SI8211131A8 - Process for obtaining pyrazine derivatives - Google Patents

Description

PROCEDURE FOR OBTAINING PYRAZINE DERIVATIVES

Technical field

The invention relates to the field of synthesis of organic compounds. According to the International Classification, the designation of the invention is C 07 D 241/24; A 61 K 31/495.

Technical problem

The invention solves the technical problem of a new process for the preparation of pyrazine N-oxide, which has a hypolipemic and hypoglycemic effect, while showing no undesirable side effects characteristic of pyridine derivatives. The process is suitable for industrial production because it is simpler than the procedures of earlier science and is done with more suitable starting materials.

The state of the art

The process for the preparation of the compounds of formula (I) below is described by Pitrd, Boveri and Grablz in Chem. Ber. 1966, 99, p. 364, This process involves the reaction of a compound of the formula:

H.

with potassium permanganate to give a compound of formula (I) in which n has a value of 0. This compound is subsequently subjected to N-oxidation.

While this procedure from the earlier sciences may be satisfactory for laboratory synthesis, it has not proved suitable in industrial production. Potassium permanganate is very toxic and the formation of manganese dioxide as a by-product makes it difficult to purify and store the product.

-la

Description of a solution to a technical problem with an Exemplary Example

The invention relates to a process for preparing a compound of the formula:

(I) in which R 1 represents a hydrogen atom or a lower alkyl group, R ₂ represents a hydroxyl group, an alkoxy group of 1-6 carbon atoms or a group of the formula -NR 1 R 2, in which R 1 and R ₄ each independently represent hydrogen or an alkyl group of 1-6 carbon atoms in is 1 or 0.

The compounds of formula (I) according to the present invention are prepared by the following reaction:

(III) acidic

->

COOH (I)

The above reaction of dicyanopyrazine (III) .with an acid very surprisingly gives only a compound of formula (I) in which R ₂ represents a hydroxyl group and is 0. Suitable acids are sulfur, methanesulfonic, phosphoric, trifluoromethanesulfonic and hydrochloric

And acid. A suitable solvent is water and an appropriate acid concentration is from 30 to 50%.

Further stages of the process, which are described in British Patent 1,361,967, include N-oxidation and / or conversion of an OH group into an alkoxy group or -NR.jR ₄ group.

The N-oxidation of the compound of formula (I) is preferably carried out with some peracid, which may eventually be generated in situ. Conversion of the OH group to an alkoxy group is carried out by esterification in the usual manner, and conversion to -NR ^ R ₄ is carried out by reaction of a compound of formula (I) in which -COR _{2 is a} carboxylic group or a functional derivative thereof (e.g., halide or moiety anhydride ), with ammonia or with an amine of the formula HNR ^ R ^.

Preparation of the starting dicyanopyrazine of formula (III) involves the condensation of a diaminomaleonitrile of the formula:

^H 2 ^N X ^CN

J ( ¹¹ )

H ₂ N ' ^xJt ^' CN with the compound of the general formula CHOCOR _ir where R ^ has the meaning as previously defined. Condensation is carried out in a polar solvent at a temperature of 35 to 85 ° C. Subsequent reaction of the obtained compound of formula (III) with acid to obtain the compound of formula (I) is also carried out in polar solvent and at a temperature of 35 to 85 ° C.

«

Suitable solvent! for the condensation of diaminomaleonitrile with glyoxal or α-ketoaldehyde are water, an alcohol of 1-6 carbon atoms, or mixtures thereof. Condensation is performed overnight at pri- _; system of some acid.

Some compounds of formula (I) have hypolipemic and hypoglycemic properties, while exhibiting no undesirable side effects characteristic of pyridine derivatives. Other compounds of formula (I) are intermediates for the synthesis of compounds with this activity.

The invention is illustrated by the following examples:

pniriER 1

- _f j.

a) Aldohld fumed kiaolino (170 g 10¾ solution in water w / v) was added dropwise, aa maOonJem 1 at aobic temperature, augmentation of 100 g diominomalconitrile in amoOi 000 ml water, S00 ml ethanol 1 45 ml alolino. '

After 20 minutes, the complete temperature would go up to 00 ° C for 1 minute and then continue for a further 30 minutes · the cooling medium then cooled to 0 ° C and the product was purchased and the filters were purchased! ·

Jomj poalo iopiring to noutrolnooti oa water and auSonja, gets oo

112 from air 2,3-dioIano-5 * motil-pyrazino> mp · 9Q-100 ° C. PMR (CDCl?) Of ths "2.0 piston (o, CH _3), and beta 0:05 (s, aromatlOnl proton). *

b) Suspension of 10 g of ayr 2,3-dioionic * 5-motilpyrazine obtained as Oto Jo oploono under o) in 100 ml of ouporescent kioalino (aqueous growth «var. 50t v / v) dr21 so aa maOanjcra 3 Oaoa on tomporoturl 100 ° C.

I

- -.-4 ^-

Ronkion omofla with but geol by adding 100 g of crushed lode and ρορησ ee at pH 1 by adding 270 ml of sodium root hydrochloride (20% w / v). The aqueous phase oo is extracted with motilotilcotone> extracts aa cpojo and delivered to the neutral aa by saturated rootwater nntrium chloride.

Evaporation of the solvents in vacuo gave a solid crystalline crystalline solution from the water such that oo yields 0 g of 5-motil-2-pyrosincorbocoyl kioolino, m.p. Mp 163-167 ° C. PMR (COClg) from TMS and 2.0 delta (s, CHg), 0.9, 0.3 long (two o, ^ aromatic protons) <10.0 long (o * COOH).

EXAMPLE 2

The solution of 5-methyl-2-pyrosinecarbokeyl kiaolino (9.7 g), -substituted as Example 1 in dry dlocan (114 ml) and tributylamine (17.7 ml) was triturated with otilchloroforroiate (7.5 ml) at 0-5. ° C. After 10 minutes, add ammonia (100 ml) saturated with ammonia 1 or 3 hours at ambient temperature. The oloxone was separated and the residue was further taken up in saturated aqueous sodium bicarbonate solution (20 ml ·). The browning fluid was evaporated and the product was salted with water to give 2-carbomoyl-5-motilpyrazine (9.2 g), m.p. 204-206 ° C.

This compound (7 g) acetic acid with glooial elecochloro chloin (30 ml) is 1 35% hydrogen perocaid (20 ml) with wetting at 70 ° C for 7 hours.

After cooling, the product was filtered off and washed with water to give 2-carbamoyl-5-methylpyrazine-4-ocean (5.5 g), mp 200-200 ° C.

p-fa.N a v o d

Applicant states that most! a method known to him for the application of the invention to the industry is given in the following example:

a) Pyrogenic acid aldehyde (170 g, 10% w / v solution 'in water) was added dropwise with stirring, at room temperature, to a suspension of 100 g diaminomaleonitrile in a mixture of 800 ml water, 900 ml

And ethanol and 45 ml of acetic acid. After 20 minutes, the dissolution is complete. The temperature was raised to 80 ° C and stirring was continued for another 30 minutes.

I

The reaction mixture was cooled to 0 ° C and the product was collected by filtration. Purification by water to neutral pH and drying afforded 112 g of crude 2,3-dicyano-5-methyl-pyrazine, m.p. 98-100 ° C.

b) A suspension of 10 g of crude 2,3-dicyano-5-methylpyrazine in 100 ml of 50% aqueous solution of H ₂ SO ₄ (closed / closed) was stirred at 100 ° C for 3 hours. The reaction mixture was then quenched by the addition of 100 g of crushed ice and the pH was adjusted to 1 by the addition of 270 ml of 20% aqueous NaOH (w / v). The aqueous phase was extracted with methylethyl ketone, the extracts were combined and washed to neutral pH with saturated NaCl solution. Evaporation of the solvent in vacuo gave a solid residue which crystallized from water to give 8 g of 5-methyl-2-pyrazinecarboxylic acid, mp 163-167 ° C.

FARMITALIA CARLO ERBA SpA

Claims (1)

Process for the preparation of pyrazine derivatives of the formula: (I) ¹ 4. 0 in which R 1 represents a methyl group for condensation of a diaminomaleonitrile of formula ' H ₂ Nx / CN And, with the compound of the formula CHOCOR ^, where as jh ₂ n ^ \ cn is defined above, in water, at a temperature of 35 to 85 ° C and in the presence of acetic acid, the compound of the formula is thus obtained: wherein R, as defined above, is reacted with a solution of ¹ io sulfuric acid in water at a temperature of 85 to 100 C; and subjecting the resultant product to N-oxidation with peracetic acid at a temperature of about 70 ° C to obtain the desired compound of formula (I), wherein the peracetic acid can be generated in situ by the reaction of glacial acetic acid and hydrogen peroxide .