CA1115722A - Preparation of 2-aryl-propionic acids by direct coupling utilizing a mixed magnesium halide complex - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Intermediates useful in the preparation of 2-aryl-propionic acids having anti-inflammatory, antipyritic and anelgesic properties are disclosed. Such 2-aryl-propionic acids are prepared by the direct coupling of aryl magnesium bromides, where aryl may be 6-methoxy-2-naphthyl, 4-alkylpnenyl and 4'-fluoro-4-biphenyl with a complex of the formula CH3CH(Br)-COOMgX, wherein X is chloro or bromo. The complex is prepared by treating a Grignard reagent with alpha-bromo-propionic acid.

Description

~ r~, -- ~57Z2 BACKGROUND OF THE IMV¢NTI0~1 One of the most frequently employed synthetic methods for the preparation of arylalkanoic acids has ~een the coupling of an aryl organometallic reagent with a halo- -alkanoic acid derivative such as a haloalkanoic acid ester. This method has proven to be of particular importance for the preparation of the valuable ' anti-inflammatory agent 2-(6-methoxy-2-naphthyl)propio.nic acid. In particular, for the preparation of this compound, couplings involving an alpha-halopropionic acid ester-and 2-(6-methoxynaphthyl)copper (U.S. 3,658,863), ~' zinc (U.S. 3,663,584) and cadmium (U.S. 3,658,858 and 3,694,476)'reagents have-been utilized. One disadvantage ~.' of these procedures is that the organometallic reagent .
used 'for the coupling must be prepared from the corresponding Grignard reagent, thus necessitating an additional chemical reaction, additional reagents, and so - forth.
; In German OLS 2145650 the direct coupling of aryl magne'sium halides'with po~assium 2-iodo~xopionate was . 'described. More recently, in U.S. 3,959,364, it was shown ' that an improved direct coupling could be effected by reaction of an.aryl Grignard reagent with the lithium, sodium, magnesium or calcium salts of 2-bromopropionic ;' ~ 25 acid of the structure CH3CH(X)COM wherein X is bromo and M
' stands for OLi,'ONa, O(Mg).l/2 or O(Ca)l/2 ( cf. Table II of .
U.5. 3,959,364). However, it has been'found that the -: preparation of 2-axyl-propionic acids, especially the . valuable compound 2-(6-methoxy-2-naphthyl)propionic acid, . 30 by this method suffers from a number of inherent .

;. -2-, . ~, ~115722 disadvanta~es including preparation of halopropionate salt in the aprotic solvent media that must be employed for the coupling reaction, leading to poor results for large scale preparations.
It would, therefore, be of extreme value to have a coupling process utilizing an aryl Grignard reagent and a suitable halopropionic acid derivatlve which afforded the desired 2-aryl-propionic acids easily and in reproducible high yield and purity and was~readily adaptable to large scale commercial production.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is related to the preparation of known valuable anti-infl~ammatory agents, more specifically

2-aryl-propionic acids such as 2-(6-methoxy-2-naphthyl)-propionic acid which is described in U.S. 3,904,682, More specifically, the present invention concerns a novel ' ~rQcess for the preparation oE these valuable therapeutic agents.
Still more specifically, 'the present invention concerns a direct coupling process whereby a desirea aryl '~ magnesium bromide is coupled wlth a mixed magnesium halide ' complex of alpha-bromopropionic acid, in high yield, to afford the correspollding 2-aryl-propionic acid. A11 reference to 2-aryl-popionic acids in the specification and the'appe'nded claims is to the racemic form of these compounds.
Exemplary of the 2-aryl-propionic acids whose " preparation is within the scope of the present invention are those wherein the aryl moiety is `' 30 ~ .

-3-- . . ~ ., 6-methoxy-2-naphthyl, i.e. 2-(6-methoxy-2-naphthyl)-propionic acid;

4-alkylphenyl, wherein "alkyl" refers to straight and ':
branched chain saturated hydrocarbon groups having from S one to four carbon atoms, e.g., 2-(4-methylphenyl)propionic acid, 2-(4-isopropyl-phenyl)propionic acid and 2-(4-isobutylphenyl)propionic acid; and 4'-fluoro-4-biphenyl, i.e., 2-(4'-fluoro-4-biphenyl)-propionic acid.
, As mentioned above, the prior art U.S. Patent 3,959,364 ~
describes the preparation of arylalkanoic acids by the direct coupling of an aryl Grignard reagent ~7ith the Na, Li~,Ca l/2 and ~9 l/2 salts of alpha-bromopropionic aci~d.
It has now been found that, surprisingly, an improved ' coupling reaction,results if one employs, instead of one . of the aforementioned salts, a mixe~ magnesium halide compiex of alpha-bromopropionic acid, that is, a species of ~the formula CH~3CH(Br)COOMgX wherein X is chloro or bromo. In,fact, a dire,,ct comparison of the.magnesium salt of alpha-bromopropion1c acid (prepared by both methods -di~s'closed in U.S. 3,959,364~ and the novel complex hereof demonstrates a remark'able difference.in yield of final products obtained (about a 2-fold difference) and is set 25~ for~th in further detail in the Examples. It is an additional advantage of the present coupling process that ~' . its yields are not affected by'the preparation of the mixed magnesium hal1de compIex to the extent the yields of the coupling process of U.S. 3,959,364 are affected by the 30. method of preparation of the 2-bromopropionate salt (cf,.
U.S. 3.,959,364 column 3 lines 10 and ll).

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Tl~e mixed mac~nesium haLitlc! complcx of alplla-broJnopro-pionic acid may be prepared by treatmcrlt of the free acicl with a suitable Grignard reagent. ~hile the nature of the hydrocarborl moiety of the Grignard rea~ent is not critical it is preferrcd that the Eree hydrocarbon Eormed in tl~e reaction of alpha-bromopropiollic acid with the GLiynard reagent does not interEere with the couplin~ step or work-up. As a consequence, Gric~nard reagents clerived from hydrocarbons, that are gaseous or liquid at reaction temperatures are particularly suitable, for e~arnple alkyl magnesium Grignards ~lith l'to 12 carbon or aryl magnesium Grignards ~ith 6 'to 9 carbon atoms. Specific Grignard reagents that may be employecl for this purpose are methyl magnesium chloride, methyl magnesium bromide, ethyl 1~ mac~nesium chloride, ethyl magnesium bromide, isopropyl magnesium chloride, phenyl magnesium chloride r and o-, m-or p-tolyl magnesium chloride, and the like. Methyl magnesium chloride and methyl magnesiwn bromide are particularly pr~ferred inasmuch as the,y are readi:ly co~nercially available, inexpensive, and lead to the formation of methane gas which escapes from tlle reaction mi'xture and does not lnterfere durincJ reaction or work~lp.
It has been found that, surprisingly, the addition o~ one , of the aforesaid Gricgnard reagents to alpha-bromopropionic ~ 25 ` acid results primarily in formation oE the'aEorementioned ,, complex. ~dditlon of the ~rignard rcagent across the carbonyl moiety of the carboxylic acid, a reaction which no~mally would be expected to occur to a iarg~ clegree, appears to be minimal even when a molar excess of Grignarcl 30 , reac~ent is employ~d.

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Preparation of the mixed magnesium halide complex is normally carried out in an aprotic solvent medium comprising an ether such as diethylether, tetrahydrofuran, ;
1,2-dimethoxyethane, di-(n-butyl)ether, and the like. The solvent medium may include other aprotic solvents such as -aromatic hydrocarbons, e.g., benzene or toluene. A
preferred solvent medium for complex preparation ~s tetrahydrofuran. While the order of addition of reagents is not narrowly critical it is normally preferred to add the Grignard reagent to the alpha-bromopropionic acid.
The Grignard reagent, in solution, is preferably from about 1 to 4 M, most preferably from about 2 to about 3 M. A final complex solution for use in the direct coupling step of from about 1 to about 2 M, preferably from about 1.0 to 1.5 M is desirable. The temperature of the complex formation step is normally maintained between about -20 and +30C, preferably between about -10 and +20C.
The coupling reaction itself is suitably performed by contacting a solution of the mixed magnesium halide complex of alpha-bromopropionic acid with the aryl magnesium bromidé 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 mentioned above for the complex formation step. A particularly preferred solvent medium for the coupling reaction is tetrahydrofuran. It is -preferred that the aryl magnesium bromide solution be between 0.5 and 2 M, most preferably about 1~0 M.
The cou~ling process itself may be carried ou over a , . ~ . . , . . , . . . i, .... ..

temperature range of from about 0 to about ~100C, preferably between about lO and 60C. It is particularly preferred to allow the temperature to gradually rise during the addition stage up to about 40-60C and then to ' return to ambient temperature until the desired degree of reaction has been attained.
Although the coupling reaction may be conducted utilizing the reagents in varying proportions to one another it is pre~erred that approximately equimolar lO ~ amounts of the mixed magnesium halide complex and the aryl Grignard reagent be utilized. Preferred ratios are from about 0.9:1.1-to l.l:0.9 complex : Grignard reagent.
The reaction may be performed by conveniently contacting the two reagents in the solvent medium in any manner conventional in the art. However, it is particularly preferred to add the mixed magnesium halide complex to the Grignard reagent and to keep these reagents in intimate admixture until the desired reaction is essentialIy complete.
20 ~ ~ The time necessary for performance of the desired : . .
reaction will, of course, be influenced by the particula'r ~' choice of reagents, solvents and rèaction temperature and ' will ordinarily be adjusted by the skilled practitioner to allow for the optimum production of the desired product.
Generally however such reaction time will be in the range ~ of from about 10 minutes to about 20 hours, usually being - in the range of from about 1 to about 5 hours.
After the coupling reaction has'proceeded to,the ;
desired state of completion the reaction mixture , "

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containing the coupled complex ArylCH(CH3)COOMgX is then quenched with a dilute acid, preferably a dilute aqueous mineral acid such as hydrochloric acid or sulfuric acid, in the conventional manner for Grignard reactions. The free 2-aryl-propionic acid product may then be isolated and purified from the quenched reaction mixture by conventional means such as extraction with aqueous aIkali (e.g. aqueous sodium or potassium hydroxide), separation of the aqueous alkaline phase from the organic phase and acidification of the aqueous alkaline phase to free the desired acid, which may optionally be extracted into an organic solvent or directly purified in the usual manner ;
-such as by washing and/or crystallization. ~ - ;
If desired, the crude reaction product may be directly converted into a pharmaceutically acceptable derivative of the carboxylic acid, such as a salt, ester or amide thereof, or resolved into optical isomers.
' The process of the present invention is easily and `~ conveniently ~performed on a large scale and affords yields of purified product in the 50-75P6 range.
The following éxamples are illustrative of the process of the present invention. They are not intended to limit - the spirit or scope of tbe invention in any manner.

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Preparation of 2-(6-methoxynaphthyl)magnesium bromide.
2-Bromo-6-methoxynaphthalene (23.7 9., 0.1 mole) is dissoIved in toluene (30 ml.) and tetrahydrofuran (40 ml.) with heating. This solution is then added over a 10-15 minute period to an excess of magnesium metal (3 g., 0.12 moles), toluene (15 ml.) and tetrahydrofuran (15 ml.) under a nitrogen atmosphere. The reaction mixture is then cooled and stirred for an additional hour at 25-30C. The reaction mixt~re is then transferred away from the excess magnesium to a clean, dry vessel under nitrogen and stored at 10C to afford a 1.0 ~1 Grignard reagent.
Proceeding in a similar manner, the Grignard reagent may be prepared using tetrahydrofuran as the sole solvent.
Similarly, by utilizing less solvent, a more concentrated Grignard reagent, e.g., 1.5 ~, may be prepared. -~

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Mixed maqnesium halide complex of alpha-bromopropionic acid.
15.3 G. (0.1 mole) of alpha-bromopropionic acid and 40 ml. of toluene are cooled to 10C and a solution of 50 ml.
of 2 M methylmagnesium bromide in tetrahydrofuran/toluene :~
(1:1) is then added slowly, màintaining the temperature at 10-20C during the addition time of 15-20 minutes. The reaction mixture is- then stirred at 5C for an additional 20 minutes to afford a 1.1 M solut.ion of the complex.
Proceeding in a similar fashion, the mixed magnesium halide complex may be prepared utilizing tetrahydrofuran as the sole solvent.
Similarly, methylmagnesium bromide may be replaced by :.
other Grignard reagents such as methylmagnesium chloride, ~.
isopropylmagnesium chloride, phenylmagnesium chloride, and the like, in concentrations varying from about 1 to about 4 M. .
The mixed magnesium chloride complex of alpha-.bromo-. 20 propionic acid (prepared as described above using 3 M
; CH3MgCl in tetrahydrofuran) was isolated in crystalline form as its tetrahydro~uran monoetherate after distilling tetrahydro~uran from a tetrahydrofuran solution and was . analyzed: mp 147-155C; ir ~KBr) 1625, 1450, 1420, 1372, ;~ 2~ 1291, 1200, 1070, 1030, 988, and 890 cm ; nmr (D2O) delta . . ~ 1.8 (multiplet, 7) 3.7 (multiplet, 4), and 4.35 ppm il , .
. - (quartet, J=7). Elemental analysis calcuIated for .
C7H12BrClMgO3: Mg, 8.57~; Cl, Found: Mg, 8.63~, Cl, 12.97%.

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l~lS~Z2 _REPARATION 3 Preparation of aryl magnesium bromides 0.025 Moles o~ aryl bromide is dissolved in tetrahydro-furan (18 ml.). This solution is then added to an excess ~, S of magnesium metal (3 g, 0.02 moles), and tetrahydrofuran (7 ml.) under a nitrogen atmosphere. The temperature is maintained at 50-60C with cooling during the addition ~-period of 10-15 minutes. The reaction mlxture is then transferred away from the excess magnesium to a clean dry vessel under nitrogen and stored at 10C to afford a 1.0 M
Grignard reagent. The following'Grignard reagents were -~
prepared in this manner~
2-(6-methoxyn'aphthyl)magnesium bromide , ' 4-(4'-fluorobiphenyljmagnesium bromide 1-(4-isopropylphenyl)magnesium bromide 1-(4-isobutylphenyl)magnesium bromide 1-(4-methylphenyl)magnesium bromide ' 20 ~

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~115722 A. Preparation of the mixed magnesium halide complex of alpha-bromopropionic acid.
Alpha-bromopropionic acid (3.8 g., 0.025 moles) is dissolved in tetrahydrofuran (8 ml.), and the solution cooled to -10C. To this solution is added 3 M methyl-magnesium chloride in tetrahydrofuran (8 ml.) over a 15- ;;
minute period while maintaining the temperature at -10 to 0C. This affords a 1.1 ~I molar solution of the complex which is stored at 0C or below until use.
Similarly, replaclng 3 M methylmagnesium chloride with l M methylmagnesium bromide, the corresponding magnesium bromide complex may be prepared.
B. Preparation of the magnesium salt of alpha-bromopro-pionic acid Alpha-bromopropionic acid (3.8 g., 0.025 moles) is dissolved in methanol (6 ml.) and the solution is cooled to -10C. To this is added a 0.5 ~5 magnesium methoxide in -~
methanol solution (25 ml.) over a ten-minute period while 20 ~ maintaining the temperature at -10 to OC. Methanol is then removed under reduced pressure to yield the solid salt which is dried in vacuo at 50C ~or twelve hours to yield the dry magnesium salt (4.1 g., 0~0l25 moles, purity 97.2~). This salt is dissolved in l9 ml. of tetrahydrofuran for the coupling reaction.

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L~ ~IPL~ 1 A. The solut;on of complex from Preparation 2 is added slowly to the ~rignard solution from Prepara-tion 1, maintaining the temperature at I5-20C during the addition time of 10-15 minutes. 'l'he reaction mi~ture is allowed to warm up to room temperature and then s-tirred for two hours.
The reaction mixture is then cooled in an ice bath and a solution of 20 ml. of 12 N hydrochloric acid and 150 ml.
of water is added. ~fter stirring for 5 minutes, the t~Jo-phase system is filtered and ~he filter cake is washed ~ith 55 ml. of toluene and 50 ml. of water. rrhe organic phase is extracted with 10% potassium hydroxide solution (2 x 150 ml.) and the combined basîc eY~tracts are washed - with toluene (30 ml.) and neutralized ~ith 12 N hydro-chloric acid to pH 1. The ~rhite solid 2-(6-methoxy-2-naphthyl)pro~pionic acid is filtered under vacuum and dried at 55C in vacuo Lo afford 15.2 ~rams (66%~, m.p.
1~9.5-153.5C.
B. Alternatively, a~ter filtration, the oryanic :: .
phase may be extracted witn 10% pot~ssium hydxoxide solution (2 x lS0 ml.) which is washed with toluene (30 ~ ml.)- and filtered. 15 ~11. of methclnol and 12 ml. o~
I toluene are added, then sufficient 12 N hydrochloric acid ~ to bring the pEI to between 4 and 5. The resulting slurry .
25~ ~ is then heated to reflu~ for 1 hour, cooled and filtered~ ~-Tne precip]tate is wasbed with water (20 ml.) toluene ~2 x 3 mJ.) and hexane (2 x 3 ml.) ancl dried at 55C in vacuo to yicld 1$.0 g. ~65.1~) of product, m.p. 154.5-155DC.
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~XAMPLE 2 67 Ml. of a 1.5 M solution of the mixed magnesium chloride complex of alpha-bromopropionic acid in tetra-hydrofuran (prepared utilizing 3 M methylmagnesium chloride) is slowly added to a cooled (10C) solution of 1.5 M 2-(6-methoxynaphthyl)magensium bromide in tetra-hydrofuran (67 ml.) at a rate such that the temperature is held at 55C or below. The resulting slurry is stirred at 50C for one hour and then heated to reflux, allowing 30-40~ of the tetrahydrofuran to distill off. The reaction mixture is cooled to 50C, 30 ml. of toluene is added and the reaction mixture is quenched with aqueous hydrochloric acid and worked up as in Example lB to afford 2-(6-methoxy-2-naphthyl)propionic acid, m.p. 156-157C, in 73% yield.

A. The magnesium~salt of alpha-bromopropionic acid, i.e. [CH3CH(~Br)COO]2Mg, was prepared by reacting the acid with 1/2 molar equivalent of magnesiu~ carbonate, followed by drying the salt at 60C in vacuo.
Replacement of the mixed magnesium chloride complex used in Example 2 with this salt resulted in a 34.7~ yield of product.
B. The saIt of part A was also prepared using 1!2 molar equivalent o magnesium methoxide, methanol being :.
removed as an azeotrope. Use of the salt in the procedure of Example 2 afforded a 43.0~ yield of product.

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' ' '' ' : '' EXP~lPLE 4 Example 3A was repeated, except that 1/2 molar equivalent of anhydrous magnesium chloride was added to the magnesium salt prior to the coupling reaction. A 5.1 yield of product was obtained.

EX~IPLE 5 The procedure of Example 3B was repeated except that equimolar amounts of alpha-bromopropionic acid and magnesium methoxide were employed. The yield of product obtained was 35.1%.

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1~157Z2 EXA~PLE 6 Comparative coupliny reactions using mixed magnesium halide complexes and Mg 1/2 salts' The following coup,ling reactions, (on the sca]e indicated below) were carried out utilizing both the mixed magnesium chloride complex of alpha-bromopropionic acid (prepared as in Preparation 4A) or the magnesium salt of alpha-bromopropionic acid (prepared as in Preparation 4B) ', with,the corresponding Grignard reagent (prepared as in Preparation 3). The pro~edure (illustrated for a 0.025 mole scale),is as follows: '~
The 1.0 M solution o~ aryl magnesium bromide is cooled to 10C and the solution o~ either the magnesium salt or magnesium chloride complex in tetrahydrofuran is added 15 ' over a five-minute period while maintalning the ~, temperature'at 10 to 55C. The reaction mixture is then stirred at 25-30C for two hours. The reaction mixture is then cooled to 10C and a solution of 12N hydrochloric acid (10 ml.) and water (50 ml.) is added. Toluene (50 ml.) is then added and the aqueous phase is separated and .
discarded.' The organic phase is extracted twlce with 10~

' potassium hydroxide (S0 ml.). The basic extracts are ' '' , ~ '- combined and neutralized with hydrochloric acid to give a `
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precipitate which is filtered and dried at 50C.

The results are presented in the following table:

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' : ~ ' :, ., '', . : ': ' It can be`seen from the above, that in eclCll i n5tallCe a hi~her y;eld (approximately 2-Eold) of g~eater purity product was obtained ~rom the mixed m~c~nesium chloride complex.
S In a similar manner, comparable results may be achieved for the preparation of the follo~7in~ 2-arylpro-pionic acids~
2-(4-isobutylphenyl)propionic acid;
2-(4-meth~lphenyl)propionic acid.
If the above procedure is interrupted prior to quenching with aqueous acid, and the solvent is removed in vacuo, the coupled magnesium halide cornplexes, ArylCEI(CM3)COO~gX or etherates thereof may be isolated.
'l~he mixed magnesium chloride complex o~ 2-(6-methoxy-2-naphthyl)propionic ~cid as its tetrahydrofuran monoetherate (98.1% purity) exhibits the followin~ properties:
m.p. 113C (dec.); ir (KBr disc) 1600, 1450, 1410, l~ 1260r 1210, 1155r 1025r 923r 885~ 850; 305 alld 750 cm l;
,~ ; nm~r (D~SO-d6) delta (Tl~iS~ 1.4 (doublet, 211), 1.8 . 20 (muJ.tiplet, 4~1), 3.6 (multi.plet, 5~), 3.9 (sin~let, 3H) r .
3: ~ 7.5 (multiplet r 6II) ppm.

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Claims (8)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of a compound represented by the formula CH3-CH(Br)COOMgX or an etherate thereof, wherein X
is chloro or bromo comprising treating a Grignard reagent with alpha-bromopropionic acid in an aprotic organic solvent comprising an ether.

2. A process of claim 1, wherein said organic solvent comprises tetrahydrofuran.

3. A process of claim 1, wherein said Grignard reagent is methyl magnesium chloride or methyl magnesium bromide.

4. A process of claim 1, wherein X is chloro.

5. A process of claim 4, wherein said organic solvent comprises tetrahydrofuran.

6. A compound represented by the formula CH3-CH(Br)COOMgX or an etherate thereof wherein X is chloro or bromo, when prepared by the process of claim 1, 2 or 3.

7. The chemical compound CH3CH(Br)COOMgCl or an etherate thereof, when prepared by the process of claim 4.

8. The tetrahydrofuran monoetherate of the compound of claim 7, when prepared by the process of claim 5.