JPH0761942A - Phenol derivative and its production - Google Patents

Abstract

PURPOSE:To obtain a new phenol derivative useful as an intermediate for ferroelectric liquid crystal materials, exhibiting properties as a ferroelectric liquid crystal at low-temperature area and excellent in characteristics such as high speed responsiveness. CONSTITUTION:A compound of formula I [R1 is H or an OH protecting group; R2 is H or a 1-20C alkyl or a 2-20C alkoxyalkyl which may be substituted by halogen, respectively; m, p, q, r, s and t are 0 or 1; n is 0-10; A1 to A3 are formula II to formula VII (i is 0-3), etc.; when A1 is a condensed ring, p+q is 0 or 1 and A2 and A3 are single rings and when A1 is single ring, p+q is 1 or 2 and when p+q is 2, A2 and A3 are single rings], e.g. (-)-5- acetoxy-2-(4-(6-hydroxy-1-heptyl)-phenyl)pyrimidine. The compound is obtained by reacting a compound of formula VIII [X is halogen, OCOCF3 or OSO2R' (R' is alkyl or phenyl)] with acetylenes of formula IX in the presence of a Pd catalyst and a basic substance and hydrogenating the resultant compound of formula X.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a phenol derivative useful as an intermediate for agricultural chemicals, pharmaceuticals, organic electronic (particularly ferroelectric liquid crystal) materials, an optically active substance thereof, and a method for producing them.

[0002]

2. Description of the Related Art Conventionally, various compounds have been developed as liquid crystal materials, but few compounds have excellent characteristics such as high-speed response and become ferroelectric liquid crystal materials in a low temperature region. Development of the body is not yet sufficient, and the intermediate and its industrially advantageous production method have been desired.

[0003]

The present invention particularly provides a novel method for producing a phenol derivative which is a ferroelectric liquid crystal in a low temperature region and is useful as an intermediate of a ferroelectric liquid crystal material excellent in the above properties. To do. It is also used separately as a material for TN liquid crystal. Here, the above-mentioned ferroelectric liquid crystal material can be synthesized by the following steps.

[0004] (In the formula, R1 represents a hydrogen atom or a hydroxyl-protecting group, and R2 is substituted with a hydrogen atom, a saturated or unsaturated alkyl group having 1 to 20 carbon atoms which may be substituted with a halogen atom, or a halogen atom. 2 to 2 carbon atoms
20 alkoxyalkyl groups, m, p, q, r,
s and t are 0 or 1, n is an integer of 0 to 10, and A1, A2 and A3 are respectively When A1 is a condensed ring, p + q = 0 or 1, and A2 and A3 are monocycles, and when A1 is a monocycle, p + q = 1 or 2, and p + q =
In the case of 2, both A2 and A3 are monocycles. i and j are integers from 0 to 3, respectively. The * mark indicates an asymmetric carbon atom. )

[0005]

Based on the above, the present inventors have conducted various studies on new production methods of the compound represented by the general formula (1), and as a result, found an industrially advantageous new production method. Came to That is, the present invention has the general formula (1) (In the formula, R1 represents a hydrogen atom or a hydroxyl-protecting group, and R2 is substituted with a hydrogen atom, a saturated or unsaturated alkyl group having 1 to 20 carbon atoms which may be substituted with a halogen atom, or a halogen atom. 2 to 2 carbon atoms
20 alkoxyalkyl groups, m, p, q, r,
s and t are 0 or 1, n is an integer of 0 to 10, and A1, A2 and A3 are respectively When A1 is a condensed ring, p + q = 0 or 1, and A2 and A3 are monocycles, and when A1 is a monocycle, p + q = 1 or 2, and p + q =
In the case of 2, both A2 and A3 are monocycles. i and j are integers from 0 to 3, respectively. The * mark indicates an asymmetric carbon atom. The present invention provides a phenol derivative represented by (4), an optically active substance thereof, and a method for producing the same.

The present invention will be described in detail below. The above optically active phenol derivative (1) has the general formula (2) (In the formula, R1, m, p, q, A1, A2 and A3 have the same meanings as described above, and X is a halogen atom, OCOC.
F3 or -OSO2 R'is shown. However, R'represents a lower alkyl group which may be substituted with a fluorine atom, or a phenyl group which may be substituted. ) And a general formula (3) (In the formula, R2, n, r, s and t have the same meanings as described above.) The acetylenes represented by the formula (4) are reacted in the presence of a palladium catalyst and a basic substance. (Wherein R1, R2, m, n, p, q, r, s, t, A1
, A2 and A3 have the same meanings as described above. ) Is obtained, and then hydrogenated by using hydrogen and a hydrogenation catalyst.

Here, the raw material compound represented by the general formula (2) can be easily produced by the following method. HO-A1- (A2) p- (A3) q-X-> R1-A1-(A2) p- (A3) q-X (wherein R1 is a hydroxyl-protecting group) R1-O-A1-(A2 ) p − (A3) q −OH─ → R1 −O −A1− (A2) p − (A3) q −OCOCF3 or R1 −O −A1− (A2) p − (A3) q −OSO2R '

As R1 which is a hydroxyl-protecting group, those usually used as hydroxyl-protecting groups are used. Examples of such protecting groups include the following.
Substituted with an aliphatic acyl group such as acetyl, propionyl, butyryl, pentylyl, a halogen atom such as chlorine atom, bromine atom, an alkyl group such as methyl, ethyl, propyl, butyl, or an alkoxy group such as methoxy, ethoxy, propoxy, butoxy. Optionally a benzoyl group, a halogen atom such as a chlorine atom or a bromine atom, an alkyl group such as methyl, ethyl, propyl or butyl, or a benzyl group which may be substituted with an alkoxy group such as methoxy, ethoxy, propoxy or butoxy, Trimethylsilyl group, triethylsilyl group, dimethylphenylsilyl group, dimethylbenzylsilyl group, methyldibenzylsilyl group, tribenzylsilyl group, dimethylbutylsilyl group, methyldiphenylsilyl group, triphenylsilyl group When it is a trialkylsilyl group, a dialkylphenylsilyl group, an alkyldiphenylsilyl group, a triphenylsilyl group, an aralkyldialkylsilyl group, a diaralkylalkylsilyl group or a triaralkylsilyl group, the phenyl group or aralkyl group is a halogen atom or an alkyl group. It may be substituted with a group or an alkoxy group. Further examples include a tetrahydropyranyl group, a tetrahydrofuranyl group, and further ethers such as a 1- (alkoxy) ethyl group such as ethoxyethyl and propoxyethyl.

The other acetylenes (3) are synthesized from racemic alcohols or optically active alcohols, and the optically active alcohols are prepared, for example, by enzymatic resolution of racemic alcohols as follows, and s = 1. The esters shown are synthesized by acylation, and the ethers shown by s = 0 are synthesized by alkylation. The case of optically active alcohols is shown below.

[0010] (In the formula, R2 is a saturated or unsaturated alkyl group having 1 to 20 carbon atoms which may be substituted with a halogen atom, or 2 to 2 carbon atoms which may be substituted with a halogen atom.
0 represents an alkoxyalkyl group, and n represents an integer of 0 to 10. * Indicates an asymmetric carbon atom. )

Acetylenes (3) and halides (2)
In the reaction for obtaining the acetylene phenols (4) from and, the amount of the acetylenes (3) used is usually 0.9 to 10 times equivalent to the halide (2), but preferably 1 to 3 times equivalent. Is. As the metal catalyst, palladium-based catalysts such as palladium chloride, palladium acetate, triphenylphosphine palladium complex and palladium / carbon are used, and nickel- and rhodium-based catalysts similar to the above palladium-based catalysts are also used. The amount of these metal catalysts used is 0.001 with respect to the raw material halide (2).
~ 0.1 times equivalent range. In this reaction, in addition to the above metal catalyst, a trivalent phosphorus compound or a trivalent arsenic compound is required as a co-catalyst. (In the formula, Y represents a phosphorus atom or an arsenic atom, and R5, R
6 and R7 are the same or different and each represents an alkyl group, an aryl group, an alkoxy group, an aryloxy group or a halogen atom. ), Specifically exemplified are tri-n-butylphosphine, triphenylphosphine, tri-o-tolylphosphine, tri-o-tolylphosphite, phosphorus trichloride, triphenylarsenic and the like. It The amount of the phosphorus compound or arsenic compound used is 0.5 to 50 times equivalent, preferably 1 to 30 times equivalent to the above metal catalyst. Further, in addition to these catalysts, copper catalysts are used, and as such copper catalysts, copper iodide, copper bromide, copper chloride, copper oxide, copper cyanide, etc. are used. It is in the range of 0.001 to 0.1 times the equivalent of (2). Of course, it is possible to use more than this, but there is no particular advantage in using a large amount.

Examples of the basic substance include alkali metal carbonates, carboxylates, alkoxides, hydroxides, and organic bases, and tertiary amines or secondary amines (organic bases) are preferably used. Examples thereof include diethylamine, triethylamine, di-isopropylethylamine, tri-n-butylamine, tetramethylethylenediamine, dimethylaniline and the like. The amount of the base used is usually 1 to the halide (2).
It is 5 times equivalent. If necessary, a suitable solvent such as acetonitrile, tetrahydrofuran, dimethylformamide, hexamethylphosphorylamide, N-methylpyrrolidone, methanol or the like can be used as a reaction solvent. Further, the above base can be used as a solvent. The amount of these reaction solvents used is not particularly limited.

The above reaction is usually carried out in an inert gas such as nitrogen or argon. In the reaction, the yield of the target ester derivative can be improved by increasing the reaction temperature, but since the by-product increases at too high temperature, the reaction temperature is usually 15 to 160 ° C., preferably It is 30-140 degreeC. The reaction time is not particularly limited. In this reaction, the phenolic hydroxyl group of the halide (2) can be used in the reaction as it is without introducing a protective group, but it is generally better to introduce a protective group and react from the viewpoint of yield. After completion of the reaction, the acetylene phenols (4) can be obtained by usual means such as extraction, distillation and recrystallization. If necessary, it can be purified by column chromatography or recrystallization. In this reaction, when R2 is a hydrogen atom and t = 0, the obtained phenol derivative (4) has the following general formula (4-a). (In the formula, R1, m, n, p, q, r, A1, A2 and A3 have the same meanings as described above), and further, the general formula (5) R3 COR '(5) (In the formula, R3 is a saturated or unsaturated alkyl group having 1 to 20 carbon atoms which may be substituted with a halogen atom, or 2 to 2 carbon atoms which may be substituted with a halogen atom.
0 represents an alkoxyalkyl group, R'is a hydroxyl group, OCO
R3 or a halogen atom is shown. ), When s and t in the general formula (4) are 1
To give an ester compound. In addition, the general formula (4
-A) and the acetylene phenols represented by the general formula (6) R3-Z (6) (In the formula, R3 has the same meaning as described above, and Z is a halogen atom or -OSO2 R ". Represents a lower alkyl group or an optionally substituted phenyl group.) In the general formula (4), s is 1 and t is 0 and R 2 is substituted with a halogen atom. An acetylene alcohol derivative which is a saturated or unsaturated alkyl group having 1 to 20 carbon atoms or an alkoxyalkyl group having 2 to 20 carbon atoms which may be substituted with a halogen atom is obtained.

A detailed description will be given below. In the reaction of the above-mentioned acetylene phenols (4-a) and carboxylic acids, as the carboxylic acid, a carboxylic acid having an alkyl group represented by R2, an acid anhydride or acid chloride thereof, or an acid halide such as acid bromide is used. To be done.
Incidentally, these carboxylic acids may be either racemic or optically active form. When a solvent is used in the above reaction, examples of the solvent include tetrahydrofuran, ethyl ether, acetone, methyl ethyl ketone,
Inert to the reaction of ethers such as toluene, benzene, chlorobenzene, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, dimethylformamide, hexane, ketones, aliphatic or aromatic carbons, hydrogen halides, aprotic polar solvents, etc. Solvents may be used alone or as a mixture. The amount used is not particularly limited.

In the above reaction, when an acid anhydride or an acid halide of an aliphatic carboxylic acid is used, the amount used is required to be 1 equivalent or more times that of the acetylene phenols (4-a). Is not particularly limited, but is preferably 1.1 to 4 equivalent times.

Examples of the catalyst include dimethylaminopyridine, 4-pyrrolidinopyridine, triethylamine,
Examples thereof include organic or inorganic basic substances such as tri-n-butylamine, pyridine, collidine, imidazole sodium carbonate, sodium methylate and potassium hydrogen carbonate. Further, an organic acid or an inorganic acid such as toluenesulfonic acid, methanesulfonic acid or sulfuric acid may be used as a catalyst. When using such a catalyst, for example, when an acid halide of a carboxylic acid is used as a raw material, pyridine and triethylamine are preferably used. The amount of the catalyst used varies depending on the type of the acid anhydride or acid halide of the carboxylic acid and the catalyst used, and the like.
Although not necessarily specified, when an acid halide is used, the amount is 1 equivalent times or more with respect to the acid halide.

When a carboxylic acid is used in the above reaction, it is dehydrated and condensed in the presence of a condensing agent, usually in an amount of 1 to 2 equivalents with respect to the phenol derivative (4-a). Can also be obtained by As the condensing agent, carbodiimides such as N, N'-dicyclohexylcarbodiimide and N-cyclohexyl-N '-(4-diethylamino) cyclohexylcarbodiimide are preferably used, and if necessary, 4-dimethylaminopyridine, 4-pyrrolidino An organic base such as pyridine, pyridine or triethylamine is used in combination.
The amount of the condensing agent used is 1 to 1.5 equivalent times the carboxylic acid, and when the organic base is used in combination, the amount of the condensing agent used is 0.01 to 0.2 equivalent times the condensing agent. The reaction temperature is usually -30 to 100 ° C, preferably 0 to 80 ° C. The reaction time is not particularly limited, and the time point when the raw material (4-a) disappears can be the end point of the reaction. After completion of the reaction, acetylene phenols (4) (where S is a compound) can be obtained in good yield by an ordinary separation means such as extraction, liquid separation, concentration, etc. It can also be purified by chromatography, recrystallization and the like.

Next, acetylene phenols (4-a)
And R2 -Z (6) (wherein R2 has the same meaning as described above, Z represents a halogen atom or -OSO2 R, where R is a lower alkyl group or a phenyl group which may be substituted). It can be produced by reacting with an alkylating agent represented by n. Here, the alkylating agent means the substituent R2
It is a halogenated or sulfonic acid ester having ## STR5 ## and can be produced from the corresponding alcohol by a known method. The substituent R2 in the alkylating agent
May be an optically active substance. This reaction is usually performed in the presence of a basic substance. The amount of such an alkylating agent to be used is arbitrarily 1 equivalent or more with respect to the acetylene phenols (4-a), but is usually in the range of 1 to 5 equivalents.

The above reaction is usually carried out in the presence of a solvent,
Examples of the solvent used include tetrahydrofuran, ethyl ether, acetone, methyl ethyl ketone,
Toluene, benzene, chlorobenzene, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, hexane, dimethylformamide, dimethyl sulfoxide,
Hexamethylphosphorylamide, ethers such as N-methylpyrrolidone, ketones, aliphatic or aromatic hydrocarbons, halogenated hydrocarbons, aprotic polar solvents, and other solvents inert to the reaction may be used alone or as a mixture.
The amount of the solvent used is not particularly limited.

Examples of the basic substance include alkali metal hydrides such as sodium hydride and potassium hydride, alkali metal alkoxides such as lithium, sodium and potassium, alkali metal alcoholates such as sodium ethylate and sodium methylate, and sodium carbonate. Examples thereof include alkali metal carbonates such as potassium carbonate and butyl lithium. The basic substance is required to be 1 equivalent or more with respect to the acetylene phenols (4-a), and the upper limit is not particularly limited, but it is usually 1.1 to 5 equivalent times. The reaction temperature is generally −50 to 120 ° C., preferably −30 to 10
It is in the range of 0 ° C. The reaction time is not particularly limited, and the reaction can be terminated when the raw material (4-a) disappears. After completion of the reaction, the target acetylene phenol represented by the general formula (4) (provided that the target is separated from the reaction mixture by a conventional separation means such as extraction, liquid separation, concentration, etc.
The compound (S is O) can be isolated and, if necessary, can be purified by column chromatography, recrystallization and the like.

In the alkylation reaction, when the substituent Z of the alkylating agent is an iodine atom, silver oxide can be used instead of the above basic substance. In this case, the silver oxide is acetylene phenols (4
-A) is required to be 1 equivalent or more, and the upper limit is not particularly limited, but it is preferably 5 equivalents or more.
When the alkylation reaction is carried out in the presence of silver oxide, the amount of the alkylating agent (provided that the substituent Z is an iodine atom) is arbitrarily used in an amount of 1 equivalent or more with respect to the raw material (4-a). Is 2 to 10 equivalent times.

As a reaction solvent, an excess of an alkylating agent (provided that the substituent is an iodine atom) can be used as a solvent, and also tetrahydrofuran, ethyl ether, dioxane, acetone, methyl ethyl ketone, benzene,
Solvents inert to the reaction such as ethers such as toluene and hexane, ketones, or hydrocarbon solvents may be used alone or as a mixture. The reaction temperature is generally 0 to 150 ° C, preferably 20 to 100 ° C. The reaction time is
Usually, it is 1 hour to 20 days. The phenol derivative (1) (however, the compound in which s is O) is taken out from the reaction mixture by removing the silver salt by filtration and then adding a usual post-treatment operation such as extraction, liquid separation and concentration. Done. If necessary, it can be purified by column chromatography or the like. The method for obtaining the acetylene phenols (4) from the compound (4-a) has been described above. The following are examples of the substituent R2 in the carboxylic acid and the alkylating agent used here. Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, propenyl, 2-butenyl, 3-butenyl, 3-hexenyl. 2-butynyl, 3-hexynyl, cyclopropyl, 2,2-dimethylcyclopropyl, cyclopentyl, cyclohexyl,
Octadecyl, nonadecyl, eicosyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, methoxyhexyl, methoxyheptyl, methoxyoctyl, methoxynonyl, methoxydecyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, Ethoxyhexyl, ethoxyheptyl, ethoxyoctyl, ethoxynonyl, ethoxydecyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl,
Propoxypentyl, propoxyhexyl, propoxyheptyl, propoxyoctyl, propoxynonyl,
Propoxydecyl, butoxymethyl, butoxyethyl,
Butoxypropyl, butoxybutyl, butoxypentyl, butoxyhexyl, butoxyheptyl, butoxyoctyl, butoxynonyl, butoxydecyl, pentyloxymethyl, pentyloxyethyl, pentyloxypropyl, pentyloxybutyl, pentyloxypentyl, pentyloxyhexyl, pentyloxy. Octyl, pentyloxynonyl, pentyloxydecyl, hexyloxymethyl, hexyloxyethyl, hexyloxypropyl, hexyloxybutyl, hexyloxypentyl, hexyloxyhexyl, hexyloxyheptyl, hexyloxyoctyl, hexyloxynonyl, hexyloxydecyl, Heptyloxymethyl,
Heptyloxyethyl, heptyloxypropyl, heptyloxybutyl, heptyloxypentyl, heptyloxyhexyl, heptyloxyheptyl, heptyloxyoctyl, heptyloxynonyl, heptyloxydecyl, octyloxymethyl, octyloxyethyl, octyloxypropyl, octyloxy. Butyl,
Octyloxypentyl, octyloxyhexyl, octyloxyheptyl, octyloxynonyl, octyloxyoctyl, decyloxymethyl, decyloxyethyl, decyloxypropyl, decyloxybutyl,
Decyloxypentyl, decyloxyhexyl, decyloxyheptyl, 1-methylethyl, 1-methylpropyl, 1-methylbutyl, 1-methylpentyl, 1-methylhexyl, 1-methylheptyl, 1-methyloctyl, 1-methylnonyl, 1-methyldecyl, 2-methylpropyl, 2-methylbutyl, 2-methylpentyl, 2
-Methylhexyl, 2-methylheptyl, 2-methyloctyl, 2,3-dimethylbutyl, 2,3,3-trimethylbutyl, 3-methylpentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3,3,4-tetramethylpentyl 3-methylhexyl, 2,5-dimethylhexyl, 2-trihalomethylpropyl, 2-trihalomethylbutyl, 2-trihalomethylpentyl,
2-trihalomethylhexyl, 2-trihalomethylheptyl, 2-haloethyl, 2-halopropyl, 3-halopropyl, 3-halo-2-methylpropyl, 2,3-dihalopropyl, 2-halobutyl, 3-halobutyl, 4-halobutyl, 2,3-dihalobutyl, 2,4-dihalobutyl, 3,4-dihalobutyl, 2-halo 3-methylbutyl, 2-halo 3,3-dimethylbutyl, 2-halopentyl, 3-halopentyl, 4-halopentyl, 5-halopentyl, 2,4-dihalopentyl, 2,5-dihalopentyl, 2-halo 3-methylpentyl, 2-halo-4-methylpentyl, 2 -Halo 3-monohalomethyl-4-methylpentyl, 2-halohexyl, 3-halohexyl, 4-halohexyl, 5-halohexyl, 6-halohexyl, 2-halo Examples thereof include heptyl, 2-halooctyl, and the like (in the above examples, halo represents fluorine, chlorine or bromine).

Examples of the carboxylic acids include halomethyl, 1-haloethyl, 1-halopropyl, 1-halobutyl, 1-halopentyl, 1-halohexyl, 1-haloheptyl, 1-halooctyl and the like in addition to the above examples. These alkyl groups or certain alkoxyalkyl groups may be linear, branched or cyclic, and may be optically active groups when branched or cyclic. Among the above-exemplified carboxylic acids having the substituent R2, optically active ones are obtained by oxidation of the corresponding alcohols, reductive deamination of amino acids, and some naturally occurring or by resolution. It can be derived from the following optically active amino acids and optically active oxyacids. Further, among the alkylating agents having the substituent R2, optically active ones can be easily prepared from the corresponding alcohols by a known method. Alternatively, it can be obtained by asymmetric reduction with oxygen. Also, some can be derived from naturally occurring or optically active amino acids or optically active oxyacids obtained by optical resolution, such as: Alanine, valine, leucine, isoleucine, phenylalanine, threonine, arosreonine, homoserine, alloisoleucine, tert-
Leucine, 2-aminobutyric acid, norvaline, norleucine, ornithine, lysine, hydroxylysine, phenylglycine, aspartic acid, glutamic acid, mandelic acid, tropic acid, 3-hydroxybutyric acid, malic acid, tartaric acid or isopropylmalic acid.

Next, deprotection of R1 which is a protecting group will be described. The deprotection method has several choices depending on the type of protecting group. When R1 is an ester such as an aliphatic acyl group or a benzoyl group, it is usually hydrolyzed with an inorganic or organic acid such as hydrochloric acid, nitric acid, sulfuric acid or toluenesulfonic acid, or an alkali such as caustic soda or caustic potash. It is carried out. The amount used is usually 1 mol to 10 mol times in the case of an alkali, and 0.01 to 30 mol times in the case of an acid. Examples of the solvent include alcohols such as methanol, ethanol, propanol, tetrahydrofuran, dioxane, water, and dimethyl sulfoxide, and polar solvents. In the case of a benzyl group or ether, acetic acid, trifluoroacetic acid, trichloroacetic acid, hydroiodic acid, hydrobromic acid, etc. are used in addition to the above-mentioned acids. The amount used and the solvent may be the same as above. In the case of a silyl group, the protecting group for the hydroxyl group can be deprotected by a desilylating agent containing a fluorine anion such as tetrabutylammonium fluoride, cesium fluoride and potassium fluoride in addition to the above-mentioned acids. .

The reaction temperature is usually in the range of -30 to 150 ° C, preferably -10 to 100 ° C. The reaction time is not particularly limited. The post-treatment after completion of the reaction can be carried out, for example, by an ordinary operation as shown above, and can be purified by column chromatography or recrystallization if necessary. Next, the production method for obtaining the phenol derivative (1) by reducing the acetylene phenols (4) obtained here will be described. The reduction can be carried out by hydrogenating the acetylene phenols (4) with hydrogen and a hydrogenation catalyst. In the above reaction, a Raney nickel palladium metal catalyst is preferably used as the hydrogenation catalyst, and specific examples thereof include palladium-
Examples thereof include carbon, palladium oxide, palladium black, palladium chloride and the like. Such hydrogenation catalyst is usually 0.001 to 0.5 times by weight with respect to the acetylene phenols (4),
It is preferably used in an amount of 0.005 to 0.3 times by weight. The reaction is carried out in a solvent, and examples of the solvent include water, dioxane, tetrahydrofuran, methanol, ethanol, n-propyl alcohol, acetone, dimethylformamide, toluene, dichloromethane, ethyl acetate and other hydrocarbons, alcohols, ethers, ketones and esters. Solvents such as halogenated hydrocarbons and amides which are inert to the reaction may be used alone or as a mixture.

The above reaction is carried out under normal or elevated pressure of hydrogen, and the reaction end point is reached when the absorbed amount of hydrogen is 2 to 2 or 4 equivalent times that of the acetylene phenols (4) as the raw material. Is preferred. Reaction is -10 to 100
C., preferably 10 to 60.degree. After completion of the reaction, the desired phenol derivative (1) can be obtained by an operation such as removing the catalyst from the reaction mixture by filtration and then concentrating it, and if necessary, by recrystallization or column chromatography or the like. It can also be purified.

Next, deprotection of R1 which is a protecting group will be described. The deprotection method has several choices depending on the type of protecting group. When R1 is an ester such as an aliphatic acyl group or a benzoyl group, it is usually hydrolyzed with an inorganic or organic acid such as hydrochloric acid, nitric acid, sulfuric acid or toluenesulfonic acid, or an alkali such as caustic soda or caustic potash. It is carried out. The amount used is usually 1 mol to 10 mol times in the case of an alkali, and 0.01 to 30 mol times in the case of an acid. Examples of the solvent include alcohols such as methanol, ethanol, propanol, tetrahydrofuran, dioxane, water, and dimethyl sulfoxide, and polar solvents. In the case of a benzyl group or ether, acetic acid, trifluoroacetic acid, trichloroacetic acid, hydroiodic acid, hydrobromic acid, etc. are used in addition to the above-mentioned acids. The amount used and the solvent may be the same as above. In the case of a silyl group, the protecting group for the hydroxyl group can be deprotected by a desilylating agent containing a fluorine anion such as tetrabutylammonium fluoride, cesium fluoride and potassium fluoride in addition to the above-mentioned acids. . The reaction temperature is generally -30 to 150 ° C, preferably -10 to 100 ° C. The reaction time is not particularly limited. The post-treatment after completion of the reaction can be carried out, for example, by an ordinary operation as shown above, and can be purified by column chromatography or recrystallization if necessary.

Separately from the above phenol derivative (1), acetylene phenols represented by the general formula (4-a) are hydrogenated using hydrogen and a hydrogenation catalyst, and in the general formula (1), s = 1, After obtaining a phenol derivative in which R2 represents a hydrogen atom at t = 0, and further reacting with a carboxylic acid represented by the general formula (5), an ester derivative in which s is 1 in the general formula (1) is obtained. When reacted with the alkylating agent represented by the general formula (6), an ether derivative in which s is 0 in the general formula (1) is obtained. The method for obtaining the general formula (1-a) by hydrogenating the acetylene phenols represented by the general formula (4-a) using hydrogen and a hydrogenation catalyst is to reduce the acetylene phenols (4) described above. Can be carried out in the same manner according to the method for obtaining the phenol derivative (1).
The conditions of esterification and alkylation and purification can be carried out in the same manner as in the case of the acetylene phenols (4-a). Further, the above conditions are directly applied to the elimination of the protecting group. Examples of the compound represented by formula (1) are shown below.

4'-hydroxy-4- (1-alkyl)
-Biphenyl, 4'-hydroxy-4- (6-hydroxy-1-heptyl) -biphenyl, 4'-hydroxy-4- (6-alkoxy-1-heptyl) -biphenyl,
4'-hydroxy-4- (6-acyloxy-1-heptyl) -biphenyl, 4 "-hydroxy-4- (1-alkyl) -p-terphenyl, 4" -hydroxy-4- (6-hydroxy-1-heptyl) -p-terphenyl, 4 "-hydroxy-4- (6-alkoxy-1) -Heptyl) -p-terphenyl, 4 "-hydroxy-4- (6-acyloxy-1-heptyl) -p-terphenyl, 6-hydroxy-2- {4- (1-alkyl) -phenyl} naphthalene, 6-hydroxy-2- {4- (6-hydroxy-1-heptyl) -phenyl } Naphthalene, 6-hydroxy-2- {4- (6-alkoxy-1-heptyl) -phenyl} naphthalene, 6-hydroxy-2- {4- (6-acyloxy-1-heptyl) -phenyl} naphtha Ren, 6- (4-hydroxyphenyl) -2- (1-alkyl) naphthalene, 6- (4-hydroxyphenyl) -2- (6-hydroxy-1-heptyl) naphthalene, 6- (4-hydroxyphenyl) -2- ( 6-alkoxy-1-heptyl) naphthalene, 6- (4-hydroxyphenyl) -2- (6
-Acyloxy-1-heptyl) naphthalene, 5-hydroxy- {4- (1-alkyl) -phenyl} -pyridine, 5-hydroxy- {4- (6-hydroxy-heptyl) -phenyl} -pyridine, 5-hydroxy {4
-(6-alkoxy-1-heptyl) -phenyl} -pyridine, 5-hydroxy- {4- (6-acyloxy-1-heptyl) -phenyl} -pyridine, 2- (4-hydroxyphenyl) -5- (1-alkyl) -pyridine, 2- (4-hydroxyphenyl) ) -5- (6-Hydroxy-1-heptyl) -pyridine, 2- (4-hydroxyphenyl) -5- (6-alkoxy-1-heptyl) -pyridine, 2- (4-hydroxyphenyl) -5
-(6-Acyloxy-1-heptyl) -pyridine, 2
-Hydroxy-5- {4- (1-alkyl) -phenyl} -pyridine, 2-hydroxy-5- {4- (6-hydroxy-1-heptyl) -phenyl} -pyridine, 2
-Hydroxy-5- {4- (6-alkoxy-1-heptyl) -phenyl} -pyridine, 2-hydroxy-5- {4- (6-acyloxy-1-heptyl) -phenyl} -pyridine, 5- (4-hydroxyphenyl) -2
-(1-alkyl) pyridine, 5- (4-hydroxyphenyl) -2- (6-hydroxy-1-heptyl ans-heptenyl) pyridine, 5- (4-hydroxyphenyl) -2- (6-alkoxy-1-heptyl ans-heptenyl) pyridine, 5 -(4-hydroxyphenyl) -2- (6-acyloxy-1-heptyl) pyridine, 5
-Hydroxy-2- {4 '-(1-alkyl) -biphenyl-4-yl} -pyridine, 5-hydroxy-2- {4'-(6-hydroxy-1-heptyl) -biphenyl-4-yl} -pyridine, 5-hydroxy-2- {4 '-(6-alkoxy-1-heptyl ) -Biphenyl-4-yl} -pyridine, 5-hydroxy-2- {4 '-(6-acyloxy-1-heptyl) -biphenyl-4-yl} -pyridine, 2- (4'-hydroxy-biphenyl-4-yl) -5- (1-alkyl) -pyridine, 2- (4'-hydroxy-biphenyl-4-yl) -5- (6-hydroxy-1-heptyl) -pyridine, 2- (4'-hydroxy-biphenyl-4-yl)
-5- (6-alkoxy-1-heptyl) -pyridine,
2- (4'-hydroxy-biphenyl-4-yl) -5
-(6-Acyloxy-1-heptyl) -pyridine, 5
-(4-hydroxyphenyl) -2- {4- (1-alkyl) -phenyl} -pyridine, 5- (4-hydroxyphenyl) -2- {4- (6-hydroxy-1-heptylheptenyl) -phenyl} -pyridine, 5- (4-hydroxyphenyl) -2- {4- (6-alkoxy-1)
-Heptylheptenyl) -phenyl} -pyridine, 5- (4-hydroxyphenyl) -2- {4- (6-acyloxy-1-heptylheptenyl) -phenyl} -pyridine, 2- (4-hydroxyphenyl) -5- {4- (1-Alkyl) -phenyl} -pyridine, 2- (4-hydroxyphenyl) -5- {4- (6-hydroxy-1-heptyl) -phenyl} -pyridine, 2- (4-hydroxyphenyl) -5- {4- (6-alkoxy-1)
-Heptyl) -phenyl} -pyridine, 2- (4-hydroxyphenyl) -5- {4- (6-acyloxy-1)
-Heptyl) -phenyl} -pyridine, 5-hydroxy-2- {4- (1-alkyl) -phenyl} pyrimidine, 5-hydroxy-2- {4- (6-hydroxy-1)
-Heptyl) -phenyl} pyrimidine, 5-hydroxy-2- {4- (6-alkoxy-1-heptyl) -phenyl} pyrimidine, 5-hydroxy-2- {4- (6-acyloxy-1-heptyl) -phenyl} pyrimidine, 2- (4-hydroxyphenyl)- 5- (1-alkyl) pyrimidine, 2- (4-hydroxyphenyl) -5- (6-hydroxy-1-heptyl) pyrimidine, 2
-(4-Hydroxyphenyl) -5- (6-alkoxy-1-heptyl) pyrimidine, 2- (4-hydroxyphenyl) -5- (6-acyloxy-1-heptyl) pyrimidine, 5-hydroxy-2- {4 '-(1-alkyl) -Biphenyl-4-yl} -pyrimidine, 5-hydroxy-2- {4 '-(6-hydroxy-1-heptyl) -biphenyl-4-yl} -pyrimidine, 5-hydroxy-2- {4'-(6-alkoxy-1-heptyl) -biphenyl-4-yl} -pyrimidine, 5-hydroxy-2- {4 '-(6-Acyloxy-1-heptyl) -biphenyl-4-yl} -pyrimidine, 4'-(1-alkyl) -biphenyl-4-yl} -5-hydroxy-pyrimidine, 2- {4 '-(6-hydroxy-1-heptyl) -biphenyl-4- Ill} -5-hydroxy-pyrimidine, 2- {4 '-(6-alkoxy-1
-Heptyl) -biphenyl-4-yl} -5-hydroxy-pyrimidine, 2- {4 '-(6-acyloxy-1
-Heptyl) -biphenyl-4-yl} -5-hydroxy-pyrimidine, 5- (4-hydroxyphenyl) -2
-{4- (1-alkyl) -phenyl} -pyrimidine,
5- (4-hydroxyphenyl) -2- {4- (6-hydroxy-1-heptyl) -phenyl} -pyrimidine,
5- (4-hydroxyphenyl) -2- {4- (6-alkoxy-1-heptyl) -phenyl} -pyrimidine,
5- (4-hydroxyphenyl) -2- {4- (6-acyloxy-1-heptyl) -phenyl} -pyrimidine, 2- (4-hydroxyphenyl) -5- {4- (1
-Alkyl) -phenyl} -pyrimidine, 2- (4-hydroxyphenyl) -5- {4- (6-hydroxy-1)
-Heptyl) -phenyl} -pyrimidine, 2- (4-hydroxyphenyl) -5- {4- (6-alkoxy-1)
-Heptylheptenyl) -phenyl} -pyrimidine, 2
-(4-hydroxyphenyl) -5- {4- (6-acyloxy-1-heptylheptenyl) -phenyl} -pyrimidine, 2- {4- (5-hydroxypyrimidine-2
-Yl) phenyl} -5- (1-heptyl} -pyrimidine, 2- {4- (5-hydroxypyrimidin-2-yl) phenyl} -5- (6-hydroxy-1-heptyl} -pyrimidine, 2- {4- (5-hydroxypyrimidine -2-yl) phenyl} -5- (6-alkoxy-1-heptyl} -pyrimidine, 2- {4- (5-hydroxypyrimidin-2-yl) phenyl} -5- (6-acyloxy-1-heptyl} -pyrimidine, 5- (4-hydroxy) Phenyl) -2- {4- (1-alkyl) phenyl} pyrazine, 5- (4-hydroxyphenyl) -2- {4- (6-hydroxy-1-heptyl) phenyl} pyrazine, 5- (4-hydroxyphenyl) -2 -{4- (6-alkenyl-1-heptyl) phenyl} pyrazine, 5- (4-hydride Kishifeniru) -2 chromatography {4-(6-1 acyl OXY 1 Hepuchiru) phenyl} pyrazine, 6-1 (4-hydroxyphenyl) -3 chromatography {4-(1
-Alkyl) phenyl} pyridazine, 6- (4-hydroxyphenyl) -3- {4- (6-hydroxy-1-heptyl) phenyl} pyridazine, 6- (4-hydroxyphenyl) -3- {4- (6-alkenyl-1-heptyl) Phenyl} pyridazine, 6- (4-hydroxyphenyl) -3- {4- (6-acyloxy-1-heptyl) phenyl} pyridazine, 2- (6-hydroxynaphthalen-2-yl) -5- (1-heptyl) -pyridine, 2 -(6-hydroxynaphthalen-2-yl)
-5- (6-hydroxy-1-heptyl) -pyridine,
2- (6-hydroxynaphthalen-2-yl) -5- (6-alkoxy-1-heptyl) -pyridine, 2- (6-hydroxynaphthalen-2-yl) -5- (6
-Acyloxy-1-heptyl) -pyridine, 5- (6
-Hydroxynaphthalene-2-yl) -2- (1-alkyl) -pyridine, 5- (6-hydroxynaphthalene-2-yl) -2- (6-hydroxy-1-heptyl) -pyridine, 5- (6-hydroxynaphthalene-2) -Yl) -2- (6-alkoxy-1-heptyl) -pyridine, 5- (6-hydroxynaphthalene-2-yl) -2- (6-acyloxy-1-heptyl) -pyridine, 2-hydroxy-5- {6- (1-alkyl) naphthalene-2 -Yel) -pyridine, 2-hydroxy-5- {6- (6-hydroxy-1-heptyl) naphthalene-2-yl) -pyridine, 2-hydroxy-5- {6- (6-alkoxy-1-heptyl) naphthalene-2-yl) -pyridine, 2-hydroxy-5- {6- (6) 6-acyloxy - heptyl) over naphthalene-2
-Yl) -pyridine, 5-hydroxy-2- {6- (1
-Alkyl) naphthalene-1-yl} -pyridine, 5
-Hydroxy-2- {6- (6-hydroxy-1-heptyl) naphthalene-1-yl} -pyridine-5-hydroxy-2- {6- (6-alkoxy-1-heptyl)
Naphthalene-1-yl} -pyridine, 5-hydroxy-2- {6- (6-acyloxy-1-heptyl) naphthalen-1-yl} -pyridine, 7-hydroxy-3
-{4- (1-Alkyl) -phenyl} -isoquinoline, 7-hydroxy-3- {4- (6-hydroxy-1)
-Heptyl) -phenyl} -isoquinoline, 7-hydroxy-3- {4- (6-alkoxy-1-heptyl) -phenyl} -isoquinoline, 7-hydroxy-3- {4
-(6-Acyloxy-1-heptyl) -phenyl} -isoquinoline, 3- (4-hydroxy-phenyl) -7
-(1-Alkyl) -isoquinoline, 3- (4-hydroxy-phenyl) -7- (6-hydroxy-1-heptyl) -isoquinoline, 3- (4-hydroxy-phenyl) -7- (6-alkoxy-1-heptyl) -isoquinoline, 3- ( 4-hydroxy-phenyl) -7- (6
-Acyloxy-1-heptyl) -isoquinoline, 6-hydroxy-2- {4- (1-alkyl) -phenyl}
-Quinoline, 6-hydroxy-2- {4- (6-hydroxy-1-heptyl) -phenyl} -quinoline, 6-hydroxy-2- {4- (6-alkoxy-1-heptyl) -phenyl} -quinoline, 6-hydroxy-2- {4- (6-acyloxy-1-heptyl) -Phenyl} -quinoline, 2- (4-hydroxy-phenyl) -6- (1-alkyl) -quinoline, 2- (4-hydroxy-phenyl) -6- (6-hydroxy-1-heptyl) -quinoline, 2- (4-hydroxy-phenyl) ) -6- (6-Alkoxy-1-heptyl) -quinoline, 2
-(4-Hydroxy-phenyl) -6- (6-acyloxy-1-heptyl) -quinoline, 5-hydroxy-5
-{6- (1-Alkyl) naphthalene-2-yl} -pyrimidine, 5-hydroxy-5- {6- (6-hydroxy-1-heptyl) naphthalen-2-yl} -pyrimidine, 5-hydroxy-5- {6- (6-alkoxy-1-heptyl) naphthalene-2-yl} -Pyrimidine, 5-hydroxy-5- {6- (6-acyloxy-1-heptyl) naphthalene-2-yl} -pyrimidine, 3-hydroxy-7- {4- (1-alkyl) -phenyl} -quinoxaline, 3-hydroxy-7- {4- (6-hydroxy-1-heptyl) -phenyl } -Quinoxaline, 3-hydroxy-7- {4- (6-alkoxy-1-heptyl) -phenyl} -quinoxaline, 3-hydroxy-7- {4- (6-acyloxy-1-heptyl) -phenyl} Quinoxaline, 2-hydroxy-6-1 {4-(1 Arukiru) Feniru} Kinazorin, 2-hydroxy-6-1 {4-(6-hydroxy-1
-Heptyl) -phenyl} -quinazoline, 2-hydroxy-6- {4- (6-alkoxy-1-heptyl) -phenyl} -quinazoline, 2-hydroxy-6- {4- (6-acyloxy-1-heptyl) -phenyl} -quinazoline, and the above-mentioned substituted (6-hydroxy-1)
-Heptyl) group is 3-hydroxy-1-butyl, 4
-Hydroxy-1-pentyl, 5-hydroxy-1
-Hexyl, 6-hydroxy-1-heptyl, 7-hydroxy-1-octyl, 8-hydroxy-1-nonyl, 9-hydroxy-1-decyl, 10-hydroxy-1-undecyl, 11-hydroxy-1 dodecyl, 4-hydroxy-1-butyl, 5-hydroxy-1
-Pentyl, 6-hydroxy-1-hexyl, 7-hydroxy-1-heptyl, 8-hydroxy-1-octyl, 9-hydroxy-1-nonyl, 10-hydroxy-1-decyl, 11-hydroxy-1-undecyl, 12-hydroxy-1-dodecyl group, or a substitution ( 6-alkoxy-1
-Heptyl) group is 3-alkoxy-1-butyl,
4-alkoxy-1-pentyl, 5-alkoxy-1
-Hexyl, 6-alkoxy-1-heptyl, 7-alkoxy-1-octyl, 8-alkoxy-1-nonyl, 9-alkoxy-1-decyl, 10-alkoxy-1-undecyl, 11-alkoxy-1 dodecyl, 4-alkoxy-1-butyl, 5-alkoxy-1-pentyl, 6-alkoxy-1-hexyl, 7-alkoxy-1 -Heptyl, 8-alkoxy-1-octyl, 9-alkoxy-1-nonyl, 10-alkoxy-1-decyl, 11-alkoxy-1-undecyl, 12-alkoxy-1 dodecyl group, and the above-mentioned substituted (6-acyloxy-1-heptyl) group, 3-acyloxy-1
-Butyl, 4-acyloxy-1-pentyl, 5-acyloxy-1-hexyl, 6-acyloxy-1
-Heptyl, 7-acyloxy-1-octyl, 8-acyloxy-1-nonyl, 9-acyloxy-1-decyl, 10-acyloxy-1-undecyl, 11-acyloxy-1-dodecyl, 4-acyloxy-1
-Butyl, 5-acyloxy-1-pentyl, 6-acyloxy-1-hexyl, 7-acyloxy-1-heptyl, 8-acyloxy-1-octyl, 9-acyloxy-1-nonyl, 10-acyloxy-1-decyl, 11-acyloxy-1-undecyl, 12-acyloxy-1-dodecyl group Is. Further, it is a compound in which the alkyl group and the alkyloxy group of the above compounds replace the alkenyl group and the alkenyloxy group, respectively. Further, it is a compound in which the phenyl group of the above compound is substituted with 1 to 3 fluorine atoms. Specific examples of R2 and R3 are those exemplified as the substituent R3 shown above. Further, in the above compounds, the hydroxy group substituted by any one of A1, A2 and A3 includes a compound protected by a hydroxyl group protecting group. Examples of such protecting group are as follows.

Aliphatic acyl groups such as acetyl, propionyl, butyryl and pentyl, halogen atoms such as chlorine atom and bromine atom, alkyl groups such as methyl, ethyl, propyl and butyl or alkoxy groups such as methoxy, ethoxy, propoxy and butoxy. Optionally substituted with a benzoyl group which may be substituted with, a halogen atom such as a chlorine atom or a bromine atom, an alkyl group such as methyl, ethyl, propyl or butyl, or an alkoxy group such as methoxy, ethoxy, propoxy or butoxy. Benzyl group, trimethylsilyl group, triethylsilyl group, dimethylphenylsilyl group, dimethylbenzylsilyl group, methyldibenzylsilyl group, tribenzylsilyl group, dimethylbutylsilyl group, methyldiphenylsilyl group, triphenyl A trialkylsilyl group such as a silyl group, a dialkylphenylsilyl group, an alkyldiphenylsilyl group, a triphenylsilyl group, an aralkyldialkylsilyl group, a diaralkylalkylsilyl group or a triaralkylsilyl group, and the phenyl group or aralkyl group is a halogen atom. It may be substituted with an atom, an alkyl group, an alkoxy group or the like. Further examples include a tetrahydropyranyl group, a tetrahydrofuranyl group, and further ethers such as a 1- (alkoxy) ethyl group such as ethoxyethyl and propoxyethyl. Here, in the compound names, alkyl, alkynyl, and alkoxy represent a group having 1 to 20 carbon atoms, and an acyloxy group represents 1 carbon atom.
The groups of -19 are shown. The selection of the above protecting group is selected according to the phenol derivative (1) to be obtained. r =
In the case of an ester group as in the case of 1 and s = 1, it is more advantageous to use a silyl group or an ether group instead of an acyl group such as an acetyl group or a benzoyl group for the following deprotecting group. When s = 0, any protecting group may be used, but when R2 is a hydrogen atom and further esterified with a carboxylic acid (5), the hydroxyl group is the same protecting group as above. It is advantageous to use it.

[0031]

INDUSTRIAL APPLICABILITY The compound of the present invention is not only useful as an intermediate for liquid crystal materials but also as an intermediate for agricultural chemicals, pharmaceuticals and the like. Further, according to the method of the present invention, the phenol derivative (1) can be industrially advantageously produced. Further, when the phenol derivative of the present invention is optically active, it is industrially extremely advantageous.

[0032]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto. Example 1 2- (4-bromophenyl) -5-acetoxypyrimidine (2-1) 8.8 g (0.03 mol) was added to a four-necked flask equipped with a stirrer and a thermometer, and optically active 1-heptin-6. -Ol (3-1) 4.0 g (0.036 mol), bis (triphenylphosphine) palladium chloride 0.15 g, copper iodide 0.15 g, triphenylphosphine 0.8 g and triethylamine 50 ml were charged, and the mixture was heated to 60 to 60 ° C under a nitrogen stream.
Allow to react for 13 hours at 65 ° C. After completion of the reaction, the reaction mixture was poured into 200 ml of water and extracted with 200 ml of toluene. The obtained toluene layer was washed with 3% HCl water and water,
Concentration under reduced pressure gave a brown residue. This was purified by silica gel column chromatography (eluent: toluene-ethyl acetate) to give an optically active (-)-5-acetoxy-
2- (4- (6-hydroxy-1-heptynyl) phenyl) pyrimidine (4-1) 7.9 g (yield 81%) was obtained. Optical rotation [α] _D ²⁰ : −4.4 ° (c = 1, chloroform), melting point 99 ° C. Then obtained here (4-1)
A mixed solution of 3.6 g (11 mmol), 10 ml of methanol, 20 ml of ethyl acetate and 0.3 g of 5% palladium carbon was hydrogenated under the hydrogen pressure of 10 kg / cm ² and at 30 to 40 ° C.
After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure to give optically active (-)-5-acetoxy-2- (4- (6-hydroxy-1-heptyl) phenyl) pyrimidine (1-1).
3.5 g (yield 98%) was obtained. Optical rotation [α] _D ²⁰ : −4.
4 ° (c = 1, chloroform), melting point 78-79 ° C.
Furthermore, 0.11 g (0.5 mmol) of (1-1) was dissolved in 3 ml of tetrahydrofuran and 5 ml of methanol to give 20%.
Add 3 ml of caustic soda and react at 30-40 ° C for 7 hours. After completion of the reaction, the solvent is distilled off, 5 mL of water is added, acidified with 10% sulfuric acid, and extracted with 10 ml of ethyl acetate. The organic layer is washed with water, concentrated, and then purified by chromatography to give an optically active (-)-5-
0.14 g (yield 97%) of hydroxy-2- (4- (6-hydroxy-1-heptyl) phenyl) pyrimidine is obtained. Optical rotation [α] _D ²⁰ : -5.1 ° (c = 1, chloroform), melting point 84-87 ° C.

Example 2 1.6 g (5) of the optically active (-)-5-acetoxy-2- (4- (6-hydroxy-1-heptyl) phenyl) pyrimidine (1-1) obtained in Example 1 0.5 g (6 mmol) of acetyl chloride (5-1) was added to a mixed solution of 10 ml of pyridine, 10 ml of pyridine and 8 ml of toluene at 20 to 25 ° C. Then, the mixture is reacted at the same temperature for 2 hours. After the reaction,
The reaction solution is poured into ice water and extracted with 30 ml of toluene.
The organic layer was washed with hydrochloric acid water, water, and sodium bicarbonate water, concentrated, and then purified by chromatography to obtain an optically active (-)
-5-acetoxy-2- (4- (6-acetoxy-1-
1.8 g (yield 97%) of heptyl) phenyl) pyrimidine (1-2) was obtained. Optical rotation [α] _D ²⁰ : −4.9 ° (c =
1, chloroform)

Example 3 1.6 g (5) of the optically active (-)-5-acetoxy-2- (4- (6-hydroxy-1-heptyl) phenyl) pyrimidine (1-1) obtained in Example 1 Mmol), 30 g of ethyl iodide (6-1) and 20 g of silver oxide are reacted at 30 to 35 ° C. for 48 hours. After completion of the reaction, the reaction solution is filtered off, the filtrate is concentrated, and further purified by chromatography to give an optically active (-)-5-acetoxy-2- (4- (6-ethoxy-1-heptyl). 1.2 g (yield 68%) of phenyl) pyrimidine (1-3) was obtained. Optical rotation [α] _D ²⁰ : -5.1 ° (c = 1, chloroform). Further, (1-3) 0.7 (2 mmol) was dissolved in 8 ml of tetrahydrofuran and 8 ml of methanol, and 20
% Caustic soda (10 ml) is added, and the mixture is reacted at 30-40 ° C. for 7 hours. After the reaction was completed, the solvent was distilled off, water (20 ml) was added, and the mixture was acidified with 10% sulfuric acid, and ethyl acetate (20 m) was added.
Extract with l. The organic layer is washed with water, concentrated, and then purified by chromatography to obtain an optically active (-)
0.6 g (yield 97.5%) of -5-hydroxy-2- (4- (6-ethoxy-1-heptyl) phenyl) pyrimidine is obtained. Optical rotation [α] _D ²⁰ : -5.3 ° (c = 1, chloroform).

Example 4 In a four-necked flask equipped with a stirrer and a thermometer, 2
(4-Bromophenyl) -5-benzyloxypyrimidine (2-2) 20.4 g (0.06 mol), optically active 1-pentyn-4-ol (3-2) 5.6 g (0.066 mol), bis (tri) Phenylphosphine) palladium chloride 0.4
g, copper iodide 0.4 g, triphenylphosphine 2.08 g and triethylamine 80 ml were charged, and under a nitrogen stream,
The reaction is carried out at 60 to 65 ° C for 15 hours. After the reaction,
The reaction mixture was poured into 400 ml of water and extracted with 200 ml of toluene. The obtained toluene layer was washed with 3% HCl water and water, and then concentrated under reduced pressure to obtain a brown residue. This was purified by silica gel column chromatography (eluent: toluene-ethyl acetate) to give optically active (-)-5-benzyloxy-2- (4- (4-hydroxy-1-pentynyl) phenyl). Pyrimidine (4'-2) 15.6 g (yield 7
6%) was obtained. n _D ²⁰ 1.5862, optical rotation [α] _D ^{2 0} :-
3.9 ° (c = 1, chloroform). Next, 1.7 g (5 mmol) of the optically active (−)-5-benzyloxy-2- (4- (4-hydroxy-1-pentynyl) phenyl) pyrimidine (4′-2) obtained here, Pyridine 10m
0.5 g (6 mmol) of propionic acid chloride (5-2) was added to a mixed solution of 1 and 8 ml of toluene at 30 to 35 ° C. Then, it is made to react at the same temperature for 3 hours. After completion of the reaction, the reaction solution is poured into ice water and extracted with 30 ml of toluene. The organic layer was washed with hydrochloric acid, water, and sodium bicarbonate water, and then concentrated,
By further purifying by chromatography, 1.9 g of an optically active (−)-5-benzyloxy-2- (4- (4-propionyloxy-1-pentynyl) phenyl) pyrimidine (4-2) (yield 97 %) Was obtained. Optical rotation [α]
^{_{D 20: -4.1 ° (c =}} 1, chloroform). Then 0.4 g (1-2 mmol) of (4-2) obtained here, 5 ml of methanol, 10 ml of ethyl acetate and 0.2% of 5% palladium on carbon.
The mixed solution of g is hydrogenated under the conditions of hydrogen pressure of 15 kg / cm ² 40 to 45 ° C. After completion of the reaction, the catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the optically active (-)-5-hydroxy-2- (4-
(4-propionyloxy-1-pentyl) phenyl)
Pyrimidine (1-4) 0.4 g (yield 98%) is obtained. Optical rotation [α] _D ²⁰ : −4.9 ° (c = 1, chloroform).

Example 5 In a four-necked flask equipped with a stirrer and a thermometer, 10.1 g (0.03 mol) of 2- (4-bromophenyl) -5-tetrahydropyranyloxypyrimidine (2-3), optical activity Na 6-acetoxy 1-heptin (3-3) 4.6 g (0.03
Mol), 0.25 g of bis (triphenylphosphine) palladium chloride, 0.25 g of copper iodide, 1.3 g of triphenylphosphine and 50 ml of triethylamine, and the mixture is reacted at 55-60 ° C. for 15 hours under a nitrogen stream. After the reaction was completed, the reaction mixture was poured into 200 ml of water, and toluene 2 was added.
It was extracted with 00 ml. The resulting toluene layer is 3% HCl
After washing with water and water, the mixture was concentrated under reduced pressure to give a brown residue. This was purified by silica gel column chromatography (eluent: toluene-ethyl acetate) to give an optically active (-)
-5-tetrahydropyranyloxy-2- (4- (6-
Acetoxy-1-heptynyl) phenyl) pyrimidine (4-5) (9.2 g, yield 75%) was obtained. Optical rotation [α]
_D ²⁰ : -3.1 ° (c = 1, chloroform). Then, a mixed solution of 2.0 g (5-5 mmol) of (4-5) thus obtained, 10 ml of methanol, 10 ml of tetrahydrofuran and 0.3 g of 5% palladium on carbon was added at a hydrogen pressure of 15 kg / cm ² , 30-.
Hydrogenation is carried out at 40 ° C. After the reaction was completed, the catalyst was filtered off,
The filtrate was concentrated under reduced pressure to give an optically active (−)-5-tetrahydropyranyloxy-2- (4- (6-acetoxy-1-
2.0 g (yield 97.5%) of heptyl) phenyl) pyrimidine (1-5) is obtained. Optical rotation [α] _D ²⁰ : −3.0 ° (c =
1, chloroform). (1-5) 1.0 g obtained here
Is stirred with 10 ml of tetrahydrofuran, 3 ml of water and 0.2 g of toluenesulfonic acid at 40 ° C. for 3 hours. After completion of the reaction, the reaction solution is extracted with 20 ml of ethyl acetate. The organic layer is washed with water, concentrated, and then purified by chromatography to obtain an optically active (−)-5-hydroxy-
0.7 g of 2- (4- (6-acetoxy-1-heptyl) phenyl) pyrimidine (91% yield) is obtained. Optical rotation [α] _D ²⁰ : -5.1 ° (c = 1, chloroform)

Example 6 In a four-necked flask equipped with a stirrer and a thermometer, 4-acetoxy-4'-bromobiphenyl (2-4), 8.7 g (0.
03 mol), optically active 1-heptin-6-ol (3-
1) 4.5 g (0.04 mol), bis (triphenylphosphine) palladium chloride 0.2 g, copper iodide 0.15 g, triphenylphosphine 1 g and diethylamine 40 ml were charged and reacted at 50-60 ° C. for 20 hours under a nitrogen stream. Let After the reaction was completed, the reaction mixture was poured into 200 ml of water,
It was extracted with 200 ml of toluene. The resulting toluene layer is 3%
After washing with HCl water and water, the mixture was concentrated under reduced pressure to give a brown residue. This was purified by silica gel column chromatography (eluent: toluene-ethyl acetate) to give 4-acetoxy-4 ′-(6-hydroxy-1-heptinyl) biphenyl (4′-6) 8.1 g (yield 84%). Got Optical rotation [α] _D ²⁰ : −4.5 ° (c = 1, chloroform).
Next, a mixed solution of 1.6 g (5 mmol) of (4′-6) thus obtained, 20 g of methyl iodide (6-2) and 15 g of silver oxide is reacted at 30 to 35 ° C. for 40 hours. After completion of the reaction, the reaction solution is filtered off, the filtrate is concentrated, and further purified by chromatography to give optically active 4-acetoxy-4 ′-(6-methoxy-1-heptinyl) biphenyl (4-6). 1.4 g (81% yield) were obtained. Optical rotation [α]
_D ²⁰ : −4.9 ° (c = 1, chloroform). Then, a mixed solution of 1.0 g (3 mmol) of (4-6) thus obtained, 10 ml of methanol, 6 ml of tetrahydrofuran and 0.2 g of 5% palladium on carbon was added at a hydrogen pressure of 10 kg / cm ² , 35-4.
Hydrogenate at 0 ° C. After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure to give optically active 4-acetoxy-4'-
(6-Methoxy-1-heptyl) biphenyl (1-6)
1.0 g (yield 98%) was obtained. Optical rotation [α] _D ²⁰ : −4.
6 ° (c = 1, chloroform). Furthermore (1-3) 0.7
g (2 mmol) of dioxane 8 ml and methanol 5 ml
Dissolve in, add 8 ml of 20% caustic soda, and 30-40 ℃
React for 7 hours. After completion of the reaction, the solvent is distilled off, 20 mL of water is added, the mixture is further acidified with 10% sulfuric acid, and extracted with 20 ml of ethyl acetate. The organic layer is washed with water, concentrated, and purified by chromatography to obtain optically active 4-hydroxy-4 ′-(6-methoxy-1-heptyl) biphenyl. Optical rotation [α] _D ²⁰ : −5.2 °
(C = 1, chloroform).

Example 7 In a four-necked flask equipped with a stirrer and a thermometer, 2- (4
-Bromophenyl) -5-hydroxypyrimidine (2-
2) 5.0 g (0.02 mol), 1-butyn-3-ol (3
-4) 1.5 g (0.022 mol), bis (triphenylphosphine) palladium chloride 0.1 g, copper iodide 0.15 g,
0.7 g of triphenylphosphine and 5 of diethylamine
0 ml was charged, and the mixture was reacted under a nitrogen stream under reflux for 15 hours. After completion of the reaction, post-treatment and purification according to Example 1,
2.4 g of 5-hydroxy-2- (4- (3-hydroxy-1-butynyl) phenyl) pyrimidine (1-7) (51% yield) is obtained. Optical rotation [α] _D ²⁰ : −13 °. If acetic anhydride (3 equivalents) and pyridine (10 equivalents) were reacted with (1-7) at 40 ° C. for 5 hours to acetylate, 5-acetoxy-2- (4- (3-acetoxy) was obtained. −
This gives 1-butynyl) phenyl) pyrimidine (4-7). Next, (4-7) obtained here is dissolved in methanol and tetrahydrofuran, and hydrogen-reduced with a 5% palladium-carbon catalyst to give 5-acetoxy-2- (4-
This gives (3-acetoxy-1-butyl) phenyl) pyrimidine (1-7).

Example 8 The optically active (-)-5-benzyloxy-2- (4- (4-hydroxy-1-pentynyl) obtained in Example 4
25 g of a mixed solution of 1.7 g (5 mmol) of phenyl) pyrimidine (4′-2), 10 ml of pyridine and 10 ml of toluene was added.
At −30 ° C., 0.8 g (6 mmol) of (−)-2,2-dimethylcyclopropanecarboxylic acid chloride (5-2) is added. Then, the mixture is reacted at the same temperature for 4 hours. After completion of the reaction, the reaction solution is poured into ice water and extracted with 30 ml of toluene. The organic layer was washed with hydrochloric acid, water, and sodium bicarbonate water, and then concentrated,
By further purifying by chromatography, an optically active (−)-5-benzyloxy-2- (4- (4- (2,
2-dimethylcyclopropanecarbonyloxy) -1-
Pentynyl) phenyl) pyrimidine (4-8) 2.1 g
(Yield 95%). Optical rotation [α] _D ²⁰ : -25 °
(C = 1, chloroform). Then, a mixed solution of 0.4 g (1-8 mmol) of (4-8) obtained above, 5 ml of methanol, 10 ml of ethyl acetate and 0.02 g of 5% palladium carbon was added under the conditions of hydrogen pressure of 15 kg / cm ² and 30 to 35 ° C. Hydrogenate.
After completion of the reaction, the catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the optically active (-)-5-hydroxy-2- (4- (4- (2,
2-dimethylcyclopropanecarbonyloxy) -1-
0.4 g (yield 98%) of pentyl) phenyl) pyrimidine (1-8) is obtained. Optical rotation [α] _D ²⁰ : −33 ° (c =
1, chloroform).

Example 9 1.6 g (5) of the optically active (-)-5-acetoxy-2- (4- (6-hydroxy-1-heptynyl) phenyl) pyrimidine (1-1) obtained in Example 1 Mmol), dissolved in 10 mL of tetrahydrofuran and 2 mL of hexamethylphosphorylamide, and 0.4 g of potassium hydride at 10 ° C.
(10 ml) is added, and the mixture is reacted at the same temperature for 2 hours and further at room temperature for 5 hours. Next, butyl iodide (6-2) 3.5 (20m
l) is added and reacted at 25 to 30 ° C. for 5 hours and 40 ° C. for 5 hours. After completion of the reaction, the reaction solution is poured into ice water and extracted with ethyl acetate. The optically active (−)-5-acetoxy-2 was obtained by post-treatment purification according to Example 1 below.
-(4- (6-butoxy-1-heptynyl) phenyl)
1.4 g (yield 72%) of pyrimidine (4-9) is obtained. Optical rotation [α] _D ²⁰ : −3.4 ° (c = 1, chloroform).
Then (4-9) 0.8 g (2 mmol) obtained here,
A mixed solution of 5 ml of methanol, 10 ml of tetrahydrofuran and 0.02 g of 5% palladium-carbon was added with a hydrogen pressure of 15 kg / cm ² ,
Hydrogenation is carried out under the condition of 30 to 35 ° C. After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure to give an optically active (−)-5-acetoxy-2- (4- (6-butoxy-1-heptyl) phenyl) pyrimidine (1-9) 0.8. g (98% yield) are obtained. Optical rotation [α] _D ²⁰ : −3.3 ° (c = 1, chloroform). If (1-9) is hydrolyzed according to Example 3, it is optically active (−)-5-hydroxy-2- (4-).
This gives (6-butoxy-1-heptyl) phenyl) pyrimidine.

Example 10 In a four-necked flask equipped with a stirrer and a thermometer, 2
(4-Bromophenyl) -5-acetoxypyrimidine (2-1) 8.8 g (0.03 mol), optically active 4-ethoxy-1-pentyne (3-5) 3.4 g (0.03 mol), bis (triphenyl) Phosphine) palladium chloride 0.2 g, copper iodide 0.2 g, triphenylphosphine 1.2 g and triethylamine 40 ml were charged, and the mixture was heated to 50-55 under a nitrogen stream.
React at 10 ° C. for 10 hours. After completion of the reaction, the reaction mixture was poured into 200 ml of water and extracted with 100 ml of toluene. The obtained toluene layer was washed with 3% HCl water and water, and then concentrated under reduced pressure to obtain a brown residue. This is purified by silica gel column chromatography (eluent: toluene-ethyl acetate).
Then, the optically active (−)-5-acetoxy-2- (4-
8.1 g (yield 83%) of (6-ethoxy-1-pentynyl) phenyl) pyrimidine (4-10) is obtained. Optical rotation [α] _D ²⁰ : −3.6 ° (c = 1, chloroform). Then, a mixed solution of 1.6 g (5-10 mmol) of (4-10) obtained above, 15 ml of methanol, 10 ml of ethyl acetate and 0.2 g of 5% palladium on carbon was added at a hydrogen pressure of 15 kg / cm ² , 30-.
Hydrogenate at 45 ° C. After the reaction was completed, the catalyst was filtered off,
The filtrate is concentrated under reduced pressure to obtain 1.6 g (yield 97%) of optically active (−)-5-acetoxy-2- (4- (6-ethoxy-1-pentyl) phenyl) pyrimidine (1-10). . Optical rotation [α] _D ²⁰ : −3.5 ° (c = 1, chloroform). When (1-10) is hydrolyzed according to Example 3, optically active (−)-5-hydroxy-2- (4-) is obtained.
This gives (6-ethoxy-1-hentyl) phenyl) pyrimidine.

Example 11 2- (4-bromophenyl) -5-t-butyldimethylsilyloxypyrimidine (2-6) 11.0 g (0.03 mol),
(+)-2-Pentynylyloxy-3-butyne (3-
6) 7.7 g (0.05 mol), copper iodide 0.25 g, triphenylphosphine 1.5 g, bis (triphenylphosphine)
Palladium chloride (0.3 g) and triethylamine (80 ml) were charged, and the mixture was stirred under a nitrogen atmosphere under reflux for 10 hours. After completion of the reaction, the reaction solution is poured into ice-hydrochloric acid water, and ethyl acetate 10
Extract with 0 ml. The organic layer is further washed with water and concentrated under reduced pressure. The residue was purified by silica gel chromatography (solute solution: toluene-ethyl acetate) to give an optically active (+)-5-t-butyldimethylsilyloxy-2-
(4- (3-Pentynylyloxy-1-butynyl) phenyl) pyrimidine (4-11) 11.8 g (yield 90%) is obtained, optical rotation [α] _D ²⁰ : 12 ° (c = 1, Chloroform). Next, a mixed solution of 2.2 g (5 mmol) of (4-11) thus obtained, 15 ml of methanol, 15 ml of ethyl acetate and 0.3 g of 5% palladium on carbon was added at a hydrogen pressure of 10 kg /
Hydrogenation is carried out under the conditions of cm ² , 35 to 45 ° C. After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure to give an optically active (+)-5
2.1 g of -t-butyldimethylsilyloxy-2- (4- (3-pentynylyloxy-1-butyl) phenyl) pyrimidine (1-11) (yield 97%) is obtained, the optical rotation [α] _D ²⁰ : 11.3 ° (c = 1, chloroform). When (1-11) is dissolved in tetrahydrofuran and treated with hydrofluoric acid, it is optically active (+)-5-hydroxy-2-
This gives (4- (3-pentynylyloxy-1-butyl) phenylpyrimidine. Optical rotation [α] _D ²⁰ : -16.6 °
(C = 1, chloroform).

Example 12 2- (4-Bromophenyl) -5-benzoyloxypyrimidine (2-7) 7.1 g (0.02 mol), 5-methoxy-
3.4 g (0.03 mol) of 1-hexyne (3-6), 0.2 g of bis (triphenylphosphine) palladium chloride, 0.3 g of copper iodide, 1.3 g of triphenylphosphine, 30 ml of triethylamine and 10 ml of dimethylformamide were charged under a nitrogen stream. And react at 80 ° C for 15 hours. After completion of the reaction, the reaction mixture is poured into 100 ml of water, ethyl acetate is added, and the mixture is made weakly acidic with 10% aqueous hydrochloric acid. The organic layer was separated, washed with water, and concentrated under reduced pressure to give 5-benzoyloxy-2- (4- (5-methoxy-1-hexynyl) phenyl) pyrimidine (4-12).
9.2 g (79% yield) are obtained. Then, 1.9 g (5 mmol) of (4-12) obtained here, 15 m of methanol
l, 10 ml of ethyl acetate and 0.3 g of 5% palladium on carbon
The mixed solution of 1 is hydrogenated under the conditions of hydrogen pressure of 10 kg / cm ² and 30 to 35 ° C. After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure to give 5-benzoyloxy-2- (4- (5-methoxy-1-hexyl) phenyl) pyrimidine (1-12).
1.9 g (96% yield) are obtained. If (1-12) is hydrolyzed according to Example 3, optically active (−)-5-hydroxy-2- (4- (5-methoxy-1-hexyl)) is obtained.
Give phenyl) pyrimidine.

Example 13 0.8 g (2.5) of optically active (-)-5-acetoxy-2- (4- (6-hydroxy-1-heptinyl) phenyl) pyrimidine (1-1) obtained in Example 1 Millimolar),
20-25 in a mixed solution of 3 ml of pyridine and 8 ml of toluene.
At 0C, 0.5 g (6 mmol) of acetyl chloride (5-1) is added. Then, the mixture is reacted at the same temperature for 2 hours. End of reaction,
The reaction solution is poured into ice water and extracted with 30 ml of toluene. The organic layer was washed with aqueous hydrochloric acid, water, and aqueous sodium hydrogen carbonate, concentrated, and purified by chromatography to give an optically active (-)-
0.9 g (yield 98%) of 5-acetoxy-2- (4- (6-acetoxy-1-heptinyl) phenylpyrimidine (4-13) was obtained. Optical rotation [α] _D = −3.2 °
(C = 1, chloroform). Then obtained here (4-
13) A mixed solution of 0.7 g (2 mmol), 6 ml of methanol, 10 ml of ethyl acetate and 0.1 g of 5% palladium on carbon is hydrogenated under the hydrogen pressure of 10 kg / cm ² and 30 to 40 ° C. After completion of the reaction, the catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the optically active (-)-5-acetoxy-2- (4- (6-acetoxy-1-heptyl) phenyl) pyrimidine (1-
13) 0.7 g (yield 98%) is obtained.

Example 14 In a four-necked flask equipped with a stirrer and a thermometer, 2
7.4 g of (2,3-difluoro-4- (2′-tetrahydropyranyloxy) phenyl) -5-bromopyrimidine
(2-14) (0.02 mol), optically active 1-heptin-6
-Ol (3-8) 3.4 g (0.03 mol), bis (triphenylphosphine) palladium chloride 0.13 g, copper iodide
Charge 0.13 g, triphenylphosphine 0.26 g and triethylamine 40 ml, and in a nitrogen stream at 80 to 85 ° C.
React for 7 hours. After completion of the reaction, the reaction mixture was poured into 200 ml of water and extracted with 200 ml of toluene. The obtained toluene layer was washed with 3% HCl water and water, and then concentrated under reduced pressure to obtain a brown residue. This was purified by silica gel column chromatography (eluent: toluene-ethyl acetate) to give optically active (-)-2- (2,3-difluoro-4- (2'-tetrahydropyranyloxy) phenyl). 6.3 g (yield 78%) of -5- (6-hydroxy-1-heptynyl) pyrimidine (4-a-14) was obtained.
Optical rotation ^{[α] D 20 - 4.1 (c} = 1, chloroform).
Then, to a mixed solution of 2.0 g (5 mmol) of (4-a-14) thus obtained, 10 ml of pyridine and 8 ml of toluene, 25
Add 0.5 g (6 mmol) of acetyl chloride (5-1) at -30 ° C. After that, the reaction is performed at the same temperature for 2 hours.
After completion of the reaction, the reaction solution is poured into ice water and extracted with 30 ml of toluene. The organic layer was washed with aqueous hydrochloric acid, water, and aqueous sodium hydrogen carbonate, concentrated, and purified by chromatography to give an optically active (-)-2- (2,3-difluoro-4- (2'-tetrahydro). Pyranyloxy) phenyl) -5- (6-acetoxy-1-heptynyl) pyrimidine (4-14) 2.
2 g (97% yield) are obtained. [Α] D 20 = -8.3 ° (c
= 1, CHCl3). Then obtained here (4-14)
A mixed solution of 0,44 g (1 mmol), 6 ml of methanol, 5 ml of ethyl acetate and 0,07 g of 5% palladium carbon was hydrogenated under the hydrogen pressure of 10 kg / cm @ 2 and 30-40.degree. After completion of the reaction, the catalyst was filtered off, the filtrate was concentrated under reduced pressure,
Optically active (-)-2- (2,3-difluoro-4-
(2'-Tetrahydropyranyloxy) phenyl) -5
-(6-acetoxy-1-heptyl) pyrimidine (1-
14) 0.44 g (yield 98%) is obtained. [Α] D 20 =-
7.2 ° (c = 1, CHCl3). Further (1-14) 0.
22 g (0.5 mmol) was dissolved in 10 mL of tetrahydrofuran and 3 mL of water, and 0.02 g of p-toluenesulfonic acid was dissolved.
Is added and reacted at 30 to 35 ° C. for 6 hours. After completion of the reaction, the solvent is distilled off and the residue is extracted with 20 mL of ethyl acetate.
The organic layer is washed with water, concentrated, and purified by chromatography to give an optically active (-)-2- (2,3-
0.15 g of difluoro-4-hydroxy) phenyl) -5- (6-acetoxy-1-heptyl) pyrimidine (yield 81
%). [Α] D 20 = -9.8 ° (c = 1, CHCl
3). Furthermore, (1-14) is optically active (-)-2- (2,3-difluoro-4-hydroxy) phenyl) -5- (6-hydroxy-1 if hydrolyzed according to Example 3. -Heptyl) pyrimidine. Then, a mixed solution of 2.0 g (5 mmol) of (4-a-14) thus obtained, 40 g of hexyl iodide (6-13) and 25 g of silver oxide is reacted at 30 to 40 ° C. for 50 hours. After the reaction,
The reaction solution is filtered off, the filtrate is concentrated, and further purified by chromatography to obtain an optically active (-)-2- (2,3-
Difluoro-4- (2'-tetrahydropyranyloxy)
1.0 g (yield 43%) of phenyl) -5- (6-hexyloxy-1-heptynyl) pyrimidine is obtained. [Α] D
20 = -3.2 DEG (c = 1, CHCl3). Next, the optically active (−)-2- (2,3-difluoro-4-) obtained here was obtained.
(2'-Tetrahydropyranyloxy) phenyl) -5
-(6-hexyloxy-1-heptynyl) pyrimidine
A mixed solution of 0.49 g (1 mmol), 6 ml of methanol, 5 ml of ethyl acetate and 0.05 g of 5% palladium carbon was hydrogenated under a hydrogen pressure of 10 kg / cm @ 2 and at 30-40.degree. After completion of the reaction, the catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the optically active (-)-2- (2,3-difluoro-4- (2'-tetrahydropyranyloxy) phenyl) -5- (6 -Hexyloxy-1-heptyl) pyrimidine (1-14) 0.48
g (97% yield) are obtained. [Α] D 20 = −3.0 ° (c =
1, CHCl3). 2- (2,3-difluoro-)
4- (2'-tetrahydropyranyloxy) phenyl)
Dissolve 0.25 g (0.5 mM) of 5- (6-hexyloxy-1-heptyl) pyrimidine in 8 mL of tetrahydrofuran and 2 mL of water, add 0.2 g of p-toluenesulfonic acid, and react at 25-30 ° C for 8 hours. . After the reaction,
The solvent is distilled off and the residue is extracted with 15 mL of ethyl acetate. The organic layer was washed with water, concentrated, and then purified by chromatography to give optically active (-)-2- (2,3-difluoro-4-hydroxy) phenyl) -5- (6-hexyl). Oxy-1-heptyl) pyrimidine 0.19 g (yield 94
%). [Α] D 20 = -8.9 ° (c = 1, CHCl
3).

Example 15 The optically active (-)-2- (2,3) obtained in Example 14
-Difluoro-4- (2'-tetrahydropyranyloxy) phenyl) -5- (6-hydroxy-1-heptinyl) pyrimidine (4-14) 2.0 g (5 mmol), 6 ml methanol, 10 ml tetrahydrofuran and 5% palladium. Hydrogen pressure of 5kg / cm for a mixed solution of 0,03g carbon
2, hydrogenated at 25 to 30 ° C. for 3 hours. After completion of the reaction, the catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the optically active (-)-2- (2,3-difluoro-4- (2'-tetrahydropyranyloxy) phenyl) -5- (6 -Hydroxy-1-heptyl) pyrimidine (1-a-15) 2.0
g (yield 98.0%) is obtained. [Α] D 20 = -3.8 ° (c
= 1, CHCl3). Then, obtained here (1-a-1
5) 2.0 g (2 mmol), ethyl iodide (6-1) 2
A mixed solution of 5 g and 15 g of silver oxide was added at 25 to 30 ° C.
React for 0 hours. After completion of the reaction, the reaction solution is filtered off, the filtrate is concentrated, and further purified by chromatography to obtain an optically active (−)-2- (2,3-difluoro-4- (2′-tetrahydropyranyl). (Oxy) phenyl) -5- (6-
Ethoxy-1-heptyl) pyrimidine (1-15) 1.3
g (yield 61%) was obtained. [Α] D 20 = -4.5 ° (c =
1, CHCl3). Furthermore, (1-15) 0.87g (2m
M) was dissolved in 10 mL of tetrahydrofuran and 3 mL of water, 0 and 2 g of p-toluenesulfonic acid were added, and
The reaction is carried out at 35 ° C for 6 hours. After completion of the reaction, the solvent is distilled off and the residue is extracted with 20 mL of ethyl acetate. The organic layer was washed with water, concentrated, and purified by chromatography to give an optically active (-)-2- (2,3-difluoro-4-.
0.66 g (yield 94%) of (hydroxy) phenyl) -5- (6-ethoxy-1-heptyl) pyrimidine is obtained.
[Α] D 20 = -9.8 ° (c = 1, CHCl3).

Example 16 In a four-necked flask equipped with a stirrer and a thermometer,
(2,3-Difluoro-4-p-methylbenzyloxyphenyl) -2-bromopyrimidine (2-16) 7.8 g
(0.02 mol), 6-acetoxy-1-heptin 6.2 g
(0.04 mol), bis (triphenylphosphine) palladium chloride 0.15 g, copper iodide 0.2 g, triphenylphosphine 0.3 g and diethylamine 50 ml were charged,
The mixture is reacted under a nitrogen stream under reflux for 9 hours. After completion of the reaction, post-treatment and purification were carried out according to Example 1 to give 2- (2,3-
Difluoro-4-p-methylbenzyloxyphenyl)-
7.5 g (81% yield) of 5- (6-acetoxy-1-heptynyl) pyrimidine (4-16) is obtained. Next, 2.3 g (5 mM) of (4-16) obtained here is hydrogenated at a normal pressure of 35 to 40 ° C. using 0.1 g of 5% palladium-carbon catalyst in a solvent of 20 mL of ethyl acetate. The subsequent post-treatment purification according to Example 13 gives 2- (2,3-difluoro-4-hydroxyoxyphenyl) -5- (6-acetoxy-1-heptyl) pyrimidine 2- (2,3.
-Difluoro-4-p-methylbenzyloxyphenyl)
This gives -5- (6-hydroxy-1-heptynyl) pyrimidine. Further, 2.3 g (5 mM) of (4-16) was dissolved in 10 mL of dioxane and 10 mL of methanol to give 20
% Caustic soda (8 mL) is added, and the mixture is reacted at 30-40 ° C. for 7 hours. After the reaction was completed, the solvent was distilled off, water (20 mL) was added, and the mixture was acidified with 10% sulfuric acid, and ethyl acetate (20 mL) was added.
To extract. The organic layer is washed with water, concentrated, and then purified by chromatography to give optically active 2-
2.0 g (yield 95%) of (2,3-difluoro-4-p-methylbenzyloxyphenyl) -5- (6-hydroxy-1-heptinyl) pyrimidine (4-a-16) is obtained. [Α] D 20 = -3, 7 ° (c = 1, CHCl3).
Next, 0.84 g (2 mM) of (4-a-16) obtained here
Is dissolved in 5 mL of tetrahydrofuran and 2 mL of hexamethylphosphorylamide, and potassium hydride at 0 ° C.
2 g (3 mM) is added, and the mixture is reacted at the same temperature for 2 hours and further at room temperature for 5 hours. Next, 1.8 g (10 mM) of ethoxypropyl tosylate (6-16) was added to the mixture at 25 to 30 ° C.
For 5 hours and at 40 ° C. for 5 hours. After the reaction,
The reaction solution is poured into ice water and extracted with ethyl acetate. The following post-treatment purification is carried out according to Example 1. Optically active 2- (2,
0.53 g (yield 52%) of 3-difluoro-4-p-methylbenzyloxyphenyl) -5- (6-ethoxypropoxy-1-heptynyl) pyrimidine is obtained. [Α] D
20 = -3.3 ° (c = 1, CHCl3). Then, 0.5 g (1 mmol) of optically active 2- (2,3-difluoro-4-p-methylbenzyloxyphenyl) -5- (6-ethoxypropoxy-1-heptinyl) pyrimidine obtained here, methanol A mixed solution of 5 ml, 5 ml of tetrahydrofuran and 0,01 g of 5% palladium on carbon was added under a hydrogen pressure of 1
Hydrogenation is carried out under the conditions of 5 kg / cm 2 and 30 to 35 ° C. After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure to give an optically active 2-
(2,3-difluoro-4-p-hydroxyphenyl)-
0.39 g (yield 96%) of 5- (6-ethoxypropoxy-1-heptyl) pyrimidine is obtained. . [Α] D 20 = -4.
3 ° (c = 1, CHCl3).

Example 17 6- (2,3-difluoro-4-propionyloxyphenyl) -2-bromonaphthalene (2-17) 3.9 g (0.
01 mol), 1-butyl-4-ol 1.1 g (0.015 mol), copper iodide 0.1 g, triphenylphosphine 0.15
g, bis (triphenylphosphine) palladium chloride 0.1 g, and triethylamine 50 ml were charged, and the mixture was stirred under a nitrogen atmosphere under reflux for 12 hours. After completion of the reaction, the reaction solution is poured into ice-hydrochloric acid water and extracted with 200 ml of ethyl acetate. The organic layer is further washed with water and concentrated under reduced pressure. By purifying the obtained residue by column chromatography, 6-
(2,3-difluoro-4-propionylphenyl) -2
2.7 g (yield 72%) of-(4-hydroxy-1-butynyl) naphthalene (4-a-17) is obtained. Next, 3.0 g (8 mmol) of (4-a-17) obtained above, 1.3 g (0.01 mol) of propionic anhydride, 20 ml of pyridine and 0.5 ml of dimethylaminopyridine were added, and the mixture was reacted at 30 ° C. for 4 hours. . The following post-treatment and purification were carried out according to Example 1,
6- (2,3-difluoro-4-propionylphenyl)
3.3 g (yield 96%) of 2- (4-propionyloxy-1-butynyl) naphthalene (4-17) is obtained. Next, 2.2 g (5 mM) of (4-17) obtained here was added to 0.1% of 5% palladium-carbon catalyst in 20 mL of ethyl acetate solvent.
g, and hydrogenation is carried out at normal pressure and 35 to 40 ° C. If post-treatment purification is carried out according to Example 13, 6- (2,3
-Difluoro-4-propionylphenyl) -2- (4-
Propionyloxy-1-butyl) naphthalene (1-1
7) 2.1 g (97% yield) are obtained.

Example 18 A four-necked flask equipped with a stirrer and a thermometer was charged with 2-
(3-Fluoro-4-ethoxy-α-ethoxyphenyl)
-5 g Bromopyridine (2-18) 6.4 g (0.02 mol), optically active 4-ethoxy-1-pentyne (3-
5) 3.4 g (0.03 mol), copper iodide 0.16 g, triphenylphosphine 0.3 g, bis (triphenylphosphine) palladium (II) chloride 0.15 g, triethylamine 6
Charge 0 ml and heat and stir for 8 hours in a nitrogen atmosphere. After completion of the reaction, the reaction mixture was poured into 100 ml of water, neutralized with dilute sulfuric acid, and extracted with a mixed solution of toluene-ethyl acetate.
The obtained organic solvent layer is washed with water and then concentrated under reduced pressure to obtain a yellowish brown residue. This was purified by silica gel column chromatography (eluent: toluene-ethyl acetate),
5.6 g of optically active 2- (3-fluoro-4-ethoxy-α-ethoxyphenyl) -5- (4-ethoxy-1-pentynyl) pyridine (4-18) are obtained. (79% yield)
[Α] D 26 = −5.2 ° (c = 1, chloroform) (4-18) 1.8 g (5 mmol) is methanol 5
ml, tetrahydrofura (15 ml) and 5% palladium-carbon (0.2 g) mixed solution with hydrogen pressure of 15 kg / cm ² , 30-35.
Hydrogenate at ℃. After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure to give optically active 2- (3-fluoro-4-ethoxy-α-ethoxyphenyl) -5- (4-ethoxy-1-pentyl) pyridine (1- 18) Get 1.7 g.
(Yield 98%) [α] D 26 = −4.5 ° (c = 1, chloroform) Separately, (4-18) is optically active when hydrolyzed with an acid according to Example 14 and further reduced. This gives 2- (3-fluoro-4-hydroxyphenyl) -5- (4-ethoxy-1-pentyl) pyridine.

Example 19 4- (2,3-difluoro-4-acetoxyphenyl)-
3.7 g (0.01 mol) of 4'-bromobiphenyl (2-19), 3.9 g (0.02 mol) of 6-acetoxy-1-hexyne, 0.1 g of bis (triphenylphosphine) palladium chloride, 0.2 g of copper iodide, triphenyl Phosphine
0.2 g, 30 ml of triethylamine and 10 ml of dimethylformamide were charged and reacted at 90 ° C. for 12 hours under a nitrogen stream. After completion of the reaction, the reaction mixture is poured into 100 ml of water, ethyl acetate is added, and the mixture is made weakly acidic with 10% aqueous hydrochloric acid. After liquid separation, the organic layer is further washed with water and then concentrated under reduced pressure to give 4- (2,3-difluoro-4-acetoxyphenyl) -4 ′-(5-acetoxy-1-hexynyl) biphenyl (4-19 ) 3.3 g (77% yield) are obtained. Next, a mixed solution of 2.1 g of (4-19) (5 mmol), 10 ml of methanol, 5 ml of ethyl acetate and 0,2 g of Raney nickel was added at a hydrogen pressure of 15 kg / cm @ 2, 30-3.
Hydrogenate at 5 ° C. After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure to give optically active 4- (2,3-difluoro-).
4-acetoxyphenyl) -4 '-(5-acetoxy-
2.1 g of 1-hexyl) biphenyl (1-19) are obtained.
(Yield 97%) [α] D 26 = −2.9 ° (c = 1, chloroform) Separately, (1-19) is optically active 4- (2, if hydrolyzed according to Example 16). This gives 3-difluoro-4-hydroxyphenyl) -4 '-(5-hydroxy-1-hexyl) biphenyl.

Example 20 In a 4-necked flask equipped with a stirrer and a thermometer, 2- (6
-Phenyldimethylsilyloxy-7-fluoro-naphthalen-2-yl) -5-bromopyrimidine (2-20)
4.7 g (0.01 mol), optically active 6-acetoxy 1-
Heptin) 3.1 g (0.02 mol), bis (triphenylphosphine) palladium chloride 0.1 g, copper iodide 0.2
g, 0.2 g of triphenylphosphine and 50 ml of diethylamine are charged, and the mixture is reacted under a nitrogen stream under reflux for 9 hours. After completion of the reaction, post-treatment and purification according to Example 1 were carried out, and optically active 2- (6-phenyldimethylsilyldecyloxy-7-fluoro-naphthalen-2-yl) -5-
(6-acetoxy-1-heptinyl) pyrimidine (4-
20) 4.1 g (yield 75%) are obtained. [Α] D 20 =-
3.8 ° (c = 1, CHCl3). Obtained here (1-
19) is hydrolyzed according to Example 1 to give optically active 2- (6-phenyldimethylsilyldecyloxy-7-).
This gives fluoro-naphthalen-2-yl) -5- (6-hydroxy-1-heptynyl) pyrimidine (4-a-20). 1.5 g (3 mM) of (4-a-20) was obtained by adding a mixed solution of 5 ml of methanol, 15 ml of ethyl acetate and 0,1 g of 5% palladium-carbon to a hydrogen pressure of 10 kg / cm @ 2, 30-3.
Hydrogenate at 5 ° C. After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure to give optically active 2- (6-phenyldimethylsilyldecyloxy-7-fluoro-naphthalene-2-
1.5 g of (yl) -5- (6-hydroxy-1-heptyl) pyrimidine (1-a-20) are obtained. (Yield 96%)
[Α] D 26 = -3.5 ° (c = 1, chloroform). Next, 1.0 g (2 mM) of (1-a-20) obtained here was dissolved in 8 mL of tetrahydrofuran and 2 mL of hexamethylphosphorylamide, and 0 and 12 g of potassium hydride were added at 0 ° C.
(3 mM) is added, and the mixture is reacted at the same temperature for 2 hours and further at room temperature for 5 hours. Next, 1.7 g (10 mM) of 2-fluoroethyl iodide (6-20) was added, and the mixture was reacted at 0 ° C for 5 hours and at 30 ° C for 5 hours. After completion of the reaction, the reaction solution is poured into ice water and extracted with ethyl acetate. The following post-treatment purification is carried out according to Example 1. 0.6 g (yield 51%) of optically active 2- (6-phenyldimethylsilyldecyloxy-7-fluoro-naphthalen-2-yl) -5- (6-2-fluoroethoxy-1-heptyl) pyrimidine (1-20) )
To get [Α] D 20 = -3.2 ° (c = 1, CHCl3
). (1-20) 0.5 g is tetrahydrofuran 5
The reaction with 0.3 g of tetrabutylammonium iodide in 25 mL of water and 1 mL of water at 25 to 30 ° C. for 4 hours was carried out.
-Hydroxy-7-fluoro-naphthalen-2-yl)-
Obtain 5- (6-2-fluoroethoxy-1-heptyl) pyrimidine.

Example 21 2- (2-Fluoro-4- (2'-tetrahydropyranyloxy) phenyl) -5-bromopyridazine (2-2
1) 7.1 g (0.02 mol), 4-acetoxy-1-pentyne 5 g (0.04 mol), bis (triphenylphosphine)
Palladium chloride 0.2 g, copper iodide 0.2 g, triphenylphosphine 0.4 g, triethylamine 20 ml, N-
Charge 30 ml of methylpyrrolidone and react at 80 ° C. for 7 hours. After completion of the reaction, 2- (2,3-difluoro-4- (2′-tetrahydropyranyloxy) phenyl) -5- (4-acetoxy-1-pentynyl) was obtained by post-treatment and purification according to Example 1. ) Pyridazine (4-a-2
1) 6.5 g (yield 81%) is obtained. Next, (4-a-2
1) For 1.2 g (3 mM), a mixed solution of 5 ml of methanol, 15 ml of ethyl acetate and 0.1 g of 5% palladium carbon was hydrogenated under the conditions of hydrogen pressure of 5 kg / cm @ 2 and 30 to 35.degree.
After completion of the reaction, the catalyst was filtered off, and the filtrate was concentrated under reduced pressure.
1.2 g of (2,3-difluoro-4- (2′-tetrahydropyranyloxy) phenyl) -5- (4-acetoxy-1-pentyl) pyridazine (1-21) are obtained. (Yield 96%) [α] D 26 = −3.5 ° (c = 1, chloroform) Separately, (1-21) is 2- (2, if hydrolyzed with an acid according to Example 14). 3-difluoro-4-
This gives (2′-hydroxy) phenyl) -5- (4-acetoxy-1-pentyl) pyridazine. Further, according to Example 16, hydrolysis with an alkali produces 2-
Gives (2,3-difluoro-4- (2′-hydroxy) phenyl) -5- (4-hydroxy-1-pentyl) pyridazine

Example 22 2- (2,3-Difluoro-4-hydroxyphenyl)-
5-Bromopyrimidine (2-22) 5.7 g (0.02 mol), 5-acetoxy-1-pentyne 2.5 g (0.02 mol), bis (triphenylphosphine) palladium chloride 0.2 g, copper iodide 0.2 g, triphenylphosphine
0.4 g, 20 ml of triethylamine and 30 ml of N-methylpyrrolidone are charged and the reaction is carried out at 60 ° C. for 12 hours. After completion of the reaction, 2- (2,3-difluoro-4-hydroxyphenyl)-was obtained by post-treatment and purification according to Example 1.
4.2 g (yield 63%) of 5- (5-acetoxy-1-pentynyl) pyrimidine (4-22) is obtained. Then, (4
-22) For 1.0 g (3 mM), a mixed solution of 10 ml of methanol, 15 ml of ethyl acetate and 0.1 g of 5% palladium on carbon is hydrogenated under a hydrogen pressure of 5 kg / cm 2, at 20 to 30 ° C. After the reaction was completed, the catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give 2
-(2,3-Difluoro-4-hydroxyphenyl) -5
-(5-acetoxy-1-pentyl) pyrimidine (1-
22) 1.0 g is obtained. (Yield 97%)

Example 23 In a four-necked flask equipped with a stirrer and a thermometer,
(3-Fluoro-4- (2'-pyranyloxy) phenyl) -5-bromopyridine (2-23) 3.1 g (0.01 mol), optically active 6-methoxyacetyloxy-1-heptin 3.7 g (0.02 mol) Then, 0.1 g of copper iodide, 0.2 g of triphenylphosphine, 0.1 g of bis (triphenylphosphine) palladium (II) chloride and 40 ml of triethylamine were charged, and the mixture was heated and stirred for 8 hours in a nitrogen atmosphere. After completion of the reaction, the reaction mixture was poured into 100 ml of water and extracted with a mixed solution of toluene and ethyl acetate. The obtained organic solvent layer is washed with water and then concentrated under reduced pressure to obtain a yellowish brown residue. This is purified by silica gel column chromatography (eluent: toluene-ethyl acetate) to give 2- (3-
Fluoro-4- (2'-pyranyloxy) phenyl) -5
3.1 g of-(6-methoxyacetyloxy-1-heptynyl) pyridine (4-23) are obtained. (Yield 75%),
[Α] D 26 = −4.1 ° (c = 1, chloroform) Next, 1.2 g (3 mM) of (4-23) is a mixed solution of 10 ml of methanol, 10 ml of tetrahydrofuran and 0.1 g of 5% palladium on carbon, and hydrogen pressure of 10 kg. / Cm2, 25-
Hydrogenation is carried out at 30 ° C. After the reaction was completed, the catalyst was filtered off,
The filtrate was concentrated under reduced pressure to give 2- (3-fluoro-4- (2'-pyranyloxy) phenyl) -5- (6-methoxyacetyloxy-1-heptyl) pyridine (1-23) 1.2 g.
To get (Yield 97%) [α] D 26 = −3.6 ° (c =
1, chloroform) (1-21) can be converted into 2- (3-fluoro-4- (2′-hydroxy) phenyl) -5- (6-methoxyacetyl) by hydrolysis with an acid according to Example 14. Oxy-
1-heptyl) pyridine.

Example 24 5- (4 '-(p-chlorobenzoyloxy) biphenylen-2-yl) -2-trifluoromethanesulfonyloxypyrimidine (2-24) 4.7 g (0.01 mol),
Optically active 6-acetoxy-1-heptin (3-3) 3.
1 g (0.02 mol), bis (triphenylphosphine) palladium chloride 0.15 g, copper iodide 0.2 g, triphenylphosphine 0.2 g and triethylamine 50 ml were charged and reacted under a nitrogen stream at 80 ° C. for 9 hours. After completion of the reaction, post-treatment and purification according to Example 1 were carried out to obtain optically active 5- (4 '-(p-chlorobenzoyloxy) biphenylen-2-yl) -2- (6-acetoxy-1-heptinyl). 4.2 g (yield 78%) of pyrimidine (4-24) is obtained. [Α] D 20 = -3.0 ° (c = 1, CHCl3).
Next, 1.6 g (3 mM) of (4-24) was mixed with 10 ml of methanol, 10 ml of tetrahydrofuran and 0,05 g of 5% palladium on carbon at a hydrogen pressure of 2 kg / cm 2, 1
Hydrogenation is carried out under the condition of 5 to 20 ° C. After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure to give optically active 5- (4 '-(p-chlorobenzoyloxy) biphenylen-2-yl)-
2- (6-acetoxy-1-heptyl) pyrimidine (1
-24) Obtain 1.5 g. (Yield 92%) [α] D 26 =-
3.8 ° (c = 1, chloroform) (1-24) obtained here is hydrolyzed according to Example 1 to give optically active 5- (4′-hydroxy) biphenylen-2-yl) -2. This gives-(6-hydroxy-1-heptyl) pyrimidine.

Examples 25 to 37 Examples 1 to 10 except that the starting materials shown in Table 1 were used.
The phenol derivative (1) shown in Table 1 is obtained by sequentially performing the reaction and the post-treatment according to the above. Among the phenol derivatives (1) obtained here, the compounds of Examples 26, 27 and 31 to 37 are further hydrolyzed according to Example 1 to give compounds in which R 1 represents a hydrogen atom, In this case, Examples 26, 27, 31, 33, 34, 3
For the compound of 6, R2 also changes to a hydrogen atom.

Examples 38 to 40 The reaction and post-treatment were carried out according to Examples 8 and 3 except that (4-a-2) obtained in Example 4 was used and the starting materials shown in Table 2 were used. When sequentially performed, the phenol derivative (1) shown in Table 2 is obtained.

Examples 41 to 53 Examples 1 to 10 except that the starting materials shown in Table 3 were used.
The phenol derivative (1) shown in Table 3 is obtained by sequentially performing the reaction and the post-treatment according to the above.

Example 54 0.8 g (2.5) of optically active (-)-5-acetoxy-2- (4- (6-hydroxy-1-heptinyl) phenyl) pyrimidine (1-1) obtained in Example 1 Millimolar),
A mixed solution of 16 g of ethyl iodide (6-1) and 15 g of silver oxide is reacted at 30 to 35 ° C. for 50 hours. After completion of the reaction, the reaction solution was filtered off, the filtrate was concentrated, and further purified by chromatography to give an optically active (-)-5-acetoxy-2- (4- (6-ethoxy-1-heptinyl). Phenyl) pyrimidine (4-56) 0.6 g (yield 67%)
Is obtained. Optical rotation [α] _D ²⁰ : -5.2 ° (c = 1,
Chloroform) Next, a mixed solution of 0.35 g (1 mmol) of (4-56) obtained here, 6 ml of methanol, 5 ml of ethyl acetate and 0.07 g of 5% palladium on carbon was added at a hydrogen pressure of 10 kg / cm ² , 3
Hydrogenation is carried out under the condition of 0 to 35 ° C. After completion of the reaction, the catalyst was filtered off, and the filtrate was concentrated under reduced pressure to obtain an optically active (-)-
0.35 g of 5-acetoxy-2- (4- (6-ethoxy-1-heptyl) phenyl) pyrimidine (1-56) (yield
98%) is obtained. Furthermore, (1-56) gives optically active (-)-5-hydroxy-2- (4- (6-methoxy-1-heptyl) phenyl) pyrimidine when hydrolyzed according to Example 3.

[0060]

[Table 1]

[0061]

[Table 2]

[0062]

[Table 3]

[0063]

[Table 4]

[0064]

[Table 5]

[0065]

[Table 6]

[0066]

[Table 7]

[0067]

[Table 8]

[0068]

[Table 9]

[0069]

[Table 10]

[0070]

[Table 11]

[0071]

[Table 12]

[0072]

[Table 13]

[0073]

[Table 14]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07C 43/164 7419-4H 43/17 7419-4H 43/178 C 7419-4H 43/235 7419- 4H 69/157 9279-4H C07D 213/30 215/14 217/16 217/20 237/08 239/26 239/74 241/12 241/42 405/12 239 C09K 19/12 9279-4H 19/32 9279 −4H 19/34 9279-4H 19/40 9279-4H (72) Inventor Masayoshi Minai 2-10-1 Tsukahara, Takatsuki City, Osaka Prefecture Sumitomo Chemical Co., Ltd.

Claims (9)

[Claims] 1. A general formula (1) (In the formula, R1 represents a hydrogen atom or a hydroxyl-protecting group, and R2 is substituted with a hydrogen atom, a saturated or unsaturated alkyl group having 1 to 20 carbon atoms which may be substituted with a halogen atom, or a halogen atom. 2 to 2 carbon atoms
20 alkoxyalkyl groups, m, p, q, r,
s and t are 0 or 1, n is an integer of 0 to 10, and A1, A2 and A3 are respectively When A1 is a condensed ring, p + q = 0 or 1, and A2 and A3 are monocycles, and when A1 is a monocycle, p + q = 1 or 2, and p + q =
In the case of 2, both A2 and A3 are monocycles. i and j are integers from 0 to 3, respectively. The * mark indicates an asymmetric carbon atom. ) The phenol derivative shown by. 2. General formula (2) (In the formula, R1, m, p, q, A1, A2 and A3 have the same meanings as described above, and X is a halogen atom, OCOC.
F3 or -OSO2 R'is shown. However, R'represents a lower alkyl group which may be substituted with a fluorine atom, or a phenyl group which may be substituted. ) And a general formula (3) (In the formula, R2, n, r, s and t have the same meanings as described above.) The acetylenes represented by the formula (4) are reacted in the presence of a palladium catalyst and a basic substance. (Wherein R1, R2, m, n, p, q, r, s, t, A1
, A2 and A3 have the same meanings as described above. ) Is obtained, and then hydrogenation is carried out using hydrogen and a hydrogenation catalyst. 3. The halide represented by the general formula (2) and the general formula (3 ′) (In the formula, n and r have the same meanings as described above.) The acetylene compound represented by the general formula (4-a) is reacted with a palladium catalyst in the presence of a basic substance. (Wherein R 1, m, n, p, q, r, A 1, A 2 and A 3 have the same meanings as described above), and then acetylene phenols represented by the general formula (5) R 3 COR (5) (In the formula, R 3 is a saturated or unsaturated alkyl group having 1 to 20 carbon atoms which may be substituted with a halogen atom, or 2 to 2 carbon atoms which may be substituted with a halogen atom.
Represents an alkoxyalkyl group of 0, R'is a hydroxyl group, OC
Indicates OR3 or a halogen atom. ) Is reacted with a carboxylic acid represented by formula (4) (Wherein R1, R3, n, p, q, r, A1, A2 and A3 have the same meanings as described above), and hydrogen is added in the presence of a hydrogenation catalyst. Of the phenol derivative represented by the general formula (1), wherein s and t are 1 and R2 is a saturated or unsaturated C1-20 optionally substituted halogen atom. 2 to 2 carbon atoms which may be substituted with a saturated alkyl group or a halogen atom
A method for producing a compound having 0 alkoxyalkyl group. 4. The halide represented by the general formula (2) and the acetylenes represented by the general formula (3-a) are reacted in the presence of a palladium catalyst and a basic substance to obtain the compound represented by the general formula (4-a). ) Is obtained, and then hydrogenated with hydrogen in the presence of a hydrogenation catalyst, in the general formula (1), s = 1, t = 0 and R 2 is a hydrogen atom. The phenol derivative represented by the formula (5) is further reacted with a carboxylic acid represented by the formula (5). In the phenol derivative represented by the formula (1), s and t are 1 and R 2 is halogen. The manufacturing method of the compound which is a C1-C20 saturated or unsaturated alkyl group which may be substituted by the atom, or a C2-C20 alkoxyalkyl group which may be substituted by the halogen atom. 5. An acetylene phenol represented by the general formula (4-a) and a general formula (6) R2-Z (6) (wherein R3 has the same meaning as described above, Z is a halogen atom or- OSO2 R, wherein R represents a lower alkyl group or an optionally substituted phenyl group) is reacted with an alkylating agent represented by the general formula (4-c) (In the formula, R1, R3, n, p, q, r, A1, A2 and A3 have the same meanings as described above.) The acetylene phenols represented by Of the phenol derivatives represented by the general formula (1), wherein s is 1, t
Is 0 and R3 is a saturated or unsaturated alkyl group having 1 to 20 carbon atoms which may be substituted with a halogen atom, or 2 to 2 carbon atoms which may be substituted with a halogen atom.
A method for producing a compound having 0 alkoxyalkyl group. 6. A phenol derivative represented by the general formula (1), characterized in that the phenol derivative represented by the general formula (1-a) is reacted with an alkylating agent represented by the general formula (6). Of these, s is 1, t is 0, and R3 is a saturated or unsaturated alkyl group having 1 to 20 carbon atoms which may be substituted with a halogen atom, or 2 carbon atoms which may be substituted with a halogen atom. 20. A method for producing a compound which is an alkoxyalkyl group of 20. 7. The phenol derivative according to claim 1, which is an optically active substance. 8. A compound represented by the general formula (1) obtained in any one of claims 2, 3, 4, 5 or 6, wherein R 1 is a hydroxyl-protecting group is deprotected. A method for producing a compound of the general formula (1), wherein R1 is a hydrogen atom. 9. The method according to claim 2, 3 or 4, wherein an optically active acetylene compound is used to obtain an optically active phenol derivative represented by the general formula (1).