PL154800B1 - Method of obtaining 2(4-/2-chlorobenzamido/-ethyl-/-phenoxy)-2methyl propanic acid - Google Patents

Abstract

For novel prepn. of 2-(4-(2--chloro-benzamido) -ethyl-phenoxy)-2 -methyl-propionic acid (bezafibrate) of formula (I), a 4-chloro-benzoic-acid-thio ester of general formula (II), where R is a 2-mercapto-benzimid-azol-, 2-mercapto-benzaxazol- or pref. a 2-mercapto-benzo-thiazolo gp., is condensed with silylated 2-(4-(2-amino-ethyl)-phenoxy) -2-methyl-propionic-acid of formula (III). Active thio-esters of formula (II) are novel cpds.

Description

REPUBLIC POLAND PATENT DESCRIPTION 154,800 Additional patent to patent no. --- Int. Cl. ⁵ C07C 233/87 iSs Reported: 88 07 20 (P. 273794) IN Priority: 87 12 30 Yugoslavia CG01H OFFICE PATENT Application announced: 89 08 07 RP Patent description published: 1992 03 31

Inventors: PaveJ Zupat, Globokur, Boris Skat,

Natasa ZupanSic

The holder of the patent: ORKA tovarna zdravil n.sol. o., Horo Mesto (Yugoslavia)

METHOD OF PREPARATION OF 2- (4- (2- / 4 ^- CHI0RO-BENZAmX / ^- BTYLO_} ^- PEIOOSYj -2-MEnLOPPROPAIC ACID)

The present invention relates to a new process for the preparation of 2- (4- (2- (4-chloro-benzamido) -ethyl] -phenoxy J -2-methylpropoxy acid, also known as bezafibrate, of the formula 1 in the figure no.

The compound of formula I is a well-known agent that is used in modern medicine to reduce the concentration of -hloleaterol and blood lipids. There is an ongoing need for a new economical method of producing bezafibrate.

From the German patent specification No. 2,149,070 there is known a method for the preparation of a compound of the formula 1, which consists in the reaction of ą-chlorobenzoyl chloride and 4- (2-rmoleoyl) -phenol, the preparation of the 4- (2- (4-chlorobesoyl)) rωιisoylethyl7-fjnol with 2-bromo-4-methylpropanoic acid ethyl ester and hydrolysis of the produced ester, and from Austrian Patent Specification No. 365,167 and British Patent Specification No. 2,021,571 a method is known which involves the reaction of 4- (2- / 4) - chlorobenzoyl) - β-minoethyl-7-phenol, acetone and chloroform in an alkaline medium.

The process according to the invention consists in the condensation of the active aclonbenzoic acid thioester of formula II, in which R is 2-mercaptobenzimidazole), 2-mercaptobenzo-xazole, preferably 2-aerxyltobesothiazole, with the silHated form of the 2- (4-22 ° C) acid. '.1-nl-ethyl / -esloxy [beta] -methylopoietal of formula 3. The condernation reaction is carried out in an inert solvent, preferably methylene chloride, at a temperature ranging from room temperature to the boiling point of the solvent, preferably at 40 ° -.

2- / 4-2 - mminojty0 // - fθnox7.7-2- ^ ilethylopanoic acid, which is silitated with t.riroethylchlorosilyl or preferably C, Oo-ii / trimethylsilio / cetarnide (BSA), i.e. hexarneeyldisilazane, is available from commercially or can be produced by a method according to the Yugoslav patent application F 1086/87.

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154,800

The compound of formula 2 is a new compound and can be prepared by reacting 4-chlorobenzoyl chloride of formula 4 and 2-mercaptobenzimidazole, 2-mercaptobenzoxazole or preferably 2-mercaptobenzothiazole. All starting materials are commercially available.

The synthesis of thioesters of formula II is carried out in inert organic solvents, preferably mtylene chloride, in the presence of a base, preferably trieylamine, at a temperature from 0 ° C to the boiling point of the solvent, preferably at the boiling point of methylene chloride.

The new thioesters of formula II, which are prepared by the reaction of 4-chlorobmaoyl chloride and 2-mercaptobenzimidaool, or 2-mercaptobenzoxaool or 2-mercaptobenzothiazole in the presence of an alkali, preferably trieSylamase, are solid, stable, inorganic compounds suitable for transport and storage. They can be prepared from 4-chlorobenzoyl chloride in the m 2, 3, 4, 3, 4, 3, 4, 4, 4, 4, 4, 4, but not more, of its availability and then easily stored until used in the synthesis of the compound of Formula 1.

The new compounds are very advantageous compared to the unstable and aggressive 4-chlorobenzoyl chloride which can decompose into acid under the influence of moisture. They are reactive and react well with 2-β-2-aeminoeSyCofrZonsys 7- 2-mθSylpropanavic acid in a dry organic solvent, preferably methylene chloride, to give the compound of formula I (bezafibrate) in high yield and of good quality.

After completion of the reaction, 2-mθrkaptobθnzothiazole, which is a commercial product used in the rubber industry, can be separated from the organic layer. The desired product is bleached from the water layer.

After completion of the reaction and evaporation of the organic solvent, add water to the residue, adjust to pH 11.5 1 remove the insoluble z3zαzx> ns 2-οθ ^ 8ρΐοbenaothiazole, and isolate 2- £ 4- / 2- / 4-chloro acid from the filtrate -benzαmido / -etslo_7-fenokιyJ-2 · mrtlopcopnox at the isorlθktsoose point at pH 3.7.

The process is illustrated by the following examples, with example 2 being the prepared thioester of formula 2.

EXAMPLE 1 2- (2-) (4-) (2-) Chloro-benzamido C- (5) -hyl-7-phenoxy J -2-methylpropanoic acid.

A suspension of 22.3 δ (0.1 role) of 2- (ą- (2-mincetyOH) -funoxy-7-2-methylpropanoic acid in 500 ml of dry chloride is stirred and 30.51 δ (0) is added while stirring at room temperature. , 15 moles) Ν, ο-biz / tremrtslosillCo / crejmLLdu in 5.9 g (0.1 role) of triθSyOαemizy. The reaction mixture is triturated for 30 minutes at room temperature to silence. 30.5 δ (0.1 moa) S1-benzoiazolyl-4-chlorobenzotrate is added and the mixture is refluxed for 8 hours. After completion of the reaction, a high-pressure crunch is carried out, the mt-llm chloride is evaporated at lower pressure, 1100 ml of water are added, and the mixture is washed with rrakoys for 30 minutes. The pH of the reaction mixture is then adjusted to 11.5 with 25% ammonia, the pH of the mixture is stirred at 30 minutes and the partially dissolved is filtered off.

Aqueous hydrochloric acid (1 of 1) is added to the filtrate with vigorous stirring in room temperature until the pH is 3.7 to 3.9. After the desired pH has been reached, stirring is continued for an hour. The product is separated, washed with water and dried in a vacuum oven at 50 ° C.

30 is obtained "72 g (85%) of 2- £ 4- / 2- / 4 ~ chOooorzojmlido / _r-θ Sylq7 J fθnokzs -2-metylopropanowegc m.p. 181 to 183 ° C. The structure of the produced compound is confirmed by the spectrum of IB and Ntffi. The precipitate, which was filtered off at pH 11.5, was dried at 40 ° C in a vacuum oven and 8.5 g (51%) of purified 2-ntobenzCiaool were obtained as a by-product.

Example II. 4-chlcrcbrzsotljz S-2-bθnzzCiazoCilu. I get messed up

16.7 β (0.1 mole) of 2-mθrkaptobzonzoCiaoclu in 500 ml of dry methylene chloride and 14 ml (0.1 mole) of Tri-SiZe are added while being worn at room temperature. After dissolution was complete, 17.4 g (0.1 mol) of 4-chlorobenzoyl chloride were added dropwise with stirring. The reaction mixture is refluxed for 6 hours, cooled to room temperature, 3 ° C and washed with 100 ml of water. After stirring in an air oven, 24.5 S (90%) of S-2-benzothiazolyl with a melting point of 205 to 208 ° C is obtained. The structure of the compound is confirmed by the IR and MIR spectra.

Example III. 2- £ 4- / 2 - / - choro-bbenzamido / -atyl / -eenokey _ -2-methylpropanoic acid

A suspension of 22.3 S (0.1 mole) of 2-N-2-amelethyl-1 / -jelOxyJ7-2-meylpropanic acid in 500 ml of dry methylene chloride is added, and 30.51 g (0.15 g) are added while stirring at room temperature. mol) Ν, Ο-bis (trimethylsilyl) acetamide. The reaction mixture is stirred for 30 minutes at room temperature in order to perform the silHation. Then 30.5 g (0.1 mol) of N-HCl-benzothi? M S < 1 > -benzzUazoooyl are added and the mixture is refluxed for 6 hours. After the reaction has ended, the reaction mixture is cooled to room temperature, 500 ml of water are added, and the pH is adjusted to 11.5 with 25% amole by stirring. Stir for 1 hour, then the organic layer is separated from the aqueous layer, the organic layer is washed once more with 300 ml of water, the aqueous layers are combined, filtered and the filtrate is added in a solution of HCl (1 sec. 1), with energy, until a pH of 3.7 is obtained. to 3.9. The product which has precipitated out is stirred for an additional hour at room temperature, then it is filtered off, washed with water and dried in a vacuum oven at 50 ° C. 29.28 g (81% of 2-methylpropane-J-2-methylpropane acid, 81% 2 -Chlorobutam. 2-meekkpeoleneoazole occurs, which is then purified.

Claims (3)

Patent claims 1. A process for the preparation of 2-β, -, 22- (4-chloro-beosamido) -eyyl-7-pnooxy] -2-methylpropanoic acid of the formula I, characterized in that the active thi-chlorobenzoic acid ether of the formula II, in where R is 2-mercapeobenzimidazolloy, 2-mercaptobjnzoxaoolwy, and preferably 2 "" erkapeoleneoliaoolooy radical, is condensed with 2- (-) - mmino-ethyl / -elnsksy.7-2-e] jθtylepeaellOϊym of formula 3. A process according to claim 1, characterized in that the condensation is carried out in an inert organic solvent, preferably meeylene chloride, in the temperature range from room temperature to the boiling point of the solvent, preferably at / 0 ° C. . 3. The method according to the arist. A process as claimed in claim 1, characterized in that after the reaction is completed, the solvent is evaporated off and the water is added to the residue, the aqueous layer is made alkaline and, at pH 11.5, the 2-οθ ^ Βρΐ ^ θηζ1ζάβζ1 or 2-mercaptobenzoxol or preferably 2 -merkkaeolenecliazole, and from the filtrate, 2- / 4- / 2- / 4-chloro-bjnoatω. Lldl-ethyll7-f -nlxy J-2mjty'l <: epτQe> an.lwy, after noticing to the isoelectric point . Cl COHN -H ₂ C -H ₂ C O -C-CWH I Formula 1 154,800 Formula 2 COR CH3 NH2H2C-H2C 0 - C-OCOH AND CH3 Formula 3 Cl COCl Formula 4 Department of Publishing of the UP RP. Circulation 100 copies Price: PLN 3,000