DESCRIPTION
METHOD FOR PRODUCING OPTICALLY ACTIVE α-SUBSTITUTED PROLINE
Technical Field
[0001]
The present invention relates to an industrial method fo5 r
producing optically active α-substituted proline from a chain
ketone compound. An optically active α-substituted proline
produced by the present invention is a compound useful for
peptide structural chemistry, or as a pharmaceutical
10 intermediate.
Background Art
[0002]
Optically active α-substituted prolines are considered to
produce only a peptide having a low rotational degree of
15 freedom and a limited conformation, since they tolerate only
highly limited torsion angles in peptides containing them, and
are drawing much attention in recent years (see, for example,
non-patent document 1). Moreover, since they have structures
with less fluctuation, they are considered to be useful as
20 partial structures of highly selective pharmaceutical products,
and have been actively utilized for drug discovery studies.
[0003]
As a synthesis method of optically active α-substituted
prolines, a method using L-proline as a starting material,
25 which includes protecting amino acid with pivalaldehyde, and
performing alkylation using a strong base and an alkylating
agent is known (see, for example, non-patent document 2). An
improved method thereof is a method using chloral instead of
pivalaldehyde (see, for example, non-patent document 3).
30 However, the both methods require use of an expensive strong
base such as LDA and the like at an extremely low temperature
of -78 C, which is not industrially suitable. These methods
are also problematic in that only α-substituted proline in an S
form can be produced from economical L-proline.
35 [0004]
2
A method of synthesizing an optically active α-
substituted proline by an intramolecular cyclization reaction
using an amino acid such as L-alanine and the like as a
starting material is also known (see, for example, non-patent
document 4, patent document 1). However, the method i5 s
problematic in that an expensive strong base such as potassium
hexamethyldisilazide, lithium hexamethyldisilazide and the like
is required in the intramolecular cyclization reaction step.
On the other hand, a method of performing a similar reaction by
10 using a low cost potassium hydroxide has been reported (see
non-patent document 5); however, it requires an industrially
difficult operation of powderizing potassium hydroxide, and a
problem of low producibility resulting from the use of 30-fold
volume of DMSO as a solvent remains. In all cases, carboxyl
15 group and amino group need to be protected in the
intramolecular cyclization reaction step, which defectively
increases the total production steps due to the protection and
deprotection.
[0005]
20 A catalytic asymmetric synthesis method using an
optically active quaternary ammonium salt is also known (see,
for example, non-patent document 6). Although the method shows
very high stereoselectivity and yield, it requires use of
tertiary butyl ester as a substrate, iodide as an alkylating
25 agent, and cesium hydroxide as a base. These materials are all
industrially expensive, and this method is not suitable for
pharmaceutical or agrochemical intermediates desired to be
produced at a low cost.
[0006]
30 On the other hand, a method for obtaining optically
active α-methylproline and optically active α-methylprolinamide
by enzymatically resolving racemate of α-methylprolinamide is
also known (see non-patent document 1). In this enzymatic
resolution, Ochrobactrum anthropi NCIMB40321 and Mycobacterium
35 neoaurum ATCC25975 show an E value to be a selectivity index of
3
317 and 240, respectively, and the enzymatic resolution itself
is comparatively efficient, though synthesis of the racemate of
α-methylprolinamide, which is a starting material of resolution,
requires multisteps. To be specific, 4 steps of imine
formation by alaninamide and benzaldehyde, addition t5 o
acrylonitrile by using sodium hydride, hydrolysis of imine, and
hydrogenation are necessary, which is not preferable as a
production method aiming at an industrial production at a low
cost. Here, the E value is an index calculated by the
10 following formula from the conversion ratio (c) of the reaction
and optical purity (eeS) of the residual substrate.
E=ln[(1-c)(1-eeS)]/ln[(1-c)(1+eeS)]
A practical production method of the racemate of α-
methylprolinamide other than this method is not known, and the
15 development of an industrially superior production method of
the racemate of α-substituted prolinamide has been desired.
[0007]
As a method of producing the racemate of α-substituted
prolinamide by a small number of steps, a synthetic method by
20 hydration of 2-cyano-2-substituted pyrrolidine is considered.
Among the 2-cyano-2-substituted pyrrolidines to be a key to the
method, 2-cyano-2-methylpyrrolidine is a known compound (see
patent document 2). However, the production method thereof has
not been reported, and a practical production method is not
25 known. As a similar compound, a synthetic example of N-(1-
phenylethyl)-2-cyano-2-methylpyrrolidine has been reported (see
non-patent document 7). However, it requires specific
aminonitrile, and the object product is obtained only in a low
yield of 13%. On the other hand, in a different article by the
30 same author (see non-patent document 8), 2-cyanopyrrolidine
having a bicyclo skeleton is obtained in comparatively high
yields (maximum 80%). The difference in the results shows that
2-cyanopyrrolidine is obtained in a high yield in a system
where the bicyclo skeleton suppresses elimination of cyano
35 group, but when such stabilization is absent, it is difficult
4
to obtain 2-cyanopyrrolidine in a high yield. In addition, a
synthetic example of 2-cyanopyrrolidine having a bicyclo
skeleton from 1,7-dichloro-4-heptanone is also reported (see
non-patent document 9). It is also evident in this example
that the bicyclo skeleton is essential for achieving a hig5 h
yield. This report states that the side reaction is remarkable
in a reaction using potassium cyanide in a solvent containing
water, and a non-aqueous reaction using acetone cyanohydrin or
2-amino-2-methylpropanenitrile is necessary. However, they
10 have a risk of generating a hydrocyanic acid gas by thermal
decomposition and the like, and the method is not an
industrially preferable production method.
[0008]
Pyrrolines, particularly 2-methylpyrroline, are highly
15 useful compounds also sold as reagents. However, they are
expensive and an economical method of industrial production has
not been reported to date. For example, a production method of
2-methylpyrroline using 5-chloro-2-pentanone as a starting
material is known (for example, non-patent document 10).
20 However, since it requires 2-step reaction including
substitution of chlorine atom by azide and the like, and
cyclization while reducing with triphenylphosphine and the like,
and produces a large amount of waste, it is not an industrially
preferable method. On the other hand, a production method of
25 2-methylthiazolines using chloroacetone as a starting material
is known (see, for example, patent document 3). However, 5-
chloro-2-pentanone is known to be easily converted to
cyclopropyl methyl ketone under basic conditions (see, for
example, non-patent document 11). When the present inventors
30 tried the method of patent document 3 using aqueous ammonia, a
large amount of a cyclopropyl methyl ketone byproduct was
observed. Therefore, the method of patent document 3 cannot be
used as a production method of 2-methylpyrroline.
Document List
35 patent documents
5
[0009]
patent document 1: WO2006/110816
patent document 2: JP-A-S49-31614
patent document 3: WO2004/090152
non-patent document5 s
[0010]
non-patent document 1: Chem. Eur. J., 2009, 15, 8015.
non-patent document 2: Org. Synth., 1995, 72, 62.
non-patent document 3: Synlett, 1999, 33.
10 non-patent document 4: J. Am. Chem. Soc., 2006, 128, 15394.
non-patent document 5: J. Am. Chem. Soc., 2008, 130, 4153.
non-patent document 6: Tetrahedron, 2010, 66, 4900.
non-patent document 7: Tetrahedron Asym., 2007, 18, 290.
non-patent document 8: Tetrahedron Asym., 2006, 17, 252.
15 non-patent document 9: Heterocycles, 1997, 45, 1447.
non-patent document 10: Bull. Soc. Chim. Fr., 1986, 83.
non-patent document 11: Org. Synth., 1951, 31, 74.
Summary of the Invention
Problems to be Solved by the Invention
20 [0011]
The present invention aims to provide an industrial
method practically suitable for producing optically active α-
substituted prolines from a chain ketone compound by a small
number of steps under mild conditions.
25 Means of Solving the Problems
[0012]
The present inventors have conducted intensive studies in
an attempt to solve the aforementioned problems and found that
an optically active α-substituted proline and/or an optically
30 active α-substituted prolinamide can be obtained by reacting a
chain ketone compound with at least one selected from ammonia,
an ammonium salt, primary amine and a salt of primary amine,
and a cyanating agent to give a cyclic nitrogen-containing
compound, hydrating the cyclic nitrogen-containing compound to
35 give an α-substituted prolinamide, and resolving the α-
6
substituted prolinamide, which resulted in the completion of
the present invention.
[0013]
According to the present invention, the following
invention is provided5 .
[1] A method of producing an optically active α-substituted
proline represented by the formula (4)
[0014]
10
[0015]
wherein R1 is an optionally substituted alkyl group, an
optionally substituted aryl group, or an optionally substituted
heteroaryl group, R2 is a hydrogen atom, an optionally
substituted alkyl group, or an amino-protecting group, each R3 15
is independently a hydrogen atom, an optionally substituted
alkyl group, an optionally substituted aryl group, an
optionally substituted heteroaryl group, an optionally
substituted hydroxyl group, an optionally substituted amino
20 group, an optionally substituted thiol group, or a halogen atom,
two or more R3 optionally form one or plural ring structures,
and * shows an asymmetric carbon, or a salt thereof, and/or an
optically active α-substituted prolinamide represented by the
formula (5)
25 [0016]
7
[0017]
wherein each symbol is as defined above, or a salt thereof,
comprising the following steps (a) to (c);
(a) reacting a chain ketone compound represented by the formul5 a
(1)
[0018]
10 [0019]
wherein R1 and R3 are as defined above, and X is a halogen atom
or a sulfonyloxy group, with at least one selected from ammonia,
an ammonium salt, primary amine and a salt of primary amine,
and a cyanating agent and, where necessary, protecting a
15 nitrogen atom on the pyrrolidine ring to give a cyclic
nitrogen-containing compound represented by the formula (2)
[0020]
20 [0021]
wherein R1 and R3 are as defined above, Y is a nitrogen atom or
a nitrogen atom substituted by R2, Z is a carbon atom or a
carbon atom substituted by a cyano group, when Y is a nitrogen
atom and Z is a carbon atom, then the bond between Y and Z is a
double bond, when Y is a nitrogen atom substituted by R2 25 and Z
is a carbon atom substituted by a cyano group, then the bond
between Y and Z is a single bond, and R2 is as defined above,
or a salt thereof; and
(b) hydrating the cyclic nitrogen-containing compound
8
represented by the formula (2) or a salt thereof to give an α-
substituted prolinamide represented by the formula (3)
[0022]
5
[0023]
wherein each symbol is as defined above, or a salt thereof; and
(c) resolving the α-substituted prolinamide represented by the
10 formula (3) or a salt thereof to give an optically active α-
substituted proline represented by the formula (4) or a salt
thereof, and/or an optically active α-substituted prolinamide
represented by the formula (5) or a salt thereof.
[2] A method of producing a 2-substituted prolinamide
15 represented by the formula (3)
[0024]
[0025]
20 wherein each symbol is as defined in the aforementioned [1], or
a salt thereof, comprising the following steps (a) and (b);
(a) reacting a chain ketone compound represented by the formula
(1)
[0026]
9
[0027]
wherein each symbol is as defined in the aforementioned [1],
with at least one selected from ammonia, an ammonium salt5 ,
primary amine and a salt of primary amine, and a cyanating
agent and, where necessary, protecting a nitrogen atom on the
pyrrolidine ring to give a cyclic nitrogen-containing compound
represented by the formula (2)
10 [0028]
[0029]
15 wherein each symbol is as defined in the aforementioned [1], or
a salt thereof; and
(b) hydrating the cyclic nitrogen-containing compound
represented by the formula (2) or a salt thereof to give an α-
substituted prolinamide represented by the formula (3) or a
20 salt thereof.
[3] A method of producing a cyclic nitrogen-containing compound
represented by the formula (2)
[0030]
25
10
[0031]
wherein each symbol is as defined in the aforementioned [1], or
a salt thereof, comprising the following step (a);
(a) reacting a chain ketone compound represented by the formula
5 (1)
[0032]
10 [0033]
wherein each symbol is as defined in the aforementioned [1],
with at least one selected from ammonia, an ammonium salt,
primary amine and a salt of primary amine, and a cyanating
agent and, where necessary, protecting a nitrogen atom on the
15 pyrrolidine ring to give a cyclic nitrogen-containing compound
represented by the formula (2) or a salt thereof.
[4] A method of producing an optically active α-substituted
proline represented by the formula (4)
[0034]
20
[0035]
wherein each symbol is as defined in the aforementioned [1], or
a salt thereof, and/or an optically active α-substituted
25 prolinamide represented by the formula (5)
[0036]
11
[0037]
wherein each symbol is as defined in the aforementioned [1], or
a salt thereof, comprising the following step (c)5 ;
(c) resolving an α-substituted prolinamide represented by the
formula (3)
[0038]
10
[0039]
wherein each symbol is as defined in the aforementioned [1],
or a salt thereof, to give an optically active α-substituted
proline represented by the formula (4) or a salt thereof,
15 and/or an optically active α-substituted prolinamide
represented by the formula (5) or a salt thereof;
wherein the resolution is any of the following steps (d) to
(f):
(d) asymmetric hydrolysis of the amido group by an enzyme
20 having an amidase activity derived from Rhizopus oryzae,
(e) resolution by diastereomeric salt formation,
(f) separation by column chromatography.
[5] An α-methylprolinamide represented by the formula (8)
[0040]
12
[0041]
wherein R2 is 1-phenylethyl group, 1-(1-naphthyl)ethyl group,
1-(2-naphthyl)ethyl group, or carbamoylphenylmethyl group, or 5 a
salt thereof.
Effect of the Invention
[0042]
According to the present invention, an optically active
10 α-substituted proline and/or an optically active α-substituted
prolinamide useful for peptide structural chemistry or as key
synthetic intermediates for pharmaceutical products can be
produced efficiently from economical and easily available known
compounds.
15 Description of Embodiments
[0043]
In the present invention, R1 is an optionally substituted
alkyl group, an optionally substituted aryl group, or an
optionally substituted heteroaryl group.
20 [0044]
Examples of the “alkyl group” of the “optionally
substituted alkyl group” include a straight chain, branched
chain or cyclic alkyl group having 1 - 10 carbon atoms, for
example, a straight chain alkyl group having 1 - 10 carbon
25 atoms such as methyl group, ethyl group, n-propyl group, nbutyl
group, n-pentyl group, n-hexyl group, n-heptyl group, noctyl
group, n-nonyl group, n-decyl group and the like; a
branched chain alkyl group having 3 - 10 carbon atoms such as
isopropyl group, 1-methylpropyl group, t-butyl group and the
30 like; and a cyclic alkyl group having 3 - 10 carbon atoms such
as cyclopropyl group, cyclopentyl group, cyclohexyl group and
the like.
13
Examples of the substituent that the alkyl group
optionally has include a fluorine atom; an alkenyl group having
2 - 6 carbon atoms (e.g., vinyl group etc.); an alkoxy group
having 1 - 6 carbon atoms (e.g., methoxy group, ethoxy group
etc.); an aryl group having 6 - 10 carbon atoms (e.g., pheny5 l
group, naphthyl group etc.) optionally having 1 to 3
substituents selected from an alkyl group having 1 - 6 carbon
atoms (e.g., methyl group, ethyl group, isopropyl group etc.),
a halogen atom (e.g., fluorine atom, chlorine atom, bromine
10 atom, iodine atom), an alkenyl group having 2 - 6 carbon atoms
(e.g., vinyl group etc.), an alkoxy group having 1 - 6 carbon
atoms (e.g., methoxy group, ethoxy group etc.) and the like,
and the like. While the number of the substituents is not
particularly limited, 1 - 3 is preferable. When two or more
15 substituents are present, the kind of the substituent may be
the same or different.
As the substituted alkyl group, benzyl group, 4-
methoxybenzyl group, allyl group, 2-fluoroethyl group and the
like can be specifically mentioned.
20 [0045]
Examples of the “aryl group” of the “optionally
substituted aryl group” include an aromatic hydrocarbon group
having 6 - 10 carbon atoms, for example, phenyl group, 1-
naphthyl group, 2-naphthyl group and the like can be mentioned.
25 Examples of the substituent that the aryl group
optionally has include a halogen atom (e.g., fluorine atom,
chlorine atom, bromine atom, iodine atom); an alkyl group
having 1 - 6 carbon atoms (e.g., methyl group, ethyl group,
isopropyl group etc.); an alkenyl group having 2 - 6 carbon
30 atoms (e.g., vinyl group etc.); an alkoxy group having 1 - 6
carbon atoms (e.g., methoxy group, ethoxy group etc.); an aryl
group having 6 - 10 carbon atoms (e.g., phenyl group, naphthyl
group etc.) optionally having 1 to 3 substituents selected from
a halogen atom (e.g., fluorine atom, chlorine atom, bromine
35 atom, iodine atom), an alkyl group having 1 - 6 carbon atoms
14
(e.g., methyl group, ethyl group, isopropyl group etc.), an
alkenyl group having 2 - 6 carbon atoms (e.g., vinyl group
etc.), an alkoxy group having 1 - 6 carbon atoms (e.g., methoxy
group, ethoxy group etc.) and the like, and the like. While
the number of the substituents is not particularly limited, 1 5 -
3 is preferable. When two or more substituents are present,
the kind of the substituent may be the same or different.
[0046]
Examples of the “heteroaryl group” of the “optionally
10 substituted heteroaryl group” include a 5- or 6-membered
aromatic heterocyclic group containing, as a ring-constituting
atom besides carbon atoms, 1 to 4 heteroatoms selected from a
nitrogen atom, an oxygen atom and a sulfur atom, for example,
pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), furyl
15 (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl, 3-thienyl),
pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl),
imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl),
isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl),
oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl),
20 isothiazolyl (e.g., 3-isothiazolyl, 4-isothiazolyl, 5-
isothiazolyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-
thiazolyl), triazolyl (1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl),
oxadiazolyl (1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl),
thiadiazolyl (1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl),
25 tetrazolyl, pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl),
pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl
(e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl
(e.g., 2-pyrazinyl, 3-pyrazinyl) and the like.
Examples of the substituent that the heteroaryl group
30 optionally has include a halogen atom (e.g., fluorine atom,
chlorine atom, bromine atom, iodine atom); an alkyl group
having 1 - 6 carbon atoms (e.g., methyl group, ethyl group,
isopropyl group etc.); an alkenyl group having 2 - 6 carbon
atoms (e.g., vinyl group etc.); an alkoxy group having 1 - 6
35 carbon atoms (e.g., methoxy group, ethoxy group etc.); an aryl
15
group having 6 - 10 carbon atoms (e.g., phenyl group, naphthyl
group etc.) optionally having 1 to 3 substituents selected from
a halogen atom (e.g., fluorine atom, chlorine atom, bromine
atom, iodine atom), an alkyl group having 1 - 6 carbon atoms
(e.g., methyl group, ethyl group, isopropyl group etc.), a5 n
alkenyl group having 2 - 6 carbon atoms (e.g., vinyl group
etc.), an alkoxy group having 1 - 6 carbon atoms (e.g., methoxy
group, ethoxy group etc.) and the like, and the like. While
the number of the substituents is not particularly limited, 1 -
10 3 is preferable. When two or more substituents are present,
the kind of the substituent may be the same or different.
[0047]
Of these, R1 is preferably an optionally substituted
alkyl group, more preferably methyl group, ethyl group, n15
propyl group, n-butyl group, benzyl group or allyl group,
particularly preferably methyl group showing the property of α-
substituted proline with the simplest structure.
[0048]
In the present invention, R2 is a hydrogen atom, an
20 optionally substituted alkyl group, or an amino-protecting
group.
[0049]
Examples of the “alkyl group” of the “optionally
substituted alkyl group” include a straight chain, branched
25 chain or cyclic alkyl group having 1 - 10 carbon atoms, for
example, a straight chain alkyl group having 1 - 10 carbon
atoms such as methyl group, ethyl group, n-propyl group, nbutyl
group, n-pentyl group, n-hexyl group, n-heptyl group, noctyl
group, n-nonyl group, n-decyl group and the like; a
30 branched chain alkyl group having 3 - 10 carbon atoms such as
isopropyl group, 1-methylpropyl group, t-butyl group and the
like; and a cyclic alkyl group having 3 - 10 carbon atoms such
as cyclopropyl group, cyclopentyl group, cyclohexyl group and
the like.
35 Examples of the substituent that the alkyl group
16
optionally has include a halogen atom (e.g., fluorine atom,
chlorine atom, bromine atom, iodine atom); an alkenyl group
having 2 - 6 carbon atoms (e.g., vinyl group etc.); an alkoxy
group having 1 - 6 carbon atoms (e.g., methoxy group, ethoxy
group etc.); an alkoxycarbonyl group having 2 - 6 carbon atom5 s
(e.g., methoxycarbonyl group, ethoxycarbonyl group etc.);
carbamoyl group; carboxyl group; an aryl group having 6 - 10
carbon atoms (e.g., phenyl group, naphthyl group etc.)
optionally having 1 to 3 substituents selected from an alkyl
10 group having 1 - 6 carbon atoms (e.g., methyl group, ethyl
group, isopropyl group etc.), a halogen atom (e.g., fluorine
atom, chlorine atom, bromine atom, iodine atom), an alkenyl
group having 2 - 6 carbon atoms (e.g., vinyl group etc.), an
alkoxy group having 1 - 6 carbon atoms (e.g., methoxy group,
15 ethoxy group etc.) and the like, and the like. While the
number of the substituents is not particularly limited, 1 - 3
is preferable. When two or more substituents are present, the
kind of the substituent may be the same or different. When the
optionally substituted alkyl group has an asymmetric center, it
20 may be an R form or an S form, or a racemate.
[0050]
Specific examples of the amino-protecting group include,
but are not limited to, the following: an acyl group such as
formyl group, acetyl group, chloroacetyl group, dichloroacetyl
25 group, trichloroacetyl group, trifluoroacetyl group, propionyl
group, benzoyl group, 4-chlorobenzoyl group and the like; an
optionally substituted alkoxycarbonyl group such as
methoxycarbonyl group, ethoxycarbonyl group, t-butoxycarbonyl
group, benzyloxycarbonyl group, allyloxycarbonyl group and the
30 like; an optionally substituted arylalkyl group such as benzyl
group, 4-methoxybenzyl group, 4-bromobenzyl group, 1-
phenylethyl group, 1-(1-naphthyl)ethyl group, 1-(2-
naphthyl)ethyl group, carboxyphenylmethyl group,
carbamoylphenylmethyl group, 2-hydroxy-1-phenylethyl group and
35 the like; an optionally substituted allyl group such as allyl
17
group, crotyl group and the like; propargyl group; a sulfonyl
group such as methanesulfonyl group, p-toluenesulfonyl group,
2-nitrobenzenesulfonyl group and the like. When the aminoprotecting
group has an asymmetric center, it may be an R form
or an S form, or a racemate5 .
[0051]
Of these, R2 is preferably a hydrogen atom, an acyl group,
an optionally substituted alkoxycarbonyl group, or an
optionally substituted arylalkyl group, more preferably a
10 hydrogen atom or an easily removable acetyl group, chloroacetyl
group, trifluoroacetyl group, benzoyl group, t-butoxycarbonyl
group, benzyloxycarbonyl group, benzyl group, 4-methoxybenzyl
group, 4-bromobenzyl group, 1-phenylethyl group, 1-(1-
naphthyl)ethyl group, 1-(2-naphthyl)ethyl group, or
15 carbamoylphenylmethyl group, particularly preferably a hydrogen
atom, or benzyl group, 1-phenylethyl group, or
carbamoylphenylmethyl group, which is introducible by using
primary amine in step (a), and industrially economical.
[0052]
In the present invention, each R3 20 is independently a
hydrogen atom, an optionally substituted alkyl group, an
optionally substituted aryl group, or an optionally substituted
heteroaryl group, an optionally substituted hydroxyl group, an
optionally substituted amino group, an optionally substituted
thiol group, or a halogen atom. When possible, two or more R3 25
may form one or plural ring structures.
[0053]
Examples of the “alkyl group” of the “optionally
substituted alkyl group” include a straight chain, branched
30 chain or cyclic alkyl group having 1 - 10 carbon atoms, for
example, a straight chain alkyl group having 1 - 10 carbon
atoms such as methyl group, ethyl group, n-propyl group, nbutyl
group, n-pentyl group, n-hexyl group, n-heptyl group, noctyl
group, n-nonyl group, n-decyl group and the like; a
35 branched chain alkyl group having 3 - 10 carbon atoms such as
18
isopropyl group, 1-methylpropyl group, t-butyl group and the
like; and a cyclic alkyl group having 3 - 10 carbon atoms such
as cyclopropyl group, cyclopentyl group, cyclohexyl group and
the like.
Examples of the substituent that the alkyl grou5 p
optionally has include a halogen atom (e.g., fluorine atom,
chlorine atom, bromine atom, iodine atom); an alkenyl group
having 2 - 6 carbon atoms (e.g., vinyl group etc.); an alkoxy
group having 1 - 6 carbon atoms (e.g., methoxy group, ethoxy
10 group etc.); an aryl group having 6 - 10 carbon atoms (e.g.,
phenyl group, naphthyl group etc.) optionally having 1 to 3
substituents selected from an alkyl group having 1 - 6 carbon
atoms (e.g., methyl group, ethyl group, isopropyl group etc.),
a halogen atom (e.g., fluorine atom, chlorine atom, bromine
15 atom, iodine atom), an alkenyl group having 2 - 6 carbon atoms
(e.g., vinyl group etc.), an alkoxy group having 1 - 6 carbon
atoms (e.g., methoxy group, ethoxy group etc.) and the like,
and the like. While the number of the substituents is not
particularly limited, 1 - 3 is preferable. When two or more
20 substituents are present, the kind of the substituent may be
the same or different.
As the substituted alkyl group, benzyl group, 4-
methoxybenzyl group, allyl group, 2-chloroethyl group and the
like can be specifically mentioned.
25 [0054]
Examples of the “aryl group” of the “optionally
substituted aryl group” include an aromatic hydrocarbon group
having 6 - 10 carbon atoms, for example, phenyl group, 1-
naphthyl group, 2-naphthyl group and the like.
30 Examples of the substituent that the aryl group
optionally has include a halogen atom (e.g., fluorine atom,
chlorine atom, bromine atom, iodine atom); an alkyl group
having 1 - 6 carbon atoms (e.g., methyl group, ethyl group,
isopropyl group etc.); an alkenyl group having 2 - 6 carbon
35 atoms (e.g., vinyl group etc.); an alkoxy group having 1 - 6
19
carbon atoms (e.g., methoxy group, ethoxy group etc.); an aryl
group having 6 - 10 carbon atoms (e.g., phenyl group, naphthyl
group etc.) optionally having 1 to 3 substituents selected from
halogen atom (e.g., fluorine atom, chlorine atom, bromine atom,
iodine atom), an alkyl group having 1 - 6 carbon atoms (e.g.5 ,
methyl group, ethyl group, isopropyl group etc.), an alkenyl
group having 2 - 6 carbon atoms (e.g., vinyl group etc.), an
alkoxy group having 1 - 6 carbon atoms (e.g., methoxy group,
ethoxy group etc.) and the like, and the like. While the
10 number of the substituents is not particularly limited, 1 - 3
is preferable. When two or more substituents are present, the
kind of the substituent may be the same or different.
[0055]
Examples of the “heteroaryl group” of the “optionally
15 substituted heteroaryl group” include a 5- or 6-membered
aromatic heterocyclic group containing, as a ring-constituting
atom besides carbon atoms, 1 to 4 heteroatoms selected from a
nitrogen atom, an oxygen atom and a sulfur atom, for example,
pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), furyl
20 (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl, 3-thienyl),
pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl),
imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl),
isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl),
oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl),
25 isothiazolyl (e.g., 3-isothiazolyl, 4-isothiazolyl, 5-
isothiazolyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-
thiazolyl), triazolyl (1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl),
oxadiazolyl (1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl),
thiadiazolyl (1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl),
30 tetrazolyl, pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl),
pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl
(e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl
(e.g., 2-pyrazinyl, 3-pyrazinyl) and the like.
Examples of the substituent that the heteroaryl group
35 optionally has include a halogen atom (e.g., fluorine atom,
20
chlorine atom, bromine atom, iodine atom); an alkyl group
having 1 - 6 carbon atoms (e.g., methyl group, ethyl group,
isopropyl group etc.); an alkenyl group having 2 - 6 carbon
atoms (e.g., vinyl group etc.); an alkoxy group having 1 - 6
carbon atoms (e.g., methoxy group, ethoxy group etc.); an ary5 l
group having 6 - 10 carbon atoms (e.g., phenyl group, naphthyl
group etc.) optionally having 1 to 3 substituents selected from
a halogen atom (e.g., fluorine atom, chlorine atom, bromine
atom, iodine atom), an alkyl group having 1 - 6 carbon atoms
10 (e.g., methyl group, ethyl group, isopropyl group etc.), an
alkenyl group having 2 - 6 carbon atoms (e.g., vinyl group
etc.), an alkoxy group having 1 - 6 carbon atoms (e.g., methoxy
group, ethoxy group etc.) and the like, and the like. While
the number of the substituents is not particularly limited, 1 -
15 3 is preferable. When two or more substituents are present,
the kind of the substituent may be the same or different.
[0056]
As the optionally substituted hydroxyl group, a hydroxyl
group and a protected form thereof; an alkoxy group having 1 -
20 10 carbon atoms such as methoxy group, ethoxy group, n-propoxy
group, n-butoxy group, n-decyloxy group, 1-methylethoxy group,
1,1-dimethylethoxy group, cyclopropyloxy group, cyclohexyloxy
group and the like; an aryloxy group having 6 - 10 carbon atoms
such as phenyloxy group, 2-naphthyloxy group and the like; a
25 heteroaryloxy group such as 2-thienyloxy group, 3-pyridyloxy
group and the like can be mentioned, and the alkoxy group,
aryloxy group and heteroaryloxy group may have any substituent
selected from a halogen atom (e.g., fluorine atom, chlorine
atom, bromine atom, iodine atom); an alkyl group having 1 - 6
30 carbon atoms (e.g., methyl group, ethyl group, isopropyl group
etc.); an alkenyl group having 2 - 6 carbon atoms (e.g., vinyl
group, allyl group etc.); an alkoxy group having 1 - 6 carbon
atoms (e.g., methoxy group, ethoxy group etc.); an arylalkyl
group (e.g., benzyl group etc.) and the like. While the number
35 of the substituents is not particularly limited, 1 - 3 is
21
preferable. When two or more substituents are present, the
kind of the substituent may be the same or different.
A protecting group used as a hydroxyl protecting group is
not particularly limited as long as it can be removed under
general conditions. Specific examples thereof include an acy5 l
group such as formyl group, acetyl group, chloroacetyl group,
propionyl group, benzoyl group and the like; an optionally
substituted arylalkyl group such as benzyl group, 4-
methoxybenzyl group, 4-bromobenzyl group, 1-phenylethyl group
10 and the like; an acetal type protecting group such as
methoxymethyl group, ethoxyethyl group, benzyloxymethyl group
and the like; a silyl group such as trimethylsilyl group, tbutyldimethylsilyl
group and the like.
[0057]
15 The optionally substituted amino group optionally has any
1 or 2 substituents and/or protecting groups.
Specific examples of the substituent include, but are not
limited to, the following: an alkyl group having 1 - 6 carbon
atoms (e.g., methyl group, ethyl group, isopropyl group etc.);
20 an alkenyl group having 2 - 6 carbon atoms (e.g., vinyl group,
allyl group etc.); a hydroxyl group; an alkoxy group having 1 -
6 carbon atoms (e.g., methoxy group, ethoxy group etc.); and an
arylalkyl group (e.g., benzyl group etc.).
Specific examples of the protecting group include, but
25 are not limited to, the following: an acyl group such as formyl
group, acetyl group, chloroacetyl group, dichloroacetyl group,
trichloroacetyl group, trifluoroacetyl group, propionyl group,
benzoyl group, 4-chlorobenzoyl group and the like; an
optionally substituted alkoxycarbonyl group such as
30 methoxycarbonyl group, ethoxycarbonyl group, t-butoxycarbonyl
group, benzyloxycarbonyl group, allyloxycarbonyl group and the
like; an optionally substituted arylalkyl group such as benzyl
group, 4-methoxybenzyl group, 4-bromobenzyl group, 1-
phenylethyl group and the like; and a sulfonyl group such as
35 methanesulfonyl group, p-toluenesulfonyl group, 2-
22
nitrobenzenesulfonyl group and the like.
[0058]
As the optionally substituted thiol group, a thiol group
and a protected form thereof; an alkylthio group having 1 - 10
carbon atoms such as methylthio group, ethylthio group, 5 npropylthio
group, n-butylthio group, n-decylthio group, 1-
methylethylthio group, 1,1-dimethylethylthio group,
cyclopropylthio group, cyclohexylthio group and the like; an
arylthio group having 6 - 10 carbon atoms such as phenylthio
10 group, 2-naphthylthio group and the like; a heteroarylthio
group such as 2-thienylthio group, 3-pyridylthio group and the
like can be mentioned, and the alkylthio group, arylthio group
and heteroarylthio group may have any substituent selected from
a halogen atom (e.g., fluorine atom, chlorine atom, bromine
15 atom, iodine atom); an alkyl group having 1 - 6 carbon atoms
(e.g., methyl group, ethyl group, isopropyl group etc.); an
alkenyl group having 2 - 6 carbon atoms (e.g., vinyl group,
allyl group etc.); an alkoxy group having 1 - 6 carbon atoms
(e.g., methoxy group, ethoxy group etc.); an arylalkyl group
20 (e.g., benzyl group etc.) and the like. While the number of
the substituents is not particularly limited, 1 - 3 is
preferable. When two or more substituents are present, the
kind of the substituent may be the same or different.
A protecting group used as a thiol protecting group is
25 not particularly limited as long as it can be removed under
general conditions. Specific examples thereof include an acyl
group such as formyl group, acetyl group, chloroacetyl group,
propionyl group, benzoyl group and the like; an optionally
substituted arylalkyl group such as benzyl group, 4-
30 methoxybenzyl group, 4-bromobenzyl group, 1-phenylethyl group
and the like; an acetal type protecting group such as
methoxymethyl group, ethoxyethyl group, benzyloxymethyl group
and the like; and a silyl group such as trimethylsilyl group,
t-butyldimethylsilyl group and the like.
35 [0059]
23
Specific examples of the halogen atom are a fluorine atom,
a chlorine atom, a bromine atom, and an iodine atom.
Of these, R3 is preferably a hydrogen atom.
[0060]
In the present invention, X is a halogen atom, or 5 a
sulfonyloxy group.
[0061]
Specific examples of the halogen atom are a fluorine atom,
a chlorine atom, a bromine atom, and an iodine atom.
10 [0062]
Specific examples of the sulfonyloxy group include, but
are not limited to, the following: an optionally substituted
alkylsulfonyloxy group such as methanesulfonyloxy group,
chloromethanesulfonyloxy group, trifluoromethanesulfonyloxy
15 group and the like; an optionally substituted arylsulfonyloxy
group such as p-toluenesulfonyloxy group, pchlorobenzenesulfonyloxy
group, 2-nitrobenzenesulfonyloxy group
and the like.
[0063]
20 Of these, X is preferably a halogen atom, more preferably
a chlorine atom corresponding to an industrially economical
chain ketone compound.
[0064]
In the present invention, Y is a nitrogen atom or a
nitrogen atom substituted by R225 .
[0065]
In the present invention, Z is a carbon atom or a carbon
atom substituted by a cyano group.
[0066]
30 The chain ketone compound represented by the abovementioned
formula (1) is a compound having a leaving group such
as a halogen atom and the like at the 4-position of 1-
substituted-1-butanone.
[0067]
35 Specific examples of the chain ketone compound
24
represented by the above-mentioned formula (1) include 5-
fluoro-2-pentanone, 5-chloro-2-pentanone, 5-bromo-2-pentanone,
5-iodo-2-pentanone, 5-(methanesulfonyloxy)-2-pentanone, 5-
(chloromethanesulfonyloxy)-2-pentanone, 5-(toluenesulfonyloxy)-
2-pentanone, 6-chloro-3-hexanone, 6-bromo-3-hexanone, 1-chloro5 -
4-octanone, 6-chloro-2-methyl-3-hexanone, 4-chloro-1-
cyclopropyl-1-butanone, 4-chloro-1-cyclohexyl-1-butanone, 4-
bromo-1-cyclohexyl-1-butanone, 7-chloro-1-hepten-4-one, 4-
chloro-1-phenyl-1-butanone, 4-bromo-1-phenyl-1-butanone, 4-
10 chloro-1-(4-methoxyphenyl)-1-butanone, 4-chloro-1-(4-
chlorophenyl)-1-butanone, 4-chloro-1-(2-thienyl)-1-butanone,
and 4-chloro-1-(3-pyridyl)-1-butanone.
[0068]
The cyclic nitrogen-containing compound represented by
15 the above-mentioned formula (2) is a pyrrolidine which is a
saturated 5-membered ring amine, or a pyrroline which is an
unsaturated 5-membered ring imine having a carbon-nitrogen
double bond, and has a substituent at the 2-position.
When the cyclic nitrogen-containing compound represented
20 by the above-mentioned formula (2) is a pyrrolidine, the
compound is particularly a 2-cyanopyrrolidine represented by
the following formula (7), i.e., a compound having substituent
R1 and a cyano group at the 2-position of pyrrolidine, and
substituent R2 on the nitrogen atom of pyrrolidine.
25 The 2-cyanopyrrolidine represented by the following
formula (7) has an asymmetric center at the carbon atom to
which the cyano group is bonded. When an asymmetric center
other than this is absent in a molecule, it is generally a
racemate. When plural asymmetric centers are present in a
30 molecule, it is generally a diastereomeric mixture.
[0069]
25
[0070]
Specific examples of 2-cyanopyrrolidines represented by
the above-mentioned formula (7) include 2-cyano-2-
methylpyrrolidine, 1-acetyl-2-cyano-2-methylpyrrolidine, 1-(5 (tbutoxycarbonyl)-
2-cyano-2-methylpyrrolidine, 1-(chloroacetyl)-
2-cyano-2-methylpyrrolidine, 2-cyano-2-methyl-1-
(trifluoroacetyl)pyrrolidine, 1-benzoyl-2-cyano-2-
methylpyrrolidine, 1-(benzyloxycarbonyl)-2-cyano-2-
10 methylpyrrolidine, 1-benzyl-2-cyano-2-methylpyrrolidine, 1-(1-
phenylethyl)-2-cyano-2-methylpyrrolidine, 1-(1-(1-
naphthyl)ethyl)-2-cyano-2-methylpyrrolidine, 1-(1-(2-
naphthyl)ethyl)-2-cyano-2-methylpyrrolidine, 1-
(carbamoylphenylmethyl)-2-cyano-2-methylpyrrolidine, 2-cyano-2-
15 ethylpyrrolidine, 2-butyl-2-cyanopyrrolidine, 1-(tbutoxycarbonyl)-
2-butyl-2-cyanopyrrolidine, 2-cyano-2-(1-
methylethyl)pyrrolidine, 2-cyano-2-cyclopropylpyrrolidine, 2-
cyano-2-cyclohexylpyrrolidine, 2-allyl-2-cyanopyrrolidine, 2-
cyano-2-phenylpyrrolidine, 1-(t-butoxycarbonyl)-2-cyano-2-
20 phenylpyrrolidine, 1-benzyl-2-cyano-2-phenylpyrrolidine, 1-
benzyl-2-cyano-2-(4-methoxyphenyl)pyrrolidine, 1-benzyl-2-(4-
chlorophenyl)-2-cyanopyrrolidine, 1-benzyl-2-cyano-2-(2-
thienyl)pyrrolidine, and 1-benzyl-2-cyano-2-(3-
pyridyl)pyrrolidine.
25 [0071]
When the cyclic nitrogen-containing compound represented
by the above-mentioned formula (2) is a pyrroline, the compound
is particularly a pyrroline represented by the following
formula (6), i.e., a compound having substituent R1 at the 2-
30 position of 1-pyrroline.
[0072]
26
[0073]
Specific examples of pyrrolines represented by the abovementioned
formula (6) include 2-methyl-1-pyrroline, 2-ethyl-1-
pyrroline, 2-butyl-1-pyrroline, 2-(1-methylethyl)-1-pyrroline5 ,
2-cyclopropyl-1-pyrroline, 2-cyclohexyl-1-pyrroline, 2-allyl-1-
pyrroline, 2-phenyl-1-pyrroline, 2-(4-methoxyphenyl)-1-
pyrroline, 2-(4-chlorophenyl)-1-pyrroline, 2-(2-thienyl)-1-
pyrroline, and 2-(3-pyridyl)-1-pyrroline.
10 [0074]
The α-substituted prolinamide represented by the abovementioned
formula (3) is a compound having a substituent and a
carbamoyl group at the 2-position of pyrrolidine, and a
hydrogen atom, an optionally substituted alkyl group, or an
15 amino-protecting group on the nitrogen atom of pyrrolidine.
The α-substituted prolinamide represented by the abovementioned
formula (3) has an asymmetric center on the carbon
atom to which the carbamoyl group is bonded.
When an asymmetric center is absent except at the carbon
20 atom to which the carbamoyl group is bonded, it may be a
racemate or an optically active form of any of S form and R
form having any optical purity of 0 - 99%ee. In this case, the
optical purity is preferably not more than 80%ee, more
preferably not more than 60%ee, particularly preferably not
25 more than 50%ee.
[0075]
When plural asymmetric centers are present in a molecule,
it may be a diastereomer or a diastereomeric mixture of any
stereochemistry. In this case, the diastereomeric purity may
30 be any, and it is generally a diastereomer or a diastereomeric
mixture having any ratio of R form:S form (molar
ratio)=0.5:99.5 - 99.5:0.5 in the stereochemistry of the 2-
position of pyrrolidine. Preferably, the stereochemistry of
the 2-position is R form:S form (molar ratio)=10:90 - 90:10,
35 more preferably R form:S form (molar ratio)=20:80 - 80:20,
27
particularly preferably R form:S form (molar ratio)=25:75 -
75:25. Moreover, a mixture having a lower ratio of R form to S
form is preferable since it can be synthesized more easily.
[0076]
Specific examples of the α-substituted prolinamide5 s
represented by the above-mentioned formula (3) include α-
methylprolinamide, N-acetyl-α-methylprolinamide, N-(tbutoxycarbonyl)-
α-methylprolinamide, N-(chloroacetyl)-α-
methylprolinamide, N-(trifluoroacetyl)-α-methylprolinamide, N10
benzoyl-α-methylprolinamide, N-(benzyloxycarbonyl)-α-
methylprolinamide, N-benzyl-α-methylprolinamide, N-(1-
phenylethyl)-α-methylprolinamide, N-(1-(1-naphthyl)ethyl)-α-
methylprolinamide, N-(1-(2-naphthyl)ethyl)-α-methylprolinamide,
N-(carbamoylphenylmethyl)-α-methylprolinamide, α-
15 ethylprolinamide, α-butylprolinamide, N-(t-butoxycarbonyl)-α-
butylprolinamide, α-(1-methylethyl)prolinamide, α-
cyclopropylprolinamide, α-cyclohexylprolinamide, α-
allylprolinamide, α-phenylprolinamide, N-(t-butoxycarbonyl)-α-
phenylprolinamide, N-benzyl-α-phenylprolinamide, α-(4-
20 methoxyphenyl)prolinamide, N-benzyl-α-(4-
methoxyphenyl)prolinamide, α-(4-chlorophenyl)prolinamide, Nbenzyl-
α-(4-chlorophenyl)prolinamide, α-(2-thienyl)prolinamide,
N-benzyl-α-(2-thienyl)prolinamide, α-(3-pyridyl)prolinamide,
and N-benzyl-α-(3-pyridyl)prolinamide.
25 [0077]
The optionally active α-substituted proline represented
by the above-mentioned formula (4) is a compound having a
substituent and a carboxyl group at the 2-position of
pyrrolidine, and a hydrogen atom, an optionally substituted
30 alkyl group, or an amino-protecting group on the nitrogen atom
of pyrrolidine. The optionally active α-substituted proline
represented by the above-mentioned formula (4) is an optionally
active form having an asymmetric center on the carbon atom to
which the carboxyl group is bonded. When an asymmetric center
35 is absent other than this in a molecule, it may be any of S
28
form and R form. While the optical purity may be any, it is
preferably not less than 80%ee, more preferably not less than
90%ee, further preferably not less than 95%ee. Since
pharmaceutical products and intermediates therefor require high
optical purity, it is particularly preferably not less tha5 n
99%ee.
[0078]
When plural asymmetric centers are present in a molecule,
it may be a diastereomer or a diastereomeric mixture having any
10 stereochemistry. While the diastereomeric purity and/or
optical purity may be any, the stereochemistry of the 2-
position of pyrrolidine is preferably R form:S form (molar
ratio)=90:10 - 100:0 or R form:S form (molar ratio)=10:90 -
0:100, more preferably R form:S form (molar ratio)=97.5:2.5 -
15 100:0 or R form:S form (molar ratio)=2.5:97.5 - 0:100. Since
pharmaceutical products and intermediates therefor require high
optical purity, it is more preferably R form:S form (molar
ratio)=99:1 - 100:0 or R form:S form (molar ratio)=1:99 - 0:100,
particularly preferably R form:S form (molar ratio)=99.5:0.5 -
20 100:0 or R form:S form (molar ratio)=0.5:99.5 - 0:100.
[0079]
Specific examples of the optically active α-substituted
proline represented by the above-mentioned formula (4) include
(R)-α-methylproline, (R)-N-acetyl-α-methylproline, (R)-N-(t25
butoxycarbonyl)-α-methylproline, (R)-N-(chloroacetyl)-α-
methylproline, (R)-N-(trifluoroacetyl)-α-methylproline, (R)-Nbenzoyl-
α-methylproline, (R)-N-(benzyloxycarbonyl)-α-
methylproline, (R)-N-benzyl-α-methylproline, (R)-α-ethylproline,
(R)-α-butylproline, (R)-N-(t-butoxycarbonyl)-α-butylproline,
30 (R)-α-(1-methylethyl)proline, (R)-α-cyclopropylproline, (R)-α-
cyclohexylproline, (R)-α-allylproline, (R)-α-phenylproline,
(R)-N-(t-butoxycarbonyl)-α-phenylproline, (R)-N-benzyl-α-
phenylproline, (R)-α-(4-methoxyphenyl)proline, (R)-α-(4-
chlorophenyl)proline, (R)-α-(2-thienyl)proline, (R)-α-(3-
35 pyridyl)proline, (S)-α-methylproline, (S)-N-acetyl-α-
29
methylproline, (S)-N-(t-butoxycarbonyl)-α-methylproline, (S)-N-
(chloroacetyl)-α-methylproline, (S)-N-(trifluoroacetyl)-α-
methylproline, (S)-N-benzoyl-α-methylproline, (S)-N-
(benzyloxycarbonyl)-α-methylproline, (S)-N-benzyl-α-
methylproline, (S)-α-ethylproline, (S)-α-butylproline, (S)-5 N-
(t-butoxycarbonyl)-α-butylproline, (S)-α-(1-methylethyl)proline,
(S)-α-cyclopropylproline, (S)-α-cyclohexylproline, (S)-α-
allylproline, (S)-α-phenylproline, (S)-N-(t-butoxycarbonyl)-α-
phenylproline, (S)-N-benzyl-α-phenylproline, (S)-α-(4-
10 methoxyphenyl)proline, (S)-α-(4-chlorophenyl)proline, (S)-α-(2-
thienyl)proline, (S)-α-(3-pyridyl)proline, (2R,1’R)-N-(1’-
phenylethyl)-α-methylproline, (2R,1’S)-N-(1’-phenylethyl)-α-
methylproline, (2S,1’R)-N-(1’-phenylethyl)-α-methylproline,
(2S,1’S)-N-(1’-phenylethyl)-α-methylproline, (2R,1’R)-N-(1’-(1-
15 naphthyl)ethyl)-α-methylproline, (2R,1’S)-N-(1’-(1-
naphthyl)ethyl)-α-methylproline, (2S,1’R)-N-(1’-(1-
naphthyl)ethyl)-α-methylproline, (2S,1’S)-N-(1’-(1-
naphthyl)ethyl)-α-methylproline, (2R,1’R)-N-(1’-(2-
naphthyl)ethyl)-α-methylproline, (2R,1’S)-N-(1’-(2-
20 naphthyl)ethyl)-α-methylproline, (2S,1’R)-N-(1’-(2-
naphthyl)ethyl)-α-methylproline, (2S,1’S)-N-(1’-(2-
naphthyl)ethyl)-α-methylproline, (2R,1’R)-N-
(carbamoylphenylmethyl)-α-methylproline, (2R,1’S)-N-
(carbamoylphenylmethyl)-α-methylproline, (2S,1’R)-N-
25 (carbamoylphenylmethyl)-α-methylproline, and (2S,1’S)-N-
(carbamoylphenylmethyl)-α-methylproline.
[0080]
The optically active α-substituted prolinamide
represented by the above-mentioned formula (5) is a compound
30 having a substituent and a carbamoyl group at the 2-position of
pyrrolidine, and a hydrogen atom, an optionally substituted
alkyl group, or an amino-protecting group on the nitrogen atom
of pyrrolidine.
The optionally active α-substituted prolinamide
35 represented by the above-mentioned formula (5) is an optionally
30
active form having an asymmetric center on the carbon atom to
which the carbamoyl group is bonded. When an asymmetric center
is absent other than this in a molecule, it may be any of S
form and R form. While the optical purity may be any, it is
higher than that of the α-substituted prolinamide represente5 d
by the above-mentioned formula (3), preferably not less than
80%ee, more preferably not less than 90%ee, further preferably
not less than 95%ee. Since pharmaceutical products and
intermediates therefor require high optical purity, it is
10 particularly preferably not less than 99%ee.
[0081]
When plural asymmetric centers are present in a molecule,
it may be a diastereomer or a diastereomeric mixture of any
stereochemistry. While the diastereomeric purity may be any,
15 the stereochemistry of the 2-position of pyrrolidine is higher
than that of the α-substituted prolinamide represented by the
above-mentioned formula (3), and is preferably R form:S form
(molar ratio)=90:10 - 100:0 or R form:S form (molar
ratio)=10:90 - 0:100, more preferably R form:S form (molar
20 ratio)=97.5:2.5 - 100:0 or R form:S form (molar ratio)=2.5:97.5
- 0:100. Since pharmaceutical products and intermediates
therefor require high optical purity, it is more preferably R
form:S form (molar ratio)=99:1 - 100:0 or R form:S form (molar
ratio)=1:99 - 0:100, particularly preferably R form:S form
25 (molar ratio)=99.5:0.5 - 100:0 or R form:S form (molar
ratio)=0.5:99.5 - 0:100.
[0082]
Specific examples of the optically active α-substituted
prolinamide represented by the above-mentioned formula (5)
30 include (R)-α-methylprolinamide, (R)-N-acetyl-α-
methylprolinamide, (R)-N-(t-butoxycarbonyl)-α-methylprolinamide,
(R)-N-(chloroacetyl)-α-methylprolinamide, (R)-N-
(trifluoroacetyl)-α-methylprolinamide, (R)-N-benzoyl-α-
methylprolinamide, (R)-N-(benzyloxycarbonyl)-α-
35 methylprolinamide, (R)-N-benzyl-α-methylprolinamide, (R)-α-
31
ethylprolinamide, (R)-α-butylprolinamide, (R)-N-(tbutoxycarbonyl)-
α-butylprolinamide, (R)-α-(1-
methylethyl)prolinamide, (R)-α-cyclopropylprolinamide, (R)-α-
cyclohexylprolinamide, (R)-α-allylprolinamide, (R)-α-
phenylprolinamide, (R)-N-(t-butoxycarbonyl)-α-phenylprolinamide5 ,
(R)-N-benzyl-α-phenylprolinamide, (R)-α-(4-
methoxyphenyl)prolinamide, (R)-α-(4-chlorophenyl)prolinamide,
(R)-α-(2-thienyl)prolinamide, (R)-α-(3-pyridyl)prolinamide,
(S)-α-methylprolinamide, (S)-N-acetyl-α-methylprolinamide, (S)-
10 N-(t-butoxycarbonyl)-α-methylprolinamide, (S)-N-(chloroacetyl)-
α-methylprolinamide, (S)-N-(trifluoroacetyl)-α-
methylprolinamide, (S)-N-benzoyl-α-methylprolinamide, (S)-N-
(benzyloxycarbonyl)-α-methylprolinamide, (S)-N-benzyl-α-
methylprolinamide, (S)-α-ethylprolinamide, (S)-α-
15 butylprolinamide, (S)-N-(t-butoxycarbonyl)-α-butylprolinamide,
(S)-α-(1-methylethyl)prolinamide, (S)-α-cyclopropylprolinamide,
(S)-α-cyclohexylprolinamide, (S)-α-allylprolinamide, (S)-α-
phenylprolinamide, (S)-N-(t-butoxycarbonyl)-α-phenylprolinamide,
(S)-N-benzyl-α-phenylprolinamide, (S)-α-(4-
20 methoxyphenyl)prolinamide, (S)-α-(4-chlorophenyl)prolinamide,
(S)-α-(2-thienyl)prolinamide, (S)-α-(3-pyridyl)prolinamide,
(2R,1’R)-N-(1’-phenylethyl)-α-methylprolinamide, (2R,1’S)-N-
(1’-phenylethyl)-α-methylprolinamide, (2S,1’R)-N-(1’-
phenylethyl)-α-methylprolinamide, (2S,1’S)-N-(1’-phenylethyl)-
25 α-methylprolinamide, (2R,1’R)-N-(1’-(1-naphthyl)ethyl)-α-
methylprolinamide, (2R,1’S)-N-(1’-(1-naphthyl)ethyl)-α-
methylprolinamide, (2S,1’R)-N-(1’-(1-naphthyl)ethyl)-α-
methylprolinamide, (2S,1’S)-N-(1’-(1-naphthyl)ethyl)-α-
methylprolinamide, (2R,1’R)-N-(1’-(2-naphthyl)ethyl)-α-
30 methylprolinamide, (2R,1’S)-N-(1’-(2-naphthyl)ethyl)-α-
methylprolinamide, (2S,1’R)-N-(1’-(2-naphthyl)ethyl)-α-
methylprolinamide, (2S,1’S)-N-(1’-(2-naphthyl)ethyl)-α-
methylprolinamide, (2R,1’R)-N-(carbamoylphenylmethyl)-α-
methylprolinamide, (2R,1’S)-N-(carbamoylphenylmethyl)-α-
35 methylprolinamide, (2S,1’R)-N-(carbamoylphenylmethyl)-α-
32
methylprolinamide, and (2S,1’S)-N-(carbamoylphenylmethyl)-α-
methylprolinamide.
[0083]
The above-mentioned compounds may have a basic or acidic
functional group, and optionally form a salt. Examples of suc5 h
salt include inorganic acid salts (e.g., hydrochloride, sulfate,
nitrate, phosphate etc.); organic acid salts (e.g., acetate,
propionate, methanesulfonate, 4-toluenesulfonate, oxalate,
maleate etc.); tartaric acids (L-tartaric acid, D-tartaric acid,
10 (2S,3S)-dibenzoyltartaric acid, (2R,3R)-dibenzoyltartaric acid,
(2S,3S)-di(p-toluoyl)tartaric acid, (2R,3R)-di(ptoluoyl)
tartaric acid etc.); mandelic acids ((S)-mandelic acid,
(R)-mandelic acid etc.); amino acid derivatives (N-acetyl-Lalanine,
N-acetyl-L-phenylglycine, N-acetyl-D-phenylglycine, N15
benzyl-L-phenylglycine, N-benzyl-D-phenylglycine, N-acetyl-Lphenylalanine,
N-acetyl-L-glutamic acid, N-acetyl-L-aspartic
acid etc.); optically active sulfonic acids ((S)-10-
camphorsulfonic acid, (R)-10-camphorsulfonic acid, (S)-1-
phenylethanesulfonic acid, (R)-1-phenylethanesulfonic acid
20 etc.); alkali metal salts (e.g., sodium salt, potassium salt
etc.); alkaline earth metal salts (e.g., calcium salt,
magnesium salt etc.); and salts with organic base (e.g.,
trimethylamine salt, triethylamine salt, pyridine salt,
picoline salt, dicyclohexylamine salt etc.) and the like.
25 [0084]
The α-methylprolinamide represented by the abovementioned
formula (8) is a compound having methyl group and
carbamoyl group at the 2-position of pyrrolidine, and 1-
phenylethyl group, 1-(1-naphthyl)ethyl group, 1-(2-
30 naphthyl)ethyl group, or carbamoylphenylmethyl group on the
nitrogen atom of pyrrolidine. The substituent on the nitrogen
atom of pyrrolidine is preferably 1-phenylethyl group or
carbamoylphenylmethyl group, more preferably 1-phenylethyl
group.
35 The α-methylprolinamide has two asymmetric centers at the
33
2-position of pyrrolidine and the substituent (1’-position) on
the nitrogen atom of pyrrolidine, and may be a diastereomer or
a diastereomeric mixture of any stereochemistry. Since the
asymmetric carbon at the substituent (1’-position) on the
pyrrolidine nitrogen atom is derived from the primary amine o5 r
a salt thereof used in step (a), when the reaction is free of
epimerization, the optical purity of the primary amine used is
the asymmetric purity at the 1’-position. The absolute
configuration at the 1’-position may be any of R form, S form,
10 and racemate, and the asymmetric purity thereof may be any.
However, since the isomer at the 2-position of pyrrolidine can
be resolved by the asymmetry at the 1’-position, it is
preferably as high as possible, and is R form:S form (molar
ratio)=90:10 - 100:0 or R form:S form (molar ratio)=10:90 -
15 0:100, more preferably R form:S form (molar ratio)=97.5:2.5 -
100:0 or R form:S form (molar ratio)=2.5:97.5 - 0:100,
particularly preferably R form:S form (molar ratio)=99.5:0.5 -
100:0 or R form:S form (molar ratio)=0.5:99.5 - 0:100, for the
1’-position.
20 [0085]
Since the α-methylprolinamide represented by the abovementioned
formula (8) may form a salt with an optically active
acid and/or achiral acid, and forms diastereomeric salts
permitting resolution, it is useful. Specific examples of such
25 salt include inorganic acid salts (e.g., hydrochloride, sulfate,
nitrate, phosphate etc.); organic acid salts (e.g., acetate,
propionate, methanesulfonate, 4-toluenesulfonate, oxalate,
maleate etc.); tartaric acids (L-tartaric acid, D-tartaric acid,
(2S,3S)-dibenzoyltartaric acid, (2R,3R)-dibenzoyltartaric acid,
30 (2S,3S)-di(p-toluoyl)tartaric acid, (2R,3R)-di(ptoluoyl)
tartaric acid etc.); mandelic acids ((S)-mandelic acid,
(R)-mandelic acid etc.); amino acid derivatives (N-acetyl-Lalanine,
N-acetyl-L-phenylglycine, N-acetyl-D-phenylglycine, Nbenzyl-
L-phenylglycine, N-benzyl-D-phenylglycine, N-acetyl-L35
phenylalanine, N-acetyl-L-glutamic acid, N-acetyl-L-aspartic
34
acid etc.); optically active sulfonic acids ((S)-10-
camphorsulfonic acid, (R)-10-camphorsulfonic acid, (S)-1-
phenylethanesulfonic acid, (R)-1-phenylethanesulfonic acid
etc.) and the like. Of these, preferred are salts with
optically active acid expected to show a large difference i5 n
the solubility between diastereomeric salts, more preferred are
salts with tartaric acids, mandelic acids, and particularly
preferred are salts with L-tartaric acid, D-tartaric acid, (S)-
mandelic acid, (R)-mandelic acid, which are economical.
10 [0086]
Specific examples of the salt of N-(1’-phenylethyl)-α-
methylprolinamide with optically active acid and/or achiral
acid include (2S,1’S)-N-(1’-phenylethyl)-α-methylprolinamide Dtartrate,
(2S,1’S)-N-(1’-phenylethyl)-α-methylprolinamide L15
tartrate, (2S,1’R)-N-(1’-phenylethyl)-α-methylprolinamide Dtartrate,
(2S,1’R)-N-(1’-phenylethyl)-α-methylprolinamide Ltartrate,
(2R,1’R)-N-(1’-phenylethyl)-α-methylprolinamide Dtartrate,
(2R,1’R)-N-(1’-phenylethyl)-α-methylprolinamide Ltartrate,
(2R,1’S)-N-(1’-phenylethyl)-α-methylprolinamide D20
tartrate, (2R,1’S)-N-(1’-phenylethyl)-α-methylprolinamide Ltartrate,
(2S,1’S)-N-(1’-phenylethyl)-α-methylprolinamide (S)-
mandelate, (2S,1’S)-N-(1’-phenylethyl)-α-methylprolinamide (R)-
mandelate, (2S,1’R)-N-(1’-phenylethyl)-α-methylprolinamide (S)-
mandelate, (2S,1’R)-N-(1’-phenylethyl)-α-methylprolinamide (R)-
25 mandelate, (2R,1’R)-N-(1’-phenylethyl)-α-methylprolinamide (S)-
mandelate, (2R,1’R)-N-(1’-phenylethyl)-α-methylprolinamide (R)-
mandelate, (2R,1’S)-N-(1’-phenylethyl)-α-methylprolinamide (S)-
mandelate, (2R,1’S)-N-(1’-phenylethyl)-α-methylprolinamide (R)-
mandelate, (2S,1’S)-N-(1’-phenylethyl)-α-methylprolinamide 4-
30 toluenesulfonate, (2R,1’R)-N-(1’-phenylethyl)-α-
methylprolinamide 4-toluenesulfonate, (2S,1’S)-N-(1’-
phenylethyl)-α-methylprolinamide oxalate, and (2R,1’R)-N-(1’-
phenylethyl)-α-methylprolinamide oxalate.
[0087]
35 Step (a)
35
The cyclic nitrogen-containing compound represented by
the above-mentioned formula (2) can be synthesized by reacting
a chain ketone compound represented by the above-mentioned
formula (1) with at least one selected from ammonia, an
ammonium salt, primary amine and a salt of primary amine, and 5 a
cyanating agent.
The chain ketone compound represented by the abovementioned
formula (1) can be purchased as reagents such as 5-
chloro-2-pentanone, 4-chloro-1-phenyl-1-butanone and the like.
10 Other compounds can be freely produced by a method such as
Friedel-Crafts reaction of 3-chloropropionyl chloride and an
aromatic compound, Claisen condensation of γ-butyrolactone and
esters, followed by a treatment with hydrogen halide and the
like (see, for example, Chem. Pharm. Bull., 1989, 37, 958).

CLAIMS
1. A method of producing an optically active α-substituted
proline represented by the formula (4)
5
wherein R1 is an optionally substituted alkyl group, an
optionally substituted aryl group, or an optionally substituted
heteroaryl group, R2 is a hydrogen atom, an optionally
substituted alkyl group, or an amino-protecting group, each R3 10
is independently a hydrogen atom, an optionally substituted
alkyl group, an optionally substituted aryl group, an
optionally substituted heteroaryl group, an optionally
substituted hydroxyl group, an optionally substituted amino
15 group, an optionally substituted thiol group, or a halogen atom,
two or more R3 optionally form one or plural ring structures,
and * shows an asymmetric carbon, or a salt thereof, and/or an
optically active α-substituted prolinamide represented by the
formula (5)
20
wherein each symbol is as defined above, or a salt thereof,
comprising the following steps (a) to (c);
25 (a) reacting a chain ketone compound represented by the formula
(1)
102
wherein R1 and R3 are as defined above, and X is a halogen atom
or a sulfonyloxy group, with at least one selected from ammonia,
an ammonium salt, primary amine and a salt of primary amine5 ,
and a cyanating agent and, where necessary, protecting a
nitrogen atom on the pyrrolidine ring to give a cyclic
nitrogen-containing compound represented by the formula (2)
10
wherein R1 and R3 are as defined above, Y is a nitrogen atom or
a nitrogen atom substituted by R2, Z is a carbon atom or a
carbon atom substituted by a cyano group, when Y is a nitrogen
atom and Z is a carbon atom, then the bond between Y and Z is a
double bond, when Y is a nitrogen atom substituted by R2 15 and Z
is a carbon atom substituted by a cyano group, then the bond
between Y and Z is a single bond, and R2 is as defined above,
or a salt thereof; and
(b) hydrating the cyclic nitrogen-containing compound
20 represented by the formula (2) or a salt thereof to give an α-
substituted prolinamide represented by the formula (3)
25 wherein each symbol is as defined above, or a salt thereof; and
103
(c) resolving the α-substituted prolinamide represented by the
formula (3) or a salt thereof to give an optically active α-
substituted proline represented by the formula (4) or a salt
thereof, and/or an optically active α-substituted prolinamide
represented by the formula (5) or a salt thereof5 .
2. A method of producing a 2-substituted prolinamide
represented by the formula (3)
10
wherein each symbol is as defined in claim 1, or a salt thereof,
comprising the following steps (a) and (b);
(a) reacting a chain ketone compound represented by the formula
(1)
15
wherein each symbol is as defined in claim 1, with at least one
selected from ammonia, an ammonium salt, primary amine and a
salt of primary amino, and a cyanating agent and, where
20 necessary, protecting a nitrogen atom on the pyrrolidine ring
to give a cyclic nitrogen-containing compound represented by
the formula (2)
25
104
wherein each symbol is as defined in claim 1, or a salt
thereof; and
(b) hydrating the cyclic nitrogen-containing compound
represented by the formula (2) or a salt thereof to give an α-
substituted prolinamide represented by the formula (3) or 5 a
salt thereof.
3. A method of producing a cyclic nitrogen-containing compound
represented by the formula (2)
10
wherein each symbol is as defined in claim 1, or a salt thereof,
comprising the following step (a);
15 (a) reacting a chain ketone compound represented by the formula
(1)
20 wherein each symbol is as defined in claim 1, with at least one
selected from ammonia, an ammonium salt, primary amine and a
salt of primary amine, and a cyanating agent and, where
necessary, protecting a nitrogen atom on the pyrrolidine ring
to give a cyclic nitrogen-containing compound represented by
25 the formula (2) or a salt thereof.
4. A method of producing an optically active α-substituted
proline represented by the formula (4)
105
wherein each symbol is as defined in claim 1, or a salt thereof,
and/or an optically active α-substituted prolinamide
represented by the formula (5 5)
wherein each symbol is as defined in claim 1, or a salt thereof,
10 comprising the following step (c);
(c) resolving an α-substituted prolinamide represented by the
formula (3)
15 wherein each symbol is as defined in claim 1, or a salt
thereof, to give an optically active α-substituted proline
represented by the formula (4) or a salt thereof, and/or an
optically active α-substituted prolinamide represented by the
formula (5) or a salt thereof;
20 wherein the resolution is one or more of the following steps
(d) to (f):
(d) asymmetric hydrolysis of the amido group by an enzyme
having an amidase activity derived from Rhizopus oryzae,
106
(e) resolution by diastereomeric salt formation,
(f) separation by column chromatography.
5. An α-methylprolinamide represented by the formula (8)
5
wherein R2 is 1-phenylethyl group, 1-(1-naphthyl)ethyl group,
1-(2-naphthyl)ethyl group, or carbamoylphenylmethyl group, or a
salt thereof.