IE52992B1

IE52992B1 - Preparation of pyrazine derivatives

Info

Publication number: IE52992B1
Application number: IE1261/82A
Authority: IE
Original assignee: Erba Farmitalia
Priority date: 1981-05-28
Filing date: 1982-05-26
Publication date: 1988-04-27
Also published as: DE3219407C2; DK239482A; DK155325C; AU8412682A; HU187716B; ZA823660B; DE3219407A1; FR2506768B1; JPS57200368A; ATA203682A; IT8221517A0; CS226741B2; FI73669B; FR2506768A1; YU42766B; JPH0456034B2; IL65864A; CH649763A5; BE893317A; GR76417B

Abstract

The present invention relates to the preparation of pyrazine derivatives having the formula (1) < IMG > (1) wherein R1 is a hydrogen atom or lower alkyl; R2 is a hydroxy group, an alkoxy group having from 1 to 6 carbon atoms or a group of formula -NR3R4, in which R3 and R4 independently represent a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms; and n is 1 or 0. Compounds of formula (1) whrein n is 0 are prepared starting from diaminomaleonitrile, having formula (2) < IMG > (2) The diaminomaleonitrile is condensed with a compound of formula CHOCOR1 and the resultant compound is reacted with an acid obtaining the pyrazine derivatives of formula (1). Some of the compounds of formula (1) show hypolipaemic and hypoglycaemic activities which are free from side effects of pyridine derivatives; the others are useful intermediates therefor.

Description

The invention relates to the pyrazine derivatives having the general preparation formula (1) wherein represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, R2 represents a hydroxy group, an -alkoxy group having from 1 to 6 carbon atoms or a group of the formula -NRgR^, in which each of Rg and R^ independently represents a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, and n is 1 or 0.

The pyrazine derivatives of the general formula (1) wherein Ry is as above defined, Rj represents a hydroxy group and n is 0 may be prepared according to the invention by a process comprising condensing, in a polar solvent at a temperature of from 35°C to 85°C, diaminomaleonitrile, having formula (2) (2) Λ with a compound of the general formula CHOCOR^ wherein R^ is as above defined and reacting the resultant compound of the general formula (3) CN (3) wherein Rj is as above defined with an acid in a polar solvent at a temperature of from 35°C to 85°C. *1 - 3 Suitable solvents for the condensation of the diaminomaleonitrile with the glyoxal or a-ketoaldehyde are water, an alcohol containing from 1 to 5 carbon atoms, or a mixture thereof. The condensation reaction is preferably carried out in the presence of an acid.

The reaction of the dicyanopyrazine (3) with an acid very surprisingly gives only a compound of formula (1) wherein R2 represents a hydroxy group and n is 0. Suitable acids are sulphuric acid, methanesulphonic acid, phosphoric acid, trifluomethanesulphonic acid and hydrochloric acid.

A suitable solvent is water. Conveniently, the concentration of the acid is from 30% to 50%.

The compounds of the general formula (1) wherein n is 1 and/or R2 is other than a hydroxy group may be prepared according to the invention by the above process followed by oxidation and/or conversion of the hydroxy group R2 to an alkoxy group or a group of formula -NR^R^, in which R^ and R^ are as above defined.

The oxidation of the compounds of formula (1) is preferably performed with peracid, which may be prepared in situ; the conversion of the hydroxy group R2 to an alkoxy group is performed by esterification - 4 52993 according to the usual methods of organic chemistry; and the conversion of R2 to a group of formula NR^R^ is performed by reacting compounds of formula (1) wherein COR2 is a carboxy group or a functional derivative thereof, e.g. a halide or a mixed anhydride, with ammonia or an amine of formula HNR,R. wherein R, and R. are as defined hereinbefore. 4 3 4 The compounds of formula (1) and these further steps are described and claimed in British Patent 10 No. 1,361,967.

Some of the compounds of the general formula (1) show hypolipaemic and hypoglycaemic activities which are free from the side effects of pyridine derivatives, the others are useful intermediates thereof.

The following Examples illustrate the invention.

EXAMPLE 1 a) Pyruvic aldehyde (170 g; solution 10% in water w/v) was added dropwise, under stirring and at room temperature, to a suspension of 100 g of diamino20 -maleonitrile in a mixture of 800 ml of water, 900 ml of ethanol and 45 ml of acetic acid. After 20 minutes dissolution was complete; the temperature was raised to 80°C and stirring was continued for a further 30 minutes. The reaction mixture was then cooled to 0°C and the product was collected by 52982 - 5 filtration; after vzashing until neutrality with water and drying, 112 g of crude 2,3-dicyano-5-methyl-pyrazine was obtained, m.p. 98-100°C.

PMR (CDClj) from TMS: 2.86 (s, CH3); 8.856 (s, aromatic proton). b) A suspension of 10 g of crude 2,3-dycyano-5-methylpyrazine, obtained as described under a), in 100 ml of sulphuric acid (aqueous solution, 50% v/v) was kept under stirring for 3 hours at a temperature of 100°C. The reaction mixture was then quenched by adding 100 g of crushed ice and raised to pH 1 by adding 270 ml of aqueous sodium hydroxide solution (20% w/v) . The aqueous phase was extracted with methyl ethyl ketone; the extracts were combined and washed until neutrality with saturated sodium chloride solution.

Evaporation of the solvent in vacuo gave a solid residue which was crystallized from water to give 6 g of 5-methyl-2-pyrazinecarboxylic acid, m.p. 163-167°C.

PMR (CDC13) from TMS: 2.86(s, CH3); 8.9, 9.36(two s, aromatic protons); 10.86(s, COOH).

EXAMPLE 2 A solution of 5-methyl-2-pyrazinecarboxylic 25 acid (9.7 g), prepared as described in Example 1, in dry - 6 dioxan (114 ml) and tributylamine (17.7 ml) was treated with ethyl chloroformate (7.5 ml) at O-5°C. After 10 minutes, dioxan (190 ml) saturated with ammonia was added, and the mixture was stirred for 3 hours at room temperature. The dioxan was distilled off and the residue taken up in a saturated aqueous solution of sodium bicarbonate 20 ml. The mixture was filtered and the product washed with water to give 2-carbamoyl-5-methylpyrazine (9.2 g), m.p. 2O4-2O6°C.

This compound ( 7 g ) was heated with glacial acetic acid (30 ml ) and 35% hydrogen peroxide (20 ml) with stirring at 70°C for 7 hours.

After cooling, the product was filtered off and washed with water to give 2-carbamoyl-5-methylpyrazine-4-oxide (5.5 g), m.p. 2O6-2O8°c.

Claims

CLAIMS:

1. A process for the preparation of a compound of the general formula (1) 10 wherein R^ represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, R 2 represents a hydroxy group and n_ is 0, the process comprising condensing, in a polar solvent at a temperature of from 35°C to 85°C, diaminomaleonitrile with a compound of 15 the general formula CHOCOR^, wherein R^ is as defined in this claim, and reacting the resultant dicyanopyrazine derivative of the general formula (3) as herein defined with an acid in a polar solvent at a temperature of from 35°C to 85°C.

2. A process according to claim 1 in which the condensation of the diaminomaleonitrile with the glyoxal or α-ketoaldehyde CHOCOR^ is carried out in the presence of an acid. 53993 - 8

3. A process according to claim 1 or claim 2 in which the polar solvent in which the condensation of the diarainomaleonitrile with the glyoxal or u-ketoaldehyde CHOCOR^ is effected is water, an 5 alcohol containing from 1 to 6 carbon atoms or a mixture thereof.

4. A process according to any preceding claim in which the acid with which the dicyanopyrazine (3) is reacted is sulphuric acid, methanesulphonic acid, 10 phosphoric acid, trifluoromethanesulphonic acid or hydrochloric acid.

5. A process according to any preceding claim in which the po 1 ar solvent in which the dicyanopyrazine (3) is reacted with the acid is water.

6. A process according to any preceding claim in which the concentration in the polar solvent of the acid with which the dicyanopyrazine (3) is reacted is from 30% to 50%.

7. A process for the preparation of a compound of 20 the general formula (1) (1) - 9 5309 3 wherein n. is 0 or 1, R^ represents an alkoxy group having from 1 to 6 carbon atoms or a group of the formula NR^R^ in which each of R^ and R^ independently represents a hydrogen atom or an alkyl group having from 5 1 to 6 carbon atoms or, if n is la hydroxy group, and R^ is as defined as claim 1, the process being as claimed in any of claims 1' to 6 and further comprising oxidation and/or conversion of the hydroxy group R 2 to an alkoxy group having from 1 to 6 carbon atoms or a IQ group of the formula NR^R^ as defined in this claim.

8. A process according to claim 1, the process being substantially as described herein with reference to Example 1.

9. A process according to claim 7, the process being substantially as described herein with reference to