SE453094B - USE OF A MAGNESIUM HALOGENIDE COMPLEX OF ALFA-BROMOPROPIONIC ACID AS INTERMEDIATE FOR THE PREPARATION OF 2-ARYLPROPIONIC ACIDS - Google Patents

Abstract

Compounds of the formula aryl CH(CH3)COOMgX, in which aryl denotes 6-methoxy-2-naphthyl, 4-alkylphenyl or 4'-fluoro-4-biphenyl, and X denotes chlorine or bromine, and their etherates, are described. They are prepared by treating a solution of the corresponding arylmagnesium bromide with the solution of a complex of the formula CH3CH(Br)COOMgX in an aprotic solvent containing an ether. The compounds are important intermediates in the synthesis of known 2-arylpropionic acids of therapeutic importance.

Description

Sodium, magnesium or calcium salts of 2-bromopropionic acid with the structure CH3CH (X) COM, where X represents bromine and M represents OLi, ONa, O (Mg) š or 0 (Ca) § (cf. Table II in US 3,959,364).

However, it has been found that the preparation of 2-arylpropionic acids, in particular the valuable compound 2- (6-methoxy-2-naphthyl) propionic acid, by this process suffers from a number of disadvantages including the preparation of halopropionate salt in the suitable solvent medium, which must be used for the coupling reaction, which results in poor results in production on an industrial scale.

It would therefore be extremely valuable to have access to a coupling process using an aryl-Gridnard reactant and a suitable halopropionic acid derivative, obtaining the desired 2-arylpropionic acids in a light manner and with reproducibly high yield and purity and which could easily adapted to commercial production on an industrial scale.

It has now surprisingly been found that an improved coupling reaction is obtained if, instead of one of the above-mentioned salts, a mixed magnesium halide complex of alpha-bromopropionic acid is used, i.e. a substance of the formula CH 3 CH (Br) COOMgX, where X represents chlorine or bromine or an ether thereof. A direct comparison between the magnesium salt of alpha-bromopropionic acid (prepared by the two methods described in U.S. Pat. No. 3,959,364) and the novel complex of the invention shows a remarkable difference in the yield of the resulting end products (about twice the difference). , as described in more detail in the examples.

It is a further advantage of the present coupling process that its yields are not affected by the preparation of the mixed magnesium halide complex to the extent that the yields of the coupling process of U.S. Pat. No. 3,959,364 are affected by the method of preparation of the 2-bromopropionate salt (cf. U.S. Pat. 3,959,364, column 3, lines 10 and 11).

The mixed magnesium halide complex of alpha-bromopropionic acid is prepared by treating the free acid with a Grignard reactant. Although the nature of the hydrocarbon moiety in the Grignard reactant is not critical, it is preferred that the free hydrocarbon formed in the reaction between alpha-bromopropionic acid and the Grignard reactant does not interfere with the coupling step or work-up. Consequently, the Grignard reactant derived from hydrocarbons which are gaseous or liquid at the reaction temperatures are particularly suitable, for example alkylmagnesium-Grignard reactants having 1 to 12 carbon atoms or arylmagnesium Grignard reactants having 6 to 9 carbon atoms. Specific Grignard reactants that can be used for this purpose are methylmagnesium chloride, methylmagnesium bromide, ethylmagnesium chloride, ethylmagnesium bromide, isopropylmagnesium chloride, phenylmagnesium chloride and o-, m- and p-tolylmethane chloride and symyl. methylmagnesium bromide, since they are readily available commercially, are inexpensive and lead to the formation of methane gas, which leaves the reaction mixture and thus does not interfere with the reaction or work-up.

It has surprisingly been found that the addition of one of the above-mentioned Grignard reactants to alpha-bromopropionic acid primarily results in the formation of the above-mentioned complex. Addition of the Grignard reactant across the carbonyl moiety of the carbonic acid, which reaction would normally take place to a large extent, appears to be minimal even when using a molar excess of the Grignard reactant.

The mixed magnesium halide complex is usually prepared in an aprotic solvent medium comprising an ether, eg diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, di- (n-butyl) ether, etc. The solvent medium may include other aprotic solvents, for example aromatic hydrocarbons, e.g. benzene and toluene.

A preferred solvent medium for the preparation of the complex is tetrahydrofuran. Although the order of addition of the reactants is not strictly critical, it is generally preferred to add the Grignard reactant to the alpha-bromopropionic acid. The Grignard reactant in the solution is preferably about 1 to 4 molars, most particularly from about 2 to about 3 molars. A final complex solution for use in the direct coupling step is from about 1 to about 2 molars and is particularly desirable from about 1.0 to 1.5 molars. The temperature in the complexing step is usually kept between about -20 and 30 ° C, preferably between about -10 and 2000.

The coupling reaction itself is conveniently carried out by contacting a solution of the mixed magnesium halide complex of alpha-bromopropionic acid with the arylmagnesium bromide in an anhydrous, aprotic organic solvent medium. Suitable solvent media for the reaction include organic ethers and mixtures of organic ethers with aromatic hydrocarbons as set forth above for the complexing step. An especially preferred solvent medium for the coupling reaction is tetrahydrofuran. It is preferred that the arylmagnesium bromide solution be between 0.5 and 2 molar, most particularly about 1.0 molar.

The actual coupling process can be performed in a temperature range from about 0 to about 10,000, preferably between about 10 and 6,000.

It is very particularly preferred to allow the temperature to rise gradually during the addition step up to about 40-60 ° C and then to allow the temperature to return to room temperature until the desired degree of reaction has been reached.

Although the coupling reaction can be carried out using varying proportions of the reactants to each other, it is preferred to use approximately equimolar amounts of the mixed Å magnesium halide complex and the aryl-Grignard reactant. Suitable ratios are from about 0.9: 1.1 to 1.1: 0.9 complex: Grignard reactant.

The reaction can be carried out by conventionally bringing the two reactants into contact with each other in the solvent medium in any conventional manner. However, it is preferred to add the mixed magnesium halide complex to the Grignard reactant and keep these reactants in intimate mixing until the desired reaction is substantially complete.

The time required for carrying out the desired reaction is, of course, influenced by the particular choice of reactants, solvents and reaction temperature and is usually adjusted by those skilled in the art to obtain an optimum production of the desired compound. However, such reaction times are usually in the range of about 10 minutes to about 20 hours, usually in the range of about 1 to about 5 hours.

After the coupling reaction has proceeded to the desired stage of completion, the reaction is stopped by adding to the reaction mixture containing the coupled complex arylCH (CH5) COMgX a dilute acid, preferably a dilute aqueous mineral acid, eg hydrochloric acid or sulfuric acid, for the reactions the conventional way. The free 2-arylpropionic acid compound can then be isolated and purified from the acid-added reaction mixture by conventional methods, for example, extraction with alkaline aqueous solution, eg aqueous sodium or potassium hydroxide solution, separation of the aqueous alkaline phase from the organic phase and acidification of the aqueous alkaline phase to release the desired acid, which may optionally be extracted into an organic solvent or directly purified in the usual manner, for example by washing and / or crystallization.

The crude reaction product may, if desired, be directly converted into a pharmaceutically acceptable derivative of the carboxylic acid, for example a salt, an ester or amide thereof, or resolved into optical ismers.

The coupling reaction is carried out easily and conveniently on a factory scale and gives yields of purified product in the range of 50-75%.

The following examples illustrate the present invention. The examples are not intended to limit the spirit or scope of the invention in any way.

Preparation 1 Preparation of 2- (6-methoxynaphthyl) magnesium bromide 23.7 g (0.1 mol) of 2-bromo-6-methoxynaphthalene are dissolved in 30 ml of toluene and 40 ml of tetrahydrofuran with heating. This solution is then added over a period of 10 to 15 minutes to an excess of 3 g (0.12 mol) of magnesium metal, 15 ml of toluene and 15 ml of tetrahydrofuran under a nitrogen atmosphere. The reaction mixture is then cooled and stirred for a further hour at 25-30 ° C. The mixture is then transferred from the excess magnesium to a clean, dry vessel under nitrogen and allowed to stand at 10 ° C to form a 1.0 molar Grignard reactant.

The Grignard reactant can be prepared in a similar manner using tetrahydrofuran as the sole solvent.

In the same way, by using a smaller amount of solvent, a more concentrated Grignard reaction component can be prepared, for example 1.5 molar.

Preparation 2 Mixed magnesium halide complex of alpha-bromopropionic acid, 3 g (0.1 mol) of alpha-bromopropionic acid and 40 ml of toluene is cooled to 100 ° C and to this is slowly added a solution of about 1 ml of z-molar methylmagnesium bromide in tetrahydrofuran / toluene (1: 1), pouring the temperature at 10-20 ° C for an addition time of 15-20 minutes. The reaction mixture is then stirred at 5 ° C for an additional 20 minutes to give a 1.1 molar solution of the complex.

The mixed magnesium halide complex can be prepared in a similar manner using tetrahydrofuran as the sole solvent.

In the same way, methylmagnesium bromide can be exchanged for other Grignard reactants, eg methylmagnesium chloride, E isopropylmagnesium chloride, phenylmagnesium chloride, etc., in concentrations ranging from about 1 to about U-molar. The mixed magnesium chloride complex of alpha-bromopropionic acid (prepared as described above using 3 molar CH 5 MgCl in tetrahydrofuran) is isolated in crystalline form as its tetrahydrofuran monoetherate after distillation of tetrahydrofuran from a tetrahydrofuran solution and analyzed. M.p .: 147-15500.

IR (KBr) = 1625, 1H 50, 1372, 1291, 1200, 1070, 1030, 988 and 890 cm -1; NMR (D 2 O) delta 1.8 (multiplet, δ) 3.7 (multiplet, M) and δ, 35 ppm (quartet, J = 7) Elemental analysis for C7H12BrClMgO3: 'Mg Cl Calculated, z: 8.57 i2, u9 Found,% = 8.63 12.97 Preparation 3 Preparation of arylmagnesium bromides 0.025 mol of aryl bromide is dissolved in 18_ml tetrahydrofuran. is then added under a nitrogen atmosphere to an excess of 3 g (0.02 mol) of magnesium metal and 7 ml of tetrahydrofuran, the temperature is maintained at 50 DEG-60 DEG C. by cooling for an addition period of 10 DEG-15 DEG C. The reaction mixture is then transferred. from the excess magnesium to a clean, dry vessel under nitrogen and allowed to stand at 10 ° C to form a 1.0 molar Grignard reactant The following Grignard reactants are prepared as follows: 2- (6-methoxynaphthyl) magnesium bromide, H- (U'-fluorobiphenyl) magnesium bromide, 1- (U-isopropylphenyl) magnesium bromide, 1- (H-isobutylphenyl) magnesium bromide and 1 - (H-methylphenyl) magnesium bromide.

Preparation 4 A. Preparation of the alpha-bromopropionic acid mixed magnesium halide complex 3.8 g (0.025 mol) of alpha-bromopropionic acid are dissolved in 8 ml of tetrahydrofuran and the solution is cooled to -10 ° C. To this solution is added 3-molar methylmagnesium chloride in 8 ml of tetrahydrofuran over a period of 15 minutes while maintaining the temperature at -10 to 0 ° C. A 1.1 molar solution of the complex is obtained, which is allowed to stand at 0 ° C until used.

H 1 453 094 In the same way, the corresponding magnesium-bromide complex can be prepared by exchanging 3-molar methylmagnesium chloride for 1-molar methylmagnesium bromide.

B. Preparation of the magnesium salt of alpha-bromopropionic acid 3.8 g (0.025 mol) of alpha-bromopropionic acid are dissolved in 6 ml of methanol and the solution is cooled to -10 ° C. To this solution is added a 0.5 molar magnesium methoxide solution in 25 ml of methanol for a period of minutes while maintaining the temperature at -10 to 0 ° 0.

The methanol is then removed in vacuo to give the solid salt, which is dried in vacuo at 50 ° C for 12 hours to give the dry magnesium salt. Yield: H, 1 g (0.0125 mol).

Purity: 97.2%. This salt is dissolved in 19 ml of tetrahydrofuran for the coupling reaction.

Example 1 A. The solution of the complex from Preparation 2 is slowly added to the Grignard solution from Preparation 1, all the while maintaining the temperature at 15-20 ° C for an addition time of 10-15 minutes. The temperature of the reaction mixture is allowed to rise to room temperature and the mixture is stirred for 2 hours. The reaction mixture is then cooled in an ice bath and a solution of 20 ml of 12-normal hydrochloric acid and 150 ml of water is added. After stirring the solution for 5 minutes, filter the two-phase system and wash the filter cake with 55 ml of toluene and 50 ml of water. The organic phase is extracted with 10% potassium hydroxide solution (2 x 150 ml) and the combined basic extracts are washed with 50 ml of toluene and neutralized to a pH of 1 by means of 12-normal hydrochloric acid. The white solid 2- (6-methoxy-2-naphthyl) propionic acid is filtered off in vacuo and dried in vacuo at 55 ° C to give 15.2 g (66%). mp = 1u9.5-153.5 ° c.

B. Alternatively, after filtration, the organic phase can be extracted with a 10% potassium hydroxide solution (2 x 150 ml), which is washed with 30 ml of toluene and filtered. 15 ml of methanol and 12 ml of toluene are added and then a sufficient amount of 12-normal hydrochloric acid to bring the pH of the mixture to between H and 5. The resulting slurry is then heated at reflux for 1 hour, cooled and filtered. The precipitate is washed with 20 ml of water and 2 x 3 ml of toluene and 2 x 3 ml of hexane and dried in vacuo at 5500 to give 15.0 g (65.1%) of compound. Mp: 154.5-15500. 453 094 Example 2 67 ml of a 1.5 molar solution of the mixed magnesium chloride complex of alpha-bromopropionic acid in tetrahydrofuran (prepared using 3 moles of methylmagnesium chloride) is slowly added to a cooled to 10 ° C 1, 5-molar solution of 2- (6-methoxynaphthyl) magnesium bromide in 67 ml of tetrahydrofuran at a rate such that the temperature is maintained at 55 ° C or below. The resulting slurry is stirred for 1 hour at 50 ° C and then heated to reflux, allowing 30 - 40% of the tetrahydrofuran to distill off. The reaction mixture is cooled to 50 ° C, 30 ml of toluene are added and the mixture is quenched with hydrochloric acid and worked up as described in Example 3B to give 2- (6-methoxy-2-naphthyl) propionic acid. Yield: 73% - mp: 156-157 ° C.

Example 3 A. The magnesium salt of alpha-bromopropionic acid, i.e. (CH 3 CH (Br) -COO] 2Mg, is prepared by reacting the acid in molar equivalents of magnesium carbonate, then drying the salt in vacuo at 60 ° C.

A yield of the mixed magnesium chloride complex used in Example 2 against this salt results in a yield of 3U, 7% of the compound.

B. The salt of Part A is also prepared using one molar equivalent of magnesium methoxide, removing methanol as an azeotrope. A use of the salt in the process of Example 2 gives a yield of 43.0% of the compound.

Example N Example 3A is repeated except that one molar equivalent of anhydrous magnesium chloride is added to the magnesium salt before the coupling reaction. A yield of 5.1% of the compound is obtained.

Example 5 The procedure of Example 3 B is repeated except that equimolar amounts of alpha-bromopropionic acid and magnesium methoxide are used. A yield of 35.1% of the compound is obtained.

Example 6 Comparative coupling reactions using mixed magnesium-halide complexes and Mga salts.

The following coupling reactions (using the scale given below) are carried out using both the mixed magnesium chloride complex of alpha-bromopropionic acid (prepared as in preparation Ä A) or the magnesium salt of alpha-bromopropionic acid (prepared as in I 455 094 prepared as in Preparation UB), and corresponding Grignard reaction component (prepared as in Preparation 3). The procedure (illustrated for a 0.025 molar scale) is as follows.

A 1.0 molar solution of arylmagnesium bromide is cooled to 1000 and a solution of either the magnesium salt or the magnesium chloride complex in tetrahydrofuran is added over a period of minutes, all while maintaining the temperature at 10 - 55 ° C.

The reaction mixture is then stirred for 2 hours at 25-3000.

The reaction mixture is then cooled to 10 ° C and a solution of 10 ml of 12-normal hydrochloric acid and 50 ml of water is added. Then 50 ml of toluene are added and the aqueous phase is separated and discarded. The organic phase is extracted twice with 50 ml of 10% potassium hydroxide solution. The basic extracts are combined and neutralized with hydrochloric acid, whereby a precipitate is obtained which is filtered off and dried at 5000 DEG.

The results obtained are given in the following table. ~ fi H0-mzz pw fifi nw Rom mo n ^ om V uwëonnæs fi wmcwme www pmncwnuxsuonm o.mm mmz | ^ fl acmw fi> monmow «| = vx« Hoë mo fl o oozwawm "nam _ awsewum ^ nmV u fi sonnsm m mwhm mwhm mwhm mwhm | ^ fl zcmw fl zaonmom «| = v | fi aoE moqo ^ m>.« V u fl sopnës fl mucwms. æwv ooæm «| om« “nam w.æm * mä | ^ fl æ: wm fi nno: Hw |. = V | = fl os mmo.o uwssmuw . | wcwnw> æ mzz ^>. m V ø fl ëomnës fl mwsmms m Qwm 00 ~ = H «@nH" gsm @ .o @ How: | ^ H> nw @ fl n »°: fl« |. = v | = ace m ~ o.0 uæ.wm u ^ m. flfl v u fl ëonnës fl mwcwms =.> m uwzcmnuxsøonm om = mwz | ^ H> »mmzwxo» wE | mv | m Hos N fl. o «o.wm n ^ fl. omv u fi ëonnës fl mmcwm ms u» vm > fi owä | ^ H> »mmc fi xo» wE | wv | N Hos w fi. o 4 01 unmcm fl nw Hos nu. .nnwpcmconeox Ia unmco fi pxmmn> m nwøwcms MW R Awv xmHmEox | How2. mxm fi nuwëo fl xmpm wanna: x mums nm flfl m> m mc «: u: m> cw uwsv uw fi H # nm> nmwc fi cxnmE: <ousmm u fl mwnmws wc fi: wnnw | unmcw fi nw | Hæn <m fl mxn above i h5 m3m - a higher yield (approximately twice) of a product with a higher purity of the mixed magnesium chloride complex is maintained.

Similarly, comparable results can be obtained in the preparation of the following 2-arylpropionic acid or 2- (H-isobutylphenyl) propionic acid and 2- (H-methylphenyl) propionic acid.

By stopping the above procedure before quenching with the aqueous acid and removing the solvent in vacuo, the coupled magnesium halide complexes, arylCH (CH5) COOMgX; or ether thereof is isolated.

The mixed magnesium chloride complex of 2- (6-methoxy-2-naphthyl) -propionic acid, like its tetrahydrofuran monoetherate with a purity of 98.1%, exhibits the following properties. Mp: 11300 (dec.). IR (KBr plate): 1600, 1H50, 1U10, 1260, 1210, 1155, 1025, 923, 885, 850, 805 and 750 and more. NMR (DM 50 death) delta. (TMS) 1.1: (doublet, ZH), 1.8 (multiplet, HH), 3.6 (multiplet, 5H), 3.9 (singlect, BH), 7.5 (multiplet, 611) ppm.

Claims (2)

453 094 1-2, Patent claims Use of a compound of the formula CH3CH (Br) COOMgX or an ether thereof, wherein X represents chlorine or bromine, as an intermediate for the preparation of 2-arylpropionic acids. f Use of the compound according to claim 1 as tetrahydrofuran monoetherate.