JP2890155B2 - Method for producing diphenylmethane derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a phenol derivative or hydroquinone derivative or a synthetic intermediate thereof useful for the treatment and prevention of brain, heart, kidney and pulmonary circulatory diseases, respiratory diseases, allergies, anaphylactic shock, inflammation and the like. It relates to the method of manufacturing the body.

[0002]

2. Description of the Related Art The above-mentioned phenol derivatives and hydroquinone derivatives are described, for example, in JP-A-61-44840 and JP-A-2-152940. These compounds have the general formula

Embedded image [In the formula, R ′ represents an optionally protected hydroxyl group, R ″ represents a hydrogen atom or an optionally protected hydroxyl group, X ¹ represents a halogen atom, a lower alkyl group or a lower alkoxy group, and Y ¹ represents a methyl group. A group, a hydroxymethyl group which may be substituted or a carboxyl group which may be esterified or amidated, and m represents an integer of 3 to 15.]
Is synthesized from a diphenylmethane derivative represented by
The compound represented by the general formula (a) is represented by the general formula

Embedded image Wherein each symbol is as defined above. And a compound represented by the general formula:

Embedded image [Wherein X ¹ , Y ¹ and m are as defined above, and X ²
Represents a hydroxyl group, an acetoxy group, a lower alkoxy group or a halogen atom. And a compound represented by the formula:

[0003]

However, the production of the compound (c) requires four to five steps and has a problem that the yield is low, and the development of an industrially advantageous method is desired. I was The present inventors have conducted intensive studies on these points, and as a result, by reacting the compound (b) with a stilbene derivative which can be easily produced in the presence of a specific acid catalyst, the diphenylmethane derivative (a ) Can be manufactured.

[0004]

According to the present invention, there is provided a compound of the general formula

Embedded image [Wherein, R ¹ represents a hydroxyl group which may be protected, R ² , R
³ represents a methyl group or a methoxy group, and R ⁴ represents a hydrogen atom or a hydroxyl group which may be protected. A phenol derivative represented by the general formula

Embedded image [In the formula, X is a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group, Y is a methyl group, a hydroxymethyl group which may be O-substituted, or a carboxyl group which may be esterified or amidated. To n
Represents an integer of 1 to 15. Wherein the stilbene derivative represented by the general formula is reacted in the presence of methanesulfonic acid.

Embedded image Wherein each symbol is as defined above. And a method for producing a diphenylmethane derivative represented by the formula:

In the above general formulas (I) and (III),
Examples of the optionally protected hydroxyl group represented by R ¹ and R ⁴ include a hydroxyl group, a lower alkoxy group (eg, having 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy), a methoxymethyloxy group, a benzyloxy group, Lower acyloxy groups (eg, those having 1 to 4 carbon atoms such as formyloxy, acetoxy and propionyloxy), tetrahydropyranyloxy groups and the like are mentioned. The general formulas (I) and (II)
In I), R ² and R ³ are the same or different and each represents a methyl group or a methoxy group, and among them, a methyl group is preferable. In the compounds (II) and (III), examples of the halogen atom represented by X include fluorine, chlorine, and bromine.

In compounds (II) and (III), Y
The hydroxymethyl group represented by may be O-substituted, and may be an unsubstituted hydroxymethyl group or a group obtained by substituting the hydroxyl group with oxygen such as methoxymethyl, acetoxymethyl, 2-tetrahydropyranyloxymethyl, Benzyloxymethyl, nitrooxymethyl, aminocarbonyloxymethyl, substituted aminocarbonyloxymethyl (eg, methylaminocarbonyloxymethyl, ethylaminocarbonyloxymethyl,
Mono- or di-lower alkylaminocarbonyloxymethyl such as dimethylaminocarbonyloxymethyl, phenylaminocarbonyloxymethyl), cyclic aminocarbonyloxymethyl (for example, morpholinocarbonyloxymethyl, pyrrolidinocarbonyloxymethyl,
Piperazinocarbonyloxymethyl), t-butyldimethylsilyloxymethyl and the like, and examples of the esterified carboxyl group include lower alkoxycarbonyl having 2 to 4 carbon atoms such as methoxycarbonyl and ethoxycarbonyl. . The amidated carboxyl group represented by Y may be a substituted aminocarbonyl in which the amino group is substituted, or may be a cyclic aminocarbonyl. Examples of the substituent of the amino group of the substituted aminocarbonyl include methyl, ethyl, propyl,
Alkyl having 1 to 4 carbon atoms such as isopropyl and butyl, and 6 to 1 carbon atoms such as phenyl and naphthyl.
0 aryl (these may further have a substituent such as hydroxyl, amino, nitro, halogen, methyl, methoxy and the like at any position of the ring), a hydroxyl group and the like. Specific examples of the amidated carboxyl group include, for example, aminocarbonyl, mono- or dialkylaminocarbonyl (the mono- or dialkylamino is, for example, one having 1 to carbon atoms such as methylamino, ethylamino, isopropylamino, and dimethylamino). 4), aralkylamino [benzylamino, α-phenethylamino, β-phenethylamino, 1- (α-naphthyl) ethylamino] carbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl (p-hydroxyphenylamino, p- Methoxyphenylamino, m-chlorophenylamino, p
-Bromophenylamino) carbonyl, diphenylaminocarbonyl, hydroxyaminocarbonyl, N-hydroxy-N-methylaminocarbonyl, N-hydroxy-N-phenylaminocarbonyl and the like. The cyclic amino of the cyclic aminocarbonyl may have oxygen or sulfur other than nitrogen as a ring-constituting atom.
Specific examples of the membered ring and cyclic aminocarbonyl include, for example, morpholinocarbonyl, thiomorpholinocarbonyl, piperidinocarbonyl, pyrrolidinocarbonyl and the like.

In the general formulas (II) and (III), n is an integer of 1 to 15, preferably 2 to 13.
More preferably, it is an integer of 3 to 10. In the reaction of the present invention, compound (II) is used in an amount of about 0.5 to 1.5 mol, preferably 0.75 to 1.25 mol per 1 mol of compound (I).
Mol, particularly preferably in the range of 0.9 to 1.1 mol. Methanesulfonic acid, relative to compound (I),
It is used in an amount of 0.5 to 20 moles, preferably 1 to 10 moles, particularly preferably 2 to 5 moles.

As the solvent used in the reaction, a non-polar solvent,
For example, methylene chloride, chloroform, 1,2
-Dichloroethane, 1,1,2-trichloroethane, benzene, toluene and the like are preferable, and methylene chloride, chloroform or 1,2-dichloroethane is preferably used, and methylene chloride is particularly preferably used. These solvents can be used alone or as a mixture. The amount of the solvent used in the reaction is usually the amount of the compound (II
I) The amount is about 0.5 to 10 liters, preferably 1 to 5 liters per mole, but is not particularly limited to this range. The reaction is carried out at a lower temperature than the usual Friedel-Craft reaction in order to prevent the polymerization of the compound (II), usually at about -20 to 50 ° C, preferably at -5 to 3 ° C.
It is performed at about 5 ° C. The reaction time is usually about 0.5 to 24.
Hours, more preferably about 1 to 8 hours.

The target compound (II) formed by the above reaction
If I) is precipitated as crystals from the reaction solution,
The precipitated crystals can be isolated by filtration or, if necessary, may be extracted by solvent extraction with methylene chloride or the like, and then concentrated and isolated. When crystals do not precipitate from the reaction solution, they can be isolated by solvent extraction with methylene chloride or the like and then concentration. The isolated crystals can be purified by conventional means such as recrystallization and chromatography, if necessary. In addition, the starting compound (I)
Is known or can be produced according to known methods. The raw material compound (II) is partially known, and for example, has the general formula

Embedded image Wherein X is as defined above, and a compound represented by the general formula:

Embedded image A compound represented by the formula (II) wherein Y is a carboxyl group can be obtained by reacting with a compound represented by the formula: wherein n is as defined above. This reaction is usually carried out in the presence of a metal hydride such as sodium hydride or a tertiary alkoxide of an alkali metal such as sodium tert-butoxide or potassium tert-butoxide, for example, isobutanol, tert-butanol, ether, It is performed in a solvent such as tetrahydrofuran. Then, the compound (II) can be produced by converting the carboxylic acid according to a known method, if necessary.

In the target compound (III) of the present invention, R ¹ and R ⁴
In the case where both of them are hydroxyl groups, they exhibit the medicinal effects as they are (see JP-A-61-44840). Compound (III)
In the case where R ¹ and / or R ⁴ is a protected hydroxyl group, the compound can be led to a hydroxyl group compound by deprotection by a conventional method. In the compound (III), a compound in which R ¹ is a hydroxyl group and R ⁴ is hydrogen or a hydroxyl group is a compound represented by a general formula having a pharmacological action by oxidizing the compound by a conventional method.

Embedded image Wherein each symbol is as defined above. ] (See JP-A-61-44840). In the compound (III), the compound in which R ⁴ is hydrogen can be converted to a formyl compound to give a compound of the general formula

Embedded image Wherein each symbol is as defined above. (See Japanese Patent Application Laid-Open No. 2-152940), and by further reducing this compound, a general formula having a pharmacological action can be obtained.

Embedded image Wherein each symbol is as defined above. ] (See JP-A-2-152940).

[0011]

The present invention will be described in more detail with reference to Examples, Reference Examples and Comparative Examples. Reference Example 1 (Production of 7-phenyl-6-heptenoic acid) 5-carboxypentyl-triphenylphosphonium bromide (20 g) and benzaldehyde (5.6 g)
Was suspended in isopropanol (100 ml), and potassium butoxide (10.8 g) was added little by little at 25 ° C.
The reaction was performed at 0 ° C. for 2 hours. After isopropanol was distilled off under reduced pressure, hydrochloric acid was added to the residue solution to which water (100 ml) was added to make the solution acidic, followed by extraction with ethyl acetate, washing with water, drying and concentration under reduced pressure. The residue was subjected to silica gel chromatography to give 7-phenyl-6-heptenoic acid (7.6 g) as a colorless oil. Nuclear magnetic resonance spectrum (δ value based on tetramethylsilane in deuterated chloroform): 1.30-2.50 (8H), 5.50-6.55
(2H), 7.28 (5H)

Reference Example 2 (7- (4-fluorophenyl)
Production of -6-heptenoic acid) After reacting 5-carboxypentyl-triphenylphosphonium bromide (20 g) and 4-fluorobenzaldehyde (6.5 g) in the same manner as in Reference Example 1, the product was separated by silica gel chromatography. Thus, 7- (4-fluorophenyl) -6-heptenoic acid (8.3 g) was obtained as white crystals. Nuclear magnetic resonance spectrum (δ value based on tetramethylsilane in deuterated chloroform): 1.20-2.55 (8H), 5.91-6.56
(2H), 6.80-7.50 (4H)

Example 1 (Production of Compound 1) 7-phenyl-6-heptenoic acid (10 g) obtained in Reference Example 1 and 2,3,5-trimethyl-1,4-hydroquinone (5.6 g) were obtained. After suspending in dichloromethane (67 ml), methanesulfonic acid (9.6 g) was added in 25 to 3 times.
It was added dropwise at 0 ° C. After stirring at 25 ° C. for 5 hours, water (41
The precipitated crystals were collected by filtration, washed successively with dichloromethane and water, and dried under reduced pressure to give 7- (3,5,6-trimethyl-1,4-hydroquinon-2-yl) -7-phenylheptanoic acid. (13.4 g, yield 76.7%). 7- (3,5,6-trimethyl-1,4-hydroquinon-2-yl) -7-phenylheptanoic acid (13.
4 g) was dissolved in 86% acetonitrile (containing 14% water), and 34 ml of a 38% aqueous ferric chloride solution was added thereto.
Stirred at C for 1 hour. The reaction solution was cooled on ice, and the precipitated crystals were collected by filtration and further treated with 60% acetonitrile (water 4).
0%) to give 7- as yellow crystals.
(3,5,6-trimethyl-1,4-benzoquinone-2-
Yl) -7-phenylheptanoic acid (12.0 g, 90.2% yield from hydroquinone, 69.2% yield from heptenoic acid). [7- (3,5,6-trimethyl-
1,4-Hydroquinon-2-yl) -7-phenylheptanoic acid is easily oxidized, and a part of it is 7- (3,5,6-trimethyl-1,4-benzoquinon-2-yl) -7-phenylheptane Since it was an acid, the example included an oxidation reaction. Compounds 2 to 9 can be produced in the same manner as described above.

[Table 1]

Example 2 (Production of Compound 10) 7- (4-Fluorophenyl) -6-heptenoic acid (10.0 g) obtained in Reference Example 2 and 2,3,5-trimethylphenol (9.0 g) ) With dichloromethane (20
0 ml), and then dissolved in methanesulfonic acid (43.3).
g) was added dropwise at 2-5 ° C. After the reaction solution was stirred at 2-3 ° C. for 3 hours, water (100 ml) was added, the dichloromethane layer was separated, and water washing was repeated three times. Dichloromethane was distilled off under reduced pressure, and the residue obtained was subjected to silica gel chromatography to give 7- (4-fluorophenyl) -7- (2-hydroxy-3,5,6-trimethylphenyl)-as white crystals. Heptanoic acid (12.7 g, 79.0%) was obtained. Compounds 11 to 12 can be produced in the same manner as described above.

[Table 2]

Reference Example 3 7- (4-Fluorophenyl) -7- (2-hydroxy-3,4,6-trimethylphenyl) heptanoic acid (10.0 g) obtained in Example 2 and dichloromethylmethyl Ether (6.0 ml) in dichloromethane (100 m
l) Titanium tetrachloride (9.2 ml) was added to the solution at -14 to -9.
It was added dropwise at ° C. After stirring was continued for 30 minutes while keeping the reaction solution at -10 ° C, ice water (100 ml) was poured and the mixture was stirred vigorously. The dichloromethane layer was separated, washed with water, dried and concentrated under reduced pressure. The residue was recrystallized from tetrahydrofuran-isopropyl ether to give 7- (4-fluorophenyl)-.
7- (5-Formyl-2-hydroxy-3,4,6-trimethylphenyl) heptanoic acid (9.92 g) was obtained. Nuclear magnetic resonance spectrum (δ value based on tetramethylsilane in deuterated chloroform): 1.04-2.60 (10
H), 2.10 (3H), 2.45 (3H),
2.53 (3H), 4.56 (1H), 6.82-
7.36 (4H), 10.58 (1H)

Reference Example 4 7- (4-Fluorophenyl) -7- (5-formyl-2-hydroxy-3,4,4
Sodium borohydride (0.25 g) was added to a solution of 6-trimethylphenyl) heptanoic acid (5.0 g) in tetrahydrofuran (50 ml) at 2 ° C., and the mixture was stirred for 1 hour. Ethyl acetate and water were added to the reaction solution, and the mixture was stirred and separated. The organic layer was separated, and the washing with water was repeated twice. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and the resulting residue was recrystallized from tetrahydrofuran-acetonitrile to give 7-
(4-fluorophenyl) -7- (2-hydroxy-5
-Hydroxymethyl-3,4,6-trimethylphenyl)
Heptanoic acid (4.5 g) was obtained. Nuclear magnetic resonance spectrum ([delta] values were referenced to tetramethylsilane in _{DMSO-d 6): 0.96-1.55 (} 6H), 1.98-2.30
(4H), 2.07 (3H), 2.21 (6H), 4.15-4.83 (4H), 7.01 (2H),
7.21 (2H), 7.82 (1H), 11.94 (1H)

Example 3 [Synthesis of 7- (2-hydroxy-3,4,6-trimethylphenyl) -7-phenylheptanoic acid] 7-phenyl-6-heptenoic acid (10 g) and 2,3,5
After dissolving trimethylphenol (8.3 g) in dichloromethane (80 ml), methanesulfonic acid (9.4) was dissolved.
g) was added dropwise at 17-25 ° C. After stirring at 25 ° C. for 6 hours, water (80 ml) was added, and the dichloromethane layer was separated and washed three times with water. Dichloromethane was distilled off under reduced pressure, and the obtained residue was recrystallized from toluene (38 ml) to give 7- (2-hydroxy-3,4,4) as white crystals.
6-Trimethylphenyl) -7-phenylheptanoic acid (14.2 g, yield 85.2%) was obtained.

Reference Example 5 7- (2-Hydroxy-3,4,6-trimethylphenyl) -7-phenylheptanoic acid (5.0 g) was mixed with acetonitrile (25 ml), water (10 ml) and 25% ammonia water ( 1 ml), and then dissolved in a 3% aqueous solution of potassium nitrosodisulfonate (Phremy salt) (280 m2).
l) was added and the mixture was stirred at 2-4 ° C for 2 hours. The reaction solution was adjusted to acidic by adding hydrochloric acid, and the product was extracted with ethyl acetate.
The ethyl acetate layer was washed twice with water. Ethyl acetate was distilled off under reduced pressure, and the obtained residue was recrystallized from an acetonitrile-water mixture (6: 4) to give 7- as yellow crystals.
(3,5,6-trimethyl-1,4-benzoquinone-2
-Yl) -7-phenylpentanoic acid (4.90 g, yield 9)
4.1%).

Comparative Example 1 7-phenyl-6-heptenoic acid (4.7 g), 2,3,5
-Trimethylhydroquinone (5.6 g) and p-toluenesulfonic acid (18.6 g) were dissolved in 1,2-dichloroethane (94 ml) and stirred at 82 to 83 ° C for 1 hour. After evaporating the solvent under reduced pressure, the residue was purified with ethyl acetate (100 m
l) and the washing was repeated three times with water (50 ml).
The residue obtained by evaporating the ethyl acetate under reduced pressure was subjected to silica gel chromatography, and 7- (3,5,6-trimethyl-1,4-hydroquinon-2-yl) -7-phenylheptenoic acid (1 0.5 g, 18% yield). The reaction was attempted under the following conditions in the same manner as described above, but none of the desired products was obtained.

[Table 3]

[0020]

According to the method of the present invention, a desired intermediate can be produced in good yield by using raw materials that can be easily produced.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07C 51/353 C07C 51/353 59/52 59/52 59/56 59/56 59/84 59/84 59/88 59/88 67/343 67/343 69/65 69/65 69/732 69/732 Z 69/734 69/734 Z 235/34 235/34 // C07B 61/00 300 C07B 61/00 300 (56) JP-A-59-231058 (JP, A) JP-A-55-102565 (JP, A) JP-A-1-238549 (JP, A) JP-A-2-152940 (JP, A) JP-A-61-44840 (JP, A) JP, A) Chemical Abstracts (1972), Vol. 76, p. 454, column 112836C Zh. Obshch. Khim. (1983), 53 (9), p. 2098-2104 (58) Fields investigated (Int.Cl. ⁶ , DB name) C07C 39/15 C07C 37/14 C07C 41/30 C07C 43/23 C07C 51/353 C07C 59/52 C07C 59/56 C07C 59 / 84 C07C 59/88 C07C 67/343 C07C 59/65 C07C 69/732 C07C 69/734 C07C 235/34 CA (STN) REGISTRY (STN)

Claims (8)

(57) [Claims] 1. A compound of the general formula [In the formula, R ¹ represents an optionally protected hydroxyl group, R ² and R ³ are the same or different and represent a methyl group or a methoxy group, and R ⁴ represents a hydrogen atom or an optionally protected hydroxyl group. And a phenol derivative represented by the general formula: [In the formula, X is a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group, Y is a methyl group, a hydroxymethyl group which may be O-substituted, or a carboxyl group which may be esterified or amidated. To n
Represents an integer of 1 to 15. Wherein the stilbene derivative represented by the general formula is reacted in the presence of methanesulfonic acid. Wherein each symbol is as defined above. ] The manufacturing method of the diphenylmethane derivative represented by these. 2. The process according to claim 1, wherein the reaction is carried out at -20 ° C. to 50 ° C. (3) a phenol derivative (I) having a content of 0.5 to
2. The process according to claim 1, wherein the stilbene derivative (II) is reacted in a 1.5-fold molar amount. 4. The phenol derivative (I) has an amount of from 0.5 to
2. The process according to claim 1, wherein 20 times moles of methanesulfonic acid are present. 5. The method of claim 5, wherein the optionally substituted hydroxymethyl group represented by Y is a hydroxymethyl group, a methoxymethyl group, an acetoxymethyl group, a 2-tetrahydropyranyloxymethyl group, a benzyloxymethyl group, or a nitrooxymethyl group. 2. The method according to claim 1, which is a group, aminocarbonyloxymethyl group, mono- or di-lower alkylaminocarbonyloxymethyl group, phenylaminocarbonyloxymethyl group, cyclic aminocarbonyloxymethyl group or t-butyldimethylsilyloxymethyl group. Law. 6. A carboxyl group, which may be amidated, represented by Y is a carboxyl group, an aminocarbonyl group,
Mono- or di-alkylaminocarbonyl having 1 to 4 carbon atoms, benzylaminocarbonyl, α-phenethylaminocarbonyl, β-phenethylaminocarbonyl, 1- (α-naphthyl) ethylaminocarbonyl,
Phenylaminocarbonyl group, p-hydroxyphenylaminocarbonyl group, p-methoxyphenylaminocarbonyl group, m-chlorophenylaminocarbonyl group, p
-Bromophenylaminocarbonyl group, diphenylaminocarbonyl group, hydroxyaminocarbonyl group, N-
2. The process according to claim 1, which is a hydroxy-N-methylaminocarbonyl group, an N-hydroxy-N-phenylaminocarbonyl group, or a 5- or 6-membered cyclic aminocarbonyl group which may have oxygen or sulfur other than nitrogen. Law. (7) Y is a carboxyl group, aminocarbonyloxymethyl group or mono-
The method according to claim 1, which is a lower alkylaminocarbonyloxymethyl group. 8. A compound of the general formula [In the formula, R ¹ represents an optionally protected hydroxyl group, R ² and R ³ are the same or different and represent a methyl group or a methoxy group, and R ⁴ represents a hydrogen atom or an optionally protected hydroxyl group. And a phenol derivative represented by the general formula: [In the formula, X is a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group, Y is a methyl group, a hydroxymethyl group which may be O-substituted, or a carboxyl group which may be esterified or amidated. To n
Represents an integer of 1 to 15. Is reacted in the presence of methanesulfonic acid to give a stilbene derivative of the general formula Wherein each symbol is as defined above. Wherein R ¹ and / or R ⁴ in the resulting diphenylmethane derivative (III) are protected hydroxyl groups, are deprotected and then oxidized. General formula Wherein each symbol is as defined above. ] The manufacturing method of the quinone represented by these.