JP2011136913A - 2,3,5-trisubstituted tetrahydropyran derivative, and method for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a 2,3,5-trisubstituted tetrahydropyran derivative (6) which is an intermediate highly selectively producible of a 2,5-disubstituted tetrahydropyran derivative which is a liquid crystal composition, in a single process, in a high yield, and at a low cost; and a method for producing the same. <P>SOLUTION: The 2,3,5-trisubstituted tetrahydropyran derivative represented by formula (6) can be produced from an allyl ether derivative (in the formula, R<SP>1</SP>represents a 1-10C alkyl group that may be substituted with a halogen atom or a 1-4C alkoxy group, a 1-10C alkyl group, and a 1-10C haloalkyl group, or the like; R<SP>3</SP>represents a 1-10C alkyl group that may be substituted with a halogen atom or a 1-4C alkoxy group, a 3-8C cycloalkyl group that may be substituted with a 1-10C alkyl group, a 1-10C haloalkyl group, a 2-10C alkenyl group or a halogen atom, or the like; m represents an integer of 1 to 4; and X represents a halogen atom, a hydroxy group, a 1-6C acyloxy group that may be substituted with a halogen atom or a phenyl group, a 1-6C alkylsulfonyloxy group that may be substituted with a halogen atom, or a phenylsulfonyloxy group that may be substituted with a 1-10C alkyl group, a 1-10C haloalkyl group or a halogen atom). <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a 2,3,5-trisubstituted tetrahydropyran derivative useful as a production intermediate of a liquid crystal composition and a production method thereof.

A 2,5-disubstituted tetrahydropyran derivative is useful as a liquid crystal composition (for example, Patent Document 1).
Conventionally, as a method for producing a 2,5-disubstituted tetrahydropyran derivative, a method using an alkal derivative and an aryl acetate derivative as production raw materials has been disclosed (for example, Patent Document 1). According to this method, a 2,5-disubstituted tetrahydropyran derivative is produced from 4-propylcyclohexanecarbaldehyde in 7 steps, but the total yield is 3%, which is not an efficient method. Also disclosed is a method for producing a 2,5-disubstituted tetrahydropyran derivative using an alkal derivative and a 2-aryl-3-buten-1-ol derivative as production raw materials (for example, Patent Document 2).
However, a method for producing a 2,5-disubstituted tetrahydropyran derivative using the 2,3,5-trisubstituted tetrahydropyran derivative of the present invention as a production intermediate has not been reported so far.

JP 2000-8040 A International Publication No. 2006/125526

  The conventional method for producing a 2,5-disubstituted tetrahydropyran derivative has a problem that the number of steps is long and a by-product is produced by the reaction, so that the total yield is poor and the production cost is high. An object of the present invention is to provide a production intermediate capable of producing a 2,5-disubstituted tetrahydropyran derivative in a single step, high yield, high selectivity and low cost, and a production method thereof.

  As a result of intensive studies in view of the above problems, the present inventors have found that the 2,3,5-trisubstituted tetrahydropyran derivative (6) of the present invention can be produced in a single process, high yield, high selectivity and low cost. , 5-disubstituted tetrahydropyran derivatives were found to be important production intermediates, and the present invention was completed.

  That is, the present invention provides a general formula (6)

(Wherein R ¹ represents an alkyl group having 1 to 10 carbon atoms which may be substituted with a halogen atom or an alkoxy group having 1 to 4 carbon atoms; an alkyl group having 1 to 10 carbon atoms, or an alkyl group having 1 to 10 carbon atoms) A haloalkyl group, an alkenyl group having 2 to 10 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms which may be substituted with a halogen atom; an alkenyl group having 2 to 10 carbon atoms which may be substituted with a halogen atom; An alkynyl group having 2 to 8 carbon atoms which may be substituted by an atom; or an alkyl group having 1 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, a halogen atom or carbon .R ³ is of substituted halogen atoms or C 1 -C 4 alkoxy group represented by which may be a phenyl group substituted with C 1 4 alkoxy groups An optionally substituted alkyl group having 1 to 10 carbon atoms; an alkyl group having 1 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, or a carbon atom optionally substituted with a halogen atom A cycloalkyl group having 3 to 8 carbon atoms; an alkenyl group having 2 to 10 carbon atoms which may be substituted with a halogen atom; an alkynyl group having 2 to 8 carbon atoms which may be substituted with a halogen atom; a halogen atom or carbon number An alkoxy group having 1 to 4 carbon atoms which may be substituted with an alkoxy group having 1 to 4; an acyloxy group having 1 to 6 carbon atoms which may be substituted with a halogen atom; a halogen atom; an alkyl having 1 to 10 carbon atoms Substituted with a group, a haloalkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, a halogen atom or an alkoxy group having 1 to 4 carbon atoms Optionally substituted phenyl group; or substituted with an alkyl group having 1 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, a halogen atom, or an alkoxy group having 1 to 4 carbon atoms And m represents an integer of 1 to 4, and when m is 2 to 4, a plurality of R ³ may be the same or different, X is a halogen atom; An acyloxy group having 1 to 6 carbon atoms which may be substituted with a halogen atom or a phenyl group; an alkylsulfonyloxy group having 1 to 6 carbon atoms which may be substituted with a halogen atom; or Represents an alkyl group, a haloalkyl group having 1 to 10 carbon atoms, or a phenylsulfonyloxy group which may be substituted with a halogen atom.) 2,3,5-trisubstituted It relates to a tetrahydropyran derivative.

  The present invention also provides a general formula (4)

(Wherein R ¹ , R ³ and m represent the same meaning as described above. L represents a halogen atom; a hydroxyl group; an acyloxy group having 1 to 6 carbon atoms which may be substituted with a halogen atom or a phenyl group; a halogen atom. Or an alkylsulfonyloxy group having 1 to 6 carbon atoms which may be substituted with a phenylsulfonyloxy group which may be substituted with an alkyl group having 1 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms or a halogen atom And an allyl ether derivative represented by the general formula (6), which is reacted in the presence of a Bronsted acid or a Lewis acid.

(Wherein R ¹ , R ³ , X and m represent the same meaning as described above), and relates to a method for producing a 2,3,5-trisubstituted tetrahydropyran derivative represented by:

  According to the present invention, a 2,3,5-trisubstituted tetrahydropyran derivative (6) can be easily produced, and a 2,5-disubstituted tetrahydropyran derivative (11) as a liquid crystal composition is produced using the derivative. be able to.

  The present invention is described in detail below.

[About R ¹ and R ³ ]
R ¹ represents (i) an alkyl group having 1 to 10 carbon atoms which may be substituted with a halogen atom or an alkoxy group having 1 to 4 carbon atoms; (ii) an alkyl group having 1 to 10 carbon atoms; A haloalkyl group having 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms which may be substituted with a halogen atom; (iii) a carbon number having 2 to 10 which may be substituted with a halogen atom; (Iv) an alkynyl group having 2 to 8 carbon atoms which may be substituted with a halogen atom; or (v) an alkyl group having 1 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, or a carbon number It represents a phenyl group which may be substituted with an alkenyl group having 2 to 10 carbon atoms, a halogen atom or an alkoxy group having 1 to 4 carbon atoms.
R ³ represents (i) an alkyl group having 1 to 10 carbon atoms which may be substituted with a halogen atom or an alkoxy group having 1 to 4 carbon atoms; (ii) an alkyl group having 1 to 10 carbon atoms, A haloalkyl group having 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms which may be substituted with a halogen atom; (iii) a carbon number having 2 to 10 which may be substituted with a halogen atom; (Iv) an alkynyl group having 2 to 8 carbon atoms which may be substituted with a halogen atom; (vi) one having 1 carbon atom which may be substituted with a halogen atom or an alkoxy group having 1 to 4 carbon atoms; An alkoxy group having 4 carbon atoms; (vii) an acyloxy group having 1 to 6 carbon atoms which may be substituted with a halogen atom; (viii) a halogen atom; (v) having 1 to 10 carbon atoms An alkyl group, a haloalkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, a phenyl group which may be substituted with a halogen atom or an alkoxy group having 1 to 4 carbon atoms; or (ix) 1 carbon atom Represents a biphenylyl group optionally substituted by an alkyl group having 1 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, a halogen atom, or an alkoxy group having 1 to 4 carbon atoms.

The alkyl group having 1 to 10 carbon atoms represented by R ¹ and R ³ may be linear or branched, and is methyl, ethyl, propyl, isopropyl, butyl, isobutyl Group, sec-butyl group, tert-butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group and the like.
These alkyl groups having 1 to 10 carbon atoms may be substituted with a halogen atom or an alkoxy group having 1 to 4 carbon atoms. Specifically, 1-bromo-1-methylethyl group, methoxymethyl group, ethoxymethyl group, propoxymethyl group, 2-methoxyethyl group, 2-ethoxyethyl group, chloromethyl group, 2-chloroethyl group, 3- Chloropropyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, 3-fluoropropyl group, 2,2,2-trifluoroethyl group, 2,2,2-trichloroethyl group, etc. Can be illustrated.

Examples of the cycloalkyl group having 3 to 8 carbon atoms represented by R ¹ and R ³ include a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, and a cyclooctyl group.
These cycloalkyl groups having 3 to 8 carbon atoms may be substituted with an alkyl group having 1 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, or a halogen atom. Specifically, 4-methylcyclohexyl group, 4-ethylcyclohexyl group, 4-propylcyclohexyl group, 4-butylcyclohexyl group, 4-pentylcyclohexyl group, 4-vinylcyclohexyl group, 4- (1-butenyl) cyclohexyl group 4- (2-butenyl) cyclohexyl group, 4- (3-butenyl) cyclohexyl group, 4- (1-pentenyl) cyclohexyl group, 4- (2-pentenyl) cyclohexyl group, 4- (3-pentenyl) cyclohexyl group , 4- (4-pentenyl) cyclohexyl group, 3,3-difluoro-4-propylcyclohexyl group, and the like. Among these, it is preferable to use a 4-propylcyclohexyl group in terms of a good yield.

The alkenyl group having 2 to 10 carbon atoms represented by R ¹ and R ³ may be linear, cyclic or branched, and is a vinyl group, 1-propenyl group, allyl group, 2-methyl. 2-propenyl group, 1-butenyl group, 2-butenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 1-cyclopentenyl group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl Examples thereof include a group, 1-cyclohexenyl group, 4-propyl-1-cyclohexenyl group, 1-heptenyl group, 1-octenyl group and the like.
These alkenyl groups having 2 to 10 carbon atoms may be substituted with a halogen atom. Specific examples include 1,2,2-trifluorovinyl group, 2,3,3-trifluoroallyl group, 3,3,3-trifluoropropenyl group and the like.

The alkynyl group having 2 to 8 carbon atoms represented by R ¹ and R ³ may be linear or branched, and is an ethynyl group, a propargyl group, a 1-butynyl group, a 2-butynyl group, Examples include 3-butynyl group, 1-pentynyl group, 2-pentynyl group, 3-pentynyl group, 1-octynyl group and the like.
These alkynyl groups having 2 to 8 carbon atoms may be substituted with a halogen atom. Specific examples include a 3,3,3-trifluoro-1-propynyl group and a 4,4,4-trifluoro-1-butynyl group.

The phenyl group represented by R ¹ and R ³ is an alkyl group having 1 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, a halogen atom, or an alkoxy having 1 to 4 carbon atoms. It may be substituted with a group. Specifically, phenyl group, p-tolyl group, m-tolyl group, o-tolyl group, 2,4-dimethylphenyl group, 3,5-dimethylphenyl group, mesityl group, 2-ethylphenyl group, 3- Ethylphenyl group, 4-ethylphenyl group, 2,4-diethylphenyl group, 3,5-diethylphenyl group, 2-propylphenyl group, 4-propylphenyl group, 2-isopropylphenyl group, 2,4-diisopropylphenyl Group, 4-butylphenyl group, 4-tert-butylphenyl group, 2,4-di-tert-butylphenyl group, 4-pentylphenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl Group, 2,3-difluorophenyl group, 2,4-difluorophenyl group, 3,4-difluorophenyl group, 3,5-difluorophenyl group Nyl group, 2,3,4,5,6-pentafluorophenyl group, 2,3-difluoro-4-propylphenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 3,4-dichlorophenyl Group, 3,5-dichlorophenyl group, 3-bromophenyl group, 4-bromophenyl group, 4-fluoro-3-methylphenyl group, 4-fluoro-2-methylphenyl group, 2-fluoro-3-methylphenyl group P-trifluoromethylphenyl group, m-trifluoromethylphenyl group, o-trifluoromethylphenyl group, 2-vinylphenyl group, 3-vinylphenyl group, 4-vinylphenyl group, 2-allylphenyl group, 3 -Allylphenyl group, 4-allylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxy Examples include phenyl group, 4-ethoxyphenyl group, 4-ethoxy-2,3-difluorophenyl group, 2,3- (methylenedioxy) phenyl group, 3,4- (methylenedioxy) phenyl group, and the like. it can.

Examples of the alkoxy group having 1 to 4 carbon atoms represented by R ³ include methoxy group, ethoxy group, propoxy group, isopropyloxy group, butoxy group, isobutyloxy group, sec-butyloxy group, tert-butyloxy group and the like. be able to.
These alkoxy groups having 1 to 4 carbon atoms may be substituted with a halogen atom or an alkoxy group having 1 to 4 carbon atoms. Specifically, methoxymethoxy group, ethoxymethoxy group, 2-ethoxyethoxy group, 2-methoxyethoxy group, tert-butyloxymethoxy group, difluoromethoxy group, bromodifluoromethoxy group, trifluoromethoxy group, 2,2, Examples include 2-trifluoroethoxy group, 2,2,2-trichloroethoxy group, and the like. Among these, it is preferable to use an ethoxy group in terms of a good yield.

In addition, as a C1-C4 alkoxy group represented by ^R3-3 mentioned later, a methoxy group, an ethoxy group, a propoxy group, an isopropyloxy group, a cyclopropyloxy group, a butoxy group, an isobutyloxy group, sec- A butyloxy group, a tert-butyloxy group, etc. can be illustrated. Among these, it is preferable to use an ethoxy group in terms of a good yield.

Examples of the acyloxy group having 1 to 6 carbon atoms represented by R ³ include a formyloxy group and an acetoxy group.
These acyloxy groups having 1 to 6 carbon atoms may be substituted with a halogen atom. Specifically, a trifluoroacetoxy group, a trichloroacetoxy group, etc. can be illustrated.

Examples of the halogen atom represented by R ³ include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Among these, it is preferable to use a fluorine atom in terms of a good yield.

Examples of the biphenylyl group represented by R ³ include a 2-biphenylyl group, a 3-biphenylyl group, and a 4-biphenylyl group.
These biphenylyl groups may be substituted with an alkyl group having 1 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, a halogen atom, or an alkoxy group having 1 to 4 carbon atoms. Good. Specifically, 4′-methoxybiphenyl-4-yl group, 2 ′, 3′-difluoro-4′-methylbiphenyl-4-yl group, 4′-ethyl-2 ′, 3′-difluorobiphenyl-4 -Yl group, 2 ', 3'-difluoro-4'-propylbiphenyl-4-yl group, 4'-butyl-2', 3'-difluorobiphenyl-4-yl group, 2 ', 3'-difluoro- 4′-pentylbiphenyl-4-yl group, 2 ′, 3′-difluoro-4′-hexylbiphenyl-4-yl group, 2 ′, 3′-difluoro-4′-heptylbiphenyl-4-yl group, 2 ', 3'-difluoro-4'-octylbiphenyl-4-yl group, 2', 3'-difluoro-4'-nonylbiphenyl-4-yl group, 4'-decyl-2 ', 3'-difluorobiphenyl -4-yl group, 4 '-(1-butenyl) -2', 3'-difluorobiphe Nyl-4-yl group, 4 ′-(2-butenyl) -2 ′, 3′-difluorobiphenyl-4-yl group, 4 ′-(3-butenyl) -2 ′, 3′-difluorobiphenyl-4- Yl group, 2 ′, 3′-difluoro-4 ′-(1-pentenyl) biphenyl-4-yl group, 2 ′, 3′-difluoro-4 ′-(2-pentenyl) biphenyl-4-yl group, 2 ', 3'-difluoro-4'-(3-pentenyl) biphenyl-4-yl group, 2 ', 3'-difluoro-4'-(4-pentenyl) biphenyl-4-yl group, 2 ', 3' -Difluoro-4 '-(1-hexenyl) biphenyl-4-yl group, 2', 3'-difluoro-4 '-(2-hexenyl) biphenyl-4-yl group, 2', 3'-difluoro-4 '-(2-hexenyl) biphenyl-4-yl group, 2', 3'-difluoro-4 '-(4-hexenyl ) Biphenyl-4-yl group, 2 ′, 3′-difluoro-4 ′-(5-hexenyl) biphenyl-4-yl group, 2 ′, 3′-difluoro-4′-methoxybiphenyl-4-yl group, 4′-ethoxy-2 ′, 3′-difluorobiphenyl-4-yl group, 2 ′, 3′-difluoro-4′-propoxybiphenyl-4-yl group, 4′-butoxy-2 ′, 3′-difluoro Examples thereof include a biphenyl-4-yl group.

R ¹ is preferably a cycloalkyl group having 3 to 8 carbon atoms which may be substituted with an alkyl group having 1 to 10 carbon atoms, more preferably a cyclohexyl group which may be substituted with an alkyl group having 1 to 10 carbon atoms. Preferably, 4-propylcyclohexyl group is even more preferred.

[About m]
m represents an integer of 1 to 4, and when m is 2 to 4, a plurality of R ³ may be the same or different.

As the phenyl group substituted with m R ³ , a 4-ethoxy-2,3-difluorophenyl group is preferably used in terms of a good yield.

As a combination of R ¹ and a phenyl group substituted with m R ³ , R ¹ is a 4-propylcyclohexyl group, and a phenyl group substituted with m R ³ is 4 in terms of a good yield. The combination which is -ethoxy-2,3-difluorophenyl group is preferable.

[About X]
X represents a halogen atom; a hydroxyl group; an acyloxy group having 1 to 6 carbon atoms which may be substituted with a halogen atom or a phenyl group; an alkylsulfonyloxy group having 1 to 6 carbon atoms which may be substituted with a halogen atom; or Represents an alkyl group having 1 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, or a phenylsulfonyloxy group which may be substituted with a halogen atom.

  Examples of the halogen atom represented by X include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Among them, it is preferable to use a chlorine atom or a bromine atom in terms of a good yield.

Examples of the acyloxy group having 1 to 6 carbon atoms represented by X include a formyloxy group and an acetoxy group.
These C1-C6 acyloxy groups may be substituted with a halogen atom or a phenyl group. Specifically, a trifluoroacetoxy group, a benzoyloxy group, etc. can be illustrated.

Examples of the alkylsulfonyloxy group having 1 to 6 carbon atoms represented by X include a methanesulfonyloxy group and an ethanesulfonyloxy group.
These alkylsulfonyloxy groups may be substituted with a halogen atom. Specifically, a trifluoromethanesulfonyloxy group, a trichloromethanesulfonyloxy group, etc. can be illustrated. Among these, it is preferable to use a methanesulfonyloxy group in terms of a good yield.

The phenylsulfonyloxy group represented by X may be substituted with an alkyl group having 1 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, or a halogen atom. Specific examples include p-toluenesulfonyloxy group, phenylsulfonyloxy group, 4-trifluoromethylphenylsulfonyloxy group, 4-fluorophenylsulfonyloxy group and the like. Among these, it is preferable to use a p-toluenesulfonyloxy group in terms of good yield.
X is preferably a chlorine atom, a bromine atom, a p-toluenesulfonyloxy group or a methanesulfonyloxy group.

[About L]
L represents a halogen atom; a hydroxyl group; an acyloxy group having 1 to 6 carbon atoms which may be substituted with a halogen atom or a phenyl group; an alkylsulfonyloxy group having 1 to 6 carbon atoms which may be substituted with a halogen atom; or Represents an alkyl group having 1 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, or a phenylsulfonyloxy group which may be substituted with a halogen atom.
L contains a hydroxyl group and J.

  Examples of the halogen atom represented by L include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

Examples of the acyloxy group having 1 to 6 carbon atoms represented by L include a formyloxy group and an acetoxy group.
These C1-C6 acyloxy groups may be substituted with a halogen atom or a phenyl group. Specifically, a trifluoroacetoxy group, a benzoyloxy group, etc. can be illustrated.

Examples of the alkylsulfonyloxy group having 1 to 6 carbon atoms represented by L include a methanesulfonyloxy group and an ethanesulfonyloxy group.
These alkylsulfonyloxy groups may be substituted with a halogen atom. Specifically, a trifluoromethanesulfonyloxy group, a trichloromethanesulfonyloxy group, etc. can be illustrated.

  The phenylsulfonyloxy group represented by L may be substituted with an alkyl group having 1 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, or a halogen atom. Specifically, a p-toluenesulfonyloxy group , Phenylsulfonyloxy group, 4-trifluoromethylphenylsulfonyloxy group, 4-fluorophenylsulfonyloxy group and the like.

With respect to the 2,3,5-trisubstituted tetrahydropyran derivative and a method for producing the same, the following six embodiments are further preferred.
(I) General formula (6) is general formula (6a).
(II) General formula (6a) is general formula (6b),
(III) General formula (6b) is general formula (6c).
(IV) General formula (4) is general formula (4c), and general formula (6) is general formula (6a).
(V) General formula (4c) is general formula (4d), and general formula (6a) is general formula (6b).
(VI) General formula (4d) is general formula (4e), and general formula (6b) is general formula (6c).

  (I) A 2,3,5-trisubstituted tetrahydropyran derivative in which the general formula (6) is the following general formula (6a).

(In the formula, R ¹ and X represent the same meaning as described above. R ^3-1 and R ^3-2 each independently represent a hydrogen atom or a fluorine atom, and R ^3-3 represents an alkoxy group having 1 to 4 carbon atoms. Represents.)

  (II) A 2,3,5-trisubstituted tetrahydropyran derivative in which the general formula (6a) is the following general formula (6b).

(Wherein R ¹ , R ^3-3 and X have the same meaning as described above.)

  (III) A 2,3,5-trisubstituted tetrahydropyran derivative in which the general formula (6b) is the following general formula (6c).

(In the formula, R ¹ and X have the same meaning as described above.)

  (IV) General formula (4) is the following general formula (4c),

(In the above formula, R ¹ and L represent the same meaning as described above. R ^3-1 and R ^3-2 each independently represent a hydrogen atom or a fluorine atom, and R ^3-3 represents an alkoxy having 1 to 4 carbon atoms. Represents a group)
The manufacturing method of the 2,3,5- trisubstituted tetrahydropyran derivative whose general formula (6) is the following general formula (6a).

(In the above formula, R ¹ , R ^3-1 , R ^3-2 , R ^3-3 and X have the same meaning as described above.)

  (V) General formula (4c) is the following general formula (4d),

(In the formula, R ¹ , R ^3-3 and L have the same meaning as described above.)

  The manufacturing method of the 2,3,5- trisubstituted tetrahydropyran derivative whose general formula (6a) is the following general formula (6b).

(Wherein R ¹ , R ^3-3 and X have the same meaning as described above.)

  (VI) General formula (4b) is the following general formula (4c),

(Wherein R ¹ and L have the same meaning as described above.)

  The manufacturing method of the 2,3,5- trisubstituted tetrahydropyran derivative whose general formula (6b) is the following general formula (6c).

(In the formula, R ¹ and X have the same meaning as described above.)

  As a combination of L and Bronsted acid / Lewis acid and X, (I) L is a hydroxyl group, Bronsted acid is methanesulfonic acid, X is a methanesulfonyloxy group, (II) L is a hydroxyl group, Bronsted Acid is p-toluenesulfonic acid, X is p-toluenesulfonyloxy group, (III) L is hydroxyl group, Lewis acid is aluminum chloride, X is chlorine atom, (IV) L is hydroxyl group or bromine atom, Lewis A combination in which the acid is bismuth tribromide and X is a bromine atom is preferred.

  Next, the production method of the present invention will be described in detail.

  The production method of the 2,3,5-trisubstituted tetrahydropyran derivative (6) of the present invention and the production method of the 2,5-disubstituted tetrahydropyran derivative (11) using the production intermediate are shown in the following scheme. It is as follows.

(Wherein R ¹ , R ³ , m, L and X represent the same meaning as described above. R ^2a may be an optionally substituted di (C ^1-3 alkoxy) methyl group or an optionally substituted group. Represents a good bis (C1-C3 alkylthio) methyl group, Z represents a leaving group, M represents Na, MgQ, ZnQ or Li, Q represents an iodine atom, a bromine atom or a chlorine atom. Is a halogen atom; an acyloxy group having 1 to 6 carbon atoms which may be substituted with a halogen atom or a phenyl group; an alkylsulfonyloxy group having 1 to 6 carbon atoms which may be substituted with a halogen atom; or Represents a 1 to 10 alkyl group, a haloalkyl group having 1 to 10 carbon atoms, or a phenylsulfonyloxy group optionally substituted with a halogen atom.)

[About Step 1]
Step 1 is a step of producing an allyl ether derivative (1a) by reacting an allyl alcohol derivative (2) with an acetal derivative (3a) in the presence of a base.

(About R ^2a and Z)
R ^2a represents an optionally substituted di (C1-3 alkoxy) methyl group or an optionally substituted bis (C1-3alkylthio) methyl group, and Z represents a leaving group. .

Examples of the “optionally substituted di (C1-3 alkoxy) methyl group” represented by R ^2a include a dimethoxymethyl group, a diethoxymethyl group, and the like.

Examples of the “optionally substituted bis (C1-C3 alkylthio) methyl group” represented by R ^2a include bis (methylthio) methyl group, bis (ethylthio) methyl group and the like.

  Examples of the “leaving group” represented by Z include halogen atoms such as iodine atom, bromine atom and chlorine atom, sulfonyloxy groups such as methanesulfonyloxy group, trifluoromethanesulfonyloxy group and p-toluenesulfonyloxy group. It can be illustrated.

  Specifically, as the acetal derivative (3a) that can be used in the reaction of Step 1, 2-bromoacetaldehyde dimethyl acetal, 2-chloroacetaldehyde dimethyl acetal, 2-bromoacetaldehyde diethyl acetal, 2-bromoacetaldehyde bis (ethylthio) Acetal etc. can be illustrated. These acetal derivatives (3a) may be synthesized from the corresponding aldehydes in use (eg, Protective Groups in Organic Synthesis 3rd. Ed., PGM M. Wuts & TW Greene, John Wiley & Sons, Inc.). , Pp.293-368, 1999), and commercially available products can also be obtained.

The allyl alcohol derivative (2) can be easily prepared from an aldehyde corresponding to the (2) and a vinyl metal reagent.
Examples of (2) include 1- (trans-4-propylcyclohexyl) -2-propen-1-ol (2).

  Examples of the base that can be used in the reaction of Step 1 include metal alkoxides such as sodium methoxide, sodium ethoxide, and potassium tert-butoxide, alkyllithiums such as butyllithium, sec-butyllithium, and tert-butyllithium, and lithium diisopropylamide. Metal amides such as lithium 2,2,6,6-tetramethylpiperazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, sodium hexamethyldisilazide, sodium hydride, potassium hydride, etc. Examples thereof include inorganic salts such as metal hydride, sodium hydroxide, potassium hydroxide and potassium carbonate. Among these, it is preferable to use sodium hydride in terms of good yield.

In Step 1, an additive may be added to improve the yield. Examples of the additive include tetrabutylammonium iodide, sodium iodide, potassium iodide, lithium iodide and the like.
In addition, the usage-amount of an additive may be what is called a catalyst amount, and it is preferable to use about 1-10 mol% with respect to an acetal derivative (3a).

  As a solvent that can be used in the reaction of Step 1, any solvent that does not inhibit the reaction may be used. Specifically, ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, methyl-tert-butyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether, hydrocarbon solvents such as hexane, pentane, cyclohexane, Aromatic hydrocarbon solvents such as benzene, toluene, xylene, dimethyl sulfoxide, N, N-dimethylformamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-3,4,5,6-tetrahydro-2 ( 1H) -pyrimidinone, methanol, ethanol, water and the like can be exemplified. Two or more of these solvents may be mixed and used. Among these, tetrahydrofuran and 1,4-dioxane are preferably used in terms of good yield.

  The molar ratio of the allyl alcohol derivative (2) and the acetal derivative (3a) is preferably 1: 1 to 1: 5. Among these, 1: 1 to 1: 3 is more preferable in terms of a good yield.

  The molar ratio of the allyl alcohol derivative (2) and the base is not particularly limited, but usually 1: 1 to 1: 5 is preferable. Among these, 1: 1 to 1: 3 is more preferable in terms of a good yield.

  The reaction temperature is not particularly limited, but can usually be carried out at a temperature appropriately selected from the range of -78 ° C to 180 ° C. Among these, the range of 70 ° C. to 120 ° C. is preferable in terms of a good yield.

  The method for isolating the desired product from the solution after the reaction is not particularly limited. For example, the desired product can be obtained by a general method such as solvent extraction, column chromatography, preparative thin layer chromatography, preparative liquid chromatography, recrystallization or sublimation.

  Examples of the allyl ether derivative (1a) thus obtained include 2- [1- (trans-4-propylcyclohexyl) -2-propenyloxy] acetaldehyde diethyl acetal (1a).

[About step 2]
Step 2 is a step of producing an acetaldehyde derivative (1b) by deprotecting the acetal part of the allyl ether derivative (1a).

For the deprotection reaction of the acetal site, a known method (for example, Protective Groups in Organic Synthesis 3rd. Ed., PGM Wuts & TW Greene, John Wiley & Sons, Inc., pp. 293-368, 1999). Can be used. Desirable reaction conditions differ depending on the substituent R ^2a .

When the substituent R ^2a is a di (C 1 -C 3 alkoxy) methyl group such as a dimethoxymethyl group, an acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or p-toluenesulfonic acid is used. By reacting this in a solvent such as toluene, dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, dioxane, acetone, acetic acid, water, or a mixed solvent thereof, the acetaldehyde derivative (1b) is obtained in a high yield. Obtainable. Although the reaction temperature is not particularly limited, it can usually be carried out at from room temperature to about 100 ° C.
In this case, although the usage-amount of an acid does not have limitation in particular, it is preferable to use about 10-200 mol% with respect to an allyl ether derivative (1a).

When the substituent R ^2a is a bis (C 1 -C 3 alkylthio) methyl group such as a bis (ethylthio) methyl group, an inorganic salt such as mercury salt, copper salt, silver salt, thallium salt, methyl iodide An oxidizing agent such as N-chlorosuccinimide, N-bromosuccinimide, iodine, or high-valent iodide is used. The acetaldehyde derivative (1b) is obtained by carrying out the reaction in a solvent such as toluene, dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, dioxane, acetone, methanol, ethanol, acetic acid, water, or a mixed solvent thereof. Can be obtained with good yield. Although the reaction temperature is not particularly limited, it can usually be carried out at from room temperature to about 100 ° C.
In this case, the amount of the inorganic salt used is not particularly limited, but is preferably about 1 to 4 equivalents relative to the allyl ether derivative (1a), and the amount of the oxidizing agent used is the allyl ether derivative. It is preferable to use about 1 to 4 equivalents with respect to (1a).

In any of these cases, the method for isolating the target product from the solution after the reaction is not particularly limited. For example, the desired product can be obtained by a general method such as solvent extraction, column chromatography, preparative thin layer chromatography, preparative liquid chromatography, recrystallization or sublimation.
Examples of the acetaldehyde derivative (1b) thus obtained include 2- [1- (trans-4-propylcyclohexyl) -2-propenyloxy] acetaldehyde (1b).

[About step 3]
Step 3 is a step of producing the benzyl alcohol derivative (4a) by reacting the acetaldehyde derivative (1b) with the aryl metal reagent (5).

The aryl metal reagent (5) used in the reaction of Step 3 is an aryl halide compound corresponding to the metal reagent (5) and an alkyl lithium reagent such as butyl lithium, sec-butyl lithium, tert-butyl lithium, isopropyl magnesium chloride, If necessary, inorganic salts such as zinc chloride, magnesium chloride, zinc bromide, magnesium bromide, zinc trifluoromethanesulfonate using Grignard reagents such as isopropylmagnesium bromide or metals such as lithium, sodium, magnesium, zinc It can be prepared by performing a halogen-metal exchange reaction in the presence.
Here, in the general formula (5), M represents Na, MgQ, ZnQ, or Li, and Q represents an iodine atom, a bromine atom, or a chlorine atom.
Examples of the metal reagent (5) include 4-ethoxy-2,3-difluorophenylmagnesium bromide (5).

  As a solvent that can be used in the reaction of Step 3, any solvent that does not inhibit the reaction may be used. Specifically, ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, methyl-tert-butyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether, hydrocarbon solvents such as hexane, pentane, cyclohexane, Aromatic hydrocarbon solvents such as benzene, toluene and xylene can be exemplified. Two or more of these solvents may be mixed and used. Of these, tetrahydrofuran is preferably used from the viewpoint of good yield.

  The molar ratio of the acetaldehyde derivative (1b) and the aryl metal reagent (5) is not particularly limited, but is usually preferably 1: 1 to 1:10. Among these, 1: 1 to 1: 2 is more preferable in terms of a good yield.

  The reaction temperature is not particularly limited, but can usually be carried out at a temperature appropriately selected from the range of -78 ° C to 100 ° C. Among these, a range from −78 ° C. to room temperature is preferable in terms of a good yield.

  The method for isolating the desired product from the solution after the reaction is not particularly limited. For example, the desired product can be obtained by a general method such as solvent extraction, column chromatography, preparative thin layer chromatography, preparative liquid chromatography, recrystallization or sublimation.

  The benzyl alcohol derivative (4a) thus obtained includes (1RS) -1- (4-ethoxy-2,3-difluorophenyl) -2-[(1RS) -1- (trans-4-propylcyclohexyl). ) -2-propenyloxy] ethanol (4a).

[About Step 4]
Step 4 is a step of converting the benzyl alcohol derivative (4a) into the allyl ether derivative (4b).

The reagent used in Step 4 varies depending on the substituent J of (4b) to be produced.
J represents a halogen atom; an acyloxy group having 1 to 6 carbon atoms which may be substituted with a halogen atom or a phenyl group; an alkylsulfonyloxy group having 1 to 6 carbon atoms which may be substituted with a halogen atom; or carbon It represents a phenylsulfonyloxy group optionally substituted with an alkyl group having 1 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, or a halogen atom.

  Examples of the halogen atom represented by J include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

  Examples of the “acyloxy group having 1 to 6 carbon atoms” represented by J include a formyloxy group and an acetoxy group. These C1-C6 acyloxy groups may be substituted with a halogen atom or a phenyl group. Specifically, a trifluoroacetoxy group, a benzoyloxy group, etc. can be illustrated.

  Examples of the “alkylsulfonyloxy group having 1 to 6 carbon atoms” represented by J include a methanesulfonyloxy group and an ethanesulfonyloxy group. These alkylsulfonyloxy groups may be substituted with a halogen atom. Specifically, a trifluoromethanesulfonyloxy group, a trichloromethanesulfonyloxy group, etc. can be illustrated.

  The phenylsulfonyloxy group represented by J may be substituted with an alkyl group having 1 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, or a halogen atom. Specific examples include p-toluenesulfonyloxy group, phenylsulfonyloxy group, 4-trifluoromethylphenylsulfonyloxy group, 4-fluorophenylsulfonyloxy group and the like.

When the substituent J is a halogen atom, hydrogen fluoride water, hydrogen chloride water, hydrogen bromide water, boron trifluoride diethyl ether complex, aluminum chloride, titanium tetrachloride, iridium chloride, iron chloride, zinc bromide, bromide A halogenating agent such as magnesium, bismuth tribromide, phosphorus tribromide, phosphorus pentachloride, phosphorus trichloride, carbon tetrachloride-triphenylphosphine, carbon tetrabromide-triphenylphosphine is used. By performing this reaction in a solvent such as toluene, dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, dioxane, acetone, acetic acid, water, or a mixed solvent thereof, an allyl ether derivative (4b) is obtained. Can get well. Although the reaction temperature is not particularly limited, it can usually be carried out at from room temperature to about 100 ° C.
Among these, it is preferable to use phosphorus pentachloride and phosphorus tribromide.
In this case, the amount of the halogenating agent to be used is not particularly limited, but it is preferably 1 to 4 equivalents with respect to the benzyl alcohol derivative (4a).

When the substituent J is an acyloxy group having 1 to 6 carbon atoms which may be substituted with a halogen atom or a phenyl group, formic acid, acetic acid, trifluoroacetic acid, acetic anhydride, trifluoroacetic anhydride, benzoic anhydride, acetyl chloride An acylating agent such as trifluoroacetyl chloride is used. By carrying out the reaction in a solvent such as toluene, dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, dioxane, acetone, water, or a mixed solvent thereof, an allyl ether derivative (4b) is obtained in a high yield. be able to. Although the reaction temperature is not particularly limited, it can usually be carried out at from room temperature to about 100 ° C.
Among these, acetyl chloride or acetic anhydride is preferably used.
In this case, the amount of the acylating agent to be used is not particularly limited, but it is preferably 1 to 4 equivalents with respect to the benzyl alcohol derivative (4a).

The substituent J is optionally substituted with a halogen atom, an alkylsulfonyloxy group having 1 to 6 carbon atoms; or an alkyl group having 1 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, or a halogen atom. In the case of an optionally substituted phenylsulfonyloxy group, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, anhydrous methanesulfonic acid, anhydrous trifluoromethanesulfonic acid, anhydrous benzenesulfonic acid, anhydrous p-toluene A sulfonylating agent such as sulfonic acid, methanesulfonic acid chloride, trifluoromethanesulfonic acid chloride, benzenesulfonic acid chloride, or p-toluenesulfonic acid chloride is used. By carrying out the reaction in a solvent such as toluene, dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, dioxane, acetone, water, or a mixed solvent thereof, an allyl ether derivative (4b) is obtained in a high yield. be able to. Although the reaction temperature is not particularly limited, it can usually be carried out at from room temperature to about 100 ° C.
Among these, it is preferable to use methanesulfonic acid chloride or p-toluenesulfonic acid chloride.
In this case, the amount of the sulfonylating agent is not particularly limited, but it is preferably 1 to 4 equivalents with respect to the benzyl alcohol derivative (4a).

  The method for isolating the desired product from the solution after the reaction is not particularly limited. For example, the desired product can be obtained by a general method such as solvent extraction, column chromatography, preparative thin layer chromatography, preparative liquid chromatography, recrystallization or sublimation.

  The allyl ether derivative (4b) thus obtained includes (3RS) -3-[(2RS) -2-bromo-2- (4-ethoxy-2,3-difluorophenyl) ethyloxy] -3- ( (trans-4-propylcyclohexyl) propene (4b) and the like.

[About step 5]
Step 5 is a step of producing a 2,3,5-trisubstituted tetrahydropyran derivative (6) by reacting the allyl ether derivative (4) in the presence of Bronsted acid or Lewis acid.

  L is as described above. L contains a hydroxyl group and J.

  Examples of the Bronsted acid that can be used in the reaction of Step 5 include hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, and benzene. Examples include sulfonic acid and p-toluenesulfonic acid. Among these, it is preferable to use acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid in terms of a good yield. More preferably, methanesulfonic acid or p-toluenesulfonic acid is used. p-Toluenesulfonic acid monohydrate can be used.

  Examples of the Lewis acid that can be used in the reaction of Step 5 include boron trifluoride diethyl ether complex, aluminum chloride, titanium tetrachloride, iridium chloride, iron chloride, zinc bromide, magnesium bromide, bismuth tribromide, and trifluoromethane. Examples thereof include scandium sulfonate. Among these, it is preferable to use boron trifluoride diethyl ether complex, aluminum chloride or bismuth tribromide in terms of a good yield. More preferably, aluminum chloride or bismuth tribromide is used.

  The solvent that can be used in the reaction of step 5 may be any solvent that does not inhibit the reaction. Specifically, halogen solvents such as dichloromethane and chloroform, ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, methyl-tert-butyl ether, 1,2-dimethoxyethane, cyclopentylmethyl ether, hexane, pentane And hydrocarbon solvents such as cyclohexane, aromatic hydrocarbon solvents such as benzene, toluene and xylene, acetic acid, water and the like. Two or more of these solvents may be mixed and used. Among these, it is preferable to use dichloromethane from the viewpoint of good yield.

  The molar ratio of the allyl ether derivative (4) to the Bronsted acid or Lewis acid is not particularly limited, but is preferably 1: 1 to 1:10, and among them, 1: 1 is preferable in that the yield is good. To 1: 3 is more preferred.

  Although there is no restriction | limiting in particular in reaction temperature, Usually, it can carry out at the temperature suitably selected from the range of -78 degreeC to 100 degreeC. Among these, a range from −78 ° C. to room temperature is preferable in terms of a good yield.

  The method for isolating the desired product from the solution after the reaction is not particularly limited. For example, the desired product can be obtained by a general method such as solvent extraction, column chromatography, preparative thin layer chromatography, preparative liquid chromatography, recrystallization or sublimation.

As the 2,3,5-trisubstituted tetrahydropyran derivative (6) thus obtained, acetic acid (2R ^* , 3S ^* , 5R ^* )-5- (4-ethoxy-2,3-difluorophenyl)- 2- (trans-4-propylcyclohexyl) tetrahydropyran-3-yl (6), (2R ^* , 3S ^* , 5R ^* )-5- (4-ethoxy-2,3-difluorophenyl) -3-fluoro- 2- (trans-4-propylcyclohexyl) tetrahydropyran (6), methanesulfonic acid (2R ^* , 3S ^* , 5R ^* )-5- (4-ethoxy-2,3-difluorophenyl) -2- (trans- 4-propyl-cyclohexyl) tetrahydropyran-3-yl (6), p-toluenesulfonic acid ^{(2R *, 3S *, 5R} *) -5- (4- ethoxy 2,3-difluorophenyl)-2-(trans-4-propyl-cyclohexyl) tetrahydropyran-3-yl (6), benzenesulfonic acid ^{(2R *, 3S *, 5R} *) -5- (4- ethoxy - 2,3-difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran-3-yl (6), trifluoroacetic acid (2R ^* , 3S ^* , 5R ^* )-5- (4-ethoxy-2 , 3-Difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran-3-yl (6), trifluoromethanesulfonic acid (2R ^* , 3S ^* , 5R ^* )-5- (4-ethoxy-2 , 3-Difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran-3-yl (6 ^{, (2R *, 3S *,} 5R *) -3- -chloro-5- (4-ethoxy-2,3 difluorophenyl)-2-(trans-4-propylcyclohexyl) tetrahydropyran (6), (2R ^* , 3S ^* , 5R ^* )-3-bromo-5- (4-ethoxy-2,3-difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran (6), (2R ^* , 3S ^* , And 5R ^* )-3-bromo-5- (4-ethoxy-2,3-difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran (6).

[About step 6]
Step 6 is a step of reducing the 2,3,5-trisubstituted tetrahydropyran derivative (6) to produce the 2,5-disubstituted tetrahydropyran derivative (11).

  Examples of the reducing agent that can be used in the reduction reaction in Step 6 include sodium borohydride, potassium borohydride, lithium aluminum hydride, borane, diisobutylaluminum hydride, lithium borohydride, sodium cyanoborohydride, hydrogenation- sec-butyl boron lithium, hydrogenated-sec-butyl boron potassium, triethyl boron lithium hydride, zinc borohydride, tri-tert-butoxy aluminum lithium hydride, trimethoxy aluminum lithium hydride, bis (2-methoxy hydride) Ethoxy) aluminum sodium, borohydride tetra n-butylammonium, triethylsilane and the like can be exemplified. Among these, sodium borohydride or lithium aluminum hydride is preferable in terms of good yield.

In step 6, an additive may be added to improve the yield. Examples of the additive include tetrabutylammonium iodide, sodium iodide, copper iodide, cobalt chloride, sodium hydride, and alkenes such as 1-pentene, 1-decene and 1-undecene.
In addition, the usage-amount of an additive does not have a restriction | limiting in particular, However, It is preferable to use 10-100 mol% with respect to a 2,3,5- trisubstituted tetrahydropyran derivative (6).

  The solvent that can be used in the reaction of Step 6 may be any solvent that does not inhibit the reaction. Specifically, tetrahydrofuran, diethyl ether, methyl-tert-butyl ether, 1,4-dioxane, 1,2-dimethoxy Ether solvents such as ethane, cyclopentyl methyl ether, diethylene glycol dimethyl ether, hydrocarbon solvents such as hexane, pentane, cyclohexane, aromatic hydrocarbon solvents such as benzene, toluene, xylene, dimethyl sulfoxide, sulfolane, N, N-dimethyl Formamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone, 1,3-dimethyl-2-imidazolidinone, hexamethylphosphoramide, Methanol, ethanol, acetic acid, It can be exemplified, and the like. Two or more of these solvents may be mixed and used.

  The molar ratio of the 2,3,5-trisubstituted tetrahydropyran derivative (6) and the reducing agent is not particularly limited, but is usually preferably from 1: 0.2 to 1:15. Among these, 1: 0.25 to 1: 5 is more preferable in terms of a good yield.

  The reaction temperature is not particularly limited, but can usually be carried out at a temperature appropriately selected from the range of -78 ° C to 150 ° C. Among these, the range of 60 ° C. to 120 ° C. is preferable in terms of a good yield.

  The method for isolating the desired product from the solution after the reaction is not particularly limited. For example, the desired product can be obtained by a general method such as solvent extraction, column chromatography, preparative thin layer chromatography, preparative liquid chromatography, recrystallization or sublimation.

The 2,5-disubstituted tetrahydropyran derivative (11) thus obtained includes (2R ^* , 5R ^* )-5- (4-ethoxy-2,3-difluorophenyl) -2- (trans-4). -Propylcyclohexyl) tetrahydropyran (11) and the like.

[About Step 7]
In step 7, the 2,3,5-trisubstituted tetrahydropyran derivative (6) is de-HXed (X represents the same meaning as described above) to obtain the 5,6-dihydro-2H-pyran derivative (10). It is a manufacturing process.

  Examples of the de-HX agent (X represents the same meaning as described above) that can be used in the reaction of Step 7 include metal alkoxides such as potassium tert-butoxide, sodium methoxide, sodium ethoxide, butyl lithium, sec-butyl lithium. Alkyllithium such as tert-butyllithium, lithium diisopropylamide, lithium 2,2,6,6-tetramethylpiperazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, sodium hexamethyldisilazide, etc. Metal amides, metal hydrides such as sodium hydride and potassium hydride, inorganic salts such as sodium hydroxide, potassium hydroxide, potassium carbonate and lithium chloride, triethylamine, diazabicyclo [2.2.2] octane, 1,5 -Diazabicyclo [4.3.0] non 5-ene, 1,8-diazabicyclo [5.4.0] organic bases such undec-7-ene can be exemplified guanidine base such as tetramethylguanidine. Among these, it is preferable to use lithium chloride or 1,5-diazabicyclo [4.3.0] non-5-ene in terms of good yield.

  The solvent that can be used in the reaction of Step 7 may be any solvent that does not inhibit the reaction. Specifically, tetrahydrofuran, diethyl ether, 1,4-dioxane, methyl-tert-butyl ether, 1,2-dimethoxy Ether solvents such as ethane and cyclopentyl methyl ether, hydrocarbon solvents such as hexane, pentane and cyclohexane, aromatic hydrocarbon solvents such as benzene, toluene and xylene, dimethyl sulfoxide, N, N-dimethylformamide, N-methyl Examples include 2-pyrrolidone, 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone, water, and the like. Two or more of these solvents may be mixed and used. Among these, dimethyl sulfoxide is preferable in terms of a good yield.

  The molar ratio of the 2,3,5-trisubstituted tetrahydropyran derivative (6) and the de-HX agent (X represents the same meaning as described above) is not particularly limited, but usually from 1: 1. 1:10 is preferred. Among these, 1: 1 to 1: 5 is more preferable in terms of a good yield.

  The reaction temperature is not particularly limited, but can usually be carried out at a temperature appropriately selected from the range of -78 ° C to 150 ° C. Among these, the range of 80 ° C. to 120 ° C. is preferable in terms of a good yield.

  The method for isolating the desired product from the solution after the reaction is not particularly limited. For example, the desired product can be obtained by a general method such as solvent extraction, column chromatography, preparative thin layer chromatography, preparative liquid chromatography, recrystallization or sublimation.

The 5,6-dihydro-2H-pyran derivative (10) thus obtained includes (2R ^* , 5R ^* )-5- (4-ethoxy-2,3-difluorophenyl) -2- (trans- 4-propylcyclohexyl) -5,6-dihydro-2H-pyran (10).

[About step 8]
Step 8 is a step of reducing the 5,6-dihydro-2H-pyran derivative (10) to produce a 2,5-disubstituted tetrahydropyran derivative (11).

The reduction reaction in step 8 can be performed in the presence of a metal catalyst, in a hydrogen gas atmosphere, or in the presence of a hydrogen donor.
Examples of the metal catalyst include palladium carbon, palladium black, palladium alumina, palladium chloride, palladium hydroxide, Raney nickel, rhodium alumina, and the like. Among these, it is preferable to use palladium carbon which is a general-purpose catalyst in terms of a good yield.
As the solvent, the reaction can be carried out in a solvent such as toluene, dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, dioxane, methanol, ethanol, acetic acid, water, or a mixed solvent thereof.
Examples of hydrogen donors include cyclohexene, 1,4-cyclohexadiene, formic acid, decalin, ammonium formate, and the like.

  The addition amount of the metal catalyst is not particularly limited, but usually a so-called catalyst amount may be used, and it is sufficient to use about 0.1 to 1 mol% with respect to the 5,6-dihydro-2H-pyran derivative (10). . The reaction can be carried out at a hydrogen gas pressure as low as about 10 to 10 atm.

Moreover, the usage-amount of hydrogen gas does not have a restriction | limiting in particular, However, It is preferable to use equivalent amount or more with respect to a 5, 6- dihydro-2H- pyran derivative (10).
Further, when a hydrogen donor is used, the amount of the hydrogen donor used is not particularly limited, but it is preferably used in an amount equal to or greater than that of the 5,6-dihydro-2H-pyran derivative (10).

  There is no restriction | limiting in particular in reaction temperature, Usually, it can implement at the temperature chosen suitably from room temperature to 100 degreeC. By using an equal amount or more of the hydrogen donor with respect to the raw material, the target product can be obtained in good yield.

  The method for isolating the desired product from the solution after the reaction is not particularly limited. For example, the desired product can be obtained by a general method such as solvent extraction, column chromatography, preparative thin layer chromatography, preparative liquid chromatography, recrystallization or sublimation.

  According to the present invention, the compound (11) can be produced from the starting material (2) in a yield of about 40% or more. Moreover, when it goes through the process 6 from an intermediate body (6), a compound (11) can be manufactured with a yield of about 70% or more.

  Next, the present invention will be described in detail by experimental examples, but the present invention is not limited thereto.

  Regarding Experimental Examples 1 to 25, Experimental Example 1 is a method for producing an allyl alcohol derivative (2), Experimental Example 2 is Step 1, Experimental Example 3 is Step 2, Experimental Example 4 is Step 3, Experimental Example 5 is Step 4, Experimental Examples 6 to 14 show Step 5, Experimental Examples 15 to 22 show Step 6, Experimental Examples 23 to 24 show Step 7, and Experimental Example 25 shows Step 8.

Details of main reagents used in the following experimental examples are as follows.
Vinylmagnesium chloride (vinyl metal reagent); manufactured by Kanto Chemical Co., Inc., vinylmagnesium chloride, 1.4M tetrahydrofuran solution (trade name)
trans-4-propylcyclohexanecarbaldehyde (aldehyde) was prepared according to the known literature (CN101325633).
2-Bromoacetaldehyde diethyl acetal (3a): Nacalai Tesque, Bromoacetaldehyde diethyl acetal (trade name)
1-Bromo-4-ethoxy-2,3-difluorobenzene was prepared according to known literature (CN10100167).
Metallic magnesium: Wako Pure Chemical Industries, Reagent name Magnesium, Sharpened (trade name)
Iodine: manufactured by Kanto Chemical Co., Inc., reagent name Iodine (trade name)
Phosphorus tribromide: Wako Pure Chemical Industries, Phosphorus tribromide (trade name)
Boron trifluoride diethyl ether complex (Lewis acid): Wako Pure Chemical Industries, Ltd., boron trifluoride diethyl ether complex (trade name)
Methanesulfonic acid (Bronsted acid): manufactured by Tokyo Chemical Industry Co., Ltd., methanesulfonic acid (trade name)
p-Toluenesulfonic acid monohydrate (Bronsted acid): manufactured by Kanto Chemical Co., Inc., p-toluenesulfonic acid monohydrate (trade name)
Benzenesulfonic acid (Bronsted acid): manufactured by Aldrich, benzenesulfonic acid (technical grade 90%) (trade name)
Trifluoroacetic acid (Bronsted acid); manufactured by Tokyo Chemical Industry Co., Ltd., trifluoroacetic acid (trade name)
Trifluoromethanesulfonic acid (Bronsted acid): manufactured by Kishida Chemical Co., Ltd., trifluoromethanesulfonic acid (trade name)
Aluminum chloride (Lewis acid): Wako Pure Chemical Industries, Ltd., aluminum chloride (III) (trade name)
Bismuth tribromide (Lewis acid): Aldrich, bismuth tribromide (trade name)
Sodium borohydride (reducing agent): manufactured by Aldrich, sodium borohydride (trade name)
Boron hydride tetra n-butylammonium (reducing agent): manufactured by Acros, borohydride tetra n-butylammonium (trade name)
Triethylsilane (reducing agent): manufactured by Shin-Etsu Chemical Co., Ltd., triethylsilane (trade name)
Aluminium lithium hydride (reducing agent): Wako Pure Chemical Industries, aluminium lithium hydride (trade name)
Lithium chloride (de-HX agent): manufactured by Kanto Chemical Co., Ltd., lithium chloride (trade name)
1,5-diazabicyclo [4.3.0] non-5-ene (deHXing agent): manufactured by Wako Pure Chemical Industries, Ltd., 1,5-diazabicyclo [4.3.0] non-5-ene (trade name) )
10 wt% Pd / C (metal catalyst): Aldrich, palladium 10 wt% on activated carbon (trade name)

In the experimental examples, analysis was performed by the following method.
^<1 H-NMR>
¹ H-NMR was measured using a Bruker Avance 250 (250 MHz) or a Bruker Avance 500 (500 MHz). Deuterium chloroform (CDCl ₃ ) was used as a measurement solvent, and tetramethylsilane (TMS) was used as an internal standard substance.
< ¹⁹ F-NMR>
¹⁹ F-NMR was measured using a Bruker Avance 250 (235 MHz). Measurement was performed using deuterated chloroform (CDCl ₃ ) as a measurement solvent and benzotrifluoride as an internal standard substance.
< ^13C -NMR>
¹³ C-NMR was measured using Bruker Avance 500 (125 MHz). Deuterium chloroform (CDCl ₃ ) was used as a measurement solvent, and tetramethylsilane (TMS) was used as an internal standard substance.
<GCEIMS (Gas Chromatography Electron Ionization Mass Spectrometer)>
GCEIMS was measured using a Shimadzu gas chromatograph mass spectrometer (GC-2010). As measurement conditions, the injection temperature was 80 ° C., the initial temperature was 80 ° C. for 3 minutes, and then the temperature was raised to 300 ° C. over 11 minutes, followed by ionization for 29 minutes at the same temperature.

Experimental Example 1 [Method for producing allyl alcohol derivative (2)]
In Experimental Example 1, the reaction represented by the following reaction formula was performed.

To a 1.46 M tetrahydrofuran solution (20 mL, 29.2 mmol) of vinylmagnesium chloride (vinyl metal reagent) at 0 ° C. in an argon atmosphere, trans-4-propylcyclohexanecarbaldehyde (aldehyde) (3.65 g, 25.0 mmol) was obtained. ) In anhydrous tetrahydrofuran (15 mL) was added dropwise over 30 minutes, and the mixture was further stirred at 0 ° C. for 30 minutes.
To this reaction mixture was added 13% aqueous ammonium chloride solution (40 mL), and the mixture was stirred at room temperature for 20 minutes, and then extracted with diethyl ether (20 mL × 2) to obtain an organic layer. The obtained organic layers were combined, and the organic layer was washed with water (20 mL) and saturated brine (20 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give an oil. The obtained oil was purified by medium pressure column chromatography [silica gel (300 g), hexane-ethyl acetate (9: 1)] to give 1- (trans-4-propylcyclohexyl) -2-propen-1-ol ( 2) (4.17 g, yield: 92%) was obtained as a colorless oil.

The results of ¹ H-NMR of 1- (trans-4-propylcyclohexyl) -2-propen-1-ol (2) are shown below.
¹ H-NMR (250 MHz, CDCl ₃ ) δ 5.87 (ddd, J = 17.3, 10.5, 6.8 Hz, 1 H), 5.20 (brd, J = 17.3 Hz, 1 H), 5. 14 (brd, J = 10.5 Hz, 1H), 3.85 (brdd, J = 6.8, 6.8 Hz, 1H), 1.95-0.78 (m, 15H), 0.87 (t , J = 7.0 Hz, 3H).

Experimental Example 2 [About Step 1]
In Experimental Example 2, the reaction represented by the following reaction formula was performed.

1- (trans-4-propylcyclohexyl) -2-propen-1-ol (2) (7.38 g, 40.6 mmol) and 2-bromoacetaldehyde diethyl acetal (3a) (16.) at room temperature under a stream of argon. Sodium hydride (1.61 g, 40.3 mmol) was added to a 1,4-dioxane solution (40 mL) containing 0 g, 81.2 mmol), and the mixture was stirred at 100 ° C. for 8 hours. After allowing to cool, sodium hydride (1.61 g, 40.3 mmol) was added, and the mixture was stirred at 100 ° C. for 14 hours 30 minutes. After allowing to cool to room temperature, sodium hydride (1.61 g, 40.3 mmol) was added, and the mixture was stirred at 100 ° C. for 6 hr.
The reaction mixture was allowed to cool, poured into 40 mL of a saturated aqueous ammonium chloride solution cooled to 0 ° C., stirred at room temperature for 10 minutes, and extracted with diethyl ether (100 mL × 3) to obtain an organic layer. The obtained organic layers were combined, and the organic layer was washed with water (50 mL) and saturated brine (50 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give an oil. The obtained oil was purified by medium pressure column chromatography [silica gel (300 g), hexane-ethyl acetate (9: 1)] to give 2- [1- (trans-4-propylcyclohexyl) -2-propenyloxy]. Acetaldehyde diethyl acetal (1a) (10.8 g, yield: 89%) was obtained as a colorless oil.

The result of ¹ H-NMR of 2- [1- (trans-4-propylcyclohexyl) -2-propenyloxy] acetaldehyde diethyl acetal (1a) is shown below.
¹ H-NMR (250 MHz, CDCl ₃ ) δ 5.65 (ddd, J = 17.3, 10.5, 8.0 Hz, 1H), 5.19 (brd, J = 17.3 Hz, 1H), 5. 13 (brd, J = 10.5 Hz, 1H), 4.61 (dd, J = 5.8, 5.3 Hz, 1H), 3.76-3.48 (m, 5H), 3.40-3 .25 (m, 2H), 1.95 (m, 1H), 1.80-1.62 (m, 2H), 1.55-0.76 (m, 17H), 0.86 (t, J = 7.0 Hz, 3H).

Experimental Example 3 [About Step 2]
In Experimental Example 3, the reaction represented by the following reaction formula was performed.

Under argon atmosphere, 2- [1- (trans-4-propylcyclohexyl) -2-propenyloxy] acetaldehyde diethyl acetal (1a) (4.99 g, 16.7 mmol) in tetrahydrofuran (40 mL) was added with 0.5 M hydrochloric acid. (40 mL, 20 mmol) was added, and the mixture was stirred at 80 ° C. for 22 hours.
The reaction mixture was allowed to cool and extracted with diethyl ether (40 mL × 2) to obtain an organic layer. The obtained organic layers were combined, and the organic layer was washed with water (20 mL) and saturated brine (20 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give an oil. The obtained oil was purified by medium pressure column chromatography [silica gel (300 g), hexane-ethyl acetate (9: 1)] to give 2- [1- (trans-4-propylcyclohexyl) -2-propenyloxy]. Acetaldehyde (1b) (3.56 g, yield: 95%) was obtained as a colorless oil.

The results of ¹ H-NMR of 2- [1- (trans-4-propylcyclohexyl) -2-propenyloxy] acetaldehyde (1b) are shown below.
¹ H-NMR (250 MHz, CDCl ₃ ) δ 9.72 (brs, 1H), 5.65 (ddd, J = 17.3, 10.3, 8.3 Hz, 1H), 5.27 (dd, J = 10.3, 1.5 Hz, 1 H), 5.15 (dd, J = 17.3, 1.3 Hz, 1 H), 4.07 (dd, J = 17.0, 0.8 Hz, 1 H), 3 .93 (dd, J = 17.0, 0.8 Hz, 1H), 3.41 (dd, J = 8.3, 8.3 Hz, 1H), 1.99 (m, 1H), 1.83 1.65 (m, 3H), 1.55-0.75 (m, 10H), 0.87 (t, J = 7.0 Hz, 3H).

Experimental Example 4 [About Step 3]
In Experimental Example 4, the reaction represented by the following reaction formula was performed.

Iodine (10 mg) was added to a suspension of metal magnesium (545 mg, 22.4 mmol) in tetrahydrofuran (15 mL) at room temperature under an argon atmosphere, followed by 1-bromo-4-ethoxy-2,3-difluorobenzene ( 1 mL of a tetrahydrofuran solution (5.0 mL) of 5.00 g, 21.1 mmol) was added dropwise. After the iodine color disappears, the remaining tetrahydrofuran solution of 1-bromo-4-ethoxy-2,3-difluorobenzene is added dropwise at 10 ° C. over 30 minutes, and then stirred at room temperature for 2 hours. A 0.81 M tetrahydrofuran solution of 4-ethoxy-2,3-difluorophenylmagnesium bromide was prepared.
To a 0.81 M tetrahydrofuran solution (3.6 mL, 2.92 mmol) of 4-ethoxy-2,3-difluorophenylmagnesium bromide (5) at 0 ° C. in an argon atmosphere, 2- [1- (trans-4 -Propylcyclohexyl) -2-propenyloxy] acetaldehyde (1b) (427 mg, 1.91 mmol) in tetrahydrofuran (2.0 mL) was added dropwise, and the mixture was further stirred at 0 ° C. for 30 min.
To this reaction mixture, 1.2M hydrochloric acid (3.0 mL) was added, stirred at room temperature for 5 minutes, and extracted with diethyl ether (3.0 mL × 3) to obtain an organic layer. The obtained organic layers were combined, and the organic layer was washed with water (3.0 mL) and saturated brine (3.0 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give an oil. The obtained oil was purified by medium pressure column chromatography [silica gel (72 g), hexane-ethyl acetate (5: 1)], and (1RS) -1- (4-ethoxy-2,3-difluorophenyl)- 2-[(1RS) -1- (trans-4-propylcyclohexyl) -2-propenyloxy] ethanol (4a) (550 mg, yield: 75%) was obtained as a white solid.

¹ H- of (1RS) -1- (4-ethoxy-2,3-difluorophenyl) -2-[(1RS) -1- (trans-4-propylcyclohexyl) -2-propenyloxy] ethanol (4a) The results of NMR and ¹⁹ F-NMR are shown below.
¹ H-NMR (250 MHz, CDCl ₃ ) δ 7.17 (ddd, J = 9.5, 7.3, 2.3, 1H), 6.73 (ddd, J = 9.0, 7.3, 1 .8, 1H), 5.66 (m, 1H), 5.24-5.09 (m, 3H), 4.11 (q, J = 7.0 Hz, 2H), 3.72-3.16. (M, 3H), 2.87 (d, J = 2.5 Hz, 0.38H), 2.82 (d, J = 2.5 Hz, 0.62H), 1.92 (m, 1H), 1 80-1.62 (m, 3H), 1.44 (t, J = 7.0 Hz, 3H), 1.36-0.82 (m, 10H), 0.87 (t, J = 7. 0 Hz, 3H).

¹⁹ F-NMR (235 MHz, CDCl ₃ ) δ-143.3 (d, J = 19 Hz, 0.38F), -143.6 (d, J = 19 Hz, 0.62F), −160.1 (d, J = 19 Hz, 0.38 F), −160.2 (d, J = 19 Hz, 0.62 F).

Experimental Example 5 [About Step 4]
In Experimental Example 5, the reaction represented by the following reaction formula was performed.

(1RS) -1- (4-ethoxy-2,3-difluorophenyl) -2-[(1RS) -1- (trans-4-propylcyclohexyl) -2-propenyloxy] at 0 ° C. under an argon atmosphere To a solution of ethanol (4a) (39.0 mg, 0.102 mmol) in dichloromethane (1.0 mL) was added phosphorus tribromide (0.080 mL, 0.957 mmol), and the mixture was stirred at 0 ° C. for 1 hour, and then at room temperature. For 20 hours.
A 5% aqueous sodium hydrogen carbonate solution (4.0 mL) was added to the reaction mixture, and the mixture was stirred for 15 minutes and then extracted with chloroform (3.0 mL × 3) to obtain an organic layer. The obtained organic layers were combined, and the organic layer was washed with water (3.0 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give an oil. The obtained oil was purified by preparative thin phase chromatography [silica gel plate (250 mm × 250 mm × 0.50 mm), hexane-ethyl acetate (5: 1)], and (3RS) -3-[(2RS) -2-bromo- 2- (4-Ethoxy-2,3-difluorophenyl) ethyloxy] -3- (trans-4-propylcyclohexyl) propene (4b) (14.4 mg, 32% yield) was obtained as a colorless oil.

¹ H- of (3RS) -3-[(2RS) -2-bromo-2- (4-ethoxy-2,3-difluorophenyl) ethyloxy] -3- (trans-4-propylcyclohexyl) propene (4b) The results of NMR and ¹⁹ F-NMR are shown below.
¹ H-NMR (250 MHz, CDCl ₃ ) δ 7.13 (m, 1H), 6.72 (m, 1H), 5.63 (m, 1H), 5.31-5.10 (m, 3H), 4.13 (q, J = 7.0 Hz, 2H), 3.99 (m, 1H), 3.77 (m, 1H), 3.37 (m, 1H), 1.91-1.01 ( m, 13H), 1.45 (t, J = 7.0 Hz, 3H), 0.86 (t, J = 7.0 Hz, 3H), 0.85 (m, 1H).

¹⁹ F-NMR (235 MHz, CDCl ₃ ) δ-140.32 (d, J = ¹⁹ Hz, 0.5 F), −140.34 (d, J = 19 Hz, 0.5 F), −159.09 (d, J = 19 Hz, 0.5 F), −159.14 (d, J = 19 Hz, 0.5 F).

Experimental Example 6 [Regarding Step 5 (I)]
In Experimental Example 6, the reaction represented by the following reaction formula was performed.

Dichloromethane (2.0 mL) solution containing boron trifluoride diethyl ether complex (Lewis acid) (0.26 mL, 1.0 mmol) and acetic acid (0.057 mL, 1.0 mmol) at −78 ° C. under argon atmosphere (1RS) -1- (4-ethoxy-2,3-difluorophenyl) -2-[(1RS) -1- (trans-4-propylcyclohexyl) -2-propenyloxy] ethanol (4a) (38 .2 mg, 0.200 mmol) in dichloromethane (2.0 mL) was added dropwise over 30 minutes, and the temperature was slowly raised to room temperature.
To this reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution (2.0 mL), the mixture was stirred at room temperature for 5 minutes, and extracted with chloroform (3.0 mL × 3) to obtain an organic layer. The obtained organic layers were combined, and the organic layer was washed with water (3.0 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give an oil. The obtained oil was purified by preparative thin phase chromatography [silica gel plate (250 mm × 250 mm × 0.50 mm), hexane-ethyl acetate (8: 1)], and acetic acid (2R ^* , 3S ^* , 5R ^* )-5- ( 4-Ethoxy-2,3-difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran-3-yl (6) (62.3 mg, yield: 73%) and (2R ^* , 3S ^* , 5R ^* )-5- (4-Ethoxy-2,3-difluorophenyl) -3-fluoro-2- (trans-4-propylcyclohexyl) tetrahydropyran (6) (10.5 mg, yield: 14%). Each was obtained as a white solid.

¹ H- of acetic acid (2R ^* , 3S ^* , 5R ^* )-5- (4-ethoxy-2,3-difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran-3-yl (6) The results of NMR and ¹⁹ F-NMR are shown below.
Acetic acid (2R ^* , 3S ^* , 5R ^* )-5- (4-ethoxy-2,3-difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran-3-yl: ¹ H-NMR (500 MHz , CDCl ₃ ) δ 6.80 (ddd, J = 8.8, 7.3, 1.9 Hz, 1H), 6.66 (ddd, J = 8.6, 7.3, 1.9 Hz, 1H), 4.89 (ddd, J = 10.3, 10.3, 4.7 Hz, 1H), 4.09 (q, J = 7.0 Hz, 2H), 3.96 (brd, J = 10.3 Hz, 1H), 3.33 (dd, J = 11.0, 10.3 Hz, 1H), 3.24-3.17 (m, 2H), 2.33 (brd, J = 12.4 Hz, 1H), 2.06 (s, 3H), 1.82-1.67 (m, 4H), 1.59-1.42 m, 3H), 1.42 (t, J = 7.0 Hz, 3H), 1.36-1.11 (m, 6H), 0.96-0.77 (m, 2H), 0.87 ( t, J = 7.0 Hz, 3H).

¹⁹ F-NMR (235 MHz, CDCl ₃ ) δ-141.5 (d, J = 19 Hz, 1F), -158.9 (d, J = 19 Hz, 1F).

Melting point of (2R ^* , 3S ^* , 5R ^* )-5- (4-ethoxy-2,3-difluorophenyl) -3-fluoro-2- (trans-4-propylcyclohexyl) tetrahydropyran (6), ¹ H The results of -NMR and ¹⁹ F-NMR are shown below.
(2R ^* , 3S ^* , 5R ^* )-5- (4-Ethoxy-2,3-difluorophenyl) -3-fluoro-2- (trans-4-propylcyclohexyl) tetrahydropyran: melting point: 84.5-87 ¹ H-NMR (250 MHz, CDCl ₃ ) δ 6.83 (ddd, J = 9.3, 7.3, 2.0 Hz, 1H), 6.67 (ddd, J = 9.0, 7) .3, 1.8 Hz, 1H), 4.54 (dddd, J = 49.0, 10.0, 10.0, 5.0 Hz, 1H), 4.10 (q, J = 7.0 Hz, 2H) ), 3.93 (m, 1H), 3.32-3.12 (m, 3H), 2.38 (m, 1H), 2.00-1.60 (m, 6H), 1.44 ( t, J = 7.0 Hz, 3H), 1.50-1.09 (m, 7H), 1.04-0.80 (m, 2) ), 0.87 (t, J = 7.0Hz, 3H).

¹⁹ F-NMR (235 MHz, CDCl ₃ ) δ-141.9 (d, J = 19 Hz, 1F), -158.8 (d, J = 19 Hz, 1F), −184.7 (s, 1F).

Experimental Example 7 [Regarding Step 5 (II)]
In Experimental Example 7, the reaction represented by the following reaction formula was performed.

To a dichloromethane solution (2.0 mL) of methanesulfonic acid (Bronsted acid) (0.130 mL, 2.0 mmol) at −78 ° C. in an argon atmosphere, (1RS) -1- (4-ethoxy-2,3 -Difluorophenyl) -2-[(1RS) -1- (trans-4-propylcyclohexyl) -2-propenyloxy] ethanol (4a) (382 mg, 1.0 mmol) was added, and the mixture was stirred at −40 ° C. for 6 hours. Then, the temperature was raised slowly from -40 ° C to room temperature.
To this reaction mixture, a saturated aqueous sodium hydrogen carbonate solution (2.0 mL) was added, stirred at room temperature for 10 minutes, and extracted with chloroform (3.0 mL × 3) to obtain an organic layer. The obtained organic layers were combined, and the organic layer was washed with water (2.0 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give an oil. The obtained oil was purified by medium pressure column chromatography [silica gel (42 g), hexane-ethyl acetate (9: 1)] to give methanesulfonic acid (2R ^* , 3S ^* , 5R ^* )-5- ( 4-Ethoxy-2,3-difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran-3-yl (6) (415 mg, 90% yield) was obtained as a white solid.

Melting point of methanesulfonic acid (2R ^* , 3S ^* , 5R ^* )-5- (4-ethoxy-2,3-difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran-3-yl (6) The results of ¹ H-NMR and ¹⁹ F-NMR are shown below.
Melting point: 110.5 to 114.0 ° C .; ¹ H-NMR (250 MHz, CDCl ₃ ) δ 6.82 (ddd, J = 9.3, 7.3, 2.0 Hz, 1 H), 6.68 (ddd, J = 9.0, 7.3, 1.8 Hz, 1H), 4.72 (ddd, J = 10.3, 10.3, 4.8 Hz, 1H), 4.10 (q, J = 7. 0 Hz, 2H), 3.95 (ddd, J = 10.8, 3.8, 2.0 Hz, 1H), 3.35 (dd, J = 11.0, 10.8 Hz, 1H), 3.28. -3.14 (m, 2H), 3.03 (s, 3H), 2.56 (brd, J = 12.0 Hz, 1H), 2.04 (ddd, J = 12.0, 12.0, 11.3 Hz, 1H), 1.89-1.49 (m, 6H), 1.44 (t, J = 7.0 Hz, 3H), 1.38-1.07 (m, 6H) 1.04-0.78 (m, 2H), 0.87 (t, J = 7.0Hz, 3H).

¹⁹ F-NMR (235 MHz, CDCl ₃ ) δ-141.5 (d, J = 19 Hz, 1F), -158.7 (d, J = 19 Hz, 1F).

Experimental Example 8 [Regarding Step 5 (III)]
In Experimental Example 8, the reaction represented by the following reaction formula was performed.

p-Toluenesulfonic acid monohydrate (Bronsted acid) (380 mg, 2.0 mmol) was stirred at 100 ° C. under vacuum for 4 hours. After allowing to cool to room temperature, the p-toluenesulfonic acid monohydrate was dissolved in dichloromethane (1.0 mL) under an argon atmosphere, and then at -78 ° C, (1RS) -1- (4-ethoxy- 2,3-difluorophenyl) -2-[(1RS) -1- (trans-4-propylcyclohexyl) -2-propenyloxy] ethanol (4a) (382 mg, 1.0 mmol) was added at -78 ° C. Stir for 2 hours. Then, it heated up at a stretch to -55 degreeC, heated up from -55 degreeC slowly to -40 degreeC over 30 minutes, and also heated up to room temperature at once, and stirred for 30 minutes.
To this reaction mixture, a saturated aqueous sodium hydrogen carbonate solution (2.0 mL) was added, stirred at room temperature for 10 minutes, and extracted with chloroform (3.0 mL × 3) to obtain an organic layer. The obtained organic layers were combined, and the organic layer was washed with water (2.0 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give an oil. The obtained oil was purified by medium pressure column chromatography [silica gel (42 g), hexane-ethyl acetate (9: 1)] to give p-toluenesulfonic acid (2R ^* , 3S ^* , 5R ^* )-5. -(4-Ethoxy-2,3-difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran-3-yl (6) (397 mg, 74% yield) was obtained as a white solid.

p-Toluenesulfonic acid (2R ^* , 3S ^* , 5R ^* )-5- (4-ethoxy-2,3-difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran-3-yl (6) The results of melting point, ¹ H-NMR and ¹⁹ F-NMR are shown below.
Melting point: 116.5-121.5 ° C .; ¹ H-NMR (250 MHz, CDCl ₃ ) δ 7.82 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.3 Hz, 2H) 6.79 (ddd, J = 9.3, 7.0, 2.3 Hz, 1H), 6.67 (ddd, J = 9.0, 7.0, 1.8 Hz, 1H), 4.45. (Ddd, J = 10.3, 10.3, 4.8 Hz, 1H), 4.09 (q, J = 7.0 Hz, 2H), 3.90 (m, 1H), 3.26 (dd, J = 10.8, 10.5 Hz, 1H), 3.24-3.08 (m, 2H), 2.50 (m, 1H), 2.45 (s, 3H), 1.98 (ddd, J = 12.0, 11.8, 11.5 Hz, 1H), 1.71 (brd, J = 12.0 Hz, 1H), 1.58-0.95 (m, 11H), 1.4 (T, J = 7.0Hz, 3H), 0.86 (t, J = 7.0Hz, 3H), 0.82 (m, 1H), 0.40 (m, 1H).

¹⁹ F-NMR (235 MHz, CDCl ₃ ) δ-141.8 (d, J = 19 Hz, 1F), -158.8 (d, J = 19 Hz, 1F).

Experimental Example 9 [Regarding Step 5 (IV)]
In Experimental Example 9, the reaction represented by the following reaction formula was performed.

To a dichloromethane solution (4.0 mL) of benzenesulfonic acid (Bronsted acid) (350 mg, 2.0 mmol) at −78 ° C. in an argon atmosphere, (1RS) -1- (4-ethoxy-2,3-difluoro was added. Phenyl) -2-[(1RS) -1- (trans-4-propylcyclohexyl) -2-propenyloxy] ethanol (4a) (386 mg, 1.0 mmol) was added, and the temperature was slowly raised from −78 ° C. to room temperature. .
To this reaction mixture, a saturated aqueous sodium hydrogen carbonate solution (2.0 mL) was added, stirred at room temperature for 10 minutes, and extracted with chloroform (3.0 mL × 3) to obtain an organic layer. The obtained organic layers were combined, and the organic layer was washed with water (3.0 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give an oil. The obtained oil was purified by medium pressure column chromatography [silica gel (42 g), hexane-ethyl acetate (9: 1)] to give benzenesulfonic acid (2R ^* , 3S ^* , 5R ^* )-5- ( 4-Ethoxy-2,3-difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran-3-yl (6) (275 mg, 43% yield) was obtained as a white solid.

Melting point of benzenesulfonic acid (2R ^* , 3S ^* , 5R ^* )-5- (4-ethoxy-2,3-difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran-3-yl (6) The results of ¹ H-NMR and ¹⁹ F-NMR are shown below.
Melting point: 116.0 to 119.5 ° C .; ¹ H-NMR (250 MHz, CDCl ₃ ) δ 7.95 (brd, J = 7.5 Hz, 2H), 7.67 (brt, J = 7.5 Hz, 1H) 7.57 (brt, J = 7.5 Hz, 2H), 6.79 (ddd, J = 9.3, 7.5, 2.0 Hz, 1H), 6.67 (ddd, J = 9.0) , 7.5, 2.0 Hz, 1H), 4.50 (ddd, J = 10.0, 10.0, 4.5 Hz, 1H), 4.09 (q, J = 7.0 Hz, 2H), 3.91 (m, 1H), 3.31-3.12 (m, 3H), 2.49 (brd, J = 12.0 Hz, 1H), 1.98 (ddd, J = 11.8, 11 .5, 11.0 Hz, 1H), 1.72 (brd, J = 12.5 Hz, 1H), 1.58-0.95 (m, 11H), 1.44 t, J = 7.0Hz, 3H), 0.86 (t, J = 7.0Hz, 3H), 0.81 (m, 1H), 0.47 (m, 1H).

¹⁹ F-NMR (235 MHz, CDCl ₃ ) δ-141.8 (d, J = 19 Hz, 1F), -158.8 (d, J = 19 Hz, 1F).

Experimental Example 10 [Regarding Step 5 (V)]
In Experimental Example 10, the reaction represented by the following reaction formula was performed.

(1RS) -1- (4-ethoxy-2,3-difluorophenyl) -2-[(1RS) -1- (trans-4-propylcyclohexyl) -2-propenyloxy] at 0 ° C. under an argon atmosphere To a solution of ethanol (4a) (38.2 mg, 0.10 mmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (Brensted acid) (0.050 mL, 0.653 mmol), and the mixture was stirred at 0 ° C. for 1 hour. And then stirred at room temperature for 8 hours.
To this reaction mixture was added 8% aqueous sodium hydrogen carbonate solution (3.0 mL), the mixture was stirred at room temperature for 5 minutes, and extracted with chloroform (3.0 mL × 3) to obtain an organic layer. The obtained organic layers were combined, and the organic layer was washed with water (3.0 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give an oil. The obtained oil was purified by preparative thin layer chromatography [silica gel plate (250 × 250 × 0.50 mm), hexane-ethyl acetate (12: 1)] to obtain trifluoroacetic acid (2R ^* , 3S ^* , 5R ^* ). -5- (4-Ethoxy-2,3-difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran-3-yl (6) (25.9 mg, 54% yield) was obtained as a white solid. It was.

Trifluoroacetic acid ^{(2R *, 3S *, 5R} *) -5- 1 of (4-ethoxy-2,3-difluorophenyl)-2-(trans-4-propyl-cyclohexyl) tetrahydropyran-3-yl (6) The results of H-NMR and ¹⁹ F-NMR are shown below.
¹ H-NMR (250 MHz, CDCl ₃ ) δ 6.82 (ddd, J = 9.5, 7.5, 2.0 Hz, 1H), 6.68 (ddd, J = 8.8, 7.5, 1 .8 Hz, 1H), 5.06 (ddd, J = 10.3, 10.3, 4.5 Hz, 1H), 4.09 (q, J = 7.0 Hz, 2H), 4.00 (brd, J = 10.5 Hz, 1H), 3.43-3.16 (m, 3H), 2.41 (brd, J = 12.0 Hz, 1H), 1.92 (ddd, J = 12.0, 12 .0, 11.3 Hz, 1 H), 1.84-1.05 (m, 12 H), 1.44 (t, J = 7.0 Hz, 3 H), 1.02-0.72 (m, 2 H) , 0.87 (t, J = 7.0 Hz, 3H).

¹⁹ F-NMR (235 MHz, CDCl ₃ ) δ-75.4 (s, 3F), -141.5 (d, J = 19 Hz, 1F), -158.6 (d, J = 19 Hz, 1F).

Experimental Example 11 [Regarding Step 5 (VI)]
In Experimental Example 11, the reaction represented by the following reaction formula was performed.

To a dichloromethane solution (1.0 mL) of trifluoromethanesulfonic acid (Bronsted acid) (0.050 mL, 0.565 mmol) at −78 ° C. under an argon atmosphere, (1RS) -1- (4-ethoxy-2, 3-Difluorophenyl) -2-[(1RS) -1- (trans-4-propylcyclohexyl) -2-propenyloxy] ethanol (4a) (38.2 mg, 0.100 mmol) was added and at -78 ° C. Stir for 1 hour.
To this reaction mixture, 5% aqueous sodium hydrogen carbonate solution (3.0 mL) was added, stirred at room temperature for 10 minutes, and extracted with chloroform (3.0 mL × 3) to obtain an organic layer. The obtained organic layers were combined, and the organic layer was washed with water (3.0 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give an oil. According to ¹⁹ F-NMR measurement of the obtained oily substance, trifluoromethanesulfonic acid (2R ^* , 3S ^* , 5R ^* )-5- (4-ethoxy-2,3-difluorophenyl) -2- (trans-4- It was confirmed that 70% of propylcyclohexyl) tetrahydropyran-3-yl (6) was produced.

Of trifluoromethanesulfonic acid (2R ^* , 3S ^* , 5R ^* )-5- (4-ethoxy-2,3-difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran-3-yl (6) The result of ¹ H-NMR is shown below.
¹ H-NMR (250 MHz, CDCl ₃ ) δ 6.82 (ddd, J = 9.3, 7.3, 2.3 Hz, 1H), 6.68 (ddd, J = 8.8, 7.3, 1) .8 Hz, 1H), 4.95 (ddd, J = 10.3, 10.3, 4.8 Hz, 1H), 4.10 (q, J = 7.0 Hz, 2H), 3.94 (brd, J = 10.0 Hz, 1H), 3.50-3.18 (m, 3H), 2.56 (brd, J = 12.0 Hz, 1H), 2.14 (ddd, J = 12.0, 12 .0, 11.5 Hz, 1H), 2.14-0.78 (m, 14H), 1.44 (t, J = 7.0 Hz, 3H), 0.87 (t, J = 7.0 Hz, 3H).

¹⁹ F-NMR (235 MHz, CDCl ₃ ) δ-75.6 (s, 3F), -141.5 (d, J = 19 Hz, 1F), -158.4 (d, J = 19 Hz, 1F).

Experimental Example 12 [Regarding Step 5 (VII)]
In Experimental Example 12, the reaction represented by the following reaction formula was performed.

(1RS) -1- (4-ethoxy-2,3-difluorophenyl) -2-[(1RS) -1- (trans-4-propylcyclohexyl) -2-propenyloxy at −78 ° C. under argon atmosphere ] To a dichloromethane solution (1.0 mL) of ethanol (4a) (382 mg, 1.0 mmol) was added aluminum chloride (Lewis acid) (133 mg, 1.0 mmol), and the mixture was stirred at -78 ° C for 1 hour and 30 minutes. Thereafter, the mixture was stirred at −40 ° C. for 2 hours and 30 minutes.
To this reaction mixture, 8% aqueous sodium hydroxide solution (3.0 mL) and chloroform (2.0 mL) were added, stirred at room temperature for 10 minutes, and extracted with chloroform (3.0 mL × 3) to obtain an organic layer. The obtained organic layers were combined, and the organic layer was washed with water (2.0 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give an oil. The obtained oil was purified by medium pressure column chromatography [silica gel (42 g), hexane-ethyl acetate (9: 1)] to give (2R ^* , 3S ^* , 5R ^* )-3-chloro-5- (4-Ethoxy-2,3-difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran (6) (191 mg, 48% yield) was obtained as a white solid.

Melting point of (2R ^* , 3S ^* , 5R ^* )-3-chloro-5- (4-ethoxy-2,3-difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran (6), ¹ H The results of -NMR and ¹⁹ F-NMR are shown below.
Melting point: 82.0-86.0 ° C .; ¹ H-NMR (500 MHz, CDCl ₃ ) δ 6.81 (ddd, J = 9.4, 7.2, 2.2 Hz, 1 H), 6.68 (ddd, J = 9.0, 7.2, 1.8 Hz, 1H), 4.09 (q, J = 7.0 Hz, 2H), 4.00 (ddd, J = 11.0, 4.3, 2.. 1 Hz, 1 H), 3.95 (ddd, J = 10.2, 10.1, 3.3 Hz, 1 H), 3.37 (dd, J = 11.0, 11.0 Hz, 1 H), 3.20 (M, 1H), 3.18 (brd, J = 10.2 Hz, 1H), 2.47 (m, 1H), 2.05 (ddd, J = 12.0, 12.0, 10.2 Hz, 1H), 1.92 (m, 1H), 1.83-1.76 (m, 2H), 1.67 (m, 1H), 1.50 (m, 1H), 1.42 (t, J 7.0Hz, 3H), 1.37-1.11 (m, 6H), 1.00-0.80 (m, 3H), 0.87 (t, J = 7.0Hz, 3H).

¹⁹ F-NMR (235 MHz, CDCl ₃ ) δ-141.9 (d, J = 19 Hz, 1F), -158.8 (d, J = 19 Hz, 1F).

Experimental Example 13 [Regarding Step 5 (VIII)]
In Experimental Example 13, the reaction represented by the following reaction formula was performed.

(1RS) -1- (4-ethoxy-2,3-difluorophenyl) -2-[(1RS) -1- (trans-4-propylcyclohexyl) -2-propenyloxy] at 0 ° C. under an argon atmosphere Bismuth tribromide (Lewis acid) (673 mg, 1.5 mmol) was added to a dichloromethane solution (2.0 mL) of ethanol (4a) (383 mg, 1.0 mmol), and the mixture was stirred at 0 ° C. for 1 hour, and then room temperature. For 6 hours.
To this reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (2.0 mL), the insoluble material was filtered, washed with chloroform (10 mL) and water (10 mL), extracted with chloroform (5.0 mL × 3), and the organic layer was extracted. Obtained. The obtained organic layers were combined, and the organic layer was washed with water (5.0 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give an oil. The obtained oil was purified by medium pressure column chromatography [silica gel (74 g), hexane-ethyl acetate (9: 1)] to give (2R ^* , 3S ^* , 5R ^* )-3-bromo-5- (4-Ethoxy-2,3-difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran (6) (297 mg, 67% yield) was obtained as a white solid.

Melting point of (2R ^* , 3S ^* , 5R ^* )-3-bromo-5- (4-ethoxy-2,3-difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran (6), ¹ H The results of -NMR and ¹⁹ F-NMR are shown below.

Melting point: 78.0 to 81.0 ° C .; ¹ H-NMR (250 MHz, CDCl ₃ ) δ 6.81 (ddd, J = 9.3, 7.0, 2.3 Hz, 1H), 6.68 (ddd, J = 9.0, 7.0, 1.8 Hz, 1H), 4.09 (q, J = 7.0 Hz, 2H), 4.13-3.97 (m, 2H), 3.42 (dd , J = 11.0, 11.0 Hz, 1H), 3.28 (brd, J = 10.3 Hz, 1H), 3.21 (m, 1H), 2.58 (brd, J = 12.3 Hz, 1H), 2.24 (ddd, J = 12.3, 12.3, 12.0 Hz, 1H), 2.05-1.07 (m, 11H), 1.44 (t, J = 7.0 Hz) , 3H), 1.07-0.77 (m, 3H), 0.87 (t, J = 7.0 Hz, 3H).

¹⁹ F-NMR (235 MHz, CDCl ₃ ) δ-141.9 (d, J = 19 Hz, 1F), -158.8 (d, J = 19 Hz, 1F).

Experimental Example 14 [Regarding Step 5 (IX)]
In Experimental Example 14, the reaction represented by the following reaction formula was performed.

(1RS) -1-[(2RS) -2-bromo-2- (4-ethoxy-2,3-difluorophenyl) ethyloxy] -1- (trans-4-propylcyclohexyl)-at room temperature under an argon atmosphere Bismuth tribromide (Lewis acid) (2.5 mg, 0.00557 mmol) was added to a dichloromethane solution (1.0 mL) of 2-propene (4b) (44.3 mg, 0.996 mmol), and the mixture was stirred at room temperature for 4 hours. Stir.
To this reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution (2.0 mL), the mixture was stirred at room temperature for 5 minutes, and extracted with chloroform (3.0 mL × 3) to obtain an organic layer. The obtained organic layers were combined, and the organic layer was washed with water (3.0 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give an oil. The obtained oil was purified by preparative thin phase chromatography [silica gel plate (250 mm × 250 mm × 0.50 mm), hexane-ethyl acetate (15: 1)] to give (2R ^* , 3S ^* , 5R ^* )-3-bromo- 5- (4-Ethoxy-2,3-difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran (6) (30.5 mg, 69% yield) was obtained as a white solid.

¹ H-NMR of (2R ^* , 3S ^* , 5R ^* )-3-bromo-5- (4-ethoxy-2,3-difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran (6) And the result of ¹⁹ F-NMR was the same as that of Experimental Example 13.

Experimental Example 15 [Regarding Step 6 (I)]
In Experimental Examples 15 to 19, reactions shown by the following reaction formulas were performed.

Methanesulfonic acid (2R ^* , 3S ^* , 5R ^* )-5- (4-ethoxy-2,3-difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran- at 85 ° C. under argon atmosphere A dimethyl sulfoxide solution (1.0 mL) containing 3-yl (6) (32.6 mg, 0.0709 mmol) and sodium borohydride (reducing agent) (27.0 mg, 709 mmol) was stirred for 49 hours and 30 minutes. The reaction mixture was allowed to cool, further sodium borohydride (27.0 mg, 709 mmol) was added, and the mixture was stirred at 85 ° C. for 43 hr 30 min under argon atmosphere.
The reaction mixture was allowed to cool, saturated aqueous ammonium chloride solution (3.0 mL) was added, the mixture was stirred at room temperature for 10 min, and extracted with ethyl acetate (3.0 mL × 3) to obtain an organic layer. The obtained organic layers were combined, and the organic layer was washed with water (2.0 mL) and saturated brine (2.0 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give an oil. The obtained oil was purified by preparative thin phase chromatography [silica gel plate (250 mm × 250 mm × 0.50 mm), hexane-ethyl acetate (20: 1)], and (2R ^* , 5R ^* )-5- (4-ethoxy- 2,3-Difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran (11) (16.7 mg, yield 64%) was obtained as a white solid.

(2R ^* , 5R ^* )-5- (4-ethoxy-2,3-difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran (11) ¹ H-NMR, ¹⁹ F-NMR, ¹³ The results of C-NMR and GCEIMS are shown below.

¹ H-NMR (500 MHz, CDCl ₃ ) δ 6.80 (ddd, J = 9.4, 7.2, 2.1 Hz, 1H), 6.67 (ddd, J = 9.0, 7.2, 1 .7 Hz, 1H), 4.09 (q, J = 7.0 Hz, 2H), 4.00 (ddd, J = 11.0, 4.1, 2.3 Hz, 1H), 3.37 (dd, J = 11.0, 11.0 Hz, 1H), 3.09-3.01 (m, 2H), 2.20-1.92 (m, 2H), 1.81-1.69 (m, 5H) ), 1.52-1.42 (m, 2H), 1.43 (t, J = 7.0 Hz, 3H), 1.39-1.23 (m, 3H), 1.23-1.12 (M, 3H), 1.08-0.82 (m, 3H), 0.87 (t, J = 7.0 Hz, 3H).

¹⁹ F-NMR (235 MHz, CDCl ₃ ) δ-142.2 (d, J = 19 Hz, 1F), -159.3 (d, J = 19 Hz, 1F).

¹³ C-NMR (125 MHz, CDCl ₃ ) δ 149.5 (dd, J = 246, 11 Hz), 146.8 (dd, J = 8.1, 3.1 Hz), 141.6 (dd, J = 247, 15 Hz), 123.1 (d, J = 13 Hz), 121.1 (dd, J = 5.5, 4.9 Hz), 109.5 (d, J = 2.7 Hz), 82.2, 72. 4, 65.4, 43.2, 39.7, 37.5, 36.2, 33.1, 33.0, 29.7, 29.1, 28.64, 28.61, 20.0, 14.8, 14.4.

  GCEIMS (relative intensity) m / Z 143 (47), 156 (46), 184 (33), 197 (100), 241 (75), 366 (M, 6).

  Experimental Example 16 [Regarding Step 6 (II)]

Methanesulfonic acid (2R ^* , 3S ^* , 5R ^* )-5- (4-ethoxy-2,3-difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran- at 85 ° C. under argon atmosphere A dimethyl sulfoxide solution (1.0 mL) containing 3-yl (6) (46.3 mg, 0.101 mmol) and sodium borohydride (reducing agent) (19.0 mg, 0.502 mmol) was stirred for 99 hours.
The reaction mixture was allowed to cool, saturated aqueous ammonium chloride solution (3.0 mL) was added, the mixture was stirred at room temperature for 10 min, and extracted with ethyl acetate (3.0 mL × 3) to obtain an organic layer. The obtained organic layers were combined, and the organic layer was washed with water (2.0 mL) and saturated brine (2.0 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give an oil. The obtained oil was purified by medium pressure column chromatography [silica gel (28 g), hexane-ethyl acetate (6: 1)], and (2R ^* , 5R ^* )-5- (4-ethoxy-2,3- Difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran (11) (15.0 mg, 41% yield) was obtained as a white solid.

(2R ^* , 5R ^* )-5- (4-ethoxy-2,3-difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran (11) ¹ H-NMR, ¹⁹ F-NMR, ¹³ The results of C-NMR and GCEIMS were the same as in Experimental Example 15.

  Experimental Example 17 [Regarding Step 6 (III)]

Methanesulfonic acid (2R ^* , 3S ^* , 5R ^* )-5- (4-ethoxy-2,3-difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran- at 100 ° C. under argon atmosphere A dimethyl sulfoxide solution (1.0 mL) containing 3-yl (6) (46.3 mg, 0.101 mmol) and sodium borohydride (reducing agent) (19.0 mg, 0.502 mmol) was stirred for 36 hours.
The reaction mixture was allowed to cool, saturated aqueous ammonium chloride solution (3.0 mL) was added, the mixture was stirred at room temperature for 10 min, and extracted with ethyl acetate (3.0 mL × 3) to obtain an organic layer. The obtained organic layers were combined, and the organic layer was washed with water (2.0 mL) and saturated brine (2.0 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give an oil. The obtained oil was purified by preparative thin phase chromatography [silica gel plate (250 mm × 250 mm × 0.50 mm), hexane-ethyl acetate (20: 1)], and (2R ^* , 5R ^* )-5- (4-ethoxy- 2,3-Difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran (11) (18.0 mg, 51% yield) was obtained as a white solid.

(2R ^* , 5R ^* )-5- (4-ethoxy-2,3-difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran (11) ¹ H-NMR, ¹⁹ F-NMR, ¹³ The results of C-NMR and GCEIMS were the same as in Experimental Example 15.

  Experimental Example 18 [Regarding Step 6 (VI)]

Methanesulfonic acid (2R ^* , 3S ^* , 5R ^* )-5- (4-ethoxy-2,3-difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran- at 100 ° C. under argon atmosphere A dimethyl sulfoxide solution (1.0 mL) containing 3-yl (6) (46.6 mg, 0.102 mmol) and tetra n-butylammonium borohydride (reducing agent) (131 mg, 0.510 mmol) was stirred for 21 hours. did.
The reaction mixture was allowed to cool, saturated aqueous ammonium chloride solution (2.0 mL) was added, the mixture was stirred at room temperature for 10 min, and extracted with ethyl acetate (3.0 mL × 3) to obtain an organic layer. The obtained organic layers were combined, and the organic layer was washed with water (2.0 mL) and saturated brine (2.0 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give an oil. The obtained oil was purified by preparative thin phase chromatography [silica gel plate (250 mm × 250 mm × 0.50 mm), hexane-ethyl acetate (20: 1)], and (2R ^* , 5R ^* )-5- (4-ethoxy- 2,3-Difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran (11) (22.3 mg, 61% yield) was obtained as a white solid.

(2R ^* , 5R ^* )-5- (4-ethoxy-2,3-difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran (11) ¹ H-NMR, ¹⁹ F-NMR, ¹³ The results of C-NMR and GCEIMS were the same as in Experimental Example 15.

  Experimental Example 19 [Regarding Step 6 (V)]

Under an argon atmosphere, methanesulfonic acid (2R ^* , 3S ^* , 5R ^* )-5- (4-ethoxy-2,3-difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran-3-yl ( 6) To a toluene solution (0.50 mL) containing (46.6 mg, 0.102 mmol) and triethylsilane (reducing agent) (24.4 mg, 0.210 mmol), methanesulfonic acid (0.015 mL, 0.236 mmol) And stirred at 100 ° C. for 22 hours.
The reaction mixture was allowed to cool, saturated aqueous sodium hydrogen carbonate solution (2.0 mL) was added, the mixture was stirred at room temperature for 10 min, and extracted with ethyl acetate (2.0 mL × 3) to obtain an organic layer. The obtained organic layers were combined, and the organic layer was washed with water (2.0 mL) and saturated brine (2.0 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give an oil. According to ¹⁹ F-NMR measurement of the obtained oil, (2R ^* , 5R ^* )-5- (4-ethoxy-2,3-difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran (11 ) Was confirmed to be 20%.

(2R ^* , 5R ^* )-5- (4-ethoxy-2,3-difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran (11) ¹ H-NMR, ¹⁹ F-NMR, ¹³ The results of C-NMR and GCEIMS were the same as in Experimental Example 15.

Experimental Example 20 [Regarding Step 6 (VI)]
In Experimental Example 20, the reaction represented by the following reaction formula was performed.

P-Toluenesulfonic acid (2R ^* , 3S ^* , 5R ^* )-5- (4-ethoxy-2,3-difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydro at 85 ° C. under argon atmosphere A dimethyl sulfoxide solution (1.0 mL) containing pyran-3-yl (6) (53.6 mg, 0.100 mmol) and sodium borohydride (reducing agent) (19.0 mg, 0.502 mmol) was stirred for 68 hours. did.
The reaction mixture was allowed to cool, saturated aqueous ammonium chloride solution (3.0 mL) was added, the mixture was stirred at room temperature for 10 min, and extracted with ethyl acetate (3.0 mL × 3) to obtain an organic layer. The obtained organic layers were combined, and the organic layer was washed with water (2.0 mL) and saturated brine (2.0 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give an oil. The obtained oil was purified by preparative thin phase chromatography [silica gel plate (250 mm × 250 mm × 0.50 mm), hexane-ethyl acetate (20: 1)], and (2R ^* , 5R ^* )-5- (4-ethoxy- 2,3-Difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran (11) (22.1 mg, 60% yield) was obtained as a white solid.

(2R ^* , 5R ^* )-5- (4-ethoxy-2,3-difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran (11) ¹ H-NMR, ¹⁹ F-NMR, ¹³ The results of C-NMR and GCEIMS were the same as in Experimental Example 15.

Experimental Example 21 [Regarding Step 6 (VII)]
In Experimental Example 21, the reaction represented by the following reaction formula was performed.

Under an argon atmosphere, (2R ^* , 3S ^* , 5R ^* )-3-chloro-5- (4-ethoxy-2,3-difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran (6) ( To a tetrahydrofuran solution (1.0 mL) containing 26.1 mg, 0.0653 mmol) and cobalt (II) chloride (additive) (8.4 mg, 0.065 mmol), aluminium lithium hydride (reducing agent) (4. 9 mg, 0.13 mmol) was added, and the mixture was stirred at room temperature for 26 hours.
The reaction mixture was allowed to cool, 10% aqueous sodium hydroxide solution (3.0 mL) and chloroform (2.0 mL) were added, and the mixture was stirred at room temperature for 10 min, extracted with chloroform (3.0 mL × 3), and the organic layer was extracted. Obtained. The obtained organic layers were combined, and the organic layer was washed with water (2.0 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give an oil. The obtained oil was purified by preparative thin phase chromatography [silica gel plate (250 mm × 250 mm × 0.50 mm), hexane-ethyl acetate (20: 1)], and (2R ^* , 5R ^* )-5- (4-ethoxy- 2,3-difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran (11) (9.5 mg, 36% yield) was obtained as a white solid.

(2R ^* , 5R ^* )-5- (4-ethoxy-2,3-difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran (11) ¹ H-NMR, ¹⁹ F-NMR, ¹³ The results of C-NMR and GCEIMS were the same as in Experimental Example 15.

Experimental Example 22 [Regarding Step 6 (VIII)]
In Experimental Example 22, the reaction represented by the following reaction formula was performed.

(2R ^* , 3S ^* , 5R ^* )-3-bromo-5- (4-ethoxy-2,3-difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran at 100 ° C. under argon atmosphere A dimethyl sulfoxide solution (1.0 mL) containing (6) (44.5 mg, 0.100 mmol) and sodium borohydride (reducing agent) (19.0 mg, 0.502 mmol) was stirred for 17 hours.
The reaction mixture was allowed to cool, saturated aqueous ammonium chloride solution (2.0 mL) was added, the mixture was stirred at room temperature for 10 min, and extracted with ethyl acetate (3.0 mL × 3) to obtain an organic layer. The obtained organic layers were combined, and the organic layer was washed with water (2.0 mL) and saturated brine (2.0 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give an oil. The obtained oil was purified by preparative thin phase chromatography [silica gel plate (250 mm × 250 mm × 0.50 mm), hexane-ethyl acetate (20: 1)], and (2R ^* , 5R ^* )-5- (4-ethoxy- 2,3-Difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran (11) (24.3 mg, 66% yield) was obtained as a white solid.

(2R ^* , 5R ^* )-5- (4-ethoxy-2,3-difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran (11) ¹ H-NMR, ¹⁹ F-NMR, ¹³ The results of C-NMR and GCEIMS were the same as in Experimental Example 15.

Experimental Example 23 [Regarding Step 7 (I)]
In Experimental Example 23, the reaction represented by the following reaction formula was performed.

Methanesulfonic acid (2R ^* , 3S ^* , 5R ^* )-5- (4-ethoxy-2,3-difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran- at 100 ° C. under argon atmosphere A solution of N, N-dimethylformamide (0.50 mL) containing 3-yl (6) (46.0 mg, 0.100 mmol) and lithium chloride (deHXing agent) (21.2 mg, 0.500 mmol) for 25 hours Stir.
The reaction mixture was allowed to cool, water (2.0 mL) was added, and the mixture was extracted with ethyl acetate (2.0 mL × 3) to obtain an organic layer. The obtained organic layers were combined, and the organic layer was washed with water (2.0 mL) and saturated brine (2.0 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give an oil. The obtained oil was purified by preparative thin phase chromatography [silica gel plate (250 mm × 250 mm × 0.50 mm), hexane-ethyl acetate (20: 1)], and (2R ^* , 5R ^* )-5- (4-ethoxy- 2,3-Difluorophenyl) -2- (trans-4-propylcyclohexyl) -5,6-dihydro-2H-pyran (10) (23.6 mg, 65% yield) was obtained as a white solid.

¹ H- of (2R ^* , 5R ^* )-5- (4-ethoxy-2,3-difluorophenyl) -2- (trans-4-propylcyclohexyl) -5,6-dihydro-2H-pyran (10) The results of NMR, ¹⁹ F-NMR and GCEIMS are shown below.

¹ H-NMR (250 MHz, CDCl ₃ ) δ 6.83 (ddd, J = 9.8, 7.8, 2.3 Hz, 1H), 6.68 (ddd, J = 9.0, 7.8, 1 .8 Hz, 1H), 5.90 (brd, J = 10.8 Hz, 1H), 5.82 (brd, J = 10.8 Hz, 1H), 4.11 (m, 1H), 4.09 (q , J = 7.0 Hz, 2H), 3.95 (m, 1H), 3.88 (m, 1H), 3.40 (dd, J = 10.8, 9.0 Hz, 1H), 1.89 -1.72 (m, 4H), 1.58-1.02 (m, 7H), 1.44 (t, J = 7.0 Hz, 3H), 0.99-0.75 (m, 3H) , 0.87 (t, J = 7.0 Hz, 3H).

¹⁹ F-NMR (235 MHz, CDCl ₃ ) δ-143.2 (d, J = 19 Hz, 1F), -159.4 (d, J = 19 Hz, 1F).

  GCEIMS (relative intensity) m / Z41 (13), 55 (18), 69 (20), 83 (10), 143 (64), 171 (100), 184 (25), 334 (11), 364 (M , 2).

Experimental Example 24 [Regarding Step 7 (II)]
In Experimental Example 24, the reaction represented by the following reaction formula was performed.

Toluenesulfonic acid (2R ^* , 3S ^* , 5R ^* )-5- (4-ethoxy-2,3-difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran- Toluene containing 3-yl (6) (53.6 mg, 0.100 mmol) and 1,5-diazabicyclo [4.3.0] non-5-ene (deHXing agent) (33.0 mg, 0.266 mmol) The solution (1.0 mL) was stirred for 68 hours.
The reaction mixture was allowed to cool, saturated aqueous ammonium chloride solution (2.0 mL) was added, and the mixture was extracted with ethyl acetate (3.0 mL × 3) to obtain an organic layer. The obtained organic layers were combined, and the organic layer was washed with water (2.0 mL) and saturated brine (2.0 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give an oil. The obtained oil was purified by medium pressure column chromatography [silica gel (28 g), hexane-ethyl acetate (5: 1)], and (2R ^* , 5R ^* )-5- (4-ethoxy-2,3- Difluorophenyl) -2- (trans-4-propylcyclohexyl) -5,6-dihydro-2H-pyran (10) (26.7 mg, 73% yield) was obtained as a white solid.

¹ H- of (2R ^* , 5R ^* )-5- (4-ethoxy-2,3-difluorophenyl) -2- (trans-4-propylcyclohexyl) -5,6-dihydro-2H-pyran (10) The results of NMR, ¹⁹ F-NMR and GCEIMS were the same as in Experimental Example 23.

Experimental Example 25 [About Step 8]
In Experimental Example 25, the reaction represented by the following reaction formula was performed.

(2R ^* , 5R ^* )-5- (4-ethoxy-2,3-difluorophenyl) -2- (trans-4-propylcyclohexyl) -5,6-dihydro-2H-pyran at room temperature under hydrogen atmosphere An ethyl acetate solution (1.0 mL) containing (10) (22.4 mg, 0.0615 mmol) and 10 wt% Pd / C (metal catalyst) (2.2 mg) was stirred for 16 hours.
The reaction mixture was filtered and concentrated under reduced pressure to give an oil. The obtained oil was purified by preparative thin-phase chromatography [silica gel plate (250 mm × 250 mm × 0.50 mm), hexane-ethyl acetate (20: 1)] to give (2R ^* , 5R ^* )-5- (4- Ethoxy-2,3-difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran (11) (17.2 mg, 76% yield) was obtained as a white solid.

(2R ^* , 5R ^* )-5- (4-ethoxy-2,3-difluorophenyl) -2- (trans-4-propylcyclohexyl) tetrahydropyran (11) ¹ H-NMR, ¹⁹ F-NMR, ¹³ The results of C-NMR and GCEIMS were the same as in Experimental Example 15.

  The novel 2,3,5-trisubstituted tetrahydropyran derivative (6) of the present invention can be used for the production of a 2,5-disubstituted tetrahydropyran derivative (11) useful as a liquid crystal composition.

Claims (22)

General formula (6)
(Wherein R ¹ represents an alkyl group having 1 to 10 carbon atoms which may be substituted with a halogen atom or an alkoxy group having 1 to 4 carbon atoms; an alkyl group having 1 to 10 carbon atoms, or an alkyl group having 1 to 10 carbon atoms) A haloalkyl group, an alkenyl group having 2 to 10 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms which may be substituted with a halogen atom; an alkenyl group having 2 to 10 carbon atoms which may be substituted with a halogen atom; An alkynyl group having 2 to 8 carbon atoms which may be substituted by an atom; or an alkyl group having 1 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, a halogen atom or carbon .R ³ is of substituted halogen atoms or C 1 -C 4 alkoxy group represented by which may be a phenyl group substituted with C 1 4 alkoxy groups An optionally substituted alkyl group having 1 to 10 carbon atoms; an alkyl group having 1 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, or a carbon atom optionally substituted with a halogen atom A cycloalkyl group having 3 to 8 carbon atoms; an alkenyl group having 2 to 10 carbon atoms which may be substituted with a halogen atom; an alkynyl group having 2 to 8 carbon atoms which may be substituted with a halogen atom; a halogen atom or carbon number An alkoxy group having 1 to 4 carbon atoms which may be substituted with an alkoxy group having 1 to 4; an acyloxy group having 1 to 6 carbon atoms which may be substituted with a halogen atom; a halogen atom; an alkyl having 1 to 10 carbon atoms Substituted with a group, a haloalkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, a halogen atom or an alkoxy group having 1 to 4 carbon atoms Optionally substituted phenyl group; or substituted with an alkyl group having 1 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, a halogen atom, or an alkoxy group having 1 to 4 carbon atoms And m represents an integer of 1 to 4, and when m is 2 to 4, a plurality of R ³ may be the same or different, X is a halogen atom; An acyloxy group having 1 to 6 carbon atoms which may be substituted with a halogen atom or a phenyl group; an alkylsulfonyloxy group having 1 to 6 carbon atoms which may be substituted with a halogen atom; or Represents an alkyl group, a haloalkyl group having 1 to 10 carbon atoms, or a phenylsulfonyloxy group which may be substituted with a halogen atom.) 2,3,5-trisubstituted Tetrahydropyran derivative. The 2,3,5-trisubstituted tetrahydropyran derivative according to claim 1, wherein R ¹ is a cycloalkyl group having 3 to 8 carbon atoms which may be substituted with an alkyl group having 1 to 10 carbon atoms. The 2,3,5-trisubstituted tetrahydropyran derivative according to claim 1, wherein R ¹ is a cyclohexyl group which may be substituted with an alkyl group having 1 to 10 carbon atoms. The 2,3,5-trisubstituted tetrahydropyran derivative according to claim 1, wherein R ¹ is a 4-propylcyclohexyl group.   The 2,3,5-trisubstituted tetrahydropyran derivative according to any one of claims 1 to 4, wherein X is a chlorine atom, a bromine atom, a p-toluenesulfonyloxy group or a methanesulfonyloxy group. General formula (6) is the following general formula (6a)
(In the formula, R ¹ and X represent the same meaning as described above. R ^3-1 and R ^3-2 each independently represent a hydrogen atom or a fluorine atom, and R ^3-3 represents an alkoxy group having 1 to 4 carbon atoms. The 2,3,5-trisubstituted tetrahydropyran derivative according to any one of claims 1 to 5. General formula (6a) is the following general formula (6b)
(Wherein R ¹ , R ^3-3 and X represent the same meaning as described above), 2,3,5-trisubstituted tetrahydropyran derivative according to claim 6. General formula (6b) is the following general formula (6c)
(Wherein R ¹ and X represent the same meaning as described above), 2,3,5-trisubstituted tetrahydropyran derivative according to claim 7. General formula (4)
(Wherein R ¹ represents an alkyl group having 1 to 10 carbon atoms which may be substituted with a halogen atom or an alkoxy group having 1 to 4 carbon atoms; an alkyl group having 1 to 10 carbon atoms, or an alkyl group having 1 to 10 carbon atoms) A haloalkyl group, an alkenyl group having 2 to 10 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms which may be substituted with a halogen atom; an alkenyl group having 2 to 10 carbon atoms which may be substituted with a halogen atom; An alkynyl group having 2 to 8 carbon atoms which may be substituted by an atom; or an alkyl group having 1 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, a halogen atom or carbon .R ³ is of substituted halogen atoms or C 1 -C 4 alkoxy group represented by which may be a phenyl group substituted with C 1 4 alkoxy groups An optionally substituted alkyl group having 1 to 10 carbon atoms; an alkyl group having 1 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, or a carbon atom optionally substituted with a halogen atom A cycloalkyl group having 3 to 8 carbon atoms; an alkenyl group having 2 to 10 carbon atoms which may be substituted with a halogen atom; an alkynyl group having 2 to 8 carbon atoms which may be substituted with a halogen atom; a halogen atom or carbon number An alkoxy group having 1 to 4 carbon atoms which may be substituted with an alkoxy group having 1 to 4; an acyloxy group having 1 to 6 carbon atoms which may be substituted with a halogen atom; a halogen atom; an alkyl having 1 to 10 carbon atoms Substituted with a group, a haloalkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, a halogen atom or an alkoxy group having 1 to 4 carbon atoms Optionally substituted phenyl group; or substituted with an alkyl group having 1 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, a halogen atom, or an alkoxy group having 1 to 4 carbon atoms And m represents an integer of 1 to 4, and when m is 2 to 4, a plurality of R ³ may be the same or different, L is a halogen atom; An acyloxy group having 1 to 6 carbon atoms which may be substituted with a halogen atom or a phenyl group; an alkylsulfonyloxy group having 1 to 6 carbon atoms which may be substituted with a halogen atom; or An alkyl group, a haloalkyl group having 1 to 10 carbon atoms, or a phenylsulfonyloxy group optionally substituted with a halogen atom.) The reaction is carried out in the presence of Bronsted acid or Lewis acid, and the general formula (6)
(Wherein R ¹ , R ³ and m represent the same meaning as described above. X represents a halogen atom; a hydroxyl group; an acyloxy group having 1 to 6 carbon atoms which may be substituted with a halogen atom or a phenyl group; a halogen atom. Or an alkylsulfonyloxy group having 1 to 6 carbon atoms which may be substituted with a phenylsulfonyloxy group which may be substituted with an alkyl group having 1 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms or a halogen atom A method for producing a 2,3,5-trisubstituted tetrahydropyran derivative represented by: The method for producing a 2,3,5-trisubstituted tetrahydropyran derivative according to claim 9, wherein R ¹ is a cycloalkyl group having 3 to 8 carbon atoms which may be substituted with an alkyl group having 1 to 10 carbon atoms. . The method for producing a 2,3,5-trisubstituted tetrahydropyran derivative according to claim 9, wherein R ¹ is a cyclohexyl group which may be substituted with an alkyl group having 1 to 10 carbon atoms. The method for producing a 2,3,5-trisubstituted tetrahydropyran derivative according to claim 9, wherein R ¹ is a 4-propylcyclohexyl group.   The method for producing a 2,3,5-trisubstituted tetrahydropyran derivative according to any one of claims 9 to 12, wherein X is a chlorine atom, a bromine atom, a p-toluenesulfonyloxy group or a methanesulfonyloxy group. General formula (4) is the following general formula (4c)
(Wherein R ¹ and L represent the same meaning as described above, R ^3-1 and R ^3-2 each independently represent a hydrogen atom or a fluorine atom, and R ^3-3 represents an alkoxy group having 1 to 4 carbon atoms. General formula (6) is represented by the following general formula (6a)
(Wherein, R ¹ , R ^3-1 , R ^3-2 , R ^3-3 and X have the same meaning as described above), 2, 3, 5 according to any one of claims 9 to 13 -Method for producing a tri-substituted tetrahydropyran derivative. General formula (4c) is the following general formula (4d)
(Wherein R ¹ , R ^3-3 and L represent the same meaning as described above), and the general formula (6a) is represented by the following general formula (6b)
(Wherein R ¹ , R ^3-3 and X represent the same meaning as described above). The method for producing a 2,3,5-trisubstituted tetrahydropyran derivative according to claim 14. General formula (4d) is represented by the following general formula (4e)
(Wherein R ¹ and L represent the same meaning as described above), and general formula (6b) is represented by the following general formula (6c)
(Wherein R ¹ and X represent the same meaning as described above). The method for producing a 2,3,5-trisubstituted tetrahydropyran derivative according to claim 15.   The 2,3,5-trisubstituted according to any one of claims 9 to 16, wherein the Bronsted acid is acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, benzenesulfonic acid, trifluoromethanesulfonic acid or methanesulfonic acid. A method for producing a tetrahydropyran derivative.   The method for producing a 2,3,5-trisubstituted tetrahydropyran derivative according to any one of claims 9 to 16, wherein the Lewis acid is boron trifluoride-diethyl ether complex, aluminum chloride or bismuth tribromide.   The method for producing a 2,3,5-trisubstituted tetrahydropyran derivative according to any one of claims 9 to 16, wherein L is a hydroxyl group, Bronsted acid is methanesulfonic acid, and X is a methanesulfonyloxy group.   The production of a 2,3,5-trisubstituted tetrahydropyran derivative according to any one of claims 9 to 16, wherein L is a hydroxyl group, the Bronsted acid is p-toluenesulfonic acid, and X is a p-toluenesulfonyloxy group. Method.   The method for producing a 2,3,5-trisubstituted tetrahydropyran derivative according to any one of claims 9 to 16, wherein L is a hydroxyl group, the Lewis acid is aluminum chloride, and X is a chlorine atom.   The process for producing a 2,3,5-trisubstituted tetrahydropyran derivative according to any one of claims 9 to 16, wherein L is a hydroxyl group or bromine atom, the Lewis acid is bismuth tribromide, and X is a bromine atom.