SE453093B - PROCEDURE FOR PREPARING A MAGNESIUM HALOGENIDE COMPLEX OF 2-ARYL PROPIONIC ACIDS AND USING THIS FOR PREPARATION OF 2-ARYL PROPIONIC 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

453 093 2 where X represents bromine and M represents OLi, ONa, O (Mg) ¿or O (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 inherent disadvantages including the preparation of halopropionic salt. in the appropriate solvent medium, which must be used for the coupling reaction, which results in poor results in production on a factory 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 as easily can be adapted to commercial production on a factory 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 denotes chlorine or bromine. 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 that used according to the invention actually shows a remarkable difference in the yield of the final products obtained (about twice the difference nad), 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 preparation method of the 2-bromopropionate salt (cf. U.S. Patent 3,959,364, column 3, lines 10 and 11).

The mixed magnesium halide complex of alpha-bromopropionic acid can be prepared by treating the free acid with a suitable 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. As a result, Grignard reactants derived from hydrocarbons which are gaseous or liquid at the reaction temperatures are particularly suitable, e.g. atoms. Specific Grignard reactants which may be used for this purpose are methylmagnesium chloride, methylmagnesium bromide, ethylmagnesium chloride, ethylmagnesium bromide, isopropylmagnesium chloride, phenylmagnesium chloride and o-, m- and p-tolylmagnesium chloride and methylmagnylmyl, etc. available, inexpensive and leads 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 be expected to occur to a large extent, appears to be minimal even when using a molar excess of the Grignard reactant.

The preparation of the mixed magnesium halide complex is usually carried out 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 moles, most preferably from about 2 to about 3 moles. A final complex solution for use in the direct coupling step is from about 1 to about 2 moles 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 50 ° C, preferably between about -10 and 20 ° C. 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 coupling process itself can be carried out in a temperature range from about 0 to about 100 ° C, preferably between about 10 and 60 ° C.

It is very particularly preferred to allow the temperature to rise gradually during the addition step up to about iso - 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 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 so as 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 (CH 3) COMgX a dilute acid, preferably a dilute aqueous mineral acid, eg hydrochloric acid or sulfuric acid, 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 liberate the desired acid, which can optionally be extracted into an organic solvent or directly purified in the usual way, for example by washing and / or crystallization. The crude reaction product can, if desired, be directly converted to a pharmaceutically acceptable derivative of the carboxylic acid, for example a salt, an ester or amide thereof, or resolved into optical isomers.

The process according to the invention 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 method of 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 H0 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 DEG-3000 DEG C. The mixture is then transferred from the excess magnesium to a clean, dry vessel under nitrogen and allowed to stand at 10 DEG 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 HO ml of toluene is cooled to 100 ° C and then slowly added a solution of 50 nl of , keeping 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, such as methylmagnesium chloride, 453 os 6 isopropylmagnesium chloride, phenylmagnesium chloride, etc., in concentrations ranging from about 1 to about H-molar. The mixed magnesium chloride complex of alpha-bromopropionic acid (prepared as described above using 3 molar CH 3 MgCl in tetrahydrofuran) is isolated in crystalline form as its tetrahydrofuran monoetherate after distillation of tetrahydrofuran from a tetrahydrofuran solution and analyzed. Mp: lä? 155 ° C. In (xBr) = 1625, 150 °, 1372, 1291, 1200, 1070, 1030, 988 and 890 cm -1; NMB (D 2 O) delta 1.8 (multiplet, 7) 3.7 (multiplet, 4) and M, 35 ppm (quartet, J = 7). Elemental analysis for C 7 H 12 BrClMgO 3: Mg Cl Calculated, Z: 8.57 2 12, ü9 Found,%: 8.63 12.97 Preparation 3 'Preparation of arylmagnesium bromides 0.025 mol of aryl bromide is dissolved in 18 ml of tetrahydrofuran. This solution 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 - 60 ° C by cooling for an addition period of 10 - 15 minutes. 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, U- (N'-fluorobiphenyl) magnesium bromide, 1- (H-isopropylphenyl) magnesium bromide, 1- (H-isobutylphenyl) magnesium bromide and 1- (4-methylphenyl) magnesium bromide.

Preparation 4 A. Preparation of the mixed magnesium halide complex of alpha-bromopropionic acid 3.8 g: (0.025 mol) of alpha-bromopropionic acid is 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. This gives a 1.1 molar solution of the complex, which is allowed to stand at 0 ° C until used.

In the same way, the corresponding magnesium-bromide complex can be prepared by replacing 3-molar methylmagnesium chloride with 1-molar methylmagnesium bromide. h 453 093 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 ° C.

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: δ, 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 30 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 12Normal hydrochloric acid to bring the pH of the mixture to between U 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 55 ° C to give 15.0 g (65.1%) of compound. Mp: 15U, 5 - 155 ° C.

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 1.5 cooled to 10 ° C 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 - H01 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 1B 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 with Q molar equivalent of magnesium carbonate, then drying the salt in vacuo at 6000.

A yield of the mixed magnesium chloride complex used in Example 2 against this salt results in a yield of 3.7% of the compound. The salt in Part A is also prepared using one molar equivalent of magnesium methoxide, removing methanol as an azeotrope. A use of the salt in the procedure of Example 2 gives a yield of U3.0% of the compound.

Example 4 Example 3 A is repeated except that 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 5 B is repeated except that equimolar amounts of alpha-bromopropionic acid and magnesium methoxide are used. A yield of 35.12 is obtained from the compound.

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 HA) or the magnesium salt of alpha-bromopropionic acid (prepared as in preparation UB), and corresponding Grignard reactant (prepared as in Preparation 3). The procedure (illustrated for a 0.025 molar scale) is as follows.

O! A 1,0 molar solution of arylmagnesium bromide is cooled to ° C 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 25-30 ° C.

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 to give a precipitate which is filtered off and dried at 50 ° C.

The results obtained are given in the following table. @ fifi a-m = z pm fifi nw nom mo n ^ om V flfl äonnës fi mmcwmä mmm uwscmauxsuonm oqwm mms | ^ H>: mmH> monmom fl | = v | «Hos moqo oozmnwm" nam _ nmsëmuw ^ nmv w fi ëoansm mm mm> .mm Homä | ^ fl>: mmHæmonaom fl |: V | fi Hos mo.o ^ m>. fl V øwäonnëswmwcmmä æmv ooæn fi | an fi “nam w.wm * mä | ^ H>: mmwnnosHm |.: v | = HoE mmo .o amsëmum 1n: mum> m mzz ^>. n V flfl ëonnëø fi mmcmmä m own oawz fi amm fl “new m.om fi omz | ^ fl acmuwnno: Hma. = v | = Hos mNo.o« @. @@ H ^ m. fifl v u fi eoppme fi ww. .> n awnnwnvxsøonm @ .n = mm: | ^ H »» «@ = fi xo» ms | @V | w Hos N fl. ° ¶ uo.mm n ^ fl. oNV u fl eonnëswmwcwms Q »» «== @» »x = uonm m. ~> fl uwz | ^ H> »« @ = fi x0 »we | wv | ~ Hos ~«. ° ønmcw fl nø fi oog% ~ Anmunmcoaëox nu _ .umco fi uxmwn> m nwømcmë zu x ^ wv x @ H @ s ° x | fl Qw: wxm fi nuwan fl xwßw Mw wvænu: R mama nm fifi m> m wc fi cu: w>: w umev um «Hxnm> hmm: fi cxnwEc <zuøwm. v fi mmnmwz w:« cmnnm | fl nm: w «nw | It is clear from the above table that in true cases nan receives a higher yield (approximately twice) of a product down greater purity of the mixed nagnesium chloride complex.

P8 true networks, nan can obtain comparable results in the preparation of the following 2-arylproplonic acid or 2- (4-isobutyltenyl) propionic acid and 2- (4-methyltenyl) propionic acid.

Da nan interrupts the above procedure before nan attenuates with the aqueous aria and removes the solvent in vacuo. so can the coupled nitrogen halide complexes. arylCH (CH3) COOMgX. or ether thereof is isolated.

The mixed sodium chloride complex of 2- (6-methoxy-2-naphthyl) propionic acid exhibited its tetrahydroturone annoetherate with a purity of 98.1. Mp: 133 ° C (dec.). IB (KB: -p1atta): 1600. 1450, 1410, 1260. 1210. 1155. 1025, 923, 885, 850. 805 and 750 cn_l. NHR (DMSO-d 6) delta (TMS) 1.4 (doublet, ZH), 1.8 (multiplet. 48). 3.6 (multiplet, SH). 3.9 (singlet, 3H), 7.5 (multiplet. GH) ppm.

The mixed magnesium chloride complex (as tetrahydrofuran nonoetherate) of 2- (4-methyltenyl) propionic acid showed the following physicochemical data: amp: 70-79 ° C (dec.), IR (KB: -plate): 3400. 1630, 1585 1512. 1458. 1420, 1365, 1285. 1070. 8l5, '790, 730 cm_1; NHR (DHSO-d 6) delta (TMS): 1.3 (doublet 3H). 1.8 (multiplet. 4H), 2.3 (ßlnglett. 3H). 3.6 (multiplet. SH), 7.2 (multiplet. 4H) ppm.

The mixed magnesium chloride complex (sem tetrahydrofuran monoetherate) of 2- (4-isobutylphenyl) propionic acid showed the following physicochemical data: amp: 110-115 ° C (dec.): IR (nujol) 2900. 1625, 1585, 1460. 1378 l368. 1245. 1185. 1110. 1020. 910 and 720 Cm_1Z NHR (DMSO-die) delta (TMS): 0.8 (doublet. GH), 1.3 (doublet. 3H). 1.8 (multiplet, IH) 2.5 (multiplet. GH). 3.6 (multiplet, SH) and 7.2 (multiplet. 4H) ppm.

Claims (4)

453 093 12 A process for the preparation of a compound of the formula arylCH (CH 3) CO 3 H 6 X or an ether thereof, wherein aryl represents 6-netoxy-2-naphthyl. 4'-fluoro-4-biphenyl or 4- (C 1 -C 4) alkylphenyl and X represents the bridge or chlorine. k ä n n e t e c k n a t of bringing nan: a about 0.5 - 2,0- -nolar solution of an arylnagnesiunbronide. where aryl has the meaning given above. in contact down an approximately 1.0 - 2.0-nolar solution of a complex, CH3CH (Br) C00HgX. where X has the meaning given above. in an aprotic. Organic solution solvent comprising an ether at a temperature between about 0 and 100 ° C. 2. A process according to claim 1, characterized in that the solution linker diet is tetrahydrofuran. Use of a kenic compound has the formula aryl / CH (CH 3) CO 3 HgX or an ether thereof, wherein aryl represents 6-netoxy-2-naphthyl. 4'-fluoro-4-biphenyl or 4. - (C 1 -C 4) alkylphenyl and X represents the bridge or chlorine. nellan product for the removal of 2-arylpropionic acids. Use of a compound according to claim 3 as tetrahydrofuran lonoetherate.