SU519122A3 - Method for preparing substituted biphenylbutyric acid or its salt - Google Patents

Description

3 does not mean a carboxyl group, it is saponified and without B1felvv intermediate products OBTOB removed from carbon dioxide and obtaining; a compound of general formula 1. The compounds of general formula I, which are obtained from non-optically active intermediate products, are obtained in the form of racemates, which can be easily dispersed by fractional crystallization of their salts with optically active bases onto optically active isomers. Especially beneficial in this case LOS. disengagement of the racemate with quinine. General conditions of formula 1 can be translated into salts, for example, salts with a non | {{ganvic or organic base with (1 (vm. As dietary bases, diethNol. 1 | Nc | meserfolin, cyclohexylamine and piperaiirut turned out to be particularly useful as organic bases). The new starting compounds of the general formula C are obtained by reacting a ketone of the general formula iwG-CH, III where it means a halogen atom, with chr-acetic acid or one of the derivatives of the general formula NC-CH, -Gll -., M, .... -and - -.. - .., where C means. cyan-carboximide or carboxyl group esterified when not bypassed with an aliphatic or araliphatic alcohol or phenol in the presence of an inert solvent, for example carbinol, such as ethanol, from propanol, butanol, preferably in water-mixed solvent, for example in an aromatic hydrocarbon, such as benzene, and in the presence of ammonia or ammonium salts or amines, preferably tertiary, such as triethylamine, piperidine or their salts, it is advisable in the presence of the VII of acetic acid, connecting the water separator, when heated to boiling solvent. Example 1. 3- (2 -Fetrrg: 4-biphenyl-butyl acid A. 2-Cyan- (2-fluoro-4-biphenyl) -2-bentoic acid. Mixing with the connected J & heat a mixture of 10 7 g (0.5 mol) of 4 (2-fluoro-rphenyl) -acetophenone (mp. 84–85 ° C), “i2.5 g (0.5 mol of caiye} g acetic acid, 7, 5 g of ammonium acetate NIN and: L2.5 ml of glacial acetic acid 100 ml of Evrzol for 40 hours on the reverse of the cooler, then cooled, from ... asses the resulting solid precipitate and 2 2 thoroughly washed with water. 3- (2-fluoro-4-biphenyl) -2-butenoic acid with mp 202 C (decomposition, after lecrystallization from ethanol) with a yield of; 65 G (46.3% of theory). i The salt precipitated in acetone: Cyclohexyllamine melts at 168-169 ° C ped decomposition B. 3- (2-Fluoro 14-biphenyl) -butter acid. 5 g of 2-cyano-3- (2-fluoro-4-biphenyl) -2- € u1enoic acid is heated, stirring, in 2 ml of glacial acetic acid with 40 ml: hydrofluoric acid (density 2.0) for 3 hours in oil nry.aan not on-reverse refrigerator. Then, the initial reaction mixture is fed into water and the leached oil is consumed in ether. The ether solution is decolorized with sodium bisulfite solution, washed repeatedly with water, dried and the solvent is removed. After the crystallized solid has dissolved, cyclohexylamine is added to ethyl acetate, and 3- (2-fluoro-4-biphenyl) -butyric acid salt of cyclohexylamine is precipitated. The melting point of the free acid is 99-101 C. The yield is 2.2 g (47.8% of theory). Example 2. 3- (2-Fluoro-4- and phenyl) -buttonic acid., A. Ethyl 2-cyano-3- (2-fluoro-4-biphenyl) -2-butenoic acid. After stirring, with a water separator, a mixture of 107 g (0.5 mol) of 4- (2-fluorophenyl) acetophenone, 56.5 g (0.5 mol) of cyano acetic ester, 2OO ml of benzene, 7.7 mg (OD mole) ammonium acetate and 24 g (, 0.4 mole) of glacial acetic acid are heated for 9 hours on the reflux condenser. After this time, the initial reaction mixture is cooled, the benzene solution is shaken twice with water, dried and the solvent is distilled off. The remaining residue is distilled under vacuum, and 80 g (51.7% of theory) of the indicated ester is obtained with b.p. 177-178 C / 0.1 mmHg), which after some time solidifies with crystals and after recrystallization from petroleum ether / cyclohexane, melts at 55-57 ° C. B, 3- (2-Fluoro-4-biphenyl) -oil-acid. The ester obtained according to example 1A is processed in the same way as described in example 1B. Diclohexylamine salt of 3- (2-fluoro-4-biphenyl) -based acid is obtained with mp, 162-163 C in 86% yield from theory. The free acid melts: at 1OO C. Example 3. 3- (2-Chlo-4-4-bifennl) 1-butl acid. A, 2-Cyan-3- {2-pyur-4-biphenyl) -2-butenoic acid. A mixture of 23 g (OD mol) 4- (2-chlorophenyl) acetophenone (m.p., 60–62 s), 8.5 g (0.1 mol) of cyanoacetic acid, 1.5 g of ammonium acetate, and 2 , 5 ml of glacial acetic acid in 5O ml of benzene is heated, stirring, and with the water separator turned on for 12 hours on the reflux condenser. The processing is carried out as described in Example 1 A. 12 g of 2-cy | An-3- (2-chloro-4-biphenyl) -2-butenoic acid is obtained, which melts after recrystallization from ethanol at 198 ° -20 ° C ( decomposition ) . ; B. 3- (2-Chloro-4-biphenyl) -l butyl acid. The acid obtained according to Example 1A is recycled in the same manner as described in Example 1B. The 3- (2-chloro-4-biphenyl) -button Acid salt with t, mp, ISO C is obtained with a yield of 5O %: from theory. The free acid melts at: 128-129 ° C. Example 4. 3- (2-Chloro-4-bifenyl) -buttonic acid. ; A. 2-Cyano-3- (2-chloro-4-biphenyl) -2-butenoic acid ethyl ester. A mixture of 57.7 g (0.25 mol) of 4- (2-chlorophenyl) acetophenone, 28.25 g (0.25 mol) of dianoacetic ester, 3.85 g of ammonium acetate and 12 ml of glacial acetic acid in 10O ml of benzene is heated by stirring and connecting a water separator for 9 hours on a reflux condenser. The treatment is carried out as described in Example 1 A. 2-cyano-3- (2-chloro-4-bifaNyl) -2-butenoic acid ethyl ester is obtained. with bp 19O-192 C / SI; mmrt Art. with the release of 53 g (65% of rheory). B. 3- (2-Chloro-4-biphenyl) oil per acid. The ester 1 obtained according to Example 1A is processed as described in Example 1. B. Solcyclohexylsylamine 3- (2-chloro-4-biphenyl) -based acid is obtained. 179-181 C and output 6O% of theory. : The free acid melts at 128,129 ° C. j Example 5. 3- (2 -Fluoro-4-biphenip) -: - 1sl acid. ; , 2.5 g (О, ОО9 mol) of 2-cyano-3- (2-fluoro-4-6-phenyl) -butyric acid are heated, stirring, with 7 ml of hydroiodic acid (density 2, ОО) in 1 O ml of glacial acetic acid acid for 8 hours on reflux. After cooling, the mixture is extracted by shaking with ether. The ether solution is washed with a solution of bisulfate; sodium, then with water and dried. The crude 3- (2-fluoro-4-biphenyl) -mask obtained after distilling off the solvent; the sharnic acid is converted into the cyclohexylamine salt. Free-; The acid from it is melted at 99101 ° C. The yield is 1.6 g (69.5% of theory). j Example 6. 3- (2-Phr-4-biphenyl) i-butyric acid. A. Nitrile 2-cyan-3- (2-fluoro-4-biphenyl) -2 butenoic acid. Mixing with a connected water trap, 21.4 g (0.1 mol) of 4- (2-fluorophenyl) acetophenone, 6.6 g (O, 1 mol) of malonic dinitrile, 1.5 g of ammonium acetate in 70 ml of benzene with by addition of 2.5 ml of glacial acetic acid, the mixture is heated under reflux for 5 hours. The hot solution is filtered. over activated carbon and then mixed with petroleum ether (150 ml), a precipitate formed, which is sucked off and recrystallized from methanol. 8 g (30% of theory) of 2-cyano-3- (2-fluoro-4-biphenyl) -2-butenoic acid nitrile are obtained. C. m.p. , 145-146 C. B. 3- (2-Fluoro-4-biphenyl)-masl on the acid. 1 g (0.0038 mol) of 2-cyano-3- (2-fluoro-4-biphenip) -butenoic acid nitrile is heated with 8 ml of hydroiodic acid (density 2, OO) and 4 ml of glacial acetic acid for 5 hours on the reverse fridge. Re-work as in Example 1 B. Obtain 0.27 g (20.6% of theory) of 1-clohexylamine salt of 3- (2-fluoro-4-biphenyl) - - butyric acid with m.p. 160-162 ° C. The acid liberated from it melts at 991 ° .O. ° C. Example 7. 3- (2-Phylo-4-biphenyl) -buttonic acid. Amide of 2-cyano-3- (2-fluoro-4-biphenyl) -2-butenoic acid. A. Heat, mixing with the connected -. water separator, 21.4 g (O, 1 mol) of 4- (2-fluorophenyl) acetophenone, 8.4 g (O, 1 mol) of cyanacetamide, 1.5 g of ammonium acetate and 2.5 ml of glacial acetic acid in || 50 ml of benzene for 8 hours on the reverse fridge. After cooling, the precipitated precipitate is removed and then rinsed first with benzene and then with water. After recrystallization from methanol, 8.4 (30% of theory) of 2-cyanrH-fluoro-4-bifluh-n-2-mathenic acid amide is obtained with knju 196-198 S., ..,. -tw - b. 3- (2 -Fluoro-4-biphenyl)-oil per cylot. 0.2 g (О, ОО0714 mol) of 2-cyano-3- (2-fluoro-4-biphenyl) -2-butenoic acid amide is heated with 6 ml of hydroiodic acid (density 2, ОО) with 3 ml of glacial acetic acid in for 3 hours on the reverse fridge. Recycled on pr: measure 1 B. Poluchlot after cleaning black

Nikohexylamine salt, 0.1 g (54.5% of re-J ori) 3 2 -fluoro-4-biphenyl) -buttonous kielots with m.p. 99-100 C.

Example 8. Separation of racemic 3- (2-fluoro-4-biphenyl) -buttonic acid aa optically active constituents. 77.5 g (O, 3 mol) of 3- {2-fluoro-4-bif, NILE) -button Noise Acid are dissolved in 1.5 liters of ethanol and mixed with a solution containing 97.2 g (0.3 mol a) quinine in 1.5 liters of ethanol. A colorless precipitate A is obtained, which is sucked off, and the filtrate B. Sediment A is recrystallized 15 times from ethanol (always 30 l), and the right to turn shuyus 3- () torus-4-biphenyl) butyric acid is obtained. 87-88 G (from cyclohexane); + 34.5 °. The yield of 5.5 g;

Solvent is removed from filtrate B and the residue is taken up in hot methanol.

(5OO ml). Upon cooling, a precipitate precipitates. The filtrate is treated 4 more times in the same manner with methanol. The residue remaining upon evaporation of the metharol is dissolved in 500 ml of tegshog acetic ester, i is obtained by standing on a precipitate, which is refined and recrystallized from approximately SCO m acetic ester.

A levvraschayuschuyusya 3- (2 - or4-biphenyl) -buttonic acid with m.p. 8587 C (from cyclohexane);

- 33.5 with the release of 2.3 g.

 ft о р м у л а and 3 о b J) е т. and and | 1. The method of preparation of the formicone-bis-butyric acid of general formula I

sn,

CH-CHj-COOH

where is a halogen atom, or its salt, characterized by the fact that compounds of the general formula II

where i - has the specified value

h means cyan - or carboxamide.

or a carboxyl group esterified, if necessary, with an aliphatic or araliphatic alcohol or phenol,; subjected to recovery and saponification with simultaneous decarboxylation and subsequent separation of the target product in free form, either as a salt, or as racemates, or as optically active isomers.

 2; The method of claim 1, wherein the reduction is carried out with hydriodic acid when heated in a polar solvent.

Priority featured:

.17.08.72

1FI j - halogen atom;

05/03/73, method for producing substituted biphenyl butyric acid or hers. salt.