JPH0892214A - Production of new hydroquinone and benzoquinone derivative - Google Patents

Abstract

PURPOSE: To obtain a new hydroquinone and benzoquinone each useful as an intermediate for benzothiazole derivatives useful for preventing and treating diseases effective for the inhibition of leukotriene and thromboxane production. CONSTITUTION: The objective compounds are a hydroquinone derivative (a salt thereof) of formula I (R<1> is H, methyl or methoxyl; R<2> and R<3> are each H or methyl; R<4> is H or a lower alkyl; X is H, a lower alkyl, lower alkoxyl or halogen) or halogen) and a 1, 4-benzoquinone derivative (a salt thereof) of formula II [e.g. 3, 5-dimethyl-2-(hydroxy--3-pyridylmethyl)benzene-1, 4-diol of formula III and 3, 5-dimethyl-2-(hydroxy-3-pyridylmethyl)-1, 4--benzoquinone hydrochloride of formula IV, respectively]. The compound of formula I is obtained by condensation reaction between a hydroquinone derivative of formula V and an aldehyde derivative of formula VI or VII (R' is an alkyl) in the presence of an acid, and the compound of formula II is obtained by oxidation of the compound of formula I.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention is disclosed in JP-A-5-178855.
The present invention relates to a method for producing an important synthetic intermediate of a benzothiazole derivative which is useful for the prevention and treatment of diseases for which leukotriene and thromboxane production inhibitory effects are disclosed.

[0002]

2. Description of the Related Art A compound similar to the pyridinylmethyl-1,4-benzoquinone derivative represented by the general formula (IV) (V
The manufacturing method of I) is shown in Japanese Patent Application No. 4-64545. As shown in the following reaction formula (R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom, a lower alkyl group or a lower alkoxy group, and R ⁷ is a lower alkyl group), a dimethoxybenzene derivative is used as a starting material. In this method, a pyridylmethanol group is introduced and oxidized with ceric ammonium nitrate.

[0003]

[Chemical 13]

[0004]

The 2,5-dimethoxybenzene derivative used as a starting material in the conventional production method is a reagent (n-BuLi) used for introducing a pyridylmethanol group in the next reaction. It is necessary to protect the hydroxyl group from the above characteristic, and for that purpose, it is obtained by methylating a hydroquinone derivative (R ⁵ and R ⁶ have the above meanings) as shown in the following reaction formula. Considering that the methyl group (protecting group) is oxidized and demethylated in the oxidation step for producing the desired 1,4-benzoquinone after introducing the pyridylmethanol group, this methylation is a completely useless step. And is industrially disadvantageous. Further, in the oxidation reaction, the methoxy form (protective group of hydroxyl group) resists the reaction more than the hydroxy form, which imposes restrictions on the conditions of oxidation. In this respect also, the methoxy form (protective group of hydroxyl group) is disadvantageous. Is. Therefore, it has been desired to establish an industrial production method of introducing a pyridylmethanol group without protecting the hydroxyl group of the hydroquinone derivative and a subsequent inexpensive oxidation condition.

[0005]

Embedded image

Means for Solving the Problems The inventors of the present invention have conducted extensive studies on a production method of introducing a pyridylmethyl group without protecting the hydroxyl group of the hydroquinone derivative represented by the general formula (I). As a result, the hydroquinone derivative represented by the general formula (I) was treated without protecting its hydroxyl group,
A process for producing a pyridylmethylhydroquinone derivative represented by the general formula (III) by treating with a pyridyl aldehyde represented by the general formula (II) or an alkyl acetal derivative represented by the general formula (II ') in the presence of an acid was found. It was Then, a method for producing the pyridylmethyl-1,4-benzoquinone derivative (IV) under the conditions of inexpensive oxidation was established, and the present invention was completed.

The present invention will be described in detail below.

(1) Step of introducing a pyridylmethyl group

[Chemical 15] In the formula, R ¹ represents a hydrogen atom, a methyl group or a methoxy group,
R ² and R ³ are the same or different and each is a hydrogen atom or a methyl group, R ⁴ is a hydrogen atom or a lower alkyl group,
R'represents a lower alkyl group and X represents a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom.
This step comprises hydroquinone derivative (I) and pyridylaldehyde derivative (II) or its acetal derivative (I
I ′) is condensed in the presence of an acid to produce a pyridylmethyl derivative (I
This is the step of obtaining II). Examples of the acid include hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid and the like. Examples of the reaction solvent include water, methanol, ethanol, propanol, isopropanol, methylene chloride, 1,2-dichloroethane, benzene, toluene and the like. The reaction temperature is in the range of -10 ° C to 100 ° C, preferably 10 ° C to 30 ° C. Further, an acetal derivative (I obtained from a pyridyl aldehyde derivative (II) and a lower alkyl alcohol (I
In the condensation with I ′), the pyridylalkoxymethyl-1,4-hydroquinone derivative (III) can be obtained by directly adding the hydroquinone derivative (I) to the reaction solution without isolating the acetal to be produced. Is. The hydroquinone derivative of the raw material compound (I) is a product of Journal of American Chemicals.
Society (J. Am. Chem. Soc.) 194
4 years, 66, 1330, or Bulletin of the Chemical Society of Japan (Bull. Chem. Soc. Jpn.) 1992.
1, 65 obtained by the method described on page 1,522
By reducing the 4-benzoquinone derivative with sodium mild hydrosulfite, sodium acid sulfite, sodium borohydride, which are mild reducing agents, by a method known per se or in the presence of platinum oxide, palladium-carbon. Easily obtained.

(2) Step of oxidation of hydroquinone to benzoquinone

[0009]

[Chemical 16] In the formula, R ¹ represents a hydrogen atom, a methyl group or a methoxy group,
R ² and R ³ are the same or different and each is a hydrogen atom or a methyl group; R ⁴ is a hydrogen atom or a lower alkyl group;
Means a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom. This step is a step of oxidizing the hydroquinone derivative (III) to the 1,4-benzoquinone derivative (IV). As the oxidant, any mild oxidant can be used, and examples thereof include air, oxygen, and Fremy's salt (Fr
emy'salt), ferric chloride, ferric sulfate, hydrogen peroxide, peracid, silver oxide, ceric ammonium nitrate,
Nitric acid etc. can be mentioned. These reactions are usually carried out in the presence of a solvent, and examples of the solvent include methanol, acetonitrile, tetrahydrofuran, dioxane, ethyl acetate, 1,2-dimethoxyethane, acetic acid and a water-containing solvent or water containing these organic solvents and water. Is mentioned. The reaction temperature is -10 ° C to 100 ° C, preferably -10 ° C to 30 ° C, and the reaction time is 1 minute to 3 days.

In the above general formulas (III) and (IV), the lower alkyl group in the definition of R ⁴ and X is a linear or branched alkyl group having 1 to 4 carbon atoms, such as a methyl group or an ethyl group. , N-propyl group, isopropyl group,
It means an n-butyl group, an isobutyl group, an s-butyl group and the like. Of these, preferred groups include a methyl group, an ethyl group, an n-propyl group, an isopropyl group and the like. The lower alkoxy group in the definition of X includes a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group and the like, and the halogen atom includes a fluorine atom, a chlorine atom and a bromine atom. .

As described above, the present invention is a very advantageous method in industrial production. That is, it is possible to directly introduce the pyridylmethyl group without protecting the hydroxyl group of the hydroquinone derivative with a protective group such as a methyl group. As a result, oxidation to benzoquinone becomes possible under mild conditions, and inexpensive oxidation conditions can be selected.

The quinone compound (IV) produced by the present invention
JP-A-5-178855 or Japanese Patent Application No. 5-202
Thiourea H ₂ N using the reaction disclosed in No. 552
^{-C (= S) -NR 15 R} 16 (R 15 and R ¹⁶ are identical or different hydrogen atom, means a lower alkyl group or a pyridyl group) was reacted 2-amino-6-hydroxy-4- A (pyridyl-hydroxy or alkoxy-methyl) benzothiazole derivative (VII) is obtained.

[0013]

[Chemical 17]

When this is heated in acetic acid, R ⁴ O is reductively eliminated to give a 2-amino-6-hydroxy-4-pyridylmethylbenzothiazole derivative. This compound can be obtained by the method described in JP-A-5-178855, especially in Example 10.
As disclosed in, a disease in which the leukotriene and thromboxane production inhibitory action by the 5-lipoxygenase inhibitory action and the thromboxane production inhibitory action is effective,
It is especially effective in the prevention and treatment of ulcerative colitis.

【Example】

Examples of the present invention will be given below, but it goes without saying that the present invention is not limited to these examples.

Example 1 3,5-Dimethyl-2- (hydroxy-3-pyridylme
Chill) benzene-1,4-diol

[0017]

[Chemical 18]

Under ice cooling, 14 ml (0.15 mol) of 3-pyridinecarboxaldehyde was added dropwise to 250 ml of 6N hydrochloric acid, and then 2,6-dimethyl-p-hydroquinone 25 was added.
g (0.18 mol) was added, and the mixture was stirred at room temperature for 17 hours. 300 ml of water and 25 m of ethyl acetate were added to the reaction mixture.
Then, 111 g (1.32 mol) of sodium hydrogencarbonate was added little by little with vigorous stirring under ice cooling, and the mixture was stirred for 10 minutes, and the precipitated crystals were collected by filtration. This was sequentially purified with water, ethyl acetate and isopropyl ether and then dried to obtain 33.0 g (yield 91%) of the title compound. Melting point: 181-183 ° C. Elemental analysis value Calculated value as C ₁₄ H ₁₅ NO ₃ C, 68.56; H, 6.16; N, 5.71 Measured value C, 68.32; H, 6.19; N , 5.45 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ;
1.91 (3H, s), 2.07 (3H, s), 6.2
8 (1H, s), 6.45 (1H, s), 7.27 (1
H, dd, J = 4.0, 8.0 Hz), 7.57 (1
H, d, J = 8.0 Hz), 8.36 (1H, d, J =
4.0 Hz), 8.42 (1H, s). MS (FAB): m / z 246 (M + H) ⁺ .

Example 2 3,5-Dimethyl-2- (methoxy-3-pyridylmethyi)
Le) Benzene-1,4-diol hydrochloride

[0020]

[Chemical 19]

3-pyridinecarboxaldehyde 1.0
Hydrochloric acid gas was introduced into a methanol (15 ml) solution of ml (10.6 mmol) under ice cooling for 50 minutes. Next 2, 6
-Dimethyl-p-hydroquinone 1.6 g (11.6 mm
ol) was added and the mixture was stirred under ice-cooling for 1 hour, then methanol was distilled off under reduced pressure, water and ethyl acetate were added to the residue, and the mixture was neutralized with sodium hydrogen carbonate. The organic layer was separated and dried over magnesium sulfate. . After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 1) to give 1.8 g of the title compound in free form.
Got This was dissolved in 36 ml of water and ethyl acetate, 2.1 ml of 4N hydrogen chloride-ethyl acetate was added dropwise under ice cooling, and 1
After stirring for 0 minutes, the precipitated crystals were collected by filtration, washed successively with ethyl acetate and isopropyl ether, and dried to give the title compound (1.8 g, yield 58%). Mp: 177-178 Calculated C as ℃ Elemental analysis _{C 15 H 17 NO 3 · HCl} , 60.91; H, 6.13; N, 4.74 Found C, 60.54; H, 6.13 ^{; N, 4.73 1 H-NMR} (400MHz, DMSO-d 6) δ;
1.88 (3H, s), 2.09 (3H, s), 3.2
9 (3H, s), 6.14 (1H, s), 6.56 (1
H, s), 7.90 (1H, dd, J = 5.6, 8.0)
Hz), 8.14 (1H, d, J = 8.0 Hz), 8.
59 (1H, s), 8.75 (1H, d, J = 5.6H
z), 9.10 (1H, br s). MS (FAB): m / z 260 (M + H) ⁺ .

Example 3 3,5-Dimethyl-2- (hydroxy-4-pyridylme)
Chill) benzene-1,4-diol

[0023]

Embedded image

Under ice cooling, 1.0 ml (10.5 mmol) of 4-pyridinecarboxaldehyde was added dropwise to 8 ml of 6N hydrochloric acid, and then 2,6-dimethyl-p-hydroquinone.1.
59 g (11.5 mmol) was added, and the mixture was stirred at room temperature for 17 hours. 30 ml of water and 20 ml of ethyl acetate were added to the reaction mixture.
ml, and then with vigorous stirring under ice cooling, sodium hydrogen carbonate was added little by little to adjust the pH to 6.5,
The ethyl acetate layer was separated, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. 50 ml of ethyl acetate was added to the residue,
The mixture was stirred under ice-cooling for 1 hour, and the precipitated crystals were collected by filtration, washed with ethyl acetate and isopropyl ether successively, and dried to give the title compound (2.02 g, yield 79%). Mp: 158-159 Calculated C as ℃ Elemental analysis _{C 14 H 15 NO 3, 68.56} ; H, 6.16; N, 5.71 Found C, 68.52; H, 6.17; N , 5.66 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ;
1.88 (3H, s), 2.06 (3H, s), 5.9
8 (1H, br s), 6.25 (1H, s), 6.4
5 (1H, s), 7.20 (2H, d, J = 6.0H
z), 7.38 (1H, br s), 8.41 (1H,
d, J = 6.0 Hz). MS (FAB): m / z 246 (M + H) ⁺ .

Example 4 3,5-Dimethyl-2- (hydroxy-2-pyridylme
Chill) benzene-1,4-diol

[0026]

[Chemical 21]

Instead of 3-pyridinecarboxaldehyde, 1.0 ml of 2-pyridinecarboxaldehyde
(10.5 mmol) was used and treated in the same manner as in Example 1 to obtain the title compound (2.00 g, yield 78%). Melting point: 160-161 ° C. Elemental analysis value Calculated value as C ₁₄ H ₁₅ NO ₃ C, 68.56; H, 6.16; N, 5.71 Actual value C, 68.57; H, 6.14; N ^{, 5.72 1 H-NMR (400MHz} , DMSO-d 6) δ;
1.96 (3H, s), 2.04 (3H, s), 6.1
-6.2 (1H, brs), 6.13 (1H, s),
6.37 (1H, s), 7.19 (1H, dd, J =
4.8, 8.0 Hz), 7.35 (1H, br s),
7.48 (1H, d, J = 8.0 Hz), 7.73 (1
H, ddd, J = 1.8, 4.8, 8.0 Hz), 8.
41 (1H, dd, J = 1.8, 4.8Hz), 8.9
-9.0 (1H, brs). MS (FAB): m / z 245 (M) ⁺ .

Example 5 3,5-Dimethyl-2- (isopropyloxy-3-pi)
Lysylmethyl) benzene-1,4-diol hydrochloride

[0029]

[Chemical formula 22]

10 g of 3-pyridinecarboxaldehyde
(93.4 mmol) of isopropyl alcohol (10
Hydrochloric acid gas was introduced into the solution (0 ml) under ice cooling for 50 minutes, and then the solvent was distilled off under reduced pressure. Water and ethyl acetate were added to the residue and the mixture was neutralized with sodium hydrogen carbonate, and the ethyl acetate layer was separated. This was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: dichloromethane = 1: 3) to give 3-
3.44 g (yield 18%) of pyridinecarboxaldehyde diisopropyl acetal was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.1
8 (6H, d, J = 6.0Hz), 1.21 (6H,
d, J = 6.0 Hz), 3.93 (2H, qq, J =
6.0, 6.0 Hz), 5.60 (1 H, s), 7.2
9 (1H, dd, J = 4.8, 8.0 Hz), 7.81
(1H, d, J = 8.0 Hz), 8.57 (1H, d,
J = 4.8 Hz) 8.69 (1 H, s) 3-pyridinecarboxaldehyde diisopropyl acetal 3.40 g (16.2 mmol) of isopropyl alcohol (45 ml) in a solution of concentrated sulfuric acid 1.77 m.
1 was added dropwise, 3.07 g (22.2 mmol) of 2,6-dimethyl-p-hydroquinone was added thereto, and the mixture was added at room temperature to 17
Stir for hours. Distill off isopropyl alcohol under reduced pressure,
Water and ethyl acetate were added to the residue, the mixture was neutralized with sodium hydrogen carbonate, the organic layer was separated and dried over magnesium sulfate.
After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 2: 1), and 2.7 g of the free form of the title compound (yield 58
%) Was obtained. 1.0 g of this free form is converted to 15 m of ethyl acetate.
It was dissolved in 1 l and 4N hydrogen chloride-ethyl acetate 1.1 under ice cooling.
ml was added dropwise, and after stirring for 10 minutes, the precipitated crystal was collected by filtration, dissolved in 30 ml of acetonitrile by heating, and allowed to stand at room temperature for 3 hours, and the precipitated crystal was collected by filtration and dried to obtain 0.78 g of the title compound. Obtained. Melting point: 171-173 ° C. (decomposition) Elemental analysis value Calculated value as C ₁₇ H ₂₁ NO ₃ .HCl C, 63.06; H, 6.85; N, 4.33 Actual value C, 62.96; H, ^{6.74; N, 4.34 1 H-} NMR (400MHz, DMSO-d 6) δ;
1.09 (3H, d, J = 6.0Hz), 1.21 (3
H, d, J = 6.0 Hz), 1.85 (3H, s),
2.09 (3H, s), 3.62 (1H, qq, J =
6.0, 6.0 Hz), 6.36 (1H, s), 6.5
7 (1H, s), 7.93 (1H, dd, J = 5.6,
8.0 Hz), 8.15 (1H, d, J = 8.0H
z), 8.55 (1H, s), 8.77 (1H, d, J
= 5.6 Hz). MS (FAB): m / z 288 (M + H) ⁺ .

Example 6 2- (Hydroxy-3-pyridylmethyl) -5-methyl
Benzene-1,4-diol

[0032]

[Chemical formula 23]

Under ice-cooling, a solution of 3-pyridinecarboxaldehyde (1.0 ml, 11.8 ml) in tetrahydrofuran (3 ml) was added dropwise to 12 ml of 5N hydrochloric acid, and then 2
-Methyl-p-hydroquinone 1.46 g (11.8 m
1) was added, and the mixture was stirred at room temperature for 3 days. The mixture was neutralized with sodium hydrogen carbonate, extracted with ethyl acetate, washed with water and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: dichloromethane = 1: 1) to give the title compound 0.45 g (yield 18%).
Melting point: 175-176 ° C. (decomposition) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ;
1.98 (3H, s), 5.90 (1H, s), 6.4
5 (1H, s), 6.79 (1H, s), 6.84 (1
H, br s), 7.27 (1H, dd, J = 4.8,
8.0 Hz), 7.61 (1H, d, J = 8.0H
z), 8.35 (1H, d, J = 4.8Hz), 8.4
-8.5 (1H, brs), 8.50 (1H, s),
8.66 (1H, s). MS (FAB): m / z 232 (M + H) ⁺ .

Example 7 2- (Hydroxy-3-pyridylmethyl) benzene-
1,4-diol

[0035]

[Chemical formula 24]

Instead of 2,6-dimethyl-p-hydroquinone, 1.95 g (17.7 mmo) of p-hydroquinone
1, eq. ) In Example 1
Almost the same as the above [reacted at room temperature for 43 hours, and subjected to column chromatography (ethyl acetate: dichloromethane = 1: 1).
Purified in 1)], and the title compound as amorphous.
80 g (yield 35%) was obtained. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ;
5.75-5.85 (1H, br s), 5.91 (1
H, s), 6.42 (1H, dd, J = 2.8, 8.4
Hz), 6.55 (1H, d, J = 8.4 Hz), 6.
82 (1H, d, J = 2.8 Hz), 7.27 (1H,
dd, J = 4.8, 8.0 Hz), 7.64 (1H,
d, J = 8.0 Hz), 8.36 (1H, d, J = 4.
8 Hz), 8.51 (1 H, s), 8.6-8.7 (1
H, br s), 8.75-8.85 (1H, br
s). MS (FAB): m / z 218 (M + H) ⁺ .

Example 8 3,5-Dimethyl-2- (ethoxy-3-pyridylmethyi)
Le) Benzene-1,4-diol hydrochloride

[0038]

[Chemical 25]

3-Pyridinecarboxaldehyde 1.6
2.5 g (18.1 mmol) of 2,6-dimethyl-p-hydroquinone was added to 25 ml of 20% (w / w) hydrochloric acid-ethanol solution of ml (16.5 mmol), and the mixture was stirred at room temperature for 23 hours. After ethanol was distilled off under reduced pressure, water and ethyl acetate were added to the residue and neutralized with sodium hydrogen carbonate.
The organic layer was separated and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 1) to obtain 3.2 g of the free form of the title compound (yield 71%). 1.7 g of this was dissolved in 33 ml of ethyl acetate,
1.8 ml of 4N hydrogen chloride-ethyl acetate was added dropwise under ice cooling, and the mixture was stirred for 10 minutes. The precipitated crystals were collected by filtration, added with 60 ml of acetonitrile and heated under reflux for 10 minutes, then at room temperature for 1 hour.
After stirring for an hour, the precipitate was collected by filtration, washed successively with acetonitrile and isopropyl ether, and dried to give 1.1 g of the title compound. Melting point: 185-187 ° C. (decomposition) Elemental analysis value Calculated value as C ₁₆ H ₁₉ NO ₃ .HCl C, 62.03; H, 6.51; N, 4.52 Measured value C, 61.96; H, 6.59; N, 4.56 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ;
1.18 (3H, t, J = 6.8), 1.88 (3H,
s), 2.08 (3H, s), 3.47 (3H, m),
6.24 (1H, s), 6.56 (1H, s), 7.9
3 (1H, dd, J = 5.6, 8.0 Hz), 8.17
(1H, d, J = 8.0 Hz), 8.58 (1H,
s), 8.76 (1H, d, J = 5.6 Hz). MS (FAB): m / z 274 (M + H) ⁺ .

Example 9 3,5-Dimethyl-2- (hydroxy-6-methylpyrrole)
Dilmethyl) benzene-1,4-diol

[0041]

[Chemical formula 26]

Using 6-methyl-2-pyridinecarboxaldehyde in place of 3-pyridinecarboxaldehyde and treating in the same manner as in Example 1, the title compound was obtained in 88% yield. Mp: 176-178 ° C. (decomposition) Elemental analysis _{C 15 H 17 NO 3 · 0.36H} 2 O Calculated C, 67.78; H, 6.72; N, 5.27 Found C, 67. 77; H, 6.70; N, 5.22 1 H-NMR (400MHz, DMSO-d 6) δ;
2.00 (3H, s), 2.05 (3H, s), 2.4
5 (3H, s), 6.10 (1H, s), 6.2 (1
H, br s), 6.38 (1H, s), 7.18 (1
H, br s), 7.22 (1H, d, J = 8.0H
z), 7.41 (1H, s), 7.7 (1H, br
s). MS (FAB): m / z 259 (M + H) ⁺ .

Example 10 3,5-Dimethyl-2- (hydroxy-4-chloropyrpyrene)
Dilmethyl) benzene-1,4-diol

[0044]

[Chemical 27]

By using 6-chloro-2-pyridinecarboxaldehyde in place of 3-pyridinecarboxaldehyde and treating in the same manner as in Example 1, the title compound was obtained in a yield of 89%. Mp: 155-157 ° C. (decomposition) Elemental analysis C ₁₄ H ₁₄ NO ₃ Calculated C as Cl, 60.11; H, 5.04; N, 5.01 Found C, 59.94; H, 5 .16; N, 5.03 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ;
1.95 (3H, s), 2.04 (3H, s), 6.1
(2H, b), 6.36 (1H, s), 7.33 (1
H, dd, J = 2.0, 5.2 Hz), 7.37 (1
H, s), 7.61 (1H, d, J = 2.0 Hz),
8.36 (1H, d, J = 5.2 Hz). 8.75 (1H, s). MS (FAB): m / z 279 (M)
⁺ .

Example 11 2- (Hydroxy-3-pyridylmethyl) -3,5,6
-Trimethylbenzene-1,4-diol

[0047]

[Chemical 28]

2,3,5-Trimethyl-p-hydroquinone was used in place of 2,6-dimethyl-p-hydroquinone and treated in the same manner as in Example 1 to obtain the title compound in a yield of 86%. . Melting point: 206-207 ° C (decomposition) Elemental analysis value Calculated value as C ₁₅ H ₁₇ NO ₃ C, 69.48; H, 6.61; N, 5.40 Measured value C, 69.43; H, 6. ^{64; N, 5.35 1 H-} NMR (400MHz, DMSO-d 6) δ;
1.98 (3H, s), 2.02 (3H, s), 2.0
6 (3H, s), 6.18 (1H, s), 7.1 (1
H, s), 7.31 (1H, dd, J = 4.8, 8.0
Hz), 7.4 (1H, br s), 7.59 (1H,
d, J = 8.0 Hz), 8.41 (1H, d, J = 4.
8Hz), 8.46 (1H, s), 8.9 (1H, br
s). MS (FAB): m / z 260 (M + H) ⁺ .

Example 12 3,5-Dimethyl-2- (hydroxy-3-pyridylme)
Chill) -1,4-benzoquinone hydrochloride

[0050]

[Chemical 29]

3,5-dimethyl-2- (hydroxy-3)
-Pyridylmethyl) benzene-1,4-diol 30 g
(0.12 mol) was dissolved in a solution of water (60 ml) and tetrahydrofuran (60 ml), and 78 ml of concentrated nitric acid was added dropwise over 15 minutes while stirring under ice cooling. After 5 minutes, 450 ml of ethyl acetate and 60 ml of water were added, and then a solution of 64 g of sodium carbonate in water (250 ml) and sodium hydrogen carbonate 1
7.3g was added and neutralized. Next, the ethyl acetate layer was separated, washed with water and saturated brine, and dried over magnesium sulfate. After removing magnesium sulfate, 33.7 ml of 4N hydrogen chloride-ethyl acetate was added dropwise to this ethyl acetate solution under ice cooling, and the mixture was stirred for 15 minutes. The precipitated crystals were collected by filtration, washed with ethyl acetate and isopropyl ether and dried to give the title compound 3
0.4 g (yield 90%) was obtained. Melting point: 155-160 ° C. (decomposition) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ;
1.97 (3H, d, J = 1.6Hz), 1.98 (3
H, s), 6.14 (1H, s), 6.68 (1H,
d, J = 1.6 Hz), 7.95 (1H, dd, J =
5.6, 8.0 Hz, 8.40 (1H, d, J = 8.
0 Hz), 8.76 (1H, s), 8.77 (1H,
d, J = 5.6 Hz). MS (FAB): m / z244 (M + + H).

Example 13 3,5-Dimethyl-2- (methoxy-3-pyridylmethyi)
) -1,4-benzoquinone

[0053]

[Chemical 30]

3,5-dimethyl-2- (methoxy-3-)
Pyridylmethyl) benzene-1,4-diol hydrochloride (1.0 g, 3.38 mmol) was dissolved in water (3 ml) and tetrahydrofuran (2 ml), and ice-cooled concentrated nitric acid (3 ml) was added.
Was added dropwise over 5 minutes. After 5 minutes 15 ml of ethyl acetate and 2 of water
ml was added, and sodium carbonate and saturated aqueous sodium hydrogen carbonate solution were added to neutralize. The ethyl acetate layer was separated, water,
The extract was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.0 g, yield 100%) as an oil. ¹ H-NMR (400 MHz, CDCl ₃ ) δ; 2.0
7 (3H, d, J = 1.6Hz), 2.10 (3H,
s), 3.42 (3H, s), 5.90 (1H, s),
6.63 (1H, d, J = 1.6Hz), 7.26 (1
H, dd, J = 4.8, 8.0 Hz), 7.68 (1
H, d, J = 8.0 Hz), 8.50 (1H, d, J =
4.8 Hz), 8.56 (1 H, s).

Example 14 3,5-Dimethyl-2- (isopropyloxy-3-pi)
Lysylmethyl) -1,4-benzoquinone hydrochloride

[0056]

[Chemical 31]

2.3 g (8.01 mmol) of 3,5-dimethyl-2- (isopropyloxy-3-pyridylmethyl) benzene-1,4-diol was added to 34.5 of ethyl acetate.
Dissolve ml, and ferric chloride hexahydrate (FeCl ₃ · 6
H ₂ O) water 4.33g (16.03mmol) (10
ml) solution was added and vigorously stirred for 2 minutes. After the reaction was completed, under cooling with ice, 3.37 g (40.1 mmo) of sodium hydrogencarbonate was obtained.
l) was added, and Celite was pulled and filtered to remove insoluble matter.
Then, the filtrate was extracted with ethyl acetate, washed with water and saturated saline, and the ethyl acetate layer was dried over magnesium sulfate to remove magnesium sulfate, and then 4N hydrogen chloride-ethyl acetate (9.6 ml) was added to the ethyl acetate solution. The solvent was distilled off under reduced pressure to obtain 2.3 g (yield 89%) of the title compound. ¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.2
0 (3H, d, J = 6.0Hz), 1.24 (3H,
d, J = 6.0 Hz), 2.00 (3H, s), 2.0
9 (3H, d, J = 1.6Hz), 3.72 (1H, q
q, J = 6.0, 6.0 Hz), 6.21 (1H,
s), 6.67 (1H, d, J = 1.6Hz), 7.8
7 (1H, dd, J = 5.6, 8.0 Hz), 8.30
(1H, d, J = 8.0 Hz), 8.67 (1H, d,
J = 5.6 Hz), 8.77 (1H, s).

Example 15 3,5-Dimethyl-2- (hydroxy-3-pyridylme
Cyl) -1,4-benzoquinone hydrochloride 3,5-dimethyl-2- (hydroxy-3-pyridylmethyl) benzene-1,4-diol 0.5 g (2.04
mmol) 1.0 ml of water and methanol (3.0 ml)
Dissolved in a solution of cupric chloride dihydrate (CuCl ₂
2H ₂ O) 17 mg, and while blowing in air, 1
Stir for half an hour. 15 ml of ethyl acetate and 10 parts of water in the reaction solution
After adding ml, the pH was adjusted to 7 by adding saturated sodium hydrogen carbonate solution. The ethyl acetate layer was separated, washed with water and saturated brine, and dried over magnesium sulfate. After removing magnesium sulfate, 0.56 ml of 4N hydrogen chloride-ethyl acetate was added dropwise to this ethyl acetate solution under ice cooling, and the mixture was stirred for 15 minutes. The precipitated crystals were collected by filtration, washed with ethyl acetate and isopropyl ether and dried to give 0.46 g of the title compound (yield 8
1%) was obtained. The melting point and ¹ H-NMR spectrum were consistent with those of the compound of Example 12.

Application Example Next, an example of synthesizing a 2-amino-6-hydroxy-4-pyridylmethylbenzothiazole compound useful as a medicine from the quinone compound obtained in the present invention will be shown.

Application Example 1 5,7-Dimethyl-6-hydroxy-2-methylamino
-4-[(3-pyridyl) hydroxymethyl] benzothi
Azole

[0061]

[Chemical 32]

3,5-dimethyl-2- (hydroxy-3)
-Pyridylmethyl) -1,4-benzoquinone hydrochloride (Example 12) 30 g (0.11 mol) of ethanol 30
To the 0 ml suspension, 21.7 ml of concentrated hydrochloric acid and 9.68 g (0.11 mol) of methylthiourea were added under ice cooling, and
Stir for 15 h at 0 ° C. (reaction mixture once dissolved, then precipitate gradually increased). After adding 300 ml of ethyl acetate and stirring for 10 minutes, the precipitate was collected by filtration and washed with ethyl acetate and isopropyl ether to obtain a thiuronium salt. To this 300 ml suspension of ethanol, 2.9 g of 1,4-benzoquinone dissolved in 23.8 ml of tetrahydrofuran was added under ice cooling, and the mixture was kept at 4 ° C. for 4 hours and at 20 ° C. for 3 hours.
Stir for hours. Next, add 300 ml of ethyl acetate and add 10
After stirring for 1 minute, the precipitate was collected by filtration, washed with ethyl acetate and isopropyl ether, and dried to give the hydrochloride of the title compound 3
6.3 g was obtained. This was dissolved in 524 ml of water, washed with ethyl acetate and isopropyl ether, and dried in the presence of phosphorus pentoxide to give 26.9 g of the title compound (yield 80%).
Got Melting point: 201-203 ° C. (decomposition) H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.
03 (3H, s), 2.21 (3H, s), 2.88
(3H, d, J = 4.8Hz), 6.51 (1H, d,
J = 6.6 Hz), 6.55 (1H, d, J = 6.6H)
z), 7.27 (1H, dd, J = 4.8, 8.0H
z), 7.60 (1H, d, J = 8.0 Hz), 7.8
2 (1H, d, J = 4.8Hz), 7.97 (1H,
s), 8.35 (1H, d, J = 4.8Hz), 8.4
6 (1H, s). MS (FAB): m / z 316 (M + H) ⁺ . Application Example 2 5,7-Dimethyl-6-hydroxy-2-methylamino
-4-[(3-pyridyl) methyl] benzothiazole

[0063]

[Chemical 33]

5,7-Dimethyl-6-hydroxy-2-
To a solution of 5.0 g (15.9 mmol) of methylamino-4-[(3-pyridyl) hydroxymethyl] benzothiazole in 50 ml of acetic acid, 2.6 g (39.8 mmo) of zinc powder was added.
1) was added and the mixture was heated under reflux for 26 hours. After the insoluble matter was filtered off while hot, 200 ml of ethyl acetate was added, and the mixture was stirred under ice cooling for 10 minutes and the precipitate was collected by filtration. 100 ml of ethanol
Dissolve in, and under ice-cooling, 24 ml of 4N hydrochloric acid-ethyl acetate solution
Was added dropwise and the mixture was stirred for 30 minutes, then the precipitate was collected by filtration, washed with ethyl acetate and isopropyl ether, and dried to obtain 5.9 g of the hydrochloride of the title compound. This was dissolved in 100 ml of water, 75 ml of ethyl acetate was added, and saturated aqueous sodium hydrogencarbonate solution was added under ice cooling to neutralize, and the precipitate was collected by filtration. Further, the precipitate was suspended in 75 ml of ethanol, heated under reflux for 1 hour, stirred under ice-cooling for 15 minutes, then the crystals were collected by filtration, washed with ethanol and dried to give the title compound (2.9 g, yield 61%).
Got Melting point: 220-223 ° C. (decomposition) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
2.07 (3H, s), 2.20 (3H, s), 2.8
7 (3H, d, J = 4.8Hz), 4.25 (2H,
s), 7.20 (1H, dd, J = 4.8, 8.0H
z), 7.48 (1H, d, J = 8.0 Hz), 7.6
5 (1H, d, J = 4.8Hz), 7.90 (1H, b
r), 8.31 (1H, s), 8.46 (1H, s).

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Hiroshi Nishimura 1-3-4 Ota-shinta, Hasaki-cho, Kashima-gun, Ibaraki Prefecture (72) Inventor Yoji Yamagishi Kaminakichi, Chiyoda-cho, Shinji-gun, Ibaraki 2010-46

Claims (10)

[Claims] 1. A compound of the general formula (I) (Wherein R ¹ represents a hydrogen atom, a methyl group or a methoxy group, and R ² and R ³ are the same or different and represent a hydrogen atom or a methyl group) and a hydroquinone derivative represented by the general formula (II) or Formula (II ′) embedded image (Wherein, X represents a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom, and R ′ represents a lower alkyl group), and the aldehyde derivative is condensed in the presence of an acid. General formula (III): (In the formula, R ¹ is a hydrogen atom, a methyl group or a methoxy group, R ² and R ³ are the same or different and are a hydrogen atom or a methyl group, R ⁴ is a hydrogen atom or a lower alkyl group, X is a hydrogen atom, (Meaning a lower alkyl group, a lower alkoxy group or a halogen atom), and a method for producing a hydroquinone derivative or a salt thereof. 2. A compound represented by the general formula (III): (In the formula, R ¹ is a hydrogen atom, a methyl group or a methoxy group, R ² and R ³ are the same or different and are a hydrogen atom or a methyl group, R ⁴ is a hydrogen atom or a lower alkyl group, X is a hydrogen atom, A lower alkyl group, a lower alkoxy group or a halogen atom) is oxidized to oxidize a hydroquinone derivative represented by the general formula (IV): (In the formula, R ¹ is a hydrogen atom, a methyl group or a methoxy group, R ² and R ³ are the same or different and are a hydrogen atom or a methyl group, R ⁴ is a hydrogen atom or a lower alkyl group, X is a hydrogen atom, Which means a lower alkyl group, a lower alkoxy group or a halogen atom), and a method for producing a 1,4-benzoquinone derivative or a salt thereof. 3. A compound represented by the general formula (III): In the above, R ¹ and R ³ are the same or different and each represents a hydrogen atom or a methyl group, and R ² and X are hydrogen atoms, and the method for producing a hydroquinone derivative or a salt thereof according to claim 1. 4. A compound represented by the general formula (IV): Wherein R ¹ and R ³ are the same or different and each represents a hydrogen atom or a methyl group, and R ² and X are hydrogen atoms, and the method for producing a 1,4-benzoquinone derivative or a salt thereof according to claim 2. 5. A compound represented by the general formula (III): (In the formula, R ¹ is a hydrogen atom, a methyl group or a methoxy group, R ² and R ³ are the same or different and are a hydrogen atom or a methyl group, R ⁴ is a hydrogen atom or a lower alkyl group, X is a hydrogen atom, (Meaning a lower alkyl group, a lower alkoxy group or a halogen atom), and the hydroquinone derivative or a salt thereof according to claim 3. 6. A compound represented by the general formula (IV): (In the formula, R ¹ is a hydrogen atom, a methyl group or a methoxy group, R ² and R ³ are the same or different and are a hydrogen atom or a methyl group, R ⁴ is a hydrogen atom or a lower alkyl group, X is a hydrogen atom, (Meaning a lower alkyl group, a lower alkoxy group or a halogen atom), and the 1,4-benzoquinone derivative or a salt thereof according to claim 4. 7. A compound represented by the general formula (III): ^2. The hydroquinone derivative and salt thereof according to claim ¹ , wherein R ¹ and R ³ are methyl groups, and R ² and X are hydrogen atoms. 8. A compound represented by the general formula (IV): The 1,4-benzoquinone derivative derivative or a salt thereof according to claim 4, wherein R ¹ and R ³ are methyl groups, and R ² and X are hydrogen atoms. 9. A hydroquinone derivative represented by the general formula (I) and an aldehyde derivative represented by the general formula (II) or (II ′) are condensed in the presence of an acid to obtain a general formula ( A method for producing a 1,4-benzoquinone derivative represented by the general formula (IV) or a salt thereof, which comprises oxidizing the hydroquinone derivative represented by III) or a salt thereof. [Chemical 12] (In the formula, R ¹ is a hydrogen atom, a methyl group or a methoxy group, R ² and R ³ are the same or different and are a hydrogen atom or a methyl group, R ′ is a lower alkyl group, and R ⁴ is a hydrogen atom or a lower alkyl group. Group, X means a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom). 10. 3,5-Dimethyl-2- (hydroxy-3-pyridylmethyl) benzene obtained by condensing 3-pyridinecarboxaldehyde and 2,6-dimethyl-p-hydroquinone in the presence of an acid. A method for producing 3,5-dimethyl-2- (hydroxy-3-pyridylmethyl) -1,4-benzoquinone or a salt thereof, which comprises oxidizing -1,4-diol.