JPH04154773A - Thiazole derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> and R<2> are H, halogen, lower alkyl, (substituted)phenyl or (substituted)pyridyl; R<3> is OH, lower alkoxy or formula II; R<4> to R<6> are H or lower alkyl); X is amino, amido, carbonyl, alkylene, O or S] or salts thereof. EXAMPLE:4-(4-Phenylthiazol-2-ylcarbonylamino)salicylic acid. USE:Having excellent analgesic, antiinflammatory and antipyretic action and useful as an analgesic and antiinflammatory agent. PREPARATION:A compound expressed by formula III and a compound expressed by the formula PhCONCS are heated and refluxed in a solvent such as acetone for about 1-5min to afford the objective compound expressed by formula I (X is NH).

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to novel thiazole derivatives having anti-inflammatory effects.

[Prior art]

Currently, various pharmaceuticals are used clinically as non-steroidal anti-inflammatory agents. In addition, research and development are actively being carried out, and various new compounds are being created with the aim of enhancing or sustaining the action, balancing the antipyretic and analgesic effects, and reducing side effects.

[Problem to be solved by the invention]

Therefore, in view of the above circumstances, the present inventors conducted further research and found that a thiazole derivative represented by the general formula N) described below has an excellent anti-inflammatory effect, and completed the present invention.

[Means to solve the problem]

The present invention is based on the general formula [wherein R1 and R1 are the same or different and represent a hydrogen atom, a halogen atom, a lower alkyl group, a phenyl group, a substituted phenyl group, a pyridyl group, or a substituted pyridyl group, R5
represents a group represented by a hydroxyl group or a lower alkoxy group (in the formula, R5 and R6 are the same or different and represent a hydrogen atom or a lower alkyl group), R4 represents a hydrogen atom or a lower alkyl group, and X represents an amino group or an amide group. group, carbonyl group, alkylene group, oxygen atom or sulfur atom] (hereinafter referred to as "thiazole derivative (I)")
) or a pharmacologically acceptable salt thereof.

In this specification, each group means the following.

Examples of the halogen atom include fluorine, chlorine, bromine, and iodine.

The lower alkyl group may be linear or branched, preferably having 1 to 4 carbon atoms, and specifically includes methyl, ethyl, n-propyl, 1so-propyl, lobutyl, 1so-butyl, Examples include tert-butyl.

The lower alkoxy group may be linear or branched, preferably having 1 to 4 carbon atoms, and specifically,
Methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, 5ec-butoxy, tert-
Examples include butoxy.

The substituted phenyl group is represented by a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group, a trifluoromethyl group, or (in the formula, R7 and R8 are the same or different and represent a hydrogen atom or a lower alkyl group). Examples include those in which one or two groups are substituted at any position of the phenyl group.

Examples of pyridyl groups include 2-pyridyl, 3-pyridyl, and 4-pyridyl.
- Any of pyridyl may be used.

The substituted pyridyl group is represented by a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group, a trifluoromethyl group, or (in the formula, R1 and R'' are the same or different and represent a hydrogen atom or a lower alkyl group). Examples include those in which one or two pyridyl groups are substituted at any position of the pyridyl group.

Preferred examples of the alkylene group include those having 1 to 4 carbon atoms. Specific examples include methylene, ethylene, trimethylene, tetramethylene, etc., with methylene and ethylene being particularly preferred.

The substitution position of X in general formula (I) is preferably substituted at the 4 or 5 position of the salicylic acid derivative.

Further, pharmacologically acceptable salts of the thiazole derivatives of the present invention include alkali metal salts (sodium salts, potassium salts, etc.), alkaline earth metal salts (calcium salts, etc.), and the like.

The thiazole derivative (1) of the present invention is specifically produced by the following method.

(1) Compound (i) of X or -NH- in general formula (I) PhC0NC3 (In the above formula, R1, R1, R2 and R4 have the same meanings as above, and X' represents a halogen) Reaction (i) This is carried out by heating under reflux for about 1 to 5 minutes in an organic solvent such as acetone.

Reaction (ii) is carried out by heating under reflux for about 1 to 10 minutes in an organic solvent such as methanol. As the alkali carbonate, for example, potassium carbonate is preferable.

Reaction (iii) is carried out in an organic solvent such as methanol with 10 to 6
This is carried out by heating under reflux for about 0 minutes.

Examples of the halogen represented by X' include bromine and chlorine.

(2) A compound of general formula (I) in which X is -CONH- (in the above formula, R', R', R2 and R4 have the same meanings as above). This reaction is preferably carried out in an organic solvent such as methylene chloride, Approximately 5 to 10 hours under water cooling or 10 to 30°C 130
It is carried out under conditions of about 1 minute to 2 hours.

(3) A compound (i
) BuLi (In the above formula, R1, R1, R2 and R4 have the same meanings as above) Reaction (i) is carried out in an organic solvent such as tetrahydrofuran, -1
It is carried out under conditions of 10 to -90°C and 10 to 60 minutes.

Reaction (ii) is carried out in an organic solvent such as tetrahydrofuran, -
It is carried out under conditions of 100 to 0°C for about 1 to 10 hours.

Reaction (iii) is carried out in an organic solvent such as acetone under water cooling.
It is carried out under conditions of approximately 5 minutes to 5 hours.

Jones reagent is an oxidizing agent in which chromium (II) oxide is dissolved in sulfuric acid.

(4) Compounds of X or -CH, - in general formula (I) (i)KCN (In the above formula, R', R', R'', R' and X.

(same meaning as above) Reaction (i) is carried out in a mixed solvent of water and an organic solvent such as dimethylformamide or ethanol by heating under reflux for about 30 minutes to 2 hours.

Reaction (ii) is carried out in an organic solvent such as dimethylformamide,
It is carried out at 70 to 90°C for about 1 to 10 hours.

Reaction (iii) is preferably carried out in an organic solvent such as methanol or ethanol under nitrogen atmosphere by heating under reflux for about 30 minutes to 2 hours. Examples of the halogen represented by Xo include bromine and chlorine.

(5) A compound in which X is a sulfur atom in the general formula (I) (In the above formula, R1, R1, R3, R4 and Xo have the same meanings as above) This reaction is preferably carried out using an organic compound such as dimethylformamide under a nitrogen atmosphere. It is carried out in a solvent at 90 to 110° C. for about 11 to 10 hours. Examples of the halogen represented by Xo include bromine and chlorine.

(6) A compound in which X is an oxygen atom in general formula (1) (R1, R*, R3, R4 and X in the above formula).

has the same meaning as above) This reaction is carried out in an organic solvent such as dimethylformamide at 140%
It is carried out under conditions of ~160°C and lO ~15 hours. X
Examples of the halogen represented by o include bromine and chlorine.

In addition, in the present invention, it is preferable that carboxyl groups or hydroxyl groups that do not participate in the reaction be protected before the reaction. Specifically, it is protected by an alkyl group (such as methyl or ethyl), an alkoxyalkyl group (such as methoxymethyl), a trialkylsilyl group (such as tert-butyldimethylsilyl), or an aralkyl group (such as benzyl).

〔Effect of the invention〕

The thiazole derivative (I) of the present invention and its pharmacologically acceptable salts are novel compounds that have not been described in any literature, and have excellent analgesic effects on mammals such as humans, cows, horses, dogs, mice, and rats. It exhibits pharmacological effects such as anti-inflammatory and antipyretic effects, and is an industrially useful compound as a pharmaceutical agent such as analgesic and anti-inflammatory agent.

The thiazole derivative (I) and its pharmacologically acceptable salts can be administered orally or parenterally (by injection, rectally, or cutaneously) by themselves or by formulating them with known carriers by conventional means. be done.

Examples of such preparations include tablets, capsules, powders, syrups, semi-open tablets, injections, and skin patches.

The dosage of the thiazole derivative (1) and its pharmacologically acceptable salts may vary depending on the symptoms, body weight, age, sex, administration route, etc., and is usually 1 to 1,000 μ divided into one to several times a day. administered.

〔Example〕

Examples are given below to explain the present invention in detail, but the present invention is not limited to these Examples in any way.

Example 1 (1) 15 g of 4-aminosalicylic acid, 150 methanol
ml and 7.5 ml of concentrated sulfuric acid were mixed and refluxed overnight.

Half of the reaction solution was distilled off, added to saturated sodium hydrogen carbonate, and extracted with ethyl acetate.
g (yield 43%).

I Rv 2':: cm-' :3500.34
00.3200,2900.1620.1580(2)
To a suspension consisting of 0.6 g of sodium hydride (approximately 60%) and 60 mj of anhydrous tetrahydrofuran (THF), 30 ml of an anhydrous THF solution containing 2.28 g of methyl 4-aminosalicylate was added dropwise under water cooling, and then 30 ml of an anhydrous THF solution was added at room temperature. Stir for a minute. Next, 1.34 ml of chloromethyl methyl ether was added dropwise under water cooling, and the mixture was stirred at room temperature for 1.5 hours.

The reaction solution was added to cold water and extracted with ether. It was purified by silica gel column chromatography (eluent: ethyl acetate-hexane system) to obtain 1.96 g (yield: 68%) of methyl 4-amino-2-methoxybenzoate.

l Rv2'x cm-': 3400.3300
．． 3200.2900°1700, 1610.1600 (3) 4-phenylthiazol-2-ylcarboxylic acid 2
30-g of anhydrous pyridine was added to 5 g, and then 0.89 mt' of thionyl chloride was added dropwise under water cooling, and the mixture was stirred for 1.5 hours under water cooling. Next, 2.58 g of methyl 4-amino-2-methoxymethoxybenzoate was added under water cooling, and the mixture was stirred overnight. The reaction solution was added to IN hydrochloric acid under a water bath, and extracted with ethyl acetate. By purifying with silica gel column chromatography method (eluent: ethyl acetate-hexane system), 2
-methoxymethoxy-4-(4-phenylthiazole-
Methyl 2-ylcarbonylaminobenzoate 4.35g
(yield 9o%) was obtained.

TRL72:; cm-': 3400.
3300. 3050. 2900°+710.16
90.1600 (4) Methyl 2-methoxymethoxy-4-(4-phenylthiazol-2-ylcarbonylamino)benzoate 4
．． 35 g, dioxane 50 mA' and IN hydrochloric acid 10.
The solution consisting of 9- was refluxed for 30 minutes.

The reaction solution was extracted with ethyl acetate to obtain 3.59 g (yield: 93%) of methyl 4-(4-phenylthiazol-2-ylcarbonylamino)salicylate.

TRv2':', cm-': 3300.
3100. 1660. 1620. 1600+51
To 3 g of methyl 4-(4-phenylthiazol-2-ylcarbonylamino)salicylate were added 85 tnI of methanol and 25.4 ml of IN sodium hydroxide; 1.
It was refluxed for 5 hours. While cooling with water, IN hydrochloric acid was added to adjust the pH to 3, and the mixture was extracted with ethyl acetate. Recrystallize from ethyl acetate,
1.71 g (yield 59%) of 4-(4-phenylthiapour-2-ylcarbonylamino)salicylic acid was obtained.

Melting point 258-260°C I Rv 4m cm-': 3300.3
200.3050.2800°+680.1660.1
620'H-NMR (DMSO-d,) δ: 10.61 (
S, IH).

8.54 (s, I)l), 8.19 (m, 2
H), 7.83 (d, J=8.7Hz.

II), 6.65 (d, J=1.8Hz, IN
), 7.56-7.39 (m, 48) Example 2 4-(4-phenylthiazol-2-ylamino)salicylic acid (1) 6 ml of anhydrous acetone was added to 1 g of methyl 4-aminosalicylate, and under reflux, benzoyl 0.84 ml of isothiocyanate was added dropwise, and the mixture was further refluxed for 3 minutes.

The reaction solution was added to ice water, the precipitate was collected by filtration, washed with methanol, and then recrystallized from chloroform-methanol to obtain 1.81 g of N-benzoyl-N'-(3-hydroxy-4-methoxycarbonylphenyl)thiourea. (yield 91%).

I Rv 2',', cm-': 3350.3
150.3000, 1690.1660.1600 (2
) 1.7 g of benzoylthiourea obtained above.

2.13 g of anhydrous potassium carbonate and 30 g of anhydrous methanol
After refluxing the reaction solution consisting of rAI for 5 minutes, 10 ml of an anhydrous methanol solution containing 1.02 g of phenacyl bromide was added dropwise.
Refluxing was continued for an additional 30 minutes. After cooling, the reaction solution was added to IN hydrochloric acid and extracted with ethyl acetate. Purified by silica gel column chromatography (eluent: ethyl acetate-hexane system), further recrystallized with chloroform and hexane,
1.14 g (yield 68%) of methyl 4-(4-phenylthiazol-2-ylamino)salicylate was obtained.

T Rv 2:', cm-': 3300,32
00.3100.1660, 1620.1600 (3)
To 2.41 g of methyl 4-(4-phenylthiazol-2-ylamino)salicylate obtained above were added 22 ml of IN sodium hydroxide and 30 methanol, and the mixture was refluxed for 1 hour. The reaction solution was adjusted to pH 3 with IN hydrochloric acid while cooling.
Extracted with ethyl acetate.

64 g of 4-(4-phenylthiazol-2-ylamino)salicylic acid by recrystallization from ethyl acetate
(yield 71%).

Melting point; 229-231°C I Rv age; cm-': 3400.3300.3
150.2500.1610.1570'H-NMR (
DMSO-d, )δ: 10.67 (s, It(
).

7.93-7.89 (m, 2H), 7.73
(d, J=8.8)1z, IH).

7.59 (d, J=1.9Hz, IH),
7.48-7.28 (m, 48).

7.04 (dd, J=8.8. 1.9) 1z,
IH) Example 3 (1) Hydrobromic acid (47 g) was added to 15 g of 4-aminosalicylic acid.
%) 45- and 45 mt' of water were added and cooled to 0°C. Add 6.76 g of sodium nitrite to 45 ml of water.
was added dropwise so that the temperature of the reaction solution did not exceed 5°C. 16.9 g of cuprous bromide was mixed with hydrobromic acid (4
7%) The solution dissolved in 45ml was cooled with a cryogen, and the solution of the diazo compound was slowly added. Then, at room temperature,
Stirred for an hour. The reaction solution was extracted with ethyl acetate to quantitatively obtain crude 4-bromosalicylic acid.

200 ml of methanol and 7 ml of concentrated sulfuric acid were added to 6 g of 4-bromosalicylic acid obtained above, and the mixture was heated under reflux overnight. After about half of the solvent was distilled off, the mixture was extracted with ethyl acetate. It was purified by silica gel column chromatography (eluent: ethyl acetate-hexane system) to obtain 5.09 g (yield: 80%) of methyl 4-bromosalicylate.

I Rv2:', cm-': 3200.
2950. 1680. 1600 (2) 0rnl of anhydrous THF I was added to 0.97 g of sodium hydride, and a solution of 5.09 g of methyl 4-bromosalicylate in anhydrous THF (30 mm) was added dropwise under water cooling, followed by stirring at room temperature for 30 minutes. Next, 2.00 ml of chloromethyl methyl ether was added under water cooling, and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was extracted with ether and purified by silica gel column chromatography (eluent: ethyl acetate-hexane system).
-Methyl bromo-2-methoxymethoxybenzoate 5.5
5g (yield 92%) was obtained.

IR:::'cm-': 2950.
2800. 1710. 1590 (3) 5.45 g of methyl 4-bromo-2-methoxymethoxybenzoate, 20 ml of methanol and 24 ml of IN sodium hydroxide
was added and refluxed for 5 minutes. After adding water and washing with ether, IN hydrochloric acid was added to the water-cooled lower aqueous layer to adjust the pH to 3, and the mixture was extracted with ethyl acetate to obtain 4.95 g (yield: 92%) of 4-bromo-2-methoxymethoxybenzoic acid.

(4) 4-bromo-2-methoxymethoxybenzoic acid5.
Anhydrous THF20 (1++r) was added to 7g and cooled to -100°C.N-butyllithium hexane solution (1,6N
)27.3- was added dropwise and stirred at -100°C for 30 minutes. Then, 2-formyl-4-phenylthiazole 4
．． 150+nl of an anhydrous THF solution of 13g was added dropwise, then added to a water bath and stirred for 2 hours. IN hydrochloric acid was added and extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.

After filtering off the magnesium sulfate, an ether solution of diazomethane was added dropwise. Purified by silica gel column chromatography (eluent: ethyl acetate-hexane system), α-(4-
phenylthiazol-2-yl) = 4-methoxycarbonyl-3-methoxymethoxybenzyl alcohol 3.3
5g (yield 40%) was obtained.

'H-NMR (CDCf,) δ: 7.89-
7.84 (m, 21().

7.79 (d, J'8.0Hz, IH), 7.
46-7.33 (m, 5) 1).

7.20 (dd, J=8.0.1.3Hz, IH
), 6.10 (S, IH).

5.27 (s, 2H), 3.88 (s, 3H
), 3.51 (s, 3H) (5) Acetone Soml was added to 3.35 g of benzyl alcohol obtained above, and while stirring under water cooling, Jones reagent was added dropwise until it turned red, and the mixture was stirred for 5 minutes. 2-Propertool was added until it turned green, and the solid was filtered off. Distill the solvent,
The residue was extracted with ethyl acetate. By recrystallizing the organic layer from ether-hexane, 2-methoxymethoxy-4
2.61 g (yield 78%) of methyl -(4-phenylthiazol-2-ylcarbonyl)benzoate was obtained.

I Rv2':", cm-' + 3050
．． 2900. 1700. 1620 (6) Methyl 2-methoxymethoxy-4-(4-phenylthiazol-2-ylcarbonyl)benzoate obtained above 2.92
30 ml of 1,4-dioxane, 1Od of water and several drops of concentrated sulfuric acid were added to the mixture, and the mixture was refluxed for 2 hours.

Next, IN sodium hydroxide 15rR1 was added, and reflux was further performed for 10 minutes. The pH was adjusted to 3 with IN hydrochloric acid under water cooling, and the mixture was extracted with ethyl acetate. Recrystallized from chloroform,
4-(4-phenylthiazol-2-ylcarbonyl)
1.92 g (yield 77%) of salicylic acid was obtained.

Melting point 216-218°C I Rv 2':: cm-': 3400.32
50.3100.1670.1640.1620'H-
NMR (DMSO-d,) δ: 8.7+' (S,
IH).

8.32-7.99 (m, 4H), 7.91
(dd, J=1.5.8.3Hz, IH)
.

7.57-7.43 (m, 3H) Example 4 4-(4-phenylthiazol-2-ylmethyl)salicylic acid (1) 25 g of 4-methylsalicylic acid and 300 g of methanol
ml and 10 ml of concentrated sulfuric acid were added and refluxed overnight. About half of the methanol was concentrated, poured into water, and extracted with ether. Methyl 4-methylsalicylate quantitatively 27.3
I got g.

IRL/2::'cm-': 3150. 3
000. 2950. 1670. 1620(2)4
-Methyl methyl salicylate 19.25 g, anhydrous N, N
- To a solution consisting of 50 m of dimethylformamide (DMF) (! and 19.72 g of imidazole, 20.95 g of t-butyldimethylsilyl chloride was added under water cooling, and then stirred at room temperature for 2 hours. The reaction solution was extracted with ether. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-hexane system) to quantitatively obtain methyl 2-t-butyldimethylsilyloxy-4-methylbenzoate.

IR Shinji::'cm-':2950.2900,
2850. l730. l710. 1610 (3) 32.53 g of 2-1-butyldimethylsilyloxy-4-methylbenzoic acid obtained above, 200 g of carbon tetrachloride, 1.4 g of benzoyl peroxide and 21.68 g of N-bromsuccinimide. Mix and reflux for 4 hours.

The reaction solution was washed with water, and the aqueous layer was further extracted with carbon tetrachloride.

Purified by silica gel column chromatography method (eluent: ethyl acetate-hexane system), 4-bromomethyl-2-t
-43.23 g of crudely purified methyl-butyldimethylsilyloxybenzoate was obtained.

(4) Add DMF to 20 g of the crudely purified bromo compound obtained above.
Add 50 rnl and 12.5 mA' of water, then add 3.61 g of potassium cyanide under water cooling, and add 45 mA' of water under water cooling.
Stir for a minute. The reaction solution was extracted with ether. The product was purified by silica gel column chromatography (eluent: ethyl acetate-hexane system) to obtain 3.96 g (yield: 57%) of methyl 4-cyanomethylsalicylate.

IRv2nieniem-' :3400.3200.3+
00.2400.2200.1670' +5)
Anhydrous D to 0.69 g of methyl 4-cyanomethylsalicylate
MF3.6- and triethylamine 0.5 ml were added, and hydrogen sulfide gas was blown into the mixture at 80°C for 4 hours.

0.5 ml of triethylamine was added every hour. The reaction solution was added to 0.5N hydrochloric acid under water cooling, and extracted with ethyl acetate. Recrystallization from ethyl acetate-hexane gave 0.43 g (yield: 53%) of 3-hydroxy-4-methoxycarbonylphenylacetothioamide.

I Rv2:", cm-': 3350.3
200. 1660. 1640. 1580 (6) A solution of 1.9 g of the thioamide obtained above and 1.68 g of phenacyl bromide dissolved in 10 ml of anhydrous methanol was refluxed for 1 hour under a nitrogen atmosphere. The reaction solution was extracted with ethyl acetate. 4-(4-phenylthiazole-
1.33 g (yield: 49%) of methyl 2-ylmethyl)salicylate was obtained.

I Rv2':", cm-': 3200.
3100. 2900. 1670. 1610(7)
Methyl ester of salicylic acid obtained above 1.33
g of methanol 10 ml and IN sodium hydroxide 1
2nd was added and refluxed for 1 hour. The reaction solution was added to 0.5N hydrochloric acid and extracted with ethyl acetate. By recrystallizing from ethyl acetate-hexane, 1.12 g of 4-(4-phenylthiazol-2-ylmethyl)salicylic acid (yield: 88
%) was obtained.

Melting point 189.5-190. OoC I Rv 2: ; cm-' :3400.310
0.2700, 2500, 1650.1600'H-N
MR(DMSO-d@)δ: 8.00 (S, I
H).

7.98-7.93 (m, 2) (), 7.78
(d, J=8.0Hz, IH).

7.49-7.30 (m, 3H), 6.99-6.9
2 (m, 2H), 4.42 (3, 2H) Example 5 4-(4-phenylthiazol-2-yl) salicylic acid (11) Dissolve 19 g of potassium cyanide in 80 ml of water,
13.06 g of cupric cyanide was added thereto. Next, 10 g of 4-aminosalicylic acid and 10 g of sodium nitrite were added and stirred under water cooling, and 2N hydrochloric acid was added dropwise so that the temperature of the reaction solution did not exceed 5°C. After stirring at 0°C for 1 hour, the reaction solution was added to water, and insoluble materials were removed by filtration.

The filtrate was adjusted to pH 2 with concentrated hydrochloric acid and extracted with ethyl acetate. Dissolve the extract in 300+ nl of methanol and add 5 m/l of concentrated sulfuric acid.
was added and heated to reflux overnight. Concentrate the reaction solution to about half the volume,
Extracted with ethyl acetate. The product was purified by silica gel column chromatography (eluent: chloroform) to obtain 3.99 g (yield: 34%) of methyl 4-cyanosalicylate.

I Rv2':", cm-': 3400.
3150. 2950. 2200. 1670(2)
5.58 g of methyl 4-cyanosalicylate, 4.39 ml of triethylamine I and anhydrous DMF 20
m/ was added thereto, and hydrogen sulfide gas was blown into it at 80°C for 1 hour. Add the reaction solution to a 0.5 N hydrochloric acid aqueous solution,
Extracted with ethyl acetate. 5.37 g of a mixture of 4-carphoxo-3-hydroxyphenylcarbothioamide and its methyl ester was obtained. Next, 1.5 g of the obtained thioamide compound and 1.5 g of phenacyl bromide were dissolved in 40 d of anhydrous methanol, and refluxed for 40 minutes under a nitrogen stream.

Furthermore, 30 ml of IN sodium hydroxide was added to the reaction solution, and the mixture was refluxed for 1 hour. The pH was adjusted to 3 with IN hydrochloric acid under water cooling, and the mixture was extracted with ethyl acetate. By recrystallizing from ethyl acetate, 1.29 g (49% yield) of 4-(4-phenylthiazol-2-yl)salicylic acid was obtained.

Melting point 240-242°C I Rv2:', cm-': 3200.
3000. 1660. 1610'H-NMR (D
MSO-d@)δ:8.30 (s, It().

8.10-8.06 (m, 21(), 7.96
(d, J=8.7)1z, 1)1).

7.62-7.36 (m, 5H) Example 6 4-(4-phenylthiazol-2-ylthio)salicylic acid (1) 340 g of water was added to 33.947 g of methyl 4-aminosalicylate, and the mixture was concentrated. 34 ml of hydrochloric acid was added dropwise at a reaction temperature of 0.5-2°C. Furthermore, after stirring for 5 minutes at the same temperature, 14.082 g of sodium nitrite was mixed with 10 g of water.
A solution dissolved in 0- was added dropwise at a reaction temperature of 0°C. The mixture was further stirred for 27 minutes at a reaction temperature of 0°C.

Add this to 46.886 g of potassium ethyldithiocarbonate.
is dissolved in 270 ml of water, the temperature of the reaction solution is 0~
Added at 3°C. Furthermore, the reaction solution which was stirred for 30 minutes at a reaction temperature of 1.5° C. was extracted with ethyl acetate to obtain 53.04 g of a reaction mixture. This was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane system) to obtain 0-ethyl 5-(3-hydroxy-4-methoxycarbonylphenyl)dithiocarbonate 17.406
g (yield 31%) was obtained.

IR Shinji::'cm-': 3430-3020
．． 1675. 1282. 1230°1205, 1
145.1098.1035.776 (2) Sodium hydride (ABS, 60%) 1.453 under nitrogen atmosphere
25rAl of dry THF was added to g, and 7.507g of the dithiocarbonate obtained above was added to 50rAl of dry THF.
A solution dissolved in water was added dropwise under water cooling. After the addition was completed, the mixture was stirred at room temperature for 35 minutes, and then 2.6 rsl of chloromethyl methyl ether was added dropwise under ice cooling. After the dropwise addition was completed, the mixture was stirred at room temperature for 1 hour. Furthermore, 0.7 ml of chloromethyl methyl ether was added at room temperature, and the mixture was stirred for 45 minutes. Water was added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. Combine the organic layer and ethyl acetate layer to obtain crude product 9.
, 31 g was obtained. This was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane system), and 〇-ethyl S-(4-methoxycarbonyl-3-
Methoxymethoxyphenyl)dithiocarbonate 7.8
77 g (yield 90%) was obtained.

IRv2::'cm-': 1727.
1285. 1231. 1+55°1075, 104
0.778 (3) Dithiocarbonate 7 obtained above, 715 g
74 ml of IN sodium hydroxide and 73 ml of ethanol
- was added and refluxed for 2 hours and 15 minutes. The solvent was distilled off, and benzene was added to the residue for evaporation to remove water.

2-bromo-4-phenylthiazole 7, 2-bromo-4-phenylthiazole 7,
A solution of 040 g dissolved in dry DMF45mj was added at room temperature under a nitrogen atmosphere, and heated at an oil bath temperature of 100°C for 6 hours.
After stirring for an hour, 20 ml of water was added to the reaction solution at room temperature, and further 2N hydrochloric acid was added at room temperature until the pH of the solution reached 1 month. After stirring at room temperature for 1 hour and 20 minutes, 2N sodium hydroxide was added to the reaction solution under water cooling to adjust the pH to 10, and 80 ml of water was added. After washing the reaction solution with ether, 2N hydrochloric acid was added to the aqueous layer under water cooling to adjust the pH to 2. This was extracted with ethyl acetate to obtain 6.259 extracts. 140 ml of hydrochloric acid-methanol solution and 2 ml of concentrated sulfuric acid were added thereto, and the mixture was refluxed overnight. The solvent was distilled off, water was added to the residue, and the mixture was extracted with ethyl acetate. 6.23 g of extract was obtained.

This was carried out using the silica gel column chromatography method (elution solvent:
After purification using ethyl acetate-hexane system) and further recrystallization from ethyl acetate-hexane, white crystals of methyl 4-(4-phenylthiazol-2-ylthio)salicylate 2 were obtained.
．． 552 g (yield 30%) was obtained.

I Rv2:', cm-' + 3650-3250
．． 1668.1282.1202゜1155, 1104
．． 773.750.730.690 (4) To 2.497 g of methyl ester of salicylic acid obtained above, 15 ml of IN sodium hydroxide and 15 mL of ethanol were added, and the mixture was refluxed for 2 hours. The solvent was distilled off, water was added to the residue, and 2N hydrochloric acid was added thereto under water cooling to adjust the pH to 1. This was extracted with ethyl acetate and recrystallized from ethyl acetate-hexane to obtain 1.799 g (yield: 75%) of 4-(4-phenylthiazol-2-ylthio)salicylic acid as white crystals.

Melting point 211.0~2+3. OoCI Rv
2:: cu+-': 3660-3290.
3290-2770. 1636°1295, 120
4.913.900.773.748.687.673
IH-NMR (DMSO-d@) δ: 14.94-9
．． 28 (brs, 2H), 8.27 (s, IH
), 8.00-7.94 (m, 2H), 7.84 (
d, J=8.2Hz, IH), 7.52-7.35
(m, 3H), 7.09 (d.

J=1.6Hz, fH), 7.04 (dd, J
=8.2. ! , 9Hz, IN) Example 7 4-(4-phenylthiazol-2-yloxy)salicylic acid (1) 2,4-dihydroxybenzoic acid 25.531
10.g of concentrated sulfuric acid was added to a solution of 250ml of methanol. After adding Oml, the mixture was heated and stirred for 24 hours. 45 ml of triethylamine was added under water cooling, and the solvent was distilled off.

Ice water was added and the mixture was extracted with ethyl acetate to obtain 24.262 g (yield: 87%) of methyl 2,4-dihydroxybenzoate.

I Rv2:", cm-': 3300.
1640. 1500(2) 21.581 g of methyl 2,4-dihydroxybenzoate and pyridinium p-
Dihydropyran 15 was added to a solution of 1.696 g of toluenesulfonic acid dissolved in 500 ml of dry dichloromethane under water cooling.
After adding rR1, the mixture was stirred at room temperature for 10 days. The solvent was distilled off to obtain 33.96 g of a crude methyl 4-(2-tetrahydropyranoxy)salicylate.

IR Shinji::'cm-':3150. 1670
．． 1620. 1580. 15004-(2-tetrahydropyranoxy)methyl salicylate crude product 10
．． 423 g and anhydrous potassium carbonate 14. 80 ml of dry DMF was added to 202 g, and then benzyl bromide 6.
After adding 4-, the mixture was stirred at 100°C for 17 hours, water was added, and the mixture was extracted with ether. 2-benzyloxy-4-(2
14.972 g of a crude product of methyl -tetrahydropyranoxy)benzoate was obtained.

'H-NMR (CDCl2) δ: 1.4-2.1 (
m, 6H).

3.3-4.1 (m, 2H), 3.81 (s,
3H), 5.10 (m, 2f().

5.38 (brs, IH), 6.50-6.72
(m, 2H), 7.18-7.56'
(m, 5H), 7.76 (d, J=9.0Hz
, IH) 0.609 g of p-toluenesulfonic acid (-hydrate) (p-TsOH) was added to a solution of 14.972 g of the crude product obtained above dissolved in 100 td of methanol. After stirring at room temperature for 2 hours, 6 ml of triethylamine was added and the solvent was distilled off. After adding ethyl acetate, the mixture was washed with water and saturated brine. The solvent was distilled off, the methyl 2-benzyloxy-4-hydroxybenzoate was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane system), and further recrystallized from ethyl acetate-hexane. 876 g,
Obtained in 89% yield in three steps.

I Rv two? ', cm-': 330
0. 1690. 1615. 1580+3160
% Sodium hydride 1.523 g to 30 ml dry D
MF was added, and the 2-benzyloxy obtained above was added thereto.
A solution of methyl 4-hydroxybenzoate in dry DMF60- was added dropwise at O''C and stirred at that temperature for 20 minutes.At the same temperature, 7,327 g of 2-bromo-4-phenylthiazole was dissolved in dry DMF40. - was added to the solution and then heated to 150°C in an oil bath.12
After heating for an hour, water was added and extracted with ether. Purification by silica gel column chromatography (eluent; ethyl acetate-hexane system) and further crystallization from ethyl acetate resulted in 5.5 methyl 2-benzyloxy-4-(4-phenylthiazol-2-yloxy)benzoate.
16 g (yield 44%) was obtained.

I Rv 2:t cm-'; 1690,
1600. 1500 (4) 12 ml of dry dichloromethane was added to 0.410 g of methyl 2-benzyloxybenzoate obtained above to form a solution. Cool to -78℃, add 9 ml of boron tribromide, and leave at that temperature for 1 hour.
Stir for hours.

Add 15+nff of saturated sodium bicarbonate solution IN
The pH was adjusted to 4 with hydrochloric acid and extracted with ether. Purified by silica gel column chromatography (eluent: ethyl acetate-hexane system), 295 μm of methyl 4-(4-phenylthiazol-2-yloxy)salicylate (yield: 9
0%) was obtained.

IR Shinji::'cm-' + 3100.
1670. 1620. 1490 (5) 4.177 g of methyl salicylate obtained above, 2.645 g of sodium hydroxide, 120 ml of methanol and 12 ml of water
The mixture was mixed and heated under reflux for 8 hours.

The mixture was further stirred at room temperature for 52 hours. The solvent was distilled off, acidified with 3N hydrochloric acid, and extracted with ethyl acetate. Silica gel column chromatography method (eluent: acetic acid-chloroform system, ethyl acetate-hexane system or methanol-chloroform system)
The residue was purified by 1.195 g (yield 30%) of 4-(4-phenylthiazol-2-yloxy)salicylic acid by recrystallization from ethyl acetate-hexane.

Melting point 157.0-158. OoC I Rv2? ', cm-': 3000.1630
．． 1500'H-NMR (DMSO-d,) δ:
6.96 (dd, J=8.7゜2.4Hz, IH
), 7.02 (d, J=2.4Hz, IH),
7.30-7.49 (m, 3H), 7.75 (
s, 18), 7.78-7.81 (m, 2H)
.

7.92 (d, J=8.7Hz, IH) Example 8 (1) To 10 g of 5-aminosalicylic acid were added 160 methanol and 5 ml of concentrated sulfuric acid, and the mixture was refluxed for 12 hours.

The reaction solution was concentrated, poured into water, and made slightly alkaline with sodium hydrogen carbonate. Insoluble matter was filtered off, and the mother liquor was extracted with ethyl acetate. The extract was dissolved in methanol, treated with activated carbon, the solvent was distilled off, and 5.78% of methyl 5-aminosalicylate was obtained.
g (yield 53%) was obtained.

I Rv 2:; cm-': 3400.330
0.3100,3000.1670.1620(2)4
-Phenylthiazol-2-ylcarboxylic acid 2.55g
Then, 150 mt' of anhydrous methylene chloride and 1.0 mt' of pyridine were added.
Add 0.9 ml of thionyl chloride under water cooling.
was added dropwise and stirred for 2 hours under water cooling. Next, 1.00 ml of pyridine and 2.08 g of methyl 5-aminosalicylate were further added to this reaction solution, and the mixture was stirred at room temperature for 1 hour. The reaction solution was added to 0.5N hydrochloric acid and extracted with methylene chloride. Add methanol to the extract to precipitate crystals,
1.02 g (yield 23%) of methyl -(4-phenylthiazol-2-ylcarbonylamino)salicylate was obtained.

I Rv2':;cm-': 3300.
3+60. 1670. 1610 (3) To 1.69 g of methyl 5-(4-phenylthiazol-2-ylcarbonylamino)salicylate obtained above, 30-methanol and 14.3-g of IN sodium hydroxide were added,
Reflux was carried out for 45 minutes. While cooling with water, IN hydrochloric acid was added to adjust the pl to 3, and the mixture was extracted with ethyl acetate. 5-(4-phenylthiazole-2-
ylcarbonylamino) salicyl 1.27 g (yield 78
%) was obtained.

Melting point 252-253°C I Rv 2:', cm-': 3300.
3100. 1670. 1650. 1620'H-
NMR (DMSO-d@) δ: 10.67 (S,
IH).

8.49 (s, II), 8.39 (d, J=2
．． 7Hz, IH), 8.21-8.17(m, 2H
), 8.04-7.99 (dd, J=2.7.9
．． 0Hz, IH).

7, 56-7, 38 axes, 3H), 7.03 (d,
J=9Hz, IH) Example 9 5-(4-phenylthiazol-2-ylamino)salicylic acid C]) Methyl 5-aminosalicylate and benzoyl isothiocyanate were reacted in the same manner as in Example 2 (1),
By recrystallizing from chloroform-methanol,
N-benzoyl-N'-(4-hydroxy-3-methquinecarbonylphenyl)thiourea was obtained in a yield of 67%.

I Rv 2:; cm-': 3300.320
0.3000.2950.1690.1600 (2) In the same manner as in Example 2 (2), the pen and diylthiourea obtained above were reacted with anhydrous potassium carbonate, and then with phenacyl bromide, and subjected to silica gel column chromatography. The product was purified by the Gram method (eluent; ethyl acetate-hexane system) and further recrystallized from chloroform-hexane to obtain methyl 5-(4-phenylthiazol-2-ylamino)salicylate in a yield of 40%.

I Rv 2: ; cm-' :3350.310
0,2950,1670,1620.1600 (3) The methyl ester of salicylic acid obtained above was added to Example 2 (
3), the reaction solution was adjusted to pH 3 with IN hydrochloric acid under water cooling, and the precipitate was collected by filtration and washed with water and methanol to produce 5-(4-phenyl). Thiazol-2-ylamino)salicylic acid with a yield of 5
Obtained at 9%.

Melting point 285°C (decomposition) I Rv 2:; cm-': 3400°
3200. 3150. 2700. 1600'H
-NMR(DMSO-d@)δ: 10.21(b
r, IH), 8.44 (d, J=2.8Hz, 1
8), 7.97-7, 93(m, 2H), 7.7
9 (dd, J=2.8°9.0Hz, IH), 7.
46-7.28 (m, 4H), 6.98 (d, J=9
Hz, I) I) Example 10 (1) 5 g of 5-bromsalicylaldehyde, 84 g of propanediol Z, 100 ml of anhydrous benzene and a small amount of p-TsOH were mixed and refluxed for 2 hours using a Dean-5 tark water separator. The reaction solution was added to an ice-cooled saturated aqueous sodium hydrogen carbonate solution, and extracted with ether. Purified by silica gel column chromatography (eluent: ethyl acetate-hexane system), 5-bromo-2-hydroxybenzaldehyde propylene acetal 5.95 g (yield: 9
2%).

IR signif', cm-': 3350.2980.
2890. +610.1590.1500 (2) Under a nitrogen atmosphere, add anhydrous THF 50++1' to 1.01 g of sodium hydride (60%), and add 5.95 g of the propylene acetal obtained above to 50 ml of anhydrous THF under water cooling.
A solution dissolved in was slowly added dropwise, and the mixture was stirred at room temperature for 30 minutes. Again under water cooling, 2.75+J of 2-methoxyethoxymethyl chloride was added dropwise and stirred at room temperature for 1 hour. The reaction solution was added to an ice-cooled saturated aqueous sodium hydrogen carbonate solution, and extracted with ether. Silica gel column chromatography method (eluent.

5-bromo-2-
4.28 g (yield: 53 Song) of methoxyethoxymethoxybenzaldehyde propylene acetal was obtained.

I Rv2::'cm-': 2940. 2920
．． 2870. 1600. 1520 (3) A solution of 4.15 g of 5-bromo-2-methoxyethoxymethoxybenzaldehyde propylene acetal obtained above dissolved in 60+1 anhydrous THF was cooled to -98°C, and a solution of n-butyllithium hexane (1,6N ) 7.
47 m/ was added dropwise and stirred at -98°C for 30 minutes. Then, 2-formyl-4”) x Nielthiazole 2.2
A solution of 6g of anhydrous THF dissolved in 60ml of
The mixture was added dropwise at 10°C, and then the temperature was raised to -10°C over 4 hours. The reaction solution was added to water and extracted with ether. Purified by silica gel column chromatography method (eluent: ethyl acetate-hexane system) to give 3.58 g of 5-[hydroxy(4-phenylthiazol-2-yl)methyl]-2-methoxyshethoxymethoxybenzaldehyde brobylene acetal.
, a yield of 65% was obtained.

I Rv:':”cm-':3550.3300
．． 2980.2900.2820. +650 (4)
30 ml of dioxane was added to 3.47 g of propylene acetal obtained above, and 7.58 g of IN hydrochloric acid was added under water cooling, followed by stirring for 30 minutes under water cooling and then for 2 hours at room temperature.

The reaction solution was poured into ethyl acetate, and the organic layer was washed with saturated brine. The solvent was removed, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate-hexane system) to obtain α-(4-phenylthiazol-2-yl)-3-formyl-4-methoxyethoxymethoxybenzyl alcohol. z05 (yield 68%) was obtained.

I Rv 2::'cm-' :3350,3080
．． 2900, 2850, 1720.1690 (5) 50 ml of acetone was added to 1.91 g of benzyl alcohol obtained above, and then 8N Jones reagent was added under water cooling so that the reaction solution maintained an orange color. After stirring for 3 hours under water cooling, 2-propertool was added.

The reaction solution was filtered, sodium hydrogen carbonate was added to the mother liquor, and the solvent was distilled off.

0.2N hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate.

Purified by the silica gel column chromal rubrum method (eluent, chloroform-methanol system), and added 0.56 g of trifluoroacetic acid to a solution of the purified product dissolved in anhydrous methylene chloride.
- and stirred at room temperature for 20 hours. The solvent was evaporated and the residue was dissolved in IN sodium hydroxide and washed with ether. The aqueous layer was adjusted to pH 3 with IN hydrochloric acid and extracted with ethyl acetate. By recrystallizing from chloroform, 5-(4
-Phenylthiazol-2-ylcarbonyl)salicylic acid o, 72 g (yield 42%) was obtained.

Melting point 232-233°C I Rv 2:; cm-': 3500.320
0.3100.1670, 1620.1580'H-N
MR (DMSO-ds) δ: 9.42 (d, J=2
．． 3Hz.

IH), 8.66 (S, IH), 8.62 (
dd, , l'2.3.8.811z.

IH), 8.12-8.07 (m, 2H),
7.56-7.44 (m, 3H).

7.19 (d, J=8.8Hz, I) I) Example ll 5-(4-phenylthiazol-2-ylmethyl)salicylic acid (1) 10 g of 5-formylsalicylic acid to 16 ethanol
0ml and 5ml of concentrated sulfuric acid were added, and the mixture was heated under reflux for 36 hours. Thereafter, the solvent was concentrated, added to saturated brine, and extracted with ethyl acetate. It was purified by silica gel column chromatography (eluate: ethyl acetate-hexane = 1 = 1) to obtain 9.81 g of ethyl 5-formylsalicylate (yield: 84%).

I Rv2'm2 co+-' :3450,320
0.2980,2820. l680. l610(2)5
-100 g of anhydrous chloroform and 47.5 ml of pyridine were added to 9.5 g of ethyl formylsalicylate and stirred under water cooling. This reaction solution contained 3.83 m of acetyl chloride.
1 was added dropwise, and the mixture was stirred for 30 minutes under water cooling. The reaction solution was added to 300 ml of an aqueous hydrochloric acid solution (pH 3) and extracted with chloroform. 9.81 g of crude ethyl 2-acetoxy-5-formylsalicylate was obtained. 50 ml of ethanol was added to 9.8 g of the obtained crude ethyl 2-acetoxy-5-formylsalicylate, 1.57 g of sodium borohydride was added under water cooling, and the mixture was further stirred for 30 minutes under water cooling. 20% acetic acid was added, and the reaction solution was poured into water and extracted with ethyl acetate. By purifying with silica gel column chromatography (eluent: ethyl acetate-t\xane system), 5.89 g of ethyl 2-acetoxy-5-hydroxymethylbenzoate (yield: 5I%) was obtained.

! R Shinji::'cm-'+3900.3000,295
0,1760.1710.1610 (3) Add 50 mj' of anhydrous ether to 5.88 g of ethyl 2-acetoxy-5-hydroxymethylbenzoate obtained above, and dropwise add 2.34 m1' of phosphorus under water cooling for 30 minutes. , and then stirred for 15 minutes under water cooling. After adding methanol dropwise, the reaction solution was poured into 300 ml of water and extracted with ether. The product was purified by silica gel column chromatography (eluent: ethyl acetate-hexane system) to obtain 5.25 g (yield: 71%) of ethyl 2-acetoxy-5-bromomethylbenzoate.

I Rv2',', cm-' + 3450
．． 3000. 1760. 1720 (4) To 5.25 g of ethyl 2-acetoxy-5-bromomethylbenzoate obtained above, add 1.25 g of potassium cyanide, ethanol, and water (V/V = 2:I, 30 ml),
Reflux was carried out for 1 hour. The reaction solution was added to water and extracted with ethyl acetate. It was purified by silica gel column chromatography (eluent: ethyl acetate-hexane system) to obtain 2.81 g (yield: 78%) of ethyl 5-cyanomethylsalicylate.

I Rv 2:: 'cm'' +3150.3000
．． 2250.1670.1620.1600 (5) Ethyl 5-cyanomethylsalicylate obtained above was reacted with hydrogen sulfide in the presence of triethylamine in the same manner as in Example 4 (5), and recrystallized from ethyl acetate-hexane. By doing so, 3-ethoxycarbonyl-4-hydroxyphenylacetothioamide was obtained in a yield of 75%.

I Rv2'm2 cm-': 3350. 31
50. 2980. 1650. 16]0(6) The thioamide obtained above and phenacyl bromide were reacted in the same manner as in Example 4 (6) in absolute ethanol, and silica gel column chromatography method (eluent: ethyl acetate-hexane system) and further recrystallized from chloroform-hexane to obtain 5-(4-phenylthiazole-2
-ylmethyl)ethyl salicylate was obtained in a yield of 78%.

Summer Rv 2:', cm-': 3100. 3
000. 1670. 1620. 1600 (7) By adding IN sodium hydroxide and ethanol to the ethyl salicylate obtained above, subjecting it to a hydrolysis reaction in the same manner as in Example 4 (7), and recrystallizing from ethyl acetate,
5-(4-phenylthiazol-2-ylmethyl)salicylic acid was obtained in a yield of 77%.

Melting point 197-198°C I Rv2', cm-': 3400. 3
100. 1660. 1610. 1590'H-N
MR (DMSO-cll) δ: 8.00-7.93
(m.

31(), 7.84 (d, J=4.3Hz, I
H), 7.57-7.29 (m, 41().

6.96 (d, J・8.5Hz, IH), 4.
36 (S, 2H) Example 12 5-(4-phenylthiazol-2-yl)salicylic acid (11 In the same manner as in Example 5(1), hydrogen sulfide was added to a DMF solution of ethyl 5-cyanosalicylate in the presence of triethylamine. Recrystallization from ethyl acetate-hexane gave 3-ethoxycarbonyl-4-hydroxyphenylcarbothioamide in a yield of 58%.

I Rv 2:; cm-': 3400.3250.
3200.3000.1680.1620 (2) Add 10 m of absolute ethanol to 1.12 g of the thioamide obtained above.
1 was added and heated, and when reflux started, a solution of 0.99 g of phenacyl bromide in 10 rnl of absolute ethanol was added dropwise. After refluxing for 30 minutes, the reaction solution was added to water,
Extracted with ethyl acetate. Purified by silica gel column chromatography (eluent: chloroform), further crystallized from ethyl acetate-hexane, 1.40 g of ethyl 5-(4-phenylthiazol-2-yl)salicylate.
(yield 86%).

T Rv 22: cm-': 3400.310
0,3000,1680.1620.1600 (3) To 800 μl of ethyl salicylate obtained above in the same manner as in Example 5 (2), 7.38 μl of IN sodium hydroxide and 16 ml of ethanol were added, and the mixture was refluxed for 1 hour. went. By recrystallizing from ethyl acetate-hexane, 5-(4
-phenylthiazol-2-yl) salicylic acid 350■
(yield 48%).

Melting point: 228.5-229.5°C IR temperature: 3450. 31
00. 1680. 1620. 1590'H-NM
R(DMSO-d,) δ: 8.42 (d, J=2.4
Hz.

IH), 8.22-8.02 (m, 4H), 7
．． 53-7.34 (m, 3H).

7.12 (d, J=8.7Hz, II) Example 1
3 Salicylic acid (1) In the same manner as in Example 6 (1), methyl 5-aminosalicylate was made into a diazonium salt, and then reacted with potassium 〇-ethyldithiocarbonate. ) to obtain 0-ethyl 5-(4-hydroxy-3-methoxycarbonylphenyl)dithiocarbonate in a yield of 52%.
I got it.

I Rv:,,:; cm-': 3400.167
0(2) The 〇-ethyl 5-(4-hydroxy-3-methoxycarbonylphenyl)dithiocarbonate obtained above was subjected to a methoxymethylation reaction in the same manner as in Example 6(2), and subjected to silica gel column chromatography. (Eluate; ethyl acetate-hexane system)
-ethyl S-(3-methoxycarbonyl-4-methoxymethoxyphenyl)dithiocarbonate in yield 9
Obtained at 3%.

IRv2::'cm-': 1730. 159
0(3) React in the same manner as in Example 6(3) using 0-ethyl 5-(3-methoxycarbonyl-4-methoxymethoxyphenyl)dithiocarbonate and 2-bromo-4-phenylthiazole obtained above. and purified by silica gel column chromatography (eluent: ethyl acetate-hexane system) to obtain methyl 5-(4-phenylthiazol-2-ylthio)salicylate in a yield of 47.
Obtained in %.

The methyl 5-(4-phenylthiazol-2-ylthio)salicylate obtained above was subjected to a hydrolysis reaction in the same manner as in Example 6 (4) and recrystallized from ethyl acetate-hexane. -Phenylthiazol-2-ylthio)salicylic acid was obtained in a yield of 78%.

Melting point 191-192°C I Rv2';cm-': 3400.3200
．． 1670'H-NMR (DMSO-d@) δ: 8.
14(d, J=2.4Hz.

IH), 7.98 (s, IH), 7.95-7
．． 80 (m, 3h).

7.50-7.30 (m, 31(), 7.15
(d, J=8.7Hz, I)I) Example 14 5-(4-phenylthiazol-2-yloxy)salicylic acid (1) Gentisic acid was methyl esterified in the same manner as in Example 7 (1), and 2 .Methyl 5-dihydroxybenzoate was obtained quantitatively.

r Rv2:; cm-': 3330.1680 (
2) Add 450 ml of dry methylene chloride to the methyl 2,5-dihydroxybenzoate obtained above. 13.0 d of dihydrobilane was added and a catalytic amount of p-toluenesulfonic acid was added at 0''C in an ice bath. After stirring overnight at room temperature, 2 ml of triethylamine was added and the solvent was distilled off under reduced pressure. Dry T.
350 mj of HF was added, and 5.71 g of 60% sodium hydride was slowly added at 0''C in a water bath. After stirring at room temperature for 30 minutes, 9-93 ml of chloromethyl methyl ether was added dropwise at 0''C in a water bath.

Condensed water that had been stirred for 1 hour was added, and the mixture was extracted with ether.

The resulting oil was dissolved in 400 ml of methanol and a catalytic amount of p-toluenesulfonic acid was added at room temperature.

After stirring overnight at room temperature, 2 ml of triethylamine was added.
The solvent was distilled off. The resulting mixture was subjected to silica gel column chromatography (eluent: ethyl acetate-hexane system).
18.55 g (yield 74%) of methyl 5-hydroxy-2-methoxymethoxybenzoate was obtained.

IRLl2::'cm-': 33
50. 2950. 1710. 1500 (3) The above-obtained methyl 5-hydroxy-2-methoxymethoxybenzoate was reacted with 2-bromo-4-phenylthiazole in the same manner as in Example 7 (3), and then purified in the same manner as in Example 7 (3). Methyl 2-methoxymethoxy-5-(4-phenylthiazol-2-yloxy)benzoate was obtained in a yield of I9%.

T Rv 2: x' cm -' : 29
50.1730.1490 (4) Add 10 mj of methanol to 1.688 g of methyl benzoate obtained above,
IN sodium hydroxide 5rR1 was added at room temperature, and the mixture was stirred under reflux overnight. Water was added to the reaction solution, and the mixture was washed with ether. 5 ml of 1N hydrochloric acid was added to the aqueous layer in a water bath and stirred to precipitate crystals.

Collect the crystals by filtration, add 10mt of methanol and 5mf of IN hydrochloric acid.
f was added and refluxed for 5 minutes. When water was added to the reaction solution, crystals were precipitated. The crystals were collected by filtration, washed with water, and then recrystallized from methanol-water to give 5-(4-phenylthiazole-2
-yloxy) salicyl #1.25 g (yield 83%) was obtained.

Melting point +62.5-164.0°C I Rv2: cm-': 3470.
1680. 1480'H-NMR (DMSO-d@)
δ: 7.85 (m, 2H).

7.63 (dd, J=9.0.0.9)1z,
IH), 7.60 (S, 18).

7.25-7.47 (m, 3H), 7.10
(d, J=9.0Hz, IH) Example 15 5-(2-thiacylyloxy)salicylic acid (11 Example 1
Using methyl 5-hydroxy-2-methoxymethoxybenzoate obtained in 4 (21) and 2-bromothiazole, a reaction was carried out in the same manner as in Example 7 (3), and silica gel column chromatography (eluent: ethyl acetate) -hexane system) to obtain methyl 2-methoxymethoxy-5-(2-thiacyryloxy)benzoate in a yield of 44%.

IR Shinji::'cm-': 1720(2)
To 2.757 g of methyl 2-methoxymethoxy-5-(2-thiacylyloxy)benzoate was added p-toluenesulfonic acid
0.178 g of p-TsOH) and 50 ml of methanol were added, and the mixture was stirred at room temperature for 4 days. After adding 2 ml of triethylamine and distilling off the solvent, the mixture was diluted with Ku-Til and washed with water and saturated brine.

The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate-hexane system).
Methyl 5-(2-thiacylyloxy)salicylate 1.92
5 g (yield 82%) was obtained.

TRSini::'cm-': 3150. 168
0. 1620(3) 1.925 g of methyl 5-(2-thiacylyloxy)salicylate to 1.6 g of sodium hydroxide
47 g, methanol 100+J and water 10ml were added, heated at 50°C for 7 hours, and further heated under reflux for 1.5 hours [
7. After cooling, the solvent was distilled off, acidified with 4.8N hydrochloric acid, and extracted with ethyl acetate. By recrystallizing from ethyl acetate-hexane, 1.389 g (yield 73%) of 5-(2-thiacyryloxy)salicylic acid was obtained.

Melting point 171.0-172.0″C I Rv2: ; cm-’: 3150.28
00. 2500. 1660. 1620'H-NM
R(DMSO-d,) δ: 7.06 (d, J
=9.0Hz.

IH), 7.21 (d, J=3.8Hz, IH
), 7.28 (d, J=3.8Hz.

IH), 7.54 Cdd, J□9.0.3.1H
z, IH).

7.71 (d, J・3.1Hz, IH), 12
．． 2 (brs, IH) Example 16 fil Example +4 (Example 15 (
The reaction was carried out in the same manner as in +1, and purified by silica gel column chromatography (eluent: ethyl acetate-hexane system) to obtain methyl 5-(4,5-diphenylthiazol-2-yloxy)-2-methoxymethoxybenzoate. Yield 5
Obtained at 3%.

IR Shinji::'cm-': 1730. 148
0(2) Example 15 (similar to 21, 5 obtained above
-(4,5-diphenylthiazol-2-yloxy)
-Methyl 2-methoxymethoxybenzoate and p-TsOH
Methyl 5-(4,5-diphenylthiazol-2-yloxy)salicylate was obtained in a yield of 76% by stirring the methanol solution and purifying it by silica gel column chromatography (eluent: ethyl acetate-hexane system). Ta.

IRν::';"cm-': 3000.16
80. 1480(3) 5-(4,5-
Methyl diphenylthiazol-2-yloxy)salicylate was subjected to a hydrolysis reaction in the same manner as in Example +5 (31),
After purification by silica gel column chromatography (eluent: chloroform-acetic acid system), it was recrystallized from methylene chloride-hexane and 5-(4,5-diphenylthiazole-
2-yloxy)salicylic acid was obtained in a yield of 86%.

Melting point 168.0-169. OoC I Rv2',', cm-': 3000.167
0' H-NMR (CDCLI) δ: 7.04
(d, J=9.1Hz, 18), 7.2-7.3
(01,8H), 7.42-7.48 (m, 2H
), 7.53 (dd.

J=9.1.3.0Hz, IH), 7.89 (d
, J=3.0Hz, III).

10.1 (brs, 2H) Procedural master's letter (spontaneous) 1. Display of incidents 1990 Patent Application No. 277041 Name (Name) Midori Juji Co., Ltd. 4. Agent ■541 Address: 3-3-9 Hirano-cho, Chuo-ku, Osaka (Basue Building) Telephone (06) 227-1156 “Detailed description of the invention” column in the specification 6. Contents of correction (1) Reaction formula on page 9 of the specification is corrected as follows.

(2) "Methyl" is added after "4-aminosalicylic acid" on page 11, lines 18-19 of the specification.

(3) Add "methoxy" after "methoxy" on page 12, line 10 of the specification.

(4) Add ")" after "ylcarbonylamino" on page 13, lines 3-4 of the specification.

(5) r6.65 (d, J
-1,8Hz, l1l), 7.56-7.39 (
+w, 411) J to r7.56-7.39 (s,
4H), 6.65 (d, J-1,8H
z, IH) Correct to J.

(6) Specification page 20, line 14, page 21, line 4, 2
Page 6, line 8, page 27, line 6, page 30, line 6, page 32, line 16, page 38, line 6, page 39, line 13, line 42
Page 4th line, page 43, line 3, page 46, line 18, 49
Page 2nd line, page 49, line 9, page 50, line 15, 51st
"rIRv::7" on the 6th line of the page and the 12th line of the 52nd page are corrected to "rIRv2:=1", respectively.

(7) Specification page 26, line 5, page 27, line 3, 46
After “0-ethyl” on page 6th line, page 46th line 10th, page 46th line 15th, and page 46th line 19th, respectively.
- Add ノ.

(8) Page 30, line 12 of the specification, page 31, line 7, 3
"Benzyloxy" on page 1, line 13, page 32, line 2, and page 32, line 6 are respectively corrected to "benzyloxy."

(9) 'CDCl5J' on page 30, line 14 of the specification
Corrected to DC15J.

Oω specification page 30 lines 14-17 rl, 4-2.1
(m, 6H), 3.3-4.1 (wa, 21)
, 3.81 (s, 3H).

5.10 (m, 2H), 5.38 (brs, I
H), 6.50-, 6.72 (Im, 2
H), 7.18-7.56 (m, 51(L
7.76 (d, J=9.0112.1)1) J
'7.76 (d, J=9.0Hz.

IH), 7.18-7.56 (N, 5H)
, 6.50-6.72 (It.

2H), 5.38 (brs, IH),
5.10 (+*, 211), 3.81 (s
, 3H), 3.3-4.1 (m, 2t
l), 1.4-2.1 (s+.

6H)”.

(11) Specification page 33, line 10 and page 36, line 18
row 'DMSO-dhJ and rDMsO-dbJ respectively.
Correct.

Q'lJ Specification No. 33, lines 10-13 r6.96
(dd.

J=8.7.2.4Hz, IH), 7.02 (d
, J=2,411z, IH).

7.30-7.49 (m, 3)1), 7.75
(s, 1tl), 7.78-7.81 (m, 2
H), 7.92 (d, J=8.7Hz, II)
J” to r7.92 (d, J=8.7Hz, I
H), 7.78-7.81 (m, 2) 1), 7.
75 (s, IH), 7.30-7.49 (m,
38).

7.02 (d, J=2.4Hz, IN>, 6.
96 (dd, J=8.7°2.4Hz, IH)
Correct to J.

0■ “J・2・IHz” on page 35, line 8 of the specification is 1
J・2.711z Correct to J.

rJ=9Hz J on page 35, line 10 of the sub-specification is “J.
9. Correct to OH2J.

r on page 37, line 6 and page 52, line 16 of the 09 specification
"TsOH" are respectively corrected to "toluenesulfonic acid."

(+51 Specification, page 39, line 2 and page 53, line 1, “I R, CHCLS, respectively rlRν!■h)”
Correct.

q'7) Add 'gJ after r 2.05 J on page 39, line 12 of the specification.

``Jones'' on page 39, lines 15-16 of the OΦ Specification is corrected to ``rJones''.

(1(l) In the second line of page 41 of the specification, “in saturated saline” was changed to “
Correct to "saturated salt solution."

[Phase] rIRvB on page 46, line 9 of the specification; C#l-
'J rlRν! ! =-C-1”.

(21) '(p-TsOH) on page 50, line 18 of the specification
Delete.

(22) 'DMSO-di' on page 51, line 17 of the specification
J to rcDcj! , correct J.

(23) r7.06 on page 51, lines 17-20 of the specification
(d.

J=9.0)12. 1B), 7.21 (d
, J=3.8Hz, 1ll).

7.28 (d, J=3.8Hz, ll()
, 7.54 (dd, J=9.0°3.1Hz
, 18), 7.71 (d, J=3.1
Hz, l1l), 12.2 (brs, IH)
J'12.2 (brs, IH), 7.71 (
d, J=3.1Hz, Il+), 7.54
(dd, J=9.0. 3.IH2゜IH),
7.28 (d, J=3.8Hz, 1t
l), 7.21 (d.

J=3.8Hz, IH), 7.06 (d, J=
9.0Hz, E) Correct to j.

(24) Correct rcocL3 J to rCpcffis J on page 53, line 11 of the specification.

(25) r7.04 on page 53, lines 11-14 of the specification
(d.

J = 9.1Hz, IH), 7.2-7.3 (m
, 8H), 7.42-7.48 (m, 2B
), 7.53 (dd, J=9.1. 3.
0Hz+IH), 7.89 (d, J=3.0Hz
, II), 10.1 (brs.

2))'10.1 (brs, 28), 7.8
9 (d, J=3.0Hz.

JIH), ? , 53 (dd, J=9.1.
3.0) 1z, IH), 7.42-7.48 (+
*, 2B), 7.2-7.3 (m, 8)1),
7.04 (d.

J=9.1Hz, 18) Correct to J.

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) [In the formula, R^1 and R^2 are the same or different and represent a hydrogen atom, a halogen atom, a lower alkyl group, a phenyl group ,
Substituted phenyl group, pyridyl group or substituted pyridyl group,
R^3 is represented by a hydroxyl group, a lower alkoxy group, or the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^5 and R^6 are the same or different and represent a hydrogen atom or a lower alkyl group) The basis of
R^4 represents a hydrogen atom or a lower alkyl group, and X represents an amino group, an amide group, a carbonyl group, an alkylene group, an oxygen atom or a sulfur atom] or a pharmacologically acceptable salt thereof.