JPH0748282A - Optically active phenolic derivative and production thereof - Google Patents

Abstract

PURPOSE:To obtain an optically active phenolic derivative by reacting a phenolic compound with an optically active secondary carbinol compound in the presence of a tri-substituted phosphine and a diazodicarboxylate or a diazodicarboxamide. CONSTITUTION:This method for producing an optically active tri-substituted methane compound expressed by formula III (R<1> to R<4> are each H or groups without participating in the reaction or the adjacent two are mutually bound to form a ring together with C; Q is an aromatic ring; R is a group without participating in the reaction; * denotes asymmetric C) is to react a phenolic compound, expressed by formula I and unsubstituted at the o- and/or the p- position with an optically active secondary carbinol compound, expressed by formula II and having an aromatic group at the alpha-position in the presence of a tri-substituted phosphine and a diazodicarboxylate or a diazodicarboxamide in an inert solvent (e.g. 1,2-dichloroethane) at -30 to +70 deg.C. The subject compound is useful as a medicine and a synthetic intermediate therefor and has treating and preventing actions on cerebropathy, cardiopathy, nephropathy and diseases in the pulmonary circulatory and respiratory systems, allergy, inflammation, etc.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an optically active phenol derivative useful as a drug or the like and a synthetic intermediate thereof, and a novel method for producing the same. INDUSTRIAL APPLICABILITY The novel phenol derivative of the present invention has effects for treating and preventing brain, heart, kidney and lung cardiovascular diseases, respiratory diseases, allergies, anaphylactic shock, endotoxin shock, inflammation, etc., or suppressing angiogenesis by tumor cells, etc. Have.

[0002]

Thromboxane A ₂ in the Background of the Invention Arachidonic acid cascade, prostaglandin H _2, eicosanoid receptor antagonist agents such prostaglandin D _2, inhibit certain 5-lipoxygenase in initial enzyme in the biosynthesis of leukotrienes Synthetic studies of substances, substances that antagonize receptors, substances that suppress the elimination or generation of reactive oxygen species, and the like are underway. For example, JP-A-2-152940 discloses a benzene derivative having these actions. ing. However, the compounds described herein are optically inactive racemates. The method for introducing an alkyl group or an aralkyl group into the ortho position of a phenol compound is an acid-catalyzed Friedel-Crafts reaction (for example, BR Castro, “Organic Reactions,” Vol. 2).
9, John Wiley & Sons, Inc., New York, 1983.
p.1) is known as a general method. In this method, the phenol derivative obtained by condensation with α-substituted benzyl alcohol is a racemate as disclosed in, for example, JP-A-2-152940. On the other hand, it has been reported that a corresponding alkylaryl ether can be obtained in good yield in a condensation reaction of a phenol compound and an alcohol by a combination of triphenylphosphine and diethyl diazodicarboxylate, a so-called Mitsunobu reaction (for example, O. Mitsunobu, Synthesis, 1981, 1)
There is no report that directly introduces a carbon substituent into the 2-position carbon on the phenol ring as in the present case.

[0003]

DISCLOSURE OF THE INVENTION The present invention combines the active oxygen species scavenging action, the eicosanoid receptor antagonistic action such as thromboxane A ₂ , prostaglandin H ₂ , and prostaglandin D ₂ or the 5-lipoxygenase inhibiting action. Having, brain, heart, kidney and lung cardiovascular disease, respiratory disease,
It is intended to provide a novel optically active phenol derivative having an excellent pharmacological action such as an angiogenesis inhibitory action as well as a therapeutic and preventive action against allergy, anaphylactic shock, endotoxin shock, inflammation and the like. Further, the present invention is a method of introducing a carbon substituent to the 2-position carbon on the phenol ring in a relaxed and simple manner without using an acid catalyst, and the configuration of the 2-position carbon substituent of phenol can be controlled.
The present invention provides a method for producing a novel optically active phenol derivative.

[0004]

[Means for Solving the Problems] That is, the present invention provides a phenol compound (I) which is unsubstituted at the ortho or / and para position and an optically active secondary carbinol compound (II) having an aromatic ring group at the α-position. Of a tri-substituted methane compound having an aromatic ring group and a phenyl group having a hydroxyl group at the ortho or para position as a substituent characterized by reacting a tri-substituted phosphine with a diazodicarboxylate or diazodicarboxamide Method for producing optically active substance (III), and general formula

[Chemical 4] [In the formula, R ₁ represents an optionally protected hydroxyl group. R ₂
Represents a hydrogen atom, a hydroxyl group, a lower alkyl group or a lower alkoxy group. R ₃ is a hydrogen atom, a hydroxyl group, an optionally substituted alkyl group having 1 to 8 carbon atoms, an optionally substituted aralkyl group, a halogen atom, an optionally protected formyl group, or an alkyl group having 2 to 7 carbon atoms. Acyl group, carboxyl group which may be esterified or amidated, -CH
= CHR ₆ group (R ₆ is a lower alkyl group or lower acyl group.) Or -CH = NR ₇ (R ₇ is a hydroxyl group, a lower alkoxy group, lower alkenyloxy group or benzhydryloxy group.) The Show. R ₄ is an optionally substituted alkyl group having 1 to 8 carbon atoms, an optionally substituted aralkyl group, a halogen atom, an optionally protected formyl group, an acyl group having 2 to 7 carbon atoms, esterification Or an optionally amidated carboxyl group, -CH =
CHR ₆ (R ₆ is as defined above) or —CH═
NR ₇ (R ₇ is as defined above). R ₅ represents a hydrogen atom or a lower alkyl group. Alternatively, R ₂ ,
R _3, R ₄ and R ₅ are bonded to two of their adjacent one another, - (CH _{2) a} - group (a is 3 or 4.), - CH = CH -CH = CH- group, - (CH _{2) b}
-CO- group (b is 2 or 3) or-(CH
₂ ) An _l- CO-O- group (l is 1 or 2) may be formed. X represents a phenyl group or a thienyl group which may be substituted at its para-position with a halogen atom, a lower alkyl group or a lower alkoxy group. Y is a methyl group,
It represents a hydroxymethyl group which may be substituted, a carboxyl group which may be esterified or amidated, a cyano group or a tetrazolyl group. n is 3 to 1 A derivative. The above-mentioned phenol compound (I) may be such that at least one of its ortho-position and para-position is unsubstituted, and other positions may be unsubstituted,
It may be substituted with various substituents that do not participate in the reaction.

That is, the phenol compound (I) can be represented by the following general formula.

[Chemical 5] (In the formula, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same or different and represent a hydrogen atom or a group which does not participate in the reaction, and these two adjacent groups are bonded to each other to form a bond. A ring may be formed with a carbon atom on the benzene ring, provided that at least one of R ³ and R ⁵ is a hydrogen atom.) As the group represented by R ^{1 to} R ⁵ that does not participate in the reaction, For example, lower alkyl group, lower alkenyl group, lower alkoxy group, cycloalkyl group, cycloalkyloxy group, lower alkylthio group, aralkyl group, aralkyloxy group, aralkylthio group, formyl group, acyl group, acyloxy group, halogen atom, cyano Group, represented by the general formula: —CH═N-OA (wherein A represents a lower alkyl group, a lower alkenyl group or an optionally substituted aralkyl group). The group, other protected hydroxyl group of the esterified or amidated carboxyl group. Further, as an example of the case where these two adjacent groups form a ring together with the carbon atom on the benzene ring to which they are bonded, examples of the two adjacent groups of R ^{1 to} R ⁵ include, for example,
(CH _{2) a} - group (a is 3 or 4.), - CH =
CH-CH = CH- group, - (CH _{2) b} -CO- group (. B is 2 or 3), or

[Chemical 6]

Examples of the lower alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethylpropyl, hexyl, isohexyl, Examples thereof include those having 1 to 6 carbon atoms such as 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl. This lower alkyl group has, for example, one carbon atom.
~ 4 alkoxy groups (eg, methoxy, ethoxy, etc.), protected hydroxyl groups (eg, tetrahydropyranyloxy, tetrahydrofuryloxy, trimethylsilyloxy, t
-Butylsilyloxy, t-butyldimethylsilyloxy, etc.), an optionally substituted aralkyloxy group (eg, benzyloxy, diphenylmethyloxy, 4-
Methoxybenzyloxy, 4-bromobenzyloxy, etc.), an acyloxy group having 2 to 7 carbon atoms (eg, acetoxy, propionyloxy, etc.), an optionally substituted benzoyloxy group (eg, benzoyloxy, 4-methylbenzoyloxy) , 4-methoxybenzoyloxy, 4
-Bromobenzoyloxy etc.), and examples of the substituted lower alkyl group include, for example, methoxymethyl, methoxyethyl, ethoxymethyl, tetrahydropyranyloxymethyl, tetrahydropyranyloxyethyl, trimethylsilyl. Oxymethyl, trimethylsilyloxyethyl, tert-butyldimethylsilyloxymethyl, tert-butyldimethylsilyloxyethyl, benzyloxymethyl, benzyloxyethyl, diphenylmethyloxymethyl, diphenylmethyloxyethyl, 4-methoxybenzyloxymethyl, 4- Methoxybenzyloxyethyl, 4-bromobenzyloxymethyl, 4-bromobenzyloxyethyl, acetoxymethyl, acetoxyethyl, propionyloxymethyl, propioni Oxyethyl, benzoyloxymethyl, benzoyloxyethyl, 4-methylbenzoyloxymethyl, 4-methylbenzoyloxyethyl, 4-methoxybenzoyloxymethyl, 4-methoxybenzoyloxyethyl, 4-bromobenzoyloxymethyl, 4-bromobenzoyloxy Examples thereof include ethyl.

Examples of the lower alkenyl group include vinyl, 1-propenyl, 2-propenyl, 1-butenyl,
2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 5-hexenyl and the like having 2 to 6 carbon atoms can be mentioned. . These are acyl groups (eg acetyl, propionyl, butyryl,
Isobutyryl, valeryl, isovaleryl, pivaloyl,
Alkanoyl groups such as hexanoyl, for example, cyclopentanecarbonyl, cycloalkanecarbonyl such as cyclohexanecarbonyl, etc.). Examples of the lower alkoxy group include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, te.
rt-pentyloxy, 1-ethylpropoxy, hexyloxy, isohexyloxy, 1,1-dimethylbutoxy, 2,2-dimethylbutoxy, 3,3-dimethylbutoxy, 2-ethylbutoxy and the like having 1 to 6 carbon atoms Is mentioned. These may be further substituted, and examples of the substituted lower alkoxy group include those in which the substituted lower alkyl portion is the same as the substituted lower alkyl.

Examples of the cycloalkyl group include those having 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Examples of the cycloalkyloxy group include those having 3 to 6 carbon atoms such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy. Examples of the lower alkylthio group include those in which the lower alkyl portion is the above lower alkyl. Further, it may be substituted similarly to the lower alkyl. Examples of the aralkyl group include benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, (1
Examples thereof include those having 7 to 13 carbon atoms such as -naphthyl) methyl, (2-naphthyl) methyl and diphenylmethyl. These may have a substituent at any position on the benzene ring, and such a substituent has, for example, 1 carbon atom.
~ 4 alkyl (eg, methyl, ethyl, etc.), carbon number 1
4 alkoxy (eg, methoxy, ethoxy, etc.), C2-C5 alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, etc.), halogen atom (fluorine,
Chlorine, bromine, etc.). Aralkyloxy group,
Examples of the aralkylthio group include those whose aralkyl part is the above aralkyl group, and these may be substituted similarly to the aralkyl group.

The above formyl group may be substituted,
Examples of the optionally substituted formyl group include an unsubstituted formyl group and, for example, 1,3-dioxolane-
2-yl, 1,3-dioxan-2-yl, 1,3-oxathiolan-2-yl, dialkoxymethyl (alkoxy has 1 to 4 carbon atoms) and the like can be mentioned. Examples of the acyl group include lower alkanoyl groups such as acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl and hexanoyl, and cycloalkanecarbonyl groups such as cyclopentanecarbonyl group and cyclohexanecarbonyl group having 2 to 7 carbon atoms. Can be mentioned. Examples of the acyloxy group include those whose acyl moiety is the above acyl group. Examples of the halogen atom include fluorine, chlorine, bromine and the like.

The lower alkyl group represented by A in the formula —CH═N-OA is, for example, one having 1 to 4 carbon atoms such as methyl, ethyl and propyl, and the lower alkenyl group is, for example, vinyl, 1-propenyl. 1 to 1 carbon number
And the aralkyl group which may be substituted may include, for example, benzyl, 1-phenylethyl, 2-
Phenylethyl, 3-phenylpropyl, (1-naphthyl) methyl, (2-naphthyl) methyl, diphenylmethyl and the like, which may have a substituent at any position on the benzene ring, Examples of such a substituent include alkyl having 1 to 4 carbons (eg, methyl, ethyl, etc.), alkoxy having 1 to 4 carbons (eg, methoxy,
Ethoxy, etc.), alkoxycarbonyl having 2 to 5 carbon atoms (eg, methoxycarbonyl, ethoxycarbonyl, etc.),
Examples include halogen atoms (fluorine, chlorine, bromine, etc.). Examples of the esterified carboxyl group include lower alkoxycarbonyl (eg, methoxycarbonyl,
C2-C5 such as ethoxycarbonyl, tert-butyloxycarbonyl, etc., Aralkyloxycarbonyl (for example, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, benzhydryloxycarbonyl, etc.) 8 to 14), and aryloxycarbonyl (eg, phenoxycarbonyl, 4-methylphenyloxycarbonyl, 4-methoxyphenyloxycarbonyl and the like having 7 to 10 carbon atoms).

As the amidated carboxyl group,
Substituted aminocarbonyl substituted by carbamoyl and alkyl having 1 to 4 carbon atoms (eg, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, etc.), cyclic aminocarbonyl (eg, , Morpholinocarbonyl, piperidinocarbonyl, pyrrolidinocarbonyl, thiomorpholinocarbonyl, etc.), aralkylaminocarbonyl [eg, benzylaminocarbonyl, α-phenethylaminocarbonyl, β-phenethylaminocarbonyl, 1- (α-naphthyl) ethylamino Carbonyl or the like having 7 to 13 carbon atoms], phenylaminocarbonyl,
Substituted phenylaminocarbonyl (eg, p-methylphenylaminocarbonyl, 4-methoxyphenylaminocarbonyl, 4-chlorophenylaminocarbonyl,
4-bromophenylaminocarbonyl, 4-fluorophenylaminocarbonyl and the like), diphenylaminocarbonyl and the like. Examples of protected hydroxyl groups include, for example, methoxymethyloxy, tetrahydropyranyloxy, tetrahydrofuryloxy, trimethylsilyloxy, tert-butyldimethylsilyloxy, 2-
Examples thereof include those protected by a usual protective group for a hydroxyl group such as (trimethylsilyl) ethoxymethoxy.

The phenol compound (I) has an ortho position which is unsubstituted, that is, a compound of the general formula

[Chemical 7] (In the formula, R ¹ , R ² , R ³ and R ⁴ are the same or different and each represents a hydrogen atom or a group that does not participate in the reaction). Among the compounds represented by formula (I-2), those in which at least two of R ¹ , R ² , R ³ and R ⁴ are not hydrogen atoms are preferable, and those in which both R ¹ and R ² are not hydrogen atoms are more preferable. preferable. The secondary carbinol compound (II) is an optically active substance having an aromatic ring group at its α-position, and has the general formula . ).

Examples of the aromatic ring group represented by Q include an aromatic hydrocarbon group and an aromatic heterocyclic group. Examples of the aromatic hydrocarbon group include a phenyl group and a naphthyl group (1
Aryl groups such as -naphthyl group and 2-naphthyl group). The aromatic heterocyclic group contains at least one of an oxygen atom, a sulfur atom and a nitrogen atom as a ring-constituting atom, and specific examples thereof include furyl, thienyl, oxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl. Aromatic monocyclic heterocyclic groups such as benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, quinolyl, isoquinolyl,
Examples thereof include aromatic condensed heterocyclic groups such as quinoxalyl. These aromatic hydrocarbon group and aromatic heterocyclic group,
The ring may optionally have a substituent, and examples of such a substituent include a halogen atom (fluorine, chlorine,
Bromine, etc.), alkyl groups having 1 to 3 carbon atoms such as methyl and ethyl, alkoxy groups having 1 to 3 carbon atoms such as methoxy and ethoxy, formyl group, acetyl group, cyano group, phenyl group, benzoyl group, methylenedioxy group, Examples thereof include a trimethylene group, a nitro group, a trifluoromethyl group, a trifluoromethoxy group and a pentafluoroethyl group.

The group not participating in the reaction represented by R includes a hydrocarbon residue or an aromatic heterocyclic group, and the aromatic heterocyclic group includes the aromatic heterocyclic group represented by Q above. Examples of the hydrocarbon group include an aliphatic chain hydrocarbon group, an alicyclic hydrocarbon group, an aromatic hydrocarbon group, and an araliphatic hydrocarbon group. Examples of the aliphatic chain hydrocarbon group include a straight chain or branched chain aliphatic hydrocarbon group such as an alkyl group, an alkenyl group and an alkynyl group. Examples of the alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, se
c-butyl, tert-butyl, pentyl, isopentyl,
Neopentyl, tert-pentyl, 1-ethylpropyl,
Hexyl, isohexyl, 1,1-dimethylbutyl,
2,2-dimethylbutyl, 3,3-dimethylbutyl, 2
-Ethylbutyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, docosyl and the like having 1 to 22 carbon atoms can be mentioned. Of these, linear ones are preferable. Examples of the alkenyl group include vinyl,
Allyl, isopropenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-
Butenyl, 2-ethyl-1-butenyl, 3-methyl-2
-Butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 3-heptenyl , 3,7-Dioctenyl, 3,7-dinonenyl, 3,
Examples thereof include those having 2 to 22 carbon atoms such as 7-didecenyl. Of these, linear ones are preferable.

Examples of the alkynyl group include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl,
2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 3-heptynyl, 4- Examples thereof include those having 2 to 22 carbon atoms such as octynyl, 5-decynyl, 5-undecynyl, and 5,10-didodecynyl. Of these, linear ones are preferable. These alkyl group, alkenyl group and alkynyl group may have a substituent, and examples of the substituent include methoxy, acetoxy, benzoyloxy, and an alkyl group having 1 to 3 carbon atoms as a substituent (eg, methyl group). , Ethyl, etc.), carbon number 1
Benzoyloxy having an alkoxy group of 3 to 3 (eg, methoxy, ethoxy, etc.) and / or a halogen atom (fluorine, chlorine, bromine, etc.) [eg, 4-
Methylbenzoyloxy, 4-methoxybenzoyloxy, 4-chlorobenzoyloxy, 4-bromobenzoyloxy, etc.], benzyloxy, benzhydryloxy, nitroxy, substituted aminocarbonyloxy (eg methylaminocarbonyloxy, ethylaminocarbonyloxy , Phenylaminocarbonyloxy, etc.), cyclic aminocarbonyloxy (eg, morpholinocarbonyloxy, pyrrolidinocarbonyloxy,
(Piperidinocarbonyloxy, thiomorpholinocarbonyloxy, etc.), trimethylsilyloxy, tert-butyldimethylsilyloxy, and other esterified or amidated carboxyl groups. Examples of the esterified carboxyl group and the amidated carboxyl group are the same as those of R ^{1 to} R ⁵ . These substituents can be substituted at any position, but those substituted at the terminal are preferred.

The alicyclic hydrocarbon group may be saturated or unsaturated, and examples thereof include a cycloalkyl group, a cycloalkenyl group and a cycloalkadienyl group. Examples of the cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1]. Octyl, Bicyclo [3.2.
2] Nonyl, bicyclo [3.3.1] nonyl, bicyclo [4.2.1] nonyl, bicyclo [4.3.1] decyl and the like having 3 to 10 carbon atoms. Examples of the cycloalkenyl group include 2-cyclopenten-1-yl,
3-cyclopenten-1-yl, 2-cyclohexene-
Carbon number 3 such as 1-yl, 3-cyclohexen-1-yl
~ 6 are mentioned. Examples of the cycloalkadienyl group include 2,4-cyclopentadiene-1-yl, 2,4-cyclohexadiene-1-yl, 2,5-
Examples thereof include those having 5 to 7 carbon atoms such as cyclohexadiene-1-yl.

The aromatic hydrocarbon group is the same as the aromatic hydrocarbon group represented by Q, and may also have a substituent. The araliphatic hydrocarbon group means an alkyl group having the above aromatic hydrocarbon group as a substituent, and the aromatic hydrocarbon group may have the same substituent as the above aromatic hydrocarbon group. Of course, examples of the alkyl group include alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl and propyl. Examples of the araliphatic hydrocarbon group include benzyl, phenethyl, 3-phenylpropyl, (1-naphthyl) methyl, (2-naphthyl) methyl and the like, and among them, benzyl, phenethyl and the like are preferable. This araliphatic hydrocarbon group may have a substituent at any position on its aromatic ring. Examples of this substituent are the same as the above-mentioned aromatic hydrocarbon substituents.

The compound represented by the general formula (II) has Q and R
Are different from each other. The trisubstituted phosphine is usually the general formula _{^{(R 6) 3 P (IV}} ) ( wherein, R ⁶ is. Showing a phenyl group which is an alkyl group or substituted C1-8) with a compound represented by is there. The optionally substituted phenyl group represented by R ⁶ includes, for example, an unsubstituted phenyl group,
2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-methoxyphenyl and the like can be mentioned. R
Examples of the alkyl group having 1 to 8 carbon atoms represented by ⁶ include methyl, ethyl, propyl, butyl, pentyl, hexyl,
Examples include heptyl and octyl.

The diazodicarboxylate and diazodicarbosamide used in the present invention are both represented by the general formula R ⁷ --CO--N = N--CO--R ⁸ (V) (wherein R ⁷ and R ⁸ are the same or And a lower alkoxy group, a di-lower alkylamino group or a cyclic amino, which are different from each other.) (Hereinafter sometimes simply referred to as compound (V)). Examples of the lower alkoxy group represented by R ⁷ and R ⁸ include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec.
-Butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, 1-ethylpropoxy, hexyloxy, isohexyloxy, 1,1-dimethylbutoxy, 2,2-dimethylbutoxy, 3 , 3-dimethylbutoxy, 2-ethylbutoxy and the like having 1 to 6 carbon atoms, preferably those having 1 to 3 carbon atoms. These may be further substituted, and examples of the substituted lower alkoxy group are the same as the substituted lower alkyl in which the substituted lower alkyl moiety is the substituent of the phenol compound (I). Can be mentioned. Examples of the di-lower alkylamino group represented by R ⁷ and R ⁸ include dimethylamino, diethylamino, diisopropylamino and the like. Further, as the cyclic amino group represented by R ⁷ and R ⁸ ,
Examples thereof include piperidino group, pyrrolidino group and morpholino group.

The reaction in the present invention is carried out by reacting the phenol compound (I) with the optically active secondary carbinol compound (II) in the presence of the tri-substituted phosphine (IV) and the compound (V). This reaction is performed with an inert solvent such as dichloromethane, chloroform, 1,
2-dichloroethane, diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, benzene, toluene, pentane, hexane, cyclohexane, tert-
It is carried out in butanol or the like or a mixed solvent thereof in a temperature range of about -30 ° C to 70 ° C, preferably-
It is performed in a temperature range of 20 ° C to 40 ° C. In addition, the starting phenol compound (I) used in this reaction is in excess (2-fold to 15-fold molar amount, relative to compound (II)).
It is preferably carried out in a 5-fold to 10-fold molar amount). Trimethylphosphine (IV) is used in an amount of 1 to 2 times, preferably 1 to 1.2 times the mol of the phenol compound. Compound (V) is 1 against phenol compound
˜2 times mole, preferably 1 to 1.2 times mole.

In this reaction, the phenol compound (I) reacts with the optically active secondary carbinol compound to obtain an optically active tri-substituted methane compound (III). In this reaction, carbon to which the hydroxyl group of the secondary carbinol is bonded is bonded to carbon in the ortho position and / or para position of the phenol compound (I). For example, when a compound represented by the general formula (II-1) is reacted with a phenol compound represented by the general formula (I-2) in which R ³ is not hydrogen,

[Chemical 8] (Wherein each symbol has the same meaning as defined above, provided that R ³ is not hydrogen).
Further, as the phenol compound (I), those in which the para position is unsubstituted and the carbon in the ortho position is substituted, that is, in the general formula (I-1), R ³ is hydrogen and R ¹ and R ⁵ are not hydrogen. When this is reacted with secondary carbinol, the general formula

[Chemical 9] (Wherein R ¹ , R ² , R ⁴ , R ⁵ , Q and R have the same meanings as described above, provided that R ¹ and R ⁵ are not hydrogen). When both ortho and para positions are unsubstituted, they react with the secondary carbinol compound (II) at both ortho and para positions, but the ortho position reacts preferentially,
The obtained tri-substituted methane compound (III) tends to produce a larger amount of a compound having a phenol having a hydroxyl group at the ortho position than a phenol having a hydroxyl group at the para position.

The optically active tri-substituted methane compound (III) obtained in this reaction has the absolute configuration inverted from that of the compound (II), and the optical purity is almost maintained. The target compound (III) thus obtained is isolated from the reaction mixture by conventional separation and purification means such as extraction, concentration,
It can be isolated by using means such as filtration, recrystallization, column (or thin layer) chromatography and the like. The optically active compound (III) obtained by the present invention has, for example, a medicinal action per se, or is useful as a pharmaceutical intermediate. The optically active tri-substituted methane compound (III) obtained by the present invention is disclosed in
According to the method described in 52940, the compounds described in these publications can be converted into optically active forms.

Examples of the optionally protected hydroxyl group represented by R ₁ in the novel optically active phenol derivative represented by the general formula (A) of the present invention include hydroxyl group, lower alkoxy (eg, methoxy, ethoxy, propoxy, etc.). C1-4), methoxymethyloxy, benzyloxy, lower acyloxy (eg, formyloxy, acetoxy, propionyloxy and other C1-4),
Tetrahydropyranyloxy etc. are mentioned. Examples of the lower alkyl group represented by R ₂ include methyl,
Examples thereof include those having 1 to 4 carbon atoms such as ethyl, propyl, isopropyl, butyl, isobutyl and t-butyl.
Examples of the lower alkoxy group represented by R ₂ include those having 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and t-butoxy.

Examples of the optionally substituted alkyl having 1 to 8 carbon atoms represented by R ₃ and R ₄ include methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
In addition to unsubstituted alkyl such as t-butyl, pentyl, hexyl, peptyl and octyl, one or more hydroxyl groups, a lower alkoxy group as defined in the above R ₂ , halogen (eg fluorine, chlorine, bromine etc.) and / or These alkyl groups substituted by a carboxyl group (for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, carboxymethyl, 2-carboxyethyl, methoxymethyl, trifluoromethyl, chloromethyl, etc.) can be mentioned. Examples of the optionally substituted aralkyl group represented by R ₃ and R ₄ are benzyl,
Examples thereof include those having 7 to 13 carbon atoms such as 1-phenylethyl, 2-phenylethyl and diphenylmethyl, and these are 1 to 5 at any position on the benzene ring, preferably 1 to
It may have three substituents, and examples of such a substituent include a halogen atom such as fluorine, chlorine and bromine. Examples of the halogen atom represented by R ₃ and R ₄ include fluorine, chlorine, bromine and the like. Examples of the acyl group having 2 to 7 carbon atoms represented by R ₃ and R ₄ include alkylcarbonyl such as acetyl, propionyl, butyryl and valeryl.

The optionally protected formyl group represented by R ₃ and R ₄ is not only an unsubstituted formyl group but also 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-oxathiolan-2-yl, dialkoxymethyl (alkoxy has 1 to 4 carbon atoms) and the like can be mentioned. Examples of the esterified carboxyl group represented by R ₃ and R ₄ include lower alkoxycarbonyl (eg, those having 2 to 5 carbon atoms such as methoxycarbonyl, ethoxycarbonyl) and aralkyloxycarbonyl (eg, benzyloxycarbonyl having 8 to 10 carbon atoms). ), And aryloxycarbonyl (for example, phenoxycarbonyl, 4-methoxyphenyloxycarbonyl, 4-methoxyphenyloxycarbonyl and the like having 7 to 10 carbon atoms). Further, as the amidated carboxyl group represented by R ₃ and R ₄ , in addition to an unsubstituted aminocarbonyl, a substituted aminocarbonyl in which the amino group is substituted with a hydroxyl group or an alkyl group having 1 to 4 carbon atoms (for example, methylamino). Carbonyl, ethylaminocarbonyl, isopropylaminocarbonyl, dimethylaminocarbonyl, hydroxylaminocarbonyl, etc.), cyclic aminocarbonyl (eg, morpholinocarbonyl, piperidinocarbonyl, pyrrolidinocarbonyl, piperazinocarbonyl, thiomorpholinocarbonyl, etc.) To be The cyclic aminocarbonyl may have a substituent such as a lower alkyl having 1 to 2 carbon atoms and a lower alkoxy having 1 to 2 carbon atoms at any position of the ring.

Examples of the lower alkyl group represented by R ₅ and R ₆ are the same as those defined for R ₂ . The lower acyl group represented by R ₆ is acetyl,
Examples thereof include alkylcarbonyl having 2 to 6 carbon atoms such as propionyl and butyryl. Examples of the lower alkoxy group represented by R ₇ include those having 1 to 8 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, hexyloxy and octyloxy. Examples of the lower alkenyloxy group represented by R ₇ include those having 2 to 6 carbon atoms such as ethenyloxy, 1-propenyloxy, 2-propenyloxy, 1-butenyloxy and 2-butenyloxy.

The halogen atom in the substituent of the phenyl group represented by X is the same as the halogen atom represented by R ₃ , but the lower alkyl group and the lower alkoxy group are the lower alkyl group and lower alkoxy group represented by R _2. The same thing can be mentioned. The hydroxymethyl group represented by Y may be substituted, and in addition to an unsubstituted hydroxymethyl group, for example, methoxymethyl, acetoxymethyl, 2-tetrahydropyranyloxymethyl,
Benzyloxymethyl, nitrooxymethyl, aminocarbonyloxymethyl, substituted aminocarbonyloxymethyl (eg, methylaminocarbonyloxymethyl, ethylaminocarbonyloxymethyl, dimethylaminocarbonyloxymethyl, phenylaminocarbonyloxymethyl), cyclic aminocarbonyloxy Methyl (eg, morpholinocarbonyloxymethyl, pyrrolidinocarbonyloxymethyl, piperazinocarbonyloxymethyl, piperidinocarbonyloxymethyl, thiomorpholinocarbonyloxymethyl), t-butyldimethylsilyloxymethyl, etc. are also esterified. Examples of the formed carboxyl group include lower alkoxycarbonyl groups having 2 to 4 carbon atoms such as methoxycarbonyl and ethoxycarbonyl. And the like. The amidated carboxyl group represented by Y may be a substituted aminocarbonyl in which the amino group is substituted, or a cyclic aminocarbonyl. As the substituent of the amino group of the substituted aminocarbonyl, for example, alkyl having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl and butyl, and 6 to 1 carbon atoms such as phenyl and naphthyl.
Aryl of 0 (these may have a substituent such as hydroxyl, amino, nitro, halogen, methyl, methoxy 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 dialkylamino (methylamino, ethylamino, isopropylamino, dimethylamino) carbonyl, aralkylamino [benzylamino, α-phenethylamino, β- Phenethylamino, 1- (α-naphthyl) ethylamino] carbonyl, phenylaminocarbonyl, substituted phenylamino (p-hydroxyphenylamino, p-methoxyphenylamino, m-chlorophenylamino, p-bromophenylamino) carbonyl, diphenylamino Carbonyl, hydroxyaminocarbonyl, N-hydroxy-N-methylaminocarbonyl, N-hydroxy-N-phenylaminocarbonyl, and amino acid residues obtained by removing one hydrogen from the amino group of an amino acid. (Glycine residue, arginine residue, histidine residue, aspartic acid, proline residue, phenylalanine residue, alanine residue, methionine residue, etc. leucine residue) carbonyl and the like. Examples of the cyclic aminocarbonyl include morpholinocarbonyl, piperidinocarbonyl, piperazinocarbonyl, pyrrolidinocarbonyl, thiomorpholinocarbonyl and the like. Y is preferably an optionally esterified carboxyl group, and particularly preferably a carboxyl group.

The optically active phenol derivative represented by the general formula (A) of the present invention has R and S isomers.
Preferred are those in which R ₁ is a hydroxyl group, and X is a group such as phenyl, 4-methylphenyl, 4-halogenophenyl group, 2-thienyl or 3-thienyl, and Y
Is a carboxyl group and the number (n) of methylene groups is 5 to 9 in terms of pharmacological effect. R ₄ and R ₅ are bonded to each other to represent a — (CH ₂ ) _a — group or — (CH ₂ ) _b —CO— group, or R ³ and R ⁴ are bonded to each other to — (CH ₂ ) _a
- group or a - (CH ₂₎ indicate a _b -CO- group or R
₄ is —CH═NR ₇ (R ₇ is methoxy, ethoxy or 2
-Propenyloxy) is preferred. R ₁ is a hydroxyl group, R ₂ , a methyl group for all of R ₂ , R ₃ and R ₅ , R ₄ is a methyl group, a formyl group, a hydroxymethyl group or an acetyl group, X is a 4-halogenophenyl group, n is 5 and Y is Those having a carboxyl group are also preferable. The following compounds are preferable as specific compounds. * (R) -7- (4-fluorophenyl) -7- (5-
Hydroxy-6,7-dimethyl-1-oxoindane-
4-yl) heptanoic acid- (R) -7- (4-fluorophenyl) -7- (2-
Hydroxy-5-hydroxymethyl-3,4,6-trimethylphenyl) heptanoic acid. (R) -7- (4-fluorophenyl) -7- (3-
Formyl-6-hydroxy-2,4,5-trimethylphenyl) heptanoic acid. (R) -7- (3-acetyl-6-hydroxy-2,
4,5-Trimethylphenyl) -7- (4-fluorophenyl) heptanoic acid (R) -7- (4-fluorophenyl) -7- (6-
Hydroxy-4,7-dimethylindan-5-yl) heptanoic acid

A part of the optically active phenol derivative represented by the general formula (A) of the present invention can be produced by the above-mentioned method for producing an optically active substance (III) of a tri-substituted methane compound. Moreover, a part thereof can be manufactured by the following method. In the general formula (A), Y is a carbamoimooxymethyl group, an N-substituted carbamoimooxymethyl group, a hydroxyaminocarbonyl group, an N-substituted hydroxyaminocarbonyl group, a hydroxymethyl group, a carboxyl group,
The compound having an alkoxycarbonyl group, an aminocarbonyl group, a substituted aminocarbonyl group, a cyano group, or a tetrazolyl group is represented by the following reaction formula 1 from a compound in which Y is a hydroxymethyl group, a carboxyl group, an alkoxycarboxyl group, or an acyloxymethyl group. It can also be conducted by a reaction known per se.

Reaction formula 1

[Chemical 10] (Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , X and n are as defined above), R ₈ and R ₉ are alkyl groups having 1 to 3 carbon atoms, and R ₁₀ is A hydrogen atom, a lower alkyl group or an aryl group having 1 to 6 carbon atoms, R ₁₁ and R ₁₂ are hydrogen atoms,
A lower alkyl group having 1 to 6 carbon atoms, a hydroxyl group, a lower alkoxy group having 1 to 6 carbon atoms or an aryl group is shown.
However, at least one of R ₁₁ and R ₁₂ is a hydroxyl group or carbon. Alternatively, in the phenol derivative represented by the general formula (A), a compound in which R ₂ is a hydrogen atom, a lower alkyl group or a lower alkoxy group, and R ₃ is a hydrogen atom or a lower alkyl group is the R ₄ position. Can also be obtained from the corresponding compound with no substitution by a reaction known per se shown in Reaction Scheme 2 below. In addition, -C in which R ₄ and R ₅ are bonded to each other
The compound which is a group of O (CH ₂ ) _a-1- is the corresponding-(CH
₂ ) It can also be obtained by reacting a compound which is _a group with an oxidizing agent known per se [eg pyridinium chlorochromate (PCC)].

Reaction formula 2

[Chemical 11] Further, in the reaction formula 2, when R ₁ is a protected hydroxyl group, after completion of each reaction, deprotection is carried out by acidic hydrolysis or catalytic reduction known per se to give an optically active compound represented by the general formula (A). A phenol derivative can be obtained. On the other hand, as is clear from the reaction formula 2, the general formula (A)
In the above, a compound in which R ₄ is unsubstituted can also be obtained by reducing a compound in which R ₄ is a halogen atom (chlorine or bromine). Primary alkyl group, aryl group or aralkyl group, R ₁₄ is a lower alkyl group or aryl group having 1 to 6 carbon atoms, R ₁₅
Represents a lower alkyl group having 1 to 6 carbon atoms, an aryl group or an aralkyl group. Examples of the aryl group represented by R ₁₃ , R ₁₄ and R ₁₅ include phenyl and parafluorophenyl, and examples of the aralkyl group represented by R ₁₃ and R ₁₅ include benzyl and phenethyl. In the general formula (A), a compound in which R ₁ is a protected hydroxyl group can be prepared by subjecting a compound in which R _{1 in the} general formula (A) is a hydroxyl group to a method known per se, for example, methylation, methoxymethylation, tetrahydropyranylation. , Benzylation, acetylation and the like.

Among the optically active phenol derivatives represented by the general formula (A) of the present invention, those having a free carboxyl group as Y are those having thromboxane A ₂ and prostaglandin H _{2 in} an in vitro experimental system. It expresses an eicosanoid receptor antagonistic action such as prostaglandin D _2, and in an in vivo experimental system, Y is a methyl group,
In-vivo oxidation (eg, ω-oxidation, β-oxidation) or even hydroxymethyl group, optionally substituted hydroxymethyl group, optionally esterified or amidated carboxyl group or cyano group When these groups are converted to carboxyl groups by hydrolysis, they exhibit an antagonistic effect on eicosanoid receptors such as thromboxane A ₂ , prostaglandin H ₂ , and prostaglandin D ₂ . Thromboxane A ₂ is biosynthesized from arachidonic acid through prostaglandin H ₂ mainly in platelets or leukocytes in the living body. Thromboxane A ₂
The physiological actions of prostaglandin H ₂ show a strong platelet aggregation action and a vascular or bronchial smooth muscle contraction action at extremely low concentrations. For example, it is well known that thromboxane A ₂ production is generally increased in patients with thrombosis, myocardial infarction, cerebral infarction, arteriosclerosis, diabetic hypertension, asthma, etc. . Thus, compounds that antagonize the thromboxane A ₂ or prostaglandin H ₂ receptors are, for example, vasoconstrictors, vasospasms, platelet aggregates,
It is considered to be used as an antithrombotic agent, an antivasoconstrictor, an antivasospastic agent, an antihypertensive agent, an antiasthmatic agent, an antiarteriosclerotic agent for the treatment and prevention of various diseases based on thrombosis, airway contraction and the like.

Thus, the optically active phenol derivative of the general formula (A) of the present invention suppresses platelet aggregation caused by arachidonic acid, collagen, adenosine diphosphate (ADP), platelet activating factor (PAF), etc. , Thromboxane A ₂ or prostaglandin H ₂ receptors for platelet aggregation. U-44069 or U-46, which are prostaglandin H ₂ analogs known to cause airway narrowing and vasoconstriction
Inhibits the pharmacological effects of 619. In addition, it shows the action of improving arrhythmia and infarct lesion in a rat heart ischemia-reperfusion model. Furthermore, it shows the effect of improving the function of rat ischemic kidney and the effect of improving cerebral ischemic attack in spontaneously hypertensive rats.

The derivatives of the present invention have low toxicity, for example (R) -7- (4-fluorophenyl) -7- (5-hydroxy-6,7-dimethyl-1-oxoindane-4).
-Yl) heptanoic acid was administered to rats by oral administration at 1000
The dose was mg / kg / day for 2 consecutive weeks, but none of the 3 animals died. The derivative of the present invention is a pharmaceutical composition in a known dosage form, for example, as it is or in a mixture with a pharmaceutically acceptable carrier or excipient known per se by a known pharmaceutically acceptable method, for example, a tablet, It can be safely administered orally or parenterally as capsules (including soft capsules and microcapsules), solutions, injections and suppositories. The dose varies somewhat depending on the administration subject, administration route, symptoms, etc., but when administered orally to an adult patient, for example, a single dose is usually about 0.1 mg / kg to 20 mg.
It is convenient to administer about 1 / kg body weight, preferably about 0.1 mg / kg to 10 mg / kg body weight once or twice a day.
Further, the compound of the present invention is less susceptible to the inactive reaction due to in vivo metabolism due to the structure having a bulky group on the carbon at the alpha position of the side chain, and can maintain the drug effective concentration in blood for a long time. It is possible and shows excellent efficacy at low doses.

[0035]

EXAMPLES The present invention will be described in more detail with reference to Examples, Reference Examples and Experimental Examples showing pharmacological actions. Example 1 (Production of compound 2) 2,3,5-trimethylphenol (13.6 g, 0.1
0 mol), (S) -3-hydroxy-3-phenylpropylacetate (1.94 g, 10 mmol), triphenylphosphine (3.90 g, 15.0 mmol) 1,2
95% diethyldiazodicarboxylate (DEAD) (2.5 ml) in dichloroethane (60 ml) solution at room temperature
Was dripped. The mixture was stirred at the same temperature for 6 hours and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography to give (R) -3- (2-hydroxy-3,4,6-trimethylphenyl) -3-phenylpropylacetate.
94 g were obtained. Compound 3 was similarly prepared. The physical properties and spectral data of these compounds and the compounds obtained in the following examples are shown in [Table 1], [Table 2] and [Table 3].

Example 2 (Production of compound 9) 5-hydroxy-6,7-dimethylindane (0.96)
g, 5.9 mmol), methyl (S) -7- (4-fluorophenyl) -7-hydroxyheptanoate (0.30 g,
1.2 mmol), triphenylphosphine (0.46
g, 1.8 mmol) of 1,2-dichloroethane (15 ml)
Add 1 or 2 of 95% DEAD (0.33 ml) to the solution at 10 ° C.
-Dichloroethane (3 ml) solution was added dropwise over 30 minutes. The mixture was stirred at the same temperature for 1 hour and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, (R)
-7- (5-hydroxy-6,7-dimethylindane-
Methyl 4-yl) -7- (4-fluorophenyl) heptanoate (0.18 g) was obtained. Compound 1,5 in the same manner
~ 8,10-17 were produced.

Example 3 (Production of Compound 4) 2,3,5-trimethylphenol (0.80 g, 5.9)
mmol), (S) -7- (4-fluorophenyl) -7-
Methyl hydroxyheptanoate (0.30g, 1.2mmo
l), triphenylphosphine (0.46g, 1.8m
mol) in 1,2-dichloroethane (20 ml) solution at 10
A solution of 95% DEAD (0.54 ml) in 1,2-dichloroethane (5 ml) was added dropwise at 30 ° C over 30 minutes. 1 at the same temperature
The solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, (R) -7- (4-
Fluorophenyl) -7- (2-hydroxy-3,4,6
0.15 g of methyl-trimethylphenyl) heptanoate was obtained.

Example 4 (Production of Compound 4) In the same manner as in Example 3, 0.11 g of Compound 4 was obtained by using 1,1′-diazodicarbonyldi (piperidine) instead of DEAD. Example 5 (Production of Compound 4) According to the same method as in Example 3, using diisopropyldiazodicarbochelate (DIAD) instead of DEAD, 0.14 g of Compound 4 was obtained.

[0039]

[Table 1]

[0040]

[Table 2]

[0041]

[Table 3]

Example 6 (Production of Compound 18) Methyl (R) -7- (4-fluorophenyl) -7- (2-hydroxy-3,4,6-trimethylphenyl) peptanoate (0.8 g, 2 0.1 mmol), dichloromethyl methyl ether (0.62 ml) in dichloromethane (10 ml)
A solution of titanium tetrachloride (0.76 ml) in dichloromethane (3 ml) was added to the solution under an argon stream, and the temperature of the reaction solution was adjusted to -10 to 10.
The solution was added dropwise while keeping it at -12 ° C. After dropping, the mixture was stirred at the same temperature for 30 minutes, and the reaction solution was added to ice water. The mixture was extracted with ethyl acetate, and the organic layer was washed successively with water, aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was recrystallized from chloroform / hexane,
0.63 g of methyl (R) -7- (4-fluorophenyl) -7- (3-formyl-6-hydroxy-2,4,5-trimethylphenyl) heptanoate was obtained. Physical properties and spectral data are shown in [Table 4].

Example 7 (Production of Compound 19) Methyl (R) -7- (4-fluorophenyl) -7- (3-formyl-6-hydroxy-2,4,5-trimethylphenyl) peptanoate (0) 0.55 g, 1.4 mmol) in a solution of tetrahydrofuran (6 ml) under an argon stream, 1N
Sodium hydroxide (2.9 ml) was added, and the mixture was stirred at room temperature for 14 hours. 1N hydrochloric acid (2.9 ml) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was recrystallized from acetonitrile to give (R) -7- (4-fluorophenyl) -7- (3-formyl-6-hydroxy-2,4,5-trimethylphenyl). Heptanoic acid (0.4
9 g) was obtained. Physical properties and spectrum data [Table 4]
Shown in. Similarly, compounds 26, 28, 30 and 31
Was manufactured.

Example 8 (Production of Compound 20) (R) -7- (4-Fluorophenyl) -7- (3-formyl-6-hydroxy-2,4,5-trimethylphenyl) heptanoic acid (0. To a solution of 43 g (1.1 mmol) of tetrahydrofuran (7 ml) was added sodium borohydride (21.0 mg) under ice cooling, and the mixture was stirred at room temperature for 2 hours. Acetone was added and the solvent was distilled off under reduced pressure. 1N HCl was added to neutralize, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and (R) -7- (4-fluorophenyl) -7-
(2-hydroxy-5-hydroxymethyl-3,4,6-
0.38 g of trimethylphenyl) heptanoic acid was obtained. Spectral data is shown in [Table 4].

Example 9 (Production of Compound 21) (R) -3- (2-Hydroxy-3,4,6-trimethylphenyl) -3-phenylpropyl acetate (0.
To a solution of 90 g) in acetic acid (10 ml) was added dropwise a solution of bromine (0.15 ml) in acetic acid (2 ml) at room temperature. Stirred ice was added at the same temperature for 30 minutes, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography to give (R) -3- (3-bromo-6-hydroxy-2,4,5) as crystals.
-Trimethylphenyl) -3-phenylpropyl acetate (1.05 g) was obtained. Physical properties and spectral data are shown in [Table 4]. When the X-ray structural analysis of this compound was performed, it was found that the configuration of this product was R.

Example 10 (Production of Compound 22) 60% NaH (1.1 g, 27.2 mmol, 3 with hexane)
0 times to a dimethylformamide (30 ml) suspension (washed twice)
(R) -7- (4-fluorophenyl) -7- (3
A solution of -formyl-6-hydroxy-2,4,5-trimethylphenyl) heptanoic acid (5.0 g, 12.9 mmol) in dimethylformamide (20 ml) was added dropwise and 30
Stir for a minute. Methyl iodide (1.7
ml, 3.9 g, 27.2 mmol) was added dropwise at room temperature to 1.5.
Stir the time. Ice was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (R) -7-
(4-Fluorophenyl) -7- (3-formyl-6-
Methyl methoxy-2,4,5-trimethylphenyl) heptanoate (4.6 g) was obtained. Physical properties and spectral data are shown in [Table 5].

Example 11 (Production of Compound 23) A solution of methylmagnesium bromide in tetrahydrofuran (1M, 54.3 ml) was added to anhydrous tetrahydrofuran (9
0 ml) was added. (R) -7-
(4-Fluorophenyl) -7- (3-formyl-6-
A solution of methyl methoxy-2,4,5-trimethylphenyl) heptanoate (4.5 g, 10.9 mmol) in tetrahydrofuran (20 ml) was added dropwise, and the mixture was stirred at the same temperature for 30 minutes. Aqueous potassium hydrogen sulfate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, an aqueous solution of thorium hydrogencarbonate, water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (R) -7- (4-fluorophenyl).
Methyl -7- [3- (1-hydroxyethyl) -6-methoxy-2,4,5-trimethylphenyl] heptanoate (4.4 g) was obtained. Physical properties and spectral data are shown in [Table 5].

Example 12 (Production of compound 24) (R) -7- (4-fluorophenyl) -7- [3-
(1-hydroxyethyl) -6-methoxy-2,4,5-
Methyl trimethylphenyl] heptanoate (4.1 g,
A solution of 9.5 mmol) in dichloromethane (10 ml) was added to a solution of pyridinium chlorochromate (3.3 g, 15.2 mmol) in dichloromethane (20 ml) at room temperature, and the mixture was stirred at the same temperature for 2 hours. Diethyl ether was added, the insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (R) -7- (3-acetyl-6-
Methoxy-2,4,5-trimethylphenyl) -7- (4
Methyl -fluorophenyl) heptanoate (3.9 g) was obtained. Physical properties and spectral data are shown in [Table 5].

Example 13 (Production of compound 25) (R) -7- (3-acetyl-6-methoxy-2,4,5)
A solution of methyl -trimethylphenyl) -7- (4-fluorophenyl) heptanoate (2.0 g, 4.7 mmol) in dichloromethane (10 ml) was added to boron tribromide (2.0 ml,
5.3 g, 21.0 mmol) of dichloromethane (30 ml)
The solution was added dropwise at -78 ° C. The reaction solution was gradually warmed to room temperature and stirred at the same temperature for 6 hours. Add ice water at 0 ° C,
It was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (R) -7- (3-acetyl-6-hydroxy-2,
4,5-Trimethylphenyl) -7- (4-fluorophenyl) heptanoic acid (1.56 g) was obtained. Physical properties and spectral data are shown in [Table 5].

Example 14 (Production of compound 27) Methyl (R) -7- (4-fluorophenyl) -7- (5-hydroxy-6,7-dimethylindan-4-yl) heptanoate (16.0 g) , 40.2 mmol) in toluene (640 ml) was added with a mixture of pyridinium chlorochromate (43.3 g, 0.20 ml) and celite (52 g) at 0 ° C. under an argon stream, and the mixture was stirred at the same temperature for 23 hours. The insoluble matter was filtered and washed with toluene. The filtrate and washings were combined and concentrated, and the residue was subjected to silica gel column chromatography (R) -7- (4-fluorophenyl) -7.
Methyl-(5-hydroxy-6,7-dimethyl-1-oxoindan-4-yl) heptanoate (10.9 g) was obtained. This compound is the same as compound number 15. Compound 29 was prepared in a similar manner. Physical properties and spectral data are shown in [Table 6].

Reference Example 1 (Production of Compound 1-1) (R) -3,3-diphenyl-1-methyltetrahydro-1H, 3H-pyrrolo [1,2-c] [1,3,2] oxazaborole ( 1.1 g) of tetrahydrofuran (20
(1 ml) tetrahydrofuran solution (4 ml) was added at 0 ° C. 7 in this solution
A solution of methyl-(4-fluorophenyl) -7-oxoheptanoate (10.0 g, 39.6 mmol) in tetrahydrofuran (20 ml) and borane tetrahydrofuran complex 1M
A tetrahydrofuran solution (20 ml) was added dropwise at the same time over 25 minutes. Stir for 30 minutes at the same temperature Methanol (2
0 ml) was added and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain methyl (S) -7- (4-fluorophenyl) -7-hydroxyheptanoate (9.91 g). Physical properties and spectral data are shown in [Table 7]. Compound 1-2 was similarly produced.

Reference Example 2 (Production of Compound 1-3) (S) -1-Phenyl-1,3-propanediol (8.0 g, 52.6 mmol) in dichloromethane (80 m)
l) Acetic anhydride (5.5 ml) and pyridine (4.7 ml) were added to the solution at 0 ° C., and the mixture was stirred at the same temperature for 6 hours and at room temperature for 1.5 hours. The reaction solution was washed successively with aqueous sodium hydrogen carbonate solution, water and saturated brine. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography, (S) -3-
Hydroxy-3-phenylpropyl acetate (4.
8 g) was obtained. Physical properties and spectral data are shown in [Table 7].
Shown in.

Reference Example 3 (Production of Compound 1-4) (S) -1-Phenyl-1,3-propanediol (5.0 g, 32.9 mmol), 4-bromobenzoyl chloride (7.3 g, 33. 2 mmol) in dichloromethane (30 ml) at 0 ° C. triethylamine (3.1 ml)
Was dripped. The mixture was stirred at room temperature for 1 hour, and ice water was added to the reaction solution. The organic layer was washed successively with water and saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was subjected to silica gel column chromatography to obtain (S) -3-hydroxy-3-phenylpropyl-4-bromobenzoate (7.9 g). Physical properties and spectral data are shown in [Table 7].

[0054]

[Table 4]

[0055]

[Table 5]

[0056]

[Table 6]

[0057]

[Table 7]

Experimental Example 1 Thromboxane A ₂ Receptor Antagonistic Action A thromboxane A ₂ -like acting substance U- of guinea pig platelets
Inhibitory effect on 46619 aggregation Experimental method: Blood was collected from guinea pig abdominal aorta using sodium citrate as an anticoagulant (final concentration: 0.315%). Citrated blood was centrifuged at 950 rpm for 10 minutes and 2,000 rpm for 10 minutes at room temperature to obtain platelet rich plasma (PRP) and platelet poor plasma (PPP), and PRP was diluted with PPP to obtain platelets. The number was adjusted to 500,000 / μl. Platelet aggregation was measured spectroscopically using an aggregometer (Hematracer 6, manufactured by Toa Medical Electronics). 3 PRP (250 μl)
After incubating at 7 ℃ for 2 minutes, 25 μl of drug solution was added.
After a minute, U-46619 (25 μl) was added to induce aggregation. The effect of the drug was evaluated by the inhibition rate of the maximum aggregation rate of the drug treatment with respect to the maximum aggregation rate of the control group. U-46619 used the lowest concentration that yielded maximum aggregation (3 x 10
^-7 M). Experimental results: Inhibition rate is shown in [Table 8].

[Table 8]

Experimental Example 2 Thromboxane A ₂ Receptor Antagonistic Action Thromboxane A ₂ -like acting substance U-466 of human platelets
19 Inhibitory effect on aggregation Experimental method: Blood was collected from the brachial vein of a healthy male who had not taken the drug for 2 weeks or more using sodium citrate as an anticoagulant (final concentration: 0.315%). Citrated blood at 950 rpm for 10 minutes and 2,000 rpm at 1
Centrifuge at room temperature for 0 minutes to obtain platelet rich plasma (PRP) and platelet poor plasma (PPP).
Is diluted with PPP to obtain a platelet count of 300,000 platele
Adjusted to ts / μl. Platelet aggregation was measured spectroscopically using an aggregometer (Hematracer 6, Toa Medical Electronics). After incubating PRP (250 μl) at 37 ° C. for 2 minutes, the drug solution (25 μl) was added, and after 2 minutes, U
-46619 (25 μl) was added to induce aggregation. The effect of the drug was evaluated by the inhibition rate of the maximum aggregation rate of the drug-treated group with respect to the maximum aggregation rate of the control group. U-46619 used the lowest concentration that yielded maximum aggregation (10 ⁻⁵ M to 3 × 10 ^−5).
M) Experimental result: Inhibition rate is shown in [Table 9].

[Table 9]

Experimental Example 3 Thromboxane A ₂ receptor antagonism Inhibitory effect on contraction of guinea pig tracheal muscle sample by thromboxane A ₂ -like substance Experimental method: The guinea pig trachea was excised, and a short fence type sample was prepared to 95%. 10 m with aeration of O ₂ -5% CO ₂ mixed gas
1, suspended in a 37 ° C. Tyrode solution with a load of 1 g. Thromboxane A ₂ -like acting substance U-46619
The inhibitory effect of the test compound for 1 minute on the contraction reaction of the tracheal muscle specimen caused by the addition of (10 ⁻⁸ M) was examined. Experimental results: In Table 10, the 50% inhibitory concentration (IC ₅₀ ) is shown.

[Table 10]

Experimental Example 4 Thromboxane A ₂ -like substance U-
Inhibitory effect on 46619-induced guinea pig airway stenosis reaction Experimental method: Male Hartley guinea pig (body weight about 500
g) was used as 6 animals per group. 10 μg / minute of PGH ₂ analog U-46619 having a similar effect to TXA ₂
The guinea pig airway stenosis reaction by intravenous administration of kg was investigated by the Konzett-Rossler method, H. Kotzett and Earl Wrestler (Konzett,
H. and Rossler, R.) Naunyn-Schmiedebergs Arch. Experimental Experimental Pathology und Pharmacologie (Naunyn-Schmiedebergs Arch.
exp. Path. Pharmak.) 195, 71-74 (194
0) was measured. Guinea pig with urethane (1.5
g / kg, i. p. ) Under anesthesia, make a tracheotomy after fixing the dorsal position,
It was connected to a ventilator via a cannula. In addition, the side branch of the tracheal cannula is a transducer (7020 type).
Connected to. The insufflation rate is 3 to 5 ml, the insufflation rate is 70 times / min, the load pressure on the lung is 10 cmH ₂ O, and the overflowing air volume is set to Recti.-Hori via the transducer.
Recorded on -8 _s (Sanei Sokki). Galamine Triethiodide
After the treatment (1 mg / kg, iv), 10-g / kg of U-46619 dissolved in physiological saline was administered via the jugular vein cannula, and the airway stenosis reaction induced was recorded for 15 minutes. The sample is suspended in a 5% gum arabic solution, U-466
Oral administration was performed 1 hour before 19 administrations. Experimental results: shown in [Table 11]

[Table 11]

[0062]

The present invention provides an optically active phenol derivative having an excellent pharmacological action and a novel method for producing the same. In the production method, the desired product can be obtained while maintaining the optical activity of the raw material.

Continuation of the front page (51) Int.Cl. ⁶ Identification number Office reference number FI Technical indication location A61K 31/19 ADU 9454-4C 31/235 ABF 9454-4C 31/275 ABE 9454-4C B01J 31/02 102 C07C 37/16 9159-4H 39/14 9159-4H 51/353 59/52 9356-4H 67/293 67/343 69/65 9279-4H 69/732 9279-4H Z 9279-4H 69/76 Z 9279-4H A 9279-4H 69/92 9279-4H 69/94 9279-4H 235/48 7106-4H 251/48 9160-4H C07D 257/02 // C07B 61/00 300

Claims (22)

[Claims] 1. A tri-substituted phosphine and a diazodicarboxylate containing a phenol compound (I) unsubstituted in the ortho or / and para position and an optically active secondary carbinol compound (II) having an aromatic ring group in the α-position. Alternatively, a method for producing an optically active substance (III) of a tri-substituted methane compound having an aromatic ring group as a substituent and a phenyl group having a hydroxyl group at the ortho or para position, which is characterized by reacting in the presence of diazodicarboxamide. 2. The phenol compound (I) is unsubstituted at the ortho position, and the optically active compound (III) of the tri-substituted methane compound has a phenyl group having a hydroxyl group at the ortho position as a substituent. The manufacturing method according to claim 1, which is provided as one. 3. A phenol compound (I) is represented by the general formula: (In the formula, R ¹ , R ² , R ³ and R ⁴ represent a hydrogen atom or a group that does not participate in the reaction, and these two adjacent groups are bonded to each other to form a carbon atom on the benzene ring to which they are bonded. Which may form a ring), wherein the optically active secondary carbinol compound (II) has the general formula A compound represented by the formula), wherein the optically active substance (III) of the tri-substituted methane compound is represented by the general formula: The method according to claim 1, which is a compound represented by the formula (wherein each symbol has the same meaning as defined above). 4. A general formula (I-2) and a general formula (III-1).
The method according to claim 3, wherein at least two of R ¹ , R ² , R ³ and R ⁴ in each of the above are not hydrogen. 5. General formula (I-2) and general formula (III-1)
4. The method according to claim 3, wherein neither R ¹ nor R ² in each of the above is hydrogen. 6. A compound in which a tri-substituted phosphine is represented by the general formula (R ⁶ ) ₃ P (wherein R ⁶ represents an alkyl group having 1 to 8 carbon atoms or an optionally substituted phenyl group). The manufacturing method according to claim 1. 7. A diazodicarboxylate and a diazodicarboxamide are represented by the general formula R ⁷ —CO—N═N—CO—R ⁸ (wherein R ⁷ and R ⁸ are the same or different and are lower alkoxy groups, dilower alkyl). The method according to claim 1, which is a compound represented by an amino group or a cyclic amino group. 8. A general formula: [In the formula, R ₁ represents an optionally protected hydroxyl group. R ₂
Represents a hydrogen atom, a hydroxyl group, a lower alkyl group or a lower alkoxy group. R ₃ is a hydrogen atom, a hydroxyl group, an optionally substituted alkyl group having 1 to 8 carbon atoms, an optionally substituted aralkyl group, a halogen atom, an optionally protected formyl group, or an alkyl group having 2 to 7 carbon atoms. Acyl group, carboxyl group which may be esterified or amidated, -CH
= CHR ₆ group (R ₆ is a lower alkyl group or lower acyl group.) Or -CH = NR ₇ (R ₇ is a hydroxyl group, a lower alkoxy group, lower alkenyloxy group or benzhydryloxy group.) The Show. R ₄ is an optionally substituted alkyl group having 1 to 8 carbon atoms, an optionally substituted aralkyl group, a halogen atom, an optionally protected formyl group, an acyl group having 2 to 7 carbon atoms, esterification Or an optionally amidated carboxyl group, -CH =
CHR ₆ (R ₆ is as defined above) or —CH═
NR ₇ (R ₇ is as defined above). R ₅ represents a hydrogen atom or a lower alkyl group. Alternatively, R ₂ ,
R _3, R ₄ and R ₅ are bonded to two of their adjacent one another, - (CH _{2) a} - group (a is 3 or 4.), - CH = CH -CH = CH- group, - (CH _{2) b}
-CO- group (b is 2 or 3) or-(CH
₂ ) An _l- CO-O- group (l is 1 or 2) may be formed. X represents a phenyl group or a thienyl group which may be substituted at its para-position with a halogen atom, a lower alkyl group or a lower alkoxy group. Y is a methyl group,
It represents a hydroxymethyl group which may be substituted, a carboxyl group which may be esterified or amidated, a cyano group or a tetrazolyl group. n is 3 to 1 Derivative. 9. The optically active phenol derivative according to claim 8, which is an R-form. 10. The optically active phenol derivative according to claim 8, which is an S form. 11. The optically active phenol derivative according to claim 8, wherein n is an integer of 5 to 9. 12. The optically active phenol derivative according to claim 8, wherein R ₁ is a hydroxyl group. 13. The optically active phenol derivative according to claim 8, wherein Y is a carboxyl group which may be esterified or amidated. 14. R ₄ and R ₅ are bonded to each other to form-(CH ₂ ) _a.
- group (a is 3 or 4) or - (CH _{2) b} -C
The optically active phenol derivative according to claim 8, which is an O-group (b is 2 or 3). 15. R ₃ and R ₄ are bonded to each other to form-(CH ₂ ) _a
- group (a is 3 or 4) or - (CH _{2) b} -C
The optically active phenol derivative according to claim 8, which is an O-group (b is 2 or 3). 16. R ₄ is —CH═NR ₇ (R ₇ is methoxy,
It is ethoxy or 2-propenyloxy), and the optically active phenol derivative according to claim 8. 17. R ₁ is a hydroxyl group, R ₂ , R ₃ and R ₅ are all methyl groups, R ₄ is a methyl group, a formyl group, a hydroxymethyl group or an acetyl group, X is a 4-halogenophenyl group, and n is 9. 5 and Y are carboxyl groups.
The optically active phenol derivative described. 18. (R) -7- (4-Fluorophenyl)
The optically active phenol derivative according to claim 8, which is -7- (5-hydroxy-6,7-dimethyl-1-oxoindan-4-yl) heptanoic acid. 19. (R) -7- (4-Fluorophenyl)
-7- (2-hydroxy-5-hydroxymethyl-3,
The optically active phenol derivative according to claim 8, which is 4,6-trimethylphenyl) heptanoic acid. 20. (R) -7- (4-Fluorophenyl)
-7- (3-formyl-6-hydroxy-2,4,5-
9. The optically active phenol derivative according to claim 8, which is trimethylphenyl) heptanoic acid. 21. (R) -7- (3-Acetyl-6-hydroxy-2,4,5-trimethylphenyl) -7- (4
9. The optically active phenol derivative according to claim 8, which is -fluorophenyl) heptanoic acid. 22. (R) -7- (4-Fluorophenyl)
-7- (6-hydroxy-4,7-dimethylindane-
The optically active phenol derivative according to claim 8, which is 5-yl) heptanoic acid.