CA1103684A

CA1103684A - Process for preparing 2-thio-2-substituted-alkanoic acid derivatives

Info

Publication number: CA1103684A
Application number: CA309,676A
Authority: CA
Inventors: Kiyosi Kondo; Minoru Suda; Daiei Tunemoto; Akira Negishi; Kumiko Kishi
Original assignee: Sagami Chemical Research Institute
Current assignee: Sagami Chemical Research Institute
Priority date: 1977-08-18
Filing date: 1978-08-18
Publication date: 1981-06-23
Also published as: FR2400507B1; FR2400507A1; DE2836257A1; GB2007220A; GB2007220B

Abstract

ABSTRACT OF THE DISCLOSURE
Anti-inflammatory agents such as salicylic acid, pyra-zolone derivatives, indomethacin, etc. generally exhibit potent anti-inflammatory activity, but they also have serious side effects associated with them. The present invention provides a method of producing anti-inflammatory compounds not having as pronounced side effects. The compounds are 2-thio-2-substituted-alkanoic acid derivatives represented by the formula (I) (I) wherein A represents (1) a substituted-phenyl group of the formula in which y1 represents an isobutyl group or an unsubstituted-or substituted-phenoxy group wherein the substituent is a halogen atom, a trifluoromethyl group or an alkoxy group having 1 to 4 carbon atoms, or (2) a substituted-thienyl group of the formula in which y2 represents an alkyl group having 1 to 4 carbon atoms;
R represents an alkyl group having 1 to 4 carbon atoms; R3 represents a phenyl group, an alkyl-phenyl group wherein the alkyl group has 1 to 4 carbon atoms, or an alkyl group having 1 to 4 carbon atoms; and R4 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms The process comprises reacting a 2-(arylthio or alkylthio)-2-substituted-acetic acid of the formula (III)

Description

8~

1 This invention relates to a process for preparing

2-thio-2-substituted-alkanoic acid derivatives represented by the formula (I) A - - f _ COOR (I) SR
wherein A represents (1) a substituted-phenyl group of the formula yl ~
in which yl represents an isobutyl group or an unsubstituted-or substituted-phenoxy group wherein the substituent is a halogen atom, a trifluoromethyl group or an alkoxy group having 1 to 4 carbon atoms, or (2) a substituted-thienyl group of the formula y2 S
in which Y represents an alkyl group having 1 to 4 carbon atoms;
R represents an alkyl group having 1 to 4 carbon atoms; R3 represents a phenyl group, an alkylphenyl group wherein the alkyl group has 1 to 4 carbon atoms, or an alkyl group having 1 to 4 carbon atoms; and R4 represents a hydrogen atom or an alkyl group having 1 to 4 c~rbon atomsi which are useful as intermed-iates for the synthesis of various pharmaceutical agents.
Hitherto, salicyclic acid derivatives, pyrazolone derivatives, indomethacin, etc. have been used widely as anti-inflammatory agents. These agents generally exhibit a potent anti-inflammatory activity, but they are also ~nown to cause serious side~effects such as gastro-intestinal disorders, adverse affects on hematosis, etc. upon administration.
Recently, various alkanoic acid derivatives such as 11~68~

1 2-(4-isobutylphenyl?propionic acid, 4-isobutylphenylacetic acid and 2-(3-phenoxyphenyl)alkanoic acid derivatives have been interesting because of their low possibility of causing side-effects, while the anti-inflammatory activity thereof is not so potent, thereby making it possible to administer these agents over a prolonged period of time to patients.
The compounds of the formula (I) above wherein A
represents a 4-isobutylphenyl group and a 3-phenoxyphenyl group can be easily converted into the above 2-(4-isobutylphenyl) propionic acid and 4-isobutylphenylacetic acid or a 2-(3-phenoxy-phenyl)alkanoic acid derivative. Also, the compound o~ the formula (I) wherein A represents a substituted-thienyl group can be easily converted, upon reduction, into an ~-(2-thienyl) alkanoic acid which can then be converted into thiobrophenic acid having an anti-inflammatory activity, as disclosed in Japanese Patent Publication (Examined) No. 24915/74. ~urther, some esters of the above ~-(2-thienyl)alkanoic acid are known to have a high insecticidal activity, as disclosed in Japanese Patent Publication (Unexamined~No. 126826/74.
Typical conventional processes for preparing 2-(phenoxy-phenyl)alkanoic acid derivatives represented by the formula (I) wherein A represents a substitued-phenyl group includes (1) a process comprising heat-refluxing a 3-phenoxyacetophenone deriva-tive with sulfur in the presence of a secondary amine to produce a 3-phenoxyphenylacetic acid derivative, condensing the resulting compound with a carbonic acid ester to form an arylmalonic acid ester, introducing an alkyl group into the ester, followed by hydrolysis and decarbonization to obtain the desired compound, as disclosed in Japanese Patent Publication (Examined) No. 45586/76;
(2) a process comprising converting a 3-phenoxy-halobenzyl deriva-1 tive as a starting material into a corresponding cyano compound,then into an alkoxycarbonyl compound, and alkylating, hydrolyzing and decarbonizing the resulting compound in the same manner as described for the process (1) above to obtain the desired compound, as disclosed in Japanese Patent Publication (Examined) No.
45586/76; (3) a process comprising reducing a 3-phenoxyaceto-phenone derivative followed by halogenation to ohtain a 1-(3-phenoxyphenyl)haloethyl, and converting the resulting compound into a corresponding nitrile derivative and then hydrolyzing the nitrile derivative, as disclosed in Japanese Patent Publication (Examined) No. 70744/76; and (4) a process comprising converting the l-(3-phenoxyphenyl)-haloethyl used in the above process (3) into a Grignard compound and reacting the Grignard compound with carbon dioxide to produce the desired compound, as disclosed in ~apanese Patent PublicatiOn (Unexamined) No. 65729/76.
However, the above conventional processes are not considered advantageous in the production on an industrial scale for the reasons that these processes require a number of reaction steps to produce the desired compounds; the starting material, an acetophenone derivative, used in the processes (1), (3) and (4) is not easily available as an industrial raw material; a highly toxic hydrocyanic acid derivative must be used as a reagent in the processes (2) and (3); and an absolutely anhydrous condi-tion must be used in preparing the Grignard compound in the process (4).
Also, typical conventional processes for preparing CX -(2-thienyl)alkanoic acid derivatives of the formula (I) wherein A represents a substituted-thienyl group include (1) a process comprising alkylating an Cr-(2-thienyl)cyanoacetic acid ester, followed by decarbonization to produce an ~ -(2-thienyl)-il~)3684 alkanenitrile and then hydrolyzing the nitrile group, as disclosedin M. Bercot-Vatteroni, R.C. Moreau and P. Reynaud Bull. Soc.
Chim., France, 1820 (1961); and (2) a process comprising condens-ing a thiophene with ethyl chloroglyoxarate, and reacting the resulting condensate with a Grignard compound followed by reduc-tion, as disclosed in F. Climence, 0. LeLartret, R. Fournex, G. Plassard and M. ~anaux, Eur. J. Med. Chem., (1974-9), 390.
However, these processes require a number of complicated reaction steps and therefore cannot be applied to the production 10 on an industrial scale.
Further, typical conventional processes for preparing 2-isobutylphenylalkanoic acid compounds of the formula (I) wherein A represents an isobutyl-substituted phenyl group include, for example, (1) a process comprising reacting a 4-isobutylphenyl-acetic acid ester with an alkyl carbonate in the presence of a base to produce a malonic acid ester compound, reacting the resulting compound with methyl iodide to alkylate the compound, followed by hydrolysis and de^arbonization, as disclosed in Japanese Patent Publication ~Examined) No. 7491/65 (2) a process 20 comprising reacting a 4-isobutylbenzylcyanamide with a carbonic acid ester in the presence of a base to form a cyanoacetic acid ester, and methylating the ester, followed by hydrolysis and decarbonization, as disclosed in Japanese Patent Publication (Unexamined~ No. 46037/77; (3) a process comprising alkylating a substituted-phenylacetanitrile in a polar solvent in the presence of an al}cali metal hydroxide, followed by hydrolysis, as disclosed in Japanese Patent Publication (Unexamined) No. 146433~76; (4~
a process comprising converting a l-(4-isobutylphenyl)-haloethyl into a Grignard compound and reacting the Grignard compound with 30 carbon dioxide, as disclosed in Japanese Patent Publication i~L533684 1 (Unexamined) No. 39050/74; (5) a process comprising reacting an acetophenone derivative with an alkali metal cyanade and ammonium carbonate to form hydantoin, hydrolyzing the resulting hvaantoin to produce an ~-amino acid, followed by alkylation and reduction to obtain ~-phenylpropionic acid, as disclosed in Japanese Patent Publication (Unexamined) No. 18105/72; and (6) a process comprising reacting an acetophenone derivative with an ~-halo-acetic acid ester in the presence of a base to form a glycidic acid ester, decarbonizing the resulting ester to form an aldehyde followed by oxidation, as disclosed in Japanese Patent Publication (Unexamined) No. 24550/72.
However, the above conventianal processes are not advantageous for the reasons that they require a number of reac-tion steps and, in addition, highly toxic hydrocyanic acid compounds are used in the processes (2), (3) and (5) either for preparing starting nitrile compound or as a reactant; an absolutely anhydrous condition must be used in preparing the Grigna^d compound used in the process (4); and the process (6) requires very critical oxidation conditions which are very difficult to be controlled.
As a result of extensive studies on the process for preparing the compounds of the formula (I) which can easily be converted into the corresponding 2-substituted-alkanoic acid compounds, the present inventors established a process for pre-paring the compounds of the formula (I) starting with easily available compounds through 3 to 4 reaction steps which can be relatively easily performed.
That is, the present invention provides a process for preparing 2-thio-2-substituted-alkanoic acid derivatives repre-sented by the formula (I) 1~33684 A C COOR (I) SR3wherein A represents (1) a substituted-phenyl group of the formula in which yl represents an isobutyl group or an unsubstituted-or substituted-phenoxy group wherein the substituent is a halogen atom, a trifluoromethyl group or an alkoxy group having 1 to 4 carbon atoms, or (2) a substituted-thienyl group of the formula y2~
S' in which y2 represents an alkyl group having lto 4 carbon atoms;
R represents an alkyl group having 1 to 4 carbon atoms; R3 rep-resents a phenyl group, an alkylphenyl group wherein the alkyl group has 1 to 4 carbon atoms, or an alkyl group having 1 to 4 - carbon atoms; and R4 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, which comprises condensing an - aldehyde compound of the formula (V) A--CH0 (V3 wherein A is as defined above, with a haloform of the formula CHX3 wherein X represents a halogen atom and a mercaptan com-pound of the formula (IV) ~3SH (IV) wherein R is as defined above, in the presence of a base to produce a 2-(arylthio or alkylthio)-2-substituted-acetic acid of the formula (III) A - fH- COOH (III) S~3 wherein A and R3 are as defined above, and reacting the resulting lfi;'~)3~84 1 2-(arylthio or alkylthio)-2-substituted-acetic acid with an alkylating agent represented by the formula (II) RZ (II) wherein R is as defined above, and Z represents a ~logen atom, an alkyl- or arylsulfonyloxy group or a sulfuric acid ester residual group, in the presence of at least 2 mols of a base per mol of the 2-(arylthio or alkylthio)-2-substituted acetic acid, to form the compound of the formula (I) wherein R4 represents a hydrogen atom, and optionally converting the resulting compound to the compound of the formula (I) wherein R4 represents an alkyl group by esterification.
The process according to the present invention can ke illustrated by the followina reaction scheme:
A -CHO (V) First Step ¦R3SH (IV) ~¦CHX3 A- CH-COOH (III) Second Step ¦RZ (II) R

A - C - COOR (I) wherein A, R R3 and R are as defined above, and X represents a halogen atom and Z represents a halogen atom, and al~yl or arylsulfonyloxy group or a sulfuric acid ester residual group.
First Step The first step of the process of this invention comprises condensing an aldehyde derivative of the formula (V) with a halo~orm of the formula CHX3 wherein X is as defined above and a mercaptan compound of the formula (IV) in the pre-sence of a base.
-7~

1~3684 1 Examples of the base which can be used in the above condensation reaction are alkali metal h~droxides such as sodium hydroxide, potassium hydroxide and the like, alkali metal alkox-ides such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide and the like, with sodium or potassium hydroxide being preferred from the economical stand-point. These bases are generally used in an amount of from about 4 to about 10 mols, preferably 5 to 6 mols, per mol of the aldehyde derivative of the formula (V).
Examples of the haloform of the formula CHX3 are chloroform, bromoform, monobromodichloromethane, monochloro-dibromomethane and the like. Particularly preferred haloforms are chloroform and bromoform. These haloforms can be used in an amount of from about 1 to about 5 mols, preferably 1.5 to 2 mols, per mol of the aldehyde derivative of the formula (V).
Examples of the mercaptan com~ounds of the formula (IV) are thiophenol, alkylphenyl mercaptans such as tolyl mercaptan, alkyl mercaptans such as methyl mercaptan, ethyl mercaptan, butyl mercaptan and the like. These mercaptans can be used in an amount of from about 1 to about 3 mols, preferably 1.5 to 2 mols, per mol of the aldehyde derivative of the formula (V).
In carrying out the first step of the process of this invention, a solvent can be preferably used. Typical exam~les of the solvents which can be used are polar solvents such as water, alcohols such as methanol, ethanol and the like, dimethyl sulfoxide, dimethylformamide and the like. Preferred solvents are protonic solvents such as water, methanol, ethanol, etc.
because of their high solubility of the base used in the reaction.
The reaction can be generally conducted at a temperature of about 0 to about 100C, preferably from room temperature (about 1~3684 1 15 to about 30C) to a refluXing temperature of the solvent used.
The reaction time varies depending upon the reaction temperature used, but is usually for about 1 to about 30 hours.
In the above condensation, the desired intermediate, 2-(arylthio or alkylthio)-2-substituted-acetic acids of the formula (III) can be obtained in high yield. The resulting intermediate of the formula (III) can be used in the subsequent step after it is isolated from the reaction mixture and purified by conventional procedures, for example, concentration of the reactiOn mixture, extraction with a solvent and then silica gel column chromatography, etc., or the reaction mixture per se obtained by the condensation reaction can be used in the sub-sequent step.
Second Step The second step comprises reacting the 2-(arylthio or alkylthio)-2-substituted-acetic acid of the formula (III) obtained in the above First ~tep with an alkylating agent of the formula (II) in the presence of at least 2 mols, preferably 2 to 3 mols, of a base per mol of the compound of the formula (III).
Examples of alkylating agents used in the above reaction are methyl iodide, methyl bromide, ethyl bromide, dimethylsulfuric acid, diethylsulfuric acid, methyl p-toluenesulfonate, ethyl p-toluenesulfonate, propyl bromide, isopropyl bromide, butyl bromide and the like. The alkylating agents are well known in the art as widely used in organic chemistry and can easily be available as industrial raw materials.
The alkylation reaction can preferably be carried out at a temperature of about -40 to room temperature for a period of about 1 to about 5 hours usinq an approximately equimolar to a slightly molar excess of alkylating agent, e.g., about 1.5 mol, per mol of the compound of the formula (III).

~ld33684 1 As described above, the reaction should be carried in the presence of at least 2 mols of a base per mol of the compound of the formula (III). In this reaction, 1 mol of the base is consumed in the formation of a carboxylic acid salt and the remaining 1 mol of the base is used for withdrawing the hydrogen atom at the CX-position of the carboxylic acid of the formula (III). In the dianion thus formed, an alkyl group is selectively introduced into the ~ -position of the dianion upon reaction with an alkylating agent because of a high reactivity of the C~ -position thereby forming the desired compound of the formula (I). `
Examples of bases which can be used in the second step are preferably strongly basic compounds such as sodium amide, potassium amide, butyl lithium, sodium hydride and the lïke.
In carrying out the reaction, a solvent is preferably used and examples of solvents are liquid ammonia, ethers such as diethyl ether, tetrahydrofuran and the like, non-protonic polar solvents such as dimethylformamide, dimethylsulfoxide and the like.
When sodium amide or potassium amide is used as a base, liquid ammonia is preferably used as a solvent, and when butyl lithium or sodium hydride is used as a base, an ether or a non-protonic polar solvent is preferably used.
In the above reaction, the desired compounds of the formula (I) wherein R represents a hydrogen atom can be obtained in high yield. These compounds can easily be converted into the corresponding esters wherein R4 represents an alkyl group by a conventional esterification procedure which is well known in the art.
In an alternative procedure, the compounds of the ~3~84 1 formula (III) wherein A represents a substituted-phenyl group yl ~ wherein yl represents an isobutyl group can also be prepared by reacting a 2,2,2-trihalo-1-(isobutylphenyl)-ethanol of the formula (V') _cx3 (V') 0~
wherein yl represents an isobutyl group and ~ represents a halo-gen atom, with a mercaptan compound of the formula (IV) in thepresence of a base. The reaction can be effected in the same manner using the same reaction parameters as described for the reaction of the first step, but without using the haloform of the formula CHX3.
The aldehyde derivatives of the formula (V) used as starting materials of the process of this invention are well known as described in J. Med. Chem. 15, 1297; Japanese Patent Puhlication (Unexamined) No. 95623/1977; and Org. Synth. Coll Vol. III, 811. Also, these aldehyde derivatives of the formula (V) can be easily prepared by either the Vilsmeier formulation reaction or the oxidation of the corresponding benzyl alcohol, as well known in the art.
The 2,2,2-trihalo-1-(isobutylphenyl)ethanol of the formula (V') used as a starting material in the alternative procedure for preparing the compound of the formula (III) can be easily prepared by reacting isobutylbenzene with a trihalo-acetoaldehyde, e.g., chloral, as described in Reference Example 5 hereinafter described.
As described previously, the compounds of the formula 3Q ~I) prepared in accordance with the process of this invention i~3684 1 can be converted into the corresponding ~-subsLituted-alkanoic acid of the formula (VI) 4 ~VI ) A-CH-CQOR
wherein A, R and R4 are as defined above, by reducing the com-pounds of the formula (I) as described in detail in Reference Examples hereinafter described. The reduction of the compounds of the formula (I) can be achieved by various methods which are well known in the art using, for example, zinc powder in a lower aliphatic acid, tin in a mineral acid, Raney nickel, sodium metal in a protonic solvent, etc. A particularly preferred reduction method is using zinc powder in a lower aliphatic acid such as acetic acid. In this manner, the compounds of the formula (IV), for example, a - (2-thienyl)alkanoic acid, 2-(4-isobutylphenyl)propionic acid, 4-isobutylphenylacetic acid and 2-(3-phenoxyphenyl)propionic acid can be obtained in almost quantitative yield.
If desired, the compounds of the formula (III) can be sub~ected to the above reduction procedure, before alkylation in the second step, to produce the corresponding acetic acid com-pounds of the formula (VI) wherein R represents a hydrogen atom.
As is apparent to one skilled in the art, one of the advantages of the process of this invention is that, in the reduction of the compounds of the formula (I) to produce the compounds of the formula (VI), an arylthio or alkylthio group -S~ is split out to form a mercaptan compound as a by-product.
Such mercaptan compound can be recovered for re-use in the first step of the process of this invention, whereby the process of this invention can be conducted econimically.
~0 The present invention is further illustrated by the ~ )3684 1 following Examples in greater detail, but they are given for illustrative purposes only and are not to be construed as limiting the present invention. Unless otherwise indicated, all parts, percents, ratios and the like are by weight.
Example 1 ~ mixture of 1.98 g (10 mmols) of 3-phenoxybenzalde-hyde, 1.65 g (15 mmols) of thiophenol, 1.79 g (15 mmols) of chloroform and 2 ml of ethanol was stirred at room temperature (about 15 to 30C), and 10 ml of an ethanolic solution of 2.8 g (S0 mmols) of potassium hydroxide was then added dropwise to the mixture while maintaining the temperature below 45C. The reaction mixture was further stirred for an additional one hour at 45C and then allowed to stand overnight at room temperatare While stirring. The reaction mixture was then poured into a mixture of 6N sulfuric acid and ice clump to render the mixture acidic and then saturated with sodium chloride. The saturated solution was then extracted with diethyl ether and the extract was concentrated. The resulting concentrate was then charged into a silica gel column, and the column was eluted first with benzene~hexane (1:1 by volume) and then with hexane-ethyl acetate (4:1 by volume). The combined eluate was concentrated to obtain 2.58 g (77~ yield) of 2-phenylthio-2-(3-phenoxyphenyl)acetic acid.
NMR (CC14)~ of Product: 4.68 (lH, s), 6.7 - 7.4 (14H, m), 11.6 (lH, bs).
Example 2 In the same manner as described in Example 1, but using a reaction temperature not exceeding 30C, 1.68 g (50% yield) of 2-phenylthio-2-(3-phenoxyphenyl)acetic acid was obtained.
Example 3 1.10 g of 3-phenoxybenzaldehyde, 1.65 g of thiophenol 11~) ~684 1 and 1.8 g of chloroform were dissolved in 5 ml of ethanol, and to the resulting solution was added dropwise a solution of 2.0 g of potassium hydroxide in 10 ml of ethanol over a period of 90 minutes. The reaction mixture was then stirred overnight at room temperature and then worked up in the same manner as de-scribed in Example 1 to obtain 1.10 g (65~ yield) of 2-phenylthio-2-(3-phenoxyphenyl)acetic acid.
Example 4 1.10 g (5 mmols) of 3-phenoxybenzaldehyde, 0.83 g (7.5 mmols) of thiophenol, 1.3 q (5.1 mmols) of bromoform, 1.7 g (26 mmols) of potassium hydroxide (having a purity higher than 85%) and 0.424 g (10 mmols) of lithium chloride were added to a mixture of 5 ml of dioxane and 5 g of ice clump, and the result-ing mixture was stirred vigorously for 5 hours at 0C and then 19 hours at room temperature. The reaction mixture was then diluted with water, rendered acidic with hydrochloric acid and extracted with methylene chloride. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated to remove the solvent to obtain a crude prodcut of 2-phenylthio-2-(3-phenoxyphenyl)acetic acid in a quantitative yield. The resultin~ crude product was purified by column chromatography eluting with hexane-diethyl ether (10:1 by volume) to obtain 1.54 g (92% yield) of the above product in a substantially pure form.
Example 5 In the same manner as described in Example 1, but using 1.35 g of isobutyl mercaptan in place of the thiophenol, 1.40 g (44g yield) of 2-isobutylthio-2-(3-phenoxyphenyl)acetic acid was obtained.

11~3684 1 NMR (CC14) ~ of Product: 0.93 (6H, d, J=7Hz), 1.62 (lH, m~, 2.40 (2H, d, J=7Hz), 4.53 (lH, s), 6.8 - 7.4 (9H, m).
Example 6 15 ml of liquid ammonia was charged into a 50 ml flask and 0.2 g (8.7 mmols) of sodium metal was dissolved therein in the presence of a catalytic amount of ferric nitrate thereby forming a liquid ammonia suspension of sodium amide. Thereafter, 1.22 g (3.63 mmols) of 2-phenylthio-2-(3-phenoxyphenyl)acetic acid prepared as described in Example 1 dissolved in 10 ml of diethyl ether was added dropwise to the above suspension of sodium amide. The reaction mixture was then stirred for 30 minutes at a temperature of -40C and a solution of 0.75 g (5.3 mmols) of methyl iodide in 5 ml of diethyl ether was added to the reaction mixture which was then stirred for further 30 minutes at -40C. The reaction mixture was then allowed to warm slowly by removing the cooling bath used and finally heated while refluxing for lS minutes to complete the reaction. 30 ml of water was added to the reaction mixture to dissolve any solid ~0 substances and the mixture was rendered acidic with lN hydro-chloric acid followed by being extracted with diethyl ether. The etherial extract was dried over anhydrous sodium sulfate and concentrated to obtain 1.23 g of a crude 2-phenylthio-2-(3-phenoxyphenyl)propionic acid. The resulting crude product was then purified by silica gel column chromatography eluting with diethyl ether-hexane (1-5 by volume) to obtain 1.10 g (87~ yield) of the above product in a substantially pure form.
NM~ (CC14~ ~ of Product: 1.76 (3H, s), 6.7-7.3 (14H, m).
Example 7 In the same manner as described in Example 6, but using 0.67 g of dimethylsulfuric acid in place of the methyl i~36S4 1 iodide, 2-phenylthio-2-(3-phenoxyphenyl)propionic acid was obtained in 83% yield.
Example 8 A portion of the product of Example 6, 2-phenylthio-2-(3-phenoxyphenyl)propionic acid, was esterified using diazomethane to obtain a corresponding methyl ester in a quanti-tative yield.
NMR (CC14) ~ of Product: 1.73 (3H, s), 3.68 (3H, s) 6.6-7.4 (14H, m).
Example 9 6.80 g (103 mmols) of potassium hydroxide (85% purity) was dissolved in 20 ml of methanol, and the resulting solution was added dropwise to a solution of 2.24 g (20.0 mmols) of thiophenealdehyde, 3.5 g (30.0 mmols) of chloroform and 3.30 g (30 mmols) of thiophenol in 10 ml of methanol over a period of 30 minutes at room temperature. The resulting reaction mixture was stirred at room temperature for 1 hour, and heated while refluxing for 1 hour. Most of the solvent was removed by distillation under reduced pressure, and the residue was dissolved in water. The solution was rendered acidic with hydro-chloric acid, and extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate and purified by silica gel column chromatography eluting with diethyl ether-hexane (1:5 by volume) to obtain 2.03 g (41% yield) of a -phenyl-thio-thiophene-2-acetic acid.
Example 10 0.69 g (30 milli atom) of sodium metal was added to 30 ml of liquid ammonia, and a catalytic amount of ferric nitrate was added to the solution followed by stirring at -40C until the blue color of the mixture disappeared. A solution of 2.52 g 1 (10.1 mmols) of cC-phenylthio-thiophene-2-acetic acid in 10 ml of diethyl ether was added dropwise to the above mixture, followed by stirring at -40C for 30 minutes. A solution of 2.80 g (19.7 mmols) of methyl iodide in 5 ml of diethyl ether was added dropwise thereto, and the reaction mixture was stirred for further 30 minutes at -40C. The cooling bath was removed and the mixture was then stirred overnight to remove ammonia. The resulting solid was then dissolved in water, and the solution was rendered acidic with hydrochlroic acid and extracted with methylene chloride. The extract was dried over anhydrous mag-nesium sulfate and the solvent was removed by distillation to obtain 2.61 g (98~ yield) of a crude product. The crude product thus obtained was then purified by silica gel column chroma-tography using a relatively short column eluting with diethyl ether-hexane (1:5 by volume) to obtain 2.55 g (98% yield) of C~-phenylthio-~ -(2-thiophene)propionic acid in a substantially pure form.
NMR (CC14)~ of Product: 1.87 (3H, s), 6.7-7.1 (8H, m), 11.85 (lH, s) Example 11 7.50 g (113.8 mmols~ of potassium hydroxide was dis-solved in 20 ml of methanol, and the solution was added dropwise to a solution of 2.24 g (20.0 mmols) of thiophenealdehyde, 4.78 ~ (40.0 mmols) of chloroform and 2.71 g (30.0 mmols) of t-butyl mexcaptan in 10 ml of methanol at room temperature over a period of 1 hour. After stirring for 16 hours at room tempera-ture, the mixture was diluted with water and washed with methylene chloride. The mixture was then rendered acidic with hydrochloric acid and extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate, concentrated 11~3684 1 and purified by silica gel column chromatography eluting with diethyl ether-hexane (1:5 by volume) to obtain 1.09 g (24% yield) Of CX-t-butylthio-~ (2-thiophene)acetic acid.
NMR (CC14) ~ of Product: 1.37 (9H, s), 4.67 (lH, s), 6.73-7.23 (3H, m), 11.37 (lH, bs).
Example 12 11.5 g (0.2 mol) of potassium hydroxide was dissolved in 70 ml of ethanol, and 6.5 g (57.6 mmols) of thiophenol was added thereto while cooling with ice and stirring. After 10 minutes, 10.8 g (38.4 mmols) of 2,2,2-trichloro-1-(4-isobutyl-phenyl)ethanol prepared as described in Reference Example 5 dissolved in 15 ml of ethanol was added to the above mixture followed by stirring at room temperature for 12 hours. The reaction mixture was rendered acidic with dilute hydrochloric acid, extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed by distillation and the resulting residue was purified by a silica gel column chromatography eluting with ethyl acetate-n-hexane (1:4 ~y volume) to obtain 8.5 g (74~ yield) of 2-phenylthio-2-(4-isobutylphenyl)acetic acid having a melting point of 92-95C
tafter recrystallized from n-hexane).
Infrared Absorption Spectrum (cm ): 3100-2500, 1690, 1280, 910, 730.
NMR (CC14) ~ of Product: 0.90 (d, J=6Hz, 6H), 1.67-2.07 (m, lH), 2.43 (d, J=6Hz, 2H), 4.70 (s, lH), 6.87-7.65 (m, 9H), 11.87 (s, lH).
Example 13 A catalytic amount of ferric chloride and 0.23 g (10 mmols) of sodium metal were added to 20 ml of liquid ammonia 1 to prepare a suspension of sodium amide. To the resulting suspension was then added a solution of 1 g (3.33 mmols) of 2-phenylthio-2-(4-isobutylphenyl)acetic acid dissolved in 12 ml of diethyl ether. After stirring the mixture at -40C for 1 hour, a solution of 0.71 g (5.0 mmols) of methyl iodide dissolved in 6 ml of diethyl ether was added to the mixture. After stirring the mixture at -40C for 3 hours, the mixture was allowed to warm slowly to room temperature and stirred for 15 minutes. The reactiOn mixture was decomposed with lN hydrochloric acid, and extracted with diethyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation and the resulting residue was puri-fied by silica gel column chromatography eluting with ethyl acetate-n-hexane (1:4 by volume) to obtain 0.705 g (67% yield) of 2-phenylthio-2-(4-isobutylphenyl)propionic acid having a melting point of 76-79C (after recrystallized from n-hexane).
Infrared Absorption Spectrum (cm 1): 3100-2500, 1690, 1270, 920, 755, 695.
NMR Absorption Spectrum (CCl~)~ : 0.92 (d, J=6Hz, 6H), 1.77 ~s, 3Hj, 1.50-1.80 (m, lH), 2.43 (d, J=6Hz, 2H), 6.83-7.50 (m, 9H), 11.5 (broad s, lH).
Elementary Analysis:
Cal d for ClgH22O2S: C, 72.57; H, 7.05(%) Found : C, 72.42; H, 7.05(%).
~eference Example 1 330 mg of methyl 2-phenylthio-2-(3-phenoxyphenyl)-propionate obtained in Example 8 was dissolved in 2 ml of acetic acid and the solution was heated while refluxing for 1 hour in the presence of 300 mg of zinc powder. After allowing the ~q33684 1 reaction mixture to cool, it was diluted with ethyl acetate and the remaining zinc powder was removed by filtration. The fil-trate was concentrated to obtain methyl 2-(3-phenoxyphenyl)-propionate in a quantitative yield.
n26 1.5576.
NMR (CC14) ~ of Product: 1.43 (3H, d, J=7.5 Hz), 3.57 (lH, q, J=7.5 Hz), 3.63 (3H, s), 6.6-7.3 (9H, m).
~eference Exa~mple 2 .
1.11 g (3.17 mmols) of 2-phenylthio-2-(3-phenoxy-phenyl)propionic acid obtained in Example 6 was dissolved in 10 ml of acetic acid and the solution was heated while refluxing for 1 hour with stirring in the presence of 1.0 g of zinc powder.
The solid substance present in the reaction mixture was removed by filtration and washed with methylene chloride. The combined filtrate and washing was concentrated to obtain 0.86 g of a crude product which was then purified by silica gel column chromatography eluting with diethyl ether-hexane (1:5 by volume) to obtain 0.73 g (95% yield) of 2-(3-phenoxyphenyl)propionic acid. nD 1.5780.
NMR (CC14) ~ of Product: 1.48 (3H, d, J=7Hz), 3.62 (lH, q, J=7Hz), 6.6-7.6 (9H, m).
Reference Example 3 1.12 g (20 mmols) of potassium hydroxide was dissolved in 10 ml of methanol-in an argon atmosphere, and 0.6 g (5.45 mmols~ of thiophenol was added to the solution while stirring under cooling with water. After 10 minutes, a solution of 1.16 g (5 mmols) of ~ -trichloro-2-thiophenemethanol dissolved in 3 ml of methanol was added to the mixture. After lC minutes, the temperature of the mixture was gradually increased and then ~3684 1 heated under refluxing for 2 hours with vigorous stirring. The Mixture was then cooled to room temperature, and most of the solvent was removed by distillation under reduced pressure.
Diethyl ether was added to the residue and the mixture was decom-posed with dilute hydrochloric acid. The ether layer was separ-ated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with ethyl acetate-n-hexane (1:4 by volume) to obtain 940 mg (76% yield) of ~-phenylthio-thiophene-2-acetic acid as a viscous oily substance.
Infrared Absorption Spectrum (cm 1) : 3060, 1715, 1587, 1485, 1440, 1416, 1253, 750, 705, 694.
NMR (CDC13) ~ : 5.03 (s, lH), 6.52-7.60 (m, 8H), 11.47 (s, lH).
Reference Example 4 2.34 g (8.85 mmols) of ~ -phenylthio-~-(2-thiophene)-propionic acid was dissolved in 20 ml of acetic acid, and 1.5 g of zinc powder was added thereto followed by heat-refluxing for 30 minutes. An additional 1.5 g of zinc powder was added thereto followed by heat-refluxing for further 1.5 hours. Most of the solvent was then removed under reduced pressure, and methylene chloride was added to the residue. The solution was then filtered through Celite to remove solid substance. The filtrate was then concentrated and purified by silica gel column chroma-tography eluting with diethyl ether-hexane (1:10 by volume) to obtain 1.28 g (92% yield) of ~ -(2-thiophene)propionic acid as a colorless oily substance.

NMR tCC14) ~ : 1.60 (3H, d, J=7Hz), 3.93 (lH, q, J=7Hz), 6.67-6.87 (2H, m), 7.07 (lH, m).

i~3684 1 Reference Example 5 .
17.7 g (0.12 mol) of chloral was dissolved in 90 ml of dichloromethane, and 11.4 g (60 mmols) of titanium tetrachloride was added to the solution in an argon atmosphere while cooling with ice and stirring. A solution of 8.05 g (60 mmols) of iso-butylbenzene dissolved in 8 ml of dichloromethane was added there-to and the temperature of the resulting mixture was increased slowly to room temperature followed by stirring for 5 hours. The reaction mixture was then again cooled with ice, decomposed with water and extracted with dichloromethane. The organic layer was washed with water, and dried over anhydrous magnesium sulfate.
Unreacted isobutylbenzene was recovered (3.6 g; Percent Recovery, 45~, Boiling Point, 65-64C/20 mmHg) to obtain 6.8 g (73~ yield based on isobutylbenzene) of 2,2,2-trichloro-1-(4-isobutyl-phenyl)ethanol having a boiling point of 115C/0.2 mmHg.
Infrared Absorption Spectrum (cm 1): 3420, 2950, 1610, 1510, 1060, 820.
NMR Absorption Spectrum (CC14) ~ : 0.93 (d, J=6.5 ~z, 6H ), 1.56-2.50 (m, lH), 2.50 (d, J=6.5Hz, 2H), 3.~8 (broad s, lH), 5.05 (s, lH), 6.97-7.47 (m, 4H).
Reference Example 6 0.3 g (0.955 mmol) of 2-phenylthio-2-(4-isobutyl-phenyl)propionic acid was dissolved in 6 ml of acetic acid, and 0.31 g (4.8 mmols) of zinc powder was added thereto followed by heating for 3 hours with stirring. The reaction was then filtered through Celite, and the filtrate was concentrated under reduced pressure. The concentrate was extracted with diethyl ether, and the organic layer was washed with water and dried over

3~ anhydrous magnesium sulfate. The solvent was then removed by 1 distillation and the residue was purified by silica gel column chromatography eluting with ethyl acetate-n-hexane (1:9 by volume) to obtain 0.136 g (69~ yield) of 2~(4-isobutylphenyl)propionic acid having a melting point of 74-76C (after recrystallized from n-hexane).
Infrared Absorption Spectrum (cm ): 3100-2600, 1720, 1230, g30, 775.
NMR Absorption Spectrum (CC14) ~ : 0.90 (d, J=6Hz, 6H), 1.60 (d, J=7Hz, 3H), 1.4-2.07 (m, lH), 2.40 (d, J=6Hz, 2H), 3.55 (q, J=7Hz, lH), 7.00 (qAB~ J 7Hz, 4H), 11.70 (s, lH).

Claims

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

1. A process for preparing a 2-thio-2-substituted-alkanoic acid derivative represented by the formula (I) (I) wherein A represents (1) a substituted-phenyl group of the formula in which Y1 represents an isobutyl group or an unsubstituted- or substituted-phenoxy group wherein the substitutent is a halogen atom, a trifluoromethyl group or an alkoxy group having 1 to 4 carbon atoms, or (2) a substituted-thienyl group of the formula in which Y2 represents an alkyl group having 1 to 4 carbon atoms;
R represents an alkyl group having 1 to 4 carbon atoms; R3 repre-sents a phenyl group, an alkyl-phenyl group wherein the alkyl group has 1 to 4 carbon atoms, or an alkyl group having 1 to 4 carbon atoms; and R4 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, which comprises reacting a 2-(arylthio or alkylthio)-2-substituted-acetic acid of the formula (III) (III) wherein A and R3 are as defined above, with an alkylating agent represented by the formula (II) RZ (II) wherein R is as defined above and Z represents a halogen atom,

Claim 1 continued an alkyl- or arylsulfonyloxy group or a sulfuric acid ester residual group, in the presence of at least 2 mols of a base per mole of the 2-(arylthio or alkylthio)-2-substituted-acetic acid, to form the compound of the formula (I) wherein R4 represents a hydrogen atom and, optionally, converting the resulting compound to the compound of the formula (I) wherein R represents an alkyl group by esterification.
2. The process according to Claim 1, wherein said alkylat-ing is carried out at a temperature of about -40°C to room tempera-ture for about 1 to about 5 hours in the presence of a solvent.
3. The process according to Claim 1, wherein said alkylat-ing agent is used in an amount of about 1 to about 1.5 mol per mol of said 2-(arylthio or alkylthio)-2-substituted-acetic acid.

4. A process for preparing a 2-thio-2-substituted-alkanoic acid derivative represented by the formula (I) (I) wherein A represents (1) a substituted-phenyl group of the formula in which Y1 represents an isobutyl group or an unsubstituted- or substituted-phenoxy group wherein the substituent is a halogen atom, a trifluoromethyl group or an alkoxy group having 1 to 4 carbon atoms, or (2) a substituted-thienyl group of the formula
Claim 4 continued in which Y2 represents an alkyl group having 1 to 4 carbon atoms;
R represents an alkyl group having 1 to 4 carbon atoms; R3 represents a phenyl group, an alkylphenyl group wherein the alkyl group has 1 to 4 carbon atoms, or an alkyl group having 1 to 4 carbon atoms; and R4 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, which comprises condensing an aldehyde compound of the formula (V) A--CHO (V) wherein A is as defined above, with a haloform of the formula CHX3 wherein X represents a halogen atom and a mercaptan compound of the formula (IV) R3SH (IV) wherein R3 is as defined above, in the presence of a base to produce a 2-(arylthio or alkylthio)-2-substituted-acetic acid of the formula (III) (III) wherein A and R3 are as defined above, and reacting the resulting 2-(arylthio or alkylthio)-2-substituted-acetic acid with an alkylating agent represented by the formula (II) RZ (II) wherein R is as defined above, and Z represents a halogen atom, an alkyl- or arylsulfonyloxy group or a sulfuric acid ester residual group, in the presence of at least 2 mols of a base per mol of the 2-(arylthio or alkylthio)-2-substituted-acetic acid, to form the compound of the formula (I) wherein R4 represents a hydrogen atom and, optionally, converting the resulting compound to the compound of the formula (I) wherein R4 represents an alkyl group by esterification.
5. The process according to Claim 4, wherein said conden-sing is conducted using about 4 to about 10 mols of a base at a temperature of about 0 to about 100°C for a period of about 1 to about 30 hours.
6. The process according to Claim 4, wherein said conden-sing is conducted using about 1 to about 5 mols of said haloform and about 1 to about 3 mols of said mercaptan compound, per mol of said aldehyde compound of the formula (V).
7. The process according to Claim 4, wherein said alkylat-ing is carried out a temperature of about -40°C to room tempera-ture for a period of about 1 to about 5 hours in the presence of a solvent.
8. The process according to Claim 4, wherein said alkylat-ing agent is used in an amount of about 1 to about 1.5 mol per mol of said 2-(arylthio or alkylthio)-2-substituted-acetic acid.

9. A process for preparing a 2-thio-2-isobutylphenyl-alkanoic acid derivative represented by the formula (I) (I) wherein Y1 represents an isobutyl group; R represents an alkyl group having 1 to 4 carbon atoms; R3 represents a phenyl group, an alkylphenyl group wherein the alkyl group has 1 to 4 carbon atoms; and R represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, which comprises reacting a 2,2,2-trihalo-1-(isobutylphenyl)ethanol of the formula (V') (V')
Claim 9 continued wherein Y1 is as defined above and X represents a halogen atom, with a mercaptan compound of the formula (IV) R3SH (IV) wherein R3 is as defined above, in the presence of a base, to form a 2-(arylthio or alkylthio)-2-isobutylphenylacetic acid derivative of the formula (III) (III) wherein Y1 and R3 are as defined above, and alkylating the re-sulting compound with an alkylating agent represented by the formula (II) RZ (II) wherein R is as deined above and Z represents a halogen atom, an alkyl- or arylsulfonyloxy group or a sulfuric acid ester residual group, in the presence of at least 2 mols of a base per mol or said 2-(arylthio or alkylthio)-2-isobutylphenylacetic acid derivative, to form the compound of the formula (I) wherein R4 represents a hydrogen atom and, optionally, converting the resulting compound to the compound of the formula (I) wherein R4 represents an alkyl group by esterification.