DK144473B - ANALOGY PROCEDURE FOR THE PREPARATION OF THIAZOLINE DERIVATIVES OR OPTICALLY ACTIVE COMPOUNDS OR SALTS THEREOF - Google Patents

Description

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(19) DENMARK

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| p, 12) PUBLICATION <n) 144473B

DIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM

(21) Application No 5512/75 (51) IntCI. » C 07 D 277/42 (22) Filing day 5 · dec. 1975 (24) Race day 5 · dec. 1975 (41) Aim. available 7 · Jun. 1976 (44) Posted 15 Mar 1982 (86) International Application No. ~ (86) International Filing Day - (85) Continuation Day "(62) Stock Application No."

(30) Priority Dec 6 1974, 140776/74, JP

(71) Applicant _SHI0N0GI & CO. LTD., Osaka, JP.

(72) Inventor Ryozo Maeda, JP: Katsumi Hirose, JP.

(74) Clerk Th. Ostenfeld Patentbureau A / S.

(54) Analogous process for preparing thiazoline derivatives or optically active compounds or salts thereof.

The present invention relates to an analogous process for the preparation of novel thiazoline derivatives or optically active compounds or pharmaceutically acceptable salts thereof, which are valuable drug-active compounds exhibiting anti-inflammatory, analgesic, anti-rheumatic and anti-pyretic activities. ^ 3

m ojri r ^ rCHC00H

2 represents hydrogen or 4-methyl, Y represents hydrogen, 2-chloro, 2-fluoro, 2-methyl, 2-trifluoromethyl, 3-chloro, 3 -fluoro, 3-methyl,

C O

Q is 3-methoxy or 3-trifluoromethyl, Y is hydrogen, 3-chloro or 2-chloro, and R is methyl or allyl, or optically active compounds or pharmaceutically acceptable salts thereof.

144473 2

The process of the invention is peculiar to quaternizing a compound of general formula III: Γ Y1

11 O

wherein X is Y, Y and YΔ have the above meanings, R is hydrogen or an ester residue, and Z is hydrogen, carboxy or alkoxycarbonyl, with a methyl or allyl halide, an aromatic sulfonic acid ethyl ester or dimethyl sulfate at room temperature. to approx. 150 ° C to form a quaternary ammonium compound of formula IV: CH3

x ~ i * ^ Y

1 1 2 2 wherein X, Y, Y, R, RogZ have the above meanings and X represents an acid radical, after which acid elimination is performed with an alkali metal hydroxide, an alkali metal carbonate, an alkali metal hydrogen carbonate or with ammonia to form a thiazoline compound with Formula II: 2 Y'l * [il] 112 2 wherein X, Y, Y, R, R and Z have the meanings set forth above, whereupon, if necessary, the compound prepared is subjected to hydrolysis and / or decarboxylation and, if desired, to decomposition a prepared optically active compound (I) in the optical isomers and if desired transfer the compound to a salt thereof or a salt formed to the free compound.

3 144473

The process can be illustrated as shown schematically below:

CH

CH l 3

s C-COOR quaternary, n R C-COOR

ch3 X1_C—? ^ T ™ 000 "acid- 'I-N ^ N ^ iVk'y2 - r, i elimination- 12' 1

reaction_ ^ [II] .-- R

Possibly. hydrolysis and decarboxylation (Z 1 H-) 112 2 - wherein X, Y, Y, R, Z, RogX have the above meanings.

The starting compounds of the general formula [III] wherein Z represents hydrogen are disclosed in German Publication 2450617. The preparation of the starting compound wherein Z represents a carboxy or carboxyester group is also disclosed in said disclosure.

As shown in the above scheme, the starting compound [III] is subjected to quaternization. The quaternization can be done with a quaternizing agent, e.g. methyl iodide, bromide, or chloride, allyl halide (eg, allyl iodide, bromide or chloride), aromatic sulfonic acid methyl ester (eg benzenesulfonic acid methyl ester, p-toluenesulfonic acid methyl ester) or dimethyl sulfate. Although a solvent is not required for the reaction, an inactive neutral solvent may be used, e.g. an alcohol (e.g., methanol or ethanol), a hydrocarbon (e.g., benzene, toluene or xylene), an ether (e.g., ether or tetrahydrofuran), dimethylformamide, or a mixture thereof. The reaction may be carried out at a temperature from room temperature to 150 ° C for 1 to 180 hours, however, the reaction temperature and reaction time may be suitably changed in accordance with other reaction conditions. Revenue can be accelerated using pressure.

The resulting quaternary ammonium salt [IV] is subjected. As mentioned above, the acid elimination reaction as shown in the above scheme.

Hydrogen halide or aromatic sulfonic acid can be eliminated from compound [IV]. The reaction is carried out with an alkali metal hydroxide (e.g., sodium hydroxide or potassium hydroxide), an alkali metal carbonate (e.g., sodium carbonate or potassium carbonate), an alkali metal hydrogen carbonate (e.g., sodium bicarbonate or potassium hydrogen carbonate), or ammonia. The reaction is preferably carried out in solvent, e.g. water, a halohydrocarbon (e.g., chloroform or methyl chloride), a hydrocarbon (e.g., benzene, toluene or xylene) or an ether (e.g., ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, ethylene glycol dialkyl ether or diglyme). The reaction may be carried out by stirring the compound [IV] with the above-mentioned acid-eliminating agent in the presence or absence of solvent.

The resulting product can be hydrolyzed if necessary. The hydrolysis can be carried out in the manner usually used for carboxylic acid esters. The product is hydrolyzed with an acid (eg hydrochloric acid, sulfuric acid, hydrobromic acid or acetic acid) or a base (eg sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate) in water or an appropriate organic solvent containing water.

The compound [II], wherein Z represents a carboxy or alkoxycarbonyl group, is subjected to further decarboxylation, however, the decarboxylation sometimes occurs during the acid elimination reaction or hydrolysis. The decarboxylation is easily carried out in the usual manner, such as by heating the compound [IV].

Furthermore, the above hydrolysis and decarboxylation occur simultaneously when the acid elimination reaction is carried out under severe conditions, such as treatment with sodium hydroxide or potassium hydroxide.

The compound [I] thus obtained can be converted to the pharmaceutically acceptable non-toxic salts by conventional means.

Such salts include e.g. alkali metal salts (e.g.

sodium salt, potassium salt, lithium salt), alkaline earth metal salts (e.g., calcium salt, magnesium salt, barium salt) and the aluminum salts.

Furthermore, the compounds of this invention may form pharmaceutically acceptable, non-toxic salts with a variety of inorganic and organic acids. Examples of such salts are hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, thiocyanate, carbonate, acetate, oxalate, succinate, maleate, tartrate, citrate, benzoate, salicylate and phthalate.

5 .144473

The thiazoline derivatives [I] are optically active compounds that can be cleaved into d and 1 isomers. The optical cleavage can be done in a conventional manner, and both isomers can be used alone or as a mixture depending on the therapeutic requirements.

The compounds of this invention, including the pharmaceutical, non-toxic salts, exhibit anti-inflammatory, anti-rheumatic, analgesic and anti-pyretic activities. Pharmacological activity was investigated by the following methods. The results are shown in Tables I and II.

Test method 1. Acetic acid twisting method.

DS mice (20-23 g, males) are treated with an intraperitoneal injection of 0.1 ml / 10 g of 0.6% acetic acid 60 minutes after oral administration of a test compound. The number of twists or shrinks over 10 minutes. The ED ^ Q value is calculated according to Bliss' method.

2. Effect on yeast-inflamed foot.

A test compound is administered orally to Wistar rats (180-200 g, females) immediately before subcutaneous injection of 0.1 ml of the 20% yeast suspension into the plantar tissue of the foot. 2 hours later, the pain threshold is measured by pressing the foot with a plunger and calculated according to Litchfield and Wilcoxon's method [J. Pharmacol. Exp. Ther. 9j>, 99-113 (1949)].

3. Effect on accompanying arthritis.

Wistar rats (140-160 g, females) with a typical arthritis, in the foot on the 21st day after intradermal injection of dead tubercelia bacilli are selected for the test. A test compound is administered orally to the arthritis affected rat twice daily for 5 consecutive days. 5 hours after the end of the medical treatment, the change in volume of swelling of the arthritis affected foot is measured. The ED ^Q value is calculated by Bliss method.

4. Anti-edema activity.

An aqueous solution of 1% carrageenin (0.05 ml) is used as a phlogistic agent. After 30 minutes, Wistar rats (180-200 g, females) are orally administered, injecting the phlogistic agent subcutaneously into the plantar portion of the rats' feet. The volume of swelling is measured 3 hours after carrageenin and the anti-edema activity is determined by calculating the ratio of the edematous volume of the treated to the non-treated foot. The ED ^Q value is calculated by Bliss method.

5. Anti-pyretic activity.

A test compound is administered orally to Wistar rats (180-200 g, females) 16 hours after injection of 2 ml of a 15% yeast suspension into the subcutaneous tissue of the rat hip. The rectal temperature is measured every hour for 5 hours. The effective dose is calculated using Bliss' method.

6. Acute toxicity.

10 DS mice (20-23 g, males) or 10 Wistar rats (180-200 g, females) are used in groups at a specific dose level. The LD ^ value at 72 hours after oral administration of a test compound is determined. The LD, -Q value is calculated according to Bliss' method.

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9 144473

Test Method 7. Analgesic Activity (Phenylquinone Rotation Method) DS mice ((15-17 g, males and females) were treated with an intraperitoneal injection of 0.2 ml / 10 g 0.02% phenylquinone 60 minutes after oral administration of The twist syndrome was observed for 5 minutes, the ED1Q value calculated by the "Up and Down" method.

Acute toxicity and anti-edema activity were measured as described in Table I.

Table II

Conn. Compound LD_n Anti-edema inhibitor - Analgesic

No. --- 50% Dose (mg) ED

__ ^ _ X1 YM (mg / kg) 2 ^ 1Q 25 (mg / kg) 9 CH ^ H 3-CF3 1250 (p) 37 ^ OO (p) 10 CH -CH = CH H 3-C1 75θ (ρ) 56 4θθ (ρ) 11 CH H 2_CH3 750 (p) 24 400 (p) J 3-C1 12 CH3 H 2-CF3 750 (p) - 400 (p) 13 CH3 H 3-OCH3> 1500 (p) 22 28 1500 (p) 14 CH3 H 3-CH3 750 (p) 32 16 44 4θθ (ρ)

Phenylbutazone l4l4 12 33 10 144473

As shown in Tables I and II, the present thiazoline derivatives exhibit stronger anti-inflammatory, analgesic, anti-rheumatic and anti-pyretic activities than the commercially available compounds, namely indomethacin, mefenamic acid and phenylbutazone. The ED ^ Q value for anti-edema activity of calcium 2- [2-fluoro-4- (3,4-dimethyl-4-thiazol-2-ylideneamino) phenyl] propionate and calcium 2- (3-methyl-4 2-phenyl-imino-4-thiazolin-4-yl) propionate is 7.1 mg / kg and 16.4 mg / kg, respectively. The other compounds of the invention have similar pharmacological properties.

The compounds [I] and the pharmaceutically acceptable salts are therefore valuable in the treatment of various inflammations, pains and rheumatic diseases in humans and animals. They can be administered alone or in combination with a pharmaceutically acceptable carrier, orally or by injection.

The therapeutic composition contains 1 mg - 500 mg of one or more compounds of general formula [I] with or without a pharmaceutically acceptable carrier. The compound [I] is generally administered to humans and animals on the order of mefenamic acid or down to 1/30 of the practical dose thereof, i.e. that 20 to 1000 mg of compound [I] can be administered orally to the human either in a single dose or divided doses over a period of 24 hours. The compound can also be administered promptly for acute illnesses.

The present process is further illustrated in the following Examples: Example 1 2- [4- (2-methyl-4-thiazolin-2-ylidenamino) phenyl] propionic acid (1) A mixture of ethyl 2- [4- (N-thiazole) 2-ylamino) phenyl] propionate (6.3 g), methyl iodide (30 ml) and ethanol (30 ml) are heated at 50-55 ° C for 20 hours under a nitrogen atmosphere. After evaporation of ethanol and methyl iodide, the resulting residue is washed sequentially with ether and ethyl acetate to give 3-methyl-2- [4- (1-ethoxycarbonylethyl) anilino] thiazolium iodide (8.0 g). (Yield 84%).

(2) The product is dissolved in methylene chloride. The solution is washed with 10% aqueous potassium carbonate solution and evaporated to remove methylene chloride. The resulting residue is dissolved in ether. The solution is dried over potassium carbonate and evaporated to remove ether. The residue is ethyl 2- [4- (2-methyl-4-thiazolin-2-ylidenamino) phenyl] propionate (5.5 g). (Yield 83%).

IR YCC14 cm -1 1735, 1615, 1590. max NMR δ dc 2.9 (4H, aromatic), 3.5 (d, 1H), 4.2 (d, 1H), 5.9 3 q, 2H) , 6.3 (q, 2H), 6.6 (s, 3H), 8.5 (d, 1H), 8.8 (t, 3H).

(3) The product (5.5 g) is dissolved in a mixture of 20% aqueous potassium hydroxide solution (28 ml) and ethanol (28 ml) and the solution is kept at room temperature for 1 hour. After evaporation of ethanol, the solution is neutralized with hydrochloric acid, adjusted to pH 5 with acetic acid, subjected to saline with sodium chloride and then extracted with ether. The ether solution is dried over magnesium sulfate and evaporated. The residue is recrystallized from ethyl acetate to give 2- [4- (3-methyl-4-thiazolin-2-ylidenamino) phenyl] propionic acid (4.3 g), melting at 130-132 ° C. (Yield 73%).

IR γ Nu3o1 cnf1 1710 1595.

max

Analysis calculated for: C, 59.52; H, 5.36; N, 10.64; S, 12.18. Found: C, 59.79; H, 5.26; N, 10.41; S, 12.18.

Similarly hydrochloride recrystallized from ethanol melts at 154-155 ° C.

IR γNu 01 01 cm -1 1709, 2470 (wide), max

Example 2 2- [3,5-Dichloro-4- (3-methyl-4-thiazolin-2-ylidenamino) phenyl] propionic acid (1) A solution of ethyl 2- [3,5-dichloro-4- (N- thiazol-2-ylamino) phenyl] propionate (14 g) in methyl iodide (70 ml) is refluxed on an oil bath of 50-55 ° C with stirring. After removing methyl iodide, the resulting residue was dissolved in methylene chloride. The solution is washed with 12% aqueous potassium carbonate solution 12 times, dried over potassium carbonate and evaporated to remove methylene chloride. The resulting oily residue is subjected to column chromatography using silica gel. From benzene and 2% ether / benzene eluents, ethyl 2- [3,5-dichloro-4- (3-methyl-4-thiazolin-2-ylidenamino) phenyl] propionate (7.2 g) is obtained.

IR ^ C Ci4 cm cm 17 1738, 1735, 1620

ulctX

(2) A solution of the above product (6.0 g) in a mixture of ethanol (30 ml) and 20% aqueous potassium hydroxide solution (30 ml) is kept at room temperature for 1 hour. After evaporation of ethanol, the resulting solution is neutralized with hydrochloric acid and adjusted to pH 5 with acetic acid to give 2- [4,5-dichloro-4- (3-methyl-4-thiazolin-2-ylideneamino) phenyl] propionic acid as a precipitate . The precipitate is filtered off, washed with water and dried to give crystals (5 g) melting at 161-165 ° C. Recrystallization from ethyl acetate gives crystals melting at 165-167 ° C. (Yield 84%).

IR YNu301 cm-1 3125, 3075, 1710, 1600.

1 max

Analysis calc'd for 0.21 C, 2 C, 2 C, 21 C, 47.13; H, 3.65; N, 8.46; S, 9.68; Cl, 21.40.

Found: C, 47.37; H, 3.69; N, 8.67; S, 9.56; Cl, 21.17.

The product (2.4 g) is dissolved in an aqueous solution (33 ml) of sodium hydroxide (0.3 g). The solution is washed with ether and an aqueous solution (2 ml) of alkaline chloride dihydrate (533 mg) is added to the solution.

The precipitated crystals are filtered off to give the corresponding calcium salt (2.5 g), melting at 265-270 ° C (decomp.).

Example 3 2- [3-Chloro-4- (3-methyl-4-thiazolin-2-ylidenamino) phenyl] propionic acid (1) A mixture of ethyl 2- [3-chloro-4- (N-thiazole-2) -ylamino) -phenyl] propionate (3.8 g), methyl iodide (11.4 ml) and ethanol (11.4 ml) are heated at 100 ° C for 6 hours in a closed tube. The ethanol and methyl iodide are evaporated. The residue is washed with benzene and dissolved in methylene chloride. The solution is washed with 20% aqueous potassium carbonate solution and evaporated to remove methylene chloride. The residue is treated in the same manner as in Example 1 to give ethyl 2- [3-chloro-4- (3-methyl-4-thiazolin-2-ylidenamino) phenyl] propionate (2.45 g). (Yield 62%).

IR γ CCl4 cm_1 17 1735, 1615, 1585. max 13 144473 (2) The product is hydrolyzed in the same manner as in Example 1 (3) and recrystallized from ether / hexane to give 2- [3-chloro-4- (3-methyl) -4-thiazolin-2-ylidenamino) phenyl] propionic acid (2.08 g), melting at 132-133 ° C.

IR Æ301 cnf1 2500 (wide), 1950 (wide), 1720, 1580.

Analysis calculated for C C HH ^C ^N₂SCl: C, 52.61; H, 4.42; N, 9.44; S, 10.80; Cl, 11.95. Found: C, 52.83; H, 4.61; N, 9.40; S, 10.90; Cl, 11.84.

Example 4 2- [2-Chloro-4- (3,4-dimethyl-4-thiazolin-2-ylidenamino) phenyl] propionic acid (1) A solution of ethyl 2- [2-chloro-4- (N-4) methylthiazol-2-yl-amino) phenyl] propionate (9.0 g) in methyl iodide (50 ml) is refluxed on a 50 ° C oil bath for 20 hours with stirring to give a precipitate. The methyl iodide is evaporated. The residue is washed with ethyl acetate and recrystallized from ethanol / ethyl acetate, then aqueous ether to give 3,4-dimethyl-2- [2-chloro-4- (1-ethoxycarbonylethyl) anilino] thiazolium iodide (7.7 g), melting at 199-202 ° C. (Yield 60%).

IR vNu3o1 cm -1 3075, 1730, 1608. max

Analysis calculated for C C ^H₂₂O₂N₂SCI: C, 41.17; H, 4.32; N, 6.00; S, 6.87; Cl, 7.60; I, 27.19.

Found: C, 40.96; H, 4.32; N, 6.01; S, 6.79; Cl, 7.61; I, 27.17.

(2) The product (7.7 g) is dissolved in methylene chloride. The solution is washed with 20% aqueous solution of potassium carbonate three times, dried over potassium carbonate and evaporated. The residue is subjected to column chromatography using alumina. With benzene as the eluent, ethyl 2- [2-chloro-4- (3,4-dimethyl-4-thiazolin-2-ylidenamino) phenyl] propionate (5.6 g) is obtained as an oily residue.

IR ^ C 14 cm -1 1733, 1615. max (3) To the product (5.6 g) is added ethanol (30 ml) and 20% aqueous potassium hydroxide solution (30 ml). The solution is kept at room temperature for 1 hour and evaporated. The residue is neutralized and adjusted to pH 5 with hydrochloric acid and extracted with ether. The extract is washed with water, dried over magnesium sulfate and evaporated. The resulting residue (5.0 g) is recrystallized from acetone / hexane to give crystals (4.4 g), melting at 132-133 ° C. (Yield 86%).

14ΛΛ73 14 IH YNuj °]. cm-l 2A50r igoo ^ {wide) / 1718 # 1608.

ΙΩαΧ

Analysis calculated for C 14 H 15 ° 2 N 2 SCl: C, 54.10; H, 4.86; N, 9.01; S, 10.32; Cl, 11.41. Found: C, 54.38; H, 4.84; N, 8.95; S, 10.38; Cl, 11.40.

Example 5 2- [3-Fluoro-4- (3-methyl-4-thiazolin-2-ylidenamino) phenyl] propionic acid (1) A mixture of ethyl 2- [3-fluoro-4- (N-thiazole-2- ylamino) phenyl] propionate (11.1 g), methyl iodide (44.5 ml) and ethanol (44.5 ml) were heated at 50-55 ° C for 48 hours. The resulting mixture was treated in the same manner as in Examples (1) and (2) to give ethyl 2- [3-fluoro-4- (3-methyl-4-thiazolin-2-ylidenamino) phenyl] propionate (6, 8 g). (Yield 58.5%).

IR yCC14 1730, 1620, 1600. max (2) The product (6.8 g) is hydrolyzed in the same manner as in Example 1 (3) to give 2- [3-fluoro-4- (3-methyl-4-thiazoline) 2-ylidene-amino) phenyl] propionic acid (5.9 g). Recrystallization from ethyl acetate and 10% acetone / ethyl acetate in sequence gives crystals melting at 151-152 ° C. (Yield 75%).

IR γ1 So1 2500 (wide), 1900 (wide), 1710, 1580.

IIlclX

Analysis calculated for cb3H13 ° 2N2SF: C, 55.70; H, 4.64; N, 9.99; S, 11.44; F, 6.78. Found: C, 55.60; H, 4.93; N, 9.93; S, 11.57; F, 6.84.

Example 6 2- [2-Chloro-4- (3-methyl-4-thiazolin-2-ylidenamino) phenyl] propionic acid (1) A mixture of 2- [3-chloro-4- (1-diethoxycarbonylethyl) anilino] - thiazole (6.5 g), methyl iodide (40 ml) and ethanol (40 ml) are heated at 50 ° C for 24 hours. The same procedure as in Example 1 (1) gives 3-methyl-2- [3-chloro-4- (1-diethoxycarbonylethyl) anilino] thiazolium iodide (5.2 g). Recrystallization from ethanol gives crystals melting at 192-193 ° C.

IR γΝ cm -1 cm -1 1743, 1720. max.

Analysis calculated for C C CH ^O ^K₂SCll: C, 41.19; H, 4.23; N, 5.34; S, 6.11; Cl, 6.76; I, 24.18.

Found: C, 41.20; H, 4.15; N, 5.29; S, 5.99; Cl, 6.56; I, 24.11.

(2) A suspension of the product (8.8 g) in methylene chloride is washed 15 U / U73 with 20% aqueous potassium carbonate solution. The solution is washed with water, dried over potassium carbonate and evaporated to remove methylene chloride. The residue is subjected to alumina column chromatography eluted with benzene. Evaporation of the solvent yields diethyl 2-methyl-2- [2-chloro-4- (3-methyl-4-thiazolin-2-ylidenamino) phenyl] malonate (6.3 g). (Yield 94.5%).

(3) The product (6.3 g) is dissolved in a mixture of ethanol (33 ml) and 20% water potassium hydroxide solution (33 ml). The solution is kept at room temperature for 16 hours. The ethanol is evaporated. The resulting solution is adjusted to pH 6 with hydrochloric acid and evaporated to dryness under reduced pressure. The residue is extracted with hot acetone. Evaporation of the acetone gives a residue, 2-methyl-2- [2-chloro-4- (3-methyl-4-thiazolin-2-ylideneamino) phenyl] malonic acid, which decomposes at 90 ° C. The residue is heated in a water bath for 10 minutes. A dilute aqueous solution of sodium bicarbonate is added to the residue. The solution is washed out with chloroform and ether respectively, treated with activated carbon, adjusted to pH 6 with hydrochloric acid and evaporated to dryness. The resulting residue is extracted with hot acetone and evaporated. The residue is recrystallized from 10% ethanol / acetone to give 2- [2-chloro-4- (3-methyl-4-thiazolin-2-ylidenamino) phenyl] propionic acid (3.4 g), melting at 215-220 ° C (decomposition).

IR γNu => o1 cm "1 2775, 2450, 2000-1900 (wide), 1730, 1715, 1610.

ItlclX

Analysis calculated for C 13 H 13 ° 2 N 2 SCl: C, 52.61; H, 4.42; N, 9.44; S, 10.80; Cl, 11.95. Found: C, 52.83; H, 4.48; N, 9.28; S, 10.84; Cl, 12.08.

16 144473

Example 7 2- [3-Chloro-4- (3-allyl-4-thiazolin-2-ylidenamino) phenyl] propionic acid (1) A mixture of ethyl 2- [3-chloro-4- (N-thiazole-2) -ylamino) -phenyl] propionate (12 g), allyl bromide (6.1 g) and ethanol (25 ml) are heated at 70-75 ° C for 8 days. The ethanol is evaporated and the residue is washed with ether and then dissolved in methylene chloride. The solution is washed out with an aqueous potassium carbonate solution and dried over potassium carbonate. The methylene chloride is evaporated to give an oily residue (12.3 g). The residue is acetylated with anhydrous acetic acid (48 ml) under heating at 120-125 ° C for 3 hours. The resulting mixture is dissolved in benzene and extracted with 10% hydrochloric acid. The extract is washed with benzene, made alkaline with sodium bicarbonate and then extracted with ether. The residue obtained after evaporation of the ether is subjected to column chromatography using silica gel. From 50% hexane / benzene eluent and hexane / benzene (1: 2) ethyl 2- [3-chloro-4- (3-allyl-4-thiazolin-2-ylidenamino) phenyl] propionate (3.3) is obtained. g). (Yield 24.5%).

IR yCC14 1735, 1610, 1590. max '(2) The above product (3.3 g) is hydrolyzed in a similar manner to Example 1 (3) to give the above-mentioned compound (3.0 g). Recrystallization from ether / hexane gives pure product (2.78 g), melting at 114-115 ° C. (Yield 92.5%).

IR Ύ ^ ίθ1 cm -1 2500 (wide), 1950 (wide), 1720, 1600, 1570, 1550.

KlclX

Analysis calculated for C 15 H 15 ° 2 N 2 SCl: C, 55.81; H, 4.68; N, 8.68; S, 9.93; Cl, 10.98.

Found: C, 55.94; H, 4.69; N, 8.72; S, 9.90; Cl, 11.02.

17 1Λ Λ Λ 7 3

Example 8

Calcium 2- (2-phenylimino-3-methyl-4-thiazolin-4-yl) propionate (1) A mixture of ethyl 2- (2-anilinothiazol-4-yl) propionate (6.15 g), methyl iodide (17 ml) and ethanol (17 ml) are heated at 100 ° C for 11.5 hours in a sealed tube. The resulting mixture is treated with potassium carbonate in a similar manner to Example 1 (2) to give ethyl 2- (2-phenylimino-3-methyl-4-thiazolin-4-yl) propionate (1.6 g), which melts at 80-81 ° C (recrystallization from ether / hexane).

IR! S4 0111-1 1740, 1610, 1580, 690.

ΙΠαΧ

Analysis calculated for C C HH ^ gC ^NS: C, 62.04; H, 6.25; N, 9.65; S, 11.04.

Found: C, 62.20; H, 6.24; N, 9.70; S, 11.03.

(2) The product (1.6 g) is dissolved in a mixture of 95% ethanol (8 ml) and 20% aqueous solution of potassium hydroxide (8 ml). The solution is kept at room temperature for 1 hour. After evaporation of ethanol, the residue is dissolved in water. The solution is neutralized with hydrochloric acid and washed with ether. The addition of calcium chloride dihydrate (405 mg) results in a precipitate. The precipitate is filtered off and washed with water to give calcium 2- (2-phenylimino-3-methyl-4-thiazolin-4-yl) propionate (1.56 g), melting at 152-153 (decomp.).

IR YNujo1 cm "1 3300 (wide), 1550 (wide). Max

Analysis calculated for (3 33202 ^8) ^ aa, 31 ^0: C, 50.63; H, 5.23; N, 9.08; Approx. 6.50.

Found: C, 50.62; H, 5.21; N, 8.95; Ca, 6.54.

(Note: Carbon dioxide was released from the carboxy group by elemental analysis).

Examples 9-22

The following compounds are prepared by similar methods as in Examples 1-7.

yl γ2 CH3

\ XJ ^ CHCOOH

χ1 -t- i Tf i 3 CH3 18 144473

Example 1 No. χ1_γ ___ Melting point (° C) 9 H 3-CP3 H 129-132 10 H 2 ~ CH3 3-C1 168-171 (d) 11 H 2_CF3 h 128-131 12 h 3-OCH3 H 148-151 13 H 2_CH3 h 217-219 14 H 3-CH3 H HC1 198-201 15 H 2-FH 155-157 16 4-CH3 Η H 150-156 (d) 17 4-CH3 3-C1 H 126-130 (d) 18 4-CH3 3-FH 135-136 19 4-CH3 2-FH Ca, 2H20 202-204 20 4-CH3 3-CH3 H 123-126 21 4-CH3 3-C1 5-C1 198-201 22 4- CH3 2-CH3 H 147-149 d: Decomposition Ca: Calcium salt H2O: Hydrate HC1: Hydrochloride

Claims (1)

Analogy Process for Preparation of Thiazoline Derivatives of the General Is Ch3 RViHC00H [j] R2 Y1 wherein X4 represents hydrogen or 4-methyl, Y , 3-chloro, 3-fluoro, 3-methyl, 2 3-methoxy or 3-trifluoromethyl, Y represents hydrogen, 3-chloro or 2-chloro, and R represents methyl or allyl, or optically active compounds or pharmaceutically acceptable salts thereof, characterized by quaternizing a compound of general formula III: ch3 Y1 wherein X1, Y1 and Y2 have the above meanings, R represents hydrogen or an ester residue, and Z represents hydrogen, carboxy or alkoxycarbonyl, with a methyl or allyl halide, an aromatic sulfonic acid methyl ester or dimethyl sulfate at a room temperature