-200 ° C.

Polyphosphoric acid, polyphosphoric acid ethyl ester and a mixture of polyphosphoric acid and phosphorus oxychloride are preferably used as the acid condensing agent.

When treating the reaction mixture obtained after cyclization with an appropriate alcohol, the esterification takes place and the ester salt of the compound of the general formula 1 is obtained. After cooling, the ester crystallizes and can be filtered off from the reaction mixture.

From the hydrochloric acid salt of the compound of general formula. (T) a base can be isolated and / or the salt can be converted to another salt.

Compounds of general formula (I) in which R is other than hydrogen can be converted into the corresponding compounds of general formula (T), in which R is hydrogen, by acidic or basic hydrolysis. On the other hand, compounds of the general formula (l), where R is hydrogen, can be converted into the corresponding compounds of the general formula (.1), where R is alkyl containing 1-10 carbon atoms, in some cases substituted by hydroxyl , aralkyl having 7-12 carbon atoms, or cycloalkyl having 3-7 carbon atoms, by esterification carried out with a mixture of the corresponding alcohol and gaseous hydrogen chloride or a mixture of alcohol and sulfuric acid.

Salts of compounds of the general formula (I) in which R is hydrogen can be prepared with organic bases, for example, amino alcohols such as ethanolamine, or with inorganic bases preferably containing alkali metal, for example sodium.

Take p1. 13.1 g of isopropylidene-- (6-methyl, 72-pyridyl) -aminomethylene-malonate are heated in a mixture of 30.6 g of phosphorus xylene chloride and 4.0 g of phosphoric acid in an oil bath, I have. the temperature is 135-140 ° C. The heating is continued until the release of hydrogen chloride stops, and then 80 ml of ethanol is added to the reaction mixture. The resulting solution is allowed to cool and leave it in the refrigerator overnight. The precipitates are filtered off and washed with ethanol. 12.3 g (91.6%) of the hydrochloric acid salt of ethyl 6-methyl-4-oxo-4H-pyrido (1,2-a) -pyrimidine 5-3-carboxylic acid are obtained. The base was separated from the hydrochloric acid salt obtained by treating it with a solution of 10 wt.% Sodium carbonate, followed by recrystallization from ethanol. 0 Get 6-methyl-4g-ok- ethyl ester. co, -4H-pyrido- (1,2-a) -pyrimidine-13-carboxylic acid, melting at 99 ° C.

Found,%: C 62.08; H 5.14; 5 M 12.11

". Calculated,%: C 62.10; H 5.17;

N 12.06.

Example 2. As in Example 1, starting from isopropylidene (6-methyl-2-pyridyl) -aminomethylene -malonate, but decomposing the reaction mixture with isopropanol, isopropyl d-ether 6-methyl-4-oxo-4H-pyrido-{1, 2-a) „-pyrimidine-3-carboxylic acid with an yield of 88%.

Found,%: C 63.24; H 5.69; N 11.44;

C | 1, Calculated,%: C 63.41; H 5.73;

0 N 11.38.

Example 3 As in Example 1, starting from isopropylidene- (6-methyl-2-pyridyl) -aminomethyl-HJ-malonate, 5 but using n-propanol to decompose the reaction mixture, 6-methyl-4-oxo n-propyl ester is obtained. -4H-pyrido- (1,2-a) -pyrimidine-3-carboxylic acid, melting at

99-100 ° C.

%: C 63.28; H 5.70; N 11.42.

Calculated,%: C 63.41; H 5.73; N 11.38.

Example4. As in example 1,

starting from isopropylidene- (6-methyl-2-pyridyl) -aminomethylene -malonate, but using n-butanol to decompose the reaction mixture, 6-methyl-4-oxo-4H-pyridino n-butyl ester is obtained (1, 2-a) -pyrimidine-3-carboxylic acid, melting at 92 ° C.

Found,%: C 64.76; H 6.16; N10.80; C, HibNa-0 ..

Calculated,%: C 64.56) H 6.19; N 10.79.

Example 5 As in Example 1, starting from isopropylidene- (2-pyridylaminomethylene) -malonate and using ethanol to decompose the reactive ssi, 4-oxo-4H-pyrido- (1,2-a ) -pyrimidine-3-carboxylic acid, melting at 111 ° C.

Found,%: C 50.38; H 4.58; N 12.93;

C ,, H, oNj 03

Calculated,%: C 50.55; H 5.62; N 12.84.

EXAMPLE 6 As in Example 1, but starting from isopropylidene- (3-methi-2-pyridyl) -aminomethylene-malovate using ethanol to decompose the reaction mixture, 9-methyl-4-oxo-4H ethyl ester is obtained. -pyrido (1,2-pyrimidine-3-carboxylic acid, melting at 149s.

Found,%: C 62.24; H 5.31; 12.11;

N

pM2.0z

G: s

62,1o; H 5.17;

Calculated N 12,06.

Example 7: As in Example 1, but starting from isopropylidene-1: (4-methyl-2-pyridyl) -aminomethylene -malonate and using ethanol to decompose the reaction mixture, see 8-methyl ether 4-oxo-4H-pyrido (1,2-a) -pyrimidine-3-carboxylic acid, melting at 172-173 ° C.

Found,%: C 62.08; H 5.24; N 12.12;

hell 2M2.0z

Calculated,%: C 62.10; H 5.17, N 12.06.

Example 8 As in Example 1, but starting from isopropylidene-1 5-methyl-2-pyridyl) -aminomethylene -malonate and using ethanol to decompose the reaction mixture, 7-methyl-4-oxo-ethyl ester is obtained. 4H-pyrido- (1,2-a-pyrimidine-3-carboxylic acid, melting at 137 ° C.

Found,%: C 62.18; H 5.14; N 12.01;

C H -fJlOj

Calculated,%: C 62.10; H 5.17; N 12.06.

Example 9. As in Example 1, but starting from isopropylidene- (6-ethyl-2-pyridyl) -aminomethylene -malonate and using ethanol to decompose the reaction mixture, 6-ETHYL-OXO-4H-PYRIDO- (1, 2-a) pyrimidine-3-carboxylic acid, melting at 89c.

Found,%: C 63.55; H 5.74, N 11.40.

Calculated,%: C 63.41 H 5.73; N 11.38.

EXAMPLE 10 As in Example 1, starting from isopropylidene- (4,6-dimethyl-2-pyridyl) -aminomethyleneJmalonate and using ethanol to decompose the reaction mixture, 6,8-dimethyl-4- ethyl ester is obtained. oxo-4H-PYRIDO- (1, 2-a) -pyru and d-3-carboxylic acid, melting at 150 ° C.

Found,%: C63.39; H 5.80; N 11.45;

S.N.aOz

5.73, Calculated,%: C, 63.41;

H

About N 11.38.

Example 11. As in Example 1, but starting from isopropylidene- (5-chloro-2-pyridyl) -aminomethylene -malonate and using ethanol to decompose the reaction mixture, 7-chloro-4-oxo-4H-pyrido ethyl ester is obtained. - (1,2-a) pyrimidine-3-carboxylic acid, melting at 134 sec.

Found,%: C 52.41; H 3.60;

0 N 11.12; C1 14.08,

C HjNjOjCl

Calculated,%: s52.29; H 3.59; N 11.09; C1 14.03.

Example 12. As in Example 1, but starting from isopropylidene- (5-ethoc5 sicarbonyl-2-pyridyl) -aminomethylene -malonate and using ethanol to decompose the reaction mixture, 4-oxo-4H-pyrido- (1,2 -a) -pyrimidine-3,7-dicarboxylic

G acid melting at 117 ° C.

Found,%: C 56.02; H 5.20, N 10.12;

Calculated,%: C 56.11; H 5.07;

5 N 10.07.

Example 13. As in Example 1, but starting from isopropyl- (2-quinoline-aminomethylene) -malonate and using ethanol to decompose the reaction

0 mixtures, get 1-oxo-lH-pyrimido- {1, 2-a) - inolin-2-carboxylic acid ethyl ester, melting at 8990 ° C.

Found,%: C 67.14; H 4.49; N 10.32;

five

Calculated,%: C 67.16; H 4.52; N 10.46.

Example 14 As in Example 1, starting from isopropylidene- (6-methyl0 -2-pyridyl) -aminomethylene -malonate, but using methanol to decompose the reaction mixture, 6-methyl-4-oxo- methyl ester is obtained. 4H-pyrido (1,2-a) pyrig-shdin-3-carboxylic acid, melting at 137-139s.

Found,%: C 60.70; H 4.65; N 12.80;

, Calculated,%: C 60.55; H 4.62;

ABOUT

N 12.84.

Claims (2)

Example 15 As in Example 1, starting from isopropylidene- (6-methyl-2-pyridyl) -aminomethylene -malonate, but using water to decompose the reaction mixture, set the pH of the reaction mixture to 3-4 with an aqueous solution of 10 wt.% sodium carbonate, s. by subsequent filtration and drying of precipitated crystals, get 6-methyl-5-oxo-4H-pyrido- (1,2-a) -peri1 1idine-3-carboxylic acid, decomposing at 188-190 C. Found,%: C 58.75; H 3.96; N 13.68; C, oHaNa03 Calculated,%: C 58.82; H 3.95; N 13.72. Example 16 As in Example 1, but starting from isopropylidene- (4-metho-CI-2-HINOLIL) -aminomethylene-3-malonate and using ethanol to decompose the reaction mixture, 6-methoxy-1-oxo-1H-pyrido-ethyl ester is obtained. (1, -a) -quinolin-2-carboxylic acid, melting, at 130-132 ° C. Found,%: C 64.60; H 4.78; N 9.36; C 6 l4fJ204 Calculated,%: -2 64.42; H 4.73 / N 9.39, Example 17. As in Example 1, but starting from isopropylidene- (2-quinolylaminomethylene) -malonate and using methanol to decompose the reaction mixture, methyl 1-oxo-1H-pyrimide (1,2-a) -quinolin-2-carboxylic acid, melting at 167-168 ° C. Found,%: C, 66.25; H 3.89; N 11.05. .g Calculated,%: C 66.14; H 3.96; M 11.02. EXAMPLE 18 As in Example 1, but starting from isopropyl- (2-quinol aminomethylene) -malonate and using n-propanol to decompose the reaction mixture, 1-OKco-1H-pyrimido- (1 , 2-a) -quinolin-2-carboxylic acid, melting at 81-82 ° C. Found,%: C 68.94; H 4.98; N 10.05. C, bN, N., 0 Calculated,%: C 68.08; H 5.0; N 9.93. Example 19 As in Example 1, but starting from isopropylidene- (2-quinolylaminomethylene) -malonate and using isopropanol to decompose the reaction mixture, 1-oKco-1H-pyrimidine- (1,2-a-quinoline-2 -carboxylic acid, melting at 166-167 ° C. Found: C 68.18; H 5.06; N 9.65;. ° 3. Numbers,%: C 68, 08; H 5.00 / N 9.93. Pr and measures 20. As in Example 1, but starting from isopropylidene- (2-quinolylaminomethylene) -malonate and using n-butanol to decompose the reaction mixture., 1-c-1H-pyrimido n-butyl ester is obtained - (1,2-a) quino91 in-2-carboxylic acid, melting at 76-77 ° C. H Found%: C 68.80 H 5.41; N 9.48; Calculated: C 68.91; H 5.44; N 9.45. Example 21. As in Example 1, but starting from isopropylidene - {2-quinolylaminomethylene) -malonate and using benzyl alcohol to decompose the reaction mixture, 1-oxo-1H-pyrimido- (1,2-a) -quinoline- .2-carboxylic acid benzyl ester is obtained, melting at 113-114 C. Found,%: C 72.75; H 4.22; N 8.68; Calculated,%: C, 72.72; H 4.28; N 8.51, Example 22. As in Example 1, but starting from isopropylidene- (4-methoxy-2-quinolyl) -aminomethylene-malonate and using water to decompose the reaction mixture, 6-methoxy-2-OXO-1H is obtained. -PYRIMIDO- (1,2-a) -quinoline-3-carboxylic acid, melting at 220 ° C. Found:%: C 61.98; H 3.75; N 10.40; Calculated,%: C, 62.22; H 3.73; N 10.37. Ex. 23. As in Example 1, but starting from isopropylidene- (4-chloro-2-quinolyl) -aminomethylene -malonate and using water to decompose the reaction mixture, 6-chloro-2-oxo-1H-pyrimido- (1,2-a) -quinolin-3-carboxylic acid, melting at 179 ° C. Found,%: C 59.00; H 3.70; N 9.28, C1 12, H; Calculated,%: C 59.52; H 3.66) N 9.25; C1 11.71. The compounds of general formula 1 are useful intermediates in the preparation of compounds having analgesic anti-inflammatory and anti-sclerotic activities. On the other hand, they can be used alone or in a mixture with suitable inert non-toxic solid or liquid diluents or carriers and as medicines possessing antibacterial antifungal or anti-allergic activity. The compounds may be prepared as pharmaceutical formulations. For pharmaceutical purposes, the corresponding acid addition salts or salts formed by inorganic bases can also be used. As salts, salts formed with hydrochloric acid, hydrobromic acid, sulfuric acid, citric acid, fumaric acid, etc. can be preferably used. Claims 1. Method for producing pyridopyrimidine derivatives of general formula 1 / where R is hydrogen, alkyl C C, / unsubstituted or substituted by hydroxy group, aralkyl containing 7-12 carbon atoms, cycloalkyl) hydrogen, halo, hydroxy, alkoxy O, - Cg, alkeline C, - (niloxy alkynyloxy Cj-C, aralkoxy alkyl thio-C-C, alkoxycarbonyl C, -C, cyano, acyloxy trifluoromethyl, nitro; hydrogen, halo, alkyl dotted line - group - (CH-CH) -, unsubstituted or substituted by the groups R and Rf where are radical or different and mean hydrogen, halo, alkyl C —C, alkoxy, and ralkoxy Cpr-C -j, alkylthio, alkylsulfinyl alkylsulfonyl, alkoxycarbonyl or G —C — I. R together with two adjacent carbon atoms form an alkylenedioxy group containing 1-2 carbon atoms or their salts by cyclization of 2-aminopyridine derivatives when heated, This means that, in order to increase the selectivity of the process, compounds of the general formula II II IX are used as derivatives of 2-aminopyridine where R, R, dotted line, and Ne R. as defined above, and the cyclization is carried out in the presence of an acid condensing agent, then the reaction mixture is treated with water or an alcohol of the general formula TV where R has the above values, followed by transesterification of the obtained target product or / and isolation in free form or as a salt. 2. Method POP.1, characterized in that the process is carried out at a temperature of 50-200 ° C. Sources of information taken into account in the examination - 1. Lappin G.R. Cyclization of 2-amipore gidine derivatives. J.Am. Chem. Soc. XO, 3348/1948 (prototype).