SI8112479A8 - PROCESS FOR PREPARING 2-(4-isobutylfenil)-propionic acid - Google Patents

Description

CHEMISTRY INSTITUTE:

. »BORIS. KIDRIC '«· p. o;

Inventors: dr. Zupančič Boris, dipl. ing. chem. _: mgr. Mirko Sopčič, B.Sc. Martin Kokalj, B.Sc.

Process for the preparation of 2- (4-isobutylphenyl) -propionic acid

Technical field of the invention

C 07 C 63/60; A 61K 31/19.

The subject of the invention is a new process for the preparation of 2- (4isobutylphenyl) -propionic acid of the formula

CHOH,

I iCHC ^ - ^ - OHCOOH

0Hs with anti-inflammatory, analgesic and antipyretic effects Ibuprofen - as the generic name for the compound is called - is milder in its action, but a particularly important noncorticosteroid anti-inflammatory for patients who do not tolerate anti-inflammatory agents, such as. aspirin, indomethacin, phenyl butazone or oxyphenylbutazone, and pyrazoles, which, although effective, are more toxic but more toxic to the gastrointestinal tract.

Technical field of the invention

There was a need to find a new, technologically advanced process for the preparation of 2- (4-isobutylphenyl) -propionic acid by simple, safe technology, good yields and satisfactory purity.

The state of the art

In British patent file no. 971000 are indicated, several options for the synthesis of said bio-active ingredient are described, and a process resulting from isobutylacetophenone with a Willgerodt-Kindler reworking to 1- (4-isobutylphenyl) -acetic acid is described. The latter is esterified and then converted into diethyl 2- (4-isobutylphenyl) malonate, followed by methylation, hydrolysis and decarboxylation. The disadvantage of this process is in its 6 reaction steps and the relatively quite demanding technology of some reaction steps (to mention only deprotonation with sodium or sodium ethylate, which is prepared in situ). The synthesis also cannot ignore the dangers posed by operators to working with methyl iodide and diethyl carbonate, which are known carcinogens.

In the same way, a process which, according to A. KLeemann (Fharmazeutische Virkstoffe, 1978, p. 243), does not promise to the manufacturer in terms of technological accessibility of special facilities.

Starting from isobutylbenzene, chloromethylation via HLanc leads to 4-isobutylbenzyl chloride, which is converted by cyanide to 4-iso-butyl benzyl cyanide, which is deprotonated with sodium amide and by alkylation of the resulting carbanion with 2-methyl-iodenomutyl phenylidene phenyl ) -propionitrile. Alkaline hydrolysis of nitrile is followed by 2- (4-isobutylphenyl) -propionic acid decision. and i

Apart from the two basic processes, a number of new processes are still appearing in the patent literature to this day, for which it is also known whether any of them are being used, even for production purposes. So e.g. to name just a few of the most typical:

The process according to British patent no. 1160725 is carried out by the conversion of 4-iso-butylacetophenone to 3- (4-isobutylphenyl) epoxybutyric acid ester using ethyl chloroacetate. the resulting product is hydrolyzed and converted to 2 (4-isobutylphenyl) -propanol by thermal decomposition. The latter is oxidized e.g. with silver -__ nitrate to the corresponding compound. Given the low synthesis efficiency and instability of the 3- (4-isobutylphenyl) -2,3-epoxime hydrochloric acid ihtermediame alkaline salt, the process to work on an industrial scale seems less appropriate.

The further process described in Japanese patent file 77θ28 (0107 C 63) is derived from 2 (4-isobutylphenyl) -acetic acid ethyl ester, which is reacted with paraformaldehyde, tertiary hutoxide and dimethyl style f oxide via intermediate 2- (4-Iso-butylphenyl) -hydroxymethyl-ethyl acetate is reacted to 2- (4-isobutylphenyl) -acrylic acid. Hydrogenation of the latter above Pd / C yields (d, 1) -2- (4-isobutylphenyl) -propionic acid.

The process is interesting because it raises the question of the possibility of stereoselective hydrogenation and thereby the production of a pharmacologically active enantiomer with high optical purity (Stephen C. Stinson, 0 & EN, Sept. 1, 26, 1980). The discovery of a suitable stereoselective catalyst is, however, subject to the efforts of many modern molecule makers worldwide, since the production of the pharmacologically active enantiomer of 2- (4-isobutylphenyl) propionic acid may justify the length of the reaction sequence.

Description of solution to a technical problem with implementation examples

Our intention - to find a new route that would lead to a high efficiency of synthesis in a simple and economical way and would therefore be particularly suitable for industrial scale production, has, according to our experience so far, been achieved by the following procedure:

Reaction Scheme:

R = (CH ₅ ) ₂ CHCH ₂ PTO = Phase Transfer Catalysis

- 5 According to the process of the invention, 4-isobutylacetophenone is reduced with sodium borohydride in polyethylene glycol or polyethylene glycol ether of a mean molecular weight of M '200 to 400, or in a non-volatile organic solvent, such as e.g. benzene or toluene, with the addition of a catalytic amount of polyethylene glycol or. polyethylene glycol ether with M 200 to 400. It is recalled that in the present case the catalytic amount is 20 to 40 mol%. The resulting 1 (4-isobutylphenyl) -ethanol is halogenated by means of a ZnSO4-Ol ^ -complex into 1- (4-isobutylphenyl) -ethyl chloride. This compound is converted by nucleic acid substitution in a dipblar, aprotic solvent such as dimethylformamide, dimethylsulfoxide, with sodium cyanide at a temperature of 3θ ° θ to reflux in 2- (4-isobutylphenyl) propionitrile. From the nitrile, however, 2- (4-isobutylphenyl) -propionic acid is obtained by hydrolysis in a conventional manner.

All of these reactions take place in high yields, exceeding the total synthesis yield of 56% ·

The invention illustrates but does not in any way limit the embodiment:

- 6 1.1. Preparation of 1- (4-isobutylphenyl) -ethanol

Insert 1700 ml of benzene, 181.44 g of polyethylene glycol-400 (Teol, Ljubljana, JU), 42.9 g of sodium borohydride and 200 g of 4-isobutylacetophenone into a 4-well flask with an intense cooler and agitator and heat with heating during intense stirring. cushion to reflux. After six hours of boiling, the mixture is cooled to room temperature, poured into 850 ml of water and stirred for 5 minutes. 1). After deciding, shake the benzene layer three more times for 2 minutes with 850 ml of water each and dry with Na2SO4 (50 to

g). The next day, the desiccant was drained off and washed with 2 x 50 ml of benzene, which was added to the main amount evaporated on a rotary evaporator (1.5 to 2 hours; 60 ° C). Yield: 198.61 g (98.2%) of the product with η-θ: 1.5069 and a purity higher than 95% (by gas chromatography).

In an analogous way, toluene can be used as a solvent instead of benzene.

1.2. Chlorination of 1- (4-isobutylphenyl) -ethanol

In a 2 1-liter flask, mix with water, a mixture of 198.0 g of 1- (4-isobutylphenyl) ethanol 5,12 g of sound c j with a stirrer, a thermometer, a dropper and a reflux condenser (CaClg). .nkkl added 445 ml of benzene, cooled to 15 ° 0, under vigorous stirring for 10 minutes, 96 ml of thionyl chloride (Merck). When the first half of the total amount of thionyl chloride is added dropwise, the reaction mixture must be cooled with ice due to the exotherm of the reaction (bath temperature is 0 to 5 ° C). Then raise the bath temperature to 15 ° 0 ·

- 7 After the addition of S0Gl _{2 is} completed, the reaction mixture is warmed to 20 ° G and stirred at this temperature for 2 hours, then cooled to 5 ° G again and added dropwise at 5 to 10 ° 0 1112 ml of saturated aqueous solution for about 15 minutes.

After the last addition, the benzene layer was stirred and separated for 5 minutes and washed twice with 370 ml of water each time (last rinsing with water at 40 ° G). The benzene layer was evaporated on a rotary evaporator overnight (30 minutes at 70 ° 0) after drying over Na 2 SO 4. Yield: 218.92 g (100.2%) of crude product with a purity of over 90% (GG) IR spectrum: 760 cm ^- ^ belt.

1.3 Cyanidation of 1- (4-isobutylphenyl) -ethyl chloride

109.18 g of sodium cyanide (Pluka AG swiss) and 346 ml of dried dimethyl sulfur oxide (Prosjnth, Riedel-de-Ha & i AG) were introduced into a 2 l four-headed flask with a thermometer, contact thermometer, a dropper and a reflux condenser with GaGlg barrier and warm the mixture to 30 ° G with stirring while stirring with 218.92 g of 1- (4-isobutylphenyl Netilki ori da.) After 15 minutes at unchanged temperature, the chloride addition is complete followed by stirring for 20 minutes. The reaction was diluted with 346 ml of benzene and the separated inorganic salts were filtered off, the Pil t cake was washed with 34 ml of benzene and benzene (70 ° G, 30 minutes, water-jet vacuum) was evaporated from the filtrate on a rotary evaporator.

Weigh out approximately 820 g of the mixture (product with DMSO), transfer to a 1 l capillary flask and short (100 mm)

-8 column filled with Braunschveig spirals and insulated with heating tape. It is heated by means of a heating pad, and the temperature of the heating strip is controlled by a probe tied to the Herastat / Heraeusrele. Distilled in a water pump vacuum, the main fraction being trapped from 90 to 78 ° C at 55-12 Torr (7237-1579 Pa). The residual temperature in the flask is 115 ° 0 after completion of the distillation, and the distillation time is about 1.5 hours.

We weigh 214.0 g of the distillation residue and capture another 518.5 g (86.3%) of the reverse DMSO with η ^ θ: 1.4800 (Ut .: 1.4795).

The cooled distillation residue (214.0 g) was diluted with 208 ml of chloroform and shaken gently in a 1 L funnel separator twice with 208 ml of water each time (shaking the mixture vigorously). The washed chloroform layer was dried over Ifc ^ SO ^ overnight, and the filter cake was rinsed with chloroform, if necessary, then evaporated on a rotary evaporator (70 ° 0) for 20 minutes in a water jet vacuum.

Yield: 179.13 (82.5%) si

Analytics: IB spectrum-absence of 760 cm band.

In an analogous manner, dimethyl sulfamide may be used instead of dimethylsulfoxide.

1.4 ELdrolysis of 2- (4-isobutylphenyl) -propionitrile

Heat in a 500 ml quadruped flask with a thermometer, contact thermometer and agitator in 15 minutes, 179,23 6 '

2- (4-Isobutylphenyl) -propionitrile in 247 ml of 70% and stirred at this temperature for another 2 hours.

- 9 At room temperature, the cooled reaction mixture was diluted with 557 ml of ice water and 446 ml of ether, separated and the aqueous layer extracted with 111 ml of ether. The combined ether extracts were washed twice with 200 ml of water each, transferred to a 2 L flask and extracted with 891 ml of 10% NaOH for 50 minutes at room temperature. After deciding the aqueous layer, the latter was shaken twice with 446 ml of ether each and (water) precipitated from the end. H01 in an ice bath, which consumes 242 ml of HCl concentrate. Dilute the extracted oil with 200 ml of ether and, after deciding the aqueous layer, shake the oil with 150 ml of ether. The combined ether extracts were washed with 150 ml of water and the ether was evaporated on a rotary evaporator (final temperature 70 ° C, water jet vacuum).

Profit 148.6? g of crude product (63.5% calculated on isobutylacetophenone). The hydrolysis yield is 78.4%.

The crude oil is distilled from a 250 ml quadruped pumpkin via a column (5 cm) filled with spirals which is isolated by a heating strip with a probe tied to the Herastat-Heraeus relay. Distill in vacuum of the oil pump. The main fraction is the one that distils in the range of 137 cells and 152 ° 0 at a pressure of 0.1 Torr (13 Pa). 138.49 g of a light yellowish colored oil are obtained which solidify on an on-going basis. Distillation yield is 93.2%, melting point 73.5 to 75 ° 0.

Distilled 2- (4-isobutylphenyl) -propionic acid, which is colorless, is further purified by petroleum ether (40 to 7θ ° 0) so as to add 554 ml of petroleum ether to the acid and cool the solution overnight in a cooling box. The next day, crystalline slurry was made, and the filter cake was washed with 10 ml of cooled petroleum ether. Dry at 40 ° G

- 10 under vacuum over calcium chloride overnight. ,

Yield: 1 $ 1.1Og (or 56% on isobutylacetophenone) of pure, snow-white 2- (4-isobutylphenyl) -propionic acid from m.p. 74.5 to 75.5 ° 0 (Fus-O-mat, Heraeus); on a single-layer thin layer chromatogram, the IR and NMR spectra correspond to those expected. The beat-up efficiency is 94.7%.

/ 4

An indication of the best, report a known performance for

- ----— —economic exploitation of the invention

1.1. Preparation of 1- (4-isobutylphenyl) -ethanol

Insert 1700 ml of benzene, 181.44 g of polyethylene glycol-400 (Teol, Ljubljana, JU), 42.9 g of sodium borohydride and 200 g of 4-isobutyl acetophenone in a 4 l flask with an intensive cooler and agitator and heat with vigorous stirring. heating pad to reflux. After six hours of boiling, the mixture was cooled to room temperature, poured into 850 ml of water and stirred for 5 min. Pour the solution into a 3 L separator, separate the layers and shake benzene vigorously for 2 minutes with 850 ml of dilute hydrochloric acid (HCl: 1 ^ 0 = 40: 1). After deciding, shake the benzene layer three more times for 2 minutes with 850 ml of water each and dry with NagSO ^ (30 to

g) · Dry the desiccant the next day and wash it with 2 x 50 ml of benzene, which is added to the main amount which is evaporated on a rotary evaporator (1.5 to 2 hours; 60 ° 0). yield: 198.61 g (98.2%) of the product with a n ^: 1.5069 and a purity higher than 95% (by gas chromatography).

1.2. Chlorination of 1- (4-isobutylphenyl) -ethanol

In a 2 1-liter flask, stirring, 198.0 g of 1- (4-isobutylphenyl) ethanol 5 »12 g of anhydrous zinc chloride and 445 are added dropwise with a stirrer, a thermometer, a dropper and a reflux condenser (OaOl ^ bar). ml of benzene cooled to 15 ° 0 with vigorous stirring for 10 minutes 96 ml of thionyl chloride (Merck). When the first half of the total amount of thionyl chloride is added dropwise, the reaction mixture must be cooled with ice due to the exotherm of the reaction (bath temperature is 0 to 5 ° 0). The temperature of the bath is then raised to 15 ° 0.

After the addition of SOOl ^ is completed, the reaction mixture is heated to 20 ° C and stirred at this temperature for 2 hours, then cooled again to 5 ° C and added dropwise at 5 to 10 ° 0 1112 ml of saturated aqueous Na 2 Oj solution for about 15 minutes.

After the last addition, the mixture was stirred for 5 minutes, separating the benzene layer, which was washed twice with 370 ml of water each (last rinsing with water at 40 ° C). The benzene layer was evaporated on a rotary evaporator (30 minutes at 7 ° C) overnight after drying over a drying agent overnight. Yield: 218.92 g (100.2%) of crude product with a purity above 90% (GO) IR spectrum: 760 cm ^- ^ band.

1.3 Cyanidation of 1- (4-isobutylphenyl) -ethyl chloride

Add 109.18 g of sodium cyanide (Pluka AG Switzerland) and 546 ml of dried dimethylsulfoxide (Prosjnth., Riedel-de-Ha & i AG) ) and the mixture was warmed to 50 ° C with stirring while stirring with 218.92 g of 1- (4-isobutylphenyl) ethyl chloride. After 15 minutes at unchanged temperature, the chloride addition is complete followed by stirring for 20 hours. After completion of the reaction, the mixture was diluted with 546 ml of benzene and the separated inorganic salts were filtered off. Wash the filter cake with 54 ml of benzene and evaporate the benzene (? 0 °, 30 minutes, water jet vacuum) from the filtrate on a rotary evaporator.

Weigh out approximately 820 g of the mixture (product with DMSO), transfer to a 1 l capillary flask and short (100 mm)

-43 column filled with Braunsch.weig-spiral ami and insulated with heating tape. It is heated by means of a heating pad, and the temperature of the heating strip is controlled by a probe tied to the Herastat / Heraeusrele. Distilled in a vacuum water pump, and the main part is catching the fraction from 90 to 78 ° G at 55-12 Torr (7237-1579 Pa). The residual temperature in the flask is 115 ° 0 after completion of the distillation, and the distillation time is about 1.5 hours.

Weigh out 214.0 g of the distillation residue and capture another 518.5 g (86.3 reverse DMSO with η ^ θ: 1.4800 (Lit. n.p °: 1.4795).

The cooled distillation residue (214.0 g) was diluted with 208 ml of chloroform and shaken gently in a 1 L funnel separator twice with 208 ml of water each time (shaking the mixture vigorously). The washed chloroform layer was dried over N2 SO4 overnight, and the cake was washed with chloroform if necessary, then evaporated on a rotary evaporator (70 ° 0) for 20 minutes in a water-jet vacuum.

Yield: 179.13 (82.5%)

Analytics: IR spectrum-absence of 760 cm band.

1.4 Hydrolysis of 2- (4-isobutylphenyl) -propionitrile

Heat in a 500 ml quadruped flask with a thermometer, contact thermometer and agitator in 15 minutes, 179.23 g

2- (4-Isobutylphenyl) -propionitrile in 247 ml of 70% H 2 SO 4 and stirred at this temperature for another 2 hours.

-44 At room temperature, the cooled reaction mixture was diluted with 557 ml of ice water and 446 ml of ether, separated and the aqueous layer extracted with 111 ml of ether. The combined ether extracts were washed twice with 200 ml of water each, transferred to a 2 l flask and extracted with 891 ml of 10% -:; .. iNaOH for 3θ minutes at room temperature. After deciding the aqueous layer, the latter was shaken twice with 446 ml of ether each and (water) precipitated from the end. H01 in an ice bath, which consumes 242 ml of concentrated HCl. Dilute the extracted oil with 200 ml of ether and, after deciding the aqueous layer, shake the oil with 150 ml of ether. The combined ether extracts were washed with 150 ml of water and the ether was evaporated on a rotary evaporator (final temperature 7θ ° C, water jet vacuum).

Yield 148.67 g of crude product (63.5% calculated on isobutylacetophenone). The hydrolysis yield is 78.4%.

The crude oil is distilled from a 25θ ml quadruped pumpkin via a column (5 cm) filled with spirals, which is isolated by a heating strip with a probe tied to the Herastat-Heraeus relay. Distill in vacuum of the oil pump. The main fraction is the one that distils in the range 137 to 152 ° C at a pressure of 0.1 Torr (13 Pa). 138.49 g of a light yellowish colored oil are obtained which solidify on an on-going basis. Distillation yield is 93.2%, melting point 73.5 to 75 ° 0.

The distilled 2- (4-isobutylphenyl) -propionic acid, which is colorless, is further purified by petroleum ether (40 to 7 ° C) by the addition of 554 ml of petroleum ether to the solidified acid and the solution is cooled overnight in a cooling box. . The next day, crystalline porridge is made, and the filter cake is washed with 10 ml of cooled petroleum ether. Dry at 40 ° 0

-45 in a vacuum above. calcium chloride overnight. .

Yield: 131.10 g (or 56% on the isobutyacetophenone) of pure, snow-white 2- (4-isobutylphenyl) -propionic acid from the ground. 74.5 to 75.5 ° G (Rus-O-mat, Heraeus); on a single-layer thin layer chromatogram, the IR and NMR spectra correspond to those expected. Melting efficiency is 94.7%.

Claims (3)

A process for the preparation of 2- (4-isobutylphenyl) -propionic acid, characterized in that the 4-isobutylacetophenone is reduced by sodium borohydride in polyethylene glycol or polyethylene glycol ether with a medium molar mass of M 200 to 400 or in a non-polar solvent with the addition of a catalytic amount as 20-40 mol. % of polyethylene glycol or polyethylene glycol ether with M 200 to 400, the resulting 1- (4-isobutylphenyl) -ethan is halogenated with a ZnS0 ₂ Cl2 'complex in 1- (4-isobutylphenyl) -ethyl chloride and this with sodium cyanide in a dipolar aprotic solvent at a temperature of 30 [deg.] C. to reflux is converted to 2- (4-isobutylphenyl) -propionitrile, which is hydrolyzed to 2- (4-isobutylphenyl) -propionic acid. Process according to claim 1, characterized in that benzene or toluene is used as a non-polar solvent. Process according to claim 1, characterized in that dimethylformamide or dimethyl sulfoxide is used as a dipolar aprotic solvent.