PT86214B - METHOD FOR OBTAINING GLYCERIN 2-P-CHLOROPHENOXY-ISOBUTIRATE-1,3-DICYCOTINATE - Google Patents

Abstract

The invention relates to the preparation of an antiatherosclerotic agent (I) which is obtained on reaction of p-chlorophenoxy-isobutyric acid (II) with 1,3-dichloropropanol (III) in the presence of a condensation agent and further reaction of the intermediate ester (IV) obtained with an alkaline salt of nicotinic acid, in the presence of a phase transfer catalyst.

Description

SOCIEDAD ESPAÍtOLA DE ESPECIALIDADES FARKAGO-TERAPEUTICAS, S.JU PROCESS FOR OBTAINING 2-p-CHLOROMOXI-ISOBUTIRATE -1,3-DINICOTINATO DS GLICERINA ”

-2which consists of reacting p-chlorophenoxy-isobutyric acid of formula II

with 1,3-dichloropropane of formula III

C1-CH ₂ -CH-CH ₂ -C1

OH and subsequent reaction of the intermediate ester obtained with an alkaline salt of nicotinic acid in the presence of a phase transfer catalyst.

The present invention patent relates to a process for obtaining a mixed symmetrical glycerin ester, glycerin 2-p-chlorophenoxy-isobutyrate-1,3-dinicotinate, of formula I.

Compound I is an effective agent in the prevention and treatment of atherosclerosis and its sequelae, cerebral, coronary and peripheral vasculopathies, due to the effect of its normalizing, anti-cholesterinemic and microhemorrhoological action.

This latter property distinguishes it from other lipid-lowering agents, which do not have it. the double action mechanism gives compound I a clear advantage in the fight against atherosclerosis.

By Spanish Patent no. 463,218 a method for obtaining compound I is known, based on the following two steps:

Esterification of 2- (4-chlorofe noxi) -isobutyric acid (II) with 1,3-dichloro-2-propanol (III) to give rise to intermediate (IV) ·

C-COO ch ₃ I

CH ₂ C1

CH ₉ C1

I - CH

This esterification is carried out by means of acid catalysis, using, for example, sulfuric acid.

Reaction of intermediate IV with 2 vol. Of an alkaline salt of nicotinic acid (eg sodium cotinate).

Step 2

This substitution reaction is carried out specifically using dimethylformamide as a solvent and at the reflux temperature of the system.

This process has the following disadvantages:

there. - The first stage requires high reaction times, specifically 48 h.

2nd. - This long duration, linked to the fact that an acid catalyst is needed, at relatively high temperatures, means the formation of an impure IV product, through the formation of resins.

This point is of particular importance since intermediate IV is a non-distillable liquid, and therefore very difficult to purify.

Already. - In the second stage, the relative insolubility of the alkaline salts of nicotinic acid ends the need for high temperatures, specifically in the order of 1502 * 3, which helps the formation of resins and hinders the isolation and purification of compound I.

It has been found that if step one is carried out avoiding the use of acid catalysts such as sulfuric acid, a highly pure IV product is achieved.

This is achieved by using a condensing agent such as, for example, p-toluenesulfonyl chloride, using a base such as, for example, pyridine, as a catalyst, under certain conditions that prevent the formation of alcohol tosylate III as a by-product.

-7It was also discovered that, in the 2nd Step, the use of phase transfer catalysts such as, for example, tetrabutylammonium bromide, allows to reduce the thermal level necessary for the reaction (specifically from 1502 to 90-1002 G) with which decreases the formation of resins and compound I can be separated from the reaction product in high purity.

With all this, an average income increase of 40 $ is achieved - in Spanish Patent no. 463,218 - 6%.

Reaction times exceed 52 hours - in Spanish Patent no. 463,218 - at 10 hours.

process object of the present invention patent is to react p-chlorophenoxy-isobutyric acid (II),

with 1,3 ~ dichloropropanol (III),

CHgCl

I

CH-OH

I

CHgCl

III in the presence of a condensing agent, which can be trifluoroacetic anhydride ((CF ^ 00) 20) or else a sulfonyl chloride, of the general formula H-CGgCl (where R can be CH3-,

and a tertiary amine such as pyridine or triethylamine, to give rise to 1,3-dichloropropyl (IV) 2-p-chlorophenoxy-isobutyrate (IV);

IV and intermediate compound IV are reacted with an alkaline salt of nicotinic acid, in the presence of a phase transfer catalyst such as tetrabutylammonium bromide or triethylbenzylammonium chloride, to give rise to compound I.

EXAMPLES

Example 1

Μ · ΙΜΝΜΙ * · Μ ··· ΜΙΜ ··· Ι ls. Phase. Obtaining intermediate IV

In a 500 ml retort with magnetic stirring and reflux coolant, 21.45 g (0.1 mol) of p-chlorophenoxy-isobutyric acid, 12.90 g (0.1 mol) of 1, 5-dichloropropanol, 16.00 g (0.2 mol) of pyridine, 19.07 g (0.1 mol) of p-toluensulfonyl chloride and 100 ml of toluene.

The system is refluxed for 5 hours. Allow to cool, wash with water, dilute hydrochloric acid and water, and stir the organic phase with 150 ml of 10% ammonia for 10 minutes. Decant, wash with water and evaporate the solvent.

51, 50 g of yellowish viscous liquid are obtained and used in the next step without purification.

Yield: 97% ·

IV: 1740, 1585, 1435,1575, 1255 ·

*

V-

2 & Phase. Obtaining Compound I

In a 250 ml retort, provided with magnetic stirring and reflux coolant, 20.00 g (63 ml) of intermediate IV, 19.00 g (lJOiQMol) of anhydrous sodium nicotinate, 4.00 g of chloride are introduced. benzylammonium triethyl, 20 ml of dimethylformamide and 8 ml of acetonitrile. The system is refluxed for 5 h. Allow to cool and add 40 ml of water. Stir for 2 h at room temperature, filter and recrystallize from methanol.

20.77 g of white solid are obtained.

Yield t 66%.

mp 99-1002C.

IV: 1745, 1772, 1590, 1585, 1390, 1370, 1235.

Example 2 in Phase. Obtaining intermediate IV

In a 500 ml retort with magnetic stirring and reflux coolant, 21.45 g (0.1 Boi) of p-chlorophenoxy-isobutyric acid, 12.90 g (0.1 Boi) of 1, 3-dichloropropanol, 24.00 g (0.3 ox) of pyridine, 11.75 g (0.1 ox) of me-12p chloride. 99-1002 0

Claims (1)

ebiyihsioaçOes la. - Process for obtaining a symmetrical mixed ester of glycerin, glycerin 2-p-chlorophenoxyisobutyrate-1,3-dinicotinate (I), characterized by reacting p-chlorophenoxy-isobutyric acid (II). with 1,3-dichloropropanol (III), ^GH 2 ^G1 CH-OH CH ₂ C1 III in the presence of a condensing agent, which may be trifluoroacetic anhydride ((CPjC0) ₂ 0) or a sulfonyl chloride, of the general formula R-SO _{2 2} -01 where R can be CH, -, ^{then CH} 3 'and a tertiary amine such as pyridine or triethylamine, to give rise to 1,3-di-c 2-p-chlorophenoxy-isobutyrate. —14— chloropropyl (IV); ch ₃ l ³ c - coo - CH ch ₃ » ₂ α -J I CH Cl IV and the intermediate compound IV is reacted with an alkaline salt of nicotinic acid, in the presence of a phase transfer catalyst such as tetrabutylammonium bromide or triethylbenzylammonium chloride, to give rise to compound I.