HU183210B - Process for preparing complexes of 2-aryl-propionic acids - Google Patents

Description

The present invention relates to novel aryl-CH (CH.)) (OOMgX) complexes and their etherates, wherein X is chlorine or bromine and the aryl moiety is 6-methoxy-2-naphthyl and C 1-4 alkyl. alkylphenyl group, or 4'-fluoro-4-biphenyl group, which are known intrinsic to the preparation of known antiinflammatory agents, especially 2-arylpropionic acids, in particular 2- (6-methoxy-2-naphthyl) propionic acid. the latter compound is known from U.S. Patent No. 3,904,682.

The most commonly used synthetic method for the preparation of arylalkylcarboxylic acids is the coupling of organometallic aryl compounds with haloalkylcarboxylic acid derivatives such as haloalkylcarboxylic acid esters. This method is particularly important for the preparation of 2- (6-methoxy-2-naphthyl) propionic acid. This compound, as mentioned, has a valuable anti-inflammatory effect. This compound is prepared by coupling an alpha-halo-propionic acid ester with 2- (6-methoxynaphthyl) copper, zinc or cadmium as described in U.S. Pat. No. 3,658,863; and U.S. Patent Nos. 3,658,858 and 3,694,476. The disadvantage of these processes is that the organometallic reagent used for coupling must be prepared from the appropriate Grignard reagent. Thus, an additional chemical reaction, and thus additional reagents and other consumables, are required.

German Patent Application Publication No. 2,145,650 discloses a direct coupling process whereby arylmagnesium balogenides are coupled with 2-iodopropionic potassium. U.S. Patent No. 3,959,364 describes an improved direct coupling process. According to this, an aryl Grignard reagent is coupled with a lithium, sodium, magnesium or calcium salt of 2-bromopropionic acid of the formula CH ₃ CH (X) COO where X represents a bromine atom and M represents OL 1, ONa, O (Mg) _{i / 2} or O (Ca) _{) / 2} (Table II of the cited US patent). However, it has been found that this process has many disadvantages when used to prepare 2-aryl-propionic acids, in particular 2- (6-methoxy-2-naphth) -propionic acid. The halopropionic acid salt is prepared in a solvent-free medium, but the coupling thereafter is carried out in low yield. Thus, this process is not applicable on an industrial scale.

Because of the foregoing, it is of particular importance to provide a coupling process whereby the desired 2-arylpropionic acid can be easily reproduced in high yield, high purity with an appropriate aryl-Grignard reagent and can be used in industrial scale production.

In our experiments, it has been found that the above complexes of 2-arylpropionic acids can be prepared in high yield by reacting the corresponding aryl magnesium bromide with a mixed magnesium halide complex of alpha-bromopropionic acid. (The process of the present invention provides racemic 2-arylpropionic acids, so it is not mentioned further that the resulting product is racemic.)

Examples of the 2-arylpropionic acid complexes obtainable by the novel process of the present invention include 2- (6-methoxy-2-naphthyl) propionic acid, the aryl portion of which is a 6-methoxy-2-naphthyl group and such 2-arylpropionic acids. complexes of which the alkyl moiety is a 4-alkylphenyl group, wherein the alkyl moiety may be a straight or branched saturated C 1 -C 4 hydrocarbon group. Examples of such compounds are 2- (4-methylphenyl) propionic acid, 2- (4-isopropylphenyl) propionic acid and 2- (4-isobutylphenyl) propionic acid. Also mentioned is the product containing the 4'-fluoro-4-biphenyl groupG, 2- (4-fluoro-4-biphenyl) -propionic acid complexes, which can be obtained by the process according to the invention. As mentioned, U.S. Pat. No. 3,959,364 describes the preparation of arylalkylcarboxylic acids by direct coupling of an aryl-Grignard reagent to the sodium, lithium, calcium or magnesium salts of alpha-bromopropionic acid.

Surprisingly, it has been found that the yield of the coupling reaction can be increased by using a mixed magnesium halide complex of alpha-bromopropionic acid instead of the aforementioned salts. Thus, in the process of the invention, the starting compound is a compound of the formula CH ₃ CH (Br) COOMgX, wherein X is chlorine or bromine. When comparing the results obtained with the magnesium salt of alpha-bromopropionic acid (prepared by one or the other of U.S. Patent No. 3,959,364) and its new complex, we find that the yield of the latter compound is remarkable, doubles. A further advantage of the process according to the invention is that the yield of the coupling process is not affected by the preparation of the mixed magnesium halide complex, in contrast to the coupling process according to U.S. Patent No. 3,959,364, which is used with the 2-bromopropionic acid salt. (U.S. Pat. No. 3,959,364, column 3, lines 10-11).

The mixed magnesium halide complex of alpha-bromopropionic acid can be prepared by reacting the free acid with a suitable Grignard reagent. The Grignard reagent may contain any hydrocarbon moiety, however, it is preferred that the Grignard reagent, the hydrocarbon moiety released during the reaction, does not interfere with the processing of the coupling reaction and reaction product. Therefore, it is preferable to use a Grignard reagent in which the hydrocarbon moiety is a gaseous or liquid compound at the reaction temperature. Particularly preferred are, for example, C 1 -C 12 alkyl magnesium Grignard compounds and C 6 -C 9 aryl magnesium Grignard compounds. Thus, for the preparation of the complex, it is preferable to use methyl magnesium chloride, methyl magnesium bromide, ethyl inagnesium chloride, ethyl magnesium bromide, isopropyl magnesium chloride, phenylmagnesium chloride, ο-, m- or p-tolyl. magnesium chloride and the like can be used as Grignard reagent. Methyl magnesium chloride and methyl magnesium bromide are particularly preferred because they are readily available and release methane gas. This is removed from the reaction mixture and does not interfere with the reaction and processing. It has now been surprisingly found that when the above-mentioned Grignard reagents are added to alpha-bromopropionic acid, it is primarily the above-mentioned complex that is formed. The addition of the Grignard reagent to the carbonyl group of the carboxylic acid, which is the dominant reaction so far, is minimized, even if the Grignard reagent is used in a molar excess.

-2183 210

The mixed magnesium halide complex is prepared in a proton-free solvent medium. The solvent used is an ether such as diethyl ether, tetrahydrofuran, 1,2-dimethoxymethane, di-n-butyl and the like. Other nonionic compounds such as aromatic hydrocarbons such as benzene or toluene may also be used as solvents. Preferably, however, the complex is prepared in tetrahydrofuran.

The order of addition of the reagents is not strictly critical, but it is advisable to add Grignard reagent 10 to the alpha-bromopropionic acid.

The Grignard reagent is used in a solution of about 1 to about 4 molar, preferably about 2 to 3 molar. The ready-to-use solution of the complex is about 1 to 2 molar, preferably 1.0 to 1.5 molar. The complex is prepared at a temperature of -20 ° C to 15 ° C to + 30 ° C, preferably -10 ° C to + 20 ° C.

The coupling reaction itself is carried out by mixing a solution of the mixed magnesium halide complex with an aryl magnesium bromide in an anhydrous proton-free organic solvent medium. The reaction is preferably carried out in ethers or in a mixture of ethers and aromatic hydrocarbons in solvents similar to those mentioned for complexation. Particularly preferred solvent grains for the coupling reaction were tetrahydrofuran. The arylmagnesium bromide solution is preferably 0.5 to 2 molar, preferably 1.0 molar.

The coupling is carried out at a temperature of 0 ° C to 100 ° C, preferably 10 ° C to 60 ° C. It is particularly preferred that the reaction mixture be allowed to warm gradually to about 40-60 ° C during the addition of the reagent and then allowed to cool to room temperature while the reaction proceeds as desired. 35

The reagents may be mixed in various ratios, but preferably in an equimolar amount of the mixed magnesium halide complex and the aryl Grignard reagent. The ratio of complex to Grignard reagent is preferably from 10 0.9: 1.1 to 1.1: 0.9.

The reaction is carried out by contacting the two reactants in the solvent medium in any conventional manner. It has been found advantageous to add the mixed magnesium halide complex 45 to the Grignard reagent. The reagents are thoroughly mixed until the desired reaction is complete.

The time required to complete the process will, of course, depend on the reagents and solvents used and the temperature at which they are used. Adjustment of the reaction time to the optimum value for the desired product is obvious to those skilled in the art. The reaction time can range from 10 minutes to 20 hours, usually 1-5 hours.

The process of the present invention can be readily carried out on an industrial scale 55. The yield of the pure product is 50-75%.

The invention will be further illustrated by the following experiments and the following examples, without limiting the scope of the invention.

Experiment

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 under heating. The solution was then added under an atmosphere of nitrogen for ΙΟΙ 5 minutes to an excess of 3 g (0.12 mol) of magnesium metal in 15 ml of toluene and 15 ml of tetrahydrofuran. The reaction mixture was cooled and stirred at 25-30 ° C for one hour. The reaction mixture was separated from the excess magnesium and transferred to a clean, dry vessel where the nitrogen was allowed to stand at 10 ° C. 1.0 mole of Grignard reagent is obtained.

Similarly, Grignard reagent can be prepared using only tetrahydrofuran as solvent.

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

Experiment 2

Alpha-bromopropionic acid is a mixed magnesium halide complex

A mixture of alpha-bromopropionic acid (15.3 g, 0.1 mol) and toluene (40 mL) was cooled to 10 ° C. 50 ml of a 2 molar solution of methyl magnesium bromide in a 1: 1 mixture of tetraliddiofuran-toluene are slowly added. The temperature is maintained at 10-20 ° C over a period of about 15-20 minutes. The reaction mixture is then stirred at 5 ° C for 20 minutes. This gives a 1.1 M solution of the complex.

The mixed magnesium halide complex can be prepared by a similar method using only tetralurohydrofuran as the solvent.

Other Grignard reagents such as methyl magnesium chloride, isopropyl magnesium chloride or phenyl magnesium chloride may be used in place of methyl magnesium bromide in varying concentrations, from 1 mol to 4 mol.

From the appropriate tetrahydrofuran solution, the mixed magnesium chloride complex of alpha-bromopropionic acid (prepared as described above using 3M methylmagnesium chloride in tetrahydrofuran) can be crystallized by distillation of the tetralydrofuran in the form of crystals of tetrahydrofuran monoetherate. This compound melts at 147-155 ° C. The yield of α-bromopropionic acid is 90-95%.

IR (KBr): 1625, 1450, 1420, 1372, 1291, 1200,1070,1030,988 and 890 ^cm-first

NMR (D ₂ ^O): δ 1.8 (m, 7), 3.7 (m, 4), and 4.35 ppm (quartet, J = 7).

Elemental composition calculated found

C7H12BrClMgO ₃

Mg 8.57%, Cl 12.49%.

Mg 8.63%, C! 12.97%.

66 ml of a 3 molar solution of methyl magnesium chloride in THF are added in a stepwise manner while maintaining the temperature between -10 ° C and 0 ° C. Adding the reagent takes 15-20 minutes. The reaction mixture was then stirred at 0 ° C for a further 20 minutes. A 2.0 M solution of the title complex is obtained.

183,210

Experiment 3

Preparation of aryl magnesium bromides

0.025 mol of aryl bromide are dissolved in 18 ml of tetrahydrofuran. The solution was added under an atmosphere of nitrogen to a mixture of an excess of 3 g (0.02 mol) of magnesium metal and 7 ml of tetralidofuran. During the addition for about 10-15 minutes, the temperature is maintained at 50-60 ° C by cooling. The reaction mixture was then separated from the excess magnesium and transferred to a clean, dry container. Here, it is allowed to stand under nitrogen atmosphere at 10 ° C. 1.0 M Grignard reagent was obtained. By this method, the following Grignard reagents are prepared:

2- (6-methoxy-naphthyl) -magnéziuin bromide

4- (4'-fluoro-biphenyl) magnesium broniid

- (4-Isopropyl-phenyl) -magnesium bromide 1- (4-Isobutyl-phenyl) -magnesium bromide 1- (4-methyl-phenyl) -magnesium bromide.

Experiment 4

Preparation of mixed magnesium halide complexes of alpha-bromopropionic acid

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. 8 ml of a 3M solution of magnesium chloride in THF are added over 15 minutes. Meanwhile, the temperature is maintained between -10 ° C and 0 ° C. This results in a 1.1 molar solution of the complex, which is stored at 0 ° C or lower until use.

Similarly, the corresponding magnesium bromide complex is prepared using 1 molar methyl magnesium bromide instead of the 3M methyl magnesium chloride reagent.

Experiment 7

Preparation of 0.5 molar 2- (6-methoxynaphthyl) -inagnesium bromide

11.9 g (0.05 mol) of 2-bromo-o-methoxynaphthalene are dissolved in 70 ml of tetrahydrofuran with heating. The residue ¹⁵ Tot added under nitrogen 4 g (0.16 mol) of magnesium and 30 ml of tetrahydrofuran mixture. The reaction mixture containing excess metal was maintained at 50-60 ° C for 10-15 minutes by cooling. The reaction mixture was then stirred at 25-30 ° C for 1 hour 20 and then transferred to a clean, dry vessel under nitrogen to separate it from excess magnesium. The product, corresponding to 0.5 M Grignard reagent, is stored at 10 ° C.

²⁵

Experiment 8

Mixed magnesium halide complex of α-bromopropionic acid

Α-Bromopropionic acid (7.6 g, 0.05 mol) was mixed with tetrahydrofuran (80 ml) and cooled to -10 ° C. 17 ml of a 3M solution of methyl magnesium chloride in THF are added slowly while maintaining the temperature between -10 ° C and 0 ° C. The reagent is added for 15-20 minutes. The reaction mixture is then stirred for 20 minutes at 0 ° C. This gives a 1.0 M solution of the title complex.

Experiment 5: Preparation of mole 2- (6-methoxynaphthyl) magnesium bromide

2-Bromo-6-methoxynaphthalene (47.4 g, 0.2 mol) was dissolved in tetrahydrofuran (70 mL) with heating. This solution was added under a nitrogen atmosphere to a mixture of 6.1 g (0.25 mol) of magnesium and 30 ml of tetrahydrofuran. The temperature of the excess metal reaction mixture was maintained at 5060 ° C for 10 to 15 minutes with cooling. The reaction mixture was then stirred for one hour at 25-30 ° C and then separated from the excess magnesium by transferring it to a clean, dry vessel under nitrogen. The material thus obtained was stored at 10 ° C. The product is a 2.0 M Grignard reagent.

Experiment 6

Mixed magnesium halide complex of α-bromopropionic acid

30.6 g (0.2 mol) of α-bromopropionic acid are mixed with 30 ml of tetrahydrofuran and cooled to -10 ° C. Slow 4

Example 1

To the Grignard solution prepared in Experiment 1 is slowly added the solution of Complex prepared in Experiment 2. During addition for about 10 to 15 minutes, the temperature is maintained at 15-20 ° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The solvent was then removed in vacuo. The thus obtained 98% pure tetrahydrofuran monoether melted at 50-133 ° C with decomposition. The yield is about

%.

Example 2 67 ml of a 1.5 molar solution of a mixed magnesium chloride compound of alpha-bromopropionic acid complex in ⁵⁵ molar methylmagnesium chloride in 2- (6-methoxynaphthyl) magnesium bromide 1.5 molar Add to 67 ml of a 10 ° C solution of 60 in tetrahydrofuran at a rate such that the temperature remains below 55 ° C. The resulting slurry was stirred at 50 ° C for one hour, then heated to reflux while distilling the tetrahydrofuran.

2- (6-Methoxy-2-naphthyl) -propionic acid is magnesium chloride

The yield of the tetrahydrofuran monoetherate of the -4183 210 complex is about 75%.

IR (KBr pastilles): 1600, 1450, 1410, 1260, 1210, 1155, 1025, 923, 885, 850, 805 and 750 cm ^-1 . Example 3

Coupling reactions using mixed magnesium halide ¹ θ complex. i

The alpha-bromopropionyl compound prepared according to Experiment 4. Grignard reagent is prepared in an acidic felhasználd- mixed magnesium chloride complex, or 2 .: experiment of a variable is the following coupling reactions are carried out in ¹ 5 may also be mentioned below in size. The procedure performed at 0.025 M is detailed below.

The 1.0 molar solution of aryl magnesium bromide was cooled to 10 ° C and a solution of the magnesium chloride complex in tetrahydrofuran was added over 5 minutes while maintaining the temperature at 10-55 ° C. The reaction mixture was then stirred at 25-30 ° C for 2 hours.

The reaction conditions and yields are summarized in the following table:

tetrahydrofuran monoetherate of a mixed magnesium chloride complex of 2- (4-isabanylphenyl) propionic acid from suitable starting materials. This compound melts at 110-115 ° C with decomposition.

IR (Nujol): 2900.1625, 1585, 1460.1378, 1368, 1245, 1185, 1110, 1020, 910 and 720 cm @ ^-1 .

NMR: _(DMSO-d6) δ (TMS) 0.8 (d, 6H), 1.3 (d, 3H), 1.8 (m, IH), 2.5 (m, 6H); 3.6 (multiplet, 5H) and 7.2 (multiplet, 4H) ppm.

Example 4

To the Grignard solution prepared in Experiment 7, Experiment 5, the complex solution prepared in Experiment 6 was added over 1-7 minutes while maintaining the temperature of the reaction mixture at 1064 ° C. The reaction mixture was stirred for 1 hour and then allowed to stand until the temperature reached 2530 ° C. The solvent was then removed in vacuo and the resulting mixed magnesium chloride complex isolated. The product has the same physical characteristics as the product of Example 2. The yield is about 80%. .

Number of moles of Grignard reagent Grignard compound Mg complex yield 0.12 2- (6-methoxy-naphthyl) -magnesium bromide MgCl - 75% 0,025 4- (4'-fluoro-biphenyl) magnesium bromide MgCl -63% 0.05 1- (4-Isopropyl-phenyl) -magnesium bromide MgCl -58%

The solvent was removed in vacuo and the coupled magnesium halide complex was separated.

The 2- ⁽⁴ -fluoro-4-biphenyl) propionic acid mixed magnesium chloride complex in tetrahydrofuran monoéterátja 136-

Melting point 143 ° C with decomposition.

The tetrahydrofuran monoetherate of the mixed magnesium chloride complex of 2- (6-methoxy-2-naphthyl) -propionic acid is ⁴ 98.1% pure and melts at 113 ° C with decomposition.

IR spectrum (KBr pellet): 1600, 1450, 1410, 1260, 1210, 1155, 1025, 923, 885, 850 and 750 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (DMSO-d 6) δ (TMS) 1.4 (doublet, 50 2H), 1.8 (multiplet, 4H), 3.6 (multiplet 5H), 3.9 (singlet, 3H) and 7 , 5 (multiplet, 6H) ppm.

Similarly, the tetrahydrofuran 55 monoetherate of the mixed magnesium biomide complex of 2- (4-methylphenyl) propionic acid is prepared using the appropriate starting materials. This compound melts at 70-79 ° C with decomposition.

IR spectrum (KBr pastilles): 3400, 1630, 1585, 1512, 1458, 1420, 1365, 1285, 1070, 815, 790 and _cn στη -1 βν

730 cm.

NMR: _(DMSO-d6) δ (TMS) 1.3 (d, 3H), 1.8 (m, 4H), 2.3 (s, 3H), 3.6 (m, 5H) and 2.2 (multiplet, 4H) ppm.

In the same manner as described above, the compound of Example 65 is prepared

Example 5

To the Grignard solution prepared in Experiment 7, the complex solution prepared in Experiment 8 was added over 1-7 minutes while maintaining the temperature of the reaction mixture at 1064 ° C. The reaction mixture was stirred for 1 hour and then allowed to stand until its temperature reached 2530 ° C. The mixed magnesium chloride complex was isolated in a similar manner to the previous example. Its physical properties are the same as those given above. The yield is about 69%.

Claims (5)

A process for the preparation of aryl-CH (CH ₃ ) C00MgX complexes and their etherates, wherein the aryl moiety 6-methoxy-2-naphthyl, alkyl-C1-C4-alkyl, 4'-fluoro-4-biphenyl and X is chlorine or bromine, characterized in that ai) α- bromopropionic acid is reacted with an alkyl or aryl magnesium halide having 1 to 12 carbon atoms or an aryl group having 6 to 9 carbon atoms and a halogen atom containing chlorine or bromine; 183,210 in a proton-free organic solvent, preferably ether, at a temperature of -20 ° C to +30 ° C, and the resulting complex of formula CH ₃ -CH (Br) COOMgX, wherein X is as defined above, in a proton-free organic solvent, preferably an ether contacting an aryl magnesium bromide having the aryl moiety above, or ₂ ) a 0.5 to 2.0 molar solution of an aryl magnesium bromide having the same aryl moiety in a proton-free organic solvent, preferably an ether, At 0 ° C to 100 ° C, contact is made with a solution of a complex of formula CH ₃ -CH (Br) COOMgX, where X is chlorine or bromine. (Priority: December 19, 1977) 2. The method according to claim 1 embodiment for the preparation of aryl-CH _(CH3) COOMgX compounds wherein the aryl moiety is 6-methoxy-2-naphthyl group and X is chlorine or bromine, or éterátjának these compounds for preparing characterized in that the α-bromopropionic acid is reacted with methyl magnesium chloride or methyl magnesium bromide in a proton-free organic solvent, preferably an ether, and the CH ₂ CH (Br) COOMgX complex wherein X is as defined above, the resulting solution is contacted with a solution of (6-methyl-25 naphthyl) magnesium bromide in a proton-free organic solvent, preferably an ether. (Priority: February 16, 1977) 3. A process according to claim 1 or 2, wherein the process is non-proton-free organic Tetrahydrofuran was used as solvent. (Priority: February 16, 1977) A process according to claim 1 or 2, wherein the aryl magnesium bromide is reacted with CH ₃ CH (Br) COOMgX at a temperature of from 10 ° C to 60 ° C. (Priority: December 19, 1977) 5. A process according to claim 1 wherein the alkyl magnesium halide is methyl magnesium chloride or methyl magnesium bromide. (Priority. February 16, 1977)