JPS62108859A - Aminophenol derivative - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (R<1> is H, lower alkyl, phenyl-lower- alkyl, lower alkylcarbonyl; R<2> is lower alkyl, phenyl substituted with lower alkyl; R<3> is alkyl, phenyl-lower-alkyl, carboxy-lower-alkyl). EXAMPLE:2-Amino-4-methoxy-5-phenylthiophenol hydrochloride. USE:It is used as an anti-inflammatory, antiallergic, antirheumatic, analgesic, diuretic, antithrombotic, or hypotensor. It has the action to block or control the biosynthesis of prostaglandins and leucotrienes. PREPARATION:A compound of formula II (R<4> is lower alkyl) is reduced with an agent such as sodium hydrosulfite in a solvent such as ether, and, when needed, combined with aqueous ammonia to give the compound of formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to aminephenol derivatives and salts thereof.

BACKGROUND OF THE INVENTION The amine phenol derivatives and salts thereof of the present invention are novel compounds described in the literature Song Qian.

Problems to be Solved by the Invention The purpose of the present invention is to provide a compound useful as a pharmaceutical, as described later.

Means for Solving the Problems According to the present invention, an aminophenol derivative represented by the following general formula (1) is provided.

Of-(SR2 [In the formula, R1 is a hydrogen atom, a lower alkyl group,) a lower alkyl group, a lower alkylcarbonyl group, a 2-thiazolyl group that may have a lower alkyl group or a phenyl group, a benzenesulfonyl group, a lower alkylsulfonyl group,
Indicates a benzoyl group or an aminothiocarbonyl group that may be substituted with a benzoyl group. R2 represents a lower alkyl group or a phenyl group which may be substituted with a lower alkyl group. R3 represents an alkyl group, a phenyl lower alkyl group or a carboxy lower alkyl group. ) In this specification, examples of lower alkyl groups include straight chain or branched chain alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, inbutyl, tert-butyl, pentyl, and hexyl groups. Examples of the alkyl group include, in addition to the above-mentioned lower alkyl groups, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl groups. Examples of the phenyl lower alkyl group include benzyl, phenethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 3-
Phenylbutyl, 4-phenylbutyl, 2-methyl-3
Examples include -phenylpropyl, 5-phenylpentyl, 6-phenylhexyl, and the like.

Examples of lower alkylcarbonyl groups include acetyl,
Examples include ethylcarbonyl, butylcarbonyl, isobutylcarbonyl tert-butylcarbonyl, pentylcarbonyl, hexylcarbonyl, and the like. Examples of the 2-thiazolyl group that may have a lower alkyl group or a phenyl group include 2-thiazolyl, 2-(4-methylthiazolyl), 2-(4-ethylthiazolyl), 2-(4-propylthiazolyl), 2-(4-isopropylthiazolyl), 2-(4-butylthiazolyl), 2-(4
-sec-butylthiazolyl), 2-(4-pentylthiazolyl), 2-(4-hexylthiazolyl), 2-(
5-methylthiazolyl), 2-(5-ethylthiazolyl), 2-(5-propylthiazolyl), 2-(5-isopropylthiazolyl), 2-(5-butylthiazolyl)
, 2-(5-sec-butylthiazolyl), 2-
(5-pentylthiazolyl), 2-(5-hexylthiazolyl), 2-(4-phenylthiazolyl), 2-
Examples include (5-phenylthiazolyl) group. Examples of lower alkylsulfonyl groups include methanesulfonyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, and butanesulfonyl groups.

Examples of carboxy lower alkyl groups include carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, 2-carboxypropylcarboxybutyl, 5-carboxypentyl, and 6-carboxyhexyl groups.

The compound of the present invention represented by the above general formula (1) and its salt have an effect of blocking or regulating the biosynthesis of prostaglandins and leukotrienes, and have an anti-inflammatory and anti-allergic effect on animals, especially dairy animals. It has pharmacological effects such as anti-rheumatic, analgesic, diuretic, platelet aggregation inhibition, and blood pressure lowering, and is therefore an anti-inflammatory agent, anti-allergic agent, anti-rheumatic agent, analgesic, diuretic, antithrombotic agent, antihypertensive agent, etc. It is useful as a medicine.

The amine phenol derivative (1) of the present invention can be produced by various methods. A specific example thereof is shown in the reaction scheme below.

According to the above reaction scheme-1, in general formula (1), R2 is the same as above. R4 represents a lower alkyl group.
A compound of the present invention is produced in which 1 is a hydrogen atom and R3 is a lower alkyl group.

In the above, the addition reaction between 1,4-benzoquinone (2) and thiols (3) is carried out in a suitable solvent such as an alcohol such as methanol or ethanol at a temperature in the range of about 10°C to the boiling point of the solvent. Implemented. Here, thiols (
The amount of 3> to be used is not particularly limited, but is usually about an equimolar amount to 1,4-benzoquinone (2), preferably 1
．． It is preferable to set the amount to about 0 to 1.3 times by mole. Hydroquinone (4), which is an adduct, can be produced in high yield through the above reaction. Although the hydroquinone (4) may be purified, it can usually be subjected to the subsequent alkylation reaction without being purified.

The alkylation reaction is carried out according to a conventional method, for example, in the presence of a base,
It can be carried out in an inert solvent. The alkylating agents used include common ones such as methyl iodide, methyl bromide,
Examples include lower alkyl halides such as ethyl bromide and propyl bromide, and di-lower alkyl sulfates such as dimethyl sulfate and diethyl sulfate.

These alkylating agents are usually used in an amount of twice the molar amount of hydroquinone (4), preferably about 2 to 20 times the molar amount. As the base, for example, alkali hydroxides such as sodium hydroxide, hydrides such as sodium hydride, metal carbonates such as potassium carbonate, sodium alkoxides such as sodium methoxide, sodium ethoxide, etc. can be used. Normally 2~ for hydroquinone (4)
10 (used in an amount of 8 molar). As the inert solvent, for example, N,N-dimethylformamide (DMF), tetrahydrofuran (THF), water, acetone, ethanol, etc. can be used. The above alkylation reaction It proceeds well under temperature conditions in the boiling range of the solvent and thus the compound (
5) can be obtained.

The nitration reaction of the obtained compound (5) can be carried out by a conventional method,
For example, it can be easily carried out by a method using a mixed acid of nitric acid and sulfuric acid, a method of reacting a mixture of nitric acid and sulfuric acid in acetic acid, a method of reacting nitric acid in acetic acid, etc., and the conditions for each reaction are also the same as usual. It can be similar to them.

Compound (6) obtained by the above nitration reaction is then selectively dealkylated to form compound (6).
7) is obtained. The dealkylation reaction is performed using a Lewis acid known as a Lewis acid having an affinity for oxygen atoms, such as BCQ3.
, BBr 3 and other trihalogenoboranes [for example, Reagents for Organiza Synthesis by Fieser et al.
Organic Synthesis), Vol.
1, 66-67. Vol.

2, 33-35, Wiley, New York
It can be implemented by applying [see W]. That is, in a halogenated hydrocarbon solvent such as dichloromethane or chloroform, about 1/3 to 3 times the molar amount of trihalogenoborane, preferably about 1 to 1.5 times the molar amount of compound (6), -
By acting on compound (6) at a temperature range of 80 to 30°C, the elimination reaction of the alkyl group near the nitro group can be carried out with high selectivity, and thus compound (7) can be obtained.

The reduction reaction of the nitro group of compound (7) is carried out according to a conventional method, for example, using sodium hydrosulfide (Na 2820 &
) and compound (7) in ether,
This can be carried out by stirring in a suitable solvent such as THF, dioxane, ethanol, methanol, etc., or by further adding aqueous ammonia and stirring if desired.

<Reaction scheme-2> OH0H (g) (10) OR50R
3 (11) (1b) [In the formula, R2 and R3 are the same as above. R5 represents an alkyl group, a phenyl lower alkyl group, a lower alkoxycarbonyl lower alkyl group, or a carboxy lower alkyl group. ] The method shown in the above reaction scheme-2 is carried out using Fujita (S.

Fujita)'s telegram [synthesis]
sis).

2 using 5-hydroxybenzoxazoles as intermediates using the Beckmann rearrangement described in [1982, 68]
-Amino-4-alkoxyphenols, and according to this method, in general formula (1), R
A compound of the present invention in which 1 is a hydrogen atom is produced.

In the method shown in the reaction scheme-2, hydroquinone (
The acetylation reaction of 4) is carried out according to a conventional method, for example, by adding about 1 to 10 times the molar amount of BF3 to the hydroquinone (4).
- Can be demonstrated in acetic acid in the presence of an ether solution, etc., from room temperature to the boiling point of the solvent.

The oximation reaction of the acetyl compound (8) obtained above is carried out by combining compound (8) and hydroxylamine hydrochloride in a suitable solvent in the presence of a suitable base such as pyridine, potassium carbonate, triethylamine, or sodium bicarbonate. This is carried out by carrying out a condensation reaction. Here, the base and hydroxylamine hydrochloride are each preferably used in an amount of usually about 1 to 5 times the molar amount of the starting compound (8).

As the solvent, for example, methanol, ethanol, pyridine, THF, chloroform, benzene, etc. can be preferably used. The condensation reaction can be carried out at a temperature usually in the range of 0° C. to the boiling point of the solvent.

The Beckmann rearrangement reaction of the oxime (9) obtained above is carried out according to the above telegram, for example, by adding phosphorus oxychloride (POCQ3) to the oxime (9) in a mixed solvent of N,N-dimethylacetamide (DMA) and acetonitrile. The 5-hydroxybenzoxazole derivative (10) can be suitably produced by this reaction by using about 1 to 1.1 times the molar amount of the 5-hydroxybenzoxazole derivative (10) at a temperature of 0 to 30°C.

The above 5-hydroxybenzoxazole derivative (10)
The alkylation reaction can be carried out in the same manner as the usual alkylation reaction of phenol, for example, under the same conditions as the reaction for obtaining compound (5) from hydroquinone (4) shown in reaction scheme-1 above. . In addition to the various alkyl halides listed above, examples of the alkylating agent used here include methyl bromoacetate, ethyl bromoacetate, ethyl 2-bromopropionate, butyl 3-bromopropionate, propyl 4-chlorobutyrate, Lower alkoxycarbonyl lower alkyl halides such as methyl 6-bromohexanoic acid, benzyl chloride, α-phenethyl bromide, β-phenethyl chloride, (3-chloropropyl)benzene, (2-chloropropyl)benzene, (1- Chloropropyl)benzene, (4-bromobutyl)benzene, (2-bromobutyl)benzene, (5
-bromopentyl)benzene, (6-bromhexyl)
Examples include phenyl lower alkyl halides such as benzene.

The hydrolysis reaction of compound (11) obtained by the above alkylation reaction is generally preferably carried out by a method using an acid. The hydrolysis reaction using the acid is carried out using an acid having a molar ratio of about 1 to 10 times that of compound (11), such as hydrochloric acid, sulfuric acid, o- The reaction is carried out using toluenesulfonic acid or the like at a temperature range of about 30 to 120°C, and thus the target compound (1b) can be obtained.

Further, in the case of a compound in which the R5 group of compound (11) is a lower alkoxycarbonyl lower alkyl group, it can be used in ethanol, methanol, or THF.

After converting into compound (11) in which the R5 group is a carboxy lower alkyl group by hydrolysis using 0.5 to 3N alkali hydroxide in a suitable solvent such as water,
The target compound (1b) in which R3 has a carboxy lower alkyl group can also be obtained by subjecting it to a hydrolysis reaction using the above acid.

Reaction scheme-3> (1(1) (1h) [In the formula, R2
and R3 are the same as above. R6 represents a phenyl group or a lower alkyl group, R7 represents a phenyl lower alkyl group or a lower alkyl group, R8 represents a phenyl group or a lower alkyl group, and R9 represents a phenyl group or a lower alkyl group. ] According to the method shown in Reaction Scheme-3, a compound of the present invention in which R1 is a group other than a hydrogen atom in the general formula (1) is obtained.

In the above, the acylation reaction of compound (1b) is carried out in an inert solvent using a suitable acylating agent. Examples of the acylating agent include lower alkyl carbonyl halides such as acetyl chloride, acetyl bromide, propionyl chloride, butyryl chloride, isobutyryl chloride, valeryl chloride, isovaleryl chloride, pivaloyl chloride, and heptanoyl chloride; Benzoyl chloride etc. can be used. As the inert solvent, for example, THE, ether, chloroform, dichloromethane, DMF, N,N-dimethylacetamide (DMA), etc. can be used.

Further, the above acylation reaction proceeds favorably in the presence of a suitable base such as pyridine or collidine.

The acylating agent and the base are usually used in an amount of about 1 to 3 times the molar amount, preferably about 1 to 1.1 times, relative to the starting material compound (1b), and the reaction is generally carried out in an amount of about -20 to 1.1 times the molar amount.
Progresses well in the temperature range of 30°C.

Furthermore, the above acylation reaction can be carried out by combining, for example, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, bibaric acid, hexanoic acid, etc. with chlorocarbonic acid in an inert solvent such as ether, THF, chloroform, dichloromethane, etc. Active esters of lower alkylcarboxylic acids obtained by reacting equimolar amounts of ethyl and triethylamine at a temperature of about -20 to 30°C, preferably about -10 to 0°C, are added to compound (1b). Approximately -20~ when used with equimolar suspension
It can also be carried out by reacting in a temperature range of 50°C.

The reduction reaction of the compound (1C) thus obtained can be suitably carried out using 1iAQHt in an inert solvent such as ether or THF. The amount of LiAQHt used is usually about 1 to 10 times the molar amount of compound (1C), and the reaction proceeds at a temperature ranging from around 0°C to the boiling point of the solvent, and this reduction reaction Accordingly, compound (1d)
can be obtained.

Furthermore, the sulfonylation reaction of compound (1b) can be carried out using a suitable sulfonylation agent in the same inert solvent as the above-mentioned acylation reaction of compound (1b) under the same conditions. Compound (1e) is obtained by sulfonylation reaction.
can be obtained. Examples of the sulfonylating agent used here include methanesulfonyl chloride, ethanesulfonyl chloride, propanesulfonyl chloride, butanesulfonyl chloride, pentansulfonyl chloride, heptanesulfonyl chloride, and benzenesulfonyl chloride.

In addition, in the thioamidation reaction of compound (1b), for example, known benzoyl isothiocyanate is used as the raw material compound (1b).
Acetone, chloroform, D
The reaction can be carried out in an inert solvent such as MF or THF at a temperature ranging from about 0.degree. C. to the boiling point of the solvent.

Compound (1f) obtained by the above sulfonylation reaction can then be induced to compound (1h) by subjecting it to hydrolysis reaction and then cyclization reaction.This compound (1f)
The hydrolysis reaction can be carried out in the same manner as a normal alkali hydrolysis reaction, and in particular, for example, using an aqueous alkali hydroxide solution of about 5 to 309G at a molar ratio of about 5 to 30 times that of compound (1f), A method in which the reaction mixture is made acidic after being heated to the boiling point can be preferably applied.

The cyclization reaction of the compound (1g) obtained by the above hydrolysis reaction involves converting the compound (19), for example, to chloroacetaldehyde, diethylacecool, 2-chloroacetophenone, 2-bromoacetophenone, chloro- 2-propanone, chloro-2-butanone, chloro-
2-pentanone, chloro-3,3-dimethyl-2-butanone, chloro-2-hexanone, chloro-4-methyl-
2-pentanone, chloro-2-heptanone, chloro-2
It is carried out by reacting with a 1-halo-2-carbonyl lower alkyl compound such as -octanone, a 2-haloacetophenone compound, or a haloacetaldehyde synthesis. Each of the above-mentioned reaction reagents is usually used in an amount of about 1 to 3 times the molar amount of the starting compound (1 g). As the solvent, for example, inert solvents such as ethanol, methanol, acetic acid, and water can be suitably used. The reaction usually proceeds in the range of about 0°C to the boiling point of the solvent, and thus the target compound (1
h) can be obtained.

The target compound and the compound of the present invention obtained by the reactions shown in each of the above reaction schemes can be easily isolated and purified by conventional separation means. Examples of the separation means include solvent extraction, recrystallization, column chromatography, and the like.

Furthermore, the compound of the present invention thus obtained can be easily converted into a pharmaceutically acceptable acid addition salt, and the acid addition salt has the same pharmacological activity as the compound of the present invention in its free form.
The present invention also includes such acid addition salts. Examples of acidic compounds that form the above-mentioned acid addition salts include non-silicic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid; An example is acid.

EXAMPLES In order to explain the present invention in more detail, production examples of the compounds of the present invention will be given below as practical examples.

Implementation FIA1 Production of 2-amino-4-methoxy-5-phenylthiophenol hydrochloride 1-a) Production of 4-methoxy-2-phenylthioanisole 1. 4-benzoquinone 70g ethanol 10100O
77 g of thiophenol was slowly added to the solution while stirring with water cooling, and after the dropwise addition, stirring was continued for an additional 20 minutes. Next, ethanol was distilled off under reduced pressure to obtain oily 2-phenylthio-
1,4-hydroquinone was obtained. To this was added 350 mQ of dimethyl sulfate, and a solution of 280 a of potassium hydroxide in 490 mQ of water was added dropwise over 30 minutes while stirring under water cooling, and stirring was continued for an additional 30 minutes. Thereafter, the reaction mixture was transferred to about 2,000 mL of water, extracted with ether, the organic layer was washed with water, dried (MgSOa), and concentrated.
-Phenylthioanisole 153 was obtained as an oily substance.

The NMR analysis results (δ@(ppm), internal standard: tetramethylsilane, same hereinafter) are as follows.

NMR (CDCQ3) δ 7.15-7.50 (Ill, 5H) 6.70-6
．． 90 (m, 2H) 6.55-6.65 (m, 1H) 3.81 <s, 3H) 3.62 (S, 3H) This can be used in the next reaction without purification.

+-b) Production of 4-methoxy-2-nitro-5-phenylthioanisole 10g of 4-methoxy-2-phenylthioanisole was dissolved in 25m12 of acetic acid, and 4g of chain-forming M was added thereto under stirring while cooling with water.
dropwise to precipitate yellow crystals. After stirring for an additional 15 minutes at the lowest temperature, the reaction mixture was transferred to water, the crystals were collected, washed with a 1:3 mixture of ether:n-hexane, and dried under reduced pressure to give yellow crystals 9. .6g was obtained.

Melting point 164-165°C 1-c) Production of 4-methoxy-2-nido-5-phenylthiophenol After dissolving 6 g of 4-methoxy-2-nitro-5-phenylthioanisole in 130 g of dichloromethane, - 7
35.7 g of BBr was added at 8° C. and stirring was continued for an additional 20 minutes. During this time, the reaction temperature was below -20°C. The reaction mixture was then transferred to water and extracted with dichloromethane,
The organic layer was washed with water, dried (MgSot), and condensed to give yellow crystals. Ether: n-hexane-1
5 g of the target compound in the form of yellow crystals was obtained by washing with a mixed solution.

Melting point 152-153°C 1-d) Production of 2-amino-4-methoxy-5-phenylthiophenol hydrochloride 1.6 g of 4-methoxy-2-nitro-5-phenylthiophenol was dissolved in 30-THF and live ammonia. Water 20-
Dissolved in Na 2 S 20a10 (l water 40
1110 solution was added under V warm stirring and continued FR itching for about 10 minutes until the reaction mixture turned from red to colorless, then the reaction mixture was transferred to water, extracted with ether, and the organic layer was diluted with saturated saline. After washing, drying (MgSOt) and concentrating.
An oily substance was obtained.

After diluting this with ether again, 4N hydrochloric acid/ethyl acetate was added and the precipitated salt was collected to obtain 1.3 g of the target compound.

The physical properties of the obtained compound are shown in Table 1 as Example No. 0.1.

Example 2 Production of 2-amino-4-methoxy-5-n-butylthiophenol hydrochloride 2-a) Production of 2-n-butylthio-4-methoxyanisole 1. 20 g of 4-benzoquinone, n-butanethiol 18
Starting from g and 300 ml of ethanol, Example 1-
In the same manner as in a), the target compound was obtained using 100 ml of dimethyl sulfate and 140 m of a solution of potassium hydroxide in 140 m of water, and the compound was isolated by distillation.

Yield 20g Boiling point 125-130℃10.5mmHQ2-b)5-
Production of n-butylthio-4-methoxy-2-nitroanisole By the same procedure as in Example 1-b), seven 2-n-butylthio-4-methoxyanisoles and 2011+12 acetic acids were prepared.
and 'a From 3 g of nitric acid, 3.90 of the target compound in the form of yellow crystals
was manufactured.

Melting point: 93-93.5°C 2-c) Production of 5-n-butylthio-4-methoxy-2-nitrophenol By the same procedure as in Example 1-C), 5-n-butylthio-4-methoxy-2 -Nitroanisole 3.8g, B
From ar 33.9(] and dichloromethane l:/80-, 2 g of the target compound in the form of yellow crystals was prepared.

Melting point 109-110°C 2-d) 2-amino-4-methoxy-5-n-7
Production of tilthiophenol salt M salt 1.32 g of 5-n-butylthio-4-methoxy-2-nitrophenol,
Using a 40 m water solution of 20410 g of Na2S, 2511+12 concentrated aqueous ammonia and 30 m of THF, 1.3 g of the target compound was produced by adding 3 m12 of 4N hydrochloric acid/ethyl acetate.

The physical properties of the compound obtained are shown in Table 1 as Example No. 2.

Example 3 Production of 2-amino-4-methoxy-5-<4-methylphenylthio)phenol 3-a) Production of 4-methoxy-2-(4-methylphenylthio)anisole) 1.4-benzoquinone Starting from 18.7q, p-thiocresol 16.30 and 300 mQ of ethanol, 100 mQ of dimethyl sulfate was prepared in the same manner as in Example 1-a).
The desired compound was obtained using a solution of +2 and 76 g of potassium hydroxide in 140 ml of water, and purified by silica gel column chromatography (chloroform:n-hexane=3:5) to obtain 23 g of the desired compound as white crystals.

Melting point: 86-88°C 3-b) Production of 4-methoxy-5-(4-methylphenylthio)-2-nitroanisole By the same procedure as in Example 1-b), 4-methoxy-2
-(4-methylphenylthio)anisole 10g, acid 1
The target compound 9.19 in the form of yellow crystals was produced from 138 g of 138 g of 111511 acid.

Melting point 143.5145.5°C 3-c) Production of 4-methoxy-5-(4-methylphenylthio)-2-ditrophenol By the same operation as in Example 1-C), 4-methoxy-5
-(4-methylphenylthio)-2-nido072'/-
7 g of the target compound in the form of yellow crystals were prepared from 9.10% of BBr, 312.10% of BBr and 300% of dichloromethane.

Melting point: 120-122°C 3-d) Production of 2-amino-4-methoxy-5-(4-methylphenylthio)phenol By the same procedure as in Example 1-d), 4-methoxy-5
0.8 g of the target compound was produced from 1.5 g of -(4-methylphenylthio)-2-nitrophenol, 40 ~ solution of Na2S20410 (+), 18 tuna in concentrated ammonia water, and 28 mQ of THF.

The physical properties of the obtained compound are shown in Table 1 as Example No. 3.

Example 4 Production of 2-amino-4-n-propoxy-5-phenylthiophenol hydrochloride IL-a) Production of 2.5-dihydroxy-4-phenylthioacetophenone Example 1-a) t” produced 2-phenylthio-1゜4
-Hydroquinone 90 (+) was heated under reflux in vinegar 1i1t200mQ and BF3 ・Ei 20200- for 48 hours. Then, it was transferred to water, extracted with dichloromethane, and the organic layer was washed with water, dried (MQ SO2), and after condensation. , silica gel column chromatography (dichloromethane)
The resulting product was purified by using dichloromethane/n-hexane and further recrystallized to obtain the target compound 25a as pale yellow crystals.

Melting point: 149-151°C 4-b) 2.5-dihydroxy-4-phenylthioacetophenone oxime, 25 o of 2.5-dihydroxy-4-phenylthioacetophenone dissolved in 400 mQ of ethanol and 100 mQ of dichloromethane, To this was added 710 g of triethylamine (25 g) and hydroxylamine hydrochloride (13 g), and stirring was continued at room temperature for 20 hours. The reaction mixture was then transferred to water,
Extracted with dichloromethane, washed the organic layer with water, and dried (M(
1304) The crystals obtained by concentrating 1q were recrystallized from ether/n-hexane to obtain the target compound 20CI as white crystals.

Melting point 123, -124°C 4-c) Preparation of 2-methyl-6-phenylthio-5-benzoxazolole 2.5-dididroxy-4-noJylthioacetophenone oxime 6499, DMA5- and acetonitrile 15 26% of phosphorus oxychloride dissolved in water, cooled with water, and stirred.
4- was added dropwise over a period of 20 minutes, and then heated for an additional 30 minutes at the lowest temperature.
Stirring was continued for a minute.

After adding 3% sodium acetate, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine and dried (MgSO
3) and the crude product obtained by concentration was subjected to silica gel column chromatography (ethyl acetate: n-hexane = 1
:5) to obtain 4.8 g of the desired compound as white crystals.

Melting point 156-157℃ 4-d) 2-Methyl-6-phenylthio-5-〇-
Preparation of propoxybenzoxazole 2 g of 2-methyl-6-phenylthio-5-benzoxazole was added to a suspension of 330 mg of NaH in 40 mQ of DMF under air temperature stirring, and then a solution of 1.1 g of n-propyl bromide in 5 mQ of DMF was added. The reaction mixture was further stirred at room temperature for 20 hours, then transferred to water, extracted with ethyl acetate, and the aqueous layer was washed with water and dried (MU So
t) and the crude product obtained by concentration was subjected to silica gel column chromatography (ether: 0-hexane =
1:5 → 1:3) to obtain an oily target compound 1.
I got 8g @.

NMR (CDCQ3) δ 7.20-7.40 (m, 5H) 7.17 (s, 1H) 7.11 (s, IH) 3.98 (t, 2H, J=6.2>2.57 (s
, 3H) 1.60-1.90 (m, 2H) 0.97 (t, 3H, J=7.0) 4-e) 2
-Production of amino-4-n-propoxy-5-7 phenylthiophenol hydrochloride 1.89 of 2-methyl-6-phenylthio-5-n-propoxybenzoxazole was added with 7 ml of ethanol and 1.3 mL of concentrated hydrochloric acid. After heating under reflux for 1.5 hours, 5%
Transfer to an aqueous sodium bicarbonate solution, extract with chloroform, wash the organic layer with water, dry (MgSo□), and concentrate. To the resulting crude product, add 4N hydrochloric acid/ethyl acetate, and further add 100 mQ of ether. The precipitated salt was filtered and dried to obtain the target compound 1.59.

The physical properties of the obtained compound are shown in Table 1 as Example N014.

Example 5 Production of 2-amino-4-n-hexyloxy-5-phenylthiophenol hydrochloride 5-d) Production of 5-n-hexyloxy-2-methyl-6-phenylthiobenzoxazole Example 4 2-Methyl-6-phenylthio-5-benzoxazolol 2.3 (1, NaH38
0+ng, DMF40mi2 and 1-bromohexane1
．． From 6 g, 3 g of the target compound was obtained as an oily substance in the same manner as in Example 4, 4-d).

NMR (CDCQ3) δ 7.10-7.40 (m, 5H) 7.18 (s, 1H) 7, 12 (s, 1H) 4.00 (t, 2H, J=6.3) 2,
57 (s, 3H) 1, ○O-1,90 (m, 8H) 0, 8
8 (br, t, 3H)5-e) 2
-Production of amino-4-n-hexyloxy-5-phenylthiophenol hydrochloride 5-n-hexyloxy-2-methyl-6-phenylthiobenzoxazole in the same manner as 4-e in Example 4 3g, a salt i11.8ml
2 and 10 mQ of ethanol, the hydrochloride of the target compound 1
．． I got 99.

The physical properties of the obtained compound are shown in Table 1 as Example No. 5.

Example 6 Production of 2-amino-4-n-decyloxy-5-phenylthiophenol hydrochloride 6-d) 5-n-decyloxy-2-methyl-6-
Mu of phenylthiobenzoxazole From 1.5 g of 2-methyl-6-phenylthio-5-benzoxazole obtained in Example 4 (1, NaH25On+g, DMF40- and 1.4 g of 1-bromodecane, 4 of Example 4 -d)
In the same manner as above, 1.8 g of the target compound was obtained as an oily substance.

NMR (CDCQa) δ 7.10-7.40 (m, 5H) 7.18 (s, 1H) 7.11 (s, 1H) 4.00 (t, 2H, J=6.2>2.57 (s, 3H) 1.00-1.90 (+, 8H) 0,87 (br, t, 3H) 6-e) 2-amino-4-n-decyloxy-5-
Phenylthiophenol salt 15! Production Example 4 of l-salt
In the same manner as in 4-e), 5-n-decyloxy-2-
Methyl-6-phenylthiobenzoxazole 1. sg
, atMMlmQ and ethanol 6-, the hydrochloride salt of the target compound 1.29 was obtained.

The physical properties of the obtained compound are shown in Table 1 as Example No. N096.

Actual flow example 7 Production of 2-amino-4-phenethyloxy-5-phenylthiophenol hydrochloride 7-d) 2-methyl-5-phenethyloxy-6-
Production of phenylthiobenzoxazole Using 3 g of 2-methyl-6-phenylthio-5-benzoxazole obtained in Example 4, 2 CO32,6a, 40 mQ of DMF, and 2.4 g of bromoethylbenzene, 4 of Example 4 was prepared.
2 g of the target compound was obtained as an oily substance in the same manner as in step-d) except that NaH was replaced with 2 CO2.

NMR (CDCQ3) δ 7.10-7.40 (+a, l0H) 7.17 (
s, 1H) 7, 10(s, 1)-1> 4.20 (t, 2H, J=7.0) 3.04
(t, 2H, J=7.0)2, 56 (s
, 3H) 7-e) 2-amino-4-phenethyloxy-5-
Production Example 4 of Phenylthiophenol Hydrochloride 4-
In the same manner as in e), 2 g of 2-methyl-5-phenethyloxy-6-phenylthiobenzoxazole and 1 g of concentrated hydrochloric acid were added.
．． 2- and ethanol 6 threshold, the hydrochloride of the target compound]
, got 8Q.

The physical properties of the obtained compound are shown in Table 1 as Example No. 7.

Example 8 Production of 2-amino-4-carboxymethyloxy-5-phenylthiophenol hydrochloride 8-d) Production of 5-carboxymethyloxy-2-methyl-6-phenylthiobenzoxazole Obtained in Example 4 4 g of 2-methyl-6-phenylthio-5-benzoxazolol, 2 g of K2Co3 and 3.2 g of ethyl bromoacetate were suspended in DMF60-, stirred at room temperature for 20 hours, then transferred to water, and dissolved in ethyl acetate. The crude product obtained by washing the Sekimen layer with water, drying (MgSOt), and concentrating was recrystallized from ether/n-hexane to obtain 5-ethoxycarbonylmethyloxy-
2-methyl-6-phenylthiobenzoxazole 5g
1q of white crystals.

Melting point: 88-89°C Then, the obtained compound 2.59 was dissolved in 40ml of ethanol.
12, added 30 volumes of 2N aqueous sodium hydroxide solution, and stirred at room temperature for 1.5 hours.
Then 40 g of 20% acetic acid was added and the reaction mixture was extracted with dichloromethane. Inuiffi (Mo So.)
After L,'a condensation, the obtained crystals were washed with ether:n-hexane=1:1 and washed a few times to give 2 g of 5-carboxymethyloxy-thyl-6-phenylthiobenzoxazole as white crystals. Obtained.

Melting point 185-186°C 8-e) Production of 2-amino-4-carboxymethyloxy-5-phenylthiophenol hydrochloride In the same manner as 4-e) in Example 4, 5-carboxymethyloxy-2- Methyl-6-phenylthiobenzoxazole 2q, W salt Ml. 4mQ and ethanol 10m
From Q, 1.29 of the hydrochloride of the target compound was obtained.

The physical properties of the obtained compounds are shown in Table 1 in Example No. Shown as 8.

Example 9 Preparation of 2-(3-benzoylthioureido)-4-methoxy-5-phenylthiophenol 5.47q of 2-amino-4-methoxy-5-phenylthiophenol and 4.1q of benzoylisothiocyanate
10 was stirred in 100 mf2 of acetone at room temperature for 1 hour. Water was added to the reaction solution, and the precipitated crystals were collected by iP.

After drying, it was recrystallized from acetone/hexane to obtain 7.5 g of the target compound.

The physical properties of the obtained compounds are shown in Table 1 in Example No. Shown as 9.

Example 10 Production of 2-thioureido-4-methoxy-5-phenylthiophenol 2-(3-benzoylthioureido)-4-methoxy-
To 10 (l) of 5-phenylthiophenol, add 501,110 aqueous solution in which 10 (l) of sodium hydroxide is dissolved,
Refluxed for 0 minutes. After cooling, the precipitated crystals were filtered, the tP solution was made acidic with dilute hydrochloric acid, and then extracted with chloroform. After drying and concentrating, the obtained crystals were washed with ether to obtain 5.3 g of the target compound. The physical properties of the obtained compounds are shown in Table 1 in Example No. Shown as 10.

Example 11 Production of 2-(2-thiazolyl amino)-4-methoxy-5-phenylthiophenol dihydrochloride 2-thioureido-4-methoxy-5-7, lunaofenol 1.2a, chloracetaldehyde diethyl acetal 600 mq and p-1-luensulfone M30m
q was stirred for 1.5 h at 95-100 °C in acetic acid 10 s. After cooling, water was added and extracted with chloroform. After drying, it was concentrated and purified by column chromatography (developing solvent: chloroform: ethyl acetate = 7:1). The obtained oil was dissolved in 10 ml of ether, and 0.3 m of 4N hydrochloric acid-ethyl acetate solution was added thereto to obtain 180 mq of the target compound as precipitated crystals.

Example No. 1 is based on the physical properties of the obtained compound.

11.

Example 12 Production of 2-(4-methyl-2-thiazolyl-amino)-4-methoxy-5-phenylthiophenol 1.5 g of 2-thiourido-4-methoxy-5-phenylthiophenol, 1.5 g of chloro-2-propanone. The same operation as in Example 11 was performed using 3 g and 100 mQ of ethanol to obtain 0.7 g of the target compound. The physical properties of the obtained compounds are shown in Table 1 in Example No. Shown as 12.

Example 13 Production of 2-(4-phenyl-2-thiazolylamine)-4-methoxy-5-phenylthiophenol 2-thiourido-4-methoxy-5-phenylthiophenol 2,1S,2-bromoacetophenone 1 .4g
The same operation as in Example 11 was carried out using 100 mg of ethanol and 0.7 g of the target compound was obtained. The physical properties of the obtained compound are shown in Table 1 as Example No. 13.

Example 14 Preparation of 4-methoxy-2-methylsulfonylamino-5-phenylthiophenol 2.23 g of 2-amino-4-methoxy-5-phenylthiophenol and 3.57 g of pyridine were mixed with DMA13.
Dissolved in 5 mQ, methanesulfonyl chloride 1.03
(l) was added at air temperature and stirred for 3 hours. Water was added to the reaction solution, extracted with ethyl acetate, and the organic layer was washed with diluted hydrochloric acid and then with a saturated aqueous sodium bicarbonate solution. After drying,
It was concentrated and subjected to column chromatography (developing solvent: chloroform:ethyl acetate - 10:1) to obtain 1 g of the target compound. The physical properties of the obtained compounds are shown in Table 1 for Example N.
Shown as 0.14.

Example 15 Preparation of 4-methoxy-2-phenylsulfonylamine-5-phenylthiophenol 2.23 g of 2-amino-4-methoxy-5-phenylthiophenol, 1.60 CI of benzenesulfonyl chloride and 3.57 CI of pyridine.
Using g, the same operation as in Example 14 was performed to obtain 1.3 g of the target compound.

The physical properties of the obtained compounds are shown in Table 1 as Example No.

15.

Example 16 Preparation of 2-benzoylamino-4-methoxy-5=phenylthiophenol
It was dissolved in 8 ml of HF, and 9801110 ethyl chlorocarbonate was added at 0°C to -5°C, followed by stirring at -5°C for 25 minutes.

A solution of 2.19 2-amino-4-methoxy-5-phenylthiophenol dissolved in THF5- was added to this.
The mixture was added at °C and then stirred at air temperature for 21 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. After drying, it was concentrated and purified by column chromatography (developing solvent: chloroform: ethyl acetate = 25: 1) to obtain the target compound 1.
．． 959 is Kotobuki. The physical properties of the obtained compound are shown in Table 1 as Example No. 16.

Example 17 Preparation of 2-ethylcarbonylamino-4-methoxy-5-phenylthiophenol 2-amino-4-methoxy-5-phenylthiophenol 3.1Q, propion! i! 2983 mq, triethylamine 1.35 g, THFl 2n+12 and ethyl chlorocarbonate 1.45 g, and the same procedure as in Example 16 was performed to obtain 2.8 g of the target compound.

The physical properties of the obtained compounds are shown in Table 1 as Example No.

17.

Example 18 Preparation of 2-benzylamino-4-methoxy-5-phenylthiophenol Li AG! For 6 comparisons of THF solution of 385 mq of Ha,
Dissolve 1.71 J of 2-benzoylamino-4-methoxy-5-phenylthiophenol in THF under water cooling.
was added, and then stirred at air temperature for 6 hours.

Water was added to the reaction solution, and the mixture was extracted with ether. After drying, it was concentrated and purified by column chromatography (developing solvent: ether: hexane = 2:1). The diluted oil was dissolved in 101 Tl12 of ether, and 10% ethanolic solution of hydrochloric acid was added. The precipitated crystals were cleaned to obtain 800 mq of the target compound.

The physical properties of the obtained compound are shown in Table 1 as Example No. 18.

Example 1 Preparation of 4-methoxy-5-phenylthio-2-propylamine phenol. 0.8g of the compound is 1q.

The physical properties of the obtained compound are shown in Table 1 as Example No. 19.

Example 20 Production of 4-methoxy-5-n-butyldio-2-propylaminophenol hydrochloride 2-amino-5-n-butylthio-4-methoxyphenol 2.6! Ill, Propion M865ma, Triethylamine 1.18g, T
2.5 of 5-n-butylthio-2-ethylcarbonylamino-4-methoxyphenol was prepared in the same manner as in Example 16 using 16 of HF and 1.27!11 of ethyl chlorocarbonate.
30 and then this is l! A+! H4683II
The same treatment as in Example 18 was carried out using 1 g and 40 mQ of THF to obtain 1 g of the target compound.

The physical properties of the obtained compounds are shown in Table 1 as Example No.

20.

Table 1 ○R3

Claims (1)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 may have a hydrogen atom, a lower alkyl group, a phenyl lower alkyl group, a lower alkyl carbonyl group, a lower alkyl group, or a phenyl group. It represents a 2-thiazolyl group, a benzenesulfonyl group, a lower alkylsulfonyl group, a benzoyl group, or an aminothiocarbonyl group that may be substituted with a benzoyl group. R^2 represents a lower alkyl group or an aminothiocarbonyl group that may be substituted with a lower alkyl group. This represents a certain phenyl group. R^3 represents an alkyl group, a phenyl lower alkyl group, or a carboxy lower alkyl group.] An aminophenol derivative represented by the following and a salt thereof.