FI64571B - FOERFARANDE FOER FRAMSTAELLNING AV 2-ARYL-PROPIONSYRA - 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

- r_, KU extension publication. r _ B 11 UTLÄGG NI NGSSKRI FT 64 571 C Patent oyänn-Atty 12 12 1933

Patent No. 1 (51) Kv.lk. ^ lnt-Cl. 3C O? C 59/64 FINLAND I - F! N LAN D (21) P.tenttm.k.mu »- Pa« ne »n» ölinlng 7801 + 17 (22) H.lc.mlipllvi - An * öknlng »d» g 09.02.78 (23) Alkupilvi —Glltlgheud .g q2 γβ (41) Tullut | ulk1 * # k * l - Blivlt offentllg ^ qg jg

National Board of Patents and Registration Nihtivlk.lp.non j. moonLjulk.i ^ n pvm.- οί '' flo

Patent · och registerstyrelsen 'Aluekin utligd och utl.ikrlften publlcerad 31 · Oo. 03 (32) (33) (31) Requested «to the right. — Begird priorltet 16.02.77 19-12.77 USA (US) 769070, 863290 (71) Syntex Pharmaceuticals International Limited, Global House,

Church Street, Hamilton 5, Bermuda (BM) (72) Gary J. Matthews, Boulder, Colorado, Robert A. Arnold, Boulder,

Colorado, USA (US) (71 *) Leitzinger Qy (l) k) Process for the preparation of 2-aryl-propionic acid -Förfarande för framställning av 2-aryl-propionyra

The invention relates to a process for the preparation of 2-aryl-propionic acid, wherein the aryl is 6-methoxy-2-naphthyl, 4-C1-C4-alkyl-phenyl or 41-fluoro-4-biphenyl.

One of the most commonly used methods of synthesizing arylalkanoic acid 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, coupling reactions using alpha-halopropionic acid ester and 2- (6-methoxynaphthyl) copper (USA 3,658,863), zinc (USA 3,663,584) and cadmium (USA 3,658,858 and 3,694,476) reagents have been used in the preparation of this compound. 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 2,145,650 describes the direct coupling of arylmagnesium halides with potassium 2-iodopropionate. It was later shown in U.S. Patent No. 3,959,364 that direct coupling could be better accomplished by reacting an aryl Grignard reagent with lithium, sodium, magnesium, or calcium salts of 2-bromopropionic acid of formula CHgCHtXJCOM, wherein X is bromine and M is OL1, ONa, 0 (Mg) jy2 or 0 (Ca)] y2 (cf. Table II, USA 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 halopropionate 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 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.

Examples of the 2-aryl-propionic acids whose preparation is within the scope of the present invention are those in which the aryl moiety is 3,64571 6-methoxy-2-naphthyl, i. 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-isopropylphenyl) propionic acid; -isobutyl) propionic acid; and 4'-fluoro-4-biphenyl, i.e. 2- {41-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 an aryl-Grignard reagent with alpha-bromopropionic acid Na, Li, C & 2/2 and M91 / 2 'su0 - * -.

It has now surprisingly been found that the coupling reaction takes place better if a magnesium halide alloy complex of alpha-bromopropionic acid is used instead of one of the above-mentioned salts, i. compounds of formula CHgCHiBr) COOMgX wherein X is chlorine or bromine. The process according to the invention is characterized in that (a) a 0.5 to 2.0 molar solution of arylmagnesium bromide in which aryl is as defined above is contacted with 1.0 to 2.0 molar solution of a complex (CH 2 CH 2 Br) COOMgX in which X is chlorine or bromine with a molar solution in an aprotic organic solvent containing ether at a temperature between about 0 and 100 ° C and (b) quenching the reaction by acidifying the reaction mixture of step a).

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 a significant difference (about twice the difference) in the yield of the 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 2-bromopropionate salt affects the yields of the coupling process of U.S. Pat. No. 3,959,364 (cf. U.S. Pat.

4,64571

The magnesium halide alloy complex of alpha-bromopropionic acid can be prepared by treating the free acid with a suitable Grignard reagent. Although the quality of the hydrocarbon portion of the Grignard reagent is not critical, it is recommended that the free hydrocarbon formed in the reaction between alpha-bromopropionic acid and the Grigard reagent does not interfere with the coupling 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 commercially readily available, inexpensive, and result in the formation of methane gas that escapes from the reaction mixture and does not interfere with the reaction! or post-treatment. 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 the 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 the molar volume of the 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-dimethoxyethane, 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, each preferably about 2 to 3 M. It is desirable that the concentration of the finished complex solution used in the direct coupling step be about 1 to about 2 M, preferably about 1, 0 to 1.5 M. The temperature of the complexation 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 an 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 complexation step. A particularly preferred solvent for the coupling reaction is tetrahydrofuran. It is recommended that the concentration of the aryl-magnesium 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 particularly preferred to allow the temperature to rise gradually to about 40 to 60 ° C during the addition step and then return to ambient temperature. until the desired reaction rate is reached.

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 (CH 2) COOMgX 6 64571 is rapidly quenched with a dilute acid, preferably a dilute aqueous mineral acid such as hydrochloric acid or sulfuric acid.

As normally used in Grignard reactions. The free 2-aryl-propionic 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. , which may optionally be extracted into an organic solvent or purified directly in the usual manner, such as by washing and / or crystallization.

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 A to D illustrate the preparation of starting materials. Example A

Preparation of 2- (6-methoxynaphthyl) magnesium bromide 6-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.

7 64571

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.

Example B

Magnesium halide mixture complex 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 2 M methylene magnesium bromide in tetrahydrofuran / toluene is slowly added (1: 1), keeping the temperature at 10 to 20 ° C during the addition lasting 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 halide mixture 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 magnesium chloride alloy complex of alpha-bromopropionic acid (prepared as above using 3 M CH 2 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? mp. 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 c7H12BrClMgO3; Mg, 8.57%, Cl, 12.49%. Result: Mg. 8.63%, Cl, 12.97%.

Example C

8 64571

Preparation of arylmagnesium bromides 0.025 mol 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 nitrogen. 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-isopropylphenyl) magnesium bromide 1- (4-isobutylphenyl) magnesium bromide 1- (4-methylphenyl) magnesium bromide

Example D

1. Preparation of a magnesium halide alloy complex of alpha-bromopropionic acid

Alpha-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 3 M 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.

II. Preparation of the magnesium salt of alpha-bromopropionic acid

Alpha-bromopropionic acid (3.8 g, 0.025 mol) is dissolved in methanol-64571 (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 coupling reactions.

The following examples illustrate the method of the present invention.

Example 1

a) The complex solution according to Example B is slowly added according to Example I.

i Grignard solution according to i A, during which the temperature is maintained at 15 to 20 ° C during the addition lasting 10 to 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 12 N hydrochloric acid to pH 1. White solid 2- (6-methoxy-2-naphthyl) propionic acid filtered under vacuum and dried at 55 ° C under vacuum 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. 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 64571 67 ml of a 1.5 M solution of alpha-bromopropionic acid magnesium chloride mixture complex in tetrahydrofuran (prepared using 3 M methylmagnesium chloride) is slowly added to a cooled (10 ° C) solution containing 1.5 M 2-86-methoxynaphthyl) magnesium bromide in tetrahydrofuran (67 ml) at such a rate that the temperature remains at 55 ° C or lower. 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 73% yield of 3- (6-methoxy-2-naphthyl) -propionic acid, m.p. 156-157 ° C.

Example 3

The following coupling reactions (to the extent shown below) were performed using an alpha-bromopropionic acid magnesium chloride mixture complex (prepared according to Example D, I) and the corresponding Grignard reagent (prepared according to Example C). 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 the magnesium chloride complex in tetrahydrofuran is added over 5 minutes keeping the temperature between 10 and 55 ° 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: 11 64571

Measure (when using Purification Cometric Mats Actual Reagent Product se se) moles Aryl-Grignard Yield, Comment Yield

Grignard-% tit compound_ (cjj_ 2- (6-methoxynaphth 72.9 Product 0.12 moles of style) magnesium (20.1) purity = 70% bromide 96.0%

4- (4'-fluorobi-60.6 mp ° C

0.025 moles of phenyl) -magnetic (3.7) 136-142 60% Siumbromide NMR O.K.

1- (4-isopropyl-55.2 mp ° C

0.05 moles of phenyl) -magnetic (5.3) 58-64 55% Siumbromide NMR O.K.

Comparative Example I

a) Magnesium salt of alpha-bromopropionic acid, So. CCH 2 CH (Br) COO] 2Mg, 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 step Ha above 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

Comparative Example II

64571

Comparative Example Ia 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.

Comparative Example III

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

Comparative Example IV

The following coupling reactions (to the extent shown below) were performed using the magnesium salt of alpha-bromopropionic acid (prepared according to Example D, II) and the corresponding Grignard reagent (prepared according to Example C). 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 the magnesium chloride complex in tetrahydrofuran is added over 5 minutes keeping the temperature between 10 and 55 ° C. The reaction mixture is then cooled to 10 ° C and added 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: 6 4 5 71 13

Measure (when using Purification Cometric Mats Actual Quantities of Reagent Product) moles Aryl-Grignard Yield, Comment Yield

Grignard-% tit compound_j ^ j__ 2- (6-methoxynaphth 43.0 Product 0.12 moles of style) magnesium (11.9) purity = 37.4% bromide 86.8%

4- (4'-fluorobib-28.6 mp ° C

0.025 moles of phenyl) -magnetic- (1.75) 130-148 28% Siumbromide NMR O.K.

1- (4-Isopropyl-52.0 Purity of 0.05 moles of phenyl) -magnetic (5.0) 26% Siumium bromide by NMR ca. 50% - oil

From the above examples and comparative examples, 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.

14 64 571 Magnesium chloride mixture complex of 2- (6-methoxy-2-naphthyl) propionic acid has the following properties as its tetrahydrofuran monoetherate (purity 98/1%):

Sp. 113 ° C (dec.) Γ IF (KBr plate) 1600, 1450, 1410, 1260, 1210, 1155, 1025, 923, 885, 850, 805 and 750 cm -1; NMR (DMSO-D6) delta (TMS) 1.4 (doublet, 2H), 1.8 (multiplet, 4H), 3.6 (multiplet, 5H), 3.9 (singlet, 3H), 7.5 (multiplet, 6H) ppm.