FI73669B - FORMULATION OF FRAMSTAELLNING AV 5-ALKYL-2-CARBOXY PYRAZINE. - Google Patents

Description

7 3 6 6 9

METHOD FOR THE PREPARATION OF 5-ALKYL-2-CARBOXYPYRASIN -FÖRFARANDE FOR FRAMSTÄLLN I NG AV 5-ALKYL-2-CARBOXY

The invention relates to a process for the preparation of 5-alpha-2-carboxypyrazine of the general formula

COOH

JOJ

R1 [Ί where R represents a C -C -a 1 alkyl group. v 1 1 Λ

The compounds of formula (I) are described and protected by GB Patent 1,361,967 and have a blood fat and sugar lowering effect. It is further advantageous to prepare 2-carboxy-5-methylpyrazine-4-oxide from 5-methyl-2-carboxypyrazine prepared according to the invention, which. . as such is protected by said GB patent.

According to the invention, 5 - '' alkyl-2-carboxypyrazines of the formula (I) in which R: 11M is as defined above can be prepared by condensing diaminomaleonitrile of the formula H2N cn (II)

H N "'' '' '' '' '' 'CN

‘J’ with a compound of the general formula CHOCOR 4 wherein R is as defined above in a polar solvent at a temperature of 35 to 85 ° C and the compound thus obtained having the general formula 7 3 6 6 9

CM

'fr: :)

! W I

wherein R 1 has the meaning given above, is reacted with an acid in a polar solvent at a temperature of about ICC, J C.

Suitable solvents for the condensation of β-aminomaleonitrile with glyoxal or ketone dehyde include water, an alcohol containing 1 to 60 ° C or a mixture thereof. K o n d e n s a a t: 1 o r e a k t i o should preferably take place in the presence of an acid.

Reaction of dicyanopyrazine (III) with an acid yields only one compound of formula (I). A suitable acid is sulfuric acid and a suitable solvent is water. The acid concentration is preferably 30-50%.

Disyanopyrats i. Inier. and the reactions between the acids are known per se e.g. Japanese Patent Publication Nos. 53-3767, 53-12378 and 54-154776. However, in the mentioned a j ji 1 k a 1 suu ru action r e action! LI a s a is given as the final product 2-sy ano-3-k a r bok s 1 am i ·! i oy a t. s i i ni or 2-carbancyl-3-carboxyoynazine, while the strong acidic hydrolyz of the present invention alters the alkyl substituent. dicyanopyrazine to 5-alkyl-2-carboxypyratin, where both cyano groups of the starting material are hydrolyzed. In addition, the invention does not give only the 5-a1k y of formula (I) as a final product. Y1-2-carboxypyrazine, even with it, the isomeric 5-alkyl-3-carboxypyrazine is not formed in the reaction.

ti 3 7 3 6 6 9

Example a) L70 g of pyruvic aldehyde (10% aqueous w / v) were added dropwise and at room temperature with stirring a suspension of 100 g of diaminomaleonitrile 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 another 30 minutes.

The reaction mixture was then cooled to 0 ° C and the product was collected by filtration. Washed with water until neutral and dried to give 112 g of crude 2,3-dicyano-5-methylpyrazine, m.p. 9? -110uC.

NKR (CDCl 3) for TMS: 2.88 (s, CH), 8.858 (s, aromatic proton).

b) 10 g of crude 2,3-dicyano-5-methylpyrazine obtained according to a) suspended in 100 ml of sulfuric acid (50% v / v aqueous solution) were kept under stirring at 100 ° C for 3 hours. The reaction mixture was then cooled by adding 100 g of crushed ice and adjusted 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 neutral with saturated sodium chloride solution.

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

NMR (CDCl 3) for TMS: 2.8 δ (s, CH 3) δ 8.9, 9.3 δ (two s, aromatic protons), 10.8 δ (s, C 10 H).

Claims (2)

7 3 6 6 9 & F A T E N Τ Τ I V A A Τ I Y U K S E "" A process for the preparation of a 5-alkyl-i-carboxyl compound of general formula (I):. ini n v a I m 1 s 1 sniseksi, COOK Γr \ 1. W (n E Λ ^ \ · where P, is a C1 -C -a Ikyy 1 i group, a known eastern et ta compound of the general formula. Rr * V ί (111)! W; CN mif *, 'i R, is reacted with polar oxygen in a solvent such as sulfuric acid in a solvent at a temperature of about 100 ° C. Process according to Claim 1, characterized in that the reaction di cyanooyra ts ii ni n (III ', and the acid v1i1-1-1 nn, o' 'path r. Nvedegsi, already 11 o 1 nharen is about 3 ° - 50%