JPH10139768A - Production of naphthalene derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for industrially producing a naphthylmethylthiazolidinedione derivative, having lowering actions on blood sugar and lipids in blood and useful as a preventing and therapeutic agent for diabetes and hyperlipemia. SOLUTION: 6-Hydroxy-2-naphthaldehyde is reacted with 2,4-thiazolidinedione to provide 5-(6-hydroxy-2-naphthyl)methylene-2,4-thiazolidinedione, which is then reduced to produce 5-(6-hydroxy-2-naphthyl)methyl-2,4-thiazolidinedione. The resultant compound is further reacted with a benzyl derivative to produce a 5-(6-substituted benzyloxy-2-naphthyl)methyl-2,4-thiazolidinedione represented by the formula (R<1> to R<5> are each a hydrogen, a halogen atom, an alkyl group, etc.).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a novel method for producing a naphthalene derivative having a blood glucose and blood lipid lowering action.

[0002]

2. Description of the Related Art Japanese Unexamined Patent Publication (Kokai) No. 6-247945 discloses a naphthylmethylthiazolidinedione derivative having a blood glucose and blood lipid lowering action and a method for producing the same. The method is, for example, as shown in Scheme 1, by substituting a substituent from 6-acetyl-2-naphthol to a hydroxyl group,
After being converted to naphthylamine through a ckmann rearrangement reaction, it was converted to a diazonium salt, and was used as Meerwein Aryl.
In this process, a naphthylmethylthiazolidinedione derivative is produced by reacting a thiourea with a haloester to form an iminothiazolidinone, which is then hydrolyzed under acidic conditions. In this manufacturing method, the number of steps is large, and Meerwein is used.
There are drawbacks such as intense heat generation in Arylation, generation of a large amount of nitrogen, and offensive odor due to the use of acrylic esters. Furthermore, when the substituent on the hydroxyl group of the naphthalene ring is a benzyl group, depending on the substituent of the benzyl group, it may be eliminated during hydrolysis of iminothiazolidinone to thiazolidinedione under acidic conditions in the middle. is there.

[0003]

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Wherein R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are each independently a hydrogen atom, a halogen atom, an alkyl group, an aryl group, an alkoxy group, an alkoxyalkoxy group, an aryloxy group, an alkanoyloxy group, Arylcarbonyloxy group, carboxyl group, alkoxycarbonyl group, aryloxycarbonyl group, carbamoyl group,
Alkylaminocarbonyl group, arylaminocarbonyl group, an amino group, an alkylamino group, an alkanoylamino group, an arylcarbonylamino group, ethylenedioxy methyl group, a formyl group, a cyano group, a nitro group or a trihalomethyl group, R ¹⁵ is Represents a hydrogen atom, an optionally substituted alkyl group or an optionally substituted aryl group. X is ＮN— or ＣＲCR ¹⁶ — (R ¹⁶ is a hydrogen atom, a halogen atom, an alkyl group, an aryl group, an alkoxy group,
Alkoxyalkoxy, aryloxy, alkanoyloxy, arylcarbonyloxy, carboxyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, alkylaminocarbonyl, arylaminocarbonyl, amino, alkylamino, alkanoyl Represents an amino group, an arylcarbonylamino group, an ethylenedioxymethyl group, a formyl group, a cyano group, a nitro group or a trihalomethyl group. ), And n represents an integer of 0 to 3. R represents a lower alkyl group, and Z represents a halogen atom. ｝

As another production method, as shown in Scheme 2, after introducing a substituent into the hydroxyl group of 6-hydroxy-2-naphthaldehyde, the formyl group is reduced to the hydroxyl group, and naphthylmethyl halide is reacted with a halogenating agent. And a method for producing naphthylmethylthiazolidinedione by reacting with a dianion of thiazolidinedione at a low temperature. In this production method, naphthylmethyl halide produced in the middle is low in stability, and it is necessary to carry out the alkylation reaction of thiazolidinedione with a dianion at a low temperature. There's a problem.

[0006]

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(Wherein, R ^{11 to} R ¹⁵ , X and n are the same as defined above, Y represents a halogen atom, and M ⁺ represents an alkali metal ion). As shown in, after protecting the hydroxyl group of 6-hydroxy-2-naphthaldehyde with a protecting group, thiazolidinedione is dehydrated and condensed, and the resulting double bond is reduced to a single bond by a catalytic hydrogenation reaction. A method is described in which a protecting group is deprotected and a substituent is selectively introduced into a phenolic hydroxyl group. This production method also involves steps such as protection and deprotection of the phenolic hydroxyl group, and cannot be said to be a reasonable production method.

[0008]

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(Wherein R ^{11 to} R ¹⁵ , X and n are the same as defined above)

[0010]

SUMMARY OF THE INVENTION The present invention provides an industrial method for producing naphthylmethylthiazolidinedione which has a blood sugar and blood lipid lowering effect and is useful as a therapeutic agent for diabetes and hyperlipidemia. is there.

[0011]

The present invention provides 6-hydroxy-2-naphthaldehyde (formula (I) below).

[0012]

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Without protecting the hydroxyl group of
-Thiazolidinedione is dehydrated and condensed to give 5- (6-hydroxy-2-naphthyl) methylene-2,4-thiazolidinedione (formula (II) below)

[0014]

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This is then reduced to give 5- (6-hydroxy-2-naphthyl) methyl-2,4-thiazolidinedione (formula (III) below)

[0016]

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To obtain a compound represented by the general formula

[0018]

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(Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each independently a hydrogen atom, a halogen atom, an alkyl group, an aryl group, an alkoxy group, an alkoxyalkoxy group, an aryloxy group, an alkanoyloxy Group, arylcarbonyloxy group, carboxyl group, alkoxycarbonyl group, aryloxycarbonyl group, amino group,
Represents an alkylamino group, an alkanoylamino group, an arylcarbonylamino group, an ethylenedioxymethyl group, a formyl group, a cyano group, a nitro group or a trihalomethyl group, and Y represents a halogen atom, an alkylsulfonyloxy group or an arylsulfonyloxy group . And a compound represented by the general formula:

[0020]

Embedded image (Wherein, R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the same meanings as described above) and a method for producing a naphthylmethylthiazolidinedione derivative represented by the formula:

[0021]

In the present invention, 6-hydroxy-2-naphthaldehyde represented by the formula (I) is subjected to a reaction with 2,4-thiazolidinedione without protecting the hydroxyl group. For example, 6-hydroxy-2-naphthaldehyde represented by (I) and 2,4-thiazolidinedione are subjected to a dehydration-condensation reaction, preferably in the presence of a base, to give 5-(-) represented by the formula (II). 6-hydroxy-2
-Naphthyl) methylene-2,4-thiazolidinedione. Bases such as triethylamine, pyridine,
Piperidine, pyrrolidine, N-methylpyrrolidine, N-
Amines such as methylmorpholine, or sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,
Inorganic bases such as sodium acetate and potassium acetate are used, and among them, piperidine and pyrrolidine are particularly preferable. As a solvent, an alcohol solvent such as methanol, ethanol, 1-propanol, 2-propanol, or 2-methoxyethanol, or DMSO, DMF, or the like is used, and the reaction is sometimes performed in a mixed solvent thereof. Performed, among others 2-methoxyethanol,
2-propanol, DMF, DMSO are particularly preferred.
The amount of 2,4-thiazolidinedione used is 0.8 to 10 moles compared to Compound (I), preferably 1.
It is 0 to 2.0 times mol. Reaction temperature is 20-150 ° C
And preferably 50 to 120 ° C. The reaction time varies depending on the reaction conditions, but is usually 1 hour or more, preferably 1 to 10 hours.

Next, the compound (II) is reduced to produce 5- (6-hydroxy-2-naphthyl) methyl-2,4-thiazolidinedione represented by the formula (III). The reaction is carried out, for example, in a hydrogen atmosphere or in the presence of cyclohexene. When the reaction is carried out in a hydrogen atmosphere, the pressure is from a normal pressure to a pressure of 200 kg / cm ² , preferably from ^{2 to} 80 kg / cm ² . It is performed under pressure. As the catalyst, a transition metal catalyst such as palladium hydroxide, palladium carbon, palladium black, platinum oxide, platinum-carbon, and rhodium is used. The amount of use is 0.1 to compound (II).
The molar amount is from 01 to 1 times, preferably from 0.1 to 0.3 times. As the reaction solvent, methanol, ethanol, 1-
Alcohol solvents such as propanol, 2-propanol and 2-methoxyethanol, ether solvents such as dioxane, dimethoxymethane and THF, and solvents such as ethyl acetate, acetic acid, dimethylformamide and N-methylpyrrolidone are used. The reaction is usually carried out at a temperature of 0 to 150 ° C,
Preferably it is 50-100 degreeC.

Next, the compound (III) and a compound of the general formula

[0024]

Embedded image (Wherein, Y and R ^{1 to} R ⁵ have the same meanings as described above).

[0025]

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(Wherein R ^{1 to} R ⁵ have the same meanings as described above). In this reaction, the compound represented by the general formula (V) is used in a molar amount of 0.8 to 3 times, preferably 1.0 to 1.5 times the molar amount of the compound (III). The reaction is preferably performed in the presence of a base. As such a base, sodium hydride, potassium hydride, sodium carbonate, potassium carbonate and the like are used, and preferably, sodium hydride and potassium hydride are used. The amount thereof is 0.5 to 5 moles, preferably 1.0 to 3.0 moles, relative to Compound (III). Solvents include THF, dioxane, diethyl ether, DM
F, DMSO, N-methylpyrrolidone and the like are used, and the reaction is sometimes carried out in a mixed solvent thereof. Among them, DMF, DMSO and N-methylpyrrolidone are preferable.
The reaction temperature is in the range of 0 to 100 ° C, preferably 10 to 40 ° C, and the reaction time varies depending on the reaction conditions, but is usually 1 hour or more, preferably 3 to 10 hours.

The starting material, 6-hydroxy-2
-Naphthaldehyde can be obtained by a known method, for example, by dealkylating an arylalkyl ether as described in Jikken Kagaku Koza, Vol. 20, pp. 237-247. Further, as the halogen atom in the above definition, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like, and as the alkyl group, a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-hexyl group, an n- A C ₁ -C ₈ alkyl group such as an octyl group; and a C ₆ -C ₁₂ alkyl group such as a phenyl group or a naphthyl group as an aryl group.
Aryl group, the alkoxy group include a methoxy group, an ethoxy group, n- propoxy group, i- propoxy group, n- hexyloxy group, C ₁ such as n- octyloxy group -C ₈
Alkoxy group, alkoxyalkoxy The group methoxymethoxy group, methoxyethoxy group, ethoxyethoxy group, are C ₂ -C ₆ alkoxyalkoxy group such as a methoxy pentyl group, a phenoxy group as the aryloxy group, such as a naphthyloxy group A C ₆ -C ₁₂ aryloxy group having an alkanoyloxy group as an acetoxy group;
C ₂ -C such as valeryloxy group, hexanoyloxy group, etc.
₉ alkanoyloxy group, benzoyloxy group as an arylcarbonyloxy group, the C ₇ -C ₁₃ arylcarbonyloxy group such as a naphthyl carbonyl group,
The alkoxycarbonyl group is a C ₂ -C ₉ alkoxycarbonyl group such as a methoxycarbonyl group, an ethoxycarbonyl group, a butoxycarbonyl group, an octylcarbonyl group, and the aryloxycarbonyl group is a C ₂ -C ₉ alkoxycarbonyl group such as a phenyloxycarbonyl group or a naphthyloxycarbonyl group. ₇ -C ₁₃ aryloxycarbonyl group, an alkylamino as the group methylamino group, an ethylamino group, pentylamino group, dimethylamino group, the C ₁ -C ₈ alkylamino group such as a dibutylamino group, as alkanoylamino groups acetylamino group, valerylamino group, C ₂ -C ₉ alkanoylamino groups such hexanoylamino groups, C ₇ -C ₁₃ arylcarbonyl amino benzoylamino group, naphthyl carbonyl amino group such as arylcarbonylamino group Group is a trifluoromethyl group, a trichloromethyl group, or the like as a trihalomethyl group; a methylsulfonyloxy group, an ethylsulfonyloxy group, an n-propylsulfonyloxy group, a t-butylsulfonyloxy group, or the like as an alkylsulfonyloxy group. C
_{A 1-} C ₆ alkylsulfonyloxy group, a phenylsulfonyloxy group as an arylsulfonyloxy group,
C ₆ -C ₁₂ arylsulfonyloxy groups such as tolylsulfonyloxy group and naphthylsulfonyloxy are preferred.

[0028]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, which should not be construed as limiting the scope of the invention. Example 1 Method for producing compound (II) from compound (I) Toluene (250 mL) was added to aluminum powder (10.9 g, 403 mmol), and the suspension was stirred vigorously to raise the reaction temperature to 30 to 40 ° C. With control, iodine (153 g, 604 mmol) was added slowly. Thereafter, the mixture was stirred at a reaction temperature of 30 to 40 ° C for 2 hours.
Thereafter, 6-methoxy-2-naphthaldehyde (purchased from Tokyo Chemical Industry Co., Ltd.) (25.0 g, 134 mmo)
l) A toluene solution (125 mL) of
The solution was gradually added dropwise while maintaining the temperature. Then 30 ~
After stirring at 40 ° C. for 6 hours, a 3N aqueous hydrochloric acid solution (175 mL) was added to the reaction solution under ice cooling, and the mixture was stirred vigorously. The reaction solution was extracted with ethyl acetate (700 mL), and the obtained organic layer was washed with a saturated aqueous solution of sodium bisulfite (200 mL).
L), saturated aqueous sodium hydrogen carbonate solution (200 mL),
After washing with a saturated saline solution (200 mL), it was dried over magnesium sulfate. After filtration of the magnesium sulfate, the organic layer was concentrated under reduced pressure. When about 80% of the organic solvent was distilled off, concentration under reduced pressure was stopped. The obtained residue was filtered and dried under reduced pressure to obtain 6-hydroxy-2-naphthaldehyde (compound (I)) (15.7 g, yield 68%).

6-Hydroxy-2-naphthaldehyde (1.0 g, 5.81 mmol) thus obtained was dissolved in methoxyethanol (5 mL), and 2,4-thiazolidinedione (1.02 g, 8.71 mmol) was added thereto. ,
Piperidine (0.17 mL, 1.74 mmol) was added, and the mixture was stirred at 95 ° C. for 5.5 hours. After cooling the reaction solution to room temperature, a 33% aqueous acetic acid solution (16 mL) was added.
The precipitated solid was filtered, washed with methanol (10 mL), dried at 25 ° C. under reduced pressure, and then dried with 5- (6-hydroxy-2-naphthyl) methylene-2,4-thiazolidinedione (compound (II) )) (1.42 g, 90% yield).

NMR (DMSO d-6) δ 7.1-7.2 (m, 2H), 7.54 (dd, 1
H, J = 1.7, 8.8 Hz), 7.79 (d, 1H,
J = 8.8 Hz), 7.8-8.0 (m, 2H), 8.
03 (s, 1H), 10.2 (s, 1H), 12.6
(S, 1H) IR (KBr) 3396, 3140, 1730, 1587, 1325,
1186,1020,866cm ^-1 Melting point> 200 ° C (decomposition)

Example 2 Method for producing compound (III) from compound (II) a) In an autoclave, 5- (6-hydroxy-2-naphthyl) methylene-2,4-thiazolidinedione (200 mg) obtained above was obtained. , 0.74 mmol) in ethyl acetate (6 mL), palladium hydroxide (20% on carbon) (200 mg) was added, and the mixture was stirred at 100 ° C. for 5 hours under a hydrogen atmosphere pressurized to 6.0 kg / cm ^2. did. After cooling to room temperature and filtering the palladium catalyst, the filtrate was concentrated under reduced pressure to obtain a crude product. Ethyl acetate (1.6m
L) to make a homogeneous solution, and then heptane (2 m
L) was added to precipitate crystals, which were washed under reflux with heating. After cooling to room temperature, the mixture was filtered under reduced pressure to give 5- (6
-Hydroxy-2-naphthyl) methyl-2,4-thiazolidinedione (163 mg, yield 81%) was obtained.

NMR (DMSO d-6) δ 3.20 (dd, 1H, J = 9.3, 14.3H)
z), 3.48 (dd, 1H, J = 4.3, 14.0H
z), 4.97 (dd, 1H, J = 4.3, 9.3H
z), 7.06 (d, 1H, J = 8.4 Hz), 7.0
8 (s, 1H), 7.27 (d, 1H, J = 8.5H)
z), 7.60 (s, 1H), 7.62 (d, 1H, J
= 9.0 Hz), 7.69 (d, 1H, J = 9.0H)
z), 9.71 (s, 1H), 12.0 (s, 1H) IR (KBr) 3418, 3155, 3055, 1925, 1747,
1631,1392,1329,1207,866cm
^-1 melting point 231-233 ° C

B) In an autoclave, 5
-(6-hydroxy-2-naphthyl) methylene-2,4
Thiazolidinedione (400 mg, 1.48 mmol
l) was dissolved in ethyl acetate (12 mL), palladium hydroxide (water content: 50%, 20% carbon supported) (81 mg) was added, and the mixture was added under a hydrogen atmosphere pressurized to 50 kg / cm ^2.
Stirred at 0 ° C. for 6 hours. Cool to room temperature, THF
(4 mL) was added, and after filtering the palladium catalyst, the filtrate was concentrated under reduced pressure to obtain a crude product. Purification in the same manner as in b) gave 5- (6-hydroxy-2-naphthyl) methyl-2,4-thiazolidinedione (386 mg, yield 9).
6%).

C) In an autoclave, the 5 obtained above
-(6-hydroxy-2-naphthyl) methylene-2,4
-Thiazolidinedione (150 g, 0.56 mmol)
Was dissolved in ethyl acetate (4.5 L), palladium hydroxide (water content 50%, 20% carbon supported) (61 g) was added, and
Under a hydrogen atmosphere pressurized to 72-74 kg / cm ² ,
Stirred at 0 ° C. for 9 hours. Cool to room temperature, THF
(1.5 L) was added, and after filtering the palladium catalyst, the filtrate was concentrated under reduced pressure to obtain a crude product. Purification in the same manner as in b) gave 5- (6-hydroxy-2-naphthyl) methyl-2,4-thiazolidinedione (128 g, yield 8).
5%).

Example 3 Method for producing compound (VI) from compound (III) a) Sodium hydride (content: 60%, 1.74 g, 4
5.7 mmol) and DMF (206 mL).
Under ice-cooling, 5- (6-hydroxy-2-naphthyl) methyl-2,4 obtained above dissolved in DMF (44 mL).
Thiazolidinedione (5.00 g, 18.3 mmol
l) was added and the mixture was stirred at 10 to 15 ° C for 1.5 hours. Then, 2-fluoro-benzyl chloride (2.6)
mL, 22.2 mmol), and the mixture was stirred at 10 to 15 ° C for 1.5 hours and further at 20 to 25 ° C for 4 hours. A saturated aqueous ammonium chloride solution (3.3 mL) was added to terminate the reaction, heptane (64 mL) was added, and the oily substance was washed and separated, and the DMF layer was added to a saturated aqueous ammonium chloride solution (760 ml). The precipitated solid is filtered off,
The residue was dissolved in ethyl acetate (100 mL), the organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to obtain an oily crude product. The crude product was dissolved in ethyl acetate (20 mL), and heptane (40 mL) was added to precipitate crystals. Further recrystallization from toluene (24 mL) gave 5-
[6- {2-fluorobenzyloxy} -2-naphthyl] -methyl-2,4-thiazolidinedione (4.30
g, yield 62%).

NMR (DMSO d-6) δ 3.23 (dd, 1H, J = 9.5, 14.0H)
z), 3.51 (dd, 1H, J = 4.3, 14.0H
z), 4.99 (dd, 1H, J = 4.3, 9.5H
z) 5.24 (s, 2H), 7.20-7.30
(M, 4H), 7.38 (t, 1H, J = 8.8H)
z), 7.45 (s, 1H), 7.61 (t, 1H, J
= 7.5 Hz), 7.70 (s, 1H), 7.76
(D, 1H, J = 5.8 Hz), 7.79 (d, 1H,
J = 6.0 Hz), 12.03 (s, 1H) IR (KBr) 3254, 3055, 1759, 1674, 1607,
1493,1393,1325,1269,1231c
m ^-1 melting point 150-151 ° C

B) sodium hydride (content about 60%,
5.47 obtained above in DMF (44 mL) in a suspension solution of 7.47 g) DMF (500 mL)
-(6-hydroxy-2-naphthyl) methyl-2,4-
Thiazolidinedione (25.00 g, 88.3 mmol
1) was added and stirred at about 25 ° C. for 2.5 hours. Thereafter, the mixture was cooled to 15 ° C., and 2-fluoro-benzyl chloride (12.6 mL, 106.0 mmol) was added.
Stirred at 5 ° C. for 6 hours. A saturated ammonium chloride aqueous solution (16.5 mL) was added to terminate the reaction, heptane (320 mL) was added, and the oil was washed and separated, and the DMF layer was added to a saturated ammonium chloride aqueous solution (2.3 L).
The precipitated solid was separated by filtration, dissolved in ethyl acetate (100 mL), and the organic layer was washed with water and concentrated under reduced pressure to obtain an oily crude product. Dissolve the crude product in ethyl acetate (100 mL)
Heptane (200 mL) was added to precipitate crystals. Further, the product was recrystallized from toluene (110 mL) to give 5- [6- {2-fluorobenzyloxy} -2-naphthyl] -methyl-2,4-thiazolidinedione (20.
(0 g, 59% yield).

C) Under ice-cooling, sodium hydride was added to a DMF solution (6 mL) of 5- (6-hydroxy-2-naphthyl) methyl-2,4-thiazolidinedione (157 mg, 0.57 mmol) obtained above. (Content 60%, 48m
g, 12 mmol).
After stirring for 5 hours, 2,4,6-trifluoro-benzyl bromide (149 mg, 0.66 mmol) was added,
Stir at 20-25 ° C for 3 hours. The reaction solution was neutralized by adding dilute hydrochloric acid, and extracted with ethyl acetate (30 mL). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, dried over magnesium sulfate, and concentrated under reduced pressure to concentrate the crude product. Obtained. This was purified by column chromatography (ethyl acetate / heptane = 30%) and (by recrystallization) 5- [6- {2,4,6-trifluorobenzyloxy} -2-naphthyl] -methyl-2. , 4
-Thiazolidinedione (97 mg, yield 39%) was obtained.

NMR (DMSO d-6) δ 3.25 (dd, 1H, J = 9.0, 13.9H)
z), 3.53 (dd, 1H, J = 4.1, 13.9H
z), 4.99 (dd, 1H, J = 4.1, 9.0H
z) 5.19 (s, 2H), 7.16-7.48
(M, 5H), 7.70 to 7.81 (m, 3H), 1
2.03 (s, 1H) IR (KBr) 3425, 3252, 1687, 1666, 1331,
1263, 1122, 927, 844, 771 cm ^-1 melting point 166-167 ° C

D) In the same manner as in b), 5- (6-hydroxy-2-naphthyl) methyl-2,4-thiazolidinedione (432 mg, 1.58 mmol) and 2,6-
Difluorobenzyl bromide (360 mg, 1.74 m
mol) to give 5- [6- {2,6-difluorobenzyloxy} -2-naphthyl] -methyl-2,4-thiazolidinedione (366 mg, yield 58%).

NMR (DMSO d-6) δ 3.24 (dd, 1H, J = 9.3, 14.1H)
z), 3.52 (dd, 1H, J = 4.2, 14.1H
z), 4.98 (dd, 1H, J = 4.2, 9.0H
z), 5.22 (s, 2H), 7.17 (dd, 1H,
J = 3.6, 9.3 Hz), 7.20 (d, 1H, J =
8.1 Hz), 7.38 (d, 1H, J = 8.4H)
z), 7.4-7.6 (m, 2H), 7.69 (s, 1
H), 7.78 (m, 2H), 12.03 (brs, 1
H) IR (KBr) 3177, 3056, 2359, 1705, 1471,
1233,1057,926cm ^-1 melting point 160-161 ° C

E) 5- (6-Hydroxy-2-naphthyl) methyl-2,4-thiazolidinedione (306 mg, 1.12 mmol) and 2,6-
Dichlorobenzyl bromide (540 mg, 2.24 mm
ol) to give 5- [6- {2,6-dichlorolobenzyloxy} -2-naphthyl] -methyl-2,4-thiazolidinedione (102 mg, 21% yield).

NMR (DMSO d-6) δ 3.25 (dd, 1H, J = 9.3, 14.1H)
z), 3.53 (dd, 1H, J = 4.2, 14.1H
z), 4.99 (dd, 1H, J = 4.2, 9.3H
z), 5.34 (s, 2H), 7.18 (dd, 1H,
J = 2.4, 9.0 Hz), 7.39 (dd, 1H, J
= 1.5, 8.4 Hz), 7.4 to 7.6 (m, 4
H), 7.69 (s, 1H), 7.79 (d, 2H, J
= 9.0 Hz), 12.03 (brs, 1H) IR (KBr) 3277, 3057, 2359, 1682, 1437,
1225, 1163, 1013 cm ^-1 melting point 165-168 ° C

F) In the same manner as in b), 5- (6-hydroxy-2-naphthyl) methyl-2,4-thiazolidinedione (342 mg, 1.25 mmol) and 2,4-
Dichlorobenzyl chloride (732 mg, 3.75 mm
ol) to give 5- [6- {2,4-dichlorolobenzyloxy} -2-naphthyl] -methyl-2,4-thiazolidinedione (195 mg, 36% yield).

NMR (DMSO d-6) δ 3.23 (dd, 1H, J = 9.6, 14.4H)
z), 3.52 (dd, 1H, J = 4.2, 14.4H
z), 4.98 (dd, 1H, J = 4.2, 9.3H
z), 5.25 (s, 2H), 7.25 (d, 1H, J
= 8.9 Hz), 7.3 to 7.4 (m, 2H), 7.5
0 (dd, 2H, J = 1.9, 8.4 Hz), 7.58
(D, 1H, J = 1.7 Hz), 7.6 to 7.7 (m,
2H), 7.80 (t, 2H, J = 7.5 Hz), 1
2.10 (brs, 1H) IR (KBr) 3364, 3055, 1701, 1606, 1244
1041,752cm ^-1 147-149 ° C

[0046]

According to the present invention, the number of steps is smaller than that of a known method, and Meerwein, which is industrially difficult to carry out, is used.
The compound represented by the general formula (VI) can be produced without using Arylation or a low-temperature reaction, and an industrially excellent production method can be provided.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Tetsuo Sekiya 1000 Kamoshita-cho, Aoba-ku, Yokohama-shi, Kanagawa Pref.

Claims (4)

[Claims] 1. A method according to claim 1, wherein 6-hydroxy-2-naphthaldehyde and 2,4-thiazolidinedione are reacted with 6-hydroxy-naphthaldehyde.
The reaction is carried out without protecting the hydroxyl group of 2-naphthaldehyde to give 5- (6-hydroxy-2-naphthyl) methylene-2,
4-thiazolidinedione was obtained and reduced to give 5- (6
-Hydroxy-2-naphthyl) methyl-2,4-thiazolidinedione. 2. A 6-hydroxy-2-naphthaldehyde and 2,4-thiazolidinedione are subjected to a dehydration condensation reaction in the presence of a base to give 5- (6-hydroxy-2-naphthyl) methylene-2,4-. The method according to claim 1, wherein thiazolidinedione is obtained. 3. A method of converting 6-hydroxy-2-naphthaldehyde and 2,4-thiazolidinedione into 6-hydroxy-naphthaldehyde.
The reaction is carried out without protecting the hydroxyl group of 2-naphthaldehyde to give 5- (6-hydroxy-2-naphthyl) methylene-2,
4-thiazolidinedione was obtained and reduced to give 5- (6
-Hydroxy-2-naphthyl) methyl-2,4-thiazolidinedione, which was then added to the following formula (V): (Wherein Y represents a halogen atom, an alkylsulfonyloxy group or an arylsulfonyloxy group, and R ¹ ,
R ² , R ³ , R ⁴ and R ⁵ each independently represent a hydrogen atom, a halogen atom, an alkyl group, an aryl group, an alkoxy group, an alkoxyalkoxy group, an aryloxy group, an alkanoyloxy group, an arylcarbonyloxy group, a carboxyl group , An alkoxycarbonyl group, an aryloxycarbonyl group, an amino group, an alkylamino group, an alkanoylamino group, an arylcarbonylamino group, an ethylenedioxymethyl group, a formyl group, a cyano group, a nitro group or a trihalomethyl group. Wherein the compound represented by the following formula (VI) is reacted with the compound represented by the formula (VI):
A method for producing-(6-substituted benzyloxy-2-naphthyl) methyl-2,4-thiazolidinedione. Embedded image (Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above) 4. The method according to claim 3, wherein in the formula (V), Y represents a halogen atom, R ¹ represents a fluorine atom, and R ² , R ³ , R ⁴ and R ⁵ represent a hydrogen atom. Method.