WO2006001326A1 - Method for producing n-carbonyl saturated heterocyclic rings and synthetic intermediate thereof - Google Patents

Abstract

Disclosed is a novel method for producing N-carbonyl saturated heterocyclic rings. Also disclosed are an intermediate thereof, a method for producing such an intermediate, and use of the N-carbonyl saturated heterocyclic rings. Specifically disclosed is a method expressed by the following reaction scheme. (R1: H, an alkoxy, optionally substituted phenyl or the like, R2: a halogen-substituted phenyl, R3: H, OH or the like, G1: an alkylene, G2: a single bond or CH2, G3: an alkylene or the like, X: OH or the like, Y: a leaving group).

Description

 Process for producing N-carbonyl saturated heterocycles and synthetic intermediates thereof Technical Field X 1

 ---X C F

 [0001] The present invention relates to a novel process for producing a N I> -carbo saturated heterocyclic ring,

 X = X 2

 2 F =

 Provided are novel compounds for the production of nil-saturated heterocycles, methods for their production and use.

 Background art

[0002] N-carbonyl saturated heterocycles are useful as intermediates for the production of neurocun antagonists (see Patent Document 1). When synthesizing by ring closure by nuclear substitution reaction, after N-alkyl or N-sulfonyl-protected chain compound ring-closing reaction, N-alkyl or sulfonyl group is deprotected, and then nitrogen atom is carbo-cyclic. It was necessary to hesitate (Non-Patent Documents 1, 2 and 3).

 [0003] For this reason, this method has not been suitable as a method for producing an industrial N-carbo saturated heterocyclic ring having a large number of steps.

[0004] Another method is, for example, by Mitsunobu reaction using jetyl azodicarboxylate (DEAD) and triphenylphosphine (Ph P) to produce N-tert-butoxycarbol-chain dithio

 Three

 A method of synthesizing a corresponding N-carbonyl saturated heterocyclic ring from the above-mentioned (reaction formula below) is known (see Non-Patent Document 4 and Non-Patent Document 5).

 [0005]

 H

H

[0006] (In the above formula, TBDMS is tert-butyldimethylsilyl, Boc is tert-ptoxyca It is a report. )

 However, in this method, ketyl hydrazine dicarboxylate and triphenylphosphine oxide are produced as by-products, which interfere with the separation and purification of the target product, and thus are industrial N-carbohydrate. Not suitable for the production of saturated heterocycles o

 Patent Document 1: US Patent No. 6511975 Specification

 Non-Patent Document 1: Y. Jinbo et al, J. Med. Chem., 37, 2791 (1994)

 Non-Patent Document 2: G. Bettoni, et al "Tetrahedron, 36, 409 (1980)

 Non-Patent Document 3: R. A. Firestone, et al "J. Med. Chem., 27, 1037 (1984)

 Non-Patent Document 4: T. Nishi et al., Tetrahedron: Asymmetry, 9, 3251 (1998)

 Non-Patent Document 5: T. Nishi et al "Bioorg. Med. Chem. Lett., 10, 1665 (2000) Disclosure of the Invention

 Problems to be solved by the invention

[0007] As a result of intensive studies aimed at solving these problems and establishing a novel method for producing N-carbonyl saturated heterocycles, the present inventors have found that the following general formulas (1), (2 By scrutinizing the reaction conditions via the compounds of (4) and (4), it was found that N-force sulfonyl saturated heterocycles, which were difficult to synthesize in the past, were obtained in industrially high yields. Was completed.

 Means for solving the problem

[0008] The present invention provides:

 (1) The following general formula (1)

[0009] [Chemical 2]

(In the formula, R ¹ is a hydrogen atom, a C—C alkoxy group, or a substituent group j8.

 14

C — C aralkyloxy group or substituent group which may be substituted with one group R 1 represents a phenyl group which may be substituted with 1 to 3 selected groups, R ² represents a phenyl group substituted with 1 or 2 halogen atoms, and R ³ represents hydrogen. Atom, hydroxyl group, protected hydroxyl group, C—C haloalkanesulfo-loxy group, C—C alkanesulfo-luo group

 1 4 1 4 Xyl group, or substituent group j8 force optionally substituted by 1 to 3 selected groups C −

6

C represents a arylaryloxy group, G ¹ represents a C — C alkylene group, and G ² represents

10 1 6

A single bond or a methylene group, G ³ is a C — C alkylene group, a C — C alkenylene group

 2 3 2 3

 Or a C—C alkynylene group, the substituent group is a hydroxyl group, a C—C alkoxy group,

2 3 1 4

C—C represents a group that is also a halogenated alkyl group and tetrazolylca, and substituent group j8 is

14

 Tro group, halogen atom, c-c alkyl group and c-c halogenated alkyl group

 1 4 1 4

 A compound having the following general formula (2):

 [0011] [Chemical 3]

[0012]

Moreover, it shows the same meaning as above, and Υ represents a leaving group. ), And then treating the compound having the general formula (2) with a base to give the following general formula (3)

 [0013] [Chemical 4]

[0014] (where

G ² and G ³ are as defined above. ).

 Among the above, the preferred method is

 (2) is a C—C alkoxy group or a substituent group α force is selected from 1 to 3 groups selected

 14

 The way it is!

(3) the method wherein R ¹ is substituted with ¹ to 3 groups in which substituent group a force is also selected and may be a phenol group; (4) The method wherein R ² is a phenyl group substituted with 1 or 2 fluorine atoms or chlorine atoms

(5) One in which R ³ is a hydroxyl group or a protected hydroxyl group, and G ³ is a C 1 -C alkylene group

 twenty three

 Law,

(6) R ³ may be substituted with 1 to 3 groups selected from the substituent group j8 force C— C

6 1 is a arylsulfonyloxy group, and G ³ is a C 1 -C alkylene group,

 0 2 3

(7) the method wherein R ³ is a hydrogen atom and G ³ is a bur group;

(S) the method wherein G ¹ is methylene or ethylene,

(^ The method where G ¹ is ethylene,

(10) the method wherein G ² is a single bond,

(11) the method wherein G ³ is ethylene, and

 (12) The method wherein Y is black-opened benzenesulfoloxy

 It is.

 Furthermore, the present invention provides

 (13) The following general formula (4)

[0015] [Chemical 5]

(Four)

(Wherein R ² represents a phenyl group substituted with 1 or 2 halogen atoms, R ³ represents a hydrogen atom, a hydroxyl group, a protected hydroxyl group, a CC haloalkanesulfonyloxy group, C

 1 4 1

1 to 3 groups selected from C alkanesulfo-loxy group or substituent group | 8 groups

Four

Represents an optionally substituted C—C arylsulfonyloxy group, and G ¹ represents a C—C

6 10 1 6 represents a alkylene group, G ³ represents a C—C alkylene group, a C—C alkenylene group or a C—C

 2 3 2 3 2 3 Indicates an alkynylene group, and the substituent group j8 includes a nitro group, a halogen atom, and a C—C alkyl group.

 14

 And a group consisting of a C C halogenated alkyl group. Or a salt thereof

14

 And the following general formula (5)

[0017] [Chemical 6]

[In the formula, R ¹ is a hydrogen atom, a C 1 -C alkoxy group, a substituent group β force selected 1 to 3

 14

 C — C aralkyloxy group or substituent group which may be substituted with one group

 7 11

A phenyl group which may be substituted with 1 to 3 selected groups, G ² represents a single bond or a methylene group, X represents a hydroxyl group, a C—C alkyl carboxy-oxy group, C —C

 1 4 1 4 represents a alkoxycarbonyl-oxy group or a halogen atom, and the substituent group a represents a group consisting of a hydroxyl group, a C 1 -C alkoxy group, a C—C halogenated alkyl group, and a tetrazolyl group.

4 1 4

 . ) In the presence of a base and the following general formula (1)

[0019] [Chemical 7]

[0020]

G ³ has the same meaning as described above. ) And a compound having the general formula (1) is represented by the following general formula (2)

[0021] [Chemical 8]

[0022]

Moreover, it shows the same meaning as above, and Υ represents a leaving group. ), And then treating the compound having the general formula (2) with a base to give the following general formula (3)

[0023] [Chemical 9]

[0024] (where

G ² and G ³ are as defined above. ). Among the above, the preferred method is

(14) R ¹ is a C—C alkoxy group or a substituent group α force of 1 to 3 groups selected

 14

 A substituted, which may be a full group,

 (15) is a phenyl group which may be substituted with 1 to 3 groups, the substituent group α force of which is also selected,

(16) The method wherein R ² is a phenyl group substituted with 1 or 2 fluorine atoms or chlorine atoms,

(17) R ³ is a hydroxyl group or a protected hydroxyl group, and G ³ is a C—C alkylene group

 twenty three

 Method,

(18) R ³ may be substituted with 1 to 3 groups, the substituent group j8 of which is also selected C-

6

A method wherein C ³ arylsulfonyloxy group and G ³ is a CC alkylene group,

10 2 3

(19) R ³ force is a hydrogen atom, and G ³ is a bur group,

(20) the method wherein G ¹ is methylene or ethylene,

(21) The method wherein G ¹ is ethylene,

(22) the method wherein G ² is a single bond,

(23) The method wherein G ³ is ethylene,

 (24) the method wherein X is a chlorine atom or a bromine atom, and

 (25) The method wherein Y is black-opened benzenesulfoloxy

 It is.

 Furthermore, the present invention provides

 (26) The following general formula (4)

[0025] [Chemical 10]

(Wherein R ² represents a phenyl group substituted with I or two halogen atoms, R ³ represents a hydroxyl group, a C—C haloalkane sulfo-loxy group, or a C—C alkane. Sulfo-Luoxy group

I 4 I 4

Or a group of substituents j8 force C—C which may be substituted with 1 to 3 selected groups Reel sulfo-loxy group, G ¹ represents C—C alkylene group, G ³ represents C—C

 1 6 2 3 represents an alkylene group, and the substituent group j8 includes a nitro group, a halogen atom, a C—C alkyl group, and

 14

 A compound having a C-halogen alkyl group) or a salt thereof.

14

 To do.

 Among the above, preferred compounds are

(27) Compound in which R ² is a phenyl group substituted with 1 or 2 fluorine atoms or chlorine atoms,

(28) the compound wherein R ³ is a hydroxyl group,

(29) the compound wherein G ¹ is methylene or ethylene,

(30) the compound wherein G ¹ is ethylene,

(31) the compound wherein G ³ is ethylene, and

 (32) —General formula (4) is replaced by the following general formula (4 ')

[0027] [Chemical 11]

 [0028] is a compound

 And salts thereof (preferably hydrochloride, sulfate or oxalate).

 Among the above, particularly suitable compounds are

(33) A compound wherein R ² is a phenyl group substituted with 1 or 2 fluorine atoms or chlorine atoms, R 3 is a hydroxyl group, G ¹ is ethylene, and G ³ is ethylene Or its hydrochloride, sulfate or oxalate

 It is.

 Furthermore, the present invention provides

 (34) The following general formula (1)

[0029] [Chemical 12]

(Wherein R ¹ represents a hydrogen atom or a phenyl group which may be substituted with 1 to 3 groups of which substituent group α force is also selected, and R ² represents 1 or 2 Represents a phenyl group substituted with one halogen atom, R ³ represents a hydroxyl group, a protected hydroxyl group, a C —C haloalkanesulfo-luo

 14

 Selected from the group consisting of a xyl group, a C—C alkanesulfo-loxy group, or a substituent group j8

 14

Represents a C — C arylsulfonyloxy group optionally substituted with up to 3 groups, G ¹

 6 10

Represents a C — C alkylene group, G ² represents a single bond or a methylene group, and G ³ represents C — C

1 6 2 3 represents an alkylene group, a C—C alkenylene group or a C—C alkynylene group, a substituent group

 2 3 2 3

 a is a hydroxyl group, a C C alkoxy group, a C C halogenated alkyl group and tetrazolyl

 1 4 1 4

 The substituent group j8 includes a nitro group, a halogen atom, a C—C alkyl group and

 14

 c represents a group consisting of C halogenated alkyl groups. )

 14

 About.

 Among the above, preferred compounds are

 (35) is a C—C alkoxy group or a substituent group α force of 1 to 3 groups selected

 14

 A compound which is substituted or may be a full group,

(36) the compound wherein R ¹ is a phenyl group substituted with 1 to 3 groups selected from the substituent group a force,

(37) Compound in which R ² is a phenyl group substituted with 1 or 2 fluorine atoms or chlorine atoms,

(38) A compound wherein R ³ is a hydroxyl group or a protected hydroxyl group,

(39) A compound wherein G ¹ is methylene or ethylene,

(40) the compound wherein G ¹ is ethylene,

(41) The compound wherein G ² is a single bond,

(42) the compound wherein G ³ is ethylene, and

 (43) —General formula (1) is replaced by the following general formula (1 ′)

[0031] [Chemical 13]

 [0032] is a compound

 It is.

 Among the above, particularly suitable compounds are

(44) R ¹ is substituted with 1 to 3 groups selected from the substituent group a force, but is a phenol group, and R ² is 1 or 2 fluorine atoms or chlorine A compound in which a phenyl group substituted with an atom, R ³ is a hydroxyl group or a protected hydroxyl group, G ¹ is ethylene, G ² is a single bond, and G ³ is ethylene

 It is.

 Furthermore, the present invention provides

 (45) General formula (5) characterized by substantially including the following process A, process B, and process C forces

 [0033] [Chemical 14]

(Wherein R ¹ is selected from a hydrogen atom, a C 1 -C alkoxy group, and a substituent group β 1 to 3

 14

 C — C aralkyloxy group or substituent group which may be substituted with one group

 7 11

R 1 represents a phenyl group optionally substituted with 1 to 3 selected groups, R ² represents a phenyl group substituted with 1 or 2 halogen atoms, and G ¹ represents C ¹ — Represents a C alkylene group,

 1 6

G ² represents a single bond or a methylene group, G ³ represents a C—C alkylene group, and G ⁴ represents> C

 twenty three

 — OH or> S → 0, the substituent group α is a hydroxyl group, C — C alkoxy group, C — C

 1 4 1 4 represents a group consisting of an alkyl group, a rogynyl alkyl group and a tetrazolyl group.

 1 4 1 4

Show. Or a pharmacologically acceptable salt thereof: {Here, the process A is represented by the general formula (1)

[0035] [Chemical 15]

[0036]

[Wherein G ² and G ³ are as defined above, and R ³ represents a hydroxyl group, a protected hydroxyl group, a C—C haloalkanesulfo-loxy group, a C—C alkanesulfo-loxy group.

1 4 1 4

 Group or substituent group j8 force C 1 -C optionally substituted by 1 to 3 groups selected

 6 10 represents an arylsulfonyloxy group, and the substituent group j8 represents a group consisting of a nitro group, a halogen atom, a C 1 -C alkyl group, and a C C halogenated alkyl group. ]

 4 1 4

 A compound having the general formula (2)

[0037] [Chemical 16]

[0038]

[Wherein R ¹ G ² and G ³ are as defined above, and R ³ and Y are a CC haloalkane sulfo-loxy group, a C—C alkane sulfo-loxy group, or

4 1 4

 Substituent group j8 may also be substituted with one to three selected groups C—C aryls

 6 10 represents a sulfonyloxy group, the substituent group j8 is a nitro group, a halogen atom, a C 1 -C alkyl

 A group consisting of 14 groups and a C C halogenated alkyl group is shown. Is converted to a compound having

 14

 Process,

 In the process B, the compound (2) obtained in the process A is treated with a base to give a general formula (3) [0039] [Chemical Formula 17]

[0040] Rocananth

Selected from ru-loxy group, CC alkane sulfo-loxy group, or substituent group j8 A C 1 -C arylsulfoloxy group which may be substituted with 1 to 3 groups

 6 10

 The substituent group j8 is a nitro group, a halogen atom, a C—C alkyl group and a C—C halo.

 1 4 1 4 Indicates a group that also has geny alkyl group power. In which the compound (3) obtained in Step B and the general formula (6)

[0041] [Chemical 18]

[Wherein G ⁴ is as defined above. And a compound having the general formula (5) to produce a compound having the general formula (5). }

 Among the above, the preferred method is

 (46) is a C—C alkoxy group or a substituent group α force of 1 to 3 groups selected

 14

 A substituted, which may be a full group,

(47) The method wherein R ¹ is a phenyl group substituted with 1 to 3 groups selected from the substituent group a force,

(48) The method wherein R ² is a phenyl group substituted with one or two fluorine atoms or chlorine atoms,

(49) The method wherein R ^{3 in} compound (1) is a hydroxyl group or a protected hydroxyl group,

(50) the method wherein G ¹ is methylene or ethylene,

(51) The method wherein G ¹ is ethylene,

(52) The method wherein G ² is a single bond,

(53) The method wherein G ³ is ethylene, and

(54) A method in which R ³ and Y of compound (2) and compound (3) are black benzenesulfuroxy

 It is.

 “C—C alkoxy group”, “substituent group j8 or

 14

A C—C aralkyloxy group optionally substituted with 1 to 3 groups selected from Substituent group a may also be substituted with 1 to 3 groups which may also be selected, such as a “phenol group”, “a phenyl group substituted with 1 or 2 halogen atoms”, “protected” Hydroxyl group ”,“ C — C

 1 4 Alkanesulfonyloxy group ”,“ C —C haloalkanesulfonyloxy group ”,“ Substitution ”

 14

 Group j8 may also be substituted with 1 to 3 groups optionally selected C — C arylsul

 6 10

 “Honyloxy group”, “c-C alkylene group”, “C-C alkylene group”, “C-C alkylene”

 1 6 2 3 2 3 Diylene group, c-C alkynylene group, C-C halogenated alkyl group, halogen

 2 3 1 4

 "Atom", "C C alkyl group", "Leaving group", "C C alkylcarbonyloxy group" and

 1 4 1 4

 And the term `` C C alkoxycarbonyloxy group '' is defined as follows:

14

 The

[0043] "C 1 -C alkoxy group" in the definition of R ¹ and substituent group a is, for example, methoxy,

 14

Toxyl, propoxy, isopropoxy, butoxy, isobutoxy or tert-butoxy can be used. R ¹ is preferably ethoxy or tert-butoxy, and the substituent group a is preferably a C—C alkoxy group ( More preferably, it is methoxy or isopropoxy)

 13

[0044] In the definition of R ¹ "the C — C aralkyloxy group which may be substituted with 1 to 3 groups selected from the substituent group β," the aryl moiety is selected as the substituent group j8 force. 1

7 11

 C C aryl (preferably phenyl) optionally substituted by 3 groups,

 6 10

 The alkoxy moiety is c-C alkoxy (preferably methoxy, ethoxy or propoxy

 14

 And is particularly preferably methoxy), preferably benzyloxy optionally substituted with 1 to 3 groups selected from the substituent group β. Is benzyloxy or -trobenzyloxy, most preferably benzyloxy.

[0045] The "substituent group α force forceful phenyl group optionally substituted by 1 to 3 groups" in the definition of R ¹ is preferably a phenyl, 3-isopropoxyphenol- 3, 4, 5-trimethoxyphenyl or 3,5-bis (trifluoromethyl) phenol, particularly preferably 3, 4, 5-trimethoxyphenyl or 3,5— Bis (trifluoromethyl) file is most preferable, and 3, 4, 5-trimethoxy file is most preferable.

[0046] Substituent group "Norogen atom" in the definition of β and X, and "1" in the definition of R ² Alternatively, the halogen atom in the “phenyl group substituted with two halogen atoms” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. As the substituent group 8), a fluorine atom, a chlorine atom or a bromine atom is preferable, and a chlorine atom is more preferable. As X, a chlorine atom, a bromine atom or an iodine atom is preferable, and a chlorine atom is particularly preferable.

[0047] The "phenyl group substituted with 1 or 2 halogen atoms" in the definition of R ² is preferably a phenyl group substituted with 1 or 2 fluorine atoms or chlorine atoms. More preferably 4-fluorophenyl, 4-chlorophenyl, 3,4-difluorophenyl or 3,4-dicyclophenyl, and even more preferably 3,4-difluorophenyl or 3 , 4-dichlorophenol, particularly preferably 3,4-dichloromethane.

[0048] "Protected hydroxyl group" in the definition of R ³ is a hydroxyl group generally protected with a protecting group for a hydroxyl group in the field of synthetic organic chemistry, such as tert-butyl, 1, C-C branched chain alkyl groups such as 1-dimethylpropyl, 1,1,2-trimethylpropyl or 1,1-dimethylbutyl; C such as aryl or 1-methyl-2-probe

3 6 3

—C straight chain or branched 2-alkenyl group; formyl, acetyl, propionyl, buty

6

 Ril, isobutyryl, bivaloyl, valeryl, isovaleryl, otatanyl, nonanoyl, decanol, 3-methylnonanoyl, 8-methylnonanoyl, 3-ethylotatanyl, 3, 7-dimethyloctanoyl, undecanol, dodecanol, tridecanol, tridecanol, tridecanol , Pentadecanol, hexadecanol, 1-methylpentadecanol, 14-methylpentadecanol, 13,13 dimethyltetradecanol, heptadecanol, 15-methylhexadecanol, octadecanol, 1-methylheptadecanol, nonadecanol, or nonadecanol, C-C alkanoyl groups such as henecosanol; chloroacetyl, di

 1 21

 C-C halogeno such as chloroacetyl, trichloroacetyl or trifluoroacetyl

 2 4 Alkanoyl group; C—C alkoxy such as methoxyacetyl C—C alkanoyl group;

 1 4 2 4

 E) Unsaturated alkanoyl groups such as 2-methyl-2-butenoyl; C—C arylcarbonyl groups such as benzoyl, 1-naphthoyl or 2-naphthoyl; 2-bromobenzoyl

 6 10

 Or C—C halogenoaryl carbocyclic groups such as 4-chlorobenzoyl; 2, 4, 6

 6 10

 —C—C alkylated C—C aryls such as trimethylbenzoyl or P-toluoyl

1 4 6 10 Lucol group; C—C alkoxylation such as p-aryl group C—C arylalkyl A carboxylated CC aryl carbonate group such as 2 carboxybenzoyl, 3 carboxybenzoyl or 4 carboxybenzoyl; 4-trobenzoyl

 6 10

Or 2—-trobenzoyl-like C-C arylcarbonyl group; 2— (methoxy

 6 10

(Cybol) Benzyl-like C C alkoxy carbonylated C C aryl

 1 4 6 10 Carbon group; 4 C-C-reel like C-Penol

 6 10 6 10 Carbon group; tetrahydropyran-2-yl, 3 bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl or 4-methoxytetrahydro Tetrahydrobiral group or tetrahydrothiobiranyl group such as thiopyran 4-yl; Tetrahydrofuran group or tetrahydrothiofuran group such as tetrahydrofuran-2-yl or tetrahydrothiofuran-2-yl; methoxymethyl C—C alkoxymethyl groups such as ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl or tert butoxymethyl; C—C alcohols such as 2-methoxyethoxymethyl

 1 4 1 4 Xoxidation C—C alkoxymethyl group; 2, 2, 2-trichloro ethoxymethyl or bis (2-alkyl

14

C-C halogenoalkoxymethyl groups such as (roloethoxy) methyl; 1-methoxy 1-methyl

 14

C—C-alkyl such as tilethyl, 1 ethoxyethyl or 1 (isopropoxy) ethyl

 1 to 4 Calkoxy modified yl groups; 1 to 3 C—C aryl and C— such as benzyl, 1 naphthylmethyl, 2-naphthylmethyl, diphenylmethyl, triphenylmethyl or 1 naphthyl (diphenyl) methyl Aralkyl group consisting of C alkyl; (4-methoxyphenol)

6 10 1 3

C-C alkyl or C-C alkoxy groups such as-(l) diphenylmethyl, bis (4-methoxyphenyl) phenylmethyl, diphenyl (p-tolyl) methyl, tri (p-tolyl) methyl

 1 4 1 4

A triarylmethyl group having one or more aryl rings substituted with 1; 4-methylbenzyl, 2, 4, 6 trimethylbenzyl, 3, 4, 5 trimethylbenzyl, 4-methoxybenzyl, 2-nitrobenzyl, 4-nitro C-C alkyl, C-C alkoxy, halogen, nitro, such as benzyl, 4-chlorobenzene, 4-bromobenzyl or 4-cyanbenzyl

 1 4 1 4

Or a C—C aralkyl group in which the aryl ring is substituted with a cyano group; methoxycarbonyl,

 7 15

C — C alkoxycarbo group such as ethoxycarbol, tert butoxycarboro or isobutoxycarbol; C—C such as 2, 2, 2-trichloro-orthoethoxycarbo

1 4 1 4 Halogenated alkoxycarbol group; buroxycarboxyl or aryloxycar C C-alkoxycarboxyl groups such as bonyl; benzyloxycarbol,

 twenty five

 1 or 2 C-C alkoxy, such as 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-12 trobenzyloxycarbonyl, or 4-12 trobenzyloxycarbonyl Or the aryl ring is substituted with a -tro group

 14

 C—C aralkyloxycarbonyl group; or trimethylsilyl, triethylyl

7 15

 Such as lyl, isopropyldimethylsilyl, tertbutyldimethylsilyl, diisopropylmethylsilyl, ditertbutylmethylsilyl, triisopropylpropylsilyl, methyldiphenylsilyl, butyldiphenylsilyl, isopropyldiphenylsilyl, or diisopropylphenylsilyl A silyl group, preferably a C—C branched alkyl group; tetrahydride

 3 6

 Robilanyl groups; aralkyls consisting of 1 to 3 C C aryls and C C alkyls

 6 10 1 3

 A group; or C wherein the aryl ring is substituted with a C C alkyl or C C alkoxy group

 1 4 1 4 7

— A C aralkyl group, more preferably tetrahydropyran-2-yl, triphenyl

15

 Tyl, trimethylsilyl or tert butyldimethylsilyl, particularly preferably tetrahydropyran-2-yl or triphenylmethyl.

[0049] "C—C alkanesulfo-loxy group" in the definition of R ³ is preferably methanesulfur

 14

 It is hydroxyl or ethanesulfoloxy, particularly preferably methanesulfoloxy.

[0050] "C—C haloalkanesulfo-loxy group" in the definition of R ³ is the above-mentioned "halogen"

 14

 A C C alkanesulfo-loxy group substituted with an atom (preferably a fluorine atom)

 14

 Yes, preferred is trifluoromethane sulfo-oxy or pentafluoroethane sulfo-oxy, and particularly preferred is trifluoromethane sulfo-oxy.

[0051] In the definition of R ³ "substituent group β-force may be substituted with 1 to 3 groups optionally substituted C—C arylaryl-sulfoxy group", the aryl moiety is a substituent group | 8 forces selected

6 10

 A C—C arylsulfonyloxy group optionally substituted by 1 to 3 groups

 6 10

Preferred is a benzenesulfo-loxy group which may be substituted with 1 to 3 groups selected from the substituent group β force, and more preferred is benzenesulfo-loxy, 2 12 Trobenzene senorephonino reoxy, 4 or 12 trobenzene senorephonino reoxy, 4 black mouth benzene sulfonyloxy, 4 methylbenzene sulfonyloxy or 4 trifluro Romethylbenzenesulfoxy-oxy, particularly preferably 4-chlorobenzene sulfonyloxy.

[0052] "C-C alkylene group" in the definition of G ¹ is, for example, methylene, ethylene, trimethyl

 1 6

 Lene, propylene, tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene, 1,1-dimethylethylene, pentamethylene, 1,1-dimethyltrimethylene, 2,2-dimethyltrimethylene, 1,2-dimethyl It may be a linear or branched alkylene group such as a trimethylene or hexamethylene group, preferably a C—C alkylene group, and more preferably a C—C alkylene group.

 1 3 1

-c straight chain alkylene group, even more preferably methylene or ethylene, most

Three

 Preferred is ethylene.

[0053] “C—C alkylene group” in the definition of G ³ means ethylene, trimethylene or propylene

 twenty three

And preferably ethylene or trimethylene, particularly preferably ethylene. When G ³ is a C—C alkylene group, R ³ is preferably a hydroxyl group, protected water

 twenty three

 Acid group, c-c haloalkanesulfonyloxy group, c-c alkanesulfonyloxy group

1 4 1 4

 Group or substituent group j8 force C 1 -C optionally substituted by 1 to 3 groups selected

 6 10 is an arylsulfonyloxy group.

[0054] "C ³ -C alkenylene group" in the definition of G ³ means vinylene, 1 propenylene or 2

 twenty three

Propenylene, particularly preferably vinylene. G ³ is C -C Alkenile

When it is a 2 3 group, R ³ is preferably a hydrogen atom.

[0055] “C—C alkylene group” in the definition of G ³ is ethylene, 1-propylene or

 twenty three

2-propylene, particularly preferably ethylene. G ³ is C-C

When it is a 2 3 diylene group, R ³ is preferably a hydrogen atom.

[0056] “C—C halogeni 匕 alkyl group” in the definition of substituent group a and substituent group β is:

 14

 C—C alkyl group substituted with the above “norogen atom”, preferably trifluoro

 14

Methyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2, 2, 2-trichloroethyl, 2, 2, 2-trifluoroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl or 2 , 2-dibromoethyl, more preferably trifluoromethyl, trichloromethyl, difluoromethyl or fluoromethyl, and particularly preferably trifluoromethyl. [0057] "C—C alkyl group" in the definition of substituent group β means methyl, ethyl, propyl,

 14

 Sopropyl, butyl, isobutyl, sec butyl or tert butyl, preferably methyl or ethyl, particularly preferably methyl.

[0058] The leaving group in the definition of Y is, for example, a halogen atom such as a chlorine atom, a bromine atom or an iodine atom; methoxycarboxoxy or ethoxycarboxoxy.

C C alkoxycarboxyloxy group; methanesulfoloxy or ethanesulfo

twenty five

 C-C alkanesulfo-loxy groups such as -luoxy; trifluoromethanesulfo-

14

 C—C haloalkanes such as ruoxy or pentafluoroethanesulfo-luoxy

 14

 A sulfo-loxy group; or benzene sulfo-loxy, 2--trobenzene sulfoloxy, 4-12 trobenzenesulfonyloxy, 4-chlorobenzenesulfonyloxy, 4 methylbenzenesulfonyloxy or 4 trifluoromethyl Substituent group such as benzenesulfonyloxy β force optionally substituted with 1 to 3 selected groups C

 It can be a 6 C arylsulfoloxy group, preferably methanesulfoloxy, tri

Ten

 Fluoromethanesulfonyloxy, benzenesulfonyloxy, 4-nitrobenzenesulfonyloxy, 4-chlorobenzene sulfonylsulfonyl or 4-methylbenzenesulfonyloxy, and more preferably methanesulfo-oxyloxy or 4-chlorobenzene. Benzenesulfonyloxy, particularly preferably 4-chlorobenzene sulfonylsulfonyloxy.

 C—C alkyl in the C—C alkylcarbo-oxy group in the definition of X is substituted

 1 4 1 4

 Shows the same meaning as “C—C alkyl group” in the definition of group j8, preferably a bivaloyl group

 14

 It is.

 [0059] C—C alkoxy of the C—C alkoxycarboxoxy group in the definition of X is

 1 4 1 4

R ¹ and the same meaning as “C—C alkoxy group” in the definition of substituent group α,

 14

 Is a tert-butoxycarbonyl group.

The salt of the compound having the general formula (4) and the salt of the compound having the general formula (4 ′), and the pharmacologically acceptable salt of the compound having the general formula (5) are, for example, hydrochloride, sulfate Or an inorganic acid salt such as a phosphate; or an organic acid salt such as acetate, oxalate, fumarate or succinate, and may have the general formula (4) or (4 ') The salt of the compound having a preferable salt is a hydrochloride, sulfate or oxalate, and the compound having the general formula (5) The pharmacologically acceptable salt of the product is preferably hydrochloride or fumarate.

 The present invention is carried out according to the following <Method A>.

 A>

 [0060] [Chemical 19]

 O

3rd process

[0061] (where

X and Y are as defined above. )

 The first step is a step of producing compound (1) by reacting compound (4) or a salt thereof with compound (5) in an inert solvent in the presence of a base.

[0062] The inert solvent used is not particularly limited as long as it does not impair the reaction and dissolves the starting material. For example, aliphatic hydrocarbons such as hexane, heptane, lignin, or petroleum ether. Aromatic hydrocarbons such as benzene, toluene or xylene; Halogenated hydrocarbons such as methylene chloride, chlorohonolem, tetrasalt 匕 carbon, 1,2-dichlorodiethylethane, blackdien benzene or dicyclodiene benzene Esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate or jetyl carbonate; jetyl ether, diisopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl Ethers such as ether; acetone, eth Methyl ketone, isobutyl methyl ketone, isophorone Ketones such as rhone or cyclohexanone; nitrogen compounds such as nitroethane or nitrobenzene; -tolyls such as acetonitrile, propio-tolyl or isobutyric-tolyl; formamide, N, N dimethylformamide, N, N Amides such as dimethylacetamide, N-methylpyrrolidinone or hexamethylphosphorotriamide; sulfoxides or sulfones such as dimethylsulfoxide or sulfolane; such as methanol, ethanol, propanol V or butanol Water; or a mixture thereof, preferably aromatic hydrocarbons, ethers, nitriles, water or mixtures thereof, more preferably toluene, tetrahydrofuran, acetonitrile, Water or a mixture thereof

[0063]

 The base used is not particularly limited as long as it is used as a base in a normal reaction, for example, N-methylmorpholine, trimethylamine, triethylamine, trippyramine, tributylamine, N, N diisopropyl ester. Tyramine, dicyclohexylamine, N-methylbiperidine, N-methylpyrrolidine, pyridine, 4-pyrrolidinopyridin, picoline, 4 dimethylaminopyridine, 2,6-di (tert-butyl) 4-methylpyridin, imidazole, N-methyl Imidazole, quinoline, N, N dimethylaline, N, N — jetinorealine, 1, 5 diazabicyclo [4. 3. 0] nona 5 hen (DBN), 1, 4— diazabicyclo [2.2.2] It can be an organic base such as octane (DABCO) or 1,8 diazabicyclo [5.4.0] unde force—7-ene (DBU), preferably Chiruamin 及 beauty N, an N-diisopropyl E chill § Min, particularly preferably a Toryechiruamin.

[0064] The reaction temperature is usually 20 ° C to 100 ° C (preferably 5 ° C to 10 ° C), and the reaction time depends on the reaction temperature, etc. Usually 5 minutes to 24 hours (Preferably 10 minutes to 2 hours).

In the case where X is a hydroxyl group, the reaction can be achieved by reacting with a “condensing agent” in the presence or absence of the base in a solvent. The condensing agents used are phosphate esters such as jetyl phosphoryl cyanide and diphenyl phosphoryl cyanide; 1,3 dicyclohexylcarbodiimide, 1,3 diisopropylcarbodiimide, 3- (3 dimethylamino) Propyl) carbodiimides such as 11 ethyl carbodiimide; carbonyl diimides and N —Hydroxysuccinimide, 1-hydroxybenzotriazole, combinations with N hydroxys such as N-hydroxy-5-norbornene-1,3-dicarboximide; N, N, 1-disuccinimidinocarbonate, di-2-pyridyl Carbonates, carbonates such as S, S, monobis (1 ferro 1H-tetrazol-5 yl) dithiocarbonate; N, N, monobis (2-oxo-3-oxazolidyl) phosphinic chloride Phosphinic chlorides such as N, N, monodisuccinimidyl oxalate, N, N, monodiphthalimido oxalate, 1, 1, 1 bis (benzotriazolyl) oxalate 2—Chloro-1 methyl pyridyl-mu-iodide-like 2-halo 1 lower alkyl pyridi-um halides; 1, 1, 1 Imidazoles such as xalyldiimidazole, N, N, carbodidiimidazole; phosphates such as phenol diclonal phosphate, polyphosphate ester; 1 Phosphonic acid cyclic anhydride such as propanephosphonic acid cyclic anhydride Substances; halogenosulfo-sulfonic isocyanates such as chlorosulfurisocyanate; halogenosilans such as trimethylsilyl chloride and triethylsilyl chloride; lower alkanesulfol halides such as methanesulfuryl chloride; Preferred are phosphonic acid cyclic anhydrides or lower alkanesulfonuronides.

The inert solvent used is not particularly limited as long as it does not impair the reaction and dissolves the starting material. For example, aliphatic hydrocarbons such as hexane, heptane, lignin or petroleum ether; benzene , Aromatic hydrocarbons such as toluene or xylene; halogenated hydrocarbons such as methylene chloride, chlorohonolem, tetrasalt-carbon, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; , Esters such as ethyl acetate, propyl acetate, butyl acetate or jetyl carbonate; such as jetyl ether, diisopropyl ether, tert butyl methyl ether, cyclopentyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether Ethers; acetone, ethylmethyl Ketones such as ketones, isobutyl methyl ketone, isophorone or cyclohexanone; nitrogen compounds such as nitroethane or nitrobenzene; -tolyls such as acetonitrile, propio-tolyl or isobutyric-tolyl; formamide, N, N dimethylformamide, N, N dimethylacetamide, N- Mention may be made of amides such as tilpyrrolidinone or hexamethylphosphorotriamide; sulfoxides or sulfones such as dimethyl sulfoxide or sulfolane.

 The second step is a step of producing the compound (2) by converting the primary hydroxyl group of the compound (1) into a leaving group Y in the presence or absence of a base in an inert solvent.

[0066] Inert solvents used are, for example, aliphatic hydrocarbons such as hexane, heptane, lignin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; methylene chloride Or halogenated hydrocarbons such as chlorohonolem, carbon tetrachloride, 1,2-dichloroethane, black benzene or dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate or decyl carbonate; Ethers such as ter, diisopropyl ether, tert butyl methyl ether, cyclopentyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; acetone, ethyl methyl ketone, isobutyl methyl ketone, isophorone or cyclohexyl Ketones such as sanone; -toro compounds such as nitroethane or -torobenzene; -tolyls such as acetonitrile, propio-tolyl or isobutyric-tolyl; formamide, N, N dimethylformamide, N, N dimethyla Amides such as cetamide, N-methylpyrrolidinone or hexamethylphosphorotriamide; Sulfoxides or sulfones such as dimethyl sulfoxide or sulfolane; Alcohols such as methanol, ethanol, propanol or butanol; Water; or a mixture thereof It may be a mixed solution, preferably aromatic hydrocarbons, ethers, nitriles, water or a mixture thereof, more preferably toluene, tetrahydrofuran, acetonitrile, water or a mixture thereof.

[0067] Bases used are, for example, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide; alkali earths such as calcium hydroxide or barium hydroxide Metal hydroxides; alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, lithium hydrogen carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate; alkaline earth metals such as calcium carbonate or barium carbonate Carbonates; alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; alkali metal phosphates such as tripotassium phosphate or trisodium phosphate; lithium methoxide, lithium ether Sid, sodium methoxide, sodium ethoxide, sodium tert butoxide, potassium methoxide, potassium ethoxide or alkali metal alkoxides such as potassium tert butoxide; or N-methylmorpholine, trimethylamine, triethylamine, tripropylamine, Tributylamine, N, N Diisopropylethylamine, Dicyclohexylamine, N-Methylenobiperidine, N-Methylolpyrrolidine, Pyridine, 4 Pyrrolidinopyridine, Picoline, 4 Dimethylaminopyridine, 2, 6 Di (Tert-butyl) -4-methylpyridine, imidazole, N-methylimidazole, quinoline, N, N dimethylaniline, N, N jetylline, 1, 5 diazabicyclo [4. 3. 0] nona 5 (DBN), 1, 4 Jazabishi Black [2.2.2] Octane (DABCO) May be organic amines such as 1,8 diazabicyclo [5.4.0] unde force (DBU), preferably alkali metal hydroxides, particularly preferably hydroxy Sodium or potassium hydroxide.

 The amount of the base used is preferably 2 equivalents to 60 equivalents, more preferably 10 equivalents to 25 equivalents, relative to 1 equivalent of compound (4). Or can be added gradually.

 When alkali metal hydroxides are used as the base, the particle size is preferably 425 μm or less, more preferably 212 m or less, and particularly preferably 180 m or less. .

 The corresponding halide is used as a reagent for forming the leaving group Y, and as such a reagent, methanesulfuryl chloride, benzenesulfuryl chloride, 4-methylbenzenesulphoninorechloride, 4-chlorobenzenes Honinole chloride, 2-nitrobenzenesulfur chloride or 4-trobenzenesulfuryl chloride, particularly preferably 4-chlorobenzenesulfonyl chloride.

 The reaction temperature is preferably 40 ° C to 0 ° C (more preferably 35 ° C to 25 ° C or — 5 ° C to 0 ° C, particularly preferably —35 ° C to —25 ° C The reaction time varies depending on the reaction temperature and the like, and is usually 15 minutes to 24 hours (preferably 30 minutes to 2 hours).

The third step is a step of producing compound (3) by cyclizing compound (2) in the presence of a base in an inert solvent. [0068] Inert solvents used are, for example, aliphatic hydrocarbons such as hexane, heptane, lignin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; methylene chloride , Halogenated hydrocarbons such as chloroform, carbon tetrachloride, 1,2-dichloro ethane, chlorobenzene, or dichlorobenzene; ethyl formate, ethyl acetate, propyl acetate, butyl acetate or jetyl carbonate Such esters; ethers such as jetyl ether, diisopropyl ether, tert butyl methyl ether, cyclopentyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; acetone, ethyl methyl ketone, isobutyl methyl ketone, isophorone or cyclo Hexa Ketones such as non; nitroethane or -tro compounds such as trobenzene; to-tolyls such as acetonitrile, propio-tolyl or isobutyric-tolyl; formamide, N, N dimethylformamide, N, N dimethylacetamide Amides such as N-methyl 2-pyrrolidone, N-methylpyrrolidinone or hexamethyl phosphorotriamide; sulfoxides or sulfones such as dimethyl sulfoxide or sulfolane; alcohols such as methanol, ethanol, propanol or butanol Water; or a mixture thereof, preferably aromatic hydrocarbons, ethers, nitriles, water or a mixture thereof, more preferably toluene, tetrahydrofuran, acetonitrile, water Or a mixture thereof.

[0069] Bases used are, for example, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide; alkali earths such as calcium hydroxide or barium hydroxide Metal hydroxides; alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, lithium hydrogen carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate; alkaline earth metals such as calcium carbonate or barium carbonate Carbonates; alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; alkali metal phosphates such as tripotassium phosphate or trisodium phosphate; lithium methoxide, lithium ethoxide Sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium Alkali metal alcoholates Kishido, such as Umuetokishido or potassium tert-butoxide; or N- methylmorpholine, Torimechiruamin, Toriechiruamin, Toripuropirua Min, Kishiruamin Toribuchiruamin, N, N-diisopropyl E chill § Min, dicyclohexyl, N-Methylolobiperidine, N-Methylolpyrrolidine, Pyridine, 4 Pyrrolidinopyridine, Picoline, 4 Dimethylaminopyridine, 2, 6 Di (tert-butyl) -4-Methylpyridine, Imidazole, N— Methylimidazole, quinoline, N, N dimethylaniline, N, N jetylaline, 1,5 diazabicyclo [4.3.0] nona5en (DBN), 1,4 diazabicyclo [2. 2. 2] Organic amines such as octane (DABCO) or 1,8 diazabicyclo [5.4.0] Unde force 7-en (DBU), preferably alkali metal hydroxides, particularly preferred Is sodium hydroxide or potassium hydroxide.

 The amount of the base used is preferably 2 equivalents to 60 equivalents, more preferably 10 equivalents to 25 equivalents, relative to 1 equivalent of compound (4). Or can be added gradually.

 When alkali metal hydroxides are used as the base, the particle size is preferably 425 μm or less, more preferably 212 m or less, and particularly preferably 180 m or less. .

 The reaction temperature is usually -40 ° C to 20 ° C (preferably -40 ° C to 0 ° C, more preferably -35 ° C to -25 ° C or -5 ° C to 0 °. C, particularly preferably -35 ° C to -25 ° C), and the reaction time varies depending on the reaction temperature, etc., but usually 15 minutes to 24 hours (preferably 30 minutes to 6 hours) It is.

[0070] Compound (1) and compound (2) can be obtained by continuously performing the first, second and third steps without isolation.

A novel Kyun receptor antagonist [compound ( ₅ )] can be produced by reacting the compound (3) according to the following method.

[0071] [Chemical 20]

[0072] (where

 Can sulfo-loxy group, C—C alkane sulfo-loxy group, or substituent group j8

 14

 C C arylsulfonyloxy optionally substituted with 1 to 3 groups selected from

 6 10

 Substituent group j8 represents a nitro group, a halogen atom, a C—C alkyl group and C—C.

 1 4 1 Halogenated alkyl group. )

 Four

 This step is a step for producing compound (5) by reacting compound (3) and compound (6) in the presence of a base in an inert solvent.

[0073] The inert solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, hexane, heptane, lignin or petroleum ether Aliphatic hydrocarbons such as; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated carbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chloroform or dichlorobenzene Hydrogens; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate or jetyl carbonate; jetyl ether, diisopropyl ether, tert butyl methyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane or diethylene glycol dimethyl ether Such ethers; acetone, ethyl methyl ketone , Ketones such as isobutyl methyl ketone, isophorone or cyclohexanone; troethanes such as nitroethane or -trobenzene; -tolyls such as acetonitrile, propio-tolyl or isobutyryl-tolyl; Lumamide, N, N dimethylformamide, N, N dimethylacetamide, N-methyl- Amides such as 2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphoric triamide; or sulfoxides or sulfones such as dimethyl sulfoxide or sulfolane, preferably amides, ethers or -tolyls More preferred are nitriles, and particularly preferred is acetonitrile.

 [0074] The base to be used is not particularly limited as long as it is used as a base in a normal reaction. For example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; calcium carbonate Or alkaline earth metal carbonates such as barium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate; alkali metal hydrogen such as lithium hydride, sodium hydride or potassium hydride Or alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; or alkaline earth metal hydroxides such as calcium hydroxide or barium hydroxide; , N-methylmorpholine, triethylamine, tripropylamine , Tributylamine, N, N diisopropylethylamine, dicyclohexylamine, N-methylbiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4 dimethylaminopyridine, 2,6 di (tert-butyl) 4-methylpyridine , Quinoline, N, N Dimethylaniline, N, N Jetylaniline, 1,5 Diazabicyclo [4.3.0] Non-5 (DBN), 1,4-Diazabicyclo [2.2.2] octane (DABC O) Or 1, 8 diazabicyclo [5. 4. 0] organic carbonates such as undecaker 7 (DBU), preferably inorganic bases, most preferably alkali metal hydrogen carbonates It is. For the purpose of promoting the reaction, it is also useful to add a catalytic amount of an alkali metal iodide such as potassium iodide or sodium iodide.

 [0075] The reaction temperature may be, for example, 0 ° C to 150 ° C, and preferably 20 ° C to 120 ° C.

[0076] The reaction time can vary from 30 minutes to 48 hours, and preferably 1 hour to 12 hours, depending mainly on the reaction temperature, the raw material compound, the reaction reagent or the type of inert solvent used. .

 After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method.

[0077] For example, water is added to the reaction mixture, and the mixture is not miscible with toluene. The effluent is washed with water and dried over anhydrous magnesium sulfate, and then the solvent is distilled off.

 [0078] If necessary, the obtained compound can be separated and purified by a conventional method such as recrystallization, reprecipitation, or silica gel force chromatography.

 In the above <Method A>, by using the optically active form of compound (4), that is, compound (4 ′), the optically active form of compound (1), compound (2) and compound (3) is obtained. The optically active form of compound (5) can be produced by carrying out the reaction according to <Method> using the optically active form of compound (3).

[0079] In the compound (4 '), a compound in which R ³ is a hydroxyl group and G ³ is an ethylene group can be produced by, for example, the following method C.

 <Oji method>

[0080] [Chemical 21]

4th process 5th process

 (7) (9)

[In the formula, R ² and G ¹ are as defined above.]

The fourth step is a step of producing a 3-butene-1-ol compound (8) by reacting the propene derivative (7) with paraformaldehyde. This step can be carried out according to the method of Okachi et al. (Organic Letters 2002, 4, 1667-1669) or a trifluoroborane complex compound (for example, trifluoroborane; trifluoroborane 'methyl ether complex). Trifluoroboranes such as trifluoroborane · ethyl ether complexes, trifluoroborane · _n -butyl ether complexes. C -C alkyl ether complexes; trifluoroborane 'methylsulfide

 14

 Trifluoroborane 'C—C alkylsulfide complexes such as complexes; or trifluorobora

 14

'Tetrahydrofuran complex, preferably trifluoroborane' C—C alkyl One ter complex, more preferably a trifluoroborane'ethyl ether complex. ) And bases (e.g., alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide; lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate or potassium bicarbonate) Alkali metal carbonates such as lithium hydride, alkali metal hydrides such as sodium hydride or potassium hydride; alkali metal phosphates such as tripotassium phosphate or trisodium phosphate; lithium methoxy , Lithium methoxide, sodium methoxide, sodium ethoxide, sodium tert butoxide, strong alkali metal alkoxides such as methoxide, potassium ethoxide or potassium tert butoxide; or N-methylmorpholine, triethylamine, tributylamine N, N-diisopro Pyrethylamine, dicyclohexylamine, N-methylbiperidine, pyridine, 4 pyrrolidinopyridine, picoline, 4-dimethylaminopyridine, 2,6 di (tert-butyl) -4-methylpyridine, quinoline, N, N dimethylamine It can be organic amines such as niline or N, N jetyl dilin, preferably alkali metal hydroxides, alkali metal alkoxides or organic amines, more preferably alkali metal alkoxides. Or organic amines, particularly preferably sodium methoxide or triethylamine.) It can be carried out by reacting propene derivative (7) with paraformaldehyde in the presence of.

 For the latter method, preferably the reaction is carried out in an inert solvent (e.g. aromatic hydrocarbons such as benzene, toluene or xylene; such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate or jetyl carbonate). Esters; -tolyls such as acetonitrile, propio-tolyl or isobutyric-tolyl; or dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, black benzene, dichlorobenzene, trichloromethylolene benzene or It may be a halogenated hydrocarbon such as trifluoromethylbenzene, preferably a halogenated hydrocarbon, and more preferably dichloromethane.

The amount of paraformaldehyde used is 1.0 to 10.0 equivalents (preferably 1.0 to 2.0 equivalents) relative to 1 equivalent of the propene derivative (7). The amount of borane complex compound is 1.0 to 10.0 equivalents per 1 equivalent of propene derivative (7) ( The amount of the base used is preferably 0.1 equivalent to 1.0 equivalent (preferably 0 equivalent) to 1 equivalent of the propene derivative (7). 3 equivalents to 0.8 equivalents). The reaction temperature is usually 10 ° C to 20 ° C (preferably 5 ° C to 5 ° C), and the reaction time is usually 1 hour to 20 hours (preferably 1 hour to 8 ° C). Time).

[0083] When carrying out the former method (Okachi et al. Method), it is necessary to use the same amount of molecular sieve as the weight of the propene derivative (7), and it is difficult to recover and reuse the molecular sieve. However, the former method is disadvantageous in that it is not suitable for industrial implementation. In contrast, the latter method, it is possible to produce 3-butene 1-ol compound (8) without the use of molecular sieves, industrial practice [this; to ₀

 The fifth step is a step for producing compound (9) by asymmetric epoxidation of 3-butene-1-ol compound (8). This step is carried out according to the method of Okachi et al. (Organic Letters 2003, 5, 85-87), or in an inert solvent, molecular sieves and zirconium (IV) alkoxide (for example, zirconium (IV) ethoxide, zirconium (IV) propoxide, zirconium (IV) isopropoxide, zirconium (IV) butoxide or zirconium (IV) tert butoxide, preferably zirconium (IV) isopropoxide or zirconium (IV) tert butoxide And an optically active tartaric acid diester (eg, dimethyl tartrate, decyl tartrate, diisopropyl tartrate, dibutyl tartrate or di tert butyl tartrate tartrate) in the presence of an asymmetric catalyst (eg, m — Black perbenzoic acid, 3, 5-dinitroperbenzoic acid, o Carboxyperbenzoic acid, peracetic acid, pertriflu It can be rosacetic acid, perphthalic acid, tamen hydroperoxide, isopropyl cumyl hydroperoxide, preferably tamen hydroperoxide or isopropyl cumyl hydroperoxide, most preferably tamen hydroperoxide It can be carried out by asymmetric epoxidation with the action of hydroperoxide).

[0084] The inert solvent used is, for example, an aromatic hydrocarbon such as benzene, toluene or xylene; an ester such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate or ethyl carbonate; methylene chloride Halogenated hydrocarbons such as black mouth form, carbon tetrachloride, 1,2-dichloroethane, black mouth benzene and dichlorobenzene; Ethers such as tellurium, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or diethylene glycol dimethyl ether; ketones such as acetone or methylethyl ketone; Examples of the solvent include aromatic hydrocarbons and halogenated hydrocarbons, and particularly preferable is toluene.

 The amount of molecular sieve used is 0.02 to 1 times the weight of the 3 butene 1 ol compound (8), preferably 0.05 to 0.15 times the weight. The

 The amount of zirconium (IV) alkoxide used is 0.01 to 1 equivalent, preferably 0.1 to 0.5 equivalent, relative to 1 equivalent of 3-butene-1-ol compound (8). . The amount of the optically active tartaric acid diester used is 0.02 to 2.2 equivalents, preferably 0.21 to 1.1 equivalents, relative to 1 equivalent of the 3 butene 1 ol compound (8).

[0085] The amount of the oxidizing agent used is preferably 0.5 to 10 equivalents, preferably 1 to 1.5 equivalents, with respect to 1 equivalent of 3 butene 1-ol compound (8). It is.

 [0086] The reaction temperature is usually 0 ° C to 80 ° C (preferably 10 ° C to 30 ° C), and the reaction time is usually 1 hour to 5 days (preferably 2 hours). 2 days).

In the sixth step, the asymmetric epoxy compound (9) and the amino alcohol compound (10) are combined with an inert solvent (for example, aromatic hydrocarbons such as benzene, toluene or xylene; Esters such as acetyl, ethyl acetate, propyl acetate, butyl acetate or jetyl carbonate; halogenated like methylene chloride, black mouth form, carbon tetrachloride, 1,2-dichloroethane, black mouth benzene or dichloro mouth benzene Hydrocarbons; ethers such as jetyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; ketones such as acetone or methyl ethyl ketone; acetonitrile, propio-tolyl or isobutyl -Tolyls such as -Tolyl; Formamide, N, N Dimethylforma De, N, N-dimethyl § Seto amides, N- methyl-2 - pyrrolidone, amides such as N- methylpyrrolidinone or to Kisamechirurin triamide; dimethylsulfoxide or sulfoxide or sulfones such as sulfolane obtained, Preferred are aromatic hydrocarbons or halogenated hydrocarbons, and more preferred is toluene. ) In which the compound (4′a) is produced.

[0087] The reaction temperature is usually -20 ° C to 150 ° C (preferably 30 ° C to 80 ° C), and the reaction time is usually 10 minutes to 3 days (preferably 30 ° C). Minutes to 1 day).

 Further, the compound (4), the compound (4 ′), the compound (4′a), the compound (5) and the optically active substance thereof may be an acid (the acid is, for example, hydrogen chloride, sulfuric acid or phosphoric acid) as desired. Or an organic acid such as acetic acid, oxalic acid, fumaric acid, or succinic acid), and a salt or pharmacologically acceptable. Can lead to salt.

 [0088] The compounds used as starting materials in the above <Method B> and <Method C> are, for example, US Pat. No. 6,159,967, US Pat. No. 6511975, and David TM et al, J. Amer. Chem. Soc. 69, 851 (1947) can be easily produced from the compounds disclosed therein.

 The invention's effect

 [0089] According to the present invention, N-carbonyl saturated heterocycles that have been difficult to synthesize in the past can be obtained industrially in high yield.

 BEST MODE FOR CARRYING OUT THE INVENTION

[0090] The present invention will be described more specifically with reference to the following examples and reference examples, but the present invention is not limited to these examples.

[0091] The enantiomeric excess in each example was a value based on analysis by high performance liquid chromatography (HPLC), and the enantiomeric excess was analyzed under the conditions of the following "HPLC conditions".

 <HPLC conditions>

 Column: CHRALCEL AD (Brand name, manufactured by Daicel Engineering Co., Ltd.)

 4. 6 X 250mm

 Moving layer: Hexane: EtOH = 94: 6

 Column temperature: 40 ° C

Detection: UV (220nm) PPP) 9Z'Z '(Ηΐ' ΖΗ 6'f 're'9'Π = ί 'ΡΡΡ) SO: dg (QO α' ^ζ 00) Η 顺 -H _T

.频 _{^{0/0 · ¾Γ% 8 ·}} 96 ^ Μ) Έ Ζ呦^] ¾遨粼¾ Ding ¾ transliteration 01, one. OS stop S teaching. : F

q ifT «^^ os M ^ o ₀ o oioz ° ^ q ifT«

^ 翻 "[¾ ^ 、 つ 縱 縱 08 ベ) (ΐοππυ ο-D ^ i 'L. · Π¾ tii). O ^ n ^m o ^ — / ^ ^m o ^ z ^ ^ m -M ^ ^

^ (^ D ^ p, — s)] — One (/ é cm ^^ — 'ε) — ε— () (z M)

Es-8 ^ T 'erssi' ο 'ιει' ^ · τεΐ 'IS'SSI' Γ

9ZI '9S "9Z'9S" T9 '8S 9 '89 "8S'SL'Z'0V £ f: ^ dd g (QO ^ QD' ZH 001) H ND _gI

• (HI 'ZH Z'Z = [' P) S9 "Z

'(HI' ZH S "8 = f 'P) LVL' (HI '^ H Z'Z'S" 8 = f 'PP) 9S "Z' (HI '^ HS"9' 6 "Ζ '0 · ΐΐ = ί "'PPP) S9'S' {HZ ^<Z H 'S = f 8ST' (HI 'ZH 6'f' 8 · 9 '0 · ΐΐ = ί"' PPP) ZVZ '(Ηΐ' ^ Η SI = f 'Ρ) WZ' (Ηΐ 'ΖΗ ζ · ζΐ = Γ' Ρ) 98 '(HZ' ^Ζ Η 'S = f') S9 '(Ηΐ' ^ Η 8 · 9 '6 "Ζ' · ΐ = ί "'ρρρ) ει' (ΗΪ 'ΖΗ 6''ε · 9' νη = ί 'ΡΡΡ) 6" ΐ: ^ dd g (α〇 ^ε α one' ^Z HW OO ^) H NH _T

. · Ηί¾¾ 一 / /

邈 纖 OSS 邈 izi ^oui

继 缀 I ^ra 0 氺) (ΐοπ υο9 9) §

9 ^ W ^ {\ ° ^ \ 9 · Ι) ¾9 · 86 / — ^ e, ^ —S ^ 继 缀 bee βΟΗ / — ^ e [/ yZ--'ε) -z-)] -S ^ ¾ ^ Sp}%

/ — Be: -ε Ί- [^

― 'Ε) — ε— () d W)

 (Zone number)

MSlT0 / S00Zdf / X3d 9 丽 900 OAV f 氺 ^ ¾. _nffl i ^ra os

B: — S 'I-[^. (Λ ^-^^ ^ -Ζ) →--' S) -S- (HS)

^ (^ D ^ p, — s)] — One (/ é cm ^^ — 'ε) — ε— () (^ M)

 6 · ΐε 'ID' ZZ'f 'N' 8S-S Ή 'SVZf' D: puno ^ -iYZ £ 'ID'. Z '' N -6V Ή: 6S'S 'D: 1 H ^ O ^ I HD ^ opo

 • (HI 'ZH Z'Z = [' P) SZ

Z '(HI' ZH S "8 = f 'P) ZS'Z' (HI '^ H Z'Z'S" 8 = f 'PP) SZ HZ' ^Ζ Η Υ = ί 8 T '(H ΐ ' ^Ζ Η Vf' 0 · 6 '0 · ΐΐ = ί "' ΡΡΡ) Ζ9Τ '(Ηΐ' ^ Η 6 · 'V' 0 · ΐΐ = ί"'ΡΡΡ)6ST' (Ηΐ '^ Η Ζ ΐ = Γ 'Ρ) VZ' (Ηΐ 'ΖΗ = 1 1 = 1 "' Ρ) Ζτ '{ΗΖ' ^) SI'S- SO'S '(Ηΐ' ZH V '0 · 6' 6 ^ ΐ = Γ 'PPP) fZ'Z' (Ηΐ 'ΖΗ'6'η = ί 'ΡΡΡ) SO ： ^ dd g (aO ^ D' ^ H 00 ^) H NH _T. · 29 * ¾ί) §Ι 呦 ^^ ¾ 遨 粼 ¾ 丁 ¾ 翻 01 OS stop S teaching

Our Γ · Π 鷇 S teaching, a ^ouraj 6 OS) ™ 'οτ 继 缀 厶 / ^ 邈 S— ι つ H

Ζΐοιυε 、 ^ 继 缀 ποοτ Rin SO) (Ioraras 'LZ) ^ Z · 8 / — ^^ Be ^: — S' I-{iJ. (Λ ^-^^ ^ -Ζ) →-{Λ ^ — ^ ^ ^ ^-'S) -S- (HS)

 w-Λ ^^ ^-ε Ί- [^ (^ e ^ p, — s)] — One (/ é cm ^^ ― 'ε) — ε— () (ε ¾ϊ 第)

• 06 ·, S -9S 2 'ID: 60 ·,' Ν -62 "S Ή: 6Γΐ 'D: puno ^ · ₉ · f' S -99 2 'ID: 80 ·,' N -62" S Ή : 66 · ΐ 'D: OS HS-ON ID HDP ^ PD -P

 • (HI 'ZH Z'Z = [' P) SZ "Z

'(HI' ZH S "8 = f 'P) 9S" Z' (HI '^ H Z'Z' S "8 = f 'PP) 9 ^"' (H2 '^ H' S = f 6ZT '( HI 'z H 6 ·' 6 · 8 '0 · ΐΐ = ί "' ΡΡΡ) 99 · ε '(Ηΐ' ^ Η Γ3 '9'S' 0 · ΐΐ = ί" 'ΡΡΡ) SST' (Ηΐ '^ Η Ζ 1 = 1 "

'ρ) sex' (ΗΪ 'ΖΗ ζ i = f' ρ) ζζτ '{ηζ' ^Ζ Η 's = f π · ε' (HI 'ZH 9'S' 6 · 8 '^ = ['

MSll0 / S00Zdf / X3d εε 9 丽 900 OAV Was extracted with 25 ml of cyclopentyl methyl ether. The organic layers were matched, washed with 25 ml of 20% aqueous sodium chloride solution, and concentrated under reduced pressure. To the obtained oily substance, 50 ml of acetone and 0.2 ml of methanol were heated to 40 to 50 ^° C. 1.84 g (14.6 mmol) of oxalic acid was calorie-free and stirred at the same temperature for 1 hour or more. Cool to 20-30 ° C and stir for more than 30 minutes. The precipitated crystals were collected by filtration and dried at 50 ° C. under reduced pressure for 10 hours or more to obtain 4.35 g of the title compound (purity 98.0%, yield 77.6%).

^J H-NMR (400 MHz, CD OD) δ ppm: 2.03 (ddd, J = 14.6, 4.9, 4.4 Hz, IH), 2.23 (ddd

 Three

 , J = 14.6, 9.0, 5.4 Hz, IH), 3.02—3.12 (m, 2H), 3.34 (d, J = 12.7 Hz, IH), 3.45 (d, J = l 2.7 Hz, IH), 3.58 (ddd , J = 11.0, 5.4, 4.9 Hz, IH), 3.67 (ddd, J = 11.0, 9.0, 4.4 Hz, 1 H), 3.77 (t, J = 5.4 Hz, 2H), 7.44 (dd, J = 8.5, 2.2 Hz, IH), 7.57 (d, J = 8.5 Hz, IH), 7.75 (d, J = 2.2 Hz, IH).

 Anal. Calcd for C H CI NO-(COOH): C, 43.77; H, 4.98; N, 3.65; CI, 18.46. Fo

 12 17 2 3 2

und: C, 43.58; H, 4.93; N, 3.67; CI, 18.08.

 Example 5 2-[(2R) -2- (3,4-Dichlorophenol) 4- (3,4,5-Trimethoxybenzoyl) morpholine 2yl] ethyl 4-chlorobenzene sulfonate

(3R) — 3— (3, 4 Dichlorophenol) 4-[(2 Hydroxyethyl) amino] — 1, 3 — Butanediol 0.5 Sulfate 9. 56 g (27.9 mmol) Acetonitrile 100 ml Triethylamine 5.64 g (55.7 mmol) was added to the solution, and the mixture was stirred at 20 to 25 ° C. for 10 minutes or more. After adding 5 ml of water to the mixture, it was cooled to 0-5 ° C. Next, a solution of 6.75 g (29.3 mmol) of trimethoxybenzoyl chloride in 34 ml of toluene was added dropwise at 5 ° C. or lower and stirred at 0 to 5 ° C. for 30 minutes. This mixture was cooled to −20 to −10 ° C., and then added with 50 ml of a solution of 12.05 g (57. lmmol) of 4-chlorobenzene chlorochloride in 50 ml of acetonitrile. Next, 5.57 g (139.3 mmol) of sodium hydroxide having a particle size of 180 / zm or less was added at −5 ° C. or less. After cooling to −20 to −10 ° C., 16.71 g (417.8 mmol) of sodium hydroxide having a particle size of 180 m or less was added at −5 ° C. or less. After stirring at 15 ° C for 2 hours, 120 ml of water was added dropwise at 5 ° C or lower, the insoluble matter was filtered, and the organic layer was separated. The organic layer was concentrated, and after adding 100 ml of toluene and 50 ml of water, the organic layer was separated. The separated organic layer was then concentrated to 25 ml and stirred at 50 ° C. for about 1 hour. After cooling at 0 to 5 ° C, the mixture was further stirred for 1 hour. Precipitate The crystals were collected by filtration and dried at 50 ° C. under reduced pressure for 15 hours to obtain 14.6 g of the title compound (purity 99.1%, yield 80.5%).

 1H-NMR (400 MHz, CDC1) δ ppm: 2.00-2.25 (m, 1H), 2.25—2.50 (m, 1H), 3.30—3.

 Three

 90 (m, 6H), 3.86 (s, 9H), 4.00—4.15 (m, 1H), 4.15—4.30 (m, 1H), 6.52 (s, 2H), 6.70— 7.90 (m, 7H).

 Example 6 2-[(2R)-2-(3, 4 Dichlorophenol) 1 4- (3, 4, 5 Trimethoxybenzoyl) morpholine 2 yl] ethyl 4 Chlorobenzene sulfonate

(3R) — 3-— (3,4-Dichlorophenol) 4-[(2 Hydroxyethyl) amino] — 1, 3-Butanediol 0.5 Sulfate 4. 78 g (13.9 mmol) Acetonitrile 50 ml Add 2.82 g (27.9 mmol) of triethylamine to the solution, 20-25. Stir at C for 10 min. After adding 2.5 ml of water to the mixed solution, it was cooled to 0 to 5 ° C. Next, a solution of 3.37 g (14.6 mmol) of trimethoxybenzoyl chloride in 17 ml of toluene was added dropwise at 5 ° C. or lower and stirred at 0 to 5 ° C. for 30 minutes. The mixture was cooled to −30 to 35 ° C., and then added with 25 ml of a solution of 6.03 g (28.6 mmol) of acetonitrile and 25 ml of acetonitrile. Next, while maintaining −35 to −25 ° C., 0.28 g (7 Ommol) of sodium hydroxide having a particle size of 180 m or less was added 40 times at intervals of 1.5 to 3 minutes. After stirring at 35 to 25 ° C. for 3 to 4 hours, 75 ml of water was added dropwise at 5 ° C. or lower, and the insoluble matter was filtered to separate the organic layer. The organic layer was concentrated, 50 ml of toluene and 25 ml of 5% sodium bicarbonate solution were added, and the organic layer was separated. Next, the separated organic layer was concentrated to 30 ml and stirred at 50 ° C. for 1 hour. Ethylcyclohexane (10 ml) was added, and the mixture was stirred at the same temperature for 1 hour. After cooling to 20 to 25 ° C. and stirring for 1 hour, the precipitated crystals were collected by filtration. The crystals were dried under reduced pressure at 50 ° C. for 15 hours to obtain 7.24 g of the title compound (purity 99.0%, yield 79.8%).

 (Example 7) tert-butyl 2- (3,4-dichlorophenyl) -2— [2- (trityloxy) ethyl] morpholine 4 carboxylate

To a mixed solution of 120 ml of toluene and 240 ml of acetone was added 2—2 g (61.4 mmol) of 3— (3,4-dichloromethane) 3-butyl trityl ether, and then 16.4 g of sodium bicarbonate ( 195.2 mmol) was added. A solution of OXONE ™ 40. Og (65. Ommol) in 240 ml of water was added dropwise at 30 ° C or lower. After stirring for 2 hours at 25-30 ° C, sodium thiosulfate A solution of pentahydrate 3.23 g (13. Ommol) in 30 ml of water was added and stirred for 10 minutes. The solution was concentrated under reduced pressure until the liquid volume became 390 ml, and 240 ml of methylene chloride was added. After extraction, the organic layer was washed with 210 ml of water and concentrated under reduced pressure.

[0092] To this mixture, toluene was adjusted to a cask liquid volume of 120 ml, and 90 ml of ethanol was added. Next, 16.6 g (97.2 mmol) of lithium perchlorate trihydrate and 19.6 ml (326.5 mmol) of 2 aminoethanol were added and refluxed for 7 hours. After cooling, 210 ml of toluene and 120 ml of water were added for extraction, and the organic layer was washed with 120 ml of water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.

 [0093] One-sixth of the obtained oily substance was dissolved in 10 ml of toluene, and 2.61 g (12. Ommol) of di-tert butyl dicarbonate was added thereto, and the mixture was stirred at 25-30 ° C for 1.5 hours. Stir. The mixture was cooled to −10 ° C. or lower, 1.69 g (16.7 mmol) of triethylamine was added, and 5 ml of toluene in 1.65 g (14.4 mmol) of methanesulfur chloride was added dropwise at 5 ° C. or lower. After stirring for 10 hours at 0 ° C to 0 ° C, the organic layer was washed successively with 25 ml of water at 0 to 1 ° C and 25 ml of saturated aqueous sodium hydrogen carbonate solution at 0 to 1 ° C.

 [0094] To the separated organic layer, 20 ml of 0 to 1 ° C ethanol and 37.5 ml of 0 to 1 ° C toluene were added, and the mixture was cooled to -15 to -10 ° C. 28% sodium methoxide-methanol solution (5.25 g, 27.2 mmol) was added dropwise at a temperature of -10 ° C or lower. The mixture was warmed to 20 ° C and stirred for 1.5 hours. The organic layer was separated by washing twice with 25 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. As a result of quantifying the obtained crude product by the absolute calibration curve method by HPLC, it was shown that 5.69 g (yield: 89.9%) of the target compound was contained.

 1H-NMR (400 MHz, CDC1) δ ppm: 1.42 (s, 9H), 1.80—2.00 (m, 1H), 2.05—2.25 (m,

 Three

 1H), 2.45-2.65 (m, 1H), 2.95—3.14 (m, 2H), 3.15—3.30 (m, 1H), 3.30—3.50 (m, 1H), 3.50-3.65 (m, 1H), 3.65— 3.80 (m, 1H), 4.55-4.75 (m, 1H), 7.06-7.48 (m, 18H). (Embodiment 8) 2-[(2R)-2- (3, 4-dichrome mouth file)- 4 (Fulacetyl) morpholine 2yl] ethyl 4 black mouth benzenesulfonate

(3R) —3— (3,4 dichlorophenol) 4— [(2 Hydroxyethyl) amino] butane mono 1,3 diol 0.5 sulphate 14.3 g (41.8 mmol) in 225 ml acetonitrile Add triethylamine (10.6 g, 104.3 mmol) and water (15 ml) at 20-25 ° C for 10 minutes.

m 纖纖 继 m0l ^^^ O) (louiuig '8 ^) §01 · 6be> ^ /-l — — cm ^^

-Ζ Ί ^ ^ Ι, llij¾g¾ (lorarag '6 ^) §99 · ΐ, ¾ ^ Ma 、, 纖 (纖^ουι

-DI '6: # 驟 一 e / 峯

, One

HZ 'ω) SI' l— 1 'I HZ' ω) SS'Z— 6 '(Ηΐ' ^ Η 2 "2 = f 'Ρ) 8S"Z' (Ηΐ '^ Η S "8 = f' Ρ ) 9S "Z '(HS' ω) 6ΓΖ- ^ ΓΖ '(Ηΐ' ^ Η Ζ · Ζ 'S'8 = f' ΡΡ) ZVL '{ΗΖ' ω) 10 — 6 · 9 '(Ηΐ' ζ ω 6'εΐ = ί "'Ρ) I' f '(Ηΐ' ΖΗ ε · 9 '9 · 9' ε · 0ΐ = ί"'ΡΡΡ)SO''(HI' ΖΗ 8 · 9 'ΓΖ'ε'οι = ί "'ΡΡ

 Ρ) 8 Τ '(Ηΐ' ΖΗ 0 "3ΐ = Γ 'Ρ) 89 · ε' (Ηΐ '^ Η 0" 3ΐ = Γ' Ρ) S9T '{ΗΖ' ^) 9 'S-9S'S' (Ηΐ '

 9ε · ε— 9ζ · ε '(ΗΪ' ΖΗ 6 · εΐ = ί "'ρ) ζτ' (ΗΪ 'ω) sre-sox' (HI 'ΖΗ ε · 9' 8 · 9 '9 ~ = ί

'ΡΡΡ) fVZ' (Ηΐ 'ΖΗ 9 · 9' ΓΖ '9 · ΐ = ί "' ΡΡΡ): dg (3Q3 'z ₀₀ ) 顺-H _T

m ^^ m ^ m ^ ^o ^ m ^ m ^ ^ w ^ m, stop «0.

One. S— ¾a ^ourai 0 ^Ό

) ^§ 08

, "DijQ L ^ aj¾a ^ou ra¾ Έ2) 6 Ma ^ 邈 氺 ^ Stop ^ ¹¹¹ " ^^^^. :

[S600]

(% S · Ζ9 ¾ί) ³ 9 ΊΙΛ ^ ^ / — ^ Δ-Ζ- (Λ ^-^^ ^ -Ζ) -Ν- [/

 ■ ^^ pd, ¾ ^ — (/ é cm ^ ^ — '£) -Ζ- (HS)]-N

^^ ^ Ma f, ¾ <¾ ^^ 鷇 »tilt ° ^ m ^ m

. _η Stop «Q. s¾ p¾i ^ / fH-4 ^ "d ora ra s · 8)

MSll0 / S00Zdf / X3d ζε 9 丽 900 OAV , 掣

W 寨 e 濰 峯 Amazing ¾¾-^ / 一 Π 鐮 ¾ Τ ^ ½¾ ^ [9600]

• (HI 'ZHO = 1 "' Ρ) SVL '(Ηΐ' ZH S'8 = f 'Ρ) ZVL' (HI 'ZH O'Z' ε · 8 = ί" 'ΡΡ) ZZ'L HZ ZL' £ '(HI' ^ H 0 "S = f 'P) ZVZ' (HI '^ H 0" S = f' P

) ZVZ '(HI' ZH 9'S '9 · 9'6'W = f 'PPP) 9VZ' (HI '^ HS'S' 9 · 9 '6'W = f' PPP) OVZ '(H ΐ' () ^s ) ΐ6 · ΐ: ^ dd g (3Q3 'ZH 00,) H NH _T (% 6 ·

88 bandits ii--time ^^ base _{^{E, 0/0 · 68 ¾ί)}} 9 - ££% ^ m

 CHdH 缀 Baye ί ^ Μ ^^-^-^^ ^丟

ζ.纖 μ «οε beet ί) (ΐ ^ου ^ ¾ · χ9ΐ) ^§ 90 · 9ε / — —” [—Be:

— 縱 縱 ¾ (ΐοπ υζε ΈΙ% OS M) ^s

98

. ½ translation "[" Hfi¾ (ΐ ^{ου υ} οε · ζ

S) ¾9 -Z ^ — ^ _o , ^ P ^ m: / (ΛΙ) Ma-r: / ^ ^. :

½ οε, tiip ^ difficult (ΐ ^{ου υ} τ '69) §92 · 91-α ΐ ^Έ ο ·

, Ye, ¾ ^. ζΤ0Ζ, stop ^^

 / —

, Oj ςτο m

(Touiuig -92) §26

-Ζ

, 縱 ¾ (ΐ〇 rarag -Z) V ^ L9 '9: # / 1e ^ e; ^ 峯 Κ, 3. Tsu ^ 5. "[ζΤθ

^ D rw kobe ^? ^

 -^-χ- ^: -ε- 'ε) — ε (zu

. $ ^: ^^ $ lyre (% τ

MSlT0 / S00Zdf / X3d 8ε 9 丽 900 OAV

Claims

 The scope of the claims

The following general formula (1)

 [Chemical 1]

(Wherein R ¹ is selected from a hydrogen atom, a C—C alkoxy group, and a substituent group j8 1 to 3

 14

C—C aralkyloxy group which may be substituted with one group or substituent group α force selection

 7 11

R 1 represents a phenyl group which may be substituted with 1 to 3 selected groups, R ² represents a phenyl group substituted with 1 or 2 halogen atoms, and R ³ represents hydrogen. Atom, hydroxyl group, protected hydroxyl group, C—C haloalkanesulfo-loxy group, C—C alkanesulfo-luo group

 1 4 1 4

Xi group or substituent group j8 force C 1-3 which may be substituted with 1 to 3 selected groups

6

C represents a arylsulfonyloxy group, G ¹ represents a C—C alkylene group, and G ² represents

10 1 6

A single bond or a methylene group, G ³ is a C—C alkylene group, a C—C alkenylene group

 2 3 2 3

Or a C—C alkynylene group, the substituent group is a hydroxyl group, a C—C alkoxy group,

2 3 1 4

 C—C represents a group that is also a halogenated alkyl group and tetrazolylca, and substituent group j8 is

14

Tro group, halogen atom, c-c alkyl group and c-c halogenated alkyl group

 1 4 1 4

A compound having the following general formula (2):

 [Chemical 2]

(Where

G ² and G ³ are as defined above, and Y represents a leaving group. ), And then treating the compound having the general formula (2) with a base to give the following general formula (3)

[Chemical 3]

G ³ has the same meaning as described above. ).

[2] R ¹ is substituted with 1 to 3 groups selected from a C—C alkoxy group or a substituent group α force.

 14

 The method of claim 1, wherein the method is a phenyl group.

[3] The method according to claim ¹ , wherein R ¹ is a phenyl group which may be substituted with 1 to 3 groups which also select a substituent group α force.

[4] The R ² is a phenyl group substituted with 1 or 2 fluorine atoms or chlorine atoms.

4. The method according to claim 1, wherein the force is selected from 1 to claim 3.

[5] R ³ is a hydroxyl group or a protected hydroxyl group, and G ³ is C—C

 The method according to any one of claims 1 to 4, wherein the selected force is a 2 3 alkylene group.

[6] R ³ may be substituted with 1 to 3 groups selected from the substituent group j8 force C—C

6 10 Reylsulfonyloxy group, and G ³ is a CC alkylene group.

 twenty three

 The method according to any one of Claims 4 selected from Claim 4.

[7] The method according to any one of claims 1 to 4, wherein R ³ is a hydrogen atom, and G ³ is a bur group.

[8] G ¹ is methylene or ethylene, the method described in any force 1 wherein is selected from claims 1 to 7.

[9] The method according to any one of claims 1 to 7, wherein G ¹ is ethylene.

[10] The method according to any one of [1] to [9], wherein G ² is a single bond.

[11] The method G ³ is, to an ethylene, as described in any force 1 wherein is selected from claims 1 to 10.

[12] γ force is selected from claims 1 to 11 which is chlorobenzene benzenesulfonyloxy !, a method according to any one of the above. The following general formula (4)

[Chemical 4]

(Wherein IT represents a phenyl group substituted with 1 or 2 halogen atoms, R ³ represents a hydrogen atom, a hydroxyl group, a protected hydroxyl group, a CC haloalkanesulfonyloxy group, C

 1 4 1

1 to 3 groups selected from C alkanesulfo-loxy group or substituent group | 8 groups

Four

C ¹ represents an optionally substituted C — C aryloloxy group, G ¹ represents a C — C

6 10 1 6 represents a alkylene group, G ³ represents a C — C alkylene group, a C — C alkenylene group, or a C — C

 2 3 2 3 2 3 Indicates an alkynylene group, and the substituent group j8 includes a nitro group, a halogen atom, and a C — C alkyl group.

 14

And a group consisting of a C C halogenated alkyl group. Or a salt thereof

14

And the following general formula (5)

[Chemical 5]

 0

X person _G 2. R ¹ (5)

(In the formula, R ¹ is a hydrogen atom, a C—C alkoxy group, or a substituent group j8.

 14

C — C aralkyloxy group or substituent group which may be substituted with one group

 7 11

A phenyl group which may be substituted with 1 to 3 selected groups, G ² represents a single bond or a methylene group, X represents a hydroxyl group, a C—C alkyl carboxy-oxy group, C —C

 1 4 1 4 represents a alkoxycarbonyl-oxy group or a halogen atom, and the substituent group a represents a group consisting of a hydroxyl group, a C 1 -C alkoxy group, a C—C halogenated alkyl group, and a tetrazolyl group.

4 1 4

 . ) In the presence of a base and the following general formula (1)

[Chemical 6]

 2 〇

^R II 1

R _G 3 ₍₁₎

OH G ¹ ,

OH (Where

G ² and G ³ are as defined above. And a compound having the general formula (1) is represented by the following general formula (2)

 [Chemical 7]

(Where

G ² and G ³ are as defined above, and Y represents a leaving group. ), And then treating the compound having the general formula (2) with a base to give the following general formula (3)

 [Chemical 8]

G ³ has the same meaning as described above. ).

[14] R ¹ is substituted with 1 to 3 groups selected from C ¹ -C alkoxy group or substituent group a force

 14

 14. The method according to claim 13, wherein the method is a phenyl group.

[15] The method according to claim 13, wherein R ¹ is a phenyl group which may be substituted with 1 to 3 groups of which substituent group α force is also selected.

[16] R ² is a 1 or 2 fluorine atoms or substituted phenyl group with a chlorine atom, claim

The method of any one of claims 1 to 15, wherein the force is selected from 13 to 15.

[17] The claim, wherein R ³ is a hydroxyl group or a protected hydroxyl group, and G ³ is a C—C alkylene group.

 twenty three

 17. The method according to claim 1, wherein the force is selected from items 13 to 16.

[18] R ³ may be substituted with 1 to 3 groups selected from the substituent group j8 force C —C

A 6 10 -reylsulfonyloxy group, and G ³ is a C 1 -C alkylene group.

 twenty three

 The method according to claim 1, wherein any force selected from claim 16.

[19] The method according to any one of claims 13 to 16, wherein R ³ is a hydrogen atom and G ³ is a bur group! [20] The method G ¹ is, that is methylene or ethylene, as described in any mosquitoゝ1 wherein is selected from claims 13 to claim 19.

[21] G ¹ is ethylene, the method described in any force 1 wherein is selected from claims 13 to claim 19.

[22] The method G ² is a single bond, as described in item 1 one selected from claims 13 to claim 21.

[23] G ³ is ethylene, the method described in any force 1 wherein is selected from claims 13 to claim 22.

 [24] The method according to any one of claims 13 to 23, wherein X is a chlorine atom or a bromine atom.

 [25] The γ force is selected from claims 13 to 24, which is chlorobenzene benzenesulfonyloxy !, the method according to any one of the above.

 [26] General formula (4)

 [Chemical 9]

(In the formula, R ² represents a phenyl group substituted with 1 or 2 halogen atoms, IT represents a hydroxyl group, a C—C haloalkanesulfo-loxy group, a C—C alkanesulfo-loxy group.

1 4 1 4

 Or substituent group j8 force optionally substituted with 1 to 3 selected groups C—C

6 10 represents a reelsulfonyloxy group, G ¹ represents a C—C alkylene group, and G ³ represents a C—C

 1 6 2 3 represents an alkylene group, and the substituent group j8 includes a nitro group, a halogen atom, a C—C alkyl group, and

 14

 Or a salt thereof having a group consisting of C-halogenated alkyl groups.

 14

27. The compound or the salt thereof according to claim 26, wherein R ² is a phenyl group substituted with 1 or 2 fluorine atoms or chlorine atoms.

[28] The compound or salt thereof according to claim 26 or claim 27, wherein R ³ is a hydroxyl group.

[29] The compound or the salt thereof according to any one of claims 26 to 28, wherein G ¹ is methylene or ethylene. [30] The compound or salt thereof according to any one of claims 26 to 28, wherein G ¹ is ethylene.

[31] G ³ is ethylene, I匕合or a salt thereof as described in 1, wherein any one selected from claims 26 to claim 30.

[32] General formula (4) is replaced by the following general formula (4 ')

[Chemical 10]

 32. The compound or salt thereof according to any one of claims 26 to 31, which is selected from the group consisting of:

[33] R ² is a phenyl group substituted with 1 or 2 fluorine atoms or chlorine atoms, R ³ is a hydroxyl group, G ¹ is ethylene, and G ³ is ethylene. 33. A compound according to claim 32 or a hydrochloride, sulfate or oxalate thereof.

 [34] The following general formula (1)

 [Chemical 11]

(In the formula, R ¹ represents a hydrogen atom or a phenyl group which may be substituted with 1 to 3 groups of which substituent group α force is also selected, and R ² represents 1 or 2 halogen atoms. Represents a phenyl group substituted with an atom. R ³ represents a hydroxyl group, a protected hydroxyl group, a C—C haloalkanesulfo-luo

 14

 Selected from the group consisting of a xyl group, a C—C alkanesulfo-loxy group, or a substituent group j8

 14

Represents a C — C arylsulfonyloxy group optionally substituted with up to 3 groups, G ¹

 6 10

Represents a C — C alkylene group, G ² represents a single bond or a methylene group, and G ³ represents C — C

1 6 2 3 represents an alkylene group, a C—C alkenylene group or a C—C alkynylene group, a substituent group

 2 3 2 3

 a is a hydroxyl group, a C C alkoxy group, a C C halogenated alkyl group and tetrazolyl

 1 4 1 4

The substituent group j8 includes a nitro group, a halogen atom, a C—C alkyl group and c represents a group consisting of halogenated alkyl groups. ).

 Four

 35. The compound according to claim 34, wherein the compound is substituted with 1 to 3 groups selected from a force C 1 -C alkoxy group or a substituent group α force, and is a phenyl group.

[36] The compound according to claim 34, wherein R ¹ is a phenyl group which may be substituted with 1 to 3 groups of which substituent group α force is also selected.

[37] R ² is a 1 or 2 fluorine atoms or substituted phenyl group with a chlorine atom, claim

37. The compound according to claim 1, wherein the compound is selected from 34 to 37.

[38] Selected from claims 34 to 37, wherein R ³ is a hydroxyl group or a protected hydroxyl group.

¾ Any one of the compounds described in 1.

[39] The compound according to item ¹ , wherein G ¹ is methylene or ethylene, selected from claims 34 to 38.

[40] The compound according to any one of claims 34 to 38, wherein G ¹ is ethylene.

[41] G ² is a single bond, compounds described in 1, wherein any one selected from claims 34 to claim 40.

[42] G ³ is ethylene, compounds described in any force 1 wherein is selected from claims 34 to claim 41.

[43] General formula (1) is the following general formula (1 ')

 [Chemical 12]

 43. A compound according to any one of claims 34 to 42, selected from:

[44] R ¹ is a phenyl group which may be substituted with 1 to 3 groups selected from substituent group a, and R ² is 1 or 2 fluorine atoms or chlorine A phenyl group substituted with an atom;

44. The compound according to claim 43, wherein R ³ is a hydroxyl group or a protected hydroxyl group, G ¹ is ethylene, G ² is a single bond, and G ³ is ethylene.

[45] General formula (5) characterized by substantially including the following Step A, Step B, and Step C forces [Chemical 13]

(In the formula, R ¹ is a hydrogen atom, a C—C alkoxy group, or a substituent group j8.

 14

C — C aralkyloxy group or substituent group which may be substituted with one group

 7 11

R 1 represents a phenyl group optionally substituted with 1 to 3 selected groups, R ² represents a phenyl group substituted with 1 or 2 halogen atoms, and G ¹ represents C ¹ — Represents a C alkylene group,

 1 6

G ² represents a single bond or a methylene group, G ³ represents a C—C alkylene group, and G ⁴ represents> C

 twenty three

 — OH or> S → 0, the substituent group α is a hydroxyl group, C — C alkoxy group, C — C

 1 4 1 4 represents a group consisting of a halogenoalkyl group and tetrazolylca, and the substituent group β is a group consisting of a nitro group, a halogen atom, a C—C alkyl group and a C—C halogenated alkyl group.

 1 4 1 4

Show. Or a pharmacologically acceptable salt thereof:

 {Where, step Α is the general formula (1)

[Chemical 14]

[Where

G ² and G ³ are as defined above, and R ³ is a hydroxyl group, a protected hydroxyl group, a C 1 -C haloalkane sulfo-oxy group, a C 2 -C alkane sulfo-loxy group.

1 4 1 4

Group or substituent group j8 force C —C optionally substituted with 1 to 3 selected groups

 6 10 represents an arylsulfonyloxy group, and the substituent group j8 represents a group consisting of a nitro group, a halogen atom, a C—C alkyl group, and a C C halogenated alkyl group. ]

 4 1 4

A compound having the general formula (2)

[Chemical 15]

G ² and G ³ have the same meanings as defined above, R ³ and Y are each, C _i - C halo alkanesulfonyl - Ruokishi group, C-C alkanesulfonyl - Ruokishi group, or location

4 1 4

Substituent group j8 may also be substituted with one to three selected groups C—C aryls

 6 10 represents a sulfonyloxy group, the substituent group j8 is a nitro group, a halogen atom, a C 1 -C alkyl

 A group consisting of 14 groups and a C C halogenated alkyl group is shown. Is converted to a compound having

 14

Process,

In step B, the compound (2) obtained in step A is treated with a base to give a general formula (3)

[Chemical 16]

Rocanans

Selected from sulfonyloxy group, CC alkanesulfonyloxy group, or substituent group

 14

A C 1 -C arylsulfonyloxy group which may be substituted with 1 to 3 groups

 6 10

The substituent group j8 is a nitro group, a halogen atom, C 1 -C

 1 4 alkyl group and C -C

 1 4 A group of halogenoalkyl groups. In which the compound (3) obtained in Step B and the general formula (6)

 [Chemical 17]

[Wherein G ⁴ is as defined above. And a compound having the general formula (5) to produce a compound having the general formula (5). }.

R ¹ is substituted with 1 to 3 groups selected from a C—C alkoxy group or a substituent group α force. 46. The method of claim 45, wherein the method is a phenyl group.

[47] The method according to claim 45, wherein R ¹ is a phenyl group which may be substituted with 1 to 3 groups, the substituent group α force of which is also selected.

[48] The R ² is a phenyl group substituted with 1 or 2 fluorine atoms or chlorine atoms.

48. A method according to any one of the preceding claims, wherein the force is selected from 45 to 47.

[49] The method according to any one of claims 45 to 48, wherein R ³ of the compound (1) is a hydroxyl group or a protected hydroxyl group.

[50] The method G ¹ is, that is methylene or ethylene, as described in any mosquitoゝ1 wherein is selected from claims 45 to claim 49.

[51] G ¹ is ethylene, the method described in any force 1 wherein is selected from claims 45 to claim 49.

[52] The method G ² is a single bond, as described in item 1 one selected from claims 45 to claim 51.

[53] G ³ is ethylene, the method described in any force 1 wherein is selected from claims 45 to claim 52.

[54] The method according to any one of claims 45 to 53, wherein R ³ and Υ of compound (2) and compound (3) are black benzenesulfoloxy.

 [55] General formula (7)

[Chemical 18]

(Wherein R ² represents a phenol group substituted with 1 or 2 halogen atoms) and paraformaldehyde are reacted in the presence of a trifluoroborane complex compound and a base. General formula (8)

[Chemical 19]

(Wherein R ² is as defined above). [56] General formula (7)

[Chemical 20]

(Wherein R ² represents a phenol group substituted with 1 or 2 halogen atoms) and paraformaldehyde are reacted in the presence of a trifluoroborane complex compound and a base. General formula (8)

[Chemical 21]

(Wherein R ² has the same meaning as described above), and then the compound having the general formula (8) (wherein R ² has the same meaning as described above) In an active solvent, an oxidizing agent is allowed to act in the presence of molecular sieves and zirconium (IV) alkoxide, an optically active tartaric acid diester, and an asymmetric catalyst to be prepared, and the general formula (9)

[Chemical 22]

(Wherein R ² is as defined above).

[57] The R ² is a phenyl group substituted with 1 or 2 fluorine atoms or chlorine atoms.

57. A method according to claim 55 or claim 56.

 [58] The trifluoroborane complex is a trifluoroborane 'C — C alkyl ether complex.

 14

 58. A method according to any one of claims 55 to 57 selected from.

 [59] The method according to any one of claims 55 to 57, wherein the trifluoroborane complex compound is a trifluoroborane-ethyl ether complex.

 [60] The method according to any one of claims 55 to 59, wherein the base is an alkali metal hydroxide, an alkali metal alkoxide, or an organic amine.

[61] The claims 55 to 5 wherein the base is an alkali metal alkoxide or an organic amine. 9. The method according to any one of the above, selected from 9.

[62] The method according to any one of claims 55 to 59, wherein the base is sodium methoxide or triethylamine.

[63] zirconium (IV) alkoxide is zirconium (IV) isopropoxide or zirconium

 64. The method of any one of claims 56 to 62, wherein (IV) tert-butoxide is selected.

 64. The optically active tartaric acid diester is diisopropyl tartrate.

63. The method according to any one of the above, selected from 63.

[65] The process according to any one of claims 56 to 64, wherein the oxidizing agent is tamen hydroperoxide or isopropylcumyl hydroperoxide.