FI82442C - Process for the preparation of 2-arylpropionic acid-magnesium halide complexes and its use in the preparation of 2-arylpropionic acid - Google Patents

Description

1 82442 Process for the preparation of 2-aryl-propionic acid-magnesium halide compound and its use in the preparation of 2-aryl-propionic acid

By dividing separated from patent application 780417 Avdelad ur patent application 780417

The invention relates to a magnesium halide complex of arylpropionic acid of the formula arylCH (CH3) COOMgX or an etherate thereof, wherein aryl is 6-methoxy-2-naphthyl, 4'-fluoro-4-biphenyl or 4- (C1-C4) - alkylphenyl and X is bromine or chlorine.

One of the most commonly used methods of synthesizing arylalkanoic acids has been the coupling of an aryl organometallic reagent with a haloalkanoic acid derivative such as a haloalkanoic acid ester. This method has proved to be particularly important in the preparation of the valuable anti-inflammatory agent 2- (6-methoxy-2-naphthyl) propionic acid. More specifically, this compound has been prepared using coupling reactions using alpha-halopropionic acid ester and 2- (6-methoxynaphthyl) copper (US 3,658,863), zinc (US 3,663,584) and cadmium (US 3,658,858 and 3,694,476) reagents. One disadvantage of these methods is that the organometallic reagent used in the coupling must be prepared from the corresponding Grignard reagent and thus an additional chemical reaction, additional reagents, etc. are required.

German patent publication 21 45 650 describes the direct coupling of an aryl magnesium halide with potassium 2-iodopropionate. It was later shown in U.S. Patent 3,959,364 that direct coupling could be better accomplished by reacting 2,82442 aryl-Grignard reagents with lithium, sodium, magnesium, or calcium salts of 2-bromopropionic acid of structure CH 3 CH (X) COM, wherein X is bromine and M is OLi, ONa, O (Mg) i / 2 or O (Ca) x / 2 (cf. Table II, US 3,959,364). However, it has been found that when this process produces 2-aryl-propionic acids, especially valuable 2- (6-methoxy-2-naphthyl) -propionic acid, the process has a number of process-specific disadvantages, including the preparation of a halogenopropionate salt in an aprotic solvent to be used in the coupling reaction. , resulting in poor results in large scale manufacturing.

Therefore, it is important to find a coupling process using an aryl-Grignard reagent and a suitable halopropionic acid derivative to obtain the desired 2-arylpropionic acids easily and repeatedly in high yields and purity and which can be easily applied to large scale commercial production.

The present invention relates to the preparation of known valuable anti-inflammatory agents, in particular to the preparation of 2-arylpropionic acids such as 2- (6-methoxy-2-naphthyl) propionic acid disclosed in U.S. Patent 3,904,682. More specifically, the present invention relates to a new process for the preparation of these valuable therapeutic agents.

In particular, the present invention relates to a direct coupling process in which the desired arylmagnesium bromide is coupled in high yield with a magnesium halide alloy complex of alpha-bromopropionic acid to give the corresponding 2-arylpropionic acid. All references in the specification and claims to 2-arylpropionic acids refer to the racemic form of these compounds.

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Examples of the 2-aryl-propionic acids whose preparation is within the scope of the present invention include compounds in which the aryl moiety is 6-methoxy-2-naphthyl, i.e.: 2- (6-methoxy-2-naphthyl) -propionic acid; 4-alkylphenyl, where "alkyl" means straight-chain or branched saturated hydrocarbon groups having 1 to 4 carbon atoms, for example, 2- (4-methylphenyl) propionic acid, 2- (4-isopropylphenyl) propionic acid and 2- ( 4-isobutylphenyl) propionic acid; and 4'-fluoro-4-biphenyl, i.e. 2- (4 * - E-fluoro-4-biphenyl) propionic acid.

As mentioned above, prior U.S. Patent 3,959,364 describes the preparation of arylalkanoic acids by direct coupling of the aryl-Grignard reagent with the Na, Li, Cai / 2 and Mgi / 2 salts of alpha-bromopropionic acid.

It has now surprisingly been found that the coupling reaction takes place better if an magnesium halide alloy complex of alpha-bromopropionic acid is used instead of one of the above-mentioned salts, i. compounds of formula CH3CH (Br) C00MgX wherein X is chlorine or bromine. In fact, a direct comparison of the magnesium salt of alpha-bromopropionic acid (prepared by both methods disclosed in U.S. Patent 3,959,364) and the accompanying novel complex shows that there is a significant difference (about twice the difference) in the yield of finished products obtained, as shown in more detail in the examples. . A further advantage of the present coupling process is that the preparation of the magnesium halide alloy complex does not affect its yields to the same extent as the preparation of the 4,82442 2-bromopropionate salt affects the yields of the coupling process of U.S. Patent 3,959,364 (cf.

U.S. 3,959,364, vertical row 3, rows 10 and 11).

Aβ-bromopropionic acid magnesium halide mixture can be prepared by treating the free acid with a suitable Grignard reagent. 11a. Although the quality of the hydrocarbon portion of the Grignard reagent is not critical, it is recommended that step or post-treatment. Thus, Grignard reagents derived from gaseous or liquid hydrocarbons at the reaction temperature are particularly preferred, for example, alkylmagnesium-Grignard compounds having 1 to 12 carbons or arylmagnesium-Grignard compounds having 6 to 9 carbon atoms. Grignard reagents useful for this purpose include methylmagnesium chloride, methylmagnesium bromide, ethylmagnesium chloride, methylmagnesium bromide, isopropylmagnesium chloride, phenylmagnesium chloride and o-, m- or p-tolylmagnesium) chloride and the like. Methylmagnesium chloride and methylmagnesium bromide are particularly preferred because they are readily available commercially, inexpensive, and result in the formation of methane gas that exits the reaction mixture and does not interfere with the reaction or work-up. Surprisingly, it has been found that the addition of one of the above-mentioned Grignard reagents to alpha-bromopropionic acid mainly results in the formation of the above-mentioned complex. The addition of Grignard reagent to the carbonyl portion of the carboxylic acid, which would normally be expected to occur on a large scale, appears to be minimal even when a molar excess of Grignard reagent is used.

The preparation of the magnesium halide alloy complex is usually carried out in an aprotic solvent containing an ether such as diethyl ether, tetrahydrofuran 1,2-dimethoxy-82442 ethane, di- (n-butyl) ether and the like. The solvent may contain other aprotic solvents such as aromatic hydrocarbons, for example benzene or toluene. The preferred solvent for the preparation of the complex is tetrahydrofuran. Although the order of addition of the reagents is not absolutely critical, it is usually desirable to add the Grignard reagent to alpha-bromopropionic acid. The Grignard reagent, in solution, is preferably about 1 to 4 M, most preferably about 2 to 3 M. It is desirable that the concentration of the finished clump solution used in the direct coupling step be about 1 to about 2 M, preferably about 1.0 to 1.5 H. The temperature of the coextraction step is usually maintained between about -20 and + 30 ° C, preferably between about -10 and + 20 ° C.

The coupling reaction itself is conveniently carried out by contacting a solution of the alpha-bromopropionic acid magnesium halide mixture complex with arylmagnesium bromide in an anhydrous aprotic organic solvent. Suitable solvents for the reaction include organic ethers and mixtures of organic ethers with aromatic hydrocarbons, as mentioned above in connection with the clumping step. A particularly preferred solvent for the coupling reaction is tetrahydrofuran. It is recommended that the concentration of the arylmagnesium bromide solution be between 0.5 and 2 M, preferably about 1.0 M.

The coupling reaction itself can be carried out over a wide temperature range of about 0 to about + 100 ° C, preferably between about 10 and 60 ° C. It is especially preferred to allow the temperature to gradually rise to about 40-60 ° C during the addition step and then return to ambient temperature until the desired degree of reaction is reached.

Although the coupling reaction can be performed using reagents in different proportions relative to each other, it is recommended that approximately equal molar amounts of the 6,82442 magnesium halide alloy complex and the aryl-Grignard reagent be used. Recommended ratios are about 0.9: 1.1 to 1.1: 0.9 complex. Grignard reagent.

The reaction may be conveniently carried out by contacting both reagents in a solvent in any manner conventional in the art. However, it is particularly preferred to add the magnesium halide mixture complex to the Grignard reagent and to keep these reagents as an effective mixture until the desired reaction is substantially complete.

The time required to carry out the desired reaction will, of course, depend on the choice of reagents, solvents and reaction temperature. The person skilled in the art will usually adjust the time so that the optimum amount of the desired product is formed. However, this reaction time is generally from about 10 minutes to about 20 hours, and usually from about 1 to about 5 hours.

After the coupling reaction has progressed as desired, the reaction mixture containing the coupled complex arylCH (CH2) -COOMgX is quenched rapidly with a dilute acid, preferably a dilute aqueous mineral acid such as hydrochloric acid or sulfuric acid, as is normally used in Grignard reactions. The free 2-arylpropionic acid product can then be isolated and purified from the quenched reaction mixture in the usual manner, such as by extraction with aqueous alkali (e.g. aqueous sodium or potassium hydroxide), separation of the aqueous alkaline phase from the organic phase and acidification of the aqueous alkaline phase. extracted into an organic solvent or purified directly in the usual manner, such as by washing and / or crystallization.

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If desired, the crude reaction product can be directly converted to a pharmaceutically acceptable derivative of the carboxylic acid, such as a salt, ester or amide thereof, or separated into optical isomers.

The process according to the present invention can be easily and expediently carried out on a large scale, the yields of the purified product being between 50 and 75%.

The following examples illustrate the method of the present invention. They do not limit in any way the spirit and scope of the invention.

Preparation 1 Preparation of 2-16-methoxynaphthylammonium bromide 2-Bromo-6-methoxynaphthalene (23.7 g, 0.1 mol) is dissolved in toluene (30 ml) and tetrahydrofuran (40 ml) with heating. This solution is then added over 10-15 minutes under a nitrogen atmosphere to a mixture of excess magnesium metal (3 g, 0.12 mol), toluene (15 mL) and tetrahydrofuran (15 mL). The reaction mixture is then cooled and stirred for a further hour at 25-30 ° C. The reaction mixture is then transferred off excess magnesium to a clean, dry vessel under nitrogen and stored at 10 ° C to give 1.0 M Grignard reagent.

By proceeding in a similar manner, the Grignard reagent can be prepared using tetrahydrofuran as the sole solvent.

Similarly, a more concentrated Grignard reagent, e.g., 1.5 M, can be prepared using less solvent.

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Preparation 2

To a magnesium halide mixture of alpha-bromopropionic acid 15.3 g (0.1 mol) of alpha-bromopropionic acid and 40 ml of toluene are cooled to 10 [deg.] C. and then a solution of 50 ml of 2M methylmagnesium bromide in tetrahydrofuran / toluene is slowly added. (1: 1), keeping the temperature at 10 to 20 ° C during the addition for 15 to 20 minutes. The reaction mixture is then stirred at 5 ° C for a further 20 minutes to give a 1.1 M solution of the complex.

By proceeding in the same manner, a magnesium halogen alloy complex can be prepared using tetrahydrofuran as the sole solvent.

Similarly, methylmagnesium bromide can be replaced with other Grignard reagents, such as methylmagnesium chloride, isopropylmagnesium chloride, phenylmagnesium chloride, and the like, at concentrations ranging from about 1 to about 4 M.

The alpha-bromopropionic acid magnesium chloride mixture complex (prepared as above using 3 M CH 3 MgCl in tetrahydrofuran) was isolated in crystalline form as its tetrahydrofuran monoetherate after distilling off the tetrahydrofuran from the tetrahydrofuran solution. The product was analyzed:

Sp. 147-155 ° C; IR (KBr) 1625, 1450, 1420, 1372, 1291, 1200, 1070, 1030, 988 and 890 cm-1; NMR (D 2 O) delta 1.8 (multiplet, δ) 3.7 (multiplet, 4) and 4.35 ppm (quartet, J = 7).

Elemental analysis calculated for C7Hi2BrClMgO3:

Mg, 8.57%, Cl, 12.49%.

Yield: Mg, 8.63%, Cl, 12.97%.

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Preparation 3

Preparation of arylmanisium bromides 0.025 moles of aryl bromide are dissolved in tetrahydrofuran (18 ml). This solution is then added to excess magnesium metal (3 g, 0.02 mol) and tetrahydrofuran (7 mL) under a nitrogen atmosphere. The temperature is maintained by cooling to 50-60 ° C during the addition for 10-15 minutes. The reaction mixture is then removed from excess magnesium in a clean dry vessel under nitrogen and stored at 10 ° C to give 1.0 M Grignard reagent. In this way, the following Grignard reagents were prepared: 2- (6-methoxynaphthyl) magnesium bromide 4- (4'-fluorobiphenyl) magnesium bromide 1- (4-isopropyl phenyl) magnesium bromide 1- (4-isobutylphenyl) magnesium bromide 1- (4-methylphenyl) magnesium bromide

Preparation 4 A. Preparation of Ais-fa-bromopropionic acid manium halide mixture

A 1α-bromopropionic acid (3.8 g, 0.025 mol) is dissolved in tetrahydrofuran (8 ml) and the solution is cooled to -10 ° C. To this solution is added 3M methylmagnesium chloride in tetrahydrofuran (8 ml) over 15 minutes, maintaining the temperature between -10 and 0 ° C. This gives a 1.1 M molar solution of the complex, which is stored at 0 ° C or higher before use.

In a similar manner, the corresponding magnesium bromide complex can be prepared by replacing 3 M methylmagnesium chloride with 1 M methylmagnesium bromide.

10 82 442 B. Preparation of the malium salt of alpha-bromopropionic acid

Alpha-bromopropionic acid (3.8 g, 0.025 mol) is dissolved in methanol (6 mL) and the solution is cooled to -10 ° C. To this is added 0.5 M magnesium methoxide in methanol solution (25 ml) over 10 minutes, keeping the temperature between -10 and 0 ° C. The methanol is then removed under reduced pressure to give a solid salt which is dried at 50 ° C under vacuum for 12 hours.

This gives a dry magnesium salt (4.1 g, 0.0125 mol, purity 97.2%). This salt is dissolved in 19 ml of tetrahydrofuran for the coupling reaction.

Example 1 A. The coarsex solution from Preparation 2 is slowly added to the Grignard solution of Preparation 1, keeping the temperature at 15-20 ° C during the addition of 10-15 minutes. The reaction mixture is allowed to warm to room temperature and then stirred for 2 hours. The reaction mixture is cooled in an ice bath and 20 ml of 12 N hydrochloric acid and 150 ml of water are added. After stirring for 5 minutes, the biphasic system is filtered and the filter cake is washed 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 toluene (30 ml) and neutralized with 12N hydrochloric acid to pH 1. The white solid 2- (6-methoxy-2-naphthyl) -propionic acid is filtered off under vacuum and dried at 55 ° C in vacuo to give 15.2 g (66%) of product, m.p. 149.5-153.5 ° C.

B. Alternatively, after filtration, the organic phase can be extracted with 10% potassium hydroxide solution (2 x 150 ml), washed with toluene (30 ml) and filtered. 15 ml of methanol and 12 ml of toluene are added, followed by enough 12 N hydrochloric acid to bring the pH to 4-5.

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The resulting slurry is then heated at reflux for 1 hour, cooled and filtered. The precipitate is washed with water (20 ml), toluene (2 x 3 ml) and hexane (2 x 3 ml) and dried in vacuo at 55 ° C to give 15.0 g (65.1%) of product, m.p. 154.5 - 155 ° C.

Example 2 67 ml of a 1.5 M solution of alpha-bromopropionic acid magnesium chloride mixture in tetrahydrofuran (prepared using 3 M methylmagnesium chloride) is slowly added to a cooled (10 ° C) solution of 1.5 M 2- (6-methoxynaphthyl) magnesium bromide in tetrahydrofuran ( 67 ml) at a rate such that the temperature remains at or below 55 ° C.

The resulting slurry is stirred for 1 hour at 50 ° C and then heated to reflux to allow 30-40% distillation of tetrahydrofuran. The reaction mixture is cooled to 50 ° C, 30 ml of toluene are added and the reaction is quenched with aqueous hydrochloric acid and the reaction mixture is treated according to Example IB to give 2- (6-methoxy-2-naphthyl) -propionic acid in 73% yield, m.p. 156-157 ° C.

Example 3 A. Magnesium salt of alpha-bromopropionic acid, i. [CH 3 CH (Br) C 10] 2 Mg, was prepared by reacting the acid with 1/2 molar equivalent of magnesium carbonate, after which the salt was dried in vacuo at 60 ° C.

When the magnesium chloride mixture complex used in Example 2 was replaced with this salt, the product was obtained in 34.7% yield.

B. The salt of Part A was also prepared using 1/2 molar equivalent of magnesium methoxide, with the methanol removed as an azeotrope. Using this salt in the method of Example 2, the product was obtained in 43.0% yield.

12 82 442 ♦

Example 4

Example 3A was repeated, but before the coupling reaction, 1/2 molar equivalent of anhydrous magnesium chloride was added to the magnesium salt. The product was obtained in 5.1% yield.

Example 5

Example 3B was repeated, but equal molar amounts of alpha-bromopropionic acid and magnesium methoxide were used. The yield of the obtained product was 35.1%.

Example 6

Comparison of coupling reactions using magnesium haloenide alloy complexes and Mqi / 2 salts

The following coupling reactions (to the extent shown below) were performed using both alpha-bromopropionic acid magnesium chloride mixture complex (prepared as in Preparation = a) or alpha-bromopropionic acid magnesium salt (prepared as in Preparation 4B) and the corresponding Grignard reagent (prepared in Preparation 3) . The procedure (illustrated for 0.025 mol) is as follows:

A 1.0 M solution of arylmagnesium bromide is cooled to 10 ° C and a solution of either a magnesium salt or a magnesium chloride complex in tetrahydrofuran is added over 5 minutes keeping the temperature between 10 and 50 ° 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 12 N hydrochloric acid (10 ml) and water (50 ml) is added. Toluene (50 ml) is added and the aqueous phase is separated and discarded. The organic phase is extracted twice with 10% potassium hydroxide (50 ml). The basic extracts are combined and neutralized with hydrochloric acid to give a precipitate which is filtered and dried at 50 ° C.

The results obtained are shown in the following table:

Purification

Aryl-

Yield (%) yield of Grignard product

Dimension (bromide) _ £ _3 _) _ £ _%) _ 0.12 2- (6-methoxynaphthyl) -1 72.9 (1) 70 _ (20.1) _ 0.12 2- (6-methoxynaphthyl) -2 43.0 (2) 37.4 - (11.9) - 0.025 4- (4'-fluorobiphenyl) -1,60.9 (3)% 60- (3.7) _ 0.025 4- (4'-fluorobiphenyl) -2,280, 6 (4) <28 - (1.75) - 0.05 1- (4-isopropylphenyl) -1,5,5 (5) 1,5- (5,3) _0.05 1- (4-isopropylphenyl) -2 52.0 (6) 1 26 _ (5.0) _

Measure = (when using stoichiometric amounts of reagents) moles of Grignard compound = MgCl clump 2 = Mgi / 2 salt

Comments (1) Product purity = 96.0% (2) Product purity = 86.8% (3) Sp. 136-152 ° C NMR O.K.

(4) Sp. 130-138 ° C

(5) SP. 58-64 ° C NMR O.K.

(6) Purity of the product by NMR about 50% - oil i4 82442

From the above, it can be seen that in each case a higher yield (about 2-fold) of purer product was obtained from the magnesium chloride alloy complex.

Similarly, comparable results can be obtained in the preparation of the following 2-arylpropionic acids: 2- (4-isobutylphenyl) propionic acid, 2- (4-methylphenyl) propionic acid.

If the above procedure is stopped before quenching with aqueous acid and the solvent is removed in vacuo, the coupled magnesium halide complexes, arylCH (CH 2) -COOmgX, or their ethers can be isolated.

The magnesium chloride mixture complex of 2- (6-methoxy-2-naphthyl) propionic acid has the following properties as its tetrahydrofuran monoetherate (purity 98.1%): m.p. 113 ° C (ha j); IR (Kbr plate) 1600, 1450, 1410, 1260, 1210, 1155, 1025, 923, 885, 850 and 750 cm-1; NMR (DMSO-d 6) delta (TMS) 1.4 (doublet, 2H), 1.8 (multipet, 4H), 3.6 (multipet, 5H), 3.9 (singlet, 3H, 7.5) (multiplet, 6H) ppm.

Similarly, the following mixed magnesium chloride complexes of 2-acyl acids (tetrahydrofuran monoetherate) have been isolated, the properties of which are listed below: 2-Aryl-propionic acid Properties 2- (4-methylphenyl) - m.p. 70-79 ° C (dec.); IR (KBr plate): propionic acid 3400, 1630, 1585, 1512, 1458, 1420, 1365, 1285, 1070, 815, 790, 730 cm-1; NMR (DMSO-d 6) delta (TMS): 1.3 (doublet, 3H), 1.8 (multiplet, 4H), 2.3 (signal, 3H), 3.6 (multiplet, 5H), 7.2 (multiplet, 4H) ppm; is 82442 2- (4-isobutylphenyl) -sp. 110-115 ° C (dec.) / IR (nujol) propionic acid 2900, 1625, 1585, 1460, 1378, 1368, 1245, 1185, 1110, 1020, 910 and 720 cm-1; NHR (DMSO-d 6) delta (TMS): 0.8 (doublet, 6H), 1.3 (doublet, 3H), 1.8 (multiplet, 1H), 2.5 (multiplet, 6H), 3 , 6 (multiplet, 5H) and 7.2 (multiplet, 4H) ppm.

According to Example 6, a mixed magnesium chloride complex of 2- (6-methoxy-2-naphthyl) propionic acid as tetrahydrofuran monoetherate and 2- (6-methoxy-2-naphthyl) propionic acid are obtained under the coupling conditions specified in the following table:

Solvent temperatures. Yield of dl-acid

Dimension * _Solvent_ratio ** <> C% *** yield% 0.12 tetrahydrofuran / toluene 60/140 15-20 63.3 59.3 0.12 tetrahydrofuran / toluene 85/115 10-20 69.8 66, 8 0.12 tetrahydrofuran / toluene 100/100 10-20 75.5 72.0 0.12 tetrahydrofuran 200/0 10-50 76.9 72.9 0.12 tetrahydrofuran 200/0 10-20 73.6 69, 6 0.12 tetrahydrofuran 150/150 10-50 68-70 65-67 * (using stoichiometric amounts of reagent) moles of Grignard ** ml / ml *** 2- (6-methoxy-2-naphthyl) -propionic acid mixed magnesium chloride complex tetrahydrofuraanimonoeteräättina.

Yields of the mixed magnesium chloride complex of 2- (6-methoxy-2-naphthyl) propionic acid have been obtained by quenching the coupling before acidification, while corresponding yields of 2- (6-methoxy-2-naphthyl) propionic acid have been obtained without isolating the complex.

Claims (2)

A process for the preparation of a magnesium halide complex of 2-arylpropionic acid of the formula aryl-CH (CH3) C00MgX or a tetrahydrofuran ether thereof, wherein aryl is 6-methoxy-2-naphthyl, 4'-fluoro-4-biphenyl or 4- (C1 -C 4) alkylphenyl and X is bromine or chlorine, characterized in that the arylmagnesium bromide whose aryl is 6-methoxy-2-naphthyl, 4'-fluoro-4-biphenyl or 4- (C 1 -C 4) alkylphenyl is about 0, A 5 to 2.0 molar solution is contacted with a solution of a complex of the formula CH 3 CH (Br) COOMgX, wherein X is chlorine or bromine, in a 1.0 to 2.0 molar solution in tetrahydrofuran or a mixture of tetrahydrofuran and an aromatic hydrocarbon. between 0 and 100 ° C. i7 82442