U.S. patent application number 15/786953 was filed with the patent office on 2018-03-22 for process for producing heterocyclic compound.
This patent application is currently assigned to Takeda Pharmaceuticals Company Limited. The applicant listed for this patent is Takeda Pharmaceuticals Company Limited. Invention is credited to Sayuri Hirano, Ryoji Tsuruoka, Masatoshi Yamada, Mitsuhisa Yamano.
Application Number | 20180079741 15/786953 |
Document ID | / |
Family ID | 54071932 |
Filed Date | 2018-03-22 |
United States Patent
Application |
20180079741 |
Kind Code |
A1 |
Yamada; Masatoshi ; et
al. |
March 22, 2018 |
PROCESS FOR PRODUCING HETEROCYCLIC COMPOUND
Abstract
The present invention provides a method of efficiently producing
an optically active
6-(3-aminopiperidin-1-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine
derivative. The optically active piperidine-3-carboxamide or a
derivative thereof, which is obtained by subjecting
1,4,5,6-tetrahydropyridine-3-carboxamide or a derivative thereof to
an asymmetric reduction in the presence of a catalyst, is used as
an intermediate.
Inventors: |
Yamada; Masatoshi; (Osaka,
JP) ; Hirano; Sayuri; (Osaka, JP) ; Tsuruoka;
Ryoji; (Osaka, JP) ; Yamano; Mitsuhisa;
(Osaka, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Takeda Pharmaceuticals Company Limited |
Osaka |
|
JP |
|
|
Assignee: |
Takeda Pharmaceuticals Company
Limited
Osaka
JP
|
Family ID: |
54071932 |
Appl. No.: |
15/786953 |
Filed: |
October 18, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
15125299 |
Sep 12, 2016 |
9809569 |
|
|
PCT/JP2015/057541 |
Mar 13, 2015 |
|
|
|
15786953 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
B01J 2531/827 20130101;
A61P 3/10 20180101; B01J 2540/225 20130101; C07D 211/78 20130101;
C07D 211/60 20130101; C07F 9/5027 20130101; B01J 2531/822 20130101;
B01J 31/2226 20130101; B01J 2531/0263 20130101; B01J 2531/842
20130101; B01J 2531/0266 20130101; C07B 2200/07 20130101; B01J
2231/645 20130101; C07F 15/0046 20130101; A61P 43/00 20180101; C07D
401/04 20130101; B01J 2531/824 20130101; C07F 17/02 20130101; B01J
31/2452 20130101; B01J 31/2295 20130101; B01J 2531/0205 20130101;
B01J 2531/821 20130101; B01J 31/2409 20130101 |
International
Class: |
C07D 401/04 20060101
C07D401/04; C07F 17/02 20060101 C07F017/02; B01J 31/22 20060101
B01J031/22; C07F 9/50 20060101 C07F009/50; C07D 211/78 20060101
C07D211/78; C07D 211/60 20060101 C07D211/60; C07F 15/00 20060101
C07F015/00; B01J 31/24 20060101 B01J031/24 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 14, 2014 |
JP |
2014-052809 |
Claims
1. A method of producing an optically active form of a compound
represented by the formula: ##STR00068## wherein R.sup.1 is a
hydrogen atom, an optionally substituted hydrocarbon group, an
optionally substituted heterocyclic group, or a protecting group;
R.sup.2, R.sup.3 and R.sup.4 are independently a hydrogen atom or a
substituent; R.sup.5 and R.sup.6 are independently a hydrogen atom,
an optionally substituted hydrocarbon group, or an optionally
substituted heterocyclic group; or R.sup.1 and R.sup.2 in
combination, R.sup.2 and R.sup.3 in combination, R.sup.3 and
R.sup.4 in combination, or R.sup.5 and R.sup.6 in combination
optionally form a 5- to 8-membered ring together with the adjacent
atoms, and the carbon atom marked with * is an asymmetric carbon
atom, or a salt thereof, which comprises subjecting a compound
represented by the formula: ##STR00069## wherein each symbol is as
defined above, or a salt thereof, to a hydrogenation reaction in
the presence of an organic metal complex.
2. The method according to claim 1, wherein the organic metal
complex is a transition metal complex.
3. The method according to claim 2, wherein the transition metal
complex is a ruthenium complex.
4. The method according to claim 3, wherein the ruthenium complex
is represented by the formula: [Ru(OCOR.sup.a).sub.2L*] (VIII)
wherein R.sup.a is an optionally substituted C.sub.1-3 alkyl group;
and L.sup.a is a diphosphine ligand.
5. The method according to claim 1, wherein the hydrogenation
reaction is performed in the presence of an alkali metal halide or
a compound represented by the formula: ##STR00070## wherein
R.sup.A, R.sup.B, R.sup.C and R.sup.D are independently a hydrogen
atom, or an optionally substituted hydrocarbon group; and X is a
halogen atom.
6. A compound represented by the formula: ##STR00071## wherein R is
an optionally substituted hydrocarbon group.
7. An optically active form of a compound represented by the
formula: ##STR00072## wherein R is an optionally substituted
hydrocarbon group, and the carbon atom marked with * is an
asymmetric carbon atom.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. application Ser.
No. 15/125,299, which is the U.S. National Stage application of
PCT/JP2015/057541, filed Mar. 13, 2015, which claims priority from
Japanese application 2014-052809, filed Mar. 14, 2014.
TECHNICAL FIELD
[0002] The present invention relates to a production method of an
optically active
6-(3-aminopiperidin-1-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine
derivative which is useful as a dipeptidylpeptidase inhibitor, and
various intermediates useful therefor, and production methods
thereof.
BACKGROUND OF THE INVENTION
[0003] An optically active
6-(3-aminopiperidin-1-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine
derivative is known to be useful as a dipeptidylpeptidase inhibitor
and an agent for the treatment of diabetes.
[0004] Patent Document 1 discloses a method of producing a
6-(3-aminopiperidin-1-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine
derivative by reacting optically active 3-aminopiperidine with a
6-chloro-2,4-dioxo-1,2,3,4-tetrahydropyrimidine derivative.
[0005] Patent Document 2 discloses a method of efficiently
producing an optically active 8-(3-aminopiperidin-1-yl)xanthine
derivative by subjecting racemic 3-aminopiperidine to acylation
with phthalic anhydride, subjecting the obtained 3-phthalimide
piperidine to optical resolution with optically active tartaric
acid, coupling the obtained optically resolved compound with a
xanthine ring, and subjecting the obtained compound to
deacylation.
[0006] Patent Document 3 discloses a method of optically resolving
racemic piperidine-3-carboxamide with optically active lactic
acid.
[0007] Patent Document 4 discloses a method of producing an
optically active piperidine-3-carboxamide derivative by subjecting
recemic piperidine-3-carboxamide to stereoselective hydrolysis with
an enzyme derived from a microorganism, derivatizing the obtained
optically active piperidine-3-carboxamide, and removing optically
active nipecotic acid from the mixture.
[0008] In addition, the document also discloses a method of
producing optically active 3-aminopiperidine by subjecting an
optically active piperidine-3-carboxamide derivative to Hofmann
rearrangement.
[0009] Non-Patent Document 1 discloses a method of producing an
optically active nipecotate ester derivative by subjecting a
tetrahydropyridinecarboxylate ester derivative to asymmetric
reduction with a ruthenium complex.
DOCUMENT LIST
Patent Document
[0010] Patent Document 1: WO 2007/035629 [0011] Patent Document 2:
JP 2011-201908 [0012] Patent Document 3: WO 2011/010579 [0013]
Patent Document 4: WO 2008/102720
Non-Patent Document
[0013] [0014] Non-Patent Document 1: Eur. J. Org. Chem. 2006, p.
4343-4347.
SUMMARY OF THE INVENTION
Problems to be Solved by the Invention
[0015] The aim of the present invention is to provide a method of
efficiently producing an optically active
6-(3-aminopiperidin-1-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine
derivative using a relatively inexpensive raw material
compound.
[0016] The other aim of the present invention is to provide various
intermediates useful for producing an optically active
6-(3-aminopiperidin-1-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine
derivative, and production methods thereof.
Means of Solving the Problems
[0017] The present inventors have conducted intensive studies to
solve the above-mentioned problems, and have found that optically
active piperidine-3-carboxamide or a derivative thereof can be
efficiently obtained by subjecting
1,4,5,6-tetrahydropyridine-3-carboxamide or a derivative thereof to
an asymmetric reduction in the presence of a catalyst, and an
optically active
6-(3-aminopiperidin-1-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine
derivative can be efficiently produced from the obtained compound
as an intermediate, and completed the present invention based on
these findings.
[0018] Accordingly, the present invention provides the
following.
[1] A method of producing an optically active form of a compound
represented by the formula:
##STR00001##
wherein [0019] R.sup.1 is a hydrogen atom, an optionally
substituted hydrocarbon group, an optionally substituted
heterocyclic group, or a protecting group; [0020] R.sup.2, R.sup.3
and R.sup.4 are independently a hydrogen atom or a substituent;
[0021] R.sup.5 and R.sup.6 are independently a hydrogen atom, an
optionally substituted hydrocarbon group, or an optionally
substituted heterocyclic group; or [0022] R.sup.1 and R.sup.2 in
combination, R.sup.2 and R.sup.3 in combination, R.sup.3 and
R.sup.4 in combination, or R.sup.5 and R.sup.6 in combination
optionally form a 5- to 8-membered ring together with the adjacent
atoms, and [0023] the carbon atom marked with * is an asymmetric
carbon atom, [0024] or a salt thereof, which comprises subjecting a
compound represented by the formula:
##STR00002##
[0024] wherein each symbol is as defined above, [0025] or a salt
thereof, to a hydrogenation reaction in the presence of an organic
metal complex. [2] The method according to the above-mentioned [1],
wherein the organic metal complex is a transition metal complex.
[3] The method according to the above-mentioned [2], wherein the
transition metal complex is a ruthenium complex. [4] The method
according to the above-mentioned [3], wherein the ruthenium complex
is represented by the formula:
[0025] [Ru(OCOR.sup.a).sub.2L.sup.a] (VIII)
wherein [0026] R.sup.a is an optionally substituted C.sub.1-3 alkyl
group; and [0027] L.sup.a is a diphosphine ligand. [5] The method
according to the above-mentioned [1], wherein the hydrogenation
reaction is performed in the presence of an alkali metal halide or
a compound represented by the formula:
##STR00003##
[0027] wherein [0028] R.sup.A, R.sup.B, R.sup.C and R.sup.D are
independently a hydrogen atom, or an optionally substituted
hydrocarbon group; and [0029] X is a halogen atom. [6] A compound
represented by the formula:
##STR00004##
[0029] wherein R is an optionally substituted hydrocarbon group.
[7] An optically active form of a compound represented by the
formula:
##STR00005##
wherein [0030] R is an optionally substituted hydrocarbon group,
and [0031] the carbon atom marked with * is an asymmetric carbon
atom. [8] A method of producing an optically active form of a
compound represented by the formula:
##STR00006##
[0031] wherein [0032] R.sup.2', R.sup.3' and R.sup.4' are
independently a hydrogen atom, an optionally substituted
hydrocarbon group, or an optionally substituted heterocyclic group;
or [0033] R.sup.2' and R.sup.3' in combination, or R.sup.3' and
R.sup.4' in combination optionally form a 5- to 8-membered ring
together with the adjacent atoms; [0034] R.sup.7 and R.sup.8 are
independently an optionally substituted hydrocarbon group, a
hydrogen atom, or an optionally substituted heterocyclic group; and
[0035] the carbon atom marked with * is an asymmetric carbon atom,
or a salt thereof, which comprises reacting an optically active
form of a compound represented by the formula:
##STR00007##
[0035] wherein each symbol is as defined above, [0036] or a salt
thereof, with a compound represented by the formula:
##STR00008##
[0036] wherein [0037] L.sup.1 is a leaving group, and [0038] the
other symbols are as defined above, [0039] or a salt thereof. [9] A
method of producing an optically active form of a compound
represented by the formula:
##STR00009##
[0039] wherein [0040] R.sup.2', R.sup.3' and R.sup.4' are
independently a hydrogen atom, an optionally substituted
hydrocarbon group, or an optionally substituted heterocyclic group,
or [0041] R.sup.2' and R.sup.3' in combination, or R.sup.3' and
R.sup.4' in combination optionally form a 5- to 8-membered ring
together with the adjacent atoms; [0042] R.sup.7 and R.sup.8 are
independently an optionally substituted hydrocarbon group, a
hydrogen atom, or an optionally substituted heterocyclic group; and
[0043] the carbon atom marked with * is an asymmetric carbon atom,
[0044] or a salt thereof, which comprises subjecting an optically
active form of a compound represented by the formula:
##STR00010##
[0044] wherein each symbol is as defined above, [0045] or a salt
thereof, to a rearrangement reaction. [10] The method according to
the above-mentioned [9], which further comprises (1) a step of
subjecting a compound represented by the formula:
##STR00011##
[0045] wherein each symbol is as defined in the above-mentioned
[9], [0046] or a salt thereof, to a hydrogenation reaction in the
presence of an organic metal complex to give an optically active
form of a compound represented by the formula:
##STR00012##
[0046] wherein each symbol is as defined in the above-mentioned
[9], or a salt thereof; and (2) a step of reacting an optically
active form of a compound represented by the formula:
##STR00013##
wherein each symbol is as defined above, [0047] or a salt thereof,
with a compound represented by the formula:
##STR00014##
[0047] wherein [0048] L.sup.1 is a leaving group; and [0049] the
other symbols are as defined in the above-mentioned [9], [0050] or
a salt thereof to give an optically active form of a compound
represented by the formula:
##STR00015##
[0050] wherein each symbol is as defined above, [0051] or a salt
thereof. [11] A ruthenium complex represented by the formula:
[0051] [Ru(OCOR.sup.a').sub.2L.sup.a'] (VIII')
wherein [0052] R.sup.a' is a trifluoromethyl group; and [0053]
L.sup.a' is an optically active diphosphine ligand selected from
(1) an optically active form consisting of a compound represented
by the formula:
##STR00016##
[0053] Or
[0054] the formula:
##STR00017##
or a mixture thereof, and (2) an optically active form of a
compound represented by the formula:
##STR00018##
wherein the bond marked with * is a chiral axis.
Effect of the Invention
[0055] According to the present invention, an optically active
6-(3-aminopiperidin-1-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine
derivative can be efficiently produced with high purity in high
yield.
[0056] The derivative is useful as a dipeptidylpeptidase inhibitor
and an agent for the treatment of diabetes.
[0057] In addition, according to the present invention, various
intermediates for producing an optically active
6-(3-aminopiperidin-1-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine
derivative, and efficient production methods thereof can be
provided.
[0058] Moreover, according to the present invention, a ruthenium
complex useful for a hydrogenation reaction can be provided.
DETAILED DESCRIPTION OF THE INVENTION
[0059] The present invention is explained in detail in the
following.
[0060] The definition of each substituent used in the present
specification is described in detail in the following. Unless
otherwise specified, each substituent has the following
definition.
[0061] In the present specification, examples of the "halogen atom"
include fluorine, chlorine, bromine and iodine.
[0062] In the present specification, examples of the "C.sub.1-6
alkyl group" include methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl,
1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl,
2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl.
[0063] In the present specification, examples of the "optionally
halogenated C.sub.1-6 alkyl group" include a C.sub.1-6 alkyl group
optionally having 1 to 7, preferably 1 to 5, halogen atoms.
Specific examples thereof include methyl, chloromethyl,
difluoromethyl, trichloromethyl, trifluoromethyl, ethyl,
2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl,
pentafluoroethyl, propyl, 2,2-difluoropropyl,
3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl,
isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl,
5,5,5-trifluoropentyl, hexyl and 6,6,6-trifluorohexyl.
[0064] In the present specification, examples of the "C.sub.2-6
alkenyl group" include ethenyl, 1-propenyl, 2-propenyl,
2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl,
3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,
4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and 5-hexenyl.
[0065] In the present specification, examples of the "C.sub.2-6
alkynyl group" include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl,
2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl,
4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl
and 4-methyl-2-pentynyl.
[0066] In the present specification, examples of the "C.sub.3-10
cycloalkyl group" include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl,
bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl and adamantyl.
[0067] In the present specification, examples of the "optionally
halogenated C.sub.3-10 cycloalkyl group" include a C.sub.3-10
cycloalkyl group optionally having 1 to 7, preferably 1 to 5,
halogen atoms. Specific examples thereof include cyclopropyl,
2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl,
difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and
cyclooctyl.
[0068] In the present specification, examples of the "C.sub.3-10
cycloalkenyl group" include cyclopropenyl, cyclobutenyl,
cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
[0069] In the present specification, examples of the "C.sub.6-14
aryl group" include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl,
2-anthryl and 9-anthryl.
[0070] In the present specification, examples of the "C.sub.7-16
aralkyl group" include benzyl, phenethyl, naphthylmethyl and
phenylpropyl.
[0071] In the present specification, examples of the "C.sub.1-6
alkoxy group" include methoxy, ethoxy, propoxy, isopropoxy, butoxy,
isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.
[0072] In the present specification, examples of the "optionally
halogenated C.sub.1-6 alkoxy group" include a C.sub.1-6 alkoxy
group optionally having 1 to 7, preferably 1 to 5, halogen atoms.
Specific examples thereof include methoxy, difluoromethoxy,
trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy,
isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy,
pentyloxy and hexyloxy.
[0073] In the present specification, examples of the "C.sub.3-10
cycloalkyloxy group" include cyclopropyloxy, cyclobutyloxy,
cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and
cyclooctyloxy.
[0074] In the present specification, examples of the "C.sub.1-6
alkylthio group" include methylthio, ethylthio, propylthio,
isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio
and hexylthio.
[0075] In the present specification, examples of the "optionally
halogenated C.sub.1-6 alkylthio group" include a C.sub.1-6
alkylthio group optionally having 1 to 7, preferably 1 to 5,
halogen atoms. Specific examples thereof include methylthio,
difluoromethylthio, trifluoromethylthio, ethylthio, propylthio,
isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio and
hexylthio.
[0076] In the present specification, examples of the "C.sub.1-6
alkyl-carbonyl group" include acetyl, propanoyl, butanoyl,
2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl,
2,2-dimethylpropanoyl, hexanoyl and heptanoyl.
[0077] In the present specification, examples of the "optionally
halogenated C.sub.1-6 alkyl-carbonyl group" include a C.sub.1-6
alkyl-carbonyl group optionally having 1 to 7, preferably 1 to 5,
halogen atoms. Specific examples thereof include acetyl,
chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl,
butanoyl, pentanoyl and hexanoyl.
[0078] In the present specification, examples of the "C.sub.1-6
alkoxy-carbonyl group" include methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl,
pentyloxycarbonyl and hexyloxycarbonyl.
[0079] In the present specification, examples of the "C.sub.6-14
aryl-carbonyl group" include benzoyl, 1-naphthoyl and
2-naphthoyl.
[0080] In the present specification, examples of the "C.sub.7-16
aralkyl-carbonyl group" include phenylacetyl and
phenylpropionyl.
[0081] In the present specification, examples of the "5- to
14-membered aromatic heterocyclylcarbonyl group" include
nicotinoyl, isonicotinoyl, thenoyl and furoyl.
[0082] In the present specification, examples of the "3- to
14-membered non-aromatic heterocyclylcarbonyl group" include
morpholinylcarbonyl, piperidinylcarbonyl and
pyrrolidinylcarbonyl.
[0083] In the present specification, examples of the "mono- or
di-C.sub.1-6 alkyl-carbamoyl group" include methylcarbamoyl,
ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl and
N-ethyl-N-methylcarbamoyl.
[0084] In the present specification, examples of the "mono- or
di-C.sub.7-16 aralkyl-carbamoyl group" include benzylcarbamoyl and
phenethylcarbamoyl.
[0085] In the present specification, examples of the "C.sub.1-6
alkylsulfonyl group" include methylsulfonyl, ethylsulfonyl,
propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl
and tert-butylsulfonyl.
[0086] In the present specification, examples of the "optionally
halogenated C.sub.1-6 alkylsulfonyl group" include a C.sub.1-6
alkylsulfonyl group optionally having 1 to 7, preferably 1 to 5,
halogen atoms. Specific examples thereof include methylsulfonyl,
difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl,
propylsulfonyl, isopropylsulfonyl, butylsulfonyl,
4,4,4-trifluorobutylsulfonyl, pentylsulfonyl and hexylsulfonyl.
[0087] In the present specification, examples of the "C.sub.6-14
arylsulfonyl group" include phenylsulfonyl, 1-naphthylsulfonyl and
2-naphthylsulfonyl.
[0088] In the present specification, examples of the "substituent"
include a halogen atom, a cyano group, a nitro group, an optionally
substituted hydrocarbon group, an optionally substituted
heterocyclic group, an acyl group, an optionally substituted amino
group, an optionally substituted carbamoyl group, an optionally
substituted thiocarbamoyl group, an optionally substituted
sulfamoyl group, an optionally substituted hydroxy group, an
optionally substituted sulfanyl (SH) group and an optionally
substituted silyl group.
[0089] In the present specification, examples of the "hydrocarbon
group" (including "hydrocarbon group" of "optionally substituted
hydrocarbon group") include a C.sub.1-6 alkyl group, a C.sub.2-6
alkenyl group, a C.sub.2-6 alkynyl group, a C.sub.3-10 cycloalkyl
group, a C.sub.3-10 cycloalkenyl group, a C.sub.6-14 aryl group and
a C.sub.7-16 aralkyl group.
[0090] In the present specification, examples of the "optionally
substituted hydrocarbon group" include a hydrocarbon group
optionally having substituent(s) selected from the following
Substituent group A.
[Substituent group A] [0091] (1) a halogen atom, [0092] (2) a nitro
group, [0093] (3) a cyano group, [0094] (4) an oxo group, [0095]
(5) a hydroxy group, [0096] (6) an optionally halogenated C.sub.1-6
alkoxy group, [0097] (7) a C.sub.6-14 aryloxy group (e.g., phenoxy,
naphthoxy), [0098] (8) a C.sub.7-16 aralkyloxy group (e.g.,
benzyloxy), [0099] (9) a 5- to 14-membered aromatic heterocyclyloxy
group (e.g., pyridyloxy), [0100] (10) a 3- to 14-membered
non-aromatic heterocyclyloxy group (e.g., morpholinyloxy,
piperidinyloxy), [0101] (11) a C.sub.1-6 alkyl-carbonyloxy group
(e.g., acetoxy, propanoyloxy), [0102] (12) a C.sub.6-14
aryl-carbonyloxy group (e.g., benzoyloxy, 1-naphthoyloxy,
2-naphthoyloxy), [0103] (13) a C.sub.1-6 alkoxy-carbonyloxy group
(e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy,
butoxycarbonyloxy), [0104] (14) a mono- or di-C.sub.1-6
alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy,
ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy),
[0105] (15) a C.sub.6-14 aryl-carbamoyloxy group (e.g.,
phenylcarbamoyloxy, naphthylcarbamoyloxy), [0106] (16) a 5- to
14-membered aromatic heterocyclylcarbonyloxy group (e.g.,
nicotinoyloxy), [0107] (17) a 3- to 14-membered non-aromatic
heterocyclylcarbonyloxy group (e.g., morpholinylcarbonyloxy,
piperidinylcarbonyloxy), [0108] (18) an optionally halogenated
C.sub.1-6 alkylsulfonyloxy group (e.g., methylsulfonyloxy,
trifluoromethylsulfonyloxy), [0109] (19) a C.sub.6-14
arylsulfonyloxy group optionally substituted by a C.sub.1-6 alkyl
group (e.g., phenylsulfonyloxy, toluenesulfonyloxy), [0110] (20) an
optionally halogenated C.sub.1-6 alkylthio group, [0111] (21) a 5-
to 14-membered aromatic heterocyclic group, [0112] (22) a 3- to
14-membered non-aromatic heterocyclic group, [0113] (23) a formyl
group, [0114] (24) a carboxy group, [0115] (25) an optionally
halogenated C.sub.1-6 alkyl-carbonyl group, [0116] (26) a
C.sub.6-14 aryl-carbonyl group, [0117] (27) a 5- to 14-membered
aromatic heterocyclylcarbonyl group, [0118] (28) a 3- to
14-membered non-aromatic heterocyclylcarbonyl group, [0119] (29) a
C.sub.1-6 alkoxy-carbonyl group, [0120] (30) a C.sub.6-14
aryloxy-carbonyl group (e.g., phenyloxycarbonyl,
1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl), [0121] (31) a
C.sub.7-16 aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,
phenethyloxycarbonyl), [0122] (32) a carbamoyl group, [0123] (33) a
thiocarbamoyl group, [0124] (34) a mono- or di-C.sub.1-6
alkyl-carbamoyl group, [0125] (35) a C.sub.6-14 aryl-carbamoyl
group (e.g., phenylcarbamoyl), [0126] (36) a 5- to 14-membered
aromatic heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl,
thienylcarbamoyl), [0127] (37) a 3- to 14-membered non-aromatic
heterocyclylcarbamoyl group (e.g., morpholinylcarbamoyl,
piperidinylcarbamoyl), [0128] (38) an optionally halogenated
C.sub.1-6 alkylsulfonyl group, [0129] (39) a C.sub.6-14
arylsulfonyl group, [0130] (40) a 5- to 14-membered aromatic
heterocyclylsulfonyl group (e.g., pyridylsulfonyl,
thienylsulfonyl), [0131] (41) an optionally halogenated C.sub.1-6
alkylsulfinyl group, [0132] (42) a C.sub.6-14 arylsulfinyl group
(e.g., phenylsulfinyl, naphthylsulfinyl, 2-naphthylsulfinyl),
[0133] (43) a 5- to 14-membered aromatic heterocyclylsulfinyl group
(e.g., pyridylsulfinyl, thienylsulfinyl), (44) an amino group,
[0134] (45) a mono- or di-C.sub.1-6 alkylamino group (e.g.,
methylamino, ethylamino, propylamino, isopropylamino, butylamino,
dimethylamino, diethylamino, dipropylamino, dibutylamino,
N-ethyl-N-methylamino), [0135] (46) a mono- or di-C.sub.6-14
arylamino group (e.g., phenylamino), [0136] (47) a 5- to
14-membered aromatic heterocyclylamino group (e.g., pyridylamino),
[0137] (48) a C.sub.7-16 aralkylamino group (e.g., benzylamino),
[0138] (49) a formylamino group, [0139] (50) a C.sub.1-6
alkyl-carbonylamino group (e.g., acetylamino, propanoylamino,
butanoylamino), [0140] (51) a (C.sub.1-6 alkyl) (C.sub.1-6
alkyl-carbonyl) amino group (e.g., N-acetyl-N-methylamino), [0141]
(52) a C.sub.6-14 aryl-carbonylamino group (e.g.,
phenylcarbonylamino, naphthylcarbonylamino), [0142] (53) a
C.sub.1-6 alkoxy-carbonylamino group (e.g., methoxycarbonylamino,
ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino,
tert-butoxycarbonylamino), [0143] (54) a C.sub.7-16
aralkyloxy-carbonylamino group (e.g., benzyloxycarbonylamino),
[0144] (55) a C.sub.1-6 alkylsulfonylamino group (e.g.,
methylsulfonylamino, ethylsulfonylamino), [0145] (56) a C.sub.6-14
arylsulfonylamino group optionally substituted by a C.sub.1-6 alkyl
group (e.g., phenylsulfonylamino, toluenesulfonylamino), [0146]
(57) an optionally halogenated C.sub.1-6 alkyl group, [0147] (58) a
C.sub.2-6 alkenyl group, [0148] (59) a C.sub.2-6 alkynyl group,
[0149] (60) a C.sub.3-10 cycloalkyl group, [0150] (61) a C.sub.3-10
cycloalkenyl group, and [0151] (62) a C.sub.6-14 aryl group.
[0152] The number of the above-mentioned substituents in the
"optionally substituted hydrocarbon group" is, for example, 1 to 5,
preferably 1 to 3. When the number of the substituents is two or
more, the respective substituents may be the same or different.
[0153] In the present specification, examples of the "heterocyclic
group" (including "heterocyclic group" of "optionally substituted
heterocyclic group") include (i) an aromatic heterocyclic group,
(ii) a non-aromatic heterocyclic group and (iii) a 7- to
10-membered bridged heterocyclic group, each containing, as a
ring-constituting atom besides carbon atom, 1 to 4 heteroatoms
selected from a nitrogen atom, a sulfur atom and an oxygen
atom.
[0154] In the present specification, examples of the "aromatic
heterocyclic group" (including "5- to 14-membered aromatic
heterocyclic group") include a 5- to 14-membered (preferably 5- to
10-membered) aromatic heterocyclic group containing, as a
ring-constituting atom besides carbon atom, 1 to 4 heteroatoms
selected from a nitrogen atom, a sulfur atom and an oxygen
atom.
[0155] Preferable examples of the "aromatic heterocyclic group"
include 5- or 6-membered monocyclic aromatic heterocyclic groups
such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl,
isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl,
pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,
1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl,
triazinyl and the like; and 8- to 14-membered fused polycyclic
(preferably bi or tricyclic) aromatic heterocyclic groups such as
benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl,
benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl,
imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl,
pyrazolopyridinyl, oxazolopyridinyl, thiazolopyridinyl,
imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl,
furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl,
oxazolopyrimidinyl, thiazolopyrimidinyl, pyrazolotriazinyl,
naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl, isoindolyl,
1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl,
naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl,
.beta.-carbolinyl, phenanthridinyl, acridinyl, phenazinyl,
phenothiazinyl, phenoxazinyl and the like.
[0156] In the present specification, examples of the "non-aromatic
heterocyclic group" (including "3- to 14-membered non-aromatic
heterocyclic group") include a 3- to 14-membered (preferably 4- to
10-membered) non-aromatic heterocyclic group containing, as a
ring-constituting atom besides carbon atom, 1 to 4 heteroatoms
selected from a nitrogen atom, a sulfur atom and an oxygen
atom.
[0157] Preferable examples of the "non-aromatic heterocyclic group"
include 3- to 8-membered monocyclic non-aromatic heterocyclic
groups such as aziridinyl, oxiranyl, thiiranyl, azetidinyl,
oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl,
pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl,
oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl,
thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl,
tetrahydroisooxazolyl, piperidinyl, piperazinyl,
tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl,
tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl,
tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl,
thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl,
azocanyl, diazocanyl and the like; and 9- to 14-membered fused
polycyclic (preferably bi or tricyclic) non-aromatic heterocyclic
groups such as dihydrobenzofuranyl, dihydrobenzimidazolyl,
dihydrobenzoxazolyl, dihydrobenzothiazolyl,
dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl,
tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl,
indolinyl, isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl,
tetrahydrobenzazepinyl, tetrahydroquinoxalinyl,
tetrahydrophenanthridinyl, hexahydrophenothiazinyl,
hexahydrophenoxazinyl, tetrahydrophthalazinyl,
tetrahydronaphthyridinyl, tetrahydroquinazolinyl,
tetrahydrocinnolinyl, tetrahydrocarbazolyl,
tetrahydro-.beta.-carbolinyl, tetrahydroacrydinyl,
tetrahydrophenazinyl, tetrahydrothioxanthenyl, octahydroisoquinolyl
and the like.
[0158] In the present specification, preferable examples of the "7-
to 10-membered bridged heterocyclic group" include quinuclidinyl
and 7-azabicyclo[2.2.1]heptanyl.
[0159] In the present specification, examples of the
"nitrogen-containing heterocyclic group" include a "heterocyclic
group" containing at least one nitrogen atom as a ring-constituting
atom.
[0160] In the present specification, examples of the "optionally
substituted heterocyclic group" include a heterocyclic group
optionally having substituent(s) selected from the above-mentioned
Substituent group A.
[0161] The number of the substituents in the "optionally
substituted heterocyclic group" is, for example, 1 to 3. When the
number of the substituents is two or more, the respective
substituents may be the same or different.
[0162] In the present specification, examples of the "acyl group"
include a formyl group, a carboxy group, a carbamoyl group, a
thiocarbamoyl group, a sulfino group, a sulfo group, a sulfamoyl
group and a phosphono group, each optionally having "1 or 2
substituents selected from a C.sub.1-6 alkyl group, a C.sub.2-6
alkenyl group, a C.sub.3-10 cycloalkyl group, a C.sub.3-10
cycloalkenyl group, a C.sub.6-14 aryl group, a C.sub.7-16 aralkyl
group, a 5- to 14-membered aromatic heterocyclic group and a 3- to
14-membered non-aromatic heterocyclic group, each of which
optionally has 1 to 3 substituents selected from a halogen atom, an
optionally halogenated C.sub.1-6 alkoxy group, a hydroxy group, a
nitro group, a cyano group, an amino group and a carbamoyl
group".
[0163] Examples of the "acyl group" also include a
hydrocarbon-sulfonyl group, a heterocyclylsulfonyl group, a
hydrocarbon-sulfinyl group and a heterocyclylsulfinyl group.
[0164] Here, the hydrocarbon-sulfonyl group means a hydrocarbon
group-bonded sulfonyl group, the heterocyclylsulfonyl group means a
heterocyclic group-bonded sulfonyl group, the hydrocarbon-sulfinyl
group means a hydrocarbon group-bonded sulfinyl group and the
heterocyclylsulfinyl group means a heterocyclic group-bonded
sulfinyl group.
[0165] Preferable examples of the "acyl group" include a formyl
group, a carboxy group, a C.sub.1-6 alkyl-carbonyl group, a
C.sub.2-6 alkenyl-carbonyl group (e.g., crotonoyl), a C.sub.3-10
cycloalkyl-carbonyl group (e.g., cyclobutanecarbonyl,
cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), a
C.sub.3-10 cycloalkenyl-carbonyl group (e.g.,
2-cyclohexenecarbonyl), a C.sub.6-14 aryl-carbonyl group, a
C.sub.7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic
heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic
heterocyclylcarbonyl group, a C.sub.1-6 alkoxy-carbonyl group, a
C.sub.6-14 aryloxy-carbonyl group (e.g., phenyloxycarbonyl,
naphthyloxycarbonyl), a C.sub.7-16 aralkyloxy-carbonyl group (e.g.,
benzyloxycarbonyl, phenethyloxycarbonyl), a carbamoyl group, a
mono- or di-C.sub.1-6 alkyl-carbamoyl group, a mono- or
di-C.sub.2-6 alkenyl-carbamoyl group (e.g., diallylcarbamoyl), a
mono- or di-C.sub.3-10 cycloalkyl-carbamoyl group (e.g.,
cyclopropylcarbamoyl), a mono- or di-C.sub.6-14 aryl-carbamoyl
group (e.g., phenylcarbamoyl), a mono- or di-C.sub.7-15
aralkyl-carbamoyl group, a 5- to 14-membered aromatic
heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl), a
thiocarbamoyl group, a mono- or di-C.sub.1-6 alkyl-thiocarbamoyl
group (e.g., methylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), a
mono- or di-C.sub.2-6 alkenyl-thiocarbamoyl group (e.g.,
diallylthiocarbamoyl), a mono- or di-C.sub.3-10
cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl,
cyclohexylthiocarbamoyl), a mono- or di-C.sub.6-14
aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl), a mono- or
di-C.sub.7-16 aralkyl-thiocarbamoyl group (e.g.,
benzylthiocarbamoyl, phenethylthiocarbamoyl), a 5- to 14-membered
aromatic heterocyclylthiocarbamoyl group (e.g.,
pyridylthiocarbamoyl), a sulfino group, a C.sub.1-6 alkylsulfinyl
group (e.g., methylsulfinyl, ethylsulfinyl), a sulfo group, a
C.sub.1-6 alkylsulfonyl group, a C.sub.6-14 arylsulfonyl group, a
phosphono group and a mono- or di-C.sub.1-6 alkylphosphono group
(e.g., dimethylphosphono, diethylphosphono, diisopropylphosphono,
dibutylphosphono).
[0166] In the present specification, examples of the "optionally
substituted amino group" include an amino group optionally having
"1 or 2 substituents selected from a C.sub.1-6 alkyl group, a
C.sub.2-6 alkenyl group, a C.sub.3-10 cycloalkyl group, a
C.sub.6-14 aryl group, a C.sub.7-16 aralkyl group, a C.sub.1-6
alkyl-carbonyl group, a C.sub.6-14 aryl-carbonyl group, a
C.sub.7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic
heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic
heterocyclylcarbonyl group, a C.sub.1-6 alkoxy-carbonyl group, a 5-
to 14-membered aromatic heterocyclic group, a carbamoyl group, a
mono- or di-C.sub.1-6 alkyl-carbamoyl group, a mono- or
di-C.sub.7-16 aralkyl-carbamoyl group, a C.sub.1-6 alkylsulfonyl
group and a C.sub.6-14 arylsulfonyl group, each of which optionally
has 1 to 3 substituents selected from Substituent group A".
[0167] Preferable examples of the optionally substituted amino
group include an amino group, a mono- or di-(optionally halogenated
C.sub.1-6 alkyl) amino group (e.g., methylamino,
trifluoromethylamino, dimethylamino, ethylamino, diethylamino,
propylamino, dibutylamino), a mono- or di-C.sub.2-5 alkenylamino
group (e.g., diallylamino), a mono- or di-C.sub.3-10
cycloalkylamino group (e.g., cyclopropylamino, cyclohexylamino), a
mono- or di-C.sub.6-14 arylamino group (e.g., phenylamino), a mono-
or di-C.sub.7-15 aralkylamino group (e.g., benzylamino,
dibenzylamino), a mono- or di-(optionally halogenated C.sub.1-6
alkyl)-carbonylamino group (e.g., acetylamino, propionylamino), a
mono- or di-C.sub.6-14 aryl-carbonylamino group (e.g.,
benzoylamino), a mono- or di-C.sub.7-15 aralkyl-carbonylamino group
(e.g., benzylcarbonylamino), a mono- or di-5- to 14-membered
aromatic heterocyclylcarbonylamino group (e.g., nicotinoylamino,
isonicotinoylamino), a mono- or di-3- to 14-membered non-aromatic
heterocyclylcarbonylamino group (e.g., piperidinylcarbonylamino), a
mono- or di-C.sub.1-6 alkoxy-carbonylamino group (e.g.,
tert-butoxycarbonylamino), a 5- to 14-membered aromatic
heterocyclylamino group (e.g., pyridylamino), a carbamoylamino
group, a (mono- or di-C.sub.1-6 alkyl-carbamoyl) amino group (e.g.,
methylcarbamoylamino), a (mono- or di-C.sub.7-15 aralkyl-carbamoyl)
amino group (e.g., benzylcarbamoylamino), a C.sub.1-6
alkylsulfonylamino group (e.g., methylsulfonylamino,
ethylsulfonylamino), a C.sub.6-14 arylsulfonylamino group (e.g.,
phenylsulfonylamino), a (C.sub.1-6 alkyl) (C.sub.1-6
alkyl-carbonyl) amino group (e.g., N-acetyl-N-methylamino) and a
(C.sub.1-6 alkyl) (C.sub.6-14 aryl-carbonyl) amino group (e.g.,
N-benzoyl-N-methylamino).
[0168] In the present specification, examples of the "optionally
substituted carbamoyl group" include a carbamoyl group optionally
having "1 or 2 substituents selected from a C.sub.1-6 alkyl group,
a C.sub.2-6 alkenyl group, a C.sub.3-10 cycloalkyl group, a
C.sub.6-14 aryl group, a C.sub.7-16 aralkyl group, a C.sub.1-6
alkyl-carbonyl group, a C.sub.6-14 aryl-carbonyl group, a
C.sub.7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic
heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic
heterocyclylcarbonyl group, a C.sub.1-6 alkoxy-carbonyl group, a 5-
to 14-membered aromatic heterocyclic group, a carbamoyl group, a
mono- or di-C.sub.1-6 alkyl-carbamoyl group and a mono- or
di-C.sub.7-16 aralkyl-carbamoyl group, each of which optionally has
1 to 3 substituents selected from Substituent group A".
[0169] Preferable examples of the optionally substituted carbamoyl
group include a carbamoyl group, a mono- or di-C.sub.1-6
alkyl-carbamoyl group, a mono- or di-C.sub.2-5 alkenyl-carbamoyl
group (e.g., diallylcarbamoyl), a mono- or di-C.sub.3-10
cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl,
cyclohexylcarbamoyl), a mono- or di-C.sub.6-14 aryl-carbamoyl group
(e.g., phenylcarbamoyl), a mono- or di-C.sub.7-16 aralkyl-carbamoyl
group, a mono- or di-C.sub.1-6 alkyl-carbonyl-carbamoyl group
(e.g., acetylcarbamoyl, propionylcarbamoyl), a mono- or
di-C.sub.6-14 aryl-carbonyl-carbamoyl group (e.g.,
benzoylcarbamoyl) and a 5- to 14-membered aromatic
heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl).
[0170] In the present specification, examples of the "optionally
substituted thiocarbamoyl group" include a thiocarbamoyl group
optionally having "1 or 2 substituents selected from a C.sub.1-6
alkyl group, a C.sub.2-6 alkenyl group, a C.sub.3-10 cycloalkyl
group, a C.sub.6-14 aryl group, a C.sub.7-16 aralkyl group, a
C.sub.1-6 alkyl-carbonyl group, a C.sub.6-14 aryl-carbonyl group, a
C.sub.7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic
heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic
heterocyclylcarbonyl group, a C.sub.1-6 alkoxy-carbonyl group, a 5-
to 14-membered aromatic heterocyclic group, a carbamoyl group, a
mono- or di-C.sub.1-6 alkyl-carbamoyl group and a mono- or
di-C.sub.7-15 aralkyl-carbamoyl group, each of which optionally has
1 to 3 substituents selected from Substituent group A".
[0171] Preferable examples of the optionally substituted
thiocarbamoyl group include a thiocarbamoyl group, a mono- or
di-C.sub.1-6 alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl,
ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthiocarbamoyl,
N-ethyl-N-methylthiocarbamoyl), a mono- or di-C.sub.2-6
alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl), a mono-
or di-C.sub.3-10 cycloalkyl-thiocarbamoyl group (e.g.,
cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), a mono- or
di-C.sub.6-14 aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl),
a mono- or di-C.sub.7-16 aralkyl-thiocarbamoyl group (e.g.,
benzylthiocarbamoyl, phenethylthiocarbamoyl), a mono- or
di-C.sub.1-6 alkyl-carbonyl-thiocarbamoyl group (e.g.,
acetylthiocarbamoyl, propionylthiocarbamoyl), a mono- or
di-C.sub.6-14 aryl-carbonyl-thiocarbamoyl group (e.g.,
benzoylthiocarbamoyl) and a 5- to 14-membered aromatic
heterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl).
[0172] In the present specification, examples of the "optionally
substituted sulfamoyl group" include a sulfamoyl group optionally
having "1 or 2 substituents selected from a C.sub.1-6 alkyl group,
a C.sub.2-6 alkenyl group, a C.sub.3-10 cycloalkyl group, a
C.sub.6-14 aryl group, a C.sub.7-16 aralkyl group, a C.sub.1-6
alkyl-carbonyl group, a C.sub.6-14 aryl-carbonyl group, a
C.sub.7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic
heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic
heterocyclylcarbonyl group, a C.sub.1-6 alkoxy-carbonyl group, a 5-
to 14-membered aromatic heterocyclic group, a carbamoyl group, a
mono- or di-C.sub.1-6 alkyl-carbamoyl group and a mono- or
di-C.sub.7-16 aralkyl-carbamoyl group, each of which optionally has
1 to 3 substituents selected from Substituent group A".
[0173] Preferable examples of the optionally substituted sulfamoyl
group include a sulfamoyl group, a mono- or di-C.sub.1-6
alkyl-sulfamoyl group (e.g., methylsulfamoyl, ethylsulfamoyl,
dimethylsulfamoyl, diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), a
mono- or di-C.sub.2-6 alkenyl-sulfamoyl group (e.g.,
diallylsulfamoyl), a mono- or di-C.sub.3-10 cycloalkyl-sulfamoyl
group (e.g., cyclopropylsulfamoyl, cyclohexylsulfamoyl), a mono- or
di-C.sub.6-14 aryl-sulfamoyl group (e.g., phenylsulfamoyl), a mono-
or di-C.sub.7-16 aralkyl-sulfamoyl group (e.g., benzylsulfamoyl,
phenethylsulfamoyl), a mono- or di-C.sub.1-6
alkyl-carbonyl-sulfamoyl group (e.g., acetylsulfamoyl,
propionylsulfamoyl), a mono- or di-C.sub.6-14
aryl-carbonyl-sulfamoyl group (e.g., benzoylsulfamoyl) and a 5- to
14-membered aromatic heterocyclylsulfamoyl group (e.g.,
pyridylsulfamoyl).
[0174] In the present specification, examples of the "optionally
substituted hydroxy group" include a hydroxyl group optionally
having "a substituent selected from a C.sub.1-6 alkyl group, a
C.sub.2-6 alkenyl group, a C.sub.3-10 cycloalkyl group, a
C.sub.6-14 aryl group, a C.sub.7-16 aralkyl group, a C.sub.1-6
alkyl-carbonyl group, a C.sub.6-14 aryl-carbonyl group, a
C.sub.7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic
heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic
heterocyclylcarbonyl group, a C.sub.1-6 alkoxy-carbonyl group, a 5-
to 14-membered aromatic heterocyclic group, a carbamoyl group, a
mono- or di-C.sub.1-6 alkyl-carbamoyl group, a mono- or
di-C.sub.7-16 aralkyl-carbamoyl group, a C.sub.1-6 alkylsulfonyl
group and a C.sub.6-14 arylsulfonyl group, each of which optionally
has 1 to 3 substituents selected from Substituent group A".
[0175] Preferable examples of the optionally substituted hydroxy
group include a hydroxy group, a C.sub.1-6 alkoxy group, a
C.sub.2-6 alkenyloxy group (e.g., allyloxy, 2-butenyloxy,
2-pentenyloxy, 3-hexenyloxy), a C.sub.3-10 cycloalkyloxy group
(e.g., cyclohexyloxy), a C.sub.6-14 aryloxy group (e.g., phenoxy,
naphthyloxy), a C.sub.7-16 aralkyloxy group (e.g., benzyloxy,
phenethyloxy), a C.sub.1-6 alkyl-carbonyloxy group (e.g.,
acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), a
C.sub.6-14 aryl-carbonyloxy group (e.g., benzoyloxy), a C.sub.7-16
aralkyl-carbonyloxy group (e.g., benzylcarbonyloxy), a 5- to
14-membered aromatic heterocyclylcarbonyloxy group (e.g.,
nicotinoyloxy), a 3- to 14-membered non-aromatic
heterocyclylcarbonyloxy group (e.g., piperidinylcarbonyloxy), a
C.sub.1-6 alkoxy-carbonyloxy group (e.g., tert-butoxycarbonyloxy),
a 5- to 14-membered aromatic heterocyclyloxy group (e.g.,
pyridyloxy), a carbamoyloxy group, a C.sub.1-6 alkyl-carbamoyloxy
group (e.g., methylcarbamoyloxy), a C.sub.7-16 aralkyl-carbamoyloxy
group (e.g., benzylcarbamoyloxy), a C.sub.1-6 alkylsulfonyloxy
group (e.g., methylsulfonyloxy, ethylsulfonyloxy) and a C.sub.6-14
arylsulfonyloxy group (e.g., phenylsulfonyloxy).
[0176] In the present specification, examples of the "optionally
substituted sulfanyl group" include a sulfanyl group optionally
having "a substituent selected from a C.sub.1-6 alkyl group, a
C.sub.2-6 alkenyl group, a C.sub.3-10 cycloalkyl group, a
C.sub.6-14 aryl group, a C.sub.7-16 aralkyl group, a C.sub.1-6
alkyl-carbonyl group, a C.sub.6-14 aryl-carbonyl group and a 5- to
14-membered aromatic heterocyclic group, each of which optionally
has 1 to 3 substituents selected from Substituent group A" and a
halogenated sulfanyl group.
[0177] Preferable examples of the optionally substituted sulfanyl
group include a sulfanyl (--SH) group, a C.sub.1-6 alkylthio group,
a C.sub.2-6 alkenylthio group (e.g., allylthio, 2-butenylthio,
2-pentenylthio, 3-hexenylthio), a C.sub.3-10 cycloalkylthio group
(e.g., cyclohexylthio), a C.sub.6-14 arylthio group (e.g.,
phenylthio, naphthylthio), a C.sub.7-16 aralkylthio group (e.g.,
benzylthio, phenethylthio), a C.sub.1-6 alkyl-carbonylthio group
(e.g., acetylthio, propionylthio, butyrylthio, isobutyrylthio,
pivaloylthio), a C.sub.6-14 aryl-carbonylthio group (e.g.,
benzoylthio), a 5- to 14-membered aromatic heterocyclylthio group
(e.g., pyridylthio) and a halogenated thio group (e.g.,
pentafluorothio).
[0178] In the present specification, examples of the "optionally
substituted silyl group" include a silyl group optionally having "1
to 3 substituents selected from a C.sub.1-6 alkyl group, a
C.sub.2-6 alkenyl group, a C.sub.3-10 cycloalkyl group, a
C.sub.6-14 aryl group and a C.sub.7-16 aralkyl group, each of which
optionally has 1 to 3 substituents selected from Substituent group
A".
[0179] Preferable examples of the optionally substituted silyl
group include a tri-C.sub.1-6 alkylsilyl group (e.g.,
trimethylsilyl, tert-butyl(dimethyl)silyl).
[0180] The definition of each symbol and compounds in the formulas
(I) and (II) are explained in detail in the following.
[0181] R.sup.1 is a hydrogen atom, an optionally substituted
hydrocarbon group, an optionally substituted heterocyclic group, or
a protecting group.
[0182] Preferable examples of the "hydrocarbon group" of the
"optionally substituted hydrocarbon group" represented by R.sup.1
include a C.sub.1-6 alkyl group, a C.sub.3-10 cycloalkyl group, a
C.sub.6-14 aryl group, a C.sub.7-16 aralkyl group and the like.
[0183] Preferable examples of the "heterocyclic group" of the
"optionally substituted heterocyclic group" represented by R.sup.1
include (i) an aromatic heterocyclic group and (ii) a non-aromatic
heterocyclic group, each containing 1 to 4 heteroatoms selected
from a nitrogen atom, a sulfur atom and an oxygen atom, as a
ring-constituting atom besides carbon atom.
[0184] The "protecting group" represented by R.sup.1 is an
amino-protecting group known per se, and preferable examples
thereof include amide type protecting groups such as a formyl
group, an acetyl group, a benzoyl group and the like; and carbamate
type protecting groups such as a 9-fluorenylmethoxycarbonyl group,
a tert-butoxycarbonyl group, a benzyloxycarbonyl group and the
like. The amino-protecting groups and the like described in Green
et al., Protective Groups in Organic Synthesis, 3rd Edition, 1998,
John Wiley & Sons, Inc., can be referred to for these
protecting group.
[0185] R.sup.1 is preferably a hydrogen atom.
[0186] R.sup.2, R.sup.3 and R.sup.4 are independently a hydrogen
atom or a substituent.
[0187] Preferable examples of the "substituent" represented by
R.sup.2, R.sup.3 or R.sup.4 include a halogen atom, a cyano group,
a nitro group, an optionally substituted hydrocarbon group, an
optionally substituted heterocyclic group, an acyl group, an
optionally substituted amino group, an optionally substituted
carbamoyl group, an optionally substituted hydroxy group, an
optionally substituted silyl group and the like. Among them, an
optionally substituted hydrocarbon group, and an optionally
substituted heterocyclic group are more preferable.
[0188] R.sup.2, R.sup.3 and R.sup.4 is preferably independently a
hydrogen atom, a halogen atom, a cyano group, a nitro group, an
optionally substituted hydrocarbon group, an optionally substituted
heterocyclic group, an acyl group, an optionally substituted amino
group, an optionally substituted carbamoyl group, an optionally
substituted hydroxy group, or an optionally substituted silyl
group; more preferably independently a hydrogen atom, an optionally
substituted hydrocarbon group, or an optionally substituted
heterocyclic group; particularly preferably a hydrogen atom.
[0189] R.sup.5 and R.sup.6 are independently a hydrogen atom, an
optionally substituted hydrocarbon group, or an optionally
substituted heterocyclic group.
[0190] Preferable examples of the "hydrocarbon group" of the
"optionally substituted hydrocarbon group" represented by R.sup.5
or R.sup.6 include a C.sub.1-6 alkyl group, a C.sub.3-10 cycloalkyl
group, a C.sub.6-14 aryl group, a C.sub.7-16 aralkyl group and the
like.
[0191] Preferable examples of the "heterocyclic group" of the
"optionally substituted heterocyclic group" represented by R.sup.5
or R.sup.6 include (i) an aromatic heterocyclic group and (ii) a
non-aromatic heterocyclic group, each containing 1 to 4 heteroatoms
selected from a nitrogen atom, a sulfur atom and an oxygen atom, as
a ring-constituting atom besides carbon atom.
[0192] R.sup.5 and R.sup.6 are preferably hydrogen atoms.
[0193] Alternatively, R.sup.1 and R.sup.2 in combination, R.sup.2
and R.sup.3 in combination, R.sup.3 and R.sup.4 in combination, or
R.sup.5 and R.sup.6 in combination optionally form a 5- to
8-membered ring together with the adjacent atoms.
[0194] Preferable examples of the "5- to 8-membered ring" formed by
R.sup.2 and R.sup.3 in combination, or R.sup.3 and R.sup.4 in
combination include a C.sub.5-8 cycloalkane ring, a C.sub.5-8
cycloalkene ring, a 5- to 8-membered monocyclic non-aromatic
heterocycle and the like.
[0195] Examples of the "C.sub.5-8 cycloalkane ring" exemplified as
the above-mentioned "5- to 8-membered ring" include rings such as
cyclopentane, cyclohexane, cycloheptane, cyclooctane and the
like.
[0196] Examples of the "C.sub.5-8 cycloalkene ring" exemplified as
the above-mentioned "5- to 8-membered ring" include rings such as
cyclopentene, cyclohexene, cycloheptene, cyclooctene and the
like.
[0197] Examples of the "5- to 8-membered monocyclic non-aromatic
heterocycle" exemplified as the above-mentioned "5- to 8-membered
ring" include a 5- to 8-membered monocyclic non-aromatic
heterocycle containing heteroatom(s) selected from a nitrogen atom,
a sulfur atom and an oxygen atom, as a ring-constituting atom
besides carbon atom, and specific examples thereof include rings
such as tetrahydrothiophene, tetrahydrofuran, pyrroline,
pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine,
pyrazoline, pyrazolidine, thiazoline, thiazolidine, isoxazoline,
isothiazoline, tetrahydroisothiazole (isothiazolidine),
tetrahydroisoxazole (isoxazolidine), piperidine, piperazine,
tetrahydropyridine, dihydropyridine, dihydrothiopyran,
tetrahydropyrimidine, dihydropyrimidine, tetrahydropyridazine,
dihydropyridazine, dihydropyran, tetrahydropyran,
tetrahydrothiopyran, morpholine, thiomorpholine, azepane,
diazepane, azepine, oxepane, azocane, diazocane and the like.
[0198] Preferable examples of the "5- to 8-membered ring" formed by
R.sup.1 and R.sup.2 in combination, or R.sup.5 and R.sup.6 in
combination together with the adjacent atoms include a 5- to
8-membered monocyclic nitrogen-containing non-aromatic heterocycle
and the like.
[0199] Examples of the "5- to 8-membered monocyclic
nitrogen-containing non-aromatic heterocycle" exemplified as the
above-mentioned "5- to 8-membered ring" include a 5- to 8-membered
monocyclic non-aromatic heterocycle containing at least one
nitrogen atom and optionally containing heteroatom(s) selected from
a sulfur atom and an oxygen atom, as a ring-constituting atom
besides carbon atom, and specific examples thereof include rings
such as pyrroline, pyrrolidine, imidazoline, imidazolidine,
oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazoline,
thiazolidine, isoxazoline, isothiazoline, tetrahydroisothiazole
(isothiazolidine), tetrahydroisoxazole (isoxazolidine), piperidine,
piperazine, tetrahydropyridine, dihydropyridine,
tetrahydropyrimidine, dihydropyrimidine, tetrahydropyridazine,
dihydropyridazine, morpholine, thiomorpholine, azepane, diazepane,
azocane, diazocane and the like.
[0200] In preferable embodiment,
the compound represented by the formula (I) is a compound
represented by the formula:
##STR00019##
wherein each symbol is as defined above; and the compound
represented by the formula (II) is a compound represented by the
formula:
##STR00020##
wherein each symbol is as defined above.
[0201] In more preferable embodiment,
the compound represented by the formula (I) is a compound
represented by the formula (I'); and the compound represented by
the formula (II) is a compound represented by the formula
(II').
[0202] In further more preferable embodiment,
the compound represented by the formula (I) is
1,4,5,6-tetrahydropyridine-3-carboxamide; and the compound
represented by the formula (II) is piperidine-3-carboxamide.
[0203] The compounds represented by the formulas (I) and (II) may
be each a salt.
[0204] Examples of the salts of the compounds represented by the
formula formulas (I) and (II) include metal salts, ammonium salts,
salts with an organic base, salts with an inorganic acid, salts
with an organic acid, salts with a basic or acidic amino acid, and
the like.
[0205] Preferable examples of the metal salt include alkaline metal
salts such as sodium salt, potassium salt and the like; alkaline
earth metal salts such as calcium salt, magnesium salt, barium salt
and the like; aluminum salt, and the like.
[0206] Preferable examples of the salt with an organic base include
salts with trimethylamine, triethylamine, pyridine, picoline,
2,6-lutidine, ethanolamine, diethanolamine, triethanolamine,
cyclohexylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine or
the like.
[0207] Preferable examples of the salt with an inorganic acid
include salts with hydrofluoric acid, hydrochloric acid,
hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid,
sulfurous acid, phosphoric acid, phosphorous acid, carbonic acid,
bicarbonic acid or the like.
[0208] Preferable examples of the salt with an organic acid include
salts with a carboxylic acid (i.e., an organic compound having one
or more carboxy groups; specific examples thereof include formic
acid, acetic acid, benzoic acid, trifluoroacetic acid, phthalic
acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric
acid, succinic acid, malic acid or the like); or a sulfonic acid
(i.e., an organic compound having one or more sulfo groups;
specific examples thereof include methanesulfonic acid,
trifluoromethanesulfonic acid, benzenesulfonic acid,
p-toluenesulfonic acid, camphorsulfonic acid or the like).
[0209] Preferable examples of the salt with a basic amino acid
include salts with arginine, lysine, ornithine or the like.
Preferable examples of the salt with an acidic amino acid include
salts with aspartic acid, glutamic acid or the like.
[0210] The salts of the compounds represented by the formula (I)
and (II) are each preferably a salt with an organic acid, or a salt
with an inorganic acid; more preferably a sulfonate or a salt with
sulfuric acid; still more preferably a sulfonate.
[0211] The sulfonate means a salt with an organic compound having
one or more sulfo groups, preferably a salt with a compound
represented by the formula:
R.sup.bSO.sub.3H (VII)
wherein R.sup.b is an optionally substituted hydrocarbon group.
[0212] In the above-mentioned formula (VII), preferable examples of
the "hydrocarbon group" of the "optionally substituted hydrocarbon
group" represented by R.sup.b include a C.sub.1-6 alkyl group, a
C.sub.3-10 cycloalkyl group, a C.sub.6-14 aryl group, a C.sub.7-16
aralkyl group and the like. Among them, a C.sub.1-6 alkyl group and
a C.sub.6-14 aryl group are preferable, and a C.sub.6-14 aryl group
is more preferable.
[0213] In the above-mentioned formula (VII), R.sup.b is preferably
an optionally substituted C.sub.6-14 aryl group; more preferably an
optionally substituted phenyl group; further more preferably a
phenyl group optionally substituted by C.sub.1-6 alkyl group(s);
particularly preferably a phenyl group optionally substituted by
methyl.
[0214] The above-mentioned compound represented by the formula
(VII) is specifically preferably methanesulfonic acid,
trifluoromethanesulfonic acid, benzenesulfonic acid or
p-toluenesulfonic acid, more preferably p-toluenesulfonic acid.
[0215] The compound represented by the formula (I) or a salt
thereof is preferably a salt of
1,4,5,6-tetrahydropyridine-3-carboxamide with sulfonic acid. In
addition, the optically active form of the compound represented by
the formula (II) or a salt thereof is preferably a salt of
optically active piperidine-3-carboxamide with sulfonic acid.
[0216] The compound represented by the formula (I) or a salt
thereof is particularly preferably
1,4,5,6-tetrahydropyridine-3-carboxamide p-toluenesulfonate. In
addition, the optically active form of the compound represented by
the formula (II) or a salt thereof is particularly preferably
optically active piperidine-3-carboxamide p-toluenesulfonate.
[0217] The compounds represented by the formulas (I) and (II) may
be each a solvate (e.g., a hydrate, an ethanolate, etc.) or a
non-solvate (e.g., a non-hydrate, etc.), and both are encompassed
in compounds (I) or (II).
[0218] A compound labeled with an isotope and the like is also
encompassed in the compounds represented by the formulas (I) and
(II).
[0219] A deuterium conversion form wherein .sup.1H is converted to
.sup.2H(D) is also encompassed in the compounds represented by the
formulas (I) and (II).
[0220] The definition of each symbol and compounds in the formula
(I'), formula (II'), formula (III), formula (IV), formula (V),
formula (XII) and formula (XIII) are explained in detail in the
following.
[0221] R is an optionally substituted hydrocarbon group.
[0222] Preferable examples of the "hydrocarbon group" of the
"optionally substituted hydrocarbon group" represented by R include
a C.sub.1-6 alkyl group, a C.sub.3-10 cycloalkyl group, a
C.sub.6-14 aryl group, a C.sub.7-16 aralkyl group and the like.
Among them, a C.sub.1-6 alkyl group and a C.sub.6-14 aryl group are
preferable, and a C.sub.6-14 aryl group is more preferable.
[0223] R is preferably an optionally substituted C.sub.6-14 aryl
group; more preferably an optionally substituted phenyl group;
further more preferably a phenyl group optionally substituted by
C.sub.1-6 alkyl group(s).
[0224] R is particularly preferably a phenyl group optionally
substituted by methyl.
[0225] In preferable embodiment of formula (XII), the compound
represented by the formula (XII) is a compound represented by the
following formula:
##STR00021##
[0226] In preferable embodiment of formula (XIII), the compound
represented by the formula (XIII) is a compound represented by the
following formula:
##STR00022##
[0227] R.sup.2', R.sup.3' and R.sup.4' are independently a hydrogen
atom, an optionally substituted hydrocarbon group, or an optionally
substituted heterocyclic group.
[0228] R.sup.2', R.sup.3' and R.sup.4' are preferably hydrogen
atoms.
[0229] Alternatively, R.sup.2' and R.sup.3' in combination, or
R.sup.3' and R.sup.4' in combination optionally form a 5- to
8-membered ring together with the adjacent atoms.
[0230] Preferable examples of the "5- to 8-membered ring" formed by
R.sup.2' and R.sup.3' in combination, or R.sup.3' and R.sup.4' in
combination include those similar to the preferable "5- to
8-membered ring" formed by R.sup.2 and R.sup.3 in combination, or
R.sup.3 and R.sup.4 in combination.
[0231] R.sup.7 and R.sup.8 are independently an optionally
substituted hydrocarbon group, a hydrogen atom, or an optionally
substituted heterocyclic group.
[0232] Preferable examples of the "hydrocarbon group" of the
"optionally substituted hydrocarbon group" represented by R.sup.7
include a C.sub.6-14 aryl group.
[0233] Preferable examples of the "heterocyclic group" of the
"optionally substituted heterocyclic group" represented by R.sup.7
include an aromatic heterocyclic group containing 1 to 4
heteroatoms selected from a nitrogen atom, a sulfur atom and an
oxygen atom, as a ring-constituting atom besides carbon atom.
[0234] The "hydrocarbon group" of the "optionally substituted
hydrocarbon group" represented by R.sup.7 and the "heterocyclic
group" of the "optionally substituted heterocyclic group"
represented by R.sup.7 each optionally has 1 to 5 (preferably 1 to
3) substituents at substitutable position(s). Examples of the
substituent include the above-mentioned Substituent Group A. The
substituent is preferably a halogen atom, more preferably a
fluorine atom.
[0235] R.sup.7 is preferably an optionally substituted C.sub.6-14
aryl group; more preferably an optionally substituted phenyl group;
further more preferably a phenyl group optionally substituted by 1
to 3 substituents selected from a halogen atom (e.g., a fluorine
atom) and a cyano group.
[0236] Preferable examples of R.sup.7 include a phenyl group
substituted by cyano group(s), and a phenyl group substituted by
cyano group(s) and fluorine atom(s). Among them, a phenyl group
substituted by cyano group(s) is preferable.
[0237] Preferable examples of the "hydrocarbon group" of the
"optionally substituted hydrocarbon group" represented by R.sup.8
include a C.sub.1-6 alkyl group.
[0238] R.sup.8 is preferably a hydrogen atom or a C.sub.1-6 alkyl
group; more preferably a C.sub.1-6 alkyl group; further more
preferably a methyl group.
[0239] L.sup.1 is a leaving group.
[0240] Examples of the leaving group represented by L.sup.1 include
a halogen atom; optionally halogenated C.sub.1-6 alkylsulfonyloxy
groups such as methanesulfonyloxy, ethanesulfonyloxy,
trichloromethanesulfonyloxy, trifluoromethanesulfonyloxy and the
like; C.sub.6-10 arylsulfonyloxy groups optionally having
substituent(s) such as phenylsulfonyloxy, m-nitrophenylsulfonyloxy,
p-toluenesulfonyloxy, naphthylsulfonyloxy and the like (for
example, C.sub.6-10 arylsulfonyloxy groups optionally having 1 to 3
substituents selected from a C.sub.1-6 alkyl group, a C.sub.1-6
alkoxy group and a nitro group); acyloxy groups such as
trichloroacetoxy, trifluoroacetoxy and the like, and the like.
[0241] The leaving group represented by L.sup.1 is preferably a
halogen atom, particularly preferably a chlorine atom.
[0242] In preferable embodiment,
the compound represented by the formula (I') is
1,4,5,6-tetrahydropyridine-3-carboxamide; the compound represented
by the formula (II') is piperidine-3-carboxamide; the compound
represented by the formula (IV) is a compound represented by the
formula:
##STR00023##
wherein each symbol is as defined above; and the compound
represented by the formula (V) is a compound represented by the
formula:
##STR00024##
wherein each symbol is as defined above.
[0243] In another preferable embodiment, the compound represented
by the formula (III) is a compound represented by the formula:
##STR00025##
wherein R.sup.E is a hydrogen atom or a fluorine atom; and R.sup.8
and L.sup.1 are each as defined above; the compound represented by
the formula (IV) is a compound represented by the formula:
##STR00026##
wherein each symbol is as defined above; and the compound
represented by the formula (V) is a compound represented by the
formula:
##STR00027##
wherein each symbol is as defined above.
[0244] In more preferable embodiment,
the compound represented by the formula (I') is
1,4,5,6-tetrahydropyridine-3-carboxamide; the compound represented
by the formula (II') is piperidine-3-carboxamide; the compound
represented by the formula (III) is a compound represented by the
formula:
##STR00028##
wherein each symbol is as defined above; the compound represented
by the formula (IV) is a compound represented by the formula:
##STR00029##
wherein each symbol is as defined above; and the compound
represented by the formula (V) is a compound represented by the
formula:
##STR00030##
wherein each symbol is as defined above.
[0245] R.sup.E is particularly preferably a hydrogen atom.
[0246] The compounds represented by the formulas (I') and (II') are
preferably each a salt.
[0247] Examples of the salts of the compounds represented by the
formulas (I') and (II') include those similar to the salts of the
compounds represented by the formulas (I) and (II), and preferable
examples of the "salt" include those similar to the preferable
salts of the compounds represented by the formulas (I) and
(II).
[0248] The compound represented by the formula (I') or a salt
thereof is preferably a salt of
1,4,5,6-tetrahydropyridine-3-carboxamide with sulfonic acid. In
addition, the optically active form of the compound represented by
the formula (II') or a salt thereof is preferably a salt of
optically active piperidine-3-carboxamide with sulfonic acid.
[0249] The compound represented by the formula (I') or a salt
thereof is particularly preferably
1,4,5,6-tetrahydropyridine-3-carboxamide p-toluenesulfonate. In
addition, the optically active form of the compound represented by
the formula (II') or a salt thereof is particularly preferably
optically active piperidine-3-carboxamide p-toluenesulfonate.
[0250] Examples of the salt of the compound represented by the
formulas (III), (IV) and (V) include those similar to the salts of
the compounds represented by the formulas (I) and (II).
[0251] The compounds represented by the formulas (I'), (II'),
(III), (IV) and (V) may be each a solvate (e.g., a hydrate, an
ethanolate, etc.) or a non-solvate (e.g., non-hydrate, etc.), and
both are encompassed in the compounds represented by the formulas
(I'), (II'), (III), (IV) and (V).
[0252] A compound labeled with isotope and the like is also
encompassed in the compounds represented by the formulas (I'),
(II'), (III), (IV) and (V).
[0253] A deuterium conversion form wherein .sup.1H is converted to
.sup.2H(D) is also encompassed in the compounds represented by the
formulas (I'), (II'), (III), (IV) and (V).
[0254] The production method of the optically active form of the
piperidine-3-carboxamide or a derivative thereof (the compound
represented by the formula (II)) or a salt thereof (Production
Method (A)), and the production method of the optically active form
of the
6-(3-aminopiperidin-1-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine
derivative (the compound represented by the formula (V)) or a salt
thereof using the above-mentioned compound (Production Method (B))
are explained in detail below.
[Production Method (A)]
[0255] The optically active form of the compound represented by the
formula (II) or a salt thereof can be produced according to
Production Method (A) shown in the following reaction scheme.
##STR00031##
wherein each symbol is as defined above.
[0256] The reagents and conditions used for Production Method (A)
are explained in detail below.
[0257] Production Method (A) is a method of producing the optically
active form of the compound represented by the formula (II) or a
salt thereof by subjecting the compound represented by the formula
(I) or a salt thereof to a hydrogenation reaction in the presence
of an organic metal complex.
[0258] Examples of the "organic metal complex" include typical
metal complexes such as boron complexes, aluminium complexes,
gallium complexes and the like, in addition to "transition metal
complexes (organic transition metal complexes)".
[0259] Preferable examples of the "organic metal complex" include
"transition metal complexes (organic transition metal
complexes)".
[0260] Examples of the "transition metal complex" include compounds
capable of catalyzing an asymmetric hydrogenation reaction, wherein
the "transition metal" is coordinated with a "ligand" (preferably
an optically active "ligand"). Examples of the optically active
"ligand" include phosphine ligands, diphosphine ligands, amine
ligands, diamine ligands, phosphine amine ligands and the like. The
"transition metal" is, for example, 0 to 6 valent, preferably 0 to
4 valent, particularly preferably 0 to 3 valent.
[0261] Preferable examples of "transition metal complex" include
rhodium complexes, ruthenium complexes, iridium complexes,
palladium complexes, nickel complexes, copper complexes, osmium
complexes, platinum complexes, iron complexes, gold complexes,
silver complexes, zinc complexes, titanium complexes, cobalt
complexes, zirconium complexes, samarium complexes and the like;
more preferred are rhodium complexes, ruthenium complexes, iridium
complexes, palladium complexes, nickel complexes and copper
complexes; further more preferred are rhodium complexes, ruthenium
complexes and iridium complexes; and particularly preferred are
ruthenium complexes.
[0262] Among the "transition metal complexes", specific examples of
the rhodium complex, ruthenium complex, iridium complex, palladium
complex, nickel complex and copper complex are shown below (in the
following transition metal complex, L is a diphosphine ligand, Ar
is benzene optionally having substituent(s) (the substituent is
preferably a C.sub.1-6 alkyl group), Cp* is
pentamethylcyclopentadienyl, Cp is cyclopentadienyl, cod is
1,5-cyclooctadiene, Tf is trifluoromethanesulfonyl, nbd is
norbornadiene, Ph is phenyl, Ac is acetyl, Et is ethyl, dmf is
N,N-dimethylformamide, 2-methylallyl is .eta..sup.3-2-methylallyl,
en is ethylenediamine, dpen is 1,2-diphenylethylenediamine, daipen
is 1,1-di(4-anisyl)-2-isopropyl-1,2-ethylenediamine, and n is an
integer of 1 or more. 1,2-Diphenylethylenediamine and
1,1-di(4-anisyl)-2-isopropyl-1,2-ethylenediamine are each (R)-form,
(S)-form, or a mixture of (R)-form and (S)-form (the ratio is not
limited), preferably an optically active form).
[0263] rhodium complexes: [RhCl(L)].sub.2, [RhBr(L)].sub.2,
[RhI(L)].sub.2, [RhCp*(L)].sub.2, [Rh(cod)(L)]OTf,
[Rh(cod)(L)]BF.sub.4, [Rh(cod)(L)]ClO.sub.4, [Rh(cod)(L)]PF.sub.6,
[Rh(cod)(L)]SbF.sub.6, [Rh(cod)(L)]BPh.sub.4,
[Rh(cod)(L)]B{3,5-(CF.sub.3).sub.2C.sub.6H.sub.3}.sub.4,
[Rh(nbd)(L)]OTf, [Rh(nbd)(L)]BF.sub.4, [Rh(nbd)(L)]ClO.sub.4,
[Rh(nbd)(L)]PF.sub.6, [Rh(nbd)(L)]SbF.sub.6, [Rh(nbd)(L)]BPh.sub.4,
[Rh(nbd)(L)]B{3,5-(CF.sub.3).sub.2C.sub.6H.sub.3}.sub.4,
[Rh(L)(CH.sub.3OH).sub.2]OTf, [Rh(L)(CH.sub.3OH).sub.2]BF.sub.4,
[Rh(L)(CH.sub.3OH).sub.2]ClO.sub.4,
[Rh(L)(CH.sub.3OH).sub.2]PF.sub.6,
[Rh(L)(CH.sub.3OH).sub.2]BPh.sub.4;
[0264] ruthenium complexes: [RuCl.sub.2(L)].sub.n,
[RuBr.sub.2(L)].sub.n, [RuI.sub.2(L)].sub.n, [Ru(OAc).sub.2 (L)],
[Ru(OCOCF.sub.3).sub.2 (L)], (NH.sub.2Me.sub.2)[{RuCl(L)}.sub.2
(.mu.-Cl).sub.3], (NH.sub.2Et.sub.2)[{RuCl(L)}.sub.2
(.mu.-Cl).sub.3](NH.sub.2Me.sub.2)[{RuBr(L)}.sub.2
(.mu.-Br).sub.3],
(NH.sub.2Et.sub.2)[{RuBr(L)}.sub.2(.mu.-Br).sub.3],
(NH.sub.2Me.sub.2)[{RuI(L)}.sub.2 (.mu.-I).sub.3],
(NH.sub.2Et.sub.2)[{RuI(L)}.sub.2 (.mu.-I).sub.3],
[Ru.sub.2Cl.sub.4 (L).sub.2 (NEt.sub.3)], [RuCl.sub.2
(L)(dmf).sub.n], [Ru(2-methylallyl).sub.2 (L)], [RuCl(Ar)(L)]Cl,
[RuCl(Ar)(L)]Br, [RuCl(Ar)(L)]I, [RuCl(Ar)(L)]OTf,
[RuCl(Ar)(L)]ClO.sub.4, [RuCl(Ar)(L)]PF.sub.6,
[RuCl(Ar)(L)]BF.sub.4, [RuCl(Ar)(L)]BPh.sub.4, [RuBr(Ar)(L)]Cl,
[RuBr(Ar)(L)]Br, [RuBr(Ar)(L)]I, [RuI(Ar)(L)]Cl, [RuI(Ar)(L)]Br,
[RuI(Ar)(L)]I, [Ru(L)](OTf).sub.2, [Ru(L)](BF.sub.4).sub.2,
[Ru(L)](ClO.sub.4).sub.2, [Ru(L)](PF.sub.6).sub.2,
[Ru(L)](BPh.sub.4).sub.2, [RuH(L).sub.2]Cl, [RuH(L).sub.2]OTf,
[RuH(L).sub.2]BF.sub.4, [RuH(L).sub.2]ClO.sub.4,
[RuH(L).sub.2]PF.sub.6, [RuH(L).sub.2]BPh.sub.4,
[RuH(CH.sub.3CN)(L)]Cl, [RuH(CH.sub.3CN)(L)]OTf,
[RuH(CH.sub.3CN)(L)]BF.sub.4, [RuH(CH.sub.3CN)(L)]ClO.sub.4,
[RuH(CH.sub.3CN)(L)]PF.sub.6, [RuH(CH.sub.3CN)(L)]BPh.sub.4,
[RuCl(L)]OTf, [RuCl(L)]BF.sub.4, [RuCl(L)]ClO.sub.4,
[RuCl(L)]PF.sub.6, [RuCl(L)]BPh.sub.4, [RuBr(L)]OTf,
[RuBr(L)]BF.sub.4, [RuBr(L)]ClO.sub.4, [RuBr(L)]PF.sub.6,
[RuBr(L)]BPh.sub.4, [RuI(L)]OTf, [RuI(L)]BF.sub.4,
[RuI(L)]ClO.sub.4, [RuI(L)]PF.sub.6, [RuI(L)]BPh.sub.4, [RuCl.sub.2
(L) (en)], [RuCl.sub.2 (L)(dpen)], [RuCl.sub.2 (L)(daipen)],
[RuH(.eta..sup.1-BH.sub.4)(L)(en)], [RuH
(.eta..sup.1-BH.sub.4)(L)(daipen)], [RuH
(.eta..sup.1-BH.sub.4)(L)(dpen)](in the above-mentioned
[RuCl.sub.2(L)(en)], [RuCl.sub.2(L)(dpen)] and
[RuCl.sub.2(L)(daipen)], instead of en, dpen and daipen which are
the diamine ligands, the diamine ligands such as
1,2-cyclohexanediamine, 1,2-cycloheptanediamine,
2,3-dimethylbutanediamine,
1-methyl-2,2-diphenyl-1,2-ethylenediamine,
1-isobutyl-2,2-diphenyl-1,2-ethylenediamine,
1-isopropyl-2,2-diphenyl-1,2-ethylenediamine,
1,1-di(4-anisyl)-2-methyl-1,2-ethylenediamine,
1,1-di(4-anisyl)-2-isobutyl-1,2-ethylenediamine,
1,1-di(4-anisyl)-2-benzyl-1,2-ethylenediamine,
1-methyl-2,2-dinaphthyl-1,2-ethylenediamine,
1-isobutyl-2,2-dinaphthyl-1,2-ethylenediamine,
1-isopropyl-2,2-dinaphthyl-1,2-ethylenediamine, propanediamine,
butanediamine, phenylenediamine and the like can be used);
[0265] iridium complexes: [IrCl(L)].sub.2, [IrBr(L)].sub.2,
[IrI(L)].sub.2, [IrCp*(L)].sub.2, [Ir(cod)(L)]OTf,
[Ir(cod)(L)]BF.sub.4, [Ir(cod)(L)]ClO.sub.4, [Ir(cod)(L)]PF.sub.6,
[Ir(cod)(L)]SbF.sub.6, [Ir(cod)(L)]BPh.sub.4,
[Ir(nbd)(L)]B{3,5-(CF.sub.3).sub.2C.sub.6H.sub.3}.sub.4,
[Ir(nbd)(L)]OTf, [Ir(nbd)(L)]BF.sub.4, [Ir(nbd)(L)]ClO.sub.4,
[Ir(nbd)(L)]PF.sub.6, [Ir(nbd)(L)]SbF.sub.6, [Ir(nbd)(L)]BPh.sub.4,
[Ir(nbd)(L)]B{3,5-(CF.sub.3).sub.2C.sub.6H.sub.3}.sub.4;
[0266] palladium complexes: [PdCl.sub.2 (L)], [PdBr.sub.2 (L)],
[PdI.sub.2 (L)], [Pd(.mu.-allyl)(L)]Cl, [Pd(.mu.-allyl)(L)]OTf,
[Pd(.mu.-allyl)(L)]BF.sub.4, [Pd(.mu.-allyl)(L)]ClO.sub.4,
[Pd(.mu.-allyl)(L)]PF.sub.6, [Pd(n-allyl)(L)]BPh.sub.4,
[Pd(L)](OTf).sub.2, [Pd(L)](BF.sub.4).sub.2,
[Pd(L)](ClO.sub.4).sub.2, [Pd(L)](PF.sub.6).sub.2,
[Pd(L)](BPh.sub.4).sub.2, [Pd(L).sub.2], [Pd(L).sub.2](OAc).sub.2,
[Pd(L) (H.sub.2O).sub.2](OTf).sub.2,
[Pd(L)(H.sub.2O).sub.2](BF.sub.4).sub.2, [Pd(L)
(H.sub.2O).sub.2](ClO.sub.4).sub.2, Pd(L)
(H.sub.2O).sub.2](PF.sub.6).sub.2, [Pd(L)
(H.sub.2O).sub.2](BPh.sub.4).sub.2,
[{Pd(L)}.sub.2(.mu.-OH).sub.2](OTf).sub.2,
[{Pd(L)}.sub.2(.mu.-OH).sub.2](BF.sub.4).sub.2, [{Pd(L)}.sub.2
(.mu.-OH).sub.2](ClO.sub.4).sub.2, [{Pd(L).sup.}2
(.mu.-OH).sub.2](PF.sub.6).sub.2, [{Pd(L)}.sub.2
(.mu.-OH).sub.2](BPh.sub.4).sub.2;
[0267] nickel complexes: [NiCl.sub.2(L)], [NiBr.sub.2(L)],
[NiI.sub.2(L)], [Ni(n-allyl)(L)]Cl, [Ni(cod)(L)], [Ni(nbd)(L)];
[0268] copper complexes: [CuCl(L)], [CuBr(L)], [CuI(L)], [CuH(L)],
[Cu(.eta..sup.1-BH.sub.4)(L)], [Cu(Cp)(L)], [Cu(Cp*)(L)],
[Cu(L)(CH.sub.3CN).sub.2]OTf, [Cu(L)(CH.sub.3CN).sub.2]BF.sub.4,
[Cu(L)(CH.sub.3CN).sub.2]ClO.sub.4,
[Cu(L)(CH.sub.3CN).sub.2]PF.sub.6,
[Cu(L)(CH.sub.3CN).sub.2]BPh.sub.4
[0269] Examples of the above-mentioned diphosphine ligand
represented by L include
2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (hereinafter sometimes
to be abbreviated as BINAP); BINAP derivatives having
substituent(s) such as a C.sub.1-6 alkyl group, a C.sub.6-14 aryl
group and the like on the naphthyl ring(s) of BINAP, for example,
2,2'-bis(diphenylphosphino)-6,6'-dimethyl-1,1'-binaphthyl;
BINAP derivatives wherein the naphthyl ring(s) of BINAP is/are
partially hydrogenated, for example,
2,2'-bis(diphenylphosphino)-5,6,7,8,5',6',7',8'-octahydro-1,1'-binaphthyl
(H8-BINAP); BINAP derivatives having 1 to 5 substituents such as a
C.sub.1-6 alkyl group, a halogen atom, a mono- or di-C.sub.1-6
alkylamino group, a C.sub.1-6 alkoxy group, a pyrrolidinyl group
and the like on the benzene ring(s) bonded to the phosphorus atom
of BINAP, for example,
2,2'-bis[bis(4-chlorophenyl)phosphino)-1,1'-binaphthyl,
2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl (tol-BINAP),
2,2'-bis[bis(3,5-dimethylphenyl)phosphino]-1,1'-binaphthyl
(xyl-BINAP),
2,2'-bis[bis(3,5-diethylphenyl)phosphino]-1,1'-binaphthyl,
2,2'-bis[bis(3,5-diisopropylphenyl)phosphino]-1,1'-binaphthyl,
2,2'-bis[bis(3,5-di-tert-butylphenyl)phosphino]-1,1'-binaphthyl,
2,2'-bis[bis(4-dimethylaminophenyl)phosphino]-1,1'-binaphthyl,
2,2'-bis[bis(4-dimethylamino-3,5-dimethylphenyl)phosphino]-1,1'-binaphthy-
l,
2,2'-bis[bis(4-dimethylamino-3,5-diethylphenyl)phosphino]-1,1'-binaphth-
yl,
2,2'-bis[bis(4-dimethylamino-3,5-diisopropylphenyl)phosphino]-1,1'-bin-
aphthyl,
2,2'-bis[bis(4-diethylaminophenyl)phosphino]-1,1'-binaphthyl,
2,2'-bis[bis[4-(pyrrolidin-1-yl)phenyl]phosphino]-1,1'-binaphthyl,
2,2'-bis(di-p-methoxyphenylphosphino)-1,1'-binaphthyl,
2,2'-bis[bis(3,5-dimethyl-4-methoxyphenyl)phosphino]-1,1'-binaphthyl,
2,2'-bis[bis(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-1,1'-binaphthyl
(DTBM-BINAP);
2,2'-bis(dicyclohexylphosphino)-6,6'-dimethyl-1,1'-biphenyl
(BICHEP), 2,2'-bis(diphenylphosphino)-6,6'-dimethoxybiphenyl
(MeO-BIPHEP), 2,3-bis(diphenylphosphino)butane (CHIRAPHOS),
1-cyclohexyl-1,2-bis(diphenylphosphino)ethane (CYCPHOS),
1,2-bis[(2-methoxyphenyl)phenylphosphino]ethane (DIPAMP),
1,2-bis(diphenylphosphino)propane (PROPHOS),
2,4-bis(diphenylphosphino)pentane (SKEWPHOS), SKEWPHOS derivative
having 1 to 5 substituents such as a C.sub.1-6 alkyl group and the
like on the benzene ring(s) bonded to the phosphorus atom of
SKEWPHOS, 1-[1',2-bis(diphenylphosphino)ferrocenyl]ethylenediamine
(BPPFA), 1-substituted-3,4-bis(diphenylphosphino)pyrrolidine
(DEGPHOS),
2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane
(DIOP), substituted-1,2-bisphosphoranobenzene (DuPHOS),
substituted-1,2-bisphosphoranoethane (BPE),
5,6-bis(diphenylphosphino)-2-norbornene (NORPHOS),
N,N'-bis(diphenylphosphino)-N,N'-bis(1-phenylethyl)ethylenediamine
(PNNP), 2,2'-diphenylphosphino-1,1'-bicyclopentyl (BICP),
4,12-bis(diphenylphosphino)-[2,2]-paracyclophane (PhanePHOS),
N-substituted-N-diphenylphosphino-1-[2-(diphenylphosphino)ferrocenyl]ethy-
lamine (BoPhoz),
1-[2-(disubstitutedphosphino)ferrocenyl]ethyl-disubstitutedphosphine
(Josiphos),
1-[2-(2'-disubstitutedphosphinophenyl)ferrocenyl]ethyl-disubstitutedphosp-
hine (Walphos),
2,2'-bis(.alpha.-N,N-dimethylaminophenylmethyl)-1,1'-bis(disubstitutedpho-
sphino)ferrocene (Mandyphos),
disubstitutedphosphino-2-[.alpha.-(N,N-dimethylamino)-o-disubstitutedphos-
phinophenyl-methyl]ferrocene (Taniaphos),
1,1-bis(disubstituted-phosphotano)ferrocene (FerroTANE),
7,7'-bis(diphenylphosphino)-3,3',4,4'-tetrahydro-4,4'-dimethyl-8,8'-bi(2H-
-1,4-benzoxazine) (Solphos) and the like.
[0270] The above-mentioned diphosphine ligand represented by L is
preferably an optically active form.
[0271] An optically active ligand is used as the "ligand" for the
"transition metal complex".
[0272] The "transition metal complex" can be produced from a ligand
and the other complex as a transition metal source according to a
known method (productions of rhodium complexes; Journal of the
American Chemical Society (J. Am. Chem. Soc.), vol. 94, page 6429,
1972, Organic Synthesis (Org. Synth.), vol. 67, page 33, 1989:
productions of ruthenium complexes; Journal of Organic Chemistry
(J. Org. Chem.), vol. 57, page 4053, 1992, Tetrahedron Asymmetry
(Tetrahedron Asym.), vol. 2, page 43, 1991, Journal of Organic
Chemistry (J. Org. Chem.), vol. 59, page 3064, 1994, Angewandte
Chemie International Edition (Angew. Chem., Int. Ed.), vol. 37,
page 1703, 1998: productions of iridium complexes;
[0273] Journal of Organometallic Chemistry (J. Organomet. Chem.),
vol. 428, page 213, 1992: productions of palladium complexes;
Organometallics (Organometallics), vol. 12, page 4188, 1993,
Journal of the American Chemical Society (J. Am. Chem. Soc.), vol.
121, page 5450, 1999: productions of nickel complexes; "5th Ed.,
Jikken Kagaku Koza" edited by Japan Chemical Society (Maruzen),
vol. 21, organic transition metal compound, supermolecular complex,
pages 293-294 (2004): productions of copper complexes; "5th Ed.,
Jikken Kagaku Koza" edited by Japan Chemical Society (Maruzen),
vol. 21, organic transition metal compound, supermolecular complex,
page 357 (2004), Journal of Organic Chemistry (J. Org. Chem.), vol.
63, page 6090, 1998), and can be isolated or purified by a known
means (e.g., concentration, solvent extraction, fractional
distillation, crystallization, recrystallization,
chromatography).
[0274] Among the "diphosphine ligand" represented by L, SKEWPHOS
derivative having 1 to 5 substituents such as a C.sub.1-6 alkyl
group and the like on the one benzene ring bonded to the phosphorus
atom of SKEWPHOS can be synthesized according to the method
described in the Patent Document WO 2013/146987.
[0275] The "transition metal complex" can also be prepared by
adding a "ligand" and the other complex as a transition metal
source to a reaction system. The "transition metal complex" may be
directly added to a reaction container, or may be prepared by
adding the above-mentioned "transition metal" and "ligand" to a
container. When the "transition metal complex" is prepared by
adding the "transition metal" and "ligand" to a container, the
"ligand" is used in an amount of 1- to 100-fold by mole, preferably
1 to 5-fold by mole, further more preferably 1.01 to 2.02-fold by
mole, relative to the theoretical mole required to prepare the
"transition metal complex".
[0276] For example, the rhodium complex of SKEWPHOS derivative
having 1 to 5 substituents such as a C.sub.1-6 alkyl group and the
like on the one benzene ring bonded to the phosphorus atom of
SKEWPHOS, among the "diphosphine ligand" represented by L, can be
synthesized according to the method described in the Patent
Document WO 2013/146987.
[0277] In addition, the "transition metal complex" is preferably a
ruthenium complex represented by the formula:
[Ru(OCOR.sup.a).sub.2L.sup.a] (VIII)
wherein R.sup.a is an optionally substituted C.sub.1-3 alkyl group;
and L.sup.a is a diphosphine ligand, which is exemplified by
[Ru(OAc).sub.2(L)] or [Ru(OCOCF.sub.3).sub.2(L)], among the
"ruthenium complexes".
[0278] Preferable examples of the "C.sub.1-3 alkyl group" of the
"optionally substituted C.sub.1-3 alkyl group" represented by
R.sup.a include methyl, ethyl and isopropyl, and methyl is
particularly preferable.
[0279] The "C.sub.1-3 alkyl group" of the "optionally substituted
C.sub.1-3 alkyl group" represented by R.sup.a each optionally has 1
to 5 (preferably 1 to 3) substituents at substitutable position(s).
Examples of the substituent include the above-mentioned the
above-mentioned Substituent Group A. The substituent is preferably
a halogen atom, more preferably a fluorine atom. When the number of
the substituents is plural, the respective substituents may be the
same or different.
[0280] The "optionally substituted C.sub.1-3 alkyl group"
represented by R.sup.a is preferably methyl or trifluoromethyl,
more preferably trifluoromethyl.
[0281] Examples of the diphosphine ligand represented by L.sup.a
include those similar to the diphosphine ligands exemplified as L;
among them, preferred are
2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (hereinafter sometimes
to be abbreviated as BINAP); BINAP derivatives having
substituent(s) such as a C.sub.1-6 alkyl group, a C.sub.6-14 aryl
group and the like on the naphthyl ring(s) of BINAP, for example,
2,2'-bis(diphenylphosphino)-6,6'-dimethyl-1,1'-binaphthyl; BINAP
derivatives wherein the naphthyl ring(s) of BINAP is/are partially
hydrogenated, for example,
2,2'-bis(diphenylphosphino)-5,6,7,8,5',6',7',8'-octahydro-1,1'-binaphthyl
(H8-BINAP); BINAP derivatives having 1 to 5 substituents such as a
C.sub.1-6 alkyl group and the like on the one benzene ring bonded
to the phosphorus atom of BINAP, for example,
2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl (tol-BINAP),
2,2'-bis[bis(3,5-dimethylphenyl)phosphino]-1,1'-binaphthyl
(xyl-BINAP),
2,2'-bis[bis(3,5-diethylphenyl)phosphino]-1,1'-binaphthyl,
2,2'-bis[bis(3,5-diisopropylphenyl)phosphino]-1,1'-binaphthyl,
2,2'-bis[bis(3,5-di-tert-butylphenyl)phosphino]-1,1'-binaphthyl,
2,2'-bis[bis(4-dimethylaminophenyl)phosphino]-1,1'-binaphthyl,
2,2'-bis[bis(4-dimethylamino-3,5-dimethylphenyl)phosphino]-1,1'-binaphthy-
l,
2,2'-bis[bis(4-dimethylamino-3,5-diethylphenyl)phosphino]-1,1'-binaphth-
yl,
2,2'-bis[bis(4-dimethylamino-3,5-diisopropylphenyl)phosphino]-1,1'-bin-
aphthyl,
2,2'-bis[bis(4-diethylaminophenyl)phosphino]-1,1'-binaphthyl and
2,2'-bis[bis[4-(pyrrolidin-1-yl)phenyl]phosphino]-1,1'-binaphthyl,
2,2'-bis(di-p-methoxyphenylphosphino)-1,1'-binaphthyl,
2,2'-bis[bis(3,5-dimethyl-4-methoxyphenyl)phosphino]-1,1'-binaphthyl,
2,2'-bis[bis(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-1,1'-binaphthyl
(DTBM-BINAP), 4,12-bis(diphenylphosphino)-[2,2]-paracyclophane
(PhanePHOS), and
2,2'-bis(.alpha.-N,N-dimethylaminophenylmethyl)-1,1'-bis(disubstitutedpho-
sphino)ferrocene (Mandyphos); more preferred are
2,2'-bis(diphenylphosphino)-1,1'-binaphthyl,
2,2'-bis[bis(4-chlorophenyl)phosphino)-1,1'-binaphthyl, and
2,2'-bis(.alpha.-N,N-dimethylaminophenylmethyl)-1,1'-bis(disubstitutedpho-
sphino)ferrocene (Mandyphos); and further more preferred are
2,2'-bis[bis(4-chlorophenyl)phosphino)-1,1'-binaphthyl, and
2,2'-bis(.alpha.-N,N-dimethylaminophenylmethyl)-1,1'-bis(disubstitutedpho-
sphino)ferrocene (Mandyphos).
[0282] The ruthenium complex represented by the formula (VIII) is
preferably a ruthenium complex represented by the formula:
[Ru(OCOR.sup.a').sub.2L.sup.a'] (VIII')
wherein R.sup.a' is a trifluoromethyl group; and L.sup.a' is an
optically active diphosphine ligand selected from (1) an optically
active form consisting of a compound represented by the
formula:
##STR00032##
Or
[0283] the formula:
##STR00033##
or a mixture thereof, and (2) an optically active form of a
compound represented by the formula:
##STR00034##
wherein the bond marked with * is a chiral axis.
[0284] The optically active form consisting of the above-mentioned
mixture means that a mixture (excluding a mixture of 1 mol: 1 mol)
of ruthenium complex (VIII') wherein L.sup.a, is an optically
active compound represented by the formula (IX-a) and ruthenium
complex (VIII') wherein L.sup.a, is an optically active compound
represented by the formula (IX-b) is used as a ruthenium
complex.
[0285] The ruthenium complex represented by the formula (VIII) or
(VIII') can be synthesized, for example, by reference to the method
described in JP-A-S62-265293, Tetrahedron Lettes, 39, page 4441,
1998 or the like.
[0286] These ruthenium complexes are useful as a catalyst with high
reaction selectivity in various hydrogenation reactions such as
Production Method (A) and the like.
[0287] Preferable specific examples of the ruthenium complex
include the followings: [Ru(OCOCF.sub.3).sub.2{(S)-p-Cl-binap}],
[Ru(OCOCF.sub.3).sub.2{(S)--(R)-mandyphos}], [RuCl.sub.2(S)-binap],
[Ru(OCOCF.sub.3).sub.2{(S)-binap}] and
[Ru(OCOCF.sub.3).sub.2{(S)-phanephos}]. Among the,
[Ru(OCOCF.sub.3).sub.2{(S)-binap}] and
[Ru(OCOCF.sub.3).sub.2{(S)--(R)-mandyphos}] are preferable.
[0288] While the amount of the "transition metal complex" to be
used varies depending on the reaction container, reaction procedure
and the like, it is, for example, about 1.0-about 0.00001 mol per 1
mol of the compound represented by the formula (I) or a salt
thereof, which is a substrate.
[0289] In the "hydrogenation reaction" in Production Method (A),
hydrogen gas, metal hydride, isopropanol, formic acid,
benzthiazoline, Hantzsch ester and the like can be used as a
hydrogen donor. Among them, hydrogen gas is preferably used.
[0290] When hydrogen gas is used, the hydrogenation reaction can be
carried out by batch process or continuous process. When the
hydrogenation reaction is carried out in the presence of hydrogen
gas, the hydrogen pressure is, for example, 0.001 to 200 atm,
preferably 0.1 to 15 atm.
[0291] In the "hydrogenation reaction" in Production Method (A), an
additive such as a base, an acid, a salt and the like may be added,
if necessary. The additive may be used in a mixture of two or more
kinds thereof. The additive may be added to a reaction container
before or during the "hydrogenation reaction".
[0292] Examples of the base that may be added for the
"hydrogenation reaction" in Production Method (A) include inorganic
bases and organic bases.
[0293] Examples of the inorganic base include alkali metal
hydroxides such as lithium hydroxide, potassium hydroxide, sodium
hydroxide, cesium hydroxide and the like; alkali metal alkoxides
having 1 to 6 carbon atoms such as lithium methoxide, sodium
methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide,
potassium ethoxide, lithium propoxide, sodium propoxide, potassium
propoxide, lithium isopropoxide, sodium isopropoxide, potassium
isopropoxide, potassium tert-butoxide and the like; alkali metal
thioalkoxides having 1 to 6 carbon atoms such as sodium
thiomethoxide and the like; carbonates such as sodium carbonate,
potassium carbonate, cesium carbonate and the like;
hydrogencarbonates such as sodium hydrogencarbonate, potassium
hydrogencarbonate and the like; acetates such as sodium acetate,
potassium acetate and the like; phosphorates such as tripotassium
phosphate, sodium phosphate and the like; and hydrogenphosphates
such as dipotassium hydrogenphosphate, disodium hydrogenphosphate
and the like.
[0294] Examples of the organic base include aliphatic amines such
as trimethylamine, triethylamine, N-methylmorpholine,
N,N-diisopropylethylamine, diethylamine, diisopropylamine,
cyclohexylamine, ethylenediamine and the like; aromatic amines such
as pyridine, picoline, N,N-dimethylaniline and the like; and basic
amino acids such arginine, lysine, ornithine and the like.
[0295] While the amount of the base to be used varies depending on
the kind of the solvent and the other reaction conditions, it is
generally about 0.01 mol or more per 1 mol of the compound
represented by the formula (I) or a salt thereof, which is a
substrate. The base may be used as a solvent.
[0296] Examples of the acid that may be added for the
"hydrogenation reaction" in Production Method (A) include mineral
acids (specifically hydrofluoric acid, hydrochloric acid,
hydrobromic acid, hydriodic acid, nitric acid, sulfuric acid,
sulfurous acid, phosphoric acid, phosphorous acid, carbonic acid,
bicarbonic acid and the like); carboxylic acids (i.e., compounds
having one or more carboxy groups; specifically formic acid, acetic
acid, trifluoroacetic acid, benzoic acid, phthalic acid, fumaric
acid, oxalic acid, tartaric acid, maleic acid, citric acid,
succinic acid, malic acid and the like); acidic amino acids
(specifically aspartic acid, glutamic acid and the like); and
sulfonic acids (i.e., compounds having one or more sulfo groups;
specifically methanesulfonic acid, trifluoromethanesulfonic acid,
benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid
and the like). These may be used in a mixture of two or more kinds
thereof, in necessary. Preferable examples of the acid that may be
added for the "hydrogenation reaction" in Production Method (A)
include sulfonic acid and sulfuric acid; and sulfonic acid is more
preferable.
[0297] The sulfonic acid means a compound having one or more sulfo
groups, and is preferably the above-mentioned sulfonic acid
represented by the formula (VII); more preferably methanesulfonic
acid, trifluoromethanesulfonic acid, benzenesulfonic acid or
p-toluenesulfonic acid; particularly preferably p-toluenesulfonic
acid.
[0298] While the amount of the acid to be used varies depending on
the kind of the solvent and the other reaction conditions, it is
generally about 0.01 mol or more per 1 mol of the compound
represented by the formula (I) or a salt thereof, which is a
substrate. The acid may be used as a solvent. The amount thereof is
preferably 0.05 to 1.5 mol.
[0299] Examples of the salt that may be added for the
"hydrogenation reaction" in Production Method (A) include, in
addition to the salts exemplified in the above-mentioned "inorganic
base", salts containing the above-mentioned "acid" used for the
"hydrogenation reaction" as an acid component. Among them, salts
containing a halogen anion are preferable, and examples thereof
include alkali metal halides and a compound represented by the
formula:
##STR00035##
wherein R.sup.A, R.sup.B, R.sup.C and R.sup.D are independently a
hydrogen atom, or an optionally substituted hydrocarbon group; and
X is a halogen atom, and the like.
[0300] Preferable examples of the "hydrocarbon group" of the
"optionally substituted hydrocarbon group" represented by R.sup.A,
R.sup.B, R.sup.C or R.sup.D include a C.sub.1-6 alkyl group, a
C.sub.3-10 cycloalkyl group, a C.sub.6-14 aryl group, a C.sub.7-16
aralkyl group and the like. The "hydrocarbon group" of the
"optionally substituted hydrocarbon group" represented by R.sup.A,
R.sup.B, R.sup.C or R.sup.D is particularly preferably n-butyl.
[0301] The "alkali metal halide" exemplified as the "salt" that may
be added for the "hydrogenation reaction" in Production Method (A)
means a salt consisting of a halogen atom (e.g., chlorine, bromine,
iodine) which is an anion, and an alkali metal (e.g., lithium,
sodium, potassium, cesium) which is a cation, and among them,
preferred are lithium bromide, sodium bromide, potassium bromide,
lithium chloride, sodium chloride, potassium chloride, lithium
iodide, sodium iodide and potassium iodide; more preferred are
lithium bromide, sodium bromide, potassium bromide, lithium
chloride, sodium chloride and potassium chloride; and particularly
preferred is potassium bromide. The "alkali metal halide" may be a
hydrate.
[0302] Preferable examples of the above-mentioned compound
represented by the formula (VI) include tetrabutylammonium bromide,
tetrabutylammonium chloride, tetrabutylammonium iodide and
n-butylammonium chloride.
[0303] While the amount of the compound (a salt having a halogen
anion) to be used varies depending on the kind of the solvent and
the other reaction conditions, it is generally 1 to 100 equivalent,
preferably 2 to 20 equivalent, relative to the organic metal
complex.
[0304] The "salt" that may be added for the "hydrogenation
reaction" in Production Method (A) is preferably an alkali metal
halide; and potassium bromide is particularly preferable.
[0305] The "hydrogenation reaction" in Production Method (A) is
generally carried out in a solvent. The solvent is not particularly
limited as long as it does not inhibit the reaction and dissolves
the raw material compound, organic metal complex and additive.
Examples thereof include ethers such as diethyl ether, diisopropyl
ether, tert-butyl methyl ether, diphenyl ether, tetrahydrofuran,
1,4-dioxane, methyltetrahydrofuran, 1,2-dimethoxyethane,
1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane,
anisole and the like; alcohols such as methanol, ethanol,
n-propanol, isopropanol, n-butanol, 2-butanol, tert-butanol,
3-methyl-1-butanol, 2-methyl-1-propanol, 1-pentanol, benzyl
alcohol, 2-methoxyethanol, 2-ethoxyethanol, ethylene glycol and the
like; aromatic hydrocarbons such as benzene, toluene, xylene,
cumene, chlorobenzene and the like; saturated hydrocarbons such as
hexane, heptane, pentane, cyclohexane, methylcyclohexane,
isooctane, petroleum ether and the like; amides such as
N,N-dimethylformamide, N,N-dimethylacetamide, formamide,
hexamethylphosphoramide, N-methylpyrrolidone,
1,3-dimethyl-2-imidazolidinone and the like; halogenated
hydrocarbons such as dichloromethane, chloroform, carbon
tetrachloride, 1,2-dichloroethane and the like; nitriles such as
acetonitrile, propionitrile and the like; sulfoxides such as
dimethyl sulfoxide and the like; sulfones such as dimethylsulfone,
sulfolane and the like; ketones such as acetone, ethylmethylketone,
methylisopropylketone, methylbutylketone and the like; esters such
as ethyl acetate, isopropyl acetate, n-propyl acetate, n-butyl
acetate, isobutyl acetate, methyl acetate, ethyl formate and the
like; nitromethane; water and the like. These solvents may be used
as a mixture in an appropriate ratio. Preferable examples of the
solvent to be used for the "hydrogenation reaction" in Production
Method (A) include alcohols. Among the, methanol, ethanol and
isopropanol are preferable, and isopropanol is particularly
preferable.
[0306] The amount of the solvent to be used is appropriately
determined depending on the solubility of the compound represented
by the formula (I) or a salt thereof, which is a substrate, and the
like. For example, when an alcohol (preferably isopropanol) is used
as a solvent, the reaction can be carried out from nearly in
absence of a solvent to in a 100-fold by weight or more of solvent,
relative to the compound represented by the formula (I) or a salt
thereof, which is a substrate. Generally, the solvent is preferably
used in an amount of about 2-about 100-fold by weight, relative to
the compound represented by the formula (I) or a salt thereof,
which is a substrate.
[0307] In the "hydrogenation reaction" in Production Method (A),
the reaction temperature is generally -30 to 160.degree. C.,
preferably 0 to 120.degree. C., more preferably 10 to 80.degree. C.
The reaction time is generally 0.1 to 120 hr, preferably 1 to 72
hr.
[0308] The optically active form of the compound represented by the
formula (II) or a salt thereof obtained by the "hydrogenation
reaction" may be purified by a known means (e.g., fractional
recrystallization method, chiral column method, diastereomer salt
method). In order to obtain the optically active form of the
compound represented by the formula (II) or a salt thereof with
high optical purity, it is preferably purified by fractional
recrystallization method or diastereomer salt method. When the
optically active form of the compound represented by the formula
(II) or a salt thereof is optically active piperidine-3-carboxamide
p-toluenesulfonate, it is particularly preferably directly purified
by fractional recrystallization method.
[0309] The compound represented by the formula (I) can be
synthesized, for example, according the method described in Journal
of Organic Chemistry (J. Org. Chem.), vol. 31, page 2487, 1966 or
Journal of Organic Chemistry (J. Org. Chem.), vol. 33, page 747,
1968.
[0310] Production Method (A) can be employed for producing an
optically active form of a compound having more complicated
structure or a salt thereof in combination with other reaction.
[0311] The production method of the optically active form of the
compound represented by the formula (V) or a salt thereof employing
Production Method (A) is explained below.
[Production Method (B)]
[0312] The optically active form of the compound represented by the
formula (V) or a salt thereof can be produced according to
Production Method (B) shown in the following reaction scheme.
##STR00036##
wherein each symbol is as defined above.
[0313] The reagents and conditions used for Production Method (B)
are explained in detail each step below.
[Step B-1]
[0314] Step B-1 is a step of producing the optically active form of
the compound represented by the formula (II') or a salt thereof by
subjecting the compound represented by the formula (I') or a salt
thereof to an asymmetric hydrogenation reaction, as shown in the
following reaction scheme.
##STR00037##
wherein each symbol is as defined above.
[0315] The asymmetric hydrogenation reaction of Step B-1 is carried
out in the same manner as in Production Method (A), except that the
compound represented by the formula (I') is used instead of the
compound represented by the formula (I), and thereby, the optically
active form of the compound represented by the formula (II') is
produced instead of the optically active form of the compound
represented by the formula (II).
[0316] The compound represented by the formula (I') can be
synthesized, for example, according to the method described in
Journal of Organic Chemistry (J. Org. Chem.), vol. 31, page 2487,
1966 or Journal of Organic Chemistry (J. Org. Chem.), vol. 33, page
747, 1968.
[Step B-2]
[0317] Step B-2 is a step of producing the optically active form of
the compound represented by the formula (IV) or a salt thereof by
subjecting the optically active form of the compound represented by
the formula (II') or a salt thereof obtained in Step B-1 to a
condensation reaction with the compound represented by the formula
(III) or a salt thereof, as shown in the following reaction
scheme.
##STR00038##
wherein each symbol is as defined above.
[0318] The compound represented by the formula (III) can be
synthesized, for example, according to the method described in WO
2007/035629.
[0319] While the amount of the compound represented by the formula
(III) or a salt thereof to be used varies depending on the kind of
the solvent and the other reaction conditions, it is generally 0.01
to 100 mol, preferably 0.1 to 10 mol, more preferably 0.9 to 1.1
mol, per 1 mol of the optically active form of the compound
represented by the formula (II') or a salt thereof 1 mol.
[0320] The reaction of Step B-2 is generally carried out in a
solvent, and a base may be added for the progress of the reaction.
The solvent is not particularly limited as long as it does not
inhibit the reaction and dissolves the raw material compound,
organic metal complex and additive. Examples thereof include ethers
such as diethyl ether, diisopropyl ether, tert-butyl methyl ether,
diphenyl ether, tetrahydrofuran, 1,4-dioxane,
methyltetrahydrofuran, 1,2-dimethoxyethane, 1,1-diethoxypropane,
1,1-dimethoxymethane, 2,2-dimethoxypropane, anisole and the like;
alcohols such as methanol, ethanol, n-propanol, isopropanol,
n-butanol, 2-butanol, tert-butanol, 3-methyl-1-butanol,
2-methyl-1-propanol, 1-pentanol, benzyl alcohol, 2-methoxyethanol,
2-ethoxyethanol, ethylene glycol and the like; aromatic
hydrocarbons such as benzene, toluene, xylene, cumene,
chlorobenzene and the like; saturated hydrocarbons such as hexane,
heptane, pentane, cyclohexane, methylcyclohexane, isooctane,
petroleum ether and the like; amides such as N,N-dimethylformamide,
N,N-dimethylacetamide, formamide, hexamethylphosphoramide,
N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone and the like;
halogenated hydrocarbons such as chloroform, dichloromethane,
chloroform, carbon tetrachloride, 1,2-dichloroethane and the like;
nitriles such as acetonitrile, propionitrile and the like;
sulfoxides such as dimethyl sulfoxide and the like; sulfones such
as dimethylsulfone, sulfolane and the like; ketones such as
acetone, ethylmethylketone, methylisopropylketone,
methylbutylketone and the like; esters such as ethyl acetate,
isopropyl acetate, n-propyl acetate, n-butyl acetate, isobutyl
acetate, methyl acetate, ethyl formate and the like; nitromethane;
water and the like. These solvents may be used as a mixture in an
appropriate ratio. Preferable examples of the solvent to be used in
Step B-2 include alcohols. Among them, isopropanol is particularly
preferable. When isopropanol is used as a solvent, it is preferably
used in a mixed solvent with water, and the volume ratio is
preferably isopropanol:water=9:0.01 to 1:9.
[0321] The amount of the solvent to be used is appropriately
determined depending on solubility of the optically active form of
the compound represented by the formula (II') or a salt thereof,
and the like. For example, when an alcohol (preferably isopropanol)
is used as a solvent, the reaction can be carried out from nearly
in absence of a solvent to in a 100-fold by weight or more of
solvent, relative to the optically active form of the compound
represented by the formula (II') or a salt thereof, which is a
substrate. Generally, the solvent is preferably used in an amount
of about 2-about 100-fold by weight, relative to the optically
active form of the compound represented by the formula (II') or a
salt thereof, which is a substrate.
[0322] Examples of the base that may be used in Step B-2 include
inorganic bases and organic bases.
[0323] Examples of the inorganic base include alkali metal
hydroxides such as lithium hydroxide, potassium hydroxide, sodium
hydroxide, cesium hydroxide and the like; alkali metal alkoxides
having 1 to 6 carbon atoms such as lithium methoxide, sodium
methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide,
potassium ethoxide, lithium propoxide, sodium propoxide, potassium
propoxide, lithium isopropoxide, sodium isopropoxide, potassium
isopropoxide, potassium tert-butoxide and the like; alkali metal
thioalkoxides having 1 to 6 carbon atoms such as sodium
thiomethoxide and the like; carbonates such as sodium carbonate,
potassium carbonate, cesium carbonate and the like;
hydrogencarbonates such as sodium hydrogencarbonate, potassium
hydrogencarbonate and the like; acetates such as sodium acetate,
potassium acetate and the like; phosphorates such as tripotassium
phosphate, sodium phosphate and the like; and hydrogenphosphates
such as dipotassium hydrogenphosphate, disodium hydrogenphosphate
and the like.
[0324] Examples of the organic base include aliphatic amines such
as trimethylamine, triethylamine, N-methylmorpholine,
N,N-diisopropylethylamine, diethylamine, diisopropylamine,
cyclohexylamine, ethylenediamine, 1,8-diazabicyclo[5.4.0]undecene
and the like; aromatic amines pyridine, picoline,
N,N-dimethylaniline and the like; and basic amino acids such as
arginine, lysine, ornithine and the like.
[0325] The base that may be used in Step B-2 is particularly
preferably potassium carbonate.
[0326] While the amount of the base to be used varies depending on
the kind of the solvent and the other reaction conditions, it is
generally about 0.01 mol or more, per 1 mol of the optically active
form of the compound represented by the formula (II') or a salt
thereof. The base may be used as a solvent. The amount of the base
to be used is preferably 0.5 to 10 mol, more preferably 1 to 5 mol,
per 1 mol of the optically active form of the compound represented
by the formula (II') or a salt thereof.
[0327] The reaction temperature is generally -30.degree. C. to
160.degree. C., preferably 0 to 120.degree. C., more preferably 30
to 90.degree. C. The reaction time is generally 0.1 to 120 hr,
preferably 1 to 72 hr.
[0328] The optically active form of the compound represented by the
formula (IV) or a salt thereof obtained in Step B-2 may be purified
by a known means (e.g., fractional recrystallization method, chiral
column method, diastereomer salt method).
[Step B-3]
[0329] Step B-3 is a step of producing the optically active form of
the compound represented by the formula (V) or a salt thereof by
subjecting the optically active form of the compound represented by
the formula (IV) or a salt thereof to a rearrangement reaction, as
shown in the following reaction scheme.
##STR00039##
wherein each symbol is as defined above.
[0330] The rearrangement reaction of Step B-3 is preferably carried
out using an oxidant. Examples of the "oxidant" include hypohalites
such as potassium hypochlorite, sodium hypochlorite, tert-butyl
hypochlorite, potassium hypobromite, sodium hypobromite, potassium
hypoiodite, sodium hypoiodite and the like; lead tetraacetate;
halogens such as bromine, iodine and the like; halogenated imide
reagents such as N-bromosuccinimide, N-iodosuccinimide and the
like; hypervalent iodine reagents such as iodobenzene diacetate,
[bis(trifluoroacetoxy)iodo]benzene, iodotoluenediacetate,
[bis(trifluoroacetoxy)iodo]toluene and the like, and the like.
Preferable examples of the oxidant to be used for the rearrangement
reaction of Step B-3 include hypervalent iodine reagents. Among
them, iodobenzene diacetate is more preferable.
[0331] While the amount of the oxidant to be used varies depending
on the kind of the solvent and the other reaction conditions, it is
generally 0.01 to 100 mol, preferably 0.1 to 10 mol, more
preferably 0.9 to 2 mol, per 1 mol of the optically active form of
the compound represented by the formula (IV) or a salt thereof.
[0332] In the rearrangement reaction of Step B-3, an additive such
as a base, an acid, a salt and the like may be added. The additive
may be used in a mixture of two or more kinds thereof, if
necessary. The additive may be added to a reaction container before
or during the rearrangement reaction.
[0333] Examples of the base that may be added for the rearrangement
reaction of Step B-3 include inorganic bases and organic bases.
[0334] Examples of the inorganic base include alkali metal
hydroxides such as lithium hydroxide, potassium hydroxide, sodium
hydroxide, cesium hydroxide and the like; alkali metal alkoxides
having 1 to 6 carbon atoms such as lithium methoxide, sodium
methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide,
potassium ethoxide, lithium propoxide, sodium propoxide, potassium
propoxide, lithium isopropoxide, sodium isopropoxide, potassium
isopropoxide, potassium tert-butoxide and the like; alkali metal
thioalkoxides having 1 to 6 carbon atoms such as sodium
thiomethoxide and the like; carbonates such as sodium carbonate,
potassium carbonate, cesium carbonate and the like;
hydrogencarbonates such as sodium hydrogencarbonate, potassium
hydrogencarbonate and the like; acetates such as sodium acetate,
potassium acetate and the like; phosphorates such as tripotassium
phosphate, sodium phosphate and the like; and hydrogenphosphates
such as dipotassium hydrogenphosphate, disodium hydrogenphosphate
and the like.
[0335] Examples of the organic base include aliphatic amines such
as trimethylamine, triethylamine, N-methylmorpholine,
N,N-diisopropylethylamine, diethylamine, diisopropylamine,
cyclohexylamine, ethylenediamine, 1,8-diazabicyclo[5.4.0]undecene
and the like; aromatic amines such as pyridine, picoline,
N,N-dimethylaniline and the like; and basic amino acids such as
arginine, lysine, ornithine and the like.
[0336] While the amount of the base to be used varies depending on
the kind of the solvent and the other reaction conditions, it is
generally about 0.001 mol or more, preferably 0.001 to 10 mol, more
preferably 0.01 to 2 mol, per 1 mol of the optically active form of
the compound represented by the formula (IV) or a salt thereof,
which is a substrate. The base may be used as a solvent.
[0337] Examples of the acid that may be added for the rearrangement
reaction of Step B-3 include mineral acids such as hydrofluoric
acid, hydrochloric acid, hydrobromic acid, hydriodic acid, nitric
acid, sulfuric acid, sulfurous acid and the like; phosphoric acid,
phosphorous acid, carbonic acid, bicarbonic acid; carboxylic acids
such as formic acid, acetic acid, trifluoroacetic acid, phthalic
acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric
acid, succinic acid, malic acid and the like; acidic amino acids
such as aspartic acid, glutamic acid and the like; and sulfonic
acids such as methanesulfonic acid, trifluoromethanesulfonic acid,
benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid
and the like. These may be used in a mixture of two or more kinds
thereof, if necessary.
[0338] While the amount of the acid to be used varies depending on
the kind of the solvent and the other reaction conditions, it is
generally 0.001 mol or more, preferably 0.001 to 10 mol, more
preferably 0.01 to 2 mol, per 1 mol of the optically active form of
the compound represented by the formula (IV) or a salt thereof. The
acid may be used as a solvent.
[0339] Examples of the salt that may be added for the rearrangement
reaction of Step B-3 include, in addition to the salts exemplified
in the above-mentioned "inorganic base", salts containing the
above-mentioned "acid" used for the rearrangement reaction as an
acid component. Among them, salts containing a halogen anion are
preferable, and examples thereof include the above-mentioned alkali
metal halides and the above-mentioned ammonium salt represented by
the formula (VI), and the like.
[0340] While the amount of the salt to be used varies depending on
the kind of the solvent and the other reaction conditions, it is
generally about 0.001 mol or more, preferably 0.001 to 10 mol, more
preferably 0.01 to 2 mol, per 1 mol of the optically active form of
the compound represented by the formula (IV) or a salt thereof. The
salt may be used as a solvent.
[0341] Preferable examples of the additive that may be added for
the rearrangement reaction of Step B-3 include bases, and sodium
hydroxide, pyridine, triethylamine, potassium carbonate, sodium
hydrogencarbonate and ammonium chloride are more preferable, and
pyridine is particularly preferable.
[0342] The reaction of Step B-3 is generally carried out in a
solvent. The solvent is not particularly limited as long as it does
not inhibit the reaction and dissolves the raw material compound,
organic metal complex and additive. Examples thereof include ethers
such as diethyl ether, diisopropyl ether, tert-butyl methyl ether,
diphenyl ether, tetrahydrofuran, 1,4-dioxane,
methyltetrahydrofuran, 1,2-dimethoxyethane, 1,1-diethoxypropane,
1,1-dimethoxymethane, 2,2-dimethoxypropane, anisole and the like;
alcohols such as methanol, ethanol, n-propanol, isopropanol,
n-butanol, 2-butanol, tert-butanol, 3-methyl-1-butanol,
2-methyl-1-propanol, 1-pentanol, benzyl alcohol, 2-methoxyethanol,
2-ethoxyethanol, ethylene glycol and the like; aromatic
hydrocarbons such as benzene, toluene, xylene, cumene,
chlorobenzene and the like; saturated hydrocarbons such as hexane,
heptane, pentane, cyclohexane, methylcyclohexane, isooctane,
petroleum ether and the like; halogenated hydrocarbons such as
chloroform, dichloromethane, chloroform, carbon tetrachloride,
1,2-dichloroethane and the like; nitriles such as acetonitrile,
propionitrile and the like; sulfoxides such as dimethyl sulfoxide
and the like; sulfones such as dimethylsulfone, sulfolane and the
like; ketones such as acetone, ethylmethylketone,
methylisopropylketone, methylbutylketone and the like; esters such
as ethyl acetate, isopropyl acetate, n-propyl acetate, n-butyl
acetate, isobutyl acetate, methyl acetate, ethyl formate and the
like; nitromethane; water and the like. These solvents may be used
as a mixture in an appropriate ratio. Preferable examples of the
solvent to be used in Step B-3 include alcohols and nitriles. Among
alcohols, ethanol and isopropanol are particularly preferable. When
ethanol or isopropanol is used as a solvent, it is preferably used
in a mixed solvent with water, and the volume ratio is preferably
isopropanol:water=9:1 to 1:9. Among nitriles, acetonitrile is
particularly preferable. When acetonitrile is used as a solvent, it
is preferably used in a mixed solvent with water, and the volume
ratio is preferably acetonitrile:water=9:1 to 1:9.
[0343] The amount of the solvent to be used is appropriately
determined depending on the solubility of the optically active form
of the compound represented by the formula (IV) or a salt thereof,
and the like. For example, when an alcohol (preferably ethanol,
isopropanol) or a nitrile (preferably acetonitrile) is used as a
solvent, the reaction can be carried out from nearly in absence of
a solvent to in a 100-fold by weight or more of solvent, relative
to the optically active form of the compound represented by the
formula (IV) or a salt thereof. Generally, the solvent is
preferably used in an amount of about 2-about 100-fold by weight,
relative to the optically active form of the compound represented
by the formula (IV) or a salt thereof, which is a substrate.
[0344] The reaction temperature is generally -30.degree. C. to
160.degree. C., preferably 0 to 80.degree. C., more preferably 0 to
30.degree. C. The reaction time is generally 0.1 to 120 hr,
preferably 1 to 72 hr.
[0345] The optically active form of the compound represented by the
formula (V) or a salt thereof obtained in Step B-3 may be purified
by a known means (e.g., fractional recrystallization method, chiral
column method, diastereomer salt method).
EXAMPLES
[0346] The present invention is explained in detail in the
following by referring to Reference Examples and Examples, which
are merely exemplified and not to be construed as limitative, and
the invention may be changed within the scope of the present
invention.
[0347] In the following Reference Examples and Examples, the "room
temperature" generally means about 10.degree. C. to about
35.degree. C. The chemical yield is an isolated yield (mol/mol %)
or a yield measured by high-performance liquid chromatography. The
optical purity (asymmetric yield) of an optically active form is
evaluated by enantiomeric excess (% e.e.). The enantiomeric excess
is calculated according to the following formula.
[0348] Enantiomeric excess (% e.e.)=100.times.[(R)-(S)]/[(R)+(S)]
or 100.times.[(S)-(R)]/[(R)+(S)] wherein (R) and (S) are each an
area of each enantiomer measured by high-performance liquid
chromatography.
[0349] In addition, the amount of solvent used for chromatography
is shown by % by volume, and the amount of the other is shown by %
by weight.
[0350] In proton NMR spectrum, broad and unidentified protons such
as OH and NH protons and the like are not described in data.
[0351] The abbreviations used in the specification mean the
following. [0352] s: singlet [0353] d: doublet [0354] t: triplet
[0355] q: quartet [0356] m: multiplet [0357] br: broad [0358] J:
coupling constant [0359] Hz: hertz [0360] CDCl.sub.3:
deuterochloroform [0361] DMSO-d.sub.5: deuterodimethyl sulfoxide
[0362] CD.sub.3OD: deuterated methanol [0363] .sup.1H-NMR: proton
nuclear magnetic resonance [0364] .sup.13C-NMR: .sup.13C nuclear
magnetic resonance [0365] .sup.19F-NMR: .sup.19F nuclear magnetic
resonance [0366] .sup.31P-NMR: .sup.31P nuclear magnetic resonance
[0367] RuCl.sub.2{(S)-binap}:
dichloro[(S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]ruthenium(II-
)
[0368] In the following Reference Examples and Examples, the
nuclear magnetic resonance spectrum (NMR) was measured under the
following conditions.
[0369] .sup.1H nuclear magnetic resonance spectrum (.sup.1H-NMR):
BRUKER AVANCE 500 (500 MHz) manufactured by Bruker Corporation,
internal standard material: tetramethylsilane
[0370] .sup.13C nuclear magnetic resonance spectrum (.sup.13C-NMR):
BRUKER AVANCE 500 (125 MHz) manufactured by Bruker Corporation,
internal standard material: CDCl.sub.3
[0371] .sup.19F nuclear magnetic resonance spectrum (.sup.19F-NMR):
BRUKER AVANCE 500 (202 MHz) manufactured by Bruker Corporation,
external standard material: trifluoroacetic acid
[0372] .sup.31P nuclear magnetic resonance spectrum (.sup.31P-NMR):
BRUKER AVANCE 500 (471 MHz) manufactured by Bruker Corporation,
external standard material: 85%-H.sub.3PO.sub.4 aqueous
solution
Reference Example 1
Synthesis of 1,4,5,6-tetrahydropyridine-3-carboxamide
##STR00040##
[0374] Nicotinamide (50.00 g) [mw. 122.12, 0.409 mol], 5% Pd/C
(5.00 g) and methanol (500 mL) were placed in an autoclave (1 L).
The system was purged with hydrogen gas, and the mixture was
stirred at 45.degree. C. for 14 hr under constant hydrogen pressure
(0.1 MPa). After the system was freed from pressure, the Pd/C was
removed by filtration on hot through membrane filter, and the
filtrate was concentrated under reduced pressure. To the residue
was added methanol (100 mL), and the mixture was aged at room
temperature for 1 hr, and filtered under reduced pressure. The
substance collected by filtration was washed with methanol (50 mL),
and dried at 50.degree. C. under reduced pressure to give the
desired compound. White crystalline powder, 35.52 g, yield 68%.
[0375] .sup.1H-NMR (500 MHz, CDCl.sub.3, TMS) .delta. (ppm)
1.72-1.76 (m, 2H), 2.15 (t, J=6.31 Hz, 2H), 3.05-3.15 (m, 2H), 7.38
(s, 1H).
[0376] (The protons derived from NH, OH and COOH were not
detected)
[0377] .sup.13C-NMR (125 MHz, CDCl.sub.3, CDCl.sub.3) .delta. (ppm)
20.03, 39.75, 94.15, 143.62, 173.99.
[0378] Anal. Calcd for C.sub.6H.sub.10N.sub.2O:C, 57.12; H, 7.99;
N, 22.21. Found:C, 57.11; H, 8.09; N, 22.10.
[0379] ESI-MS:m/z 127.0873 [M+H].sup.+.
[0380] IR (ATR, cm.sup.-1):3300 (.nu.NH), 3201 (.nu.NH), 3000-2800
(.nu.CH), 1622 (.nu.C.dbd.O), 1506 (.nu.C.dbd.C), 1423 (.delta.CH),
1362 (.delta.CH).
Example 1
Synthesis of 1,4,5,6-tetrahydropyridine-3-carboxamide
p-toluenesulfonate 0.85 ethanolate
##STR00041##
[0382] Nicotinamide (50.00 g) [mw. 122.12, 0.409 mol], 5% Pd/C
(5.00 g) and methanol (500 mL) were placed in an autoclave (1 L),
and the nicotinamide was dissolved. The system was purged with
hydrogen gas, and the hydrogen pressure was raised to 0.10 MPa. The
mixture was warmed to 40.degree. C., and stirred for 20 hr under
constant hydrogen pressure (0.1 MPa) at the rotation speed of 350
rpm. After the system was freed from pressure, the Pd/C was removed
by filtration on hot through membrane filter (0.5 .mu.m). The
filtrate was concentrated under reduced pressure, to the residue
(powder) was added was added methanol (100 mL), and the mixture was
stirred for 1 hr in ice bath. The crystals were collected by
filtration under reduced pressure, and washed with cooled methanol
(30 mL). To the obtained wet crystals (38.44 g) was added ethanol
(308 mL), and p-toluenesulfonic acid monohydrate (63.75 g) [mw,
190.22, 0.335 mol] was added thereto, and dissolved. The mixture
was aged at room temperature for 3.5 hr, and the crystals were
collected by filtration under reduced pressure, washed with ethanol
(100 mL), and dried at 50.degree. C. under reduced pressure to give
the desired compound. White crystalline powder, 84.09 g, yield
68%.
[0383] .sup.1H-NMR (500 MHz, D.sub.2O) .delta.(ppm) 1.72-1.76 (m,
2H), 2.15 (t, J=6.31 Hz, 2H), 3.05-3.15 (m, 2H), 7.38 (s, 1H).
[0384] (The protons derived from NH, OH and COOH was not
detected)
[0385] .sup.13C-NMR (125 MHz, D.sub.2O) .delta. (ppm) 20.03, 39.75,
94.15, 143.62, 173.99.
[0386] Anal. Calcd for C.sub.6H.sub.10N.sub.2O:C, 57.12; H, 7.99;
N, 22.21. Found:C, 57.11; H, 8.09; N, 22.10.
[0387] ESI-MS:m/z 127.0873 [M+H].sup.+.
[0388] IR (ATR, cm.sup.-1):3300 (.nu.NH), 3201 (.nu.NH), 3000-2800
(.nu.CH), 1622 (.nu.C.dbd.O), 1506 (.nu.C.dbd.C), 1423 (.delta.CH),
1362 (.delta.CH).
Reference Example 2
Synthesis of
ditrifluoroacetato[(S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]ru-
thenium(II) complex
##STR00042##
[0390] Bis(2-methylallyl)(1,5-cyclooctadiene)ruthenium(II) (6.29 g)
[mw. 319.45, 19.69 mmol] and
(S)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (12.51 g) [mw.
622.69, 20.09 mmol, 1.02 eq.] were placed in Schlenk flask, and the
system was purged seven times with argon. Acetone (253 g,
dehydrated for organic synthesis) was added thereto, and the
mixture was stirred in the range of 20 to 30.degree. C. for 1 hr.
Trifluoroacetic acid (3 mL) [d=1.535, mw. 114.02, 40.4 mmol] was
added thereto in the range of 20 to 30.degree. C., and the mixture
was stirred in the range of 30 to 35.degree. C. for 24 hr. The
reaction solution was concentrated under reduced pressure at
40.degree. C. or lower until the distillation was completed, and to
the residue was added n-hexane (250 mL, dehydrated for organic
synthesis). The mixture was heated to the range of 35 to 45.degree.
C., and stirred for 2 hr. After solid-liquid separation, the wet
substance was washed with n-hexane (50 mL, dehydrated for organic
synthesis), and dried at 50.degree. C. under reduced pressure to
give the desired compound. Pale-brown powder, 16.96 g, yield 91%.
.sup.1H-NMR (500 MHz, CDCl.sub.3, TMS) .delta. (ppm) 6.35-6.40 (m,
2H), 6.55 (br, 4H), 6.68 (br, 2H), 6.88 (br, 2H), 7.11 (br, 4H),
7.30 (br, 2H), 7.44 (br, 4H), 7.52 (br, 2H), 7.68 (br, 8H), 7.88
(br, 2H). .sup.19F-NMR (471 MHz, CDCl.sub.3, TFA) .delta. (ppm)
-76.88 (s). .sup.31P-NMR (202 MHz, CDCl.sub.3, H.sub.3PO.sub.4)
.delta. (ppm) 56.46 (s).
Example 2
Synthesis of
ditrifluoroacetato[(S)-(-)-2,2'-bis(bis(4-chlorophenyl)phosphino)-1,1'-bi-
naphthyl]ruthenium(II) complex
##STR00043##
[0392] Bis(2-methylallyl)(1,5-cyclooctadiene)ruthenium(II) (0.112
g) [mw. 319.45, 0.350 mmol] and
(S)-2,2'-bis(bis(4-chlorophenylphosphino)-1,1'-binaphthyl (0.293 g)
[mw. 760.45, 0.385 mmol] were placed in Schlenk flask, and the
system was purged seven times with argon. Dehydrated acetone (6 mL)
was added thereto, and the mixture was stirred at room temperature
for 15 min. Trifluoroacetic acid (0.053 mL) [d=1.535, mw. 114.02,
0.718 mmol] was added thereto at room temperature, and the mixture
was stirred at room temperature for 22 hr. The reaction solution
was concentrated under reduced pressure at 40.degree. C. or lower
until the distillation was completed, and to the residue was added
dehydrated n-hexane (10 mL). The mixture was heated to 40.degree.
C., and stirred for 15 min. After solid-liquid separation, the wet
substance was washed with dehydrated n-hexane (10 mL), and dried at
50.degree. C. under reduced pressure to give the desired compound.
Yellow powder.
[0393] .sup.1H-NMR (500 MHz, CD.sub.3OD, TMS) .delta. (ppm)
6.25-6.36 (m, 2H), 6.40-6.55 (m, 4H), 6.84-7.03 (m, 6H), 7.28-7.39
(m, 2H), 7.41-7.52 (m, 4H), 7.62-7.75 (m, 6H), 7.76-7.89 (m,
4H).
[0394] .sup.31P-NMR (202 MHz, CD.sub.3OD, H.sub.3PO.sub.4) .delta.
(ppm) 55.42 (s).
Example 3
Synthesis of
ditrifluoroacetato[(R.sub.p,R'.sub.p)-1,1'-bis[(S)-.alpha.-(dimethylamino-
)benzyl]-2,2'-bis(diphenylphosphino)ferrocene]ruthenium(II)
complex
##STR00044##
[0396] Bis(2-methylallyl)(1,5-cyclooctadiene)ruthenium(II) (0.112
g) [mw. 319.45, 0.350 mmol] and
(R.sub.p,R'.sub.p)-1,1'-bis[(S)-.alpha.-(dimethylamino)benzyl]-2,2'-bis(d-
iphenylphosphino)ferrocene (0.316 g) [mw. 820.76, 0.385 mmol] were
placed in Schlenk flask, and the system was purged five times with
argon. Dehydrated acetone (6 mL) was added thereto, and the mixture
was stirred at room temperature for 15 min. Trifluoroacetic acid
(0.053 mL) [d=1.535, mw. 114.02, 0.718 mmol] was added thereto at
room temperature, and the mixture was stirred at room temperature
for 22 hr. The reaction solution was concentrated under reduced
pressure at 40.degree. C. or lower until the distillation was
completed, and to the residue was added dehydrated n-hexane (10
mL). The mixture was heated to 40.degree. C., and stirred for 15
min. After solid-liquid separation, the wet substance was washed
with dehydrated n-hexane (10 mL), and dried at 50.degree. C. under
reduced pressure to give the desired compound. Yellow powder.
[0397] .sup.31P-NMR (202 MHz, CD.sub.3OD, H.sub.3PO.sub.4) .delta.
(ppm) 63.14 (s).
Example 4
Synthesis of (R)-piperidine-3-carboxamide p-toluenesulfonate
(Step 1) Synthesis of Crude (R)-piperidine-3-carboxamide
p-toluenesulfonate
##STR00045##
[0399] RuCl.sub.2{(S)-binap} (63.0 mg) [mw. 794.67, 0.0793 mmol],
1,4,5,6-tetrahydropyridine-3-carboxamide (5.00 g) [mw. 126.16,
39.63 mmol] and p-toluenesulfonic acid monohydrate (8.29 g) [mw.
190.20, 43.59 mmol] were placed in an autoclave (300 mL), and the
system was purged seven times with argon. Dehydrated methanol (100
mL) for organic synthesis was added thereto by argon pressure. The
system was purged ten times with hydrogen gas, and pressurized to
1.15 MPa, and the mixture was stirred at the internal temperature
of 65.degree. C. (the external temperature 75.degree. C.) for 18
hr. After the system was freed from hydrogen pressure, the mixture
was concentrated under reduced pressure, and to the residue was
added ethyl acetate (50 mL). The mixture was aged at room
temperature for 1 hr, and filtered under reduced pressure, and the
substance collected by filtration was washed with ethyl acetate
(appropriate amount), and dried at 50.degree. C. under reduced
pressure to give the desired compound. Pale-yellow white
crystalline powder, 10.86 g, yield 91%, optical purity 75% ee.
[0400] .sup.1H-NMR (500 MHz, D.sub.2O) .delta. (ppm) 1.55-1.72 (m,
2H), 1.76-1.97 (m, 2H), 2.29 (s, 3H), 2.65-2.76 (m, 1H), 2.88-2.99
(m, 1H), 3.00-3.07 (m, 1H), 3.12-3.22 (m, 1H), 3.22-3.29 (m, 1H),
7.27 (d, J=7.88 Hz, 2H), 7.62 (d, J=7.88 Hz, 2H). (The protons
derived from NH, OH and COOH was not detected)
[0401] .sup.13C-NMR (125 MHz, D.sub.2O) .delta. (ppm) 20.58, 25.57,
38.42, 43.93, 44.77, 125.45, 129.55, 139.74, 142.48, 177.26.
[0402] Anal. Calcd for C.sub.13H.sub.20N.sub.2O.sub.4S:C, 51.98; H,
6.71; N, 9.33; S, 10.68. Found:C, 51.20; H, 6.73; N, 9.02; S,
11.14.
[0403] ESI-MS:m/z 129.1033 (C.sub.6H.sub.12N.sub.2O) [M+H].sup.+,
m/z 171.0135 (C.sub.7H.sub.8O.sub.3S) [M-H].sup.-.
[0404] IR (ATR, cm.sup.-1):3163 (.nu.NH), 2900-2800 (.nu.CH), 1670
(.nu.C.dbd.O), 1435 (.delta.CH), 1170 (.nu.S.dbd.O).
[0405] (high-performance liquid chromatography conditions)
[0406] column: CD-Ph (manufactured by Shiseido)
[0407] mobile phase: 0.1 mol/L-aqueous hexafluoropotassium
phosphate
[0408] solution/acetonitrile (volume ratio: 95/5)
[0409] flow rate: 0.5 mL/min
[0410] detection: UV 200 nm
[0411] temperature: 25.degree. C.
[0412] retention time: (S)-form 15.2 min, (R)-form 17.0 min.
(Step 2) Purification of (R)-piperidine-3-carboxamide
p-toluenesulfonate
##STR00046##
[0414] The crude (R)-piperidine-3-carboxamide p-toluenesulfonate
obtained in Step 1 (103.57 g) [mw. 300.37, 0.3448 mol] and ethanol
(311 mL) were placed in a four-necked flask (1 L). The internal
temperature was raised to 65.degree. C., and the crude material was
completely dissolved. The mixture was stirred at the same
temperature for 15 min, and allowed to cool at air. At the time
that the internal temperature was cooled to 55.degree. C., the seed
crystals of the desired compound were added thereto. The
crystallization started slowly, and the mixture was aged at
25.degree. C. for 1 hr. The mixture was filtered under reduced
pressure, and the substance collected by filtration was washed with
ethanol (207 mL), and dried at 60.degree. C. under reduced pressure
to give the desired compound. White crystalline powder, 50.27 g,
yield 49%, optical purity >99% ee.
[0415] .sup.1H-NMR (500 MHz, D.sub.2O) .delta. (ppm) 1.55-1.71 (m,
2H), 1.76-1.87 (m, 1H), 1.86-1.96 (m, 1H), 2.28 (s, 3H), 2.65-2.75
(m, 1H), 2.88-2.99 (m, 1H), 3.00-3.07 (m, 1H), 3.12-3.22 (m, 1H),
3.22-3.29 (m, 1H), 7.26 (d, J=8.20 Hz, 2H), 7.60 (d, J=8.51 Hz,
2H).
[0416] .sup.13C-NMR (125 MHz, D.sub.2O) .delta. (ppm) 20.55, 25.55,
38.39, 43.89, 44.72, 125.42, 129.51, 139.64, 142.47, 177.28.
[0417] Anal. Calcd for C.sub.13H.sub.20N.sub.2O.sub.4S:C, 51.98; H,
6.71; N, 9.33; S, 10.68. Found:C, 51.90; H, 6.79; N, 9.24; S,
10.65.
[0418] ESI-MS:m/z 129.1035 (C.sub.6H.sub.12N.sub.2O) [M+H].sup.+,
m/z 171.0134 (C.sub.7H.sub.8O.sub.3S) [M-H].sup.-.
[0419] IR (ATR, cm.sup.-1):3159 (.nu.NH), 2950-2800 (.nu.CH), 1670
(.nu.C.dbd.O), 1435 (.delta.CH), 1171 (.nu.S.dbd.O).
[0420] [.alpha.](c 0.98, MeOH, 25.degree. C.)=-0.45.degree..
[0421] (high-performance liquid chromatography conditions)
[0422] column: CD-Ph (manufactured by Shiseido)
[0423] mobile phase: 0.1 mol/L-aqueous hexafluoropotassium
phosphate
[0424] solution/acetonitrile (volume ratio: 95/5)
[0425] flow rate: 0.5 mL/min
[0426] detection: UV 200 nm
[0427] temperature: 25.degree. C.
[0428] retention time: (S)-form 15.2 min, (R)-form 17.0 min.
Example 5
Synthesis of (R)-piperidine-3-carboxamide p-toluenesulfonate
##STR00047##
[0430]
Ditrifluoroacetato[(S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binapht-
hyl]ruthenium(II) complex (95.0 mg) [mw. 949.77, 0.100 mmol],
5-carbamoyl-1,2,3,4-tetrahydropyridin-1-ium
4-methylbenzenesulfonate (1,4,5,6-tetrahydropyridine-3-carboxamide
p-toluenesulfonate) (67.51 g) [mw. 337.53 (0.85 ethanolate), 0.200
mol] and potassium bromide (119.0 mg) [mw. 119.00, 1.000 mmol] were
placed in an autoclave (1 L), and the system was purged seven times
with argon. Dehydration 2-propanol (500 mL) for organic synthesis
was added thereto by argon pressure. The system was purged ten
times with hydrogen gas, and pressurized to 0.80 MPa, and the
internal temperature was raised to 50.degree. C. Then, the hydrogen
pressure was raised to 1.00 MPa, and the mixture was stirred under
constant pressure (1.00 MPa) at the internal temperature of
50.degree. C. for 48 hr. The system was freed from hydrogen
pressure (rotation speed 800 rpm), and purged with nitrogen gas,
and the nitrogen gas was raised to 0.15 MPa, and the mixture was
stirred at 50.degree. C. for 15 min (100% conversion, optical
purity 61% ee). The system was freed from nitrogen pressure, and
the mixture was concentrated under reduced pressure. To the residue
(powder) was added ethanol (100 mL), and the mixture was
concentrated under reduced pressure. Again, to the residue (powder)
was added ethanol (100 mL), and the mixture was concentrated under
reduced pressure. To the residue (powder) was added ethanol (180
mL), and the residue was dissolved at 70.degree. C., and the
solution was stirred at the same temperature for 10 min. The
solution was cooled to 25.degree. C. over 30 min. In the process of
cooling (at 60.degree. C.), the seed crystals of the desired
compound were added thereto. The mixture was aged for 2 hr, and
filtered under reduced pressure. The substance collected by
filtration was washed with ethanol (100 mL), and dried at
60.degree. C. under reduced pressure to give the desired compound.
White crystalline powder, 38.95 g, yield 65%, optical purity
>99% ee.
[0431] (high-performance liquid chromatography conditions)
[0432] column: CD-Ph (manufactured by Shiseido)
[0433] mobile phase: 0.1 mol/L aqueous hexafluoropotassium
phosphate
[0434] solution/acetonitrile (volume ratio: 95/5)
[0435] flow rate: 0.5 mL/min
[0436] detection: UV 200 nm
[0437] temperature: 25.degree. C.
[0438] retention time: (S)-form 15.2 min, (R)-form 17.0 min.
Example 6
Synthesis of (R)-piperidine-3-carboxamide p-toluenesulfonate
##STR00048##
[0440]
Ditrifluoroacetato[(S)-(+)-4,12-bis(diphenylphosphino)-[2,2]-paracy-
clophane]ruthenium(II) complex (3.6 mg) [mw. 949.77, 0.0379 mmol],
5-carbamoyl-1,2,3,4-tetrahydropyridin-1-ium
4-methylbenzenesulfonate (1,4,5,6-tetrahydropyridine-3-carboxamide
p-toluenesulfonate) (2.675 g) [mw. 337.53 (0.85 ethanolate), 7.926
mmol] and potassium bromide (4.7 mg) [mw. 119.00, 0.0396 mmol] were
placed in an autoclave (120 mL), and the system was purged seven
times with argon. Dehydrated 2-propanol (20 mL) for organic
synthesis was added thereto by argon pressure. The system was
purged ten times with hydrogen gas, the hydrogen pressure was
raised to 1.0 MPa, and the mixture was stirred under constant
pressure (1.00 MPa) at the internal temperature of 50.degree. C.
for 62 hr (100% conversion, optical purity 84% ee). The system was
freed from hydrogen pressure, and the mixture was concentrated
under reduced pressure. To the residue (powder) was added ethanol
(5 mL), and the mixture was concentrated under reduced pressure.
Again, to the residue (powder) was added ethanol (5 mL), and the
mixture was concentrated under reduced pressure. To the residue
(powder) was added ethanol (8 mL), the residue was dissolved at
85.degree. C., and the solution was cooled to 25.degree. C., aged
for 2 hr, and filtered under reduced pressure. The substance
collected by filtration was washed with ethanol (6 mL), and dried
at 60.degree. C. under reduced pressure to give the desired
compound. White crystalline powder, 1.813 g, yield 76%, optical
purity >99% ee.
[0441] (high-performance liquid chromatography conditions)
[0442] column: CD-Ph (manufactured by Shiseido)
[0443] mobile phase: 0.1 mol/L-aqueous hexafluoropotassium
phosphate
[0444] solution/acetonitrile (volume ratio: 95/5)
[0445] flow rate: 0.5 mL/min
[0446] detection: UV 200 nm
[0447] temperature: 25.degree. C.
[0448] retention time: (S)-form 15.2 min, (R)-form 17.0 min.
Example 7
Synthesis of (R)-piperidine-3-carboxamide p-toluenesulfonate
##STR00049##
[0450]
Ditrifluoroacetato[(S)-(-)-2,2'-bis(bis(4-chlorophenyl)phosphino)-1-
,1'-binaphthyl]ruthenium(II) complex (8.6 mg) [mw. 1087.55, 0.0079
mmol], 5-carbamoyl-1,2,3,4-tetrahydropyridin-1-ium
4-methylbenzenesulfonate (1,4,5,6-tetrahydropyridine-3-carboxamide
p-toluenesulfonate) (2.675 g) [mw. 337.53 (0.85 ethanolate), 7.926
mmol] and potassium bromide (9.4 mg) [mw. 119.00, 0.0792 mmol] were
placed in an autoclave (120 mL), and the system was purged seven
times with argon. Dehydrated methanol (20 mL) for organic synthesis
was added thereto by argon pressure. The system was purged ten
times with hydrogen gas, the hydrogen pressure was raised to 1.0
MPa, and the mixture was stirred under constant pressure (1.00 MPa)
at the internal temperature of 50.degree. C. for 21 hr. To measure
optical purity, 0.2 mL of the reaction solution was then taken, the
amine moiety was benzoylated with benzoyl chloride and
triethylamine, and the optical purity was measured (100%
conversion, optical purity 77% ee). The system was freed from
hydrogen pressure, and the mixture was concentrated under reduced
pressure. To the residue was added ethanol (7.2 mL), and the
residue was dissolved at 90.degree. C., and the solution was cooled
to 25.degree. C., aged for 2 hr, and filtered under reduced
pressure. The substance collected by filtration was washed with
ethanol (6 mL), and dried at 60.degree. C. under reduced pressure
to give the desired compound. White crystalline powder, 1.4441 g,
yield 61%, optical purity >99% ee.
[0451] (high-performance liquid chromatography conditions)
[0452] column: IC (manufactured by Daicel)
[0453] mobile phase: 0.020 mol/L-aqueous phosphoric acid
[0454] solution/acetonitrile (volume ratio: 7/3)
[0455] flow rate: 0.5 mL/min
[0456] detection: UV 200 nm
[0457] temperature: 25.degree. C.
[0458] retention time: (R)-form 12.6 min, (S)-form 16.4 min.
Example 8
Synthesis of (R)-piperidine-3-carboxamide p-toluenesulfonate
##STR00050##
[0460]
Ditrifluoroacetato[(R.sub.p,R'.sub.p)-1,1'-bis[(S)-.alpha.-(dimethy-
lamino)benzyl]-2,2'-bis(diphenylphosphino)ferrocene]ruthenium(II)
complex (9.1 mg) [mw. 1147.86, 0.0079 mmol],
5-carbamoyl-1,2,3,4-tetrahydropyridin-1-ium
4-methylbenzenesulfonate (1,4,5,6-tetrahydropyridine-3-carboxamide
p-toluenesulfonate) (2.675 g) [mw. 337.53 (0.85 ethanolate), 7.926
mmol] and potassium bromide (9.4 mg) [mw. 119.00, 0.0792 mmol] were
placed in an autoclave (120 mL), and the system was purged seven
times with argon. Dehydrated 2-propanol (20 mL) for organic
synthesis was added thereto by argon pressure. The system was
purged ten times with hydrogen gas, the hydrogen pressure was
raised to 1.0 MPa, and the mixture was stirred under constant
pressure (1.00 MPa) at the internal temperature of 50.degree. C.
for 14 hr (100% conversion, optical purity 96% ee). The system was
freed from hydrogen pressure, and the mixture was concentrated
under reduced pressure. To the residue was added ethanol (4.8 mL),
and the residue was dissolved at 90.degree. C., and the solution
was cooled to 25.degree. C., aged for 2 hr, and filtered under
reduced pressure. The substance collected by filtration was washed
with ethanol (6 mL), and dried at 60.degree. C. under reduced
pressure to give the desired compound. White crystalline powder,
2.001 g, yield 84%, optical purity >99% ee.
[0461] (high-performance liquid chromatography conditions)
[0462] column: CD-Ph (manufactured by Shiseido)
[0463] mobile phase: 0.1 mol/L-aqueous hexafluoropotassium
phosphate
[0464] solution/acetonitrile (volume ratio: 95/5)
[0465] flow rate: 0.5 mL/min
[0466] detection: UV 200 nm
[0467] temperature: 25.degree. C.
[0468] retention time: (S)-form 15.2 min, (R)-form 17.0 min.
Example 9
Synthesis of (R)-piperidine-3-carboxamide p-toluenesulfonate
##STR00051##
[0470]
Ditrifluoroacetato[(R.sub.p,R'.sub.p)-1,1'-bis[(S)-.alpha.-(dimethy-
lamino)benzyl]-2,2'-bis(diphenylphosphino)ferrocene]ruthenium(II)
complex (5.5 mg) [mw. 1147.86, 0.0048 mmol],
5-carbamoyl-1,2,3,4-tetrahydropyridin-1-ium
4-methylbenzenesulfonate (1,4,5,6-tetrahydropyridine-3-carboxamide
p-toluenesulfonate) (3.38 g) [mw. 337.53 (0.85 ethanolate), 10.01
mmol], potassium bromide (6.0 mg) [mw. 119.00, 0.050 mmol] and
p-toluenesulfonic acid monohydrate (0.19 g) [mw. 190.22, 1.00 mmol]
were placed in an autoclave (120 mL), and the system was purged
seven times with argon. Degassed and dehydrated 2-propanol (25 mL)
for organic synthesis was added thereto by argon pressure, and the
mixture was stirred for 2 hr at approximately room temperature. The
system was purged ten times with hydrogen gas, and pressurized to
0.90 MPa, and the mixture was stirred at the internal temperature
of 50.degree. C. for 20 hr, cooled to about 5.degree. C., and
stirred at the same temperature for 3 hr. The system was freed from
hydrogen pressure, and the crystals were collected by filtration
under reduced pressure, and washed with 2-propanol (5 mL), and
dried at 60.degree. C. under reduced pressure to give the desired
compound. White crystalline powder, 2.71 g, yield 90%, optical
purity >99.9% ee.
[0471] (high-performance liquid chromatography conditions)
[0472] column: CHIRALPAK AD-H (manufactured by Daicel)
[0473] mobile phase: a mixed solvent of
n-heptane/ethanol/methanol/diethylamine (volume ratio:
800/150/50/1)
[0474] flow rate: 0.8 mL/min
[0475] detection: UV 220 nm
[0476] temperature: 40.degree. C.
[0477] retention time: (S)-form 11.3 min, (R)-form 12.2 min.
Example 10
Synthesis of crude (R)-piperidine-3-carboxamide
p-toluenesulfonate
##STR00052##
[0479]
Ditrifluoroacetato[(S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binapht-
hyl]ruthenium(II) complex (4.6 mg) [mw. 949.77, 0.0048 mmol],
5-carbamoyl-1,2,3,4-tetrahydropyridin-1-ium
4-methylbenzenesulfonate (1,4,5,6-tetrahydropyridine-3-carboxamide
p-toluenesulfonate) (3.38 g) [mw. 337.53 (0.85 ethanolate), 10.01
mmol], potassium bromide (6.1 mg) [mw. 119.00, 0.0513 mmol] and
p-toluenesulfonic acid monohydrate (0.19 g) [mw. 190.22, 1.00 mmol]
were placed in an autoclave (120 mL), and the system was purged
seven times with argon. Degassed and dehydrated ethanol (25 mL) for
organic synthesis was added thereto by argon pressure, and the
mixture was stirred for 2 hr at approximately room temperature. The
system was purged ten times with hydrogen gas, and pressurized to
0.90 MPa, and the mixture was stirred under constant hydrogen
pressure (0.90 MPa) at the internal temperature of 50.degree. C.
for 20 hr, cooled to about 5.degree. C., and stirred at the same
temperature for 39 hr. The system was freed from hydrogen pressure,
and the crystals were collected by filtration under reduced
pressure, washed with ethanol (5 mL), and dried at 60.degree. C.
under reduced pressure to give the desired compound. White
crystalline powder, 1.91 g, yield 64%, optical purity 98.2% ee.
[0480] (high-performance liquid chromatography conditions)
[0481] column: CHIRALPAK AD-H (manufactured by Daicel)
[0482] mobile phase: a mixed solvent of
n-heptane/ethanol/methanol/diethylamine (volume ratio:
800/150/50/1)
[0483] flow rate: 0.8 mL/min
[0484] detection: UV 220 nm
[0485] temperature: 40.degree. C.
[0486] retention time: (S)-form 11.3 min, (R)-form 12.2 min.
Example 11
Synthesis of (R)-piperidine-3-carboxamide p-toluenesulfonate
(Step 1) Synthesis of crude (R)-piperidine-3-carboxamide
p-toluenesulfonate
##STR00053##
[0488]
Ditrifluoroacetato[(S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binapht-
hyl]ruthenium(II) complex (95.1 mg) [mw. 949.77, 0.100 mmol],
5-carbamoyl-1,2,3,4-tetrahydropyridin-1-ium
4-methylbenzenesulfonate (1,4,5,6-tetrahydropyridine-3-carboxamide
p-toluenesulfonate) (67.60 g) [mw. 337.53 (0.85 ethanolate), 200.3
mmol], potassium bromide (119.2 mg) [mw. 119.00, 1.00 mmol] and
p-toluenesulfonic acid monohydrate (3.80 g) [mw. 190.22, 20.0 mmol]
were placed in an autoclave (1 L), and the system was purged seven
times with argon. Degassed and dehydrated 2-propanol (500 mL) for
organic synthesis was added thereto by argon pressure, and the
mixture was stirred for 2 hr at approximately room temperature. The
system was purged ten times with hydrogen gas, and pressurized to
0.90 MPa, and the mixture was stirred under constant hydrogen
pressure (0.90 MPa) at the internal temperature of 50.degree. C.
for 20 hr, cooled to about 5.degree. C., and stirred at the same
temperature for 3 hr. The system was freed from hydrogen pressure,
and the crystals were collected by filtration under reduced
pressure, and washed with 2-propanol (100 mL), and dried at
60.degree. C. under reduced pressure to give the desired compound.
White crystalline powder, 56.00 g, yield 93%, optical purity 70%
ee.
[0489] (high-performance liquid chromatography conditions)
[0490] column: CHIRALPAK AD-H (manufactured by Daicel)
[0491] mobile phase: a mixed solvent of
n-heptane/ethanol/methanol/diethylamine (volume ratio:
800/150/50/1)
[0492] flow rate: 0.8 mL/min
[0493] detection: UV 220 nm
[0494] temperature: 40.degree. C.
[0495] retention time: (S)-form 11.3 min, (R)-form 12.2 min.
(Step 2) Purification of (R)-piperidine-3-carboxamide
p-toluenesulfonate
##STR00054##
[0497] The crude (R)-piperidine-3-carboxamide p-toluenesulfonate
obtained in Step 1 (55.00 g) [mw. 300.37, 183.1 mmol] and ethanol
(440 mL) were placed in a four-necked flask (1 L). The internal
temperature was raised to 78.degree. C., and the crude material was
completely dissolved. The solution was stirred at the same
temperature for 30 min, and allowed to cool under air. At the time
that the internal temperature was cooled to 60.degree. C., the seed
crystals (55 mg) of the desired compound were added thereto. The
crystallization started slowly, and the mixture was aged at
25.degree. C. for 11 hr. The mixture was filtered under reduced
pressure, and the substance collected by filtration was washed with
2-propanol (83 mL), and dried at 60.degree. C. under reduced
pressure to give the desired compound. White crystalline powder,
38.60 g, yield 70%, optical purity 99.7% ee.
[0498] (high-performance liquid chromatography conditions)
[0499] column: CHIRALPAK AD-H (manufactured by Daicel)
[0500] mobile phase: a mixed solvent of
n-heptane/ethanol/methanol/diethylamine (volume ratio:
800/150/50/1)
[0501] flow rate: 0.8 mL/min
[0502] detection: UV 220 nm
[0503] temperature: 40.degree. C.
[0504] retention time: (S)-form 11.3 min, (R)-form 12.2 min.
Example 12
Synthesis of
(R)-1-(3-(2-cyanobenzyl)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-
-yl)piperidine-3-carboxamide
##STR00055##
[0506] (R)-Piperidine-3-carboxamide p-toluenesulfonate (20.00 g)
[mw. 300.37, 66.58 mmol],
2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benz-
onitrile (18.20 g) [mw. 275.69, 66.02 mmol] and potassium carbonate
(18.20 g) [mw. 138.21, 131.7 mmol] were placed in a four-necked
flask (1 L), and isopropanol (15 mL) and water (40 mL) were added
thereto. The mixture was stirred at internal temperature of
65.degree. C. for 23 hr, and water (120 mL) was added thereto. The
mixture was cooled to 0.degree. C., aged for 2 hr, and filtered
under reduced pressure, and the substance collected by filtration
was washed with water (50 mL), and dried at 60.degree. C. under
reduced pressure to give the desired compound. White crystalline
powder, 22.97 g, yield 95%.
[0507] .sup.1H-NMR (500 MHz, CDCl.sub.3, TMS) .delta. (ppm) 1.46
(qt, J=13.0, 3.5 Hz, 1H), 1.70 (dt, J=13.5, 4.0 Hz, 1H), 1.91 (dd,
J=13.0, 3.5 Hz, 1H), 2.47 (tt, J=11.5, 3.5 Hz, 1H), 2.55 (t, J=11.5
Hz, 1H), 2.72 (t, J=11.5 Hz, 1H), 2.88 (d, J=11.5 Hz, 1H),
3.12-3.20 (dm, 1H), 3.25 (s, 3H), 5.13 (d, J=16.0 Hz, 1H), 5.32 (d,
J=16.0 Hz, 1H), 5.34 (s, 1H), 5.67 (bs, 1H), 5.73 (bs, 1H), 7.11
(d, J=8.0 Hz, 1H), 7.32 (t, J=7.5 Hz, 1H), 7.51 (td, J=8.0, 1.5 Hz,
1H), 7.61 (dd, J=7.5, 1.5 Hz, 1H).
[0508] .sup.13C-NMR (125 MHz, CDCl.sub.3, CDCl.sub.3) .delta. (ppm)
24.28, 27.30, 28.20, 42.46, 46.43, 51.91, 54.01, 91.27, 110.74,
117.68, 127.18, 128.18, 133.28, 133.61, 141.01, 152.99, 159.80,
163.01, 174.80.
[0509] ESI-MS:m/z 368.1731[M+H].sup.+, 390.1557[M+Na].sup.+,
406.1262 [M+H].sup.+.
[0510] IR (ATR, cm.sup.-1):3387, 3319, 3202 (.nu.NH), 2941, 2853
(.nu.CH), 2226 (.nu.CN), 1690, 1676, 1628 (.delta.CH).
[0511] [.alpha.](c 0.98, MeOH, 25.degree. C.)=-21.4.degree..
Example 13
Synthesis of
(R)-2-((6-(3-aminopiperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-
-1(2H)-yl)methyl)benzonitrile
##STR00056##
[0513] A mixture (1.5 L) of water and isopropanol (1/1 (v/v)) was
placed in a four-necked flask (2 L), pyridine (550 .mu.L) [d=0.98,
mw. 79.10, 6.9 mmol] and
(R)-1-(3-(2-cyanobenzyl)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-
-yl)piperidine-3-carboxamide (50.0 g) [mw. 367.40, 136 mmol] were
added successively thereto. Then, iodobenzene diacetate (48.2 g)
[mw. 322.10, 150 mmol] was added thereto, and the mixture was
stirred 20.degree. C. for 3 hr. The volatile was evaporated using
evaporator under reduced pressure, and the residual aqueous
solution was washed with ethyl acetate (500 mL, twice). The
solution was cooled to about 0.degree. C., potassium carbonate (400
g) was added thereto in several parts at 15.degree. C. or lower,
and the mixture was extracted with toluene (100 mL) and isopropanol
(150 mL). After separation, the organic layer was washed with
saturated brine (50 mL), and concentrated using evaporator under
reduced pressure. To the residue was added toluene (150 mL), and
the mixture was concentrated under reduced pressure. The residue
was suspended in toluene (100 mL), n-heptane (150 mL) was added
thereto, and the mixture was aged at room temperature for 3 hr, and
filtered under reduced pressure. The substance collected by
filtration was washed with a mixed solvent of toluene/n-heptane (2
v/3 v, 50 mL), and dried at 50.degree. C. under reduced pressure to
give the desired compound. Pale-yellow white crystalline powder,
40.3 g, yield 87%.
Reference Example 3
Synthesis of
(R)-2-((6-(3-aminopiperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-
-1(2H)-yl)methyl)benzonitrile benzoate
##STR00057##
[0515]
(R)-2-((6-(3-Aminopiperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydropyr-
imidin-1(2H)-yl)methyl)benzonitrile (35.0 g) [mw. 339.39, 103 mmol]
and isopropanol (140 mL) were placed in an round bottom flask (300
mL). The mixture was heated at 60.degree. C. to dissolve the
material, and a solution prepared by dissolving benzoic acid (13.8
g) [mw. 122.12, 113 mmol] in ethyl acetate (140 mL) was added
dropwise thereto at the same temperature. The mixture was aged at
room temperature for 18 hr, and filtered under reduced pressure.
The substance collected by filtration was washed successively with
a mixed solvent of isopropanol/ethyl acetate (1 v/1 v, 150 mL) and
ethyl acetate (50 mL), and dried at 50.degree. C. under reduced
pressure to give the desired compound. Pale-yellow white
crystalline powder, 43.9 g, yield 92%.
Example 14
Synthesis of
(R)-1-(3-(2-cyano-5-fluorobenzyl)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropy-
rimidin-4-yl)piperidine-3-carboxamide
##STR00058##
[0517] (R)-Piperidine-3-carboxamide p-toluenesulfonate (5.00 g)
[mw. 300.37, 16.65 mmol],
2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-4-f-
luorobenzonitrile (4.90 g) [mw. 293.68, 16.68 mmol] and potassium
carbonate (4.60 g) [mw. 138.21, 33.3 mmol] were placed in an
round-bottom flask (50 mL), and isopropanol (7.5 mL) and water (20
mL) were added thereto. The mixture was stirred at the internal
temperature of 65.degree. C. for 24 hr, and cooled to room
temperature. Water (30 mL) was added thereto, and the mixture was
stirred at 0.degree. C. for 1 hr. The precipitate was filtered
under reduced pressure, and the substance collected by filtration
was washed with water (10 mL), dried at 45.degree. C. under reduced
pressure to give the desired compound. White crystalline powder,
5.6 g, yield 87%.
[0518] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. (ppm) 1.45-1.60
(m, 1H) 1.62-1.72 (m, 1H) 1.80 (m, 1H) 1.92-2.07 (m, 1H) 2.49-2.59
(m, 1H) 2.64 (t, J=10.88 Hz, 1H) 2.82 (t, J=10.56 Hz, 1H) 2.94 (d,
J=11.98 Hz, 1H) 3.14-3.28 (m, 1H) 3.34 (s, 3H) 5.17 (d, J=16.39 Hz,
1H) 5.38 (d, 1H, J=16.08 Hz, 1H) 5.42 (s, 1H) 5.48 (brs, 1H) 5.66
(brs, 1H) 6.90 (dd, J=9.14 Hz, 2.52 Hz, 1H) 7.10 (td, J=8.04 Hz,
2.52 Hz, 1H) 7.70 (dd, J=8.67 Hz, 5.20 Hz, 1H).
Example 15
Synthesis of
(R)-2-((6-(3-aminopiperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-
-1(2H)-yl)methyl)-4-fluorobenzonitrile
##STR00059##
[0520] A mixture (60 mL) of water and isopropanol (1/1 (v/v)) was
placed in a four-necked flask (100 mL), and pyridine (21.4 .mu.L)
[d=0.98, mw. 79.10, 0.26 mmol] and
(R)-1-(3-(2-cyano-5-fluorobenzyl)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropy-
rimidin-4-yl)piperidine-3-carboxamide (2.00 g) [mw. 385.39, 5.19
mmol] were successively added thereto. Then, iodobenzene diacetate
(1.84 g) [mw. 322.10, 5.71 mmol] was added thereto, and the mixture
was stirred at 20.degree. C. for 3 hr. The volatile was evaporated
using evaporator under reduced pressure, and the residual aqueous
solution was washed with ethyl acetate (20 mL, twice). The solution
was cooled to about 0.degree. C., potassium carbonate (16 g) was
added thereto in several parts at 15.degree. C. or lower, and the
mixture was extracted with toluene (6 mL) and isopropanol (6 mL).
After separation, the organic layer was washed with saturated brine
(10 mL), and concentrated using evaporator under reduced pressure.
To the residue was added toluene (6 mL), and the mixture was
concentrated under reduced pressure. The residue was suspended in
toluene (6 mL), n-heptane (6 mL) was added thereto, and the mixture
was aged at 0.degree. C. for 1 hr, and filtered under reduced
pressure. The substance collected by filtration was dried at
50.degree. C. under reduced pressure to give the desired compound.
White crystalline powder, 1.6 g, yield 86%.
[0521] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. (ppm) 1.23 (d,
J=11.03 Hz, 1H) 1.30 (brs, 2H) 1.56-1.67 (m, 1H) 1.72-1.83 (m, 1H)
1.95 (dd, J=12.77 Hz, 3.94 Hz, 1H) 2.41 (m, 1H) 2.61 (m, 1H)
2.87-2.98 (m, 2H) 2.99-3.05 (m, 1H) 3.32 (s, 3H) 5.23-5.32 (m, 2H)
5.39 (s, 1H) 6.86 (dd, J=8.99 Hz, 2.36 Hz, 1H) 7.09 (td, J=8.04 Hz,
2.52 Hz, 1H) 7.69 (dd, J=8.51 Hz, 5.36 Hz, 1H).
[0522] .sup.13C NMR (126 MHz, CDCl.sub.3) .delta. ppm 28.0, 33.4,
46.1, 51.9, 59.7, 90.8, 114.6, 114.7, 115.6, 115.8, 116.4, 135.4,
135.5, 144.6, 152.7, 159.5, 162.9.
Reference Example 4
Synthesis of
(R)-2-((6-(3-aminopiperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-
-1(2H)-yl)methyl)-4-fluorobenzonitrile succinate
##STR00060##
[0524]
(R)-2-((6-(3-Aminopiperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydropyr-
imidin-1(2H)-yl)methyl)-4-fluorobenzonitrile (1.0 g) [mw. 357.38,
2.8 mmol], tetrahydrofuran (4.5 mL) and water (two drops) were
placed in an round-bottom flask (50 mL). The mixture was heated at
65.degree. C. to dissolve the material, and a solution prepared by
dissolving succinic acid (0.331 g) [mw. 118.09, 2.8 mmol] in
tetrahydrofuran (4 mL) and isopropanol (2.5 mL) was added dropwise
thereto at the same temperature. The mixture was stirred at
65.degree. C. for 30 min, aged at room temperature for 16 hr, and
stirred at 0.degree. C. for 2 hr. The precipitate was collected by
filtration under reduced pressure, and dried at 45.degree. C. under
reduced pressure to give the desired compound. White crystalline
powder, 1.2 g, yield 93%.
[0525] .sup.1H-NMR (500 MHz, DMSO) .delta. (ppm) 1.35 (d, J=8.83
Hz, 1H) 1.42-1.57 (m, 1H) 1.66-1.97 (m, 2H) 2.54-2.77 (m, 2H) 2.91
(d, J=11.35 Hz, 1H) 3.00-3.07 (m, 1H) 3.08 (m, 1H) 3.09 (s, 3H)
3.14 (m, 1H) 5.12 (d, J=16.08 Hz, 1H) 5.20 (d, J=16.39 Hz, 1H) 5.38
(s, 1H) 7.17 (dd, J=9.62 Hz, 2.36 Hz, 1H) 7.35 (td, J=8.51 Hz, 2.52
Hz, 1H) 7.95 (dd, J=8.67 Hz, 5.52 Hz, 1H).
[0526] .sup.13C NMR (126 MHz, DMSO) .delta. ppm 27.9, 31.6, 46.3,
47.0, 51.7, 55.8, 90.3, 106.9, 115.7, 117.1, 136.45, 136.53, 145.8,
152.3, 159.7, 162.7, 164.1, 166.1, 175.2.
Example 16
Synthesis of
(R)-2-((6-(3-aminopiperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-
-1(2H)-yl)methyl)benzonitrile benzoate
##STR00061##
[0528] A mixture (1250 mL) of water and isopropanol (1/1 (v/v)) was
placed in a four-necked flask (2 L), and pyridine (495 .mu.L)
[d=0.98, mw. 79.10, 6.2 mmol] and
(R)-1-(3-(2-cyanobenzyl)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-
-yl)piperidine-3-carboxamide (45.0 g) [mw. 367.40, 122 mmol] were
successively added thereto. The mixture was cooled to 10.degree. C.
Then, iodobenzene diacetate (43.50 g) [mw. 322.10, 135 mmol] was
added thereto, and the mixture was stirred at 10.degree. C. for 5
hr. Ethyl acetate (450 mL) was added thereto, and the mixture was
stirred. To the separated aqueous layer was added ethyl acetate
(450 mL), and the mixture was stirred and separated. To the aqueous
layer was added activated carbon (4.5 g), and the mixture was
stirred for 30 min. The activated carbon was removed by filtration,
and washed with water (45 mL). To the filtrate was added ethyl
acetate (450 mL), and the mixture was cooled to 10.degree. C.
Potassium carbonate (270 g) was added thereto at 20.degree. C. or
lower, and the mixture was stirred for 30 min, and separated. To
the obtained organic layer was added aqueous sodium chloride
solution (prepared by dissolving sodium chloride (24 g) in water
(80 mL)), and the mixture was stirred, and separated. The organic
layer was concentrated to about 135 mL under reduced pressure. To
the residue was added ethanol (180 mL), and the mixture was
concentrated to about 135 mL under reduced pressure. The residue
was filtered through membrane filter (0.2 micron) to remove the
insoluble substances, and washed with ethanol (32 mL). The filtrate
was heated to 70.degree. C., and benzoic acid ethanol solution
(prepared by dissolving benzoic acid (14.90 g) [mw. 122.21, 122
mmol] in ethanol (90 mL)) was added dropwise thereto over 30 min in
the range of 70 to 73.degree. C. The mixture was gradually cooled
to 30.degree. C. over 2 hr, and cooled to 0.degree. C. The mixture
was stirred at 0.degree. C. for 2 hr, and the crystals were
collected by filtration. The wet crystals were washed with cooled
ethanol (90 mL), and dried at 60.degree. C. under reduced pressure
to give the desired compound. White crystalline powder, 46.79 g,
yield 87%.
Example 17
Synthesis of
(R)-2-((6-(3-aminopiperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-
-1(2H)-yl)methyl)benzonitrile benzoate
##STR00062##
[0530] Ethanol (150 mL) and water (250 mL) were placed in a
four-necked flask (500 mL), and pyridine (513 .mu.L) [d=0.98, mw.
79.10, 6.36 mmol] and
(R)-1-(3-(2-cyanobenzyl)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimid-
in-4-yl)piperidine-3-carboxamide (50.0 g) [mw. 367.40, 136 mmol]
were successively added thereto. Then, iodobenzene diacetate (48.23
g) [mw. 322.10, 150 mmol] was added thereto, and the mixture was
stirred at 20.degree. C. for 2 hr. After left standing, the
iodobenzene of the lower layer was removed. The upper layer was
concentrated to about 250 mL under reduced pressure, to the residue
was added ethyl acetate (150 mL), and the mixture was stirred, and
separated. To the lower layer was added ethyl acetate (150 mL), and
the mixture was stirred, and separated. Ethyl acetate (150 mL) was
added thereto, and the mixture was cooled to 10.degree. C.
Potassium carbonate (107 g) was added thereto at 20.degree. C. or
lower, and the mixture was stirred for 30 min, and separated. To
the organic layer was added aqueous sodium chloride solution
(prepared by dissolving sodium chloride (8 g) in water (30 mL)),
sodium chloride (8 g) was added thereto, and the mixture was
stirred, and separated. To the organic layer were added activated
carbon (5 g) and ethanol (appropriate amount), and the mixture was
stirred for 30 min. The activated carbon was removed by filtration,
and the filtrate was concentrated to about 150 mL under reduced
pressure. To the residue was added ethanol (150 mL), and the
mixture was concentrated to about 150 mL under reduced pressure. To
the residue was added ethanol (150 mL), and the mixture was
concentrated to about 150 mL under reduced pressure. The residue
was filtered through membrane filter (0.2 micron) to remove the
insoluble substances, and washed with ethanol (40 mL). The filtrate
was heated to 70.degree. C., and benzoic acid ethanol solution
(prepared by dissolving benzoic acid (16.62 g) [mw. 122.21, 136
mmol] in ethanol (100 mL)) was added dropwise thereto in the range
of 70 to 73.degree. C. over 30 min. The mixture was stirred at
70.degree. C. for 1.5 hr, and gradually cooled to 30.degree. C.
over 2 hr, and cooled to 0.degree. C. The mixture was stirred at
0.degree. C. for 1 hr, and the crystals were collected by
filtration. The wet crystals were washed with cooled ethanol (100
mL), and dried at 60.degree. C. under reduced pressure to give the
desired compound. Pale-yellow white crystalline powder, 44.03 g,
yield 70%.
Example 18
Synthesis of (R)-piperidine-3-carboxamide p-toluenesulfonate
##STR00063##
[0532]
Ditrifluoroacetato[(S)-(+)-4,12-bis(diphenylphosphino)-[2,2]-paracy-
clophane]ruthenium(II) complex (7.1 mg) [mw. 903.72, 0.0079 mmol],
5-carbamoyl-1,2,3,4-tetrahydropyridine (1.00 g) [mw. 126.16, 7.926
mmol], p-toluenesulfonic acid monohydrate (1.508 g) [mw. 190.22,
7.926 mmol] and lithium bromide monohydrate (8.3 mg) [mw. 104.86,
0.0792 mmol] were placed in an autoclave (120 mL), and the system
was purged seven times with argon. Dehydrated methanol (20 mL) for
organic synthesis was added thereto by argon pressure. The system
was purged ten times with hydrogen gas, the hydrogen pressure was
raised to 1.0 MPa, and the mixture was stirred at the internal
temperature of 50.degree. C. for 15 hr. The system was freed from
hydrogen pressure. To measure optical purity, 0.2 mL of the
reaction solution was then taken, the amine moiety was benzoylated
with benzoyl chloride and triethylamine, and the optical purity was
measured (100% conversion, optical purity 87% ee). The mixture was
concentrated under reduced pressure. To the residue (powder) was
added ethanol (5 mL), and the mixture was concentrated under
reduced pressure. Again, to the residue (powder) was added ethanol
(5 mL), and the mixture was concentrated under reduced pressure. To
the residue (powder) was added ethanol (7.4 mL), and the residue
was dissolved at 80.degree. C. The seed crystals of the desired
compound were added thereto, and the mixture was cooled to
25.degree. C., aged for 1 hr, and filtered under reduced pressure.
The substance collected by filtration was washed with ethanol (6
mL), and dried at 60.degree. C. under reduced pressure to give the
desired compound. White crystalline powder, 1.813 g, yield 79%,
optical purity >99% ee.
[0533] (high-performance liquid chromatography conditions)
[0534] column: IC (manufactured by Daicel)
[0535] mobile phase: 0.020 mol/L aqueous phosphoric acid
solution/acetonitrile (volume ratio: 7/3)
[0536] flow rate: 0.5 mL/min
[0537] detection: UV 200 nm
[0538] temperature: 25.degree. C.
[0539] retention time: (R)-form 12.6 min, (S)-form 16.4 min.
[0540] The reaction was performed by addition of the other additive
instead of lithium bromide monohydrate, under the reaction
conditions described in the above-mentioned Example. The results
are shown below (the reaction solution was analyzed under the
analysis conditions described in the above-mentioned Example, and
concentration under reduced pressure and the treatments thereafter
were not performed).
TABLE-US-00001 TABLE 1 HPLC analysis result reaction reaction
optical purity Example additive time yield of product Example
TBAI.sup.1) 16 h 100% 83% ee 19 Example TBAB.sup.2) 16 h 100% 87%
ee 20 Example TBAB.sup.2) 16 h 100% 84% ee 21 Example TBAC.sup.3)
18 h 100% 84% ee 22 Example n-butyl 16 h 100% 85% ee 23 ammonium
chloride Example LiCl 18 h 100% 84% ee 24 Example KI 15 h 100% 82%
ee 25 .sup.1)tetrabutylammonium iodide .sup.2)tetraethylammonium
bromide .sup.3)tetrabutylammonium chloride
Example 26
Synthesis of (R)-piperidine-3-carboxamide p-toluenesulfonate
##STR00064##
[0542]
Ditrifluoroacetato[(S)-(+)-4,12-bis(diphenylphosphino)-[2,2]-paracy-
clophane]ruthenium(II) complex (7.1 mg) [mw. 903.72, 0.0079 mmol],
5-carbamoyl-1,2,3,4-tetrahydropyridin-1-ium
4-methylbenzenesulfonate (1,4,5,6-tetrahydropyridine-3-carboxamide
p-toluenesulfonate) (2.675 g) [mw. 337.53 (0.85 ethanolate), 7.926
mmol] and potassium bromide (9.4 mg) [mw. 119.00, 0.0792 mmol] were
placed in an autoclave (120 mL), and the system was purged seven
times with argon. Dehydrated methanol (20 mL) for organic synthesis
was added thereto by argon pressure. The system was purged ten
times with hydrogen gas, the hydrogen pressure was raised to 1.0
MPa, and the mixture was stirred at the internal temperature of
50.degree. C. for 17 hr. The system was freed from hydrogen
pressure, the amine moiety was benzoylated by adding triethylamine
and benzoyl chloride to 0.2 mL of the reaction solution, and the
optical purity was measured (100% conversion, optical purity 88%
ee). The mixture was concentrated under reduced pressure. To the
residue (powder) was added ethanol, and the mixture was
concentrated under reduced pressure. Again, to the residue (powder)
was added ethanol, and the mixture was concentrated under reduced
pressure. To the residue (powder) was added ethanol (7.4 mL), the
solid was completely dissolved at 80.degree. C., and the solution
was cooled to 25.degree. C. The mixture was aged at room
temperature for 6 hr, and filtered under reduced pressure. The
substance collected by filtration was washed with ethanol (6 mL),
and dried at 60.degree. C. under reduced pressure to give the
desired compound. White crystalline powder, 1.74 g, yield 73%,
optical purity >99% ee.
[0543] (high-performance liquid chromatography conditions)
[0544] column: IC (manufactured by Daicel)
[0545] mobile phase: 0.020 mol/L-aqueous phosphoric acid
solution/acetonitrile (volume ratio: 7/3)
[0546] flow rate: 0.5 mL/min
[0547] detection: UV 200 nm
[0548] temperature: 25.degree. C.
[0549] retention time: (R)-form 12.6 min, (S)-form 16.4 min.
[0550] The reaction was performed by addition of the other additive
instead of potassium bromide, under the reaction conditions
described in the above-mentioned Example. The results are shown
below (the reaction solution was analyzed under the analysis
conditions described in the above-mentioned Example, and
concentration under reduced pressure and the treatments thereafter
were not performed).
TABLE-US-00002 TABLE 2 HPLC analysis result reaction reaction
optical purity Example additive time yield of product Example LiBr
17 h 100% 89% ee 27 monohydrate Example TBAB.sup.1) 17 h 100% 88%
ee 28 .sup.1)tetraethylammonium bromide
Example 29
Synthesis of (R)-piperidine-3-carboxamide
##STR00065##
[0552]
(2S,4S)-2,4-Bis[(di-4,4'-tert-butylphenyl)phosphino]pentanerhodium(-
I) trifluoromethanesulfonic acid complex (12.2 mg) [mw. 1025.08,
0.0119 mmol] and 5-carbamoyl-1,2,3,4-tetrahydropyridine (0.0300 g)
[mw. 126.16, 0.238 mmol] were placed in a test tube equipped in
hydrogenation apparatus with eight reactors (Endeavor (registered
trademark)), the system was purged five times with argon, and
dehydrated methanol (3.0 mL) for organic synthesis was added
thereto using a syringe. The system was purged ten times with
hydrogen gas, the hydrogen pressure was raised to 1.0 MPa, and the
mixture was stirred at the internal temperature of 50.degree. C.
for 20 hr. The system was freed from hydrogen pressure. 2 mL of the
reaction solution was then taken, and the amine moiety was
benzyloxycarbonylated with triethylamine and benzyl chloroformate
to give the desired compound.
[0553] (high-performance liquid chromatography conditions)
[0554] column: AD-RH (manufactured by Daicel)
[0555] mobile phase: 0.020 mol/L-aqueous phosphoric acid
solution/acetonitrile (volume ratio: 7/3)
[0556] flow rate: 0.5 mL/min
[0557] detection: UV 220 nm
[0558] temperature: 25.degree. C.
[0559] retention time: (S)-form 12.7 min, (R)-form 14.2 min.
Example 30
Synthesis of (R)-piperidine-3-carboxamide
##STR00066##
[0561] [(1,5-Cyclooctadiene)iridium(I)]chloride dimer (4.0 mg) [mw.
671.71, 0.0119 mmol (iridium conversion)],
(2R,4R)-2,4-bis[(diphenyl)phosphino]pentane (6.3 mg) [mw. 440.49,
0.0143 mmol] and 5-carbamoyl-1,2,3,4-tetrahydropyridine (0.0300 g)
[mw. 126.16, 0.238 mmol] were placed in a test tube equipped in
hydrogenation apparatus with eight reactors (Endeavor (registered
trademark)), the system was purged five times with argon, and
dehydrated methanol (3.0 mL) for organic synthesis was added
thereto using a syringe. The system was purged ten times with
hydrogen gas, the hydrogen pressure was raised to 1.0 MPa, and the
mixture was stirred at the internal temperature of 50.degree. C.
for 20 hr. The system was freed from hydrogen pressure. 2 mL of the
reaction solution was then taken, and the amine moiety was
benzyloxycarbonylated with triethylamine and benzyl chloroformate
to give the desired compound.
[0562] (high-performance liquid chromatography conditions)
[0563] column: AD-RH (manufactured by Daicel)
[0564] mobile phase: 0.020 mol/L-aqueous phosphoric acid
solution/acetonitrile (volume ratio: 7/3)
[0565] flow rate: 0.5 mL/min
[0566] detection: UV 220 nm
[0567] temperature: 25.degree. C.
[0568] retention time: (S)-form 12.7 min, (R)-form 14.2 min.
Example 31
Synthesis of (S)-piperidine-3-carboxamide
##STR00067##
[0570] Palladium acetate (2.7 mg) [mw. 224.51, 0.0119 mmol],
(S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (8.9 mg) [mw.
622.69, 0.0143 mmol], 5-carbamoyl-1,2,3,4-tetrahydropyridine
(0.0300 g) [mw. 126.16, 0.238 mmol] and benzenesulfonic acid (37.6
mg) [mw. 158.18, 0.238 mmol] were placed in a test tube equipped in
hydrogenation apparatus with eight reactors (Endeavor (registered
trademark)), the system was purged five times with argon, and
dehydrated dichloromethane (3.0 mL) for organic synthesis was added
thereto using a syringe. The system was purged ten times with
hydrogen gas, the hydrogen pressure was raised to 1.0 MPa, and the
mixture was stirred at the internal temperature of 50.degree. C.
for 20 hr. The system was freed from hydrogen pressure. 2 mL of the
reaction solution was then taken, and the amine moiety was
benzyloxycarbonylated with triethylamine and benzyl chloroformate
to give the desired compound.
[0571] (high-performance liquid chromatography conditions)
[0572] column: AD-RH (manufactured by Daicel)
[0573] mobile phase: 0.020 mol/L-aqueous phosphoric acid
solution/acetonitrile (volume ratio: 7/3)
[0574] flow rate: 0.5 mL/min
[0575] detection: UV 220 nm
[0576] temperature: 25.degree. C.
[0577] retention time: (S)-form 12.7 min, (R)-form 14.2 min.
INDUSTRIAL APPLICABILITY
[0578] According to the present invention, an optically active
6-(3-aminopiperidin-1-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine
derivative can be efficiently produced, and therefore the present
invention is useful for commercial production of a
dipeptidylpeptidase inhibitor.
[0579] This application is based on patent application No.
2014-052809 filed on Mar. 14, 2014 in Japan, the contents of which
are encompassed in full herein.
* * * * *