CA1233479A - Method for preparing 3-benzoyl-2-mercaptopropionic acid derivatives - Google Patents

Abstract

ABSTRACT

A method for preparing 3-benzoyl-2-mercaptopropionic acid derivatives represented by the general formula (I) (wherein, X represents a hydrogen atom, a halogen atom, a hydroxy group, a lower alkyl group or a lower alkoxy group, Y represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group, Z represents an acyl group, and R represents a hydrogen atom or a lower alkyl group which comprises reacting a compound represented by the general formula

Description

~33~

The present invention relates to a method for preparing novel 3~benzoyl-2-mercaptopropionic acid derivatives, and more particularly, it relates to a method fox preparing novel 3-benzoyl~2-mercaptopropionic acid derivatives which have immunomodulative function and are effective for treatment of diseases caused by abnormal immunofunction.
In the past, there have been used the so-called immunosuppressors for treatment of autoimmune diseases such as chronic rheumatoid arthritis. In general, how-ever, the suppressive activity of the agents is mainly based on cytotoxicity. Accordingly, besause of a strong side-effect depending on the above-mentioned cytotoxicity, these agents can not be said to be appropriate as therapeutical agents of autoimmune diseases which are required to be administered continuously for a long term.
Further, in order to treat diseases related to immune/ there have been recently used the so-called immunomodulators which have the effect to xegulate the immune function, i.e., either stimulate the immune function when lowered, or suppress the immune function when augmented. However, even these agents cannot be said to be satisfactory ln aspects of effect, side-efect ~3 ~3 1 and toxicity.
As a reswlt of the earnest studies, the present inventors have found that certain 3-ben~oyl-2-mercaptopropionic acid derivatives have good immuno-modulative function, weak side-effect and weak toxicity, and thus thy present invention has been completed.

SUMMERY OF THE INVENTION
An object of the present invention is to provide a method for preparing novel 3-benzoyl-

2-mercaptopropionic acid derivatives which have immunomodulative function and are effective for treatment o diseases caused by abnormal immuno-function.
Other objects and advantages of the present invention will be apparent prom the following descrip-tions.

DETAILED DESCRIPTIONS OF THE INVENTION
The present invention is illustrated in detail hereunder.
The objective compounds to be prepared by the method of the present invention are 3-benzoyl 2-mercaptopropionic acid derivatives having the general formula:

COCH2CH < (I) ~3~

1 (wherein, X represents a hydrogen atom, a halogen atom, a hydroxy group, a lower alkyl group or a lower alkoxy group, Y represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group, Z represents an acyl group, and R represents a hydrogen atom or a lower alkyl gxoup).
Here, the halogen atom for X and Y is a fluorine, chlorine or bromine atom, and the lower alkyl group lor X and Y are a methyl group, an ethyl group, a propyl group, an isopropyl group and the like, and the lower alkoxy group for X and Y are a methoxy group, an ethoxy group and the like.
The acyl group for Z are an aliphatic acyl group such as an acetyl group, a propionyl group, a butyryl group and the like J or an aromatic acyl group such as a benzoyl group, a toluoyl group and the like.
The lower alkyl group for R are a methyl group, an ethyl group, a propyl group, an isopropyl group and the like.
Z0 The preferred objective compound to be prepared by the method of the present intention are the compounds of formula I wherein X is a hydrogen atom or a halogen atom, Y and R are each a hydrogen atom.
The present invention is a method for preparing

3-benzoyl 2-mercaptopropionic acid derivative of formula I which comprises reacting a compound having the general formula x I-COCH=CHCO2R (II) 1 (wherein, X, Y and are as defined above with a thio-carboxylic acid having the general ormula HSZ (wherein, Z i5 as defined above) in an organic solvent.
In the reaction, one to two moles of the 5 thiocarboxylic acid is employed per mole of the compound of formula II. This reaction can be carried out at -20 to 50C for 0.5 to 24 hours.
Examples of the organic solvent are methanol, ethanol, t-butanol, hexane, benzene, toluene, diethyl ether, dimethoxyethane, dioxane, dichloromethane, chloroform, carbon tetrachloride, c rbon disulfide, acetone, ethyl acetate, dime~hylformamide, hexamethyl-phosphoric triamide, dimethylsulfoxide and the like.
The compound of formula II can be prepared, or example, by the following method.

l A compound represented by the general formula K
Ye (wherein, X and Y are as defined cove i5 reacted with maleic anhydride accordiny to Friedel-Crafts reaction to give a carboxylic acid represented by the general formula \~
COCH=CHCO~H (IIa) ~3~

1 (wherein, X and Y are as defined above), iOe., the com-pound of formula II wherein R is a hydrogen atom, or (2) a methylketone compound represented by the general formula X I, wherein, X and Y are as defined above) is reacted with glyoxylic acid hydrate in the absence of solvent under reduced pressure of 1 to 100 mm~g at 80 to 120C for 2 to 10 hours for condensation to give a compound repre-s~nted by the general formula X O ~CO 2H

(wherein, X and Y are as defined above, which is then heated, or refluxed undex heating in an organic solvent (e.gO, benzene, toluene~ xylene, dioxane,. acetic acid and the like) in k prese~c~ of an acid catalyst (e.g., sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, potassium bisulfate and the like) at 80 to 120C
for dehydration for 1 to 10 hours to give the compound of formula IIa.
(3) In order to prepare the compound of formula II
wherein R is a lower alkyl group, the compound of formula IIa is reacted with a conventional alkylating agent having R' which represents the lower alkyl g.roup 1 for the above R (e.g., an alkyl halide, a dialkyl sulfate and the like) in an organic solvent (e.g., acetone, dimethylformamide, hexamethylphosphoric triamide, dimethylsulfoxide and the like) in the presence of a base (e.g., sodium carbonate, potassium carbonate lithium carbonate, sodium hydrogencarboIlate, potassium hydrogencarbonate, sodium hydrides potassium hydride, sodium hydroxide, potassium hydroxide, sodium alkoxicle and the like to give an alkyl estPr compound represented by the general formula - COC~=CHCO2R' tII~) (wherein, X, Y and R' are as defined above.
The compound of formula I has a good immuno-modulative function, low side-effect and low toxicity, and therefore they are useful therapeutical agents of the diseases caused by abnormal immunounction, for example, rheumatoid arthritis, autoimmune diseases, cancer, bacterial infectious diseases, asthma and the like. For the purposes, the compound of the present invention may be administered orally or parenterally in a conventional dosage orm such as tablets, capsules, powders, granules syrups, and injectional forms prepared according to conventional pharmaceutical practices.
The effective dosage of the compound of the present invention depends on the age, weight or response o the patient. Generally, however, the daily dosage ~23~

1 in adults may range from 0.1 to 3 g, preferably 0.3 to 1.5 g in single or divided doses.
The present invention is concxetely illustrated below by Experimants and Examples, but toe invention is not limited whereto.

Experiment 1 Effect to adjuvant arthritis (chronic rheumatoid arthritis model) 10 Female Sprague-Dawley rats, 8 weeks old, weighing 160-190 g were used per each group. Rats of each group were administered subcutaneously into the tail with a suspension of 0.6 mg of heated killed mycobacterium ~utyricum in liquid parafin. Each of the compounds I, suspended in a 5% gum arabic solution, was administered orally once. a day to rats of each group ater the sensitization. The symptoms of arthritis were evaluated by the severities of the inflammation of arthritis at each of 6 sites on limbs and ears as 5 stages which are scored as 0, 1, 2, 3 and 4 and expressed as the summing up score (24 points) at a given interval, i.e., inflammation score.
Table 1 shows the scores of the controLs (drug-untreated group) and the drug-treated group 21 days after sensitization ~33~7~

O
bq O f f g a o Ql o 3'1 1 ~.~ ___ .
. V
1 a r1 a U'~. to au ,L a) . . . . , .
f l 0 O O l f ~3 0 +1 +1~1 +1 +1 +1 u ,~ or us X
f I:: or l Jo a) ~+~
. _ _ . _ a a o o o O l g _1 0 0 O O .~ Q.
~o3 x _ .
.~-rl o , o.q ,~ ,~
....~ _ ,: _l D`

LDW

1 It is recognized from the above results that the compounds I suppress strongly the acLjuvant arthritis and possess immunomodulative and anti-arthritic activi-tie 5 .

Experiment 2 Effect tp humoral antibody formation uncler hypotensive state (Recovery effect of immunodeiciency) 6-8 Female BDFl mice, 8-12 weeks old, weighing 18-22 g were used per each group. Mice of each group were administered intravenously with 4 x 10 sheep red blood cells as antigen to ye sensitized.
Each of the compounds I, suspended in 5~ gum arabic saline solution, was administered intraperitoneal-ly to mice of each group 2 hours after the sensitizationO
Number of antibody forming cells in the spleen cells of mice was dete.rmined 4 days after the sensiti2a-tion according to the method of Cunningham and Szenberg (Immunology, volO 14, page 599, 1968).
The results are shown in Table 2.

_ g _ ~2~3~

__ _ _ .
ra ., Q
a o o ; o co ,~ o Lr) or U ~.~J O OD O a a ..,. ..~.
O O l So Us , .,~ En h O
_ ta O
3 0 us a) o Pi o a R us te ~# a * Q rt O ' ,, l 0 u ) co O O I; a .a us or co Ino us O
_~ co o o n o~o to o In l l i o +l 1-1 +1 +1+1 +1 +1 +1 n mu lo o l ero t:n o o O ox o r_ to g v En our ED f s: l Q
CO er W C OD

Z OW

U
,, v o o o ,~ o o U
tn ,~ o _~ o o ~1 a _~
_~ o X I-___ ,~
_ _ ,~ or Z;

1 It is recognized from the above results that the compounds of formula I increase the number of antibody-forming cells and have the recovery effect of immunodeiciency.

S Experiment 3 Effect to delayed-type footpad reaction (Cellular immunostimulation) 6-8 Female BDFl mice, 8-12 weeks old, weighing 18-22 g were used per each groupu Mice of each group lQ were administered subcutaneously into the right footpad with 1 x 10 sheep red blood cells as antigen to be sensitized Each of the compounds I, suspended in a 5%
gum arabic saline solution, was administered intra-peritoneally to mice of each group 2 hours after thesensitization.
Four days after the sensitization, mice of each group were administered subcutaneously into the left footpad with 1 x 10 sheep red blood cells, and the ZO increase of thickness of swelling footpad was determlned according to the method of Lagrange et al (Journal of Experimental Medicine/ vol. 139, page 528, 1974).
The results are shown in Table 3.

~33 , .~

O .t a O f d o a o o o o o ... ...
--Irk _Ir~l l h .q O O Pi .,1 a) l us Us 3 ,~
Ul~

o a C) 0,_ * ic Pi O~q rl O an ,~ a

4~ . . er O
O l . O O O
tJ~ f l CO ~9 I) C) a 4~ +l +l +l +l +l +l O O
l O ~rl O l a v v ,51 -I . . . . . Us al l Jo Jo a _l o En tQ X r~a:) ,1 us a us En X
O OH h lo O O l H $ l ~rl . _ _ _ 3 by OOO OOO ~O~1 U~Ul Us O _l o O
Q ~J r-l V
_ . _ , Z

3~
1 It is recognized from the above results that the compounds of formula I stimulate the delayed type footpad reaction and have the cellular immunopotentiating effect.

Experiment 4 Acute toxicity test Male, 8 weeks old ICR mice (body weight of 28-32 g, 8 mice per each group were administered orally with a suspension of the compound of Example 1 in 5% gum arabic solution, and observed for 7 days, and the LD50 value was calculated.
The LD50 value of the compound of Example 1 was excess of 1000 mg/kg.

Example 1 To a solution of 1.76 g of 3-benzoylacrylic acid in 30 ml of dîethyl e~hex was added 0.8 ml of thioacetic acid, and the resulting mixture was stirred at room temperature for 5 hours. The diethyl ether was removed from the reaction mixture by evaporation under reduced pressure, and the residue was purified by silica gel column chromatography using a mixture of hexane and dichloromethane as an eluent and recrystallized from a mixture of hexane and diethyl ether to give 2,09 g of 2-acetylthio-3-benzoylpropionic acid.
m.p. 90-92C

~t~33~
1 Elementary Anal. for C12H1204S

Calcd. I C 57013, H 4.80 Found (%) : C 57.18, I 4.84 Example 2 l A mixture of 6.70 g of o-methylacetophenone and 4.60 g of glyoxylic acid hydrate was heated at 95C
under reduced pressure of 25 mmHg for 3 hours. The reaction mixture was dissolved in a 5% aqueous solution of potassium carkonate. The resulting solution was washed with ethyl acetate, made slightly acidic with dil.
hydrochloric acid, and extracted with ethyl acetate.
The organic layer was washed with water and dried over magnesium sulfate. The solvent was removed by evaporation under reduced pressure to give a viscous oil.
To the oil wexe added 10 ml of glacial acetic acid and 1 ml of conc. hydrochloric acid. The mixture was refluxed by heating with stirring for 3 hours. The acetic acid was removed from the mixture by evaporation under reduced pressure, and thy residue was dissolved in ethyl acetate. The solution was washed with water and dried over magnesium sulfate. The ethyl acetate was removed from the solution by evaporation, and the residue was recrystallized from a mixture o hexane and diethyl ether to give 4.85 g of 3-(2-methylbenzoyl)-acrylic acid.
m.p. 82-83C

~7~
1 (2) Following the procedure of Example 1 using 1.9 g of 3-(2 methylbenzoyl)acrylic acid in place of 3-benæoylacrylic acid, there was obtained 2.50 g of 2-acetylthio 3-(2-methylbenzoyl)propionic acid m.p. 106-108C
Elementary Anal. for C13H14O4S
Calcd. (%): C 58.63, H 5.30 Found (~) : C 58.63, H 5.34 Example 3 (1) Following the procedure of Example 2~ using 6.70 g of m-methylacetophenone in place o o-methyl-acetophenone, there was obtained 5.61 g of 3-(3-methyl-benzoyl)acrylic acid.
m.p. 115-117C

(2) Following the procedure of Example 1 using 1~90 g of 3-(3-methylben~oyl)acrylic acid in place of 3-benxoylacrylic acid, there was obtained 2.42 g of 2-acetylthio~3-(3-methylbenæoyl~propionic acid.
m.p. 74-76C
Elementary Anal. for C13Hl~O4S
Calcd. (%) C 58.63, H 5.30 Found (%) C 58.61, H 5.37 Example 4 Following the procedure of Example 1 using 1.90 g of 3-(4-methylbenzoyl)acrylic acid in place oE

~33~
1 3-~enzoylacrylic acid; there was obtalned 1.60 g of 2 acetylthio-3-(4-methylbenzoyl)propionic acid.
m.p. 81-85C
Elementary Anal for C~3Hl~O4S
Calcd. I C 58.63, H 5.30 Found (%): C 58.88, 5.33 Example 5 Following the procedure of Example 1 viny 2.18 g of 3-(4-isopropylbenzoyl)acrylic acid in place of 3-benzoylacrylic acid, there was obtained 2.29 g of 2-acetylthio-3-(4-i~opropylbenzoyl~propionic acid.
m.p. 84~86C
Elementary Anal. or C15H18O4S
Calcd. I C 61.20, H 6.16 Found (~) : C 61.09, H 6.16 Example 6 Following the procedure of Example 1 using 1.92 g of 3-(4-hydroxybenzoyl)acrylic acid in place of 3-benzoylacrylic acid, there was obtained 2.11 g of 2=acetylthio-3-(3-hydroxybenzoyl~propionic acid.
m.p. 147-148C (decomposition Elementary Anal. for C12H12OSS
Calcd. (%): C 53.72, H 4.51 Found (%) : C 53.46, H 4.51 1 Example 7 Following the procedure of Example 1 using 2~06 g of 3-(3~methoxybenzoyl)acrylic acid in place of 3-benzoylacrylic acid, there was obtained 2.62 g of 2-acetylthio-3-~3-methoxybenzoyl)propionic acid as an oil.

IRV cat cm 1 1740-1680 (carbonyl) NMR(CDC13), ppm: 2.38 (3EI, s), 3.58 (lH, dd, J=18Hz,

5~z), 3.69 ~lH, dd, J=18Hz, 8Hz), 3.85 (3H, s), 4.76 (lH, dd, J=8Hz, 5Hæ), 7.14 (lH, bd, J=8Hz), 7.38 (lH, t, J=8Hz), 7O50 (2H, m) Example 8 (1) on 200 ml of dichloromethane were dissolved 5.4 g of anisole and 4.98 g of maleic anhydride, and 9.95 g of anhydrous aluminum chloride was added gradually under ice-cooling with stirring. Then, the mixture was stirred at room temperature for 5 hours.
The reaction solution was concentrated under reduced pressure, and poured into a mixture of 10 ml of conc.
hydrochloric acid and 150 g of ice, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over amgnesium sulfate. The ethyl acetate was removed rom the solution my evaporation under reduced pressure, and the residue was recrystal~
lized from a mixture of hexane and diethyl ether to give 3.85 g of 3-(4-methoxybenzoyl)acrylic acid.

~2~
l m.p. 108-110C

(2) Following the procedure of Example l usiny 2.06 g o 3~(4-methoxybenzoyl)acrylic acid in place of 3~ben~oylacrylic acid, there was obtained 2.12 g of 2-acetyl~hio 3-(4~methoxybenzoyl)propionic acid.
m.p. 122-123.5C
Elementary Anal. for Cl3Hl4~5S
Calcd. I C 55.31, H 5.00 Found I%) : C 55.54, H 5.08 Example 9 E'ollowing the procedure of Example l using 2.11 g of 3-(2 chlorobenzoyl)acrylic acid in place of 3-benzoylacrylic acid, there was obtained 2.46 g of 2-acetylthio~3-~2-chlorobenzoyl)propiQnic acid.
m.p. 115-116C
Elementary Anal. for Cl2HllClO4S
Calcd. I C 50.28, H 3.84 Found C 50.21, H 3.96 Example 10 if Following the procedure of Example 2~(1) using 7.73 g of m chloroacetophenone in place of o methylaceto-phenone~ there was obtained 5.17 g of 3-(3-chloroben%oyl)-acrylic acid.
m.p. 150-152C

_ Lo _ 3~

1 (2) Following the procedure of Example l using 2.11 g of 3-(3 chlorobenzoyl)acrylic acid in place of 3-benzoylacrylic acid, there was obtained 2.69 g of 2-acetylthio-3-(3-chlorobenzoyl)propionic acid.
m.p. 85-86C
Elementary Anal. for C12HllClO4S
Calcd. (%): C 50.28, H 3.84 Found (%) : C 50.04, H 3.96 Example ll Following the procedura of Example 1 using 2.11 g of 3-(4-chlorobenzoyl)acrylic acid in place of 3-benzoylacrylic acid, there was obtained 2.64 g of 2-ace~ylthio-3-(4-chlorobenzoyl)propionic acid.
m.p. 68-69C
Elementary Anal. for C~2HllC104S
Calcd. C 50.28, H 3.84 Found (I : C 50.40, H 3.91 Example 12 Following the procedure of Example l using 2.55 g of 3-(4-bromobenzoyl)acrylic acid in place of 3-benzoylacrylic acid, there was obtained 2.55 g of 2-acethylthio 3-(4-bromobenzoyl)propionic acid.
m.p. 98-99C
Elementary Anal. for C12HllBrO4S
Calcd. I C 43.52, H 3.35 Fotmd (%) : C 43.70, H 3.37 _ ] g t7 1 Example 13 (1) FolLowlng the procedure of Example 8 l using 4.80 g of fluorobenzene in place ox ani~,ole, there way obtained 4.18 g of 3-(4-fluorobenzoyl)acrylic acid.
m.p. 130-131.5C

~2) Following the procedure of Example 1 using 1.94 g of 3-(4-fluorobenzoyl)acrylic acid in place o 3-benzoylacrylic acid, there was obtained 2.19 g of 2-acetylthio-3-(4-fluorobenæoyl)propionic acid.
m.p. 108-110C
Elementary Anal. for C12HllFO4S
Clad (%): C 53.33, H 4.10 Found (%) : C 53~10, H 4.17 Example 14 Following the procedure of Example 1 using - 2.04 g of 3-(2,4 dimethylben~oyl)acrylic acid in place ox 3-benzoylacrylic acid, there was obtained 2.32 g of 2-acetylthio-3 (2,4-dimethylbenzoyl)propionic acid.
m.p. 101-102~C
Elementary Anal. for C14H16O4S
Calcd. (%): C 59.98, H 5.75 Found (%) : C 59.85, H 5.80 Example 15 Following the procedure of Example 1 using 2.04 g of 3 (3,4-dimethylbenzoyl)acrylic acid in p:Lace - 2~

A

1 of 3-benzoylacrylic acid, there was obtained 2.35 g of 2-acetylthio-3-(3,4-dimethylbenzoyl)propionic acid as an oil.

IRv HC13, cm : 1710-1680 (carbonyl) NMR(CDC13), ppm: 2.30 (6H, s)~ 2.36 (3H, s), 3.54 (lH~ dd~ J-16Hz~ 7Hz)r 3.66 (lH, dd, J=16Hz,

6~), 4.74 (lH, dd, J-7Hz~ 6Hæ), 7.21 (lH~ d/
J=8Hz), 7.66 (.lH, d, J=8Hz)~ 7.72 (lH, d, J-8Hz)~ 10.10 ( lH, bs) Example 16 l Following the procedure of Example 8-(1) using 6.90 g of 1,2-dimethoxybenzene in place of ani~ole, there was obtained 4.37 g of 3-(3,4-dimethoxybenzoyl~-acrylic acid.
m.p. 174-175C

(2) Following the procedure of Example 1 using 2.36 g of 3-(3,4-dimethoxy~enzoyl)acrylic acid in place of 3-benzoylacrylic acid, there was obtained 2.53 g of 2-acetylthio-3-~3,4-dimethoxybenzoyl)propionic acid.
m.p. 110-112C
Elementaxy Anal. for C14H16O6S
Calcd. I C 53.84, H 5.16 Found (%) : C 53.69~ H 5.09 ~3~
1 Example 17 Following the procedure of Example 1 using 2.45 g of 3-~2,4 dichlorobenzoyl)acrylic acid in place of 3-benzoylacrylic acid, there was obtained 2.70 y of 2 acetylthio-3-(2,4-dichlorobenzoyl)propionic acid.
m.p. 73-74.5C
Elementaxy Anal. for C12HloC12O~S
Calcd. I%): C 44.88, H 3.14 Found (~) : C 44.74~ H 3.14 Example 18 Following the procedure of Example 1 using 2.45 g of 3-(3,4 dichlorobenzoyl)acrylic acid in place of 3-benzoylacrylic acid, there was obtained 2.63 g of 2-acetylthio-3-(3,4-dichlorobenzoyl~propionic acid.
~.p. 102.5-105C
Elementary Anal. for C12HloC12O4S
Calcd. (.~): C 44.88, H 3.14 Found (~) : C 45.05, H 3.19 Example 19 1.90 g of methyl 3-benzoylacrylate was dis-solved in 30 ml of diethyl ether, and 0.~ ml of thio-acetic acid was added thereto. The mixture was stirred or 5 hours at room temperature. The reaction solution was washed, in tuxn, with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and dried over magnesium sulfate The diethyl ether was q 1 removed from the solution by evapsration~ and the residue was purified by silica gel column chromatography usiny a mixture of hexane and diethyl ether as an eluent, and then recrystallized from the same mixture to give 2.42 g of methyl 2-acetylthio-3-benzoylpropionate.
m.p, 53.5-54C
Elementary Anal. for C13H1404S
Calcd. (%) C 58.63, H 5 30 Found (%~ : C 53.88, H 5.30 Example 20 Following the procedure of Example 19 using 2.04 g of ethyl 3-benzoylacrylate in place of methyl 3-benzoylacrylate, there was obtained 2.60 g of ethyl 2-acetylthio-3-benzoylpropi~nate as an oil IRvmax , cm : 1740 (ester, thioester), 1690 (ketone) NMR(CDC13), ppm: 1.27 (3H, t, J=7Hzl~ 2.38 ~3H, s), 3.58 ~lH, dd, J=16Hæ, 5Hz), 3.74 l dd, J=16Hz, 7Hz~, 4.23 (2H, q, J=7Hzl, 4.73 ~lH, dd, J-7Hz, 5Hz~, 7.44-7.64 (3HI m), 7.98 (2H, d, J=8Hz Example 21 (1) To a solution of 3.52 g of 3-benzoylacrylic acid in 30 ml of dimethylformamide were added 8 ml of isopropyl~romide, 5.5 g of potassium carbonate and a catalystic amount of sodium iodide. The mixture was t_ l stirred at room emperature for 4 hours and allowed to stand overnight. To the xeaction solut:ion was added water, the mixture was ex-tracted with diethyl ether, and the diethyl ether layer was washed with water and dried over magnesium sulfate. The diethyl ether was removed from the solution by evaporation, and the residue was purified by silica geI column chromatography using a mixture of hexan~ and diethyl ether as an eluent to give 2.27 g of isopropyl 3-benzoylacrylate as an oil.

IRvneat, cm : 1720 (ester), 1670 (ketone) NMR~CDC13), ppm: 1.34 (6H, d, J=6Hz), 5.17 (lH, heptet, J=6Hz), 6087 (lH, d, J=16Hz),

7.46-7.70 (3H, my, 7.89 ~lH, d, J=16Hz),

8.01 t2H, d, J=8~z) (2) Following the proceduxe of Example 19 using 2.18 g of isopropyl 3-benzoylacryla~e in place of methyl 3-benzoylacrylate, there was obtained 2.85 g of isopropyl 2-acetyl~hio-3-ben20ylpropionate as an oil.

IRvmeaat, cm 1 1730 jester, thioester), 1685 ~ketone) NM~(CDCl3), ppm: 1.23 ~3H, d, J=6Hz), 1.31 (3H, d, J=6Hz), 2.38 (3H, s), 3.54 (lH, dd, J-18Hz, 4Hz), 3.72 (lH, dd, JY18Hz, 7Hz), 4.69 (lH, dd, J=7Hz, 4Hz), 5.06 (lH, heptet, J-6Hz), 7.43-7.70 (3H, m), 7.38 (2H, d, J=8Hz) ~3~

1 Example 22 Following the procedure of Example 19 using 2.20 g of ethyl 3-(4-hydroxybenzoyl)acrylate in place of methyl 3-benzoylacrylate, there was obtained 2.78 g of ethyl 2-acetylthio-3 (4-hydroxybenzoyl)propionate as an oil.

IRvmax , cm : 167Q-1730 (carbonyl~

NMR(CDC13), ppm: 1.26 (3~, t, J=8Hz), 2.37 (3H, s), 3.52 (lH, dd, J=18Hz, 5Hz), 3.63 ~lH, dd~
J=18Mz, 8Hz), 4.21 ~2H, q, J-8Hz), 4.70 (lH, dd, J=8Hz, 5Hz), 6.84 ~2H, d, J=8Hz), 7.80 (2H, d, J=8Hz) Example 23 l To a solution of 4.22 g of 3O~4-chlorobenzoyl~-acrylic acid in 40 ml of dimethylformamide were added 3.68 g of diethyl sulfate and 1.36 g of potassium carbo-nate, and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added diethyl ether. The mixture was washed, in turn, with water, a saturated aqueous solution of sodium hydro-gencarbonate and water, and dried over magnesium sulfate.
The diethyl ether was removed from the mixture by evaporation, and the residue was recrystalliæed from hexane to give 2.68 g of ethyl 3-(4-chloro~enzoyl)-acrylateO
m.p. 62.5-63.5C

~3~

1 (2) Following the pxocedure of Example 19 using2.39 g of ethyl 3-(4-chlorobenzoyl)acry:Late in place of methyl 3-benzoylacrylate, there was obtained 3.05 g of ethyl 2-acetylthio-3-(4-chlorobenzoy:L]propionate as an oil.

IRvmax , cm : 1740 (ester, thioester), 1580 (ketone) NMR(CDC13), ppm: 1.16 ~3H, t, J~7Hz~, 2.38 (3H, s), 3.51 ~lH, dd, J=16Hz, 5Hz), 3.69 (lH, dd, J-16Hz, 7Hz), 4.22 (2H, q, J-7Hz), 4.71 (lH, dd, J=7Hz, 5Hz), 7.45 (2H, d, J=8Hz) r 7.91 ~2H, d, J=8Hz) Example 24 (.1) Following the procedure of Example 23-(1) using 4~08 g of 3-(2,4-dimethylbenzoyl)acrylic acid in place of 3-(4-chlorobenzoyl)acrylic acid, there was obtained 4.00 g of ethyl 3-(2,4-dimethylbenzoyl)acrylate as an oil IRvneaat, cm : 1720 (ester), 1670 (ketone) NMR(CDC13), ppm: 1.10 (3H, t, J-7Hzl, 2.36 (3H, s), 2.63 (3H, s)~ 4.05 (2H, q, J=7Hz), 6.18 (lH, d, J=12Hz), Ç.89 ~lH, d, J=12Hz), 7.05 (lH, do J=8Hz), 7.11 (lH, 5), 7.62 (lH, d, J=8Hz) (2) Following the procedure of Example 19 using 2.32 g of ethyl 3-(2,4-dimethylbenzoyllacrylate in place ~L~33~

1 of methyl 3-henzoylacrylate, there was obtained 2.99 g of ethyl 2-acetylthio-3-(2,4~dimethylbenzoyl)propionate as an oil.

IRvmaxt~ cm 1 1740 (ester7 thioester), 1680 (ketone) NMR(CDC13), ppm: 1.27 (3H, t, J=7Hz), 2.36 (3H, so, 2.38 (3H, s), 2.47 (lH, dd, J 18Hz, 6Hz), 2.50 (3H, sl, 2.Z3 ~lH, dd/ J=18~z, 8Hz), 4.22 (2H, q, J=7Hz), 4.70 (lH, dd, J-8Hz, 6~z), 7.07 (lH, s), 7.08 (lH, d, J=8Hz), 7.64 (lH, d, J=8Hz) Example 25 Following the procedure of Example 1 using 1.0 ml of thiopropionic acid in place of thioacetic acid there was obtained 2.10 g of 3-benzoyl-2-propionylthio-propionic acid m.p. 110-112C
Elementary Anal. for C13H14O4S

Calcd. (%) C 58.63, H 5.30 Found (~) : C 58.52, H 5.26 Example 26 Following the procedure of Example 1 using 1.65 g of thiobenzoic acid in place of thioacetic acid, there was obtain d 1.98 g of 3-benzoyl-2-benzoylthio-propionic acid.

~$~?

m.p. 142.5-144~C
Elementary Anal. for C17~I1404S
Calcd. (%): C 64.95, H 4.49 Found (%): C 65.17, H 4057

Claims (9)

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

1. A method for preparing 3-benzoyl-2-mercaptopropionic acid derivatives represented by the general formula (I) (wherein, X represents a hydrogen atom, a halogen atom, a hydroxy group, a lower alkyl group or a lower alkoxy group, Y represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group, Z represents an aliphatic or aromatic acyl group, and R
represents a hydrogen atom or a lower alkyl group) which comprises reacting a compound represented by the general formula (II) (wherein, X, Y and R are defined above) with a thiocarboxylic acid having the general formula HSZ (wherein Z is as defined above) in an organic solvent.

2. A method of Claim 1, wherein the halogen atom for X
and Y is a fluorine, chlorine or bromine atom.

3. A method of Claim 1, wherein the lower alkyl group for X and Y is a methyl, ethyl, propyl or isopropyl group.

4. A method of Claim 1, wherein the lower alkoxy group for X and Y is a methoxy or ethoxy group.

5. A method of Claim 1, wherein the acyl group for Z is an acetyl, propionyl, butyryl, benzoyl or toluoyl group.

6. A method of Claim 1, wherein the lower alkyl group for R is a methyl, ethyl, propyl or isopropyl group.

7. A method of Claim 1, wherein the reaction of the compound of formula II with thioacetic acid is carried out at a temperature of -20 to 50°C for 0.5 to 24 hours.

8. A method of Claim 1, wherein one to two moles of thioacetic acid is employed per mole of the compound of formula II.

9. A method of Claim 1, wherein the organic solvent is methanol, ethanol, t-butanol, hexane, benzene, toluene, diethyl ether, dimethoxyethane, dioxane, dichloromethane, chloroform, carbon tetrachloride, carbon disulfide, acetone, ethyl acetate, dimethylformamide, hexamethylphosphoric triamide or dimethylsulfoxide.