CA1133916A - Process for preparing aromatic acetic acids - Google Patents

Abstract

ABSTRACT

A process is disclosed for the preparation of an aromatic acatic acid of the formula ArCH2COOH - (I) wherein Ar represents a substituted or unsubstituted aromatic group.

Description

~33~6 This invention relates to a process for preparing an aromatic acetic acid represented by the formula ArC~2COOH (I) wherein Ar is a substituted or unsubstituted aromatic group.
~ore particularly, this invention relates to a process for preparing an aromatic acetic acid represented by the formula ~I) above which comprises reacting an aromatic aldehyde repre-sented by the formula ArCHO - ------------ - (II) wherein Ar is a substituted or unsubstituted aromatic group, with an alkanethiol represented by the formula RSH - (III) wherein R is an alkyl group, and a trihalomethane represented by the formula ~CX3 (IV) wherein X is a halogen atom, in the presence of a base in a mi~ed medium of water and a non-protonic polar solvent.
Certain types of substituted aromatic acetic acids have been known to exhibit antipyretic, anti-inflammatory, analgesic and antispasmodic activities and have been practically used as pharmaceuticals. Also, some of the aromatic acetic acids are utilized as chemical modifier for antibiotics and, in addition, are used as raw materials for the production of new types of pyrethroid insecticidal agents. Accordingly, develop-ment on a novel process for easily synthesizing these useful substituted aromatic acetic acids will greatlylcontribute to the chemical industry.

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Hitherto, the above type of compounds have been prepared by the following processes:
1) Process comprising heating a halobenzene and an a-halo-acetic a_id ester in the presence of copper powder [refer to Th. Zinc~e, Ber., 2, 738 (1869)].

2) Process comprising con~erting a halogsnated benzyl as raw material into a Grignard rea~ent followed by carboxylation [refer to J. Houben, ~er., 35, 2523 (1902)1.

3) Process by Arndt-Eistert-Wolff reaction of diazoaceto-10 ~ phenone [refer to L. Wolff, Ann., 394, 43 (1912)].

4) Process comprising acetylatins an aromatic compound followed by heating together with ammonium polysulfide and then hydrolysis tWoE~ Bachmann et al., J. Amer. Chem. Soc., 65, 1329 (19~3)].

5) Process comprising treating a halogenated benzyl with sodium cyanide, potassium cyanide or the like to form an aromatic substituted acetonitrile which is then hydrolyzed with an alkali or an acid into the aromatic acetic acids [refer to A.W. Hofmann, Ber., 7, 519 (1874); R~ Adams and A.F. Thal, Orq. Synth., Coll. Vol. Ij 436 (1947)].

6) Process comprising reacting an aromatic aldehyde with formaldehyde mercaptal S-oxide followed by treating with a mineral acid to convert into the aromatic acetic acid deriva-tives lrefer to ~. Ogura et al., Tetra. Letters, 1383 (1972)].

7) Process comprising synthesis of aromatic acids by treat-ing a 2,2,2-trihalo-1-arylethanol with water, an alcohol, a mercapta~ or an amine in the presence of a base to prepare the corresponding -oxy, ~-thio or ~-amino-substituted aromatic acetic acid and removing the ~-substituent by reduction pro-cedure trefer to Japanese Patent Application Publication (Unexamined) Nos. 112836/1978 and 112868/1978].

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However, in the processes 1) and q), the reaction condi-tions are very difficult to determine and also the reaction yield is generally low. In carrying out the process 2), anhydrous reaction condition must be established. The process 3) requires unstablc diazo compounds as starting materials.
In the proce~s 5), the starting material halogenated benzyls are noteasily available and, in addition, the process must proceed via a highly toxic cyanide. The process 6) requires a number of reaction steps. The process 7) also requires a number of reaction steps since the process requires the synthesis of an c-substituted-phenyl acetic acid and then reduction.
Such disadvanta~es associated with these conventional processes prevent the practical use of these processes in industry and in general when substituents to be retained on the aromatic ring have previously been introduced into the aromatic ring, these conventional processes cannot easily be used practically.
- As a result of extensive researches in order to eliminate the disadvantages of the conventional processes, the present invenotrs found a process for the synthesis of the desired aromatic acetic acids represented by the formula tI~ above ~hrough a one-step reaction from aromatic aldehydes represented by the formula (II) which are easily available in industry and completed the present invention.
, Examples of aromatic aldehydes represented ~y the formula (II) above used as starting materials are (alkyl-substituted phenyl)aldehydes such as benzaldehyde, tolualdehyde, ethylbenz-aldehyde and the like, (aryl-substituted phenyl)aldehydes such as phenylbenzaldehyde, (mono- or dialkoxy-substituted phenyl)-ildehydes and (aryloxy-substituted phenyl)aldehydes such as anisaldehyde, etho~ybenzaldehyde, allyloxybenzaldehyde, benzyl-oxybenzaldehyde, piperonal, phenyloxybenzaldehyde, benzyloxy-benzaldehyde and the like, (halo-substituted phenyl)aldehydes :

, ,:' ~ ' , ' ' , .. :
: : :~:, .:

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such as chloroben~aldehyde, bromobenzaldehyde and the like, lalkyl, alkoxy or aryloxyhalo-di-substituted phenyl)aldehydes such as aminobenzaldehyde, meth~l chLorobenzaldehyde, methoxy-chlorobenzaldehyde, allyloxychlorobenzaldehyde, phenoxychloro-benzaldeh~de and the like, unsubstituted or substituted aromatic aldehydcs such as thiophenealdehyde, furylaldehyde, naphthyl-aldehyde and the like. These aldehydes are easily available in industry.
Examples of alkanethiols represented by the formula(III) above used as starting material in the present invention are methanethiol, ethanethiol, propanethiol, butanethiol and the like. For ease in handling and availability, lower alkane-thiols are preferably used.
~xamples of trihalomethanes of the formula (IV) above ~hich can be used are tribromomethane, trichloromethane, di-bromochloromethane, dichlorobromomethane and the like.
The present invention is conducted in the presence of a base as an essential requirement. The bases include alkali metal hydroxides such as potassium hydroxide, sodium hydroxide, lithium hydroxide and the like, alXali metal carb~nates such as sodium carbonate, potassium carbonate and the like. Pra-ferably, alkali metal hydroxides are used as base since the reaction time can be shortened and the yield of the product can be impro~ed.
The present invention is also conducted in a mixed solvent of water and a non-protonic polar solvent as an essential requirement. Examples of non-protonic polar solvents which can be ~sed are sulfoxides such as dimethyl sulfoxide, sulfones such as sulforane, amides such as dimethylformamide, dimethyl-acetamide, hexamethylphosphoramide and the like, nitriles such as acetonitrile and the li~e, ethers such as tetrahydrofuran, dimethoxyethane, diglyme and the like, or a mixture thereof.
~he use of dimethylformamide is preferred in order to obtain the desired compound in high selectivity and high yield.

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From the standpoints of yield and reaction selectivity, water and a non-protonic polar solvent are preferably used at a ratio of about l:l by volume.
The reaction i5 carried out by dissolving the com-ounds of the formulae (II), ~III) and (IV) in the above medium and then adding thereto a base dissolved in the above medium, but the order of addition can be changed depending upon the type of the starting aldehyde (II). ~he alkanethiol (III) is pre-ferably used in an amount of 2 to 7 times in equivalent with respect to the ar~matic aldehyde (II). The trihalomethane is used in an equal amount to a slightly excess amount. The base is preferably used in a stoichiometrically required amount, i.e., 5 to 8 equivalents, with respect to the stdrting materi-al (II). The reaction does not require speciric heating or cooling and proceeds easily at room temperature, but, if neces-sary, the reaction can be carried out wlth slightly cooling or heating to promote the reaction and to improve the yield.
According to the present invention, the aromatic acetic acid represented by the formula ~I) above corresponding to the aromatic aldehyde represented by the formula (II) above can be prepared. ~xamples of aromatic acetic acids obtained by the present invention are (alkyl-substituted phenyl)acetic acids such as (methyl-substituted phenyl~acetic acid, (ethyl-sub-stituted phenyl)acetic acid and the like, (aryl-substituted ~ phenyl)acetic acids such as (phenyl-substituted phenyl)acetic acid and the like, (mono- or dialkoxy-subs~ituted phenyl)-acetic acids and (aryloxy-substituted phenyl)acetic acids such .

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as (methoxy-substituted phenyl)acetic acid, ~ethoxy-substituted phenyl)acetic acid, (allyloxy-substituted phenyl)ace~ic acid, ~benzyloxy-substituted phenyl)acetic acid, (methylenedioxy-substituted phenyl)acetic acid, (phenoxy-substituted phenyl)-acetic acid and the like, (halo-substituted phenyl)acetic acids such as (chloro-substitute~ phenyl)acetic acid, (bromo-substi-tuted phenyl)acetic acid and the like, (amino-substituted phenyl)acetic acid, (alkyl- or alkoxy, aryloxy, halo-substituted phenvl)acetic acids such as methoxychloro-di-substituted phenyl)-acetic acid, (ethylchloro-di-substituted phenyl)acetic acid, (methoxychloro-di-substituted phenyl)acetic acid, (allyloxy-chloro-di-substituted phenyl)acetic acid, (phenoxychloro-di-substituted phenyl?acetic acid and the like, unsub~tituted or substituted aromatic acetic acids such as pheny~acetic acid, thienylacetic acid, furylacetic acid, naphthylacetic acid and the like.
In considering the present invention form the reaction mechanism, the main reaction route for obtaining the aromatic acetic acids (I) from the aromatic aldehydes (II) can be represented by the following reaction scheme.

ArC80 + CHX3 Base -~ Ar-CH-Cx3 (II) (IV) 0 ~

(~ase) ' . ' .,,' : . :~' ' '' , ' .

-ArCHCOX ~ R5~ ~ O
T~ase 9 ~ ~ase _ RSH (III

¦~ase ArC~COSR - - ~ ArCH2COSR
SR
~ 8ase ArCH2COOH ~ RS~
(I) ~Regeneration) That is, the reaotion proceeds via the formation of a 2,2,2-trihalo-1-arylethanol by addition reaction of an aromatic aldehyde and a trihalomethane in the presence of a base, the for~ation Oc a dihalo epoxide b~ a base, the ring-openin~ reac-tion of the epoxide by a mercaptide anion, the cleavage of an ~-thio substituent from an a-thio-substituted aromatic acetic acid derivative by the mercaptide anion, hydrolysis, etc. The use of a highly nucleophilic alkanethiol (Il) and the above-descrl~ed polar mixed medium which enables a smooth nucleo-philic substitution reaction makes it easy that the mercaptide anion acts nucleophilically on the ~-thio-substituted aromatic acetic acid derivative produced as intermediate, whereby the ~L33~6 aromatic acetic acid frcm which the ~-thio substituent has been removed can be obtained directly.
The present invention is further illustrated in greater detail by the following Examples and Comparative Examples.

Exam~e 1 To a 50~ dimethyl sulfoxide aqueous solution (25 ml) were added methyl mercaptan (0.95 g, 20 mmoles), an aqueous solu-tion (5 ml) of potassium hydroxide (0.3 g, 5.3 ~moles), a dimethyl sulfoxide solution (5 ml) of o-benzyloxybenzaldehyde tl.06 g, 5 mmoles) and then bromoform (1.52 g, 6 mmoles) while cooling with ice-water and stirri~g, and the mixture was stirred for 30 minutes. Potassium hydroxide (2.0 g, 3; mmoles) dis-solved in a S0~ dimethyl sulfoxide aqueous solution (15 ml) was added dropwise to the reaction mixture. After completion of the addition, the mixture was stirred at room temperature overnight and at 70C for 2 hours. ~fter cooling to room tem-perature, water and diethyl ether were added thereto and tne ether-soluble .material was removed. The aqueous layer was ren-dered acidic with dilute hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silic~ gel column chromatography , to a~Eord 0.78 g (64~) of p-benzyloxyphenylacetic acid.
N~R (CDC13, ~TMS): 3.68 (s, 2H),'5.03 ts, 2H), 6.73-7.53 (m, 9H), 10.~ tbs, lH).

~33~6 Example 2 To a 50% dimethyl sul~oxide aqueous solution tS0 ml) were added ethyl mercaptan (3.5 ml, 47 mmoles), an aqueous solution (10 ml) of potassium hydroxide (0.6 g, 10 ~moles), a solution of 2-thienyl aldehyde (1.12 g, 10 mmoles) in dimethyl sulfoxide (10 ml) and then bromoform (3.04 g, 12.2 mmoles) in an argon atmosphere .~hile cooling with ice--~ater and stirring, and the mixture was stirred for 1 hour. Potassium hydroxide (3.04 g, 46 mmoles) dissolved in a 50~ dimethyl sulfoxide aqueous solution (30 ml) was added dropwise to the reaction mix-ture. After cornpletion of the addition, the mixture was stirred for 2 hours and then at room temperature for 3 hours. Water and diethyl ether were¦added to the reaction mixture and the ether-soluble material was removed. The aqueous layer was rendered acidic with dilute hydrochloric acid and extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel chromatography to afford 0.82 g (58~) of thienylacetic acid.
NMR (CDC13, ~TMS): 3.8 (s, 2H), 6.80-7.23 (m, 3H), 11.2 ~bs, lH).

Example 3 To a 50% dimethyl sulfoxide aqueous solution (50 ml) were added methyl mercaptan (2.5 g, 52 mmoles), an aqueous solu-tion llO ml) of potassium hydroxide (0.6 g, 10 mmoles), a solu-tion of p-methoxybenzaldehyde (1.36 g, 10 mmoles) in dimethyl sulfoxide (10 ml) and then bromoform ~3.04 g, 12.2 mmoles) _g _ :

: - : . . . .

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while cooling with ice water and stirring, and the mixture was stirred for one hour. Potassium hydroxide (3.04 g, 46 ~oles) dissolved in a S0~ aqueous solution of dimethyl sulfoxide (30 ml) was added dropwise to the reaction mixture. After completion of the addition, the mixture was stirred overnight at room temperature and then 2 hours at 70C. Aft2r allowing the mixture to cool to room temperature, water and diethyl ether were added to the reaction mixture and the ether-soluble material was removed. The aqueous layer was rendered acidic ~-ith dilute hydrochloric acid and extracted with ethyl acetate.
The extract was washed with water, dried o~er anhydrous magne-sium sulfate and filtered. The filtrate was concentrated and purified by silica gel chromatography to afford 1.64 g of crystals. Upon measurement of N~IR spectrum of the resulting crystals and gas chromatography determination of the correspond-ing methyl ester obtained by treating the crystals with dia70-methane (2% EGA, 1 m, temperature increase at a rate of 1C/min from lS~ C), the isolated crystals were found to be a mixture of p-methoxyphenylacetic acid and ~-methylthio-p-~ethoxyphenyl-acetic acid at a ratio of 92:8. That is, the yield o~ p-methoxyphenylacetic acid was 87% based on p-methoxybenzaldehyde.

Examples 4 - 28 In the same manner as Example 3, aromatic acetic acids w~re synthesized using the aromatic aldehydes as starting materials shown in the following reaction scheme. The re-sults obtained are shown in Table I.

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RSH (III), HC8r3, Potassium Hydroxide Ar-CHO - - -~ Ar-CH2COOH
50~ Dimethyl Sulfoxide Aqueous Solution ~II) (I) Table I

Example Ar R ~IIX) Yi~ld (~) 4 Ph Me 52 " Et 77 6 n n-Pr 4 9 7 " i-Pr 31

8 ~ t-Bu 53

9 CH3 ~ Me 57 " Et 72 11 " n-Pr 76 12 " i-Pr 43 13 " t-Bu 70 14 C1 ~ Me 55 " Et 82 16 " n-Pr 71 17 " i-Pr 73 18 " t-Bu 35 19 MeO ~ Et 79 " n-Pr 87 21 " i-Pr 84 22 n t-Bu 92 .
23 Ph O ~ Me 30 2 4 Me2N ~ Me 3 ~ ~335~gL6 Example _ Ar _ R (III) Yield (%) ~ ~ Me 58 26 ~ " 64 27 " Et 88 28 ~ ~e 59 Example 29 To a mixed solvent of acetoni~rile (25 ml) and water (10 ml) were added l-methyl-2-formyl-5-p-methylbenzoylpyrrole (1.135 g, 5 mmoles), bromoform ~1.;4 g, 6.1 mmoles) and ethyl mercaptane tl.61 g, 26 mmols, 1.94 ml). A solution of potassium hydroxida (1.57 g, 28 mmols) dissolved in water (7.5 ml) and acetonitrile (25 ml) was added dropwise thereto at r.t. under stirring.
After the addition was over, the reaction mixture was stirred overnight at r.t. and heated under stirring at 80C in a hot-water bath for 2 hrs. After allowing the mixture to cool to r.t., water (50 ml) was added thereto, diiuted and washed with ether. The aqueous layer was taken out and acidified with HCl.
The reac~lon mixture became white turbid to form a solid.
This solid was extracted with ether, dried and concentrated to afford 0.9 g of 5-p-methylbenzoyl-1-methylpyrrole-2-acetic acid.
Yield 70~.
m.p.: 155 - 156C
NMR tCDC13): ~2.37 ~3H, s), 3.69 (2H, s), 3.89 (3EI, s), 6.06 ~lH, d, J=4Elz), 6.62 ~lH, d, J=4Hz), 7.18 ~2H, d, J=8Hz), 7.6~ (2H, d, J=8Hz).
IR ~K~r): 3425, 2940, 2900, 1700, 1610 cm 1.

- ~ : : :: ,~ :

.: ;- : :. , . : :; , :

- : : . .:: .~., : :

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om~arative Exarnple 1 (Embodiment where i-propanol was used as a reaction solvent and the a-phenylthio group was cleaved.) To a solution of thiophenol (1.65 g, 1; mmoles)~ bromo-form (3.04 g, 12 m~oles), and p-methoxybenzaldehyde (1.4 g,

10 m~oles) dissolved in i-propanol (50 ml) was added a solution of potassium hydroxide (3.4 g, 53 mmoles) dissolved in i-propanol (50 ml) while cooling with ice-water and stirring.
A~ter c_mpletion of the addition, the mixture was stirred overnight at room temperature and then refluxed for 3 hours.
After allowing the mixture to cool to room te~perature, water and diethyl ehter were added thereto to remove ether-soluble material. The aqueous la~er was rendered acidic with dilute hydrochloric acid and extracted with chloroform. The extract was washed with water, dried sver anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography to afford a-phenylthio-p-methoxyphenylacetic acid (2.69 g, 96~).
NMR ~CDC13, ~T~S): 3.74 (s, 3H), 4.79 ~s, lA), ~.02 (m, 2n aromatic's H), 9.84 (bs, lH).

Comearative E~amole 2 ~Fmbod~ent where ethanol was used as a reaction solvent and the a-phenylthio group was not cleaved.) 25 ~ The experiment was conducted using the same starting materi-~ls ant the same reaction procedures as used in Comparative Example 1 but using ethanol as a reaction solvent also resultad in the production of a-phenylthio-p-metho~yphenylac_tic acid ~2~35 g, 84~).
3~

Claims (8)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows.

1. A process for preparing an aromatic acetic acid represented by the formula ArCh2COOH

wherein Ar is a substituted or unsubstituted aromatic group, characterized by reacting an aromatic aldehyde represented by the formula ArCHO

wherein Ar is as defined above with an alkanethiol represented by the formula RSH
wherein R is an alkyl group, and a trihalomethane represented by the formula wherein X is a halogen atom, in the presence of a base in a mixed medium of water and a non-protonic polar solvent.

2. The process according to Claim 1 wherein said base is used in an amount of 5 to 8 equivalents.

3. The process according to Claim 1 wherein the volume ratio of said water and said non-protonic polar soi-vent is 1:1.

4. The process according to Claim 1 , 2 or 3 wherein said base is an alkali metal hydroxide.

5. The process according to Claim 1, 2 or 3 wherein in R is a lower alkyl group.

6. The process according to Claim 1, 2 or 3 wherein said non-protonic polar solvent is dimethyl sulfoxide.

7. The process according to Claim 1 in which the Ar group represents wherein X is CH3 or C1 and Y is H or CH3.

8. The process according to Claim 1 in which the Ar group represents