CS212718B2 - Method of preparing 8-ethyl-5-oxo-5,8-dihydropyrido/2,3-d/-pyrimidine-6-carboxyl acids - Google Patents

Description

A compound of formula (I) wherein R is a pyrrolidine residue, i. 8-ethyl-5-oxo-5,8-dihydro-2-pyrrolidinopyrido (2,3-d) pyrimidine-6-carboxylic acid was first disclosed in British Patent No. 1,129,358 as an antibacterial agent against both Gram positive and Gram negative bacteria, especially Shigella, Salmonella and Klebsiella. Later this compound was referred to as pyromidine acid.

A compound of formula I wherein R is a piperazine moiety, i.e. 8-ethyl-5-oxo-5,8-dihydro-2-piperazinopyrido (2,3-d) pyrimidine-6-carboxylic acid, has been described in DOS 2,338,325 and 2,341,146. This was later. a compound referred to as pipemidinoic acid, which has even better antibacterial properties than pyromidinoic acid, especially against Pseudomonas aeruginosa or Mycobacterium tuberculosis. It is currently used as an active ingredient in urinary tract antiseptics.

The aforementioned patent publication also describes a process for the preparation of pyromidine and pipemidinoic acid.

In the case of a known procedure. the pyrimidine derivative of general formula 1 is mentioned in the reaction

(I) with an acid derivative. methylenemalone of formula 2,

СООС ₂ Н ₅ (1)

II \ сн соос ₂ и ₅

I X where

Y is NHR ', where

R 'is hydrogen or ethyl when X is ethoxy or halogen when X is NHR' in which R 'is ethyl,

R ¹ is lower alkyl, lower alkoxy or lower alkylthio.

The compounds of formula (3) obtained,

COOC, Ur ^COOC Z = 6 (III) where

R 'and R _t are as defined above, are cyclized to compounds of formula 4,

0 N ^ · COOC.Hr ^R 'V in Z Э (IV)

where

R1 is as defined above by heating, and optionally N-ethylated when R1 is a hydrogen atom.

Then, in the compound of formula 4, a pyrrolidone or piperazine residue is introduced at the R-position, usually by reacting the compound in which R is methylthio in reaction with pyrrolidine in ethanol or with piperazine hexahydrate in dimethylsulfoxide and then hydrolyses The total residue is approximately 16% of the theoretical amount.

The literature also teaches that the pyrrolidine or piperazine moiety can also be introduced into the compound of formula (1) in the same manner, but attempts have been made to find that the compounds of formula (1) are virtually non-reactive with pyrrolidone or piperazine, and the method is practically not feasible.

It has now been unexpectedly found that a compound of formula I can be obtained by condensing a 4-aminopyrimidine derivative of formula II,

where

Z represents a methylsulfonyl or methylsulfinyl radical, with piperazine or pyrrolidine to give the compound of formula (A),

where

R is as defined above, this compound is ethylated to a compound of formula B,

where

R is as defined above, which is condensed with ethyl ethoxymethylene cyanoacetate of the formula

CN /

C'žH5OCH = C \

COOC ₂ H ₅ to a compound of Formula C 1 CN

R

'COOC.Hr CH ^{3 1}

(C) where

R is as defined above and is hydrolyzed in the presence of a solvent in an alkaline medium after previous cyclization, if any.

Compared with the known processes, high yields can be achieved in the process according to the invention.

The starting compounds of formula (II) are novel and can be obtained by partial (Z = -methylsulfinyl) or complete (Z = = methylsulfonyl) oxidation of 2-methylthio-4-aminopyrimidine according to Wheeler, Bristol-Am. Chem. Jour. , 447 (1905), for example by treatment with hydrogen peroxide in acetic acid.

The reaction of the compound of formula II with piperazine or pyrrolidone proceeds easily and in good yield. The reaction is carried out in high-boiling organic solvents, for example dimethylsulfoxide or dimethylformamide, preferably dimethylsulfoxide at a temperature of 100 to 150 ° C, preferably 140 ° C.

Ethylation is carried out, for example, by treatment with diethyl sulfate or preferably ethyl iodide in the presence of the above solvents at a temperature of 80 to 120 ° C, preferably 110 to 115 ° C.

The condensation with ethylethoxymethylene cyanoacetate is carried out in a solvent, for example dimethylformamide, dimethylsulfoxide or toluene, at a temperature of 100 to 140 degrees Celsius, preferably 120 ° C.

The use of ethylethoxymethylene cyanoacetate as a condensing agent yields high yields higher than the known condensation by the methylenemalonic acid derivative.

The heat cycling is carried out in the presence of a solvent, for example ethyl polysulphate, polyphosphoric acid or diphenyl ether, optionally at a temperature of 80 to 180 ° C, preferably 160 ° C.

Hydrolysis is carried out at - alkaline '-' medium, for example in the presence of - alkali metal hydroxides or alkaline earth metal at room temperature to 100 ° C ^Q

The individual intermediates can be isolated or used in the resulting reaction mixture - without prior isolation.

The invention will be illustrated by the following example.

Example

(a) 2-Piperazino-4-aminopyrimidine

A mixture of 2-methylsulfinyl-4-aminopyrimidine (3.14 g), piperazine (6.88 g) and dimethylsulfoxide (12.5 ml) was heated to 140 ° C with stirring for 3 hours. The reaction mixture was evaporated to dryness and the residue was recrystallized from ethanol to give 3.79 g of 2-piperazino-4-aminopyrimidine (78%), m.p. 202-210 ° C.

(b) 2-Piperazino-4- (N-ethylaminopyrimidine)

1.79 g of 2-piperazino-4-aminopyrimidine are dissolved in a mixture of 3.65 ml of a 20% aqueous potassium carbonate solution and 20 ml of dimethylformamide and then mixed with 0.54 g of ethyl iodide with stirring at room temperature. The reaction mixture was then heated at 100-115 ° C for 2 hours. After heating, the solvent was evaporated, the residue was mixed with water and extracted with chloroform. The organic phase is evaporated to dryness and the residue is recrystallized from isopropanol to give 1.8 g of 2-piperazine-4- (N-ethylaminopyrimidine), m.p. 151-155 ° C, in 87% yield. ..

c) Ethyl N- (2-piperazino-4-pyrimidinyl ¹⁾ -Nmthylaminomethylcnkyanoacetát

2.07 g of 2-piperidino-4- (N-ethylaminopyrimidine) and 1.6 g of ethyl ethoxymethylene cyanoacetate are dissolved in 8.5 ml of dimethyl sulfoxide. The reaction mixture was heated at 120 ° C with stirring for 4 hours. After cooling the reaction mixture overnight, a pale yellow precipitate formed which was recrystallized from isopropanol. 2.52 g of ethyl N- (2-piperazino-4-pyrimidinyl) -N-ethylaminomethylenecyanoacetate of melting point 130 DEG-134 DEG C. are obtained in a yield of 76% of theory.

d) 5,8-Dihydro-8-ethyl-2-piperazino-5-oxopyrido- (2,3-d) pyrimidine-6-carboxylic acid

3.3 g of ethyl N- (2-piperazino-4-pyrimidinyl) -N-ethylaminomethylene cyanoacetate and 15 g of ethyl polyphosphate were heated at 150-160 ° C for 2.5 hours with stirring. After heating was complete, the reaction mixture was cooled and poured onto -40 g of ice. The mixture was then neutralized with sodium bicarbonate and extracted with chloroform. The organic layer was evaporated to dryness and the residue was mixed with 20 ml of 15% sodium hydroxide solution. The reaction mixture was then heated at -100 ° C for 1 hour and, after cooling, neutralized with acetic acid. The precipitate was filtered off and recrystallized from dimethylformamide / ethanol (1: 1) to give 1.8 g of 5,8-dihydro-8-ethyl-2-piperazino-5-oxopyrido in 60% yield. (2,3-d) pyrimidine-6-carboxylic acid, m.p. 253-258 ° C.

The total yield is 26% of the theoretical amount.

If pyrrolidine is used instead of piperazine, the procedure is analogous and similar results are obtained.

Production of starting material

2.82 g (0.02 moles) of 2-methylthio-4-aminopyrimidine in 26.3 ml of acetic acid are mixed with 13.9 g of acetic anhydride and a mixture of 6.7 g ( 0.06 mol) 30% hydrogen peroxide and 9.07 g acetic anhydride. The reaction mixture was stirred at room temperature for 2 hours, evaporated to dryness and neutralized with 21% ammonia solution. The neutralized mixture was extracted with chloroform, the solvent was evaporated and the residue was crystallized from ethanol. 2.7 g of 2-methylsulphinyl-4-aminopyrimidine of melting point 188 DEG-194 DEG C. are obtained in a yield of 85% of theory.

Similarly, 2-methylsulfonyl-4-aminopyrimidine can be obtained except that more hydrogen peroxide is required.

Claims (5)

SUBJECT 1. A process for the production of 8-ethyl-5-oxo-5,8-dihydro-pyrido (2,3-d) pyrimidine-6-carboxylic acid of formula I, in I ^{С г. Н} 5 tl) where R is a pyrrolidine or piperazine moiety characterized by condensing a 4-aminopyrimidine derivative of formula (II), N (li) where Z represents a methylsulfonyl or methylsulfinyl radical, with piperazine or pyrrolidine to give the compound of formula (A), N ^ 1 IA> where R is as defined above, this compound being ethylated to a compound of formula (B), N) OF THE INVENTION where R is as defined above, which is condensed with ethyl ethoxymethylene cyanoacetate of the formula CN / C2H5OCH = C \ COOC2H5 to a compound of formula (C) / CN (Uc ⁾ where R is as defined above, cyclized in the presence or absence of solvent and then hydrolyzed in an alkaline medium. 2. The process of claim 1, wherein the reaction to Compound A is carried out in a high boiling organic solvent at a temperature of 100 to 150 ° C. 3. A process according to claim 1, wherein the compound of formula A is ethylated by treatment with ethyl iodide. 4. The process according to claim 1, wherein the condensation to compound C is carried out in an organic solvent, preferably dimethylsulfoxide, at a temperature of 100 to 140 ° C. 5. The process according to claim 1, wherein the cyclization is carried out in ethyl phosphate at a temperature of 150 to 160 [deg.] C. and the hydrolysis is carried out at room temperature up to 100 [deg.] C.