DESCRIPTION
METHOD FOR PRODUCING 5-HYDROXYPIPERIDINE-2-CARBOXYLIC
ACID
TECHNICAL FIELD
[0001]
The present invention relates to a method for producing (2S,5S)/(2R,5R)-5-
hydroxypiperidine-2-carboxylic acid and synthetic intermediates thereof.
(2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid, which is produced by the
method of the present invention, is useful as a synthetic intermediate for a β-
lactamase inhibitor and the like.
BACKGROUND ART
[0002]
(2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid is a useful
intermediate for the synthesis of an agent and the like that inhibits β-lactamases in
bacteria exhibiting the resistance against the β-lactam class of antibiotics, which β-
lactamases are the major cause of the resistance in the bacteria.
A production method using glutamic acid or pyroglutamic acid as a starting
raw material has been known as a method for producing (2S,5S)/(2R,5R)-5-
hydroxypiperidine-2-carboxylic acid. Specifically, Patent Document 1 describes
that a protected 5-hydroxypiperidine-2-carboxylic acid compound as an intermediate
of N-protected oxo-azacycloalkylcarboxylic acids is produced from pyroglutamic
acid as a starting raw material through the homologation process to increase carbon
atoms and the cyclization process.
2
Moreover, Non-Patent Document 1 describes that a protected 5-
hydroxypiperidine-2-carboxylic acid compound is produced from glutamine as a
starting raw material through the homologation process to increase carbon atoms and
the cyclization process.
Non-Patent Document 2 describes that a mixture of stereoisomers of a
protected 5-hydroxypiperidine-2-carboxylic acid compound is produced from a
protected glutamic acid compound as a starting raw material through the
homologation process to increase carbon atoms and the cyclization process.
Non-Patent Document 3 describes that a protected 5-hydroxypiperidine-2-
carboxylic acid compound is produced from a protected pyroglutamic acid
compound as a starting raw material through the homologation process to increase
carbon atoms and the cyclization process.
Patent Document 2 describes that a protected 5-hydroxypiperidine-2-
carboxylic acid compound is produced from a protected pyroglutamic acid
compound as a starting raw material through the homologation process to increase
carbon atoms and the cyclization process in one step.
PRIOR ART DOCUMENTS
[Patent Documents]
[0003]
Patent Document 1: WO2010/126820
Patent Document 2: WO2006/125974
[Non-Patent Documents]
[0004]
Non-Patent Document 1: P. D. Bailey et al., Chem. Commun. 1996, 349.
Non-Patent Document 2: P. D. Bailey et al., Tetrahedron Lett. 1988, 29, 2231.
3
Non-Patent Document 3: M. A. Letavic et al., Bioorg. Med. Chem. Lett. 2002, 12,
1387.
SUMMARY OF THE INVENTION
TECHNICAL PROBLEM
[0005]
The method described in Patent Document 1 to produce (2S,5S)/(2R,5R)-5-
hydroxypiperidine-2-carboxylic acid requires a very expensive iridium catalyst to be
used and therefore is not suitable for the industrial production.
The production method described in Non-Patent Document 1 is difficult to
be employed in the industrial production because the method also requires an
expensive rhodium catalyst to be used and, furthermore, comprises the step of using
diazomethane, which is difficult to use in industrial applications.
The production method described in Non-Patent Document 2 is likewise
difficult to be employed in the industrial production because the method also
comprises the step of using diazomethane, which is difficult to use in industrial
applications, and further comprises a problem regarding an obtainable compound, in
which the compound is obtained as a mixture of stereoisomers.
The production methods described in Non-Patent Document 3 and Patent
Document 2 are likewise difficult to be employed in the industrial production
because the methods comprise the step of using TMS diazomethane, which is
expensive and difficult to use in industrial applications. Furthermore, the
production method described in Patent Document 2 requires an expensive rhodium
catalyst to be used. Either of the production methods described in Non-Patent
Document 3 and Patent Document 2 requires the reaction to be performed at a quite
low temperature and therefore is difficult to be employed in the industrial production.
4
In view of the above-mentioned problems, an object of the present
invention is to provide a method for producing (2S,5S)/(2R,5R)-5-hydroxypiperidine-
2-carboxylic acid and synthetic intermediates thereof including achiral and chiral
molecules, the method available for practical use in the industrial production.
SOLUTION TO PROBLEM
[0006]
The inventors have intensively studied to solve the above-described
problems and consequently found that optically active substances of (2S,5S)/(2R,5R)-
5-hydroxypiperidine-2-carboxylic acids can be efficiently synthesized by using
particular synthetic intermediates, and thereby completed the present invention.
[0007]
That is, the present invention is as follows.
<1> A method for producing (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic
acid represented by the formula (10) below:
, the method comprising (i) the step 4 of:
removing the protecting group from the hydroxyl group in a compound
represented by the formula (7) below:
5
(wherein P represents a protecting group, R3 represents an alkyl group containing 1
to 4 carbon atoms, and A represents an alkyl group containing 1 to 10 carbon atoms,
an aryl group containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to 4
carbon atoms, or an aralkyloxy group containing 7 to 20 carbon atoms)
to synthesize a compound represented by the formula (8) below:
(wherein R3 represents an alkyl group containing 1 to 4 carbon atoms, and A
represents an alkyl group containing 1 to 10 carbon atoms, an aryl group containing 6
to 12 carbon atoms, an alkyloxy group containing 1 to 4 carbon atoms, or an
aralkyloxy group containing 7 to 20 carbon atoms).
[0008]
<2> The method for producing (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-
carboxylic acid according to <1>, the method further comprising (ii) the step 5 of:
(a) in the compound (8), hydrolyzing the ester groups, allowing one of the carboxyl
groups to react with the hydroxyl group to allow the lactonization, and further
decarboxylating the other carboxyl group; or
(b) in the compound (8), hydrolyzing the ester groups, decarboxylating one of the
carboxyl groups to form a stereoisomeric mixture of a 2-monocarboxylic acid, and
then isomerizing and lactonizing the stereoisomeric mixture;
to synthesize a compound represented by the formula (9) below:
6
(wherein A represents an alkyl group containing 1 to 10 carbon atoms, an aryl group
containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to 4 carbon atoms,
or an aralkyloxy group containing 7 to 20 carbon atoms).
[0009]
<3> The method for producing (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-
carboxylic acid according to <1> or <2>, further comprising (iii) the step 6 of:
cleaving the amide bond in the compound (9) and hydrolyzing the lactone
in the compound (9) to synthesize (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic
acid.
[0010]
<4> The method for producing (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-
carboxylic acid according to <2> or <3>, wherein the step of decarboxylating the
carboxyl group in the step 5(a) or the step 5(b) is performed in the presence of an
organic base.
[0011]
<5> A method for producing the compound represented by the formula (7)
below:
7
(wherein P represents a protecting group, R3 represents an alkyl group containing 1
to 4 carbon atoms, and A represents an alkyl group containing 1 to 10 carbon atoms,
an aryl group containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to 4
carbon atoms, or an aralkyloxy group containing 7 to 20 carbon atoms),
the method comprising the step 1 of:
protecting the hydroxyl group with a protecting group in a compound
represented by the formula (1) below:
(wherein X represents Cl, Br, or I, and R1 represents a hydrogen atom or an
optionally substituted alkyl group containing 1 to 4 carbon atoms)
to synthesize a compound represented by the formula (2) below:
(wherein X represents Cl, Br, or I, R1 represents a hydrogen atom or an optionally
substituted alkyl group containing 1 to 4 carbon atoms, and P represents a protecting
group)
and then reducing the ester group in the compound (2) to synthesize a
compound represented by the formula (3) below:
(wherein X represents Cl, Br, or I, and P represents a protecting group).
[0012]
8
<6> The method for producing the compound (7) according to <5>, wherein the
method comprises (i) the step 2 of:
esterifying the hydroxyl group in the compound (3) to a sulfonate group to
synthesize a compound represented by the formula (4) below:
(wherein X represents Cl, Br, or I, R2 represents an aryl group containing 6 to 12
carbon atoms, an alkyl group containing 1 to 10 carbon atoms, or an aralkyl group
containing 7 to 20 carbon atoms)
and allowing the compound (4) to react with a compound represented by the formula
(5) below:
(wherein R3 represents an alkyl group containing 1 to 4 carbon atoms, and A
represents an alkyl group containing 1 to 10 carbon atoms, an aryl group containing 6
to 12 carbon atoms, an alkyloxy group containing 1 to 4 carbon atoms, or an
aralkyloxy group containing 7 to 20 carbon atoms)
to synthesize a compound represented by the formula (6) below:
(wherein X represents Cl, Br, or I, P represents a protecting group, R3 represents an
alkyl group containing 1 to 4 carbon atoms, and A represents an alkyl group
9
containing 1 to 10 carbon atoms, an aryl group containing 6 to 12 carbon atoms, an
alkyloxy group containing 1 to 4 carbon atoms, or an aralkyloxy group containing 7
to 20 carbon atoms);
and
(ii) the step 3 of:
cyclizing the compound (6) to synthesize the compound represented by the
formula (7) below:
(wherein P represents a protecting group, R3 represents an alkyl group containing 1
to 4 carbon atoms, and A represents an alkyl group containing 1 to 10 carbon atoms,
an aryl group containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to 4
carbon atoms, or an aralkyloxy group containing 7 to 20 carbon atoms).
[0013]
<7> The method for producing the compound (7) according to <6>, wherein the
reaction of the compound (4) with the compound (5) in the step 2 is performed in the
presence of an iodide salt.
[0014]
<8> The method for producing the compound (7) according to <6> or <7>,
wherein the cyclizing reaction of the compound (6) in the step 3 is performed in the
presence of a quaternary ammonium salt.
[0015]
10
<9> The method for producing (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-
carboxylic acid according to any one of <1> to <4>, wherein the compound (7) is
synthesized by the method according to any one of <5> to <8>.
[0016]
<10> A method for producing the compound represented by the formula (8), the
method comprising (i) the step 4 of:
removing the protecting group from the hydroxyl group in the compound
represented by the formula (7) below:
(wherein P represents a protecting group, R3 represents an alkyl group containing 1
to 4 carbon atoms, and A represents an alkyl group containing 1 to 10 carbon atoms,
an aryl group containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to 4
carbon atoms, or an aralkyloxy group containing 7 to 20 carbon atoms)
to synthesize the compound represented by the formula (8) below:
(wherein R3 represents an alkyl group containing 1 to 4 carbon atoms, and A
represents an alkyl group containing 1 to 10 carbon atoms, an aryl group containing 6
to 12 carbon atoms, an alkyloxy group containing 1 to 4 carbon atoms, or an
aralkyloxy group containing 7 to 20 carbon atoms).
11
[0017]
<11> A method for producing the compound represented by the formula (9), the
method comprising
(i) the step 4 of:
removing the protecting group from the hydroxyl group in the compound
represented by the formula (7) below:
(wherein P represents a protecting group, R3 represents an alkyl group containing 1
to 4 carbon atoms, and A represents an alkyl group containing 1 to 10 carbon atoms,
an aryl group containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to 4
carbon atoms, or an aralkyloxy group containing 7 to 20 carbon atoms)
to synthesize the compound represented by the formula (8) below:
(wherein R3 represents an alkyl group containing 1 to 4 carbon atoms, and A
represents an alkyl group containing 1 to 10 carbon atoms, an aryl group containing 6
to 12 carbon atoms, an alkyloxy group containing 1 to 4 carbon atoms, or an
aralkyloxy group containing 7 to 20 carbon atoms)
and (ii) the step 5 of:
12
(a) in the compound (8), hydrolyzing the ester groups, allowing one of the carboxyl
groups to react with the hydroxyl group to allow the lactonization, and further
decarboxylating the other carboxyl group; or
(b) in the compound (8), hydrolyzing the ester groups, decarboxylating one of the
carboxyl groups to form a stereoisomeric mixture of a 2-monocarboxylic acid, and
then isomerizing and lactonizing the stereoisomeric mixture;
to synthesize the compound represented by the formula (9) below:
(wherein A represents an alkyl group containing 1 to 10 carbon atoms, an aryl group
containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to 4 carbon atoms,
or an aralkyloxy group containing 7 to 20 carbon atoms).
[0018]
<12> A compound represented by the formula (9a) below:
(wherein A’ represents an aryl group containing 6 to 12 carbon atoms or an alkyl
group containing 1 to 10 carbon atoms).
[0019]
<13> A compound or a salt thereof, the compound represented by the formula
(11a) below:
13
(wherein A’ represents an aryl group containing 6 to 12 carbon atoms or an alkyl
group containing 1 to 10 carbon atoms)
or the formula (11b) below:
(wherein A’ represents an aryl group containing 6 to 12 carbon atoms or an alkyl
group containing 1 to 10 carbon atoms).
[0020]
<14> A compound represented by the formula (8) below or a dicarboxylic acid
salt thereof:
(wherein R3 represents an alkyl group containing 1 to 4 carbon atoms, and A
represents an alkyl group containing 1 to 10 carbon atoms, an aryl group containing 6
to 12 carbon atoms, an alkyloxy group containing 1 to 4 carbon atoms, or an
aralkyloxy group containing 7 to 20 carbon atoms).
[0021]
<15> A compound represented by the formula (7) below:
14
(wherein P represents a protecting group, R3 represents an alkyl group containing 1
to 4 carbon atoms, and A represents an alkyl group containing 1 to 10 carbon atoms,
an aryl group containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to 4
carbon atoms, or an aralkyloxy group containing 7 to 20 carbon atoms).
[0022]
<16> A compound represented by the formula (6a) below:
(wherein X represents Cl, Br, or I, P’ represents a tetrahydropyranyl group,
methoxymethyl group, ethoxyethyl group, tert-butyl group, or tert-butyldimethylsilyl
group, and R3 represents an alkyl group containing 1 to 4 carbon atoms, and A
represents an alkyl group containing 1 to 10 carbon atoms, an aryl group containing 6
to 12 carbon atoms, an alkyloxy group containing 1 to 4 carbon atoms, or an
aralkyloxy group containing 7 to 20 carbon atoms).
[0023]
<17> A compound represented by the formula (4a) below:
15
(wherein X represents Cl, Br, or I, P’ represents a tetrahydropyranyl group,
methoxymethyl group, ethoxyethyl group, tert-butyl group, or tert-butyldimethylsilyl
group, and R2 represents an aryl group containing 6 to 12 carbon atoms, an alkyl
group containing 1 to 10 carbon atoms, or an aralkyl group containing 7 to 20 carbon
atoms).
[0024]
<18> A compound represented by the formula (3a) below:
(wherein X represents Cl, Br, or I, and P’ represents a tetrahydropyranyl group,
methoxymethyl group, ethoxyethyl group, tert-butyl group, or tert-butyldimethylsilyl
group).
[0025]
<19> A compound represented by the formula (2a) below:
(wherein X represents Cl, Br, or I, R1 represents a hydrogen atom or an optionally
substituted alkyl group containing 1 to 4 carbon atoms, P’’ represents a
tetrahydropyranyl group or ethoxyethyl group).
ADVANTAGEOUS EFFECT OF THE INVENTION
[0026]
The present invention can provide (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-
carboxylic acid and a production method therefor excellent in safety and operability
and available for practical use in the industrial production. Moreover, the present
16
invention can provide novel synthetic intermediates for the production of
(2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid. (2S,5S)/(2R,5R)-5-
hydroxypiperidine-2-carboxylic acid, which is produced by the production method of
the present invention, is available as a starting material in the production of a β-
lactamase inhibitor and the like.
BRIEF DESCRIPTION OF THE DRAWINGS
[0027]
Figure 1 shows one aspect of the scheme for the synthesis of (2S,5S)/(2R,5R)-5-
hydroxypiperidine-2-carboxylic acid. In the drawing, X represents Cl, Br, or I. P
represents a protecting group. A represents an alkyl group containing 1 to 10
carbon atoms, an aryl group containing 6 to 12 carbon atoms, an alkyloxy group
containing 1 to 4 carbon atoms, or an aralkyloxy group containing 7 to 20 carbon
atoms. R1 represents a hydrogen atom or an optionally substituted alkyl group
containing 1 to 4 carbon atoms. R2 represents an aryl group containing 6 to 12
carbon atoms, an alkyl group containing 1 to 10 carbon atoms, or an aralkyl group
containing 7 to 20 carbon atoms. R3 represents an alkyl group containing 1 to 4
carbon atoms.
DESCRIPTION OF THE EMBODIMENTS
[0028]
Now, the present invention will be described in detail.
In the present specification, the “compound represented by the formula (1)”
may be referred to as the “compound (1)” and this is true of any compounds
represented by the other formulae.
In the present specification, Cl refers to a chlorine atom, Br refers to a
bromine atom, I refers to an iodine atom, and Et refers to an ethyl group.
17
[0029]
[1] Production method
The present invention is characterized in that optically active substances of
(2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acids are produced by using a
particular synthetic intermediate represented by the formula (8) below:
(wherein R3 represents an alkyl group containing 1 to 4 carbon atoms, and A
represents an alkyl group containing 1 to 10 carbon atoms, an aryl group containing 6
to 12 carbon atoms, an alkyloxy group containing 1 to 4 carbon atoms, or an
aralkyloxy group containing 7 to 20 carbon atoms)
or the formula (9) below:
(wherein A represents an alkyl group containing 1 to 10 carbon atoms, an aryl group
containing 6 to 12 carbon atoms, or an alkyloxy group containing 1 to 4 carbon
atoms, an aralkyloxy group containing 7 to 20 carbon atoms).
[0030]
The compound (8) can be synthesized by ordinary procedures of organic
chemistry and is preferably synthesized by the step 4 below.
18
The step 4 is a method to produce the compound represented by the
formula (8) (the compound (8)) from a compound (7) as a raw material.
In the step 4, the protecting group can be removed from the hydroxyl group
in the compound represented by the formula (7) below:
(wherein P represents a protecting group, R3 represents an alkyl group containing 1
to 4 carbon atoms, and A represents an alkyl group containing 1 to 10 carbon atoms,
an aryl group containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to 4
carbon atoms, or an aralkyloxy group containing 7 to 20 carbon atoms)
to synthesize the compound represented by the formula (8) below:
(wherein R3 represents an alkyl group containing 1 to 4 carbon atoms, and A
represents an alkyl group containing 1 to 10 carbon atoms, an aryl group containing 6
to 12 carbon atoms, an alkyloxy group containing 1 to 4 carbon atoms, or an
aralkyloxy group containing 7 to 20 carbon atoms).
[0031]
Conditions commonly used in deprotection of each protection group can be
employed as conditions for the deprotection. Typically, an acid or a combination of
an acid catalyst and an alcohol is used.
19
As the acid used for the deprotection, an inorganic acid such as
hydrochloric acid, sulfuric acid, phosphoric acid and the like, or an organic acid such
as methanesulfonic acid, p-toluenesulfonic acid, oxalic acid, trifluoroacetic acid,
formic acid, acetic acid and the like is typically used and hydrochloric acid or ptoluenesulfonic
acid is preferably used.
As the acid catalyst, an inorganic acid such as hydrochloric acid, sulfuric
acid and the like, or an organic acid such as methanesulfonic acid, p-toluenesulfonic
acid and the like is typically used and hydrochloric acid or p-toluenesulfonic acid is
preferably used.
As the alcohol, methanol, ethanol, n-propanol, 2-propanol, n-butanol or the
like is typically used and methanol is preferably used.
For example, in cases where P in the formula (7) is tetrahydropyranyl group
or ethoxyethyl group, hydrochloric acid is preferably applied as a catalyst in
methanol solvent and the deprotection can easily be achieved in this method.
[0032]
Out of compounds represented by the formula (8), a compound represented
by the formula (8a) below:
(wherein Ac represents an acetyl group)
is crystalline and therefore is easily isolated and purified by crystallization after the
deprotection so that the compound (8a) of high purity can be synthesized. Because
(2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid of high purity can be
synthesized by performing the synthesis using the compound (8a) of high purity, the
compound (8a) is particularly preferable as the synthetic intermediate. As the
20
crystallization solvent, for example, toluene or a mixed solvent of toluene and
heptane can be used.
Incidentally, R3 and A in the compound (8) are synonymous with R3 and A
in the compound (5) described below.
[0033]
The compound (9) can be synthesized by ordinary procedures of organic
chemistry and is preferably synthesized by the step 5 below.
The step 5 is a method to produce the compound represented by the
formula (9) (the compound (9)) from the compound (8) as a raw material. The
following step 5(a) or 5(b) is preferable as the step 5.
[0034]
In the step 5(a), in the compound (8), the ester groups are hydrolyzed, one
of the carboxyl groups is allowed to react with the hydroxyl group to allow the
lactonization, and the other carboxyl group is further decarboxylated to synthesize
the compound represented by the formula (9) below:
(wherein A represents an alkyl group containing 1 to 10 carbon atoms, an aryl group
containing 6 to 12 carbon atoms, an alkyl group containing 1 to 10 carbon atoms, an
aryl group containing 6 to 12 carbon atoms, or an alkyloxy group containing 1 to 4
carbon atoms, an aralkyloxy group containing 7 to 20 carbon atoms).
[0035]
In the step 5(a), the ester groups in the compound (8) are first hydrolyzed.
A base is used in the hydrolysis of the ester groups.
21
Water, methanol, ethanol or the like is used as a reaction solvent.
As the base, sodium hydroxide, potassium hydroxide or the like can be
used and sodium hydroxide is preferable among others.
The amount of the base to be used is typically 2- to 10-fold, preferably 2- to
5-fold, relative to the amount of the compound (8) on the molar basis.
The reaction temperature is not particularly limited but is typically 0°C to
50°C and preferably 0°C to 10°C.
The reaction time is not particularly limited but is typically for 1 to 24
hours and preferably for 5 to 10 hours.
[0036]
Next, one of the carboxyl groups is allowed to react with the hydroxyl
group to allow the lactonization after the ester groups in the compound (8) are
hydrolyzed (ester degradation).
To perform the decarboxylation reaction after the lactonization, the
dicarboxylic acid obtained by the ester degradation is first allowed to react with a
dehydrating agent to induce the carboxyl group in the cis position with respect to the
hydroxyl group at position 5 to be lactonized.
As the dehydrating agent, a commonly used dehydrating agent such as, for
example, acetic anhydride, acetyl chloride, or thionyl chloride can be used.
The reaction solvent is not particularly limited as long as it does not inhibit
the reaction, but acetic acid or a mixed solvent of acetic acid and toluene is
preferably used.
[0037]
The amount of the dehydrating agent to be used is typically 1- to 20-fold,
preferably 1- to 5-fold, relative to the amount of the compound (8), in which the ester
groups have been hydrolyzed, on the molar basis.
[0038]
22
The reaction temperature is not particularly limited but is typically 0°C to
80°C and preferably 30°C to 60°C.
The reaction time is not particularly limited but is typically 1 to 12 hours
and preferably 2 to 5 hours.
[0039]
After one of the carboxyl groups is lactonized, the other carboxyl group is
further decarboxylated.
When the other remaining carboxyl group is further decarboxylated,
protonation occurs after the decarboxylation in a stereoselective manner due to the
steric structure fixed by the lactonization and thus the compound (9) in the 5-acyl-2-
oxa-5-azabicyclo[2.2.2]octan-3-one structure having a hydroxyl group and a
carboxyl group in the cis position is obtained.
The decarboxylation can proceed even by simply heating (simple heating)
but the addition of an organic base such as triethylamine or pyridine promotes the
reaction and enables the reaction to proceed at a low temperature so that it is
preferable.
The reaction temperature of the decarboxylation by simple heating is
typically 100°C to 130°C, while it is typically 60°C to 90°C in cases where an
organic base is added.
The reaction solvent is not particularly limited as long as it does not inhibit
the reaction, but acetic acid or a mixed solvent of acetic acid and toluene is
preferably used.
[0040]
The amount of the organic base to be used is typically 0.1- to 2-fold,
preferably 0.2- to 1-fold, relative to the amount of the lactonized compound (8) on
the molar basis.
23
The reaction time is not particularly limited but is typically 1 to 12 hours
and preferably 2 to 5 hours.
[0041]
In the step 5(b), in the compound (8), the ester groups are hydrolyzed, one
of the carboxyl groups is decarboxylated to form a stereoisomeric mixture of a 2-
monocarboxylic acid, and then the stereoisomeric mixture is isomerized and
lactonized to synthesize the compound represented by the formula (9) below:
(wherein A represents an alkyl group containing 1 to 10 carbon atoms, an aryl group
containing 6 to 12 carbon atoms, or an alkyloxy group containing 1 to 4 carbon
atoms, an aralkyloxy group containing 7 to 20 carbon atoms).
[0042]
In the step 5(b), the hydrolysis of the ester groups in the compound (8) can
be performed under the same conditions as those in the step 5(a).
After the ester groups in the compound (8) are hydrolyzed, one of the
carboxyl groups is decarboxylated to form a stereoisomeric mixture of a 2-
monocarboxylic acid.
In the step 5(b), since decarboxylation is first performed, the dicarboxylic
acid obtained by the ester degradation is first subjected to the decarboxylation to
form a stereoisomeric mixture of a 2-monocarboxylic acid.
The decarboxylation can proceed even by simply heating (simple heating)
but the addition of an organic base such as triethylamine or pyridine promotes the
reaction and enables the reaction to proceed at a low temperature.
24
The reaction temperature of the decarboxylation by simple heating is
typically 100°C to 130°C, while it is typically 60°C to 90°C in cases where an
organic base is added.
The reaction solvent is not particularly limited as long as it does not inhibit
the reaction, but acetic acid or a mixed solvent of acetic acid and methanol is
preferably used.
[0043]
The amount of the organic base to be used is typically 0.1- to 2-fold,
preferably 0.2- to 1-fold, relative to the amount of the compound (8), in which the
ester groups have been hydrolyzed, on the molar basis.
The reaction time is not particularly limited but is typically 1 to 12 hours
and preferably 2 to 5 hours.
[0044]
Next, the stereoisomeric mixture is isomerized and lactonized. When the
stereoisomeric mixture of the 2-monocarboxylic acid is isomerized and lactonized, a
stereoisomer having the carboxyl group at position 2 in the cis position with respect
to the hydroxyl group at position 5 is immediately lactonized with a dehydrating
agent and a stereoisomer having the carboxyl group at position 2 in the trans position
with respect to the hydroxyl group at position 5 is isomerized to the stereoisomer
having the carboxyl group at position 2 in the cis position and then lactonized.
Consequently, the compound (9) in the 5-acyl-2-oxa-5-azabicyclo[2.2.2]octan-3-one
structure having a hydroxyl group and a carboxyl group in the cis position is
eventually obtained from all types of the stereoisomers of the 2-monocarboxylic acid.
Examples of an agent used in this step to perform dehydration and isomerization at
the same time (a dehydrating and isomerizing/lactonizing agent) include acetic
anhydride, a combination of acetic anhydride and an amine, trifluoroacetic anhydride,
a combination of trifluoroacetic anhydride and an amine, a combination of a
25
chlorocarbonate ester and an amine, and the like; and acetic anhydride or a
combination of acetic anhydride and an amine is preferable among others.
[0045]
The amount of the dehydrating and isomerizing/lactonizing agent to be
used is typically 1- to 20-fold, preferably 1- to 5-fold, relative to the amount of the
stereoisomeric mixture of the 2-monocarboxylic acid on the molar basis.
In cases where a combination with an amine is used, pyridine, triethylamine
or like is used as the amine, and triethylamine is particularly preferable. The
amount of the amine to be used is typically 0.1- to 3-fold, preferably 0.2- to 1-fold,
relative to the amount of the stereoisomeric mixture of the 2-monocarboxylic acid on
the molar basis.
The reaction temperature is not particularly limited but is typically 20°C to
130°C and preferably 60°C to 90°C.
The reaction time is not particularly limited but is typically 1 to 12 hours
and preferably 2 to 5 hours.
[0046]
In the steps 5(a) and 5(b), the synthetic schemes can also be performed
without isolation and purification during the course of synthesis from the
dicarboxylic acid derived by the ester degradation to the compound (9).
In that case, for example, the compound (9) can be synthesized by
dissolving a disodium salt of the dicarboxylic acid in acetic acid, adding acetic
anhydride for the intramolecular lactone formation, then adding triethylamine and
heating the mixture for the decarboxylation.
Moreover, for example, the compound (9) can also be synthesized by
dissolving a disodium salt of the dicarboxylic acid in acetic acid, adding
triethylamine followed by heating for the decarboxylation to form a stereoisomeric
mixture of a 2-monocarboxylic acid, then adding acetic anhydride and heating the
26
mixture. In this case, sodium acetate as a by-product can be deposited by addition
of a poor solvent such as toluene and then removed by filtration.
In the step 5(a) or 5(b), in cases where A in the compound (9) to be
synthesized is benzyloxy group, the compound is crystalline and therefore is isolated
and purified by crystallization so that the compound (9) of high purity can be
synthesized. Because (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid of
high purity can be synthesized by performing the synthesis using the compound (9)
of high purity, the compound (9) is particularly preferable as the synthetic
intermediate. As the crystallization solvent, for example, a mixed solvent of
toluene and heptane can be used.
Incidentally, A in the compound (9) is synonymous with A in the
compound (5) described below.
[0047]
Here, the compound (7) as a raw material can be synthesized by ordinary
procedures of organic chemistry and is preferably synthesized by the steps (1) to (3)
below.
The step 1 is a step of producing a compound represented by the formula
(3) (the compound (3)) from a compound represented by the formula (1) (the
compound (1)) as a raw material.
The hydroxyl group in a compound represented by the formula (1) below:
(wherein X represents Cl, Br, or I, and R1 represents a hydrogen atom or an
optionally substituted alkyl group containing 1 to 4 carbon atoms)
is protected with a protecting group to synthesize a compound represented by the
formula (2) below:
27
(wherein X represents Cl, Br, or I, R1 represents a hydrogen atom or an optionally
substituted alkyl group containing 1 to 4 carbon atoms, and P represents a protecting
group)
and then the ester group in the compound (2) is reduced to synthesize a compound
represented by the formula (3) below:
(wherein X represents Cl, Br, or I, and P represents a protecting group).
[0048]
The compound (1) is a starting raw material of the step 1.
X in the formula (1) represents Cl, Br, or I, and X preferably represents Cl.
R1 represents a hydrogen atom or an optionally substituted alkyl group containing 1
to 4 carbon atoms, and R1 preferably represents an optionally substituted alkyl group
containing 1 to 4 carbon atoms. Examples of the alkyl group include, for example,
methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl
group, sec-butyl group, tert-butyl group, and the like. Examples of the substituent
in the alkyl group include halogen atoms, alkoxy groups, and the like.
The compound (1) can easily be synthesized in accordance with a known
method, for example, a method described in Tetrahedron: Asymmetry, 12(12), 1713
(2001) and the like. Moreover, a commercial product can be used as the compound
(1) represented by the formula (1), in which X represents Cl or Br and R1 represents
a methyl group or ethyl group.
[0049]
28
First, the hydroxyl group in the compound (1) is protected with a protecting
group to synthesize the compound (2).
Ether protecting groups are preferable as the protecting group. It is the
reason for the use of an ether protecting group that ether protecting groups are
advantageous in the resistance to the basic conditions in the following steps.
Incidentally, the oxygen atom binding to the protecting group P in the compound (2)
is derived from the hydroxyl group.
Examples of the protecting group include tetrahydropyranyl group,
methoxymethyl group, ethoxyethyl group, tert-butyl group, or tert-butyldimethylsilyl
group. Those protecting groups can be introduced by protecting a hydroxyl group
through the reaction with a combination of reaction agents, such as a combination of
dihydropyran and an acid catalyst, methoxymethyl chloride and
diisopropylethylamine, ethyl vinyl ether and an acid catalyst, isobutylene and an acid
catalyst, and tert-butyldimethylsilyl chloride and imidazole, respectively. A
preferable protecting group is tetrahydropyranyl group, methoxymethyl group,
ethoxyethyl group, tert-butyl group, or tert-butyldimethylsilyl group. Among
others, tetrahydropyranyl group is preferable as the protecting group because it has
high safety.
[0050]
In cases where tetrahydropyranyl group is used as the protecting group, for
example, dihydropyran and an acid catalyst such as methanesulfonic acid, ptoluenesulfonic
acid or pyridinium p-toluenesulfonate can be applied to the
compound (1) in a reaction solvent to obtain the compound (2).
The reaction solvent is not particularly limited as long as the reaction is
allowed to proceed, but toluene, heptane, dichloromethane, ethyl acetate and the like
can be used. Moreover, the reaction can be allowed to proceed even in the absence
of a solvent.
29
[0051]
The amount of dihydropyran to be used is typically 1- to 10-fold, preferably
1- to 1.5-fold, relative to the amount of the compound (1) on the molar basis.
The amount of the acid catalyst to be used is typically 0.001- to 0.1-fold,
preferably 0.002- to 0.02-fold, relative to the amount of the compound (1) on the
molar basis.
[0052]
The reaction temperature is not particularly limited but is typically 0°C to
80°C and preferably 20°C to 60°C.
The reaction time is not particularly limited but is typically 0.5 to 10 hours
and preferably 1 to 3 hours.
[0053]
Moreover, X in the compound (2) represents Cl, Br, or I, and X preferably
represents Cl.
In the compound (2), R1 represents a hydrogen atom or an optionally
substituted alkyl group containing 1 to 4 carbon atoms, and R1 preferably represents
an optionally substituted alkyl group containing 1 to 4 carbon atoms. Examples of
the alkyl group include, for example, methyl group, ethyl group, n-propyl group,
isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, and
the like. Examples of the substituent in the alkyl group include halogen atoms,
alkoxy groups, and the like.
In the compound (2), P represents a protecting group, preferably
tetrahydropyranyl group, methoxymethyl group, ethoxyethyl group, tert-butyl group,
or tert-butyldimethylsilyl group, and particularly preferably tetrahydropyranyl group.
[0054]
Next, the ester group in the compound (2) is reduced to synthesize the
compound (3).
30
In the reduction of the ester group in the compound (2) to alcohol, a
hydride reducing agent is preferably used. For example, an aluminium hydride
reducing agent such as lithium aluminium hydride, diisobutylaluminium hydride or
sodium bis(methoxyethoxy)aluminium hydride, or a boron hydride reducing agent
such as sodium borohydride, lithium borohydride, calcium borohydride or borane
can be used. Among others, an aluminium hydride reducing agent or lithium
borohydride is preferably used because of its high reaction activity in the reduction
of esters.
[0055]
For example, an aluminium hydride reducing agent can be applied to the
compound (2) in a reaction solvent to synthesize the compound (3).
The reaction solvent is not particularly limited as long as the reaction is
allowed to proceed, but tetrahydrofuran, toluene and the like can be used.
Moreover, the reaction can be allowed to proceed even in the absence of a solvent.
[0056]
The amount of the hydride reducing agent to be used is, in terms of hydride,
typically 2- to 10-fold, preferably 2- to 3-fold, relative to the amount of the
compound (2) on the molar basis.
[0057]
The reaction temperature is not particularly limited but is typically 0°C to
80°C and preferably 0°C to 20°C.
The reaction time is not particularly limited but is typically 0.5 to 10 hours
and preferably 1 to 3 hours.
Incidentally, X and P in the compound (3) are synonymous with X and P in
the compound (2).
[0058]
31
The step 2 is a step of producing a compound represented by the formula
(6) (the compound (6)) from the compound (3) as a raw material.
[0059]
The hydroxyl group in the compound (3) is esterified with a sulfonate
group to synthesize a compound represented by the formula (4) below:
(wherein X represents Cl, Br, or I, R2 represents an aryl group containing 6 to 12
carbon atoms, an alkyl group containing 1 to 10 carbon atoms, or an aralkyl group
containing 7 to 20 carbon atoms)
and then the compound (4) is allowed to react with a compound represented by the
formula (5) below:
(wherein R3 represents an alkyl group containing 1 to 4 carbon atoms, and A
represents an alkyl group containing 1 to 10 carbon atoms, an aryl group containing 6
to 12 carbon atoms, an alkyloxy group containing 1 to 4 carbon atoms, or an
aralkyloxy group containing 7 to 20 carbon atoms)
to synthesize a compound represented by the formula (6) below:
32
(wherein X represents Cl, Br, or I, P represents a protecting group, R3 represents an
alkyl group containing 1 to 4 carbon atoms, and A represents an alkyl group
containing 1 to 10 carbon atoms, an aryl group containing 6 to 12 carbon atoms, an
alkyloxy group containing 1 to 4 carbon atoms, or an aralkyloxy group containing 7
to 20 carbon atoms).
[0060]
First, the hydroxyl group in the compound (3) is esterified with a sulfonate
group to synthesize the compound (4).
In the esterification of the hydroxyl group in the compound (3) with a
sulfonate group, a combination of a commonly used alkylsulfonyl chloride and a
base, or a combination of a commonly used arylsulfonyl chloride and a base can be
employed. For example, a combination of methanesulfonyl chloride or ptoluenesulfonyl
chloride and triethylamine can be employed.
For example, an alkylsulfonyl chloride or arylsulfonyl chloride and a base
can be applied to the compound (3) in a reaction solvent to synthesize the compound
(4).
The reaction solvent is not particularly limited as long as the reaction is
allowed to proceed, but toluene, methylene chloride, tetrahydrofuran, ethyl acetate
and the like can be used. Moreover, the reaction can be allowed to proceed even in
the absence of a solvent.
Moreover, an organic base such as pyridine or triethylamine, or an
inorganic base such as sodium bicarbonate or sodium hydroxide can be used as the
base.
[0061]
The amount of the alkylsulfonyl chloride or arylsulfonyl chloride to be used
is typically 1- to 2-fold, preferably 1- to 1.2-fold, relative to the amount of the
compound (3) on the molar basis.
33
The amount of the base to be used is typically 1- to 2-fold, preferably 1- to
1.5-fold, relative to the amount of the compound (3) on the molar basis.
[0062]
The reaction temperature is not particularly limited but is typically 0°C to
50°C and preferably 0°C to 20°C.
The reaction time is not particularly limited but is typically 0.5 to 5 hours
and preferably 1 to 2 hours.
Incidentally, X and P in the compound (4) are synonymous with X and P in
the compound (2).
Moreover, in the compound (4), R2 represents an aryl group containing 6 to
12 carbon atoms, an alkyl group containing 1 to 10 carbon atoms, or an aralkyl group
containing 7 to 20 carbon atoms, preferably represents an aryl group containing 6 to
7 carbon atoms, an alkyl group containing 1 to 3 carbon atoms, or an aralkyl group
containing 7 to 11 carbon atoms, and more preferably represents a methyl group.
Examples of the aryl group include, for example, phenyl group, tolyl group, naphthyl
group, biphenyl group, and the like. Examples of the alkyl group include, for
example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group,
isobutyl group, sec-butyl group, tert-butyl group, pentyl group, hexyl group, heptyl
group, octyl group, and the like. Examples of the aralkyl group include, for
example, benzyl group, phenethyl group, and the like.
[0063]
Next, the compound (4) is allowed to react with compound (5) to
synthesize the compound (6).
In the compound (5), R3 represents an alkyl group containing 1 to 4 carbon
atoms, and preferably an alkyl group containing 1 to 2 carbon atoms. Examples of
the alkyl group include, for example, methyl group, ethyl group, n-propyl group,
34
isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, and
the like.
Moreover, in the compound (5), A represents an alkyl group containing 1 to
10 carbon atoms, an aryl group containing 6 to 12 carbon atoms, an alkyloxy group
containing 1 to 4 carbon atoms, or an aralkyloxy group containing 7 to 20 carbon
atoms, preferably represents an aryl group containing 6 to 10 carbon atoms, an alkyl
group containing 1 to 3 carbon atoms, an alkyloxy group containing 1 to 4 carbon
atoms, or an aralkyloxy group containing 7 to 11 carbon atoms, and more preferably
represents a methyl group. Examples of the aryl group include, for example, phenyl
group, naphthyl group, biphenyl group, and the like. Examples of the alkyl group
include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, nbutyl
group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, hexyl
group, heptyl group, octyl group, and the like. Examples of the alkyloxy group
include methyloxy group, ethyloxy group, n-propyloxy group, isopropyloxy group,
n-butyloxy group, isobutyloxy group, tert-butyloxy group, and the like. Examples
of the aralkyloxy group include benzyloxy group, phenethyloxy group, and the like.
A commercial product can be used as the compound (5). A compound (5)
can be available, for example, from TateyamaKasei Co., Ltd.
[0064]
When the reaction between the compound (4) and the compound (5) is
performed, a base is necessary to generate an anion at the α-position in the
compound (5). For this purpose, the reaction is preferably performed in the
presence of, for example, a strong base such as sodium hydride, sodium
hexamethyldisilazane, lithium hexamethyldisilazane, lithium diisopropylamide,
sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, sodium methoxide,
sodium hydroxide, or potassium hydroxide; or a weak base such as cesium carbonate,
potassium carbonate, or sodium carbonate. The reaction is preferably performed in
35
the presence of a base, such as, among others, sodium hydride, sodium tert-butoxide,
potassium tert-butoxide, sodium ethoxide, cesium carbonate or potassium carbonate.
[0065]
The amount of the base to be used is typically not less than 0.8-fold,
preferably 0.8- to 1.2-fold in cases of a strong base and 0.8- to 3-fold in cases of a
weak base, relative to the amount of the substrate (the compound (5)) on the molar
basis.
[0066]
The reaction solvent is not particularly limited as long as it can dissolve the
substrate, but aprotic polar solvents such as dimethylsulfoxide, N,Ndimethylformamide,
N,N-dimethylacetamide, N-methylpyrrolidone and the like;
alcohol solvents such as methanol, ethanol, propanol, butanol and the like; ether
solvents such as tetrahydrofuran, diethyl ether, methyl-tert-butyl ether,
methylcyclopropyl ether and the like; and mixed solvents thereof with a hydrocarbon
solvent such as toluene, hexane, or heptane, or with a halohydrocarbon solvent such
as dichloromethane, chloroform, or 1,2-dichloroethane are preferably used. Even
more preferably, dimethylsulfoxide, N,N-dimethylformamide, N-methylpyrrolidone,
tetrahydrofuran, mixed solvents thereof with toluene, a mixed solvent of ethanol and
toluene are used.
[0067]
The reaction temperature is not particularly limited but is typically 0°C to
130°C and preferably 20°C to 80°C.
[0068]
The reaction time is not particularly limited but is typically for 1 to 24
hours and preferably 1 to 5 hours.
[0069]
36
In this step, an iodide salt is preferably added for the purpose of promoting
the reaction and increasing the selectivity. As examples of the iodide salt, iodide
salts represented by MI (M refers to an alkali metal) are preferable and, among others,
iodide salts such as potassium iodide, sodium iodide and the like are preferable.
The amount of these salts to be added is 0.02- to 1-fold, preferably 0.2- to 0.4-fold,
relative to the amount of the substrate (the compound (4)) on the molar basis.
The amount of the compound (5) to be used for the compound (4) is 1- to
2-fold, preferably 1- to 1.2-fold, relative to the amount of the compound (4) on the
molar basis.
[0070]
Incidentally, in the compound (6), X and P are synonymous with X and P
in the compound (2), and R3 and A are synonymous with R3 and A in the compound
(5).
[0071]
The step 3 is a step of producing a compound represented by the formula
(7) (the compound (7)) from the compound (6) as a raw material.
[0072]
The compound (6) is cyclized to synthesize a compound represented by the
formula (7) below:
(wherein P represents a protecting group, R3 represents an alkyl group containing 1
to 4 carbon atoms, and A represents an alkyl group containing 1 to 10 carbon atoms,
37
an aryl group containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to 4
carbon atoms, or an aralkyloxy group containing 7 to 20 carbon atoms).
[0073]
A base is required in the step 3. As the base, for example, a strong base
such as sodium hydride, sodium hexamethyldisilazane, lithium hexamethyldisilazane,
lithium diisopropylamide, sodium tert-butoxide, potassium tert-butoxide, sodium
ethoxide, sodium methoxide, sodium hydroxide, or potassium hydroxide; or a weak
base such as cesium carbonate, potassium carbonate, or sodium carbonate is used,
and sodium hydride, sodium tert-butoxide, potassium tert-butoxide, cesium
carbonate or potassium carbonate is preferably used.
[0074]
The amount of the base to be used is typically not less than 1-fold,
preferably 1- to 2-fold in cases of a strong base and 1- to 3-fold in cases of a weak
base, relative to the amount of the substrate (the compound (6)) on the molar basis.
The reaction solvent is not particularly limited as long as it can dissolve the
substrate (the compound (6)), but aprotic polar solvents such as dimethylsulfoxide,
N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone or the like;
or ether solvents such as tetrahydrofuran, diethyl ether, methyl-tert-butyl ether,
methylcyclopropyl ether and the like; and mixed solvents thereof with a hydrocarbon
solvent such as toluene, hexane, or heptane, or with a halohydrocarbon solvent such
as dichloromethane, chloroform, or 1,2-dichloroethane are preferably used, and N,Ndimethylformamide,
N-methylpyrrolidone, tetrahydrofuran, and mixed solvents
thereof with toluene are even more preferably used.
[0075]
The reaction temperature is not particularly limited but is typically 0°C to
130°C, preferably 10°C to 50°C in cases of a strong base, and preferably 80°C to
130°C in cases of a weak base.
38
The reaction time is not particularly limited but is typically for 1 to 24
hours and preferably 1 to 6 hours.
[0076]
This step is preferably performed in the presence of a quaternary
ammonium salt such as tetrabutylammonium bromide and the like for the purpose of
promoting the reaction and increasing the selectivity. The amounts of these salts to
be used are 0.02- to 1-fold, preferably 0.2- to 0.4-fold, relative to the amount of the
substrate (the compound (6)) on the molar basis.
[0077]
Moreover, the step 2 and the step 3 can also be performed in series without
isolation and purification of the compound (6) during the course of synthesis. In
that case, the step 3 can be performed by adding a base to the reaction mixture after
the reaction of the step 2 has been completed.
Incidentally, in the compound (7), P is synonymous with P in the
compound (2), and R3 and A are synonymous with R3 and A in the compound (5).
[0078]
In the present invention, (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic
acid is preferably synthesized with the following step 6.
[0079]
The step 6 is a step of producing a compound represented by the formula
(10) (the compound (10)) from the compound (9) as a raw material.
[0080]
The lactone in the compound (9) is hydrolyzed and the amide bond in the
compound (9) is cleaved to synthesize (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-
carboxylic acid represented by the formula (10) below:
39
.
[0081]
The hydrolysis of the lactone and the cleavage of the amide bond in the
compound (9) may be allowed to proceed at the same time.
Commonly used conditions can be employed in the cleavage of the amide
bond. For example, in cases where A is an alkyl group or aryl group, the cleavage
can easily be achieved by applying a strong acid as a catalyst, such as hydrochloric
acid, hydrobromic acid and the like, in a reaction solvent.
As the reaction solvent, water, or aqueous solvents such as aqueous dioxane,
aqueous dimethoxyethane, aqueous acetone and the like are used.
The amount of the strong acid to be used is typically 1- to 10-fold,
preferably 1- to 2-fold, relative to the amount of the compound (9) on the molar basis.
The reaction temperature is not particularly limited but is typically 0°C to
100°C and preferably 80°C to 100°C.
The reaction time is not particularly limited but is typically 1 to 12 hours
and preferably 3 to 6 hours.
In the hydrolysis of the lactone, an acid or a base, for example,
hydrochloric acid or sodium hydroxide is used in accordance with a commonly
employed hydrolysis procedure.
As the reaction solvent, water, methanol, ethanol and the like are used.
[0082]
The amount of the acid or base to be used is typically 1- to 10-fold,
preferably 1- to 2-fold, relative to the amount of the compound (9) after the cleavage
of the amide bond on the molar basis.
40
[0083]
The reaction temperature is not particularly limited but is typically 0°C to
100°C and preferably 60°C to 100°C.
The reaction time is not particularly limited but is typically 1 to 12 hours
and preferably 8 to 12 hours.
[0084]
In the step 6, in cases where the compound (9) is a compound represented
by the formula (9a):
(wherein A’ represents an alkyl group containing 1 to 10 carbon atoms or an aryl
group containing 6 to 12 carbon atoms),
for example, the addition of hydrochloric acid followed by heating enables the
hydrolysis of the lactone and the acetyl group to be performed at the same time.
In this case, because the resulting (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-
carboxylic acid is a hydrochloride, the removal of hydrochloric acid and the like can
be achieved with ion exchange resins in accordance with a commonly employed
procedure for the purification of amino acids. Moreover, the hydrochloric acid is
neutralized using lithium hydroxide or lithium carbonate to produce lithium chloride,
or alternatively using triethylamine to produce triethylamine hydrochloride. Then
the reaction mixture is concentrated and followed by the addition of an alcohol,
acetone and the like, so that the lithium chloride and triethylamine hydrochloride can
be removed.
[0085]
41
Incidentally, in the compound (9a), A’ represents an alkyl group containing
1 to 10 carbon atoms or an aryl group containing 6 to 10 carbon atoms, and
preferably represents an alkyl group containing 1 to 3 carbon atoms or an aryl group
containing 6 carbon atoms. Examples of the aryl group include, for example,
phenyl group. Examples of the alkyl group include, for example, methyl group,
ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, secbutyl
group, tert-butyl group, pentyl group, hexyl group, heptyl group, octyl group,
and the like.
[0086]
Moreover, because (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid
is crystalline, it can be purified by performing recrystallization. As the
recrystallization solvent, for example, a water/ethanol mixed system, a
methanol/acetone mixed system and the like can be used.
[0087]
In the steps 1 to 5 of the present invention, it is preferable in the
compounds (1) to (9) that X represents Cl, R1 and R3 represent an ethyl group, R2
represents a methyl group or p-tolyl group, A represents a methyl group or phenyl
group, and P represents a tetrahydropyranyl group or methoxymethyl group,
ethoxyethyl group, tert-butyldimethylsilyl group or tert-butyl group.
In the present invention, (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic
acid is preferably produced by coupling the sulfonate ester of an optically active 4-
halo-3-protected hydroxybutanol (the compound (4)), which is derived from an
optically active 4-halo-3-hydroxybutanoate ester (the compound (1)), to an
acylaminomalonate diester (the compound (5)) to obtain an optically active 2-
acylamino-2-[4-halo-3-protected hydroxybutyl]-malonate diester (the compound
(6)); performing cyclization and deprotection on it to obtain an optically active 1-
acyl-5-hydroxypiperidine-2,2-dicarboxylate diester (the compound (8)); and then
42
hydrolyzing the ester, followed by (a) forming a lactone from the hydroxyl group at
position 5 and one of the dicarboxylates at position 2, and decarboxylating the
remaining carboxylate, or (b) decarboxylating to form a stereoisomeric mixture of a
2-monocarboxylic acid, and isomerizing and lactonizing the 2-monocarboxylic acid,
to obtain 5-acyl-2-oxa-5-azabicyclo[2.2.2]octan-3-one (the compound (7)); and
finally performing deprotection and hydrolysis. Accordingly the optically active
substances can be efficiently synthesized.
[0088]
[2] Novel compounds
The present invention relates to the novel compounds indicated below.
These novel compounds are useful as synthetic intermediates for a β-lactamase
inhibitor and the like.
The novel compounds of the present invention can be produced by the
production method of the present invention. Moreover, they can also be
synthesized by ordinary procedures of organic chemistry since this specification has
indicated the structures thereof.
[0089]
(A) Compounds represented by the formula (2a) below:
(wherein X represents Cl, Br, or I, R1 represents a hydrogen atom or an optionally
substituted alkyl group containing 1 to 4 carbon atoms, P’’ represents a
tetrahydropyranyl group or ethoxyethyl group).
X represents Cl, Br, or I, and preferably Cl.
R1 represents a hydrogen atom or an optionally substituted alkyl group
containing 1 to 4 carbon atoms, and preferably an optionally substituted alkyl group
43
containing 1 to 4 carbon atoms. Examples of the alkyl group include, for example,
methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl
group, sec-butyl group, tert-butyl group, and the like. Examples of the substituent
in the alkyl group include halogen atoms, alkoxy groups, and the like.
P’’ represents a tetrahydropyranyl group, or ethoxyethyl group.
Among the compounds (2a), compounds represented by the formulae
below are particularly preferable:
.
[0090]
(B) Compounds represented by the formula (3a) below:
(wherein X represents Cl, Br, or I, and P’ represents a tetrahydropyranyl group,
methoxymethyl group, ethoxyethyl group, tert-butyl group, or tert-butyldimethylsilyl
group).
P’ represents a tetrahydropyranyl group, methoxymethyl group,
ethoxyethyl group, tert-butyl group, or tert-butyldimethylsilyl group.
Incidentally, in the compounds (3a), X is synonymous with X in the
compound (2a).
[0091]
44
Among the compounds (3a), compounds represented by the formulae
below are particularly preferable:
.
[0092]
(C) Compounds represented by the formula (4a) below:
(wherein X represents Cl, Br, or I, P’ represents a tetrahydropyranyl group,
methoxymethyl group, ethoxyethyl group, tert-butyl group, or tert-butyldimethylsilyl
group, and R2 represents an aryl group containing 6 to 12 carbon atoms, an alkyl
45
group containing 1 to 10 carbon atoms, or an aralkyl group containing 7 to 20 carbon
atoms).
[0093]
R2 represents an aryl group containing 6 to 12 carbon atoms, an alkyl group
containing 1 to 10 carbon atoms, or an aralkyl group containing 7 to 20 carbon atoms,
preferably represents an aryl group containing 6 to 7 carbon atoms, an alkyl group
containing 1 to 3 carbon atoms, or an aralkyl group containing 7 to 11 carbon atoms,
and more preferably represents a methyl group. Examples of the aryl group include,
for example, phenyl group, tolyl group, naphthyl group, biphenyl group, and the like.
Examples of the alkyl group include, for example, methyl group, ethyl group, npropyl
group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tertbutyl
group, pentyl group, hexyl group, heptyl group, octyl group, and the like.
Examples of the aralkyl group include, for example, benzyl group, phenethyl group,
and the like.
Incidentally, in the compounds (4a), X is synonymous with X in the
compound (2a) and P’ is synonymous with P’ in the compound (3a).
[0094]
Among the compounds (4a), compounds represented by the formulae
below are particularly preferable:
46
.
[0095]
(D) Compounds represented by the formula (6a) below:
(wherein X represents Cl, Br, or I, P’ represents a tetrahydropyranyl group,
methoxymethyl group, ethoxyethyl group, tert-butyl group, or tert-butyldimethylsilyl
group, and R3 represents an alkyl group containing 1 to 4 carbon atoms, and A
represents an alkyl group containing 1 to 10 carbon atoms, an aryl group containing 6
to 12 carbon atoms, an alkyloxy group containing 1 to 4 carbon atoms, or an
aralkyloxy group containing 7 to 20 carbon atoms).
[0096]
R3 represents an alkyl group containing 1 to 4 carbon atoms, and preferably
an alkyl group containing 1 to 2 carbon atoms. Examples of the alkyl group include,
for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl
group, isobutyl group, sec-butyl group, tert-butyl group, and the like.
47
A represents an alkyl group containing 1 to 10 carbon atoms, an aryl group
containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to 4 carbon atoms,
or an aralkyloxy group containing 7 to 20 carbon atoms, preferably represents an
alkyl group containing 1 to 3 carbon atoms, an aryl group containing 6 to 10 carbon
atoms, an alkyloxy group containing 1 to 4 carbon atoms, or an aralkyloxy group
containing 7 to 11 carbon atoms, and more preferably represents a methyl group and
phenyl group. Examples of the aryl group include, for example, phenyl group,
naphthyl group, biphenyl group, and the like. Examples of the alkyl group include,
for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl
group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, hexyl group,
heptyl group, octyl group, and the like. Examples of the alkyloxy group include
methyloxy group, ethyloxy group, n-propyloxy group, isopropyloxy group, nbutyloxy
group, isobutyloxy group, tert-butyloxy group, and the like. Examples of
the aralkyloxy group include benzyloxy group, phenethyloxy group, and the like.
Incidentally, in the compounds (6a), X is synonymous with X in the
compound (2a) and P’ is synonymous with P’ in the compound (3a).
[0097]
Among the compounds (6a), compounds represented by the formulae
below are particularly preferable:
48
49
(wherein Ac represents an acetyl group and Bz represents a benzoyl group).
[0098]
(E) Compounds represented by the formula (7) below:
(wherein P represents a protecting group, R3 represents an alkyl group containing 1
to 4 carbon atoms, and A represents an alkyl group containing 1 to 10 carbon atoms,
an aryl group containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to 4
carbon atoms, or an aralkyloxy group containing 7 to 20 carbon atoms).
[0099]
P represents a protecting group and preferably represents a
tetrahydropyranyl group, methoxymethyl group, ethoxyethyl group, tert-butyl group,
or tert-butyldimethylsilyl group.
Incidentally, in the compounds (7), R3 and A are synonymous with R3 and
A in the compound (6a).
[0100]
Among the compounds (7), compounds represented by the formulae below
are particularly preferable:
50
51
(wherein Ac represents an acetyl group and Bz represents a benzoyl group).
[0101]
(F) Compounds represented by the formula (8) below or dicarboxylic acid salts
thereof:
(wherein R3 represents an alkyl group containing 1 to 4 carbon atoms, and A
represents an alkyl group containing 1 to 10 carbon atoms, an aryl group containing 6
to 12 carbon atoms, an alkyloxy group containing 1 to 4 carbon atoms, or an
aralkyloxy group containing 7 to 20 carbon atoms).
Incidentally, in the compounds (8), R3 and A are synonymous with R3 and
A in the compound (6a).
[0102]
Among the compounds (8), compounds represented by the formulae below
are particularly preferable:
52
(wherein Ac represents an acetyl group and Bz represents a benzoyl group).
Among these, the compound (8a) is preferable as a synthetic intermediate
since it is crystalline and thus can be isolated and purified by crystallization.
[0103]
(G) Compounds represented by the formula (9a) below:
(wherein A’ represents an alkyl group containing 1 to 10 carbon atoms or an aryl
group containing 6 to 12 carbon atoms).
A’ represents an alkyl group containing 1 to 10 carbon atoms or an aryl
group containing 6 to 12 carbon atoms, and preferably represents an alkyl group
containing 1 to 3 carbon atoms or an aryl group containing 6 carbon atoms.
Examples of the alkyl group include, for example, methyl group, ethyl group, npropyl
group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tertbutyl
group, pentyl group, hexyl group, heptyl group, octyl group, and the like.
Examples of the aryl group include phenyl group, naphthyl group and the like.
[0104]
53
Among the compounds (9a), compounds represented by the formulae
below are particularly preferable:
(wherein Ac represents an acetyl group and Bz represents a benzoyl group).
[0105]
(H) A compound or a salt thereof, the compound represented by the formula (11a)
below:
(wherein A’ represents an alkyl group containing 1 to 10 carbon atoms or an aryl
group containing 6 to 12 carbon atoms)
[0106]
or the formula (11b) below:
54
(wherein A’ represents an alkyl group containing 1 to 10 carbon atoms or an aryl
group containing 6 to 12 carbon atoms).
Incidentally, in the compounds (11a) and (11b), A’ is synonymous with A’
in the compound (9a).
[0107]
Among the compounds (11a) or (11b), compounds represented by the
formulae below are particularly preferable:
.
EXAMPLES
55
[0108]
Now, the present invention will be described in further detail by way of
Examples but the present invention is not limited by these Examples.
[0109]
[Example 1] Production of (3S)-4-chloro-3-(tetrahydropyran-2-yloxy)-butan-1-ol (a
compound of the formula (3), wherein X = Cl, and P = tetrahydropyranyl group)
In a 50-mL reactor, 1.50 g (9 mmol) of ethyl (3S)-4-chloro-3-
hydroxybutanoate ester (a compound of the formula (1), wherein X = Cl, and R1 =
ethyl group), 1.51 g (18 mmol) of dihydropyran, 29 μL (0.45 mmol) of
methanesulfonic acid and 15 mL of toluene were placed and the mixture was stirred
for 0.5 hour at room temperature, followed by the addition of 250 μL (1.8 mmol) of
triethylamine to stop the reaction. This mixture was washed with water, dried, and
then concentrated to obtain 3.14 g of an oily crude ethyl (3S)-4-chloro-3-
(tetrahydropyran-2-yloxy)-butanoate ester (a compound of the formula (2), wherein
X = Cl, P = tetrahydropyranyl group, and R1 = ethyl group).
[0110]
1H-NMR (400MHz, CDCl3) δ1.23 (3H, m), 1.44-1.85 (6H, m), 2.58-2.80 (2H, m),
3.47-3.95 (4H, m), 4.17 (2H, m), 4.20-4.37 (1H, m), 4.73-4.80 (1H, m).
[0111]
Next, the obtained crude ethyl (3S)-4-chloro-3-(tetrahydropyran-2-yloxy)-
butanoate ester (a compound of the formula (2), wherein X = Cl, P =
tetrahydropyranyl group, and R1 = ethyl group) was dissolved in 15 mL of dry
tetrahydrofuran (hereinafter referred to as “THF”), and 0.34 g (9 mmol) of lithium
aluminium hydride was added thereto and the mixture was stirred for 2 hours at 5°C,
followed by the addition of 1 mL of ethyl acetate and then 1 mL of water to degrade
an excess amount of the reducing agent and stop the reaction. This mixture was
filtered through Celite and purified by silica gel column chromatography to obtain
56
1.43 g of an oil of (3S)-4-chloro-3-(tetrahydropyran-2-yloxy)-butan-1-ol (a
compound of the formula (3), wherein X = Cl, and P = tetrahydropyranyl group) (the
total yield through the two steps: 73%).
[0112]
1H-NMR (400MHz, CDCl3) δ1.45-2.08 (8H, m), 3.35-4.13 (8H, m), 4.68-4.76 (1H,
m).
[0113]
[Example 2] Production of (3S)-4-chloro-3-(tetrahydropyran-2-yloxy)-butyl
methanesulfonate ester (a compound of the formula (4), wherein X = Cl, P =
tetrahydropyranyl group, and R2 = methyl group)
In a 50-mL reactor, 1.43 g (6.8 mmol) of the (3S)-4-chloro-3-
(tetrahydropyran-2-yloxy)-butan-1-ol (a compound of the formula (3), wherein X =
Cl, and P = tetrahydropyranyl group) obtained in Example 1, 1.05 mL (7.5 mmol) of
triethylamine and 14 mL of toluene were placed, and 0.56 mL (7.18 mmol) of
methanesulfonyl chloride was added thereto at 5°C and the mixture was stirred for 1
hour at 5°C. This reaction liquid was washed with water, dried, and then
concentrated to obtain 2.13 g of an oily crude (3S)-4-chloro-3-(tetrahydropyran-2-
yloxy)-butyl methanesulfonate ester (a compound of the formula (4), wherein X = Cl,
P = tetrahydropyranyl group, and R2 = methyl group) (yield: 97%).
[0114]
1H-NMR (400MHz, CDCl3) δ1.48-1.60 (4H, m), 1.72-1.85 (2H, m), 1.97-2.20 (2H,
m), 3.02 (3H, s), 3.50-4.12 (5H, m), 4.30-4.45 (2H, m), 4.68 (1H, m).
[0115]
[Example 3] Production of (3S)-4-chloro-3-(tetrahydropyran-2-yloxy)-butyl
methanesulfonate ester (a compound of the formula (4), wherein X = Cl, P =
tetrahydropyranyl group, and R2 = methyl group)
57
In a 1-L reactor, 30 g (180.18 mmol) of ethyl (3S)-4-chloro-3-
hydroxybutanoate ester (a compound of the formula (1), wherein X = Cl, and R1 =
ethyl group), 18.16 g (216.22 mmol) of dihydropyran, 0.44 g (1.80 mmol) of
pyridinium p-toluenesulfonate and 240 mL of toluene were placed and the mixture
was stirred for 10 hours at 45°C to obtain a solution of ethyl (3S)-4-chloro-3-
(tetrahydropyran-2-yloxy)-butanoate ester (a compound of the formula (2), wherein
X = Cl, P = tetrahydropyranyl group, and R1 = ethyl group) in toluene.
Then, 70 mL (252.25 mmol) of a 70% solution of sodium
bis(methoxyethoxy)aluminium hydride in toluene was added to this reaction liquid at
5°C to 10°C and the mixture was stirred for 7 hours at 5°C to 10°C. To this
reaction liquid, 22.7 mL of water, 31.59 g of magnesium sulfate, and 22.7 mL of
water were added sequentially at 5°C to 10°C and the mixture was stirred for 1 hour
at 5°C to 10°C and left to stand overnight at 5°C, followed by the filtration of solids.
Then, the filtrate was washed with saturated brine, dried, and subsequently
concentrated to obtain 247.39 g of (3S)-4-chloro-3-(tetrahydropyran-2-yloxy)-butan-
1-ol (a compound of the formula (3), wherein X = Cl, and P = tetrahydropyranyl
group) in toluene solution (the total yield through the two steps: 91%).
Next, to 237.3 g of this solution (containing 32.59 g (156.33 mmol) of (3S)-
4-chloro-3-(tetrahydropyran-2-yloxy)-butan-1-ol (a compound of the formula (3),
wherein X = Cl, and P = tetrahydropyranyl group)), 17.37 g (171.96 mmol) of
triethylamine was added and then 18.79 g (164.15 mmol) of methanesulfonyl
chloride was added thereto at 5°C to 12°C and the mixture was stirred for 1 hour at
5°C to 10°C. This reaction liquid was washed with water, dried, and then
concentrated to obtain 51.72 g (pure content: 43.92 g) of crude (3S)-4-chloro-3-
(tetrahydropyran-2-yloxy)-butyl methanesulfonate ester (a compound of the formula
(4), wherein X = Cl, P = tetrahydropyranyl group, and R2 = methyl group) (the total
yield through the three steps: 89%).
58
[0116]
[Example 4-1] Production of (3S)-4-chloro-3-methoxymethyloxy-butyl
methanesulfonate ester (a compound of the formula (4), wherein X = Cl, P =
methoxymethyl group, and R2 = methyl group)
In a 50-mL reactor, 1.50 g (9.01 mmol) of ethyl (3S)-4-chloro-3-
hydroxybutanoate ester (a compound of the formula (1), wherein X = Cl, and R1 =
ethyl group), 2.02 mL (11.71 mmol) of diisopropylethylamine and 15 mL of toluene
were placed and 1.18 g (11.71 mmol) of methoxymethyl chloride was added thereto
at room temperature and the mixture was stirred at room temperature. After the
completion of the reaction, the reaction liquid was washed with water, dried, and
then concentrated to obtain 2.54 g of crude ethyl (3S)-4-chloro-3-
methoxymethyloxy-butanoate ester (a compound of the formula (2), wherein X = Cl,
P= methoxymethyl group, and R1 = ethyl group).
[0117]
1H-NMR (400MHz, CDCl3) δ1.26 (3H, t, J=7.6Hz), 2.60-2.75 (2H, m), 3.38 (3H, s),
3.67 (2H, d, J=5.2Hz), 4.15 (2H, q, J=7.3Hz), 4.23 (1H, m), 4.71 (2H, dd, J=6.8,
22Hz).
[0118]
Next, 2.54 g of this crude ethyl (3S)-4-chloro-3-methoxymethyloxybutanoate
ester (a compound of the formula (2), wherein X = Cl, P= methoxymethyl
group, and R1 = ethyl group) was dissolved in 14 mL of toluene, and then 2.75 mL
(9.91 mmol) of a 70% solution of sodium bis(methoxyethoxy)aluminium hydride in
toluene was added thereto at 5°C to 10°C and the mixture was stirred for 1 hour at
5°C to 10°C. To this reaction liquid, 1.8 mL of water, 0.56 g of sodium sulfate, and
0.68 g of magnesium sulfate were added sequentially at 5°C to 10°C, and the mixture
was stirred for 1 hour at 5°C to 10°C and filtered to remove solids. Then, the
filtrate was washed with saturated brine, dried, and subsequently concentrated to
59
obtain a solution of (3S)-4-chloro-3-methoxymethyloxy-butan-1-ol (a compound of
the formula (3), wherein X = Cl, P = methoxymethyl group) in toluene.
[0119]
1H-NMR (400MHz, CDCl3) δ1.78-1.95 (2H, m), 3.43 (3H, s), 3.58-3.67 (2H, m),
3.98 (1H, m), 4.74 (2H, dd, J=7.2, 24Hz).
[0120]
Next, 1.57 mL (11.29 mmol) of triethylamine was added to this solution
and then 0.83 mL (10.72 mmol) of methanesulfonyl chloride was added thereto at
5°C to 10°C and the mixture was stirred for 1 hour at 5°C to 10°C. This reaction
liquid was washed with water, dried, and then concentrated to obtain 1.39 g of (3S)-
4-chloro-3-methoxymethyloxy-butyl methanesulfonate ester (a compound of the
formula (4), wherein X = Cl, P = methoxymethyl group, and R2 = methyl group) (the
total yield through the three steps: 62%).
[0121]
1H-NMR (400MHz, CDCl3) δ1.98-2.15 (2H, m), 3.01 (3H, s), 3.40 (3H, s), 3.59-3.68
(2H, m), 3.92 (1H, m), 4.36 (1H, m), 4.71 (2H, dd, J=8.0, 13.6Hz).
[0122]
[Example 4-2] Production of (3S)-4-chloro-3-(1-ethoxyethyloxy)-butyl
methanesulfonate ester (a compound of the formula (4), wherein X = Cl, P =
ethoxyethyl group, and R2 = methyl group)
In a 1-L reactor, 5.02 g (30.13 mmol) of ethyl (3S)-4-chloro-3-
hydroxybutanoate ester (a compound of the formula (1), wherein X = Cl, and R1 =
ethyl group), 2.39 g (33.14 mmol) of ethyl vinyl ether, 0.08 g (0.30 mmol) of
pyridinium p-toluenesulfonate and 25 mL of toluene were placed and the mixture
was stirred for 3 hours at 40°C to obtain a solution of ethyl (3S)-4-chloro-3-(1-
ethoxyethyloxy)-butanoate ester (a compound of the formula (2), wherein X=Cl,
P=ethoxyethyl group, and R1 = ethyl group) in toluene.
60
[0123]
1H-NMR (400MHz, CDCl3) δ1.18-1.36 (9H, m), 2.58-2.77 (2H, m), 3.23-3.75 (4H,
m), 4.10-4.35 (3H, m), 4.82 (1H, m).
[0124]
Then, 70 mL (252.25 mmol) of a 70% solution of sodium
bis(methoxyethoxy)aluminium hydride in toluene was added to this reaction liquid at
5°C to 10°C and the mixture was stirred for 1 hour at 5°C to 10°C. To this reaction
liquid, 3.25 mL of water, 9.53 g of magnesium sulfate, and 3.25 mL of water were
added sequentially at 5°C to 10°C, and the mixture was stirred for 4 hours at 5°C to
10°C and filtered to remove solids. Then, the filtrate was washed with saturated
brine, dried, and subsequently concentrated to obtain 5.81 g (pure content: 5.44 g) of
(3S)-4-chloro-3-(1-ethoxyethyloxy)-butan-1-ol (a compound of the formula (3),
wherein X = Cl, and P = ethoxyethyl group) in toluene solution (the total yield
through the two steps: 92%).
[0125]
1H-NMR (400MHz, CDCl3) δ1.17-1.29 (3H, m), 1.30-1.37 (3H, m), 1.61-1.72 (0.6H,
m), 1.80-2.00 (2H, m), 3.02 (0.4H, m), 3.50-3.90 (6H, m), 3.92-4.08 (1H, m), 4.79-
4.86 (1H, m).
[0126]
Next, to 4.44 g of this solution (containing 4.16 g (21.17 mmol) of (3S)-4-
chloro-3-(1-ethoxyethyloxy)-butan-1-ol (a compound of the formula (3), wherein X
= Cl, and P = ethoxyethyl group)), 20 mL of toluene and 2.35 g (23.29 mmol) of
triethylamine were added and then 2.55 g (22.23 mmol) of methanesulfonyl chloride
was added thereto at 5°C to 15°C and the mixture was stirred for 0.5 hour at 5°C to
10°C. This reaction liquid was washed with water, dried, and then concentrated to
obtain 10.83 g (pure content: 5.33 g) of crude (3S)-4-chloro-3-(1-ethoxyethyloxy)-
61
butyl methanesulfonate ester (a compound of the formula (4), wherein X = Cl, P =
ethoxyethyl group, and R2 = methyl group) in toluene solution (yield: 92%).
[0127]
1H-NMR (400MHz, CDCl3) δ1.20 (3H, t, J=5.9Hz), 1.32 (3H, d, J=7.4Hz), 1.92-2.19
(2H, m), 2.99 (3H, s), 3.43-3.71 (4H, m), 3.88 (0.5H, m), 4.02 (0.5H, m), 4.26-4.40
(2H, m), 4.78 (1H, m).
[0128]
[Example 4-3] Production of (3S)-4-chloro-3-tert-butyldimethylsilyloxy-butyl
methanesulfonate ester (a compound of the formula (4), wherein X = Cl, P = tertbutyldimethylsilyl
group, and R2 = methyl group)
In a 50-mL reactor, 5.00 g (30.01 mmol) of ethyl (3S)-4-chloro-3-
hydroxybutanoate ester (a compound of the formula (1), wherein X = Cl, and R1 =
ethyl group), 3.06 g (45.02 mmol) of imidazole and 25 mL of dichloromethane were
placed and 5.88 g (39.01 mmol) of tert-butyldimethylsilyl chloride and 1.18 g (11.71
mmol) of methoxymethyl chloride were added thereto on ice and the mixture was
stirred at room temperature. After the completion of the reaction, the reaction
liquid was washed with water and with saturated aqueous sodium bicarbonate
solution, dried, and the concentrated to obtain 8.01 g of crude ethyl (3S)-4-chloro-3-
tert-butyldimethylsilyloxy-butanoate ester (a compound of the formula (2), wherein
X = Cl, P = tert-butyldimethylsilyl group, and R1 = ethyl group) (yield: 95%).
[0129]
1H-NMR (400MHz, CDCl3) δ0.05 (3H, s), 0.11 (3H, s), 0.88 (9H, s), 1.26 (3H, t,
J=7.4Hz), 2.49-2.73 (2H, m), 3.52 (2H, s), 4.14 (2H, m), 4.31 (1H, m).
[0130]
Next, 8.01 g of this crude ethyl (3S)-4-chloro-3-tert-butyldimethylsilyloxybutanoate
ester (a compound of the formula (2), wherein X=Cl, P=tertbutyldimethylsilyl
group, and R1 = ethyl group) was dissolved in 25 mL of toluene,
62
and 9.5 mL (34.24 mmol) of a 70% solution of sodium
bis(methoxyethoxy)aluminium hydride in toluene was added thereto at 5°C to 15°C
and the mixture was stirred for 2.5 hours at 5°C to 10°C. To this reaction liquid,
2.05 mL of acetic acid and 5.55 mL of water were added sequentially at 5°C to 10°C,
and the mixture was stirred for 0.5 hour at room temperature and filtered to remove
solids. Then, the filtrate was washed with saturated brine, dried, and subsequently
concentrated to obtain 4.66 g (pure content: 4.28 g) of (3S)-4-chloro-3-tertbutyldimethylsilyloxy-
butan-1-ol (a compound of the formula (3), wherein X = Cl,
and P = tert-butyldimethylsilyl group) in toluene solution (yield: 63%).
[0131]
1H-NMR (400MHz, CDCl3) δ0.14 (6H, s), 0.92 (9H, s), 1.80-2.01 (3H, m), 3.52 (2H,
m), 3.81 (2H, m), 4.10 (1H, m).
[0132]
Next, 23 mL of toluene and 2.17 mL (21.46 mmol) of triethylamine were
added to this solution and then 2.35 g (20.49 mmol) of methanesulfonyl chloride was
added thereto at 5°C to 10°C and the mixture was stirred for 1 hour at 5°C to 10°C.
This reaction liquid was washed with water, dried, and then concentrated to obtain
6.09 g (pure content: 5.46 g) of (3S)-4-chloro-3-tert-butyldimethylsilyloxy-butyl
methanesulfonate ester (a compound of the formula (4), wherein X = Cl, P = tertbutyldimethylsilyl
group, and R2 = methyl group) in toluene solution (yield: 96%).
[0133]
1H-NMR (400MHz, CDCl3) δ0.10 (6H, s), 0.89 (9H, s), 1.90-1.99 (1H, m), 2.06-2.17
(1H, m), 3.02 (3H, s), 3.47 (2H, m), 4.03 (1H, m), 4.28-4.40 (2H, m).
[0134]
[Example 4-4] Production of (3S)-4-chloro-3-tert-butyloxy-butyl methanesulfonate
ester (a compound of the formula (4), wherein X = Cl, P = tert-butyl group, and R2 =
methyl group)
63
In a 100-mL reactor, 7.51 g (45.11 mmol) of ethyl (3S)-4-chloro-3-
hydroxybutanoate ester (a compound of the formula (1), wherein X = Cl, and R1 =
ethyl group) and 18 mL of n-hexane were placed and 0.47 g (4.51 mmol) of
concentrated sulfuric acid and 6.17 g (110.07 mmol) of isobutylene were added
thereto on ice and the mixture was stirred for 18 hours at 30-35°C. Then, the
reaction liquid was washed with saturated aqueous sodium bicarbonate solution,
dried, then concentrated, and purified by silica gel chromatography to obtain 4.92 g
of ethyl (3S)-4-chloro-3-tert-butyloxy-butanoate ester (a compound of the formula
(2), wherein X = Cl, P = tert-butyl group, and R1 = ethyl group) (yield: 49%).
[0135]
1H-NMR (400MHz, CDCl3) δ1.20 (9H, s), 1.28 (3H, t, J=8Hz), 2.51-2.76 (2H, m),
3.48-3.60 (2H, m), 4.15 (3H, m).
[0136]
Next, 4.92 g (22.11 mmol) of this crude ethyl (3S)-4-chloro-3-tertbutyloxy-
butanoate ester (a compound of the formula (2), wherein X = Cl, P = tertbutyl
group, and R1 = ethyl group) was dissolved in 25 mL of toluene, and 8 mL
(28.74 mmol) of a 70% solution of sodium bis(methoxyethoxy)aluminium hydride in
toluene was added thereto at 5°C to 15°C and the mixture was stirred for 2 hours at
5°C to 10°C. To this reaction liquid, 0.77 mL of ethanol, 3.41 g of citric acid, and
20 mL of water were added sequentially at 5°C to 10°C and the mixture was stirred
for 0.5 hour at 5°C to 10°C, and the separated organic phase was washed with
saturated brine, dried, then concentrated, and then purified by silica gel
chromatography to obtain 3.29 g of (3S)-4-chloro-3-tert-butyloxy-butan-1-ol (a
compound of the formula (3), wherein X = Cl and P = tert-butyl group) (yield: 82%).
[0137]
1H-NMR (400MHz, CDCl3) δ1.25 (9H, s), 1.80-1.88 (1H, m), 1.94-2.03 (1H, m),
2.58 (1H, brm), 3.44-3.56 (2H, m), 3.75 (1H, m), 3.83 (1H, m), 3.96 (1H, m).
64
[0138]
Next, to 2.25 g (12.47 mmol) of the obtained (3S)-4-chloro-3-tertbutyloxy-
butan-1-ol (a compound of the formula (3), wherein X = Cl and P = tertbutyl
group), 23 mL of toluene and 2.24 mL (16.21 mmol) of triethylamine were
added and 1.01 mL (13.09 mmol) of methanesulfonyl chloride was added thereto at
5°C to 10°C and the mixture was stirred for 2 hours at 5°C to 10°C. This reaction
liquid was washed with water, dried, and then concentrated to obtain 4.23 g (pure
content: 3.19 g) of (3S)-4-chloro-3-tert-butyloxy-butyl methanesulfonate ester (a
compound of the formula (4), wherein X = Cl, P = tert-butyl group, and R2 = methyl
group) in toluene solution (yield: 99%).
[0139]
1H-NMR (400MHz, CDCl3) δ1.23 (9H, s), 1.88-1.96 (1H, m), 2.12-2.21 (1H, m),
3.02 (3H, s), 3.39-3.57 (2H, m), 3.86 (1H, m), 4.35 (2H, m).
[0140]
[Example 4-5] Production of (3S)-4-chloro-3-methoxymethyloxy-butyl ptoluenesulfonate
ester (a compound of the formula (4), wherein X = Cl, P =
methoxymethyl group, and R2 = p-tolyl group)
To 2.22 g (pure content: 2.00 g, 11.86 mmol) of the (3S)-4-chloro-3-
methoxymethyloxy-butan-1-ol (a compound of the formula (3), wherein X = Cl, P =
methoxymethyl group) obtained in accordance with Example 4, 9 mL of toluene and
1.00 g (13.10 mmol) of pyridine were added, and 2.40 g (12.50 mmol) of ptoluenesulfonyl
chloride and 29 mg (0.24 mmol) of 4-dimethylaminopyridine were
added thereto at room temperature and the mixture was stirred for 16 hours at 40°C.
This reaction liquid was washed with water, dried, then concentrated, and purified by
silica gel chromatography to obtain 1.75 g of (3S)-4-chloro-3-methoxymethyloxybutyl
p-toluenesulfonate ester (a compound of the formula (4), wherein X = Cl, P =
methoxymethyl group, and R2 = p-tolyl group) (yield: 46%).
65
[0141]
1H-NMR (400MHz, CDCl3) δ1.88-2.03 (2H, m), 2.46 (3H, s), 3.35 (3H, s), 3.53-3.66
(2H, m), 3.87 (1H, m), 4.09-4.20 (4H, m), 4.61 (2H, m), 7.35 (2H, d, J=8.4Hz), 7.79
(2H, d, J=8.4Hz).
[0142]
[Example 4-6] Production of (3S)-4-chloro-3-(1-ethoxyethyloxy)-butyl ptoluenesulfonate
ester (a compound of the formula (4), wherein X = Cl, P =
ethoxyethyl group, and R2 = p-tolyl group)
To 1.31 g (pure content: 6.23 mmol) of the (3S)-4-chloro-3-(1-
ethoxyethyloxy)-butan-1-ol (a compound of the formula (3), wherein X = Cl, and P =
ethoxyethyl group) obtained in accordance with Example 4-2, 6.1 mL of toluene,
0.69 g (6.85 mmol) of triethylamine, 1.19 g (6.23 mmol) of p-toluenesulfonyl
chloride and 0.76 g (6.23 mmol) of 4-dimethylaminopyridine were added and the
mixture was stirred for 33 hours at 40°C. This reaction liquid was washed with
water, dried, then concentrated, and purified by silica gel chromatography to obtain
0.95 g (pure content: 0.44 g) of (3S)-4-chloro-3-(1-ethoxyethyloxy)-butyl ptoluenesulfonate
ester (a compound of the formula (4), wherein X = Cl, P =
ethoxyethyl group, and R2 = p-tolyl group) (yield: 20%).
[0143]
1H-NMR (400MHz, CDCl3) δ1.12-1.38 (6H, m), 1.80-2.10 (2H, m), 2.43 (3H, s),
3.40-3.85 (4H, m), 3.93-4.23 (3H, m), 4.80 (1H, m), 7.36 (2H, m), 7.80 (2H, m).
[0144]
[Example 5] Production of diethyl (3S)-2-acetylamino-2-[4-chloro-3-
(tetrahydropyran-2-yloxy)-butyl]malonate ester (a compound of the formula (6),
wherein X = Cl, P = tetrahydropyranyl group, R3 = ethyl group, and A = methyl
group)
66
In a 20-mL reactor, 0.10 g (0.46 mmol) of diethyl acetaminomalonate ester
(a compound of the formula (5), wherein R3 = ethyl group and A = methyl group)
and 1 mL of toluene were placed, and 180 μL (0.46 mmol) of 20% sodium ethoxide
was added thereto and the mixture was stirred for 1.5 hours at 25°C. To this
mixture, 0.5 mL of the toluene solution containing 0.15 g (pure content: 0.13 g, 0.46
mmol) of the crude (3S)-4-chloro-3-(tetrahydropyran-2-yloxy)-butyl
methanesulfonate ester (a compound of the formula (4), wherein X = Cl, P =
tetrahydropyranyl group, and R2 = methyl group) obtained in Example 2, 0.08 g
(0.46 mmol) of potassium iodide, and 1 mL of ethanol were added at 25°C and
heated to reflux overnight. Ethyl acetate was added to this reaction liquid and the
resulting reaction liquid was washed with water , dried, then concentrated, and
purified by silica gel column chromatography to obtain 0.12 g of diethyl (3S)-2-
acetylamino-2-[4-chloro-3-(tetrahydropyran-2-yloxy)-butyl]malonate ester (a
compound of the formula (6), wherein X = Cl, P = tetrahydropyranyl group, R3 =
ethyl group, and A = methyl group) (yield: 63%).
[0145]
[Example 6] Production of diethyl (3S)-2-acetylamino-2-[4-chloro-3-
(tetrahydropyran-2-yloxy)-butyl]malonate ester (a compound of the formula (6),
wherein X = Cl, P = tetrahydropyranyl group, R3 = ethyl group, and A = methyl
group)
In a 50-mL reactor, 0.68 g (3.15 mmol) of diethyl acetaminomalonate ester
(a compound of the formula (5), wherein R3 = ethyl group and A = methyl group)
and 3.4 mL of N,N-dimethylformamide were placed, and 0.29 g (3.00 mmol) of
sodium tert-butoxide was added thereto and the mixture was stirred for 1 hour at
30°C. To this mixture, 4 mL of the toluene solution containing 1.01 g (pure
content: 0.86 g, 3.00 mmol) of the crude (3S)-4-chloro-3-(tetrahydropyran-2-yloxy)-
butyl methanesulfonate ester (a compound of the formula (4), wherein X = Cl, P =
67
tetrahydropyranyl group, and R2 = methyl group) obtained in Example 3 and 0.10 g
(0.6 mmol) of potassium iodide were added at 30°C and the mixture was stirred for
7.5 hours at 60°C. This reaction liquid was washed with water, dried, and then
concentrated to obtain 1.22 g (pure content: 1.01 g) of crude diethyl (3S)-2-
acetylamino-2-[4-chloro-3-(tetrahydropyran-2-yloxy)-butyl]malonate ester (a
compound of the formula (6), wherein X = Cl, P = tetrahydropyranyl group, R3 =
ethyl group, and A = methyl group) (yield: 83%).
[0146]
1H-NMR (400MHz, CDCl3) δ1.25 (6H, m), 1.15-1.83 (8H, m), 2.03 (3H, s), 2.30-
2.50 (2H, m), 3.47-3.95 (5H, m), 4.20-4.30 (4H, m), 4.61 and 4.72 (1H, m), 6.80 (1H,
brs).
[0147]
[Example 7-1] Production of diethyl (3S)-2-acetylamino-2-(4-chloro-3-
methoxymethyloxy-butyl)malonate ester (a compound of the formula (6), wherein X
= Cl, P = methoxymethyl group, R3 = ethyl group, and A = methyl group)
In a 30-mL reactor, 0.49 g (2.27 mmol) of diethyl acetaminomalonate ester
(a compound of the formula (5), wherein R3 = ethyl group and A = methyl group)
and 2.5 mL of dimethylsulfoxide were placed, and 0.23 g (2.38 mmol) of sodium
tert-butoxide was added thereto and the mixture was stirred for 2 hours at 30°C. To
this mixture, 2.5 mL of the toluene solution containing 0.56 g (2.27 mmol) of the
crude (3S)-4-chloro-3-methoxymethyloxy-butyl methanesulfonate ester (a compound
of the formula (4), wherein X = Cl, P = methoxymethyl group, and R2 = methyl
group) obtained in Example 4 and 0.08 g (0.45 mmol) of potassium iodide were
added at 30°C and the mixture was stirred for 5 hours at 80°C. An aliquot of 200
μL was withdrawn from this reaction liquid and ethyl acetate was added thereto and
the resulting mixture was washed with water, dried, and then concentrated to obtain
25 mg of diethyl (3S)-2-acetylamino-2-(4-chloro-3-methoxymethyloxy68
butyl)malonate ester (a compound of the formula (6), wherein X = Cl, P =
methoxymethyl group, R3 = ethyl group, and A = methyl group) (yield: 94%).
[0148]
1H-NMR (400MHz, CDCl3) δ1.23 (6H, t, J=5.2Hz), 1.33-1.50 (2H, m), 2.01 (3H, s),
2.30-2.46 (2H, m), 3.36 (3H, s), 3.55 (2H, d, J=5.2Hz), 3.67 (1H, m), 4.21 (4H, q,
J=7.3Hz), 4.64 (2H, dd, J=7.2, 18Hz), 6.77 (1H, brs).
[0149]
[Example 7-2] Production of diethyl (3S)-2-acetylamino-2-(4-chloro-3-(1-
ethoxyethyloxy)-butyl)malonate ester (a compound of the formula (6), wherein X =
Cl, P = ethoxyethyl group, R3 = ethyl group, and A = methyl group)
In a 50-mL reactor, 4.95 g (22.82 mmol) of diethyl acetaminomalonate
ester (a compound of the formula (5), wherein R3 = ethyl group and A = methyl
group) and 22 mL of N,N-dimethylformamide were placed, and 2.15 g (22.40 mmol)
of sodium tert-butoxide was added thereto and the mixture was stirred for 1.5 hours
at 40°C. To this mixture, 10.83 g (pure content: 5.33 g, 19.41 mmol) of the toluene
solution containing the crude (3S)-4-chloro-3-(1-ethoxyethyloxy)-butyl
methanesulfonate ester (a compound of the formula (4), wherein X = Cl, P =
ethoxyethyl group, and R2 = methyl group) obtained in Example 4-2, 4 mL of
toluene and 0.69 g (4.16 mmol) of potassium iodide were added at 40°C and the
mixture was stirred for 2 hours at 80°C. Toluene was added to this reaction liquid
and the resulting reaction liquid was washed with water, dried, and then concentrated
to obtain 7.64 g (pure content: 7.14 g; yield: 93%) of diethyl (3S)-2-acetylamino-2-
(4-chloro-3-(1-ethoxyethyloxy)-butyl)malonate ester (a compound of the formula (6),
wherein X = Cl, P = ethoxyethyl group, R3 = ethyl group, and A = methyl group).
[0150]
69
1H-NMR (400MHz, CDCl3) δ1.15-1.32 (12H, m), 1.30-1.60 (2H, m), 2.03 (3H, s),
2.30-2.52 (2H, m), 3.47-3.83 (5H, m), 4.23 (4H, q, J=7.0Hz), 4.73 and 4.81 (1H, m),
6.78 (1H, brs).
[0151]
[Example 7-3] Production of diethyl (3S)-2-acetylamino-2-(4-chloro-3-tertbutyldimethylsilyloxy-
butyl)malonate ester (a compound of the formula (6), wherein
X = Cl, P = tert-butyldimethylsilyl group, R3 = ethyl group, and A = methyl group)
In a 50-mL reactor, 1.15 g (5.29 mmol) of diethyl acetaminomalonate ester
(a compound of the formula (5), wherein R3 = ethyl group and A = methyl group)
and 6.8 mL of N,N-dimethylformamide were placed, and 0.50 g (5.19 mmol) of
sodium tert-butoxide was added thereto and the mixture was stirred for 1 hour at
40°C. To this mixture, 1.70 g (pure content: 1.52 g, 4.81 mmol) of the toluene
solution containing the crude (3S)-4-chloro-3-tert-butyldimethylsilyloxy-butyl
methanesulfonate ester (a compound of the formula (4), wherein X = Cl, P = tertbutyldimethylsilyl
group, and R2 = methyl group) obtained in Example 4-3, 1 mL of
toluene and 0.16 g (0.96 mmol) of potassium iodide were added at 40°C and the
mixture was stirred for 4 hours at 80°C. Toluene was added to this reaction liquid
and the resulting reaction liquid was washed with water, dried, and then concentrated
to obtain 2.10 g (pure content: 1.77 g; yield: 84%) of diethyl (3S)-2-acetylamino-2-
(4-chloro-3-tert-butyldimethylsilyloxy-butyl)malonate ester (a compound of the
formula (6), wherein X = Cl, P = tert-butyldimethylsilyl group, R3 = ethyl group, and
A = methyl group).
[0152]
1H-NMR (400MHz, CDCl3) δ0.09 (6H, s), 0.90 (9H, s), 1.24 (6H, t, J=7.5Hz), 1.29-
1.55 (2H, m), 2.02 (3H, s), 2.30-2.50 (2H, m), 3.42 (2H, m), 3.83 (1H, m), 4.25 (4H,
m), 6.75 (1H, brs).
[0153]
70
[Example 7-4] Production of diethyl (3S)-2-acetylamino-2-(4-chloro-3-tert-butyloxybutyl)
malonate ester (a compound of the formula (6), wherein X = Cl, P = tert-butyl
group, R3 = ethyl group, and A = methyl group)
In a 50-mL reactor, 0.87 g (4.00 mmol) of diethyl acetaminomalonate ester
(a compound of the formula (5), wherein R3 = ethyl group and A = methyl group)
and 4.3 mL of N,N-dimethylformamide were placed, and 0.38 g (3.92 mmol) of
sodium tert-butoxide was added thereto and the mixture was stirred for 1 hour at
40°C. To this mixture, 1.25 g (pure content: 0.94 g, 3.64 mmol) of the toluene
solution containing the crude (3S)-4-chloro-3-tert-butyloxy-butyl methanesulfonate
ester (a compound of the formula (4), wherein X = Cl, P = tert-butyl group, and R2 =
methyl group) obtained in Example 4-4, 2 mL of toluene and 0.12 g (0.73 mmol) of
potassium iodide were added at 40°C and the mixture was stirred for 2 hours at 80°C.
Toluene was added to this reaction liquid and the resulting reaction liquid was
washed with water, dried, then concentrated, and purified by silica gel
chromatography to obtain 1.06 g (pure content: 0.95 g; yield: 69%) of diethyl (3S)-2-
acetylamino-2-(4-chloro-3-tert-butyloxy-butyl)malonate ester (a compound of the
formula (6), wherein X = Cl, P = tert-butyl group, R3 = ethyl group, and A = methyl
group).
[0154]
1H-NMR (400MHz, CDCl3) δ1.19 (9H, s), 1.25 (6H, t, J=7.2Hz), 1.30-1.38 (1H, m),
1.49-1.59 (1H, m), 2.03 (3H, s), 2.30-2.47 (2H, m), 3.33-3.49 (2H, m), 3.65 (1H, m),
4.27 (4H, q, J=7.2Hz), 6.78 (1H, brs).
[0155]
[Example 7-5] Production of diethyl (3S)-2-acetylamino-2-(4-chloro-3-
methoxymethyloxy-butyl)malonate ester (a compound of the formula (6), wherein X
= Cl, P = methoxymethyl group, R3 = ethyl group, and A = methyl group)
71
In a 50-mL reactor, 1.04 g (4.81 mmol) of diethyl acetaminomalonate ester
(a compound of the formula (5), wherein R3 = ethyl group and A = methyl group)
and 5.4 mL of N,N-dimethylformamide were placed, and 0.45 g (4.72 mmol) of
sodium tert-butoxide was added thereto and the mixture was stirred for 1 hour at
40°C. To this mixture, 5.1 mL of the toluene solution containing 1.80 g (pure
content: 1.41 g, 4.37 mmol) of the crude (3S)-4-chloro-3-methoxymethyloxy-butyl
p-toluenesulfonate ester (a compound of the formula (4), wherein X = Cl, P =
methoxymethyl group, and R2 = p-tolyl group) obtained in Example 4-5 and 0.15 g
(0.87 mmol) of potassium iodide were added at 40°C and the mixture was stirred for
2 hours at 80°C. Toluene was added to this reaction liquid and the resulting
reaction liquid was washed with water, dried, and then concentrated to obtain 2.08 g
(pure content: 1.45 g; yield: 90%) of diethyl (3S)-2-acetylamino-2-(4-chloro-3-
methoxymethyloxy-butyl)malonate ester (a compound of the formula (6), wherein X
= Cl, P = methoxymethyl group, R3 = ethyl group, and A = methyl group).
[0156]
[Example 8-1] Production of diethyl (3S)-2-benzoylamino-2-[4-chloro-3-
(tetrahydropyran-2-yloxy)-butyl]malonate ester (a compound of the formula (6),
wherein X = Cl, P = tetrahydropyranyl group, and R3 = ethyl group, and A = phenyl
group)
In a 30-mL reactor, 0.38 g (1.37 mmol) of diethyl benzoylaminomalonate
ester (a compound of the formula (5), wherein R3 = ethyl group and A = phenyl
group) and 1.9 mL of N,N-dimethylformamide were placed, and 0.13 g (1.37 mmol)
sodium tert-butoxide was added thereto and the mixture was stirred for 1 hour at
room temperature. To this mixture, 1.9 mL of the toluene solution containing 0.51
g (pure content: 0.39 g, 1.37 mmol) of the crude (3S)-4-chloro-3-(tetrahydropyran-2-
yloxy)-butyl methanesulfonate ester (a compound of the formula (4), wherein X = Cl,
P = tetrahydropyranyl group, and R2 = methyl group) obtained in Example 3 and
72
0.09 g (0.55 mmol) of potassium iodide were added at room temperature and the
mixture was stirred for 1 hour at 80°C. A small volume of aliquot was withdrawn
from this reaction liquid and toluene was added thereto and the resulting mixture was
washed with water, dried, and then concentrated to obtain 27 mg of crude diethyl
(3S)-2-benzoylamino-2-[4-chloro-3-(tetrahydropyran-2-yloxy)-butyl]malonate ester
(a compound of the formula (6), wherein X = Cl, P = tetrahydropyranyl group, and
R3 = ethyl group, and A = phenyl group).
[0157]
1H-NMR (400MHz, CDCl3) δ1.20 (6H, m), 1.32-1.80 (8H, m), 1.97-2.20 (1H, m),
2.40-2.57 (1H, m), 3.16-3.92 (5H, m), 4.20 (4H, m), 4.52 and 4.65 (1H, m), 7.30 (3H,
m), 7.80 (2H, m).
[0158]
[Example 8-2] Production of diethyl (3S)-2-benzoylamino-2-[4-chloro-3-
(methoxymethyloxy-butyl]malonate ester (a compound of the formula (6), wherein X
= Cl, P = methoxymethyl group, R3 = ethyl group, and A = phenyl group)
In a 50-mL reactor, 1.87 g (6.69 mmol) of diethyl benzoylaminomalonate
ester (a compound of the formula (5), wherein R3 = ethyl group and A = phenyl
group) and 5.7 mL of N,N-dimethylformamide were placed, and 0.63 g (6.57 mmol)
of sodium tert-butoxide was added thereto and the mixture was stirred for 1 hour at
40°C. To this mixture, 6 mL of the toluene solution containing 1.50 g (6.08 mmol)
of the crude (3S)-4-chloro-3-(tetrahydropyran-2-yloxy)-butyl methanesulfonate ester
(a compound of the formula (4), wherein X = Cl, P = methoxymethyl group, and R2
= methyl group) obtained in Example 3 and 0.20 g (1.22 mmol) of potassium iodide
were added at 40°C and the mixture was stirred for 2 hours at 80°C. Toluene was
added to this reaction liquid and the resulting reaction liquid was washed with water,
dried, and then concentrated to obtain 2.83 g (pure content: 2.20 g; yield: 84%) of
crude diethyl (3S)-2-benzoylamino-2-[4-chloro-3-methoxymethyloxy73
butyl]malonate ester (a compound of the formula (6), wherein X = Cl, P =
methoxymethyl group, R3 = ethyl group, and A = phenyl group).
[0159]
1H-NMR (400MHz, CDCl3) δ1.26 (6H, t, J=7.5Hz), 1.20-1.85 (8H, m), 2.45-2.65
(2H, m), 3.40-3.92 (5H, m), 4.29 (4H, m), 4.60 and 4.71 (1H, m), 7.42-7.55 (4H, m),
7.82 (2H, m).
[0160]
[Example 8-3] Production of diethyl (3S)-2-benzoylamino-2-[4-chloro-3-(1-
ethoxyethyloxy)-butyl]malonate ester (a compound of the formula (6), wherein X =
Cl, P = ethoxyethyl group, R3 = ethyl group, and A = phenyl group)
In a 30-mL reactor, 2.31 g (8.27 mmol) of diethyl benzoylaminomalonate
ester (a compound of the formula (5), wherein R3 = ethyl group and A = phenyl
group) and 8 mL of N,N-dimethylformamide were placed, and 0.78 g (8.12 mmol) of
sodium tert-butoxide was added thereto and the mixture was stirred for 2 hours at
40°C. To this mixture, 4 mL of the toluene solution containing 2.06 g (pure
content: 1.99 g, 7.52 mmol) of the crude (3S)-4-chloro-3-(1-ethoxyethyloxy)-butyl
methanesulfonate ester (a compound of the formula (4), wherein X = Cl, P =
ethoxyethyl group, and R2 = methyl group) obtained in accordance with Example 4-2
and 0.25 g (1.50 mmol) of potassium iodide were added at 40°C and the mixture was
stirred for 4.5 hours at 80°C. Toluene was added to this reaction liquid and the
resulting reaction liquid was washed with water, dried, then concentrated, and
purified by silica gel chromatography to obtain 2.31 g of diethyl (3S)-2-
benzoylamino-2-[4-chloro-3-(1-ethoxyethyloxy)-butyl]malonate ester (a compound
of the formula (6), wherein X = Cl, P = ethoxyethyl group, R3 = ethyl group, and A =
phenyl group) (yield: 67%).
[0161]
74
1H-NMR (400MHz, CDCl3) δ1.13-1.35 (12H, m), 1.40-1.63 (2H, m), 2.45-2.65 (2H,
m), 3.43-3.83 (5H, m), 4.30 (4H, m), 4.72 and 4.80 (1H, m), 7.43-7.58 (4H, m), 7.83
(2H, m).
[0162]
[Example 8-4] Production of diethyl (3S)-2-benzoylamino-2-[4-chloro-3-tertbutyldimethylsilyloxy-
butyl]malonate ester (a compound of the formula (6), wherein
X = Cl, P = tert-butyldimethylsilyl group, R3 = ethyl group, and A = phenyl group)
In a 30-mL reactor, 1.48 g (5.29 mmol) of diethyl benzoylaminomalonate
ester (a compound of the formula (5), wherein R3 = ethyl group and A = phenyl
group) and 6.8 mL of N,N-dimethylformamide were placed, and 0.50 g (5.19 mmol)
of sodium tert-butoxide was added thereto and the mixture was stirred for 1 hour at
40°C. To this mixture, 1 mL of the toluene solution containing 1.70 g (pure
content: 1.52 g, 4.81 mmol) of the crude (3S)-4-chloro-3-tert-butyldimethylsilyloxybutyl
methanesulfonate ester (a compound of the formula (4), wherein X = Cl, P =
tert-butyldimethylsilyl group, and R2 = methyl group) obtained in Example 4-3 and
0.16 g (0.96 mmol) of potassium iodide were added at 40°C and the mixture was
stirred for 4.5 hours at 80°C. Toluene was added to this reaction liquid and the
resulting reaction liquid was washed with water, dried, and then concentrated to
obtain 2.68 g of crude diethyl (3S)-2-benzoylamino-2-[4-chloro-3-tertbutyldimethylsilyloxy-
butyl]malonate ester (a compound of the formula (6), wherein
X = Cl, P = tert-butyldimethylsilyl group, R3 = ethyl group, and A = phenyl group)
(pure content: 1.95 g; yield: 81%).
[0163]
1H-NMR (400MHz, CDCl3) δ0.10 (6H, s), 0.90 (9H, s), 1.30 (6H, t, J=8.3Hz), 1.35-
1.65 (2H, m), 2.48-2.65 (2H, m), 3.43 (2H, m), 3.85 (1H, m), 4.33 (4H, m), 7.45-7.60
(4H, m), 7.84 (2H, m).
[0164]
75
[Example 8-5] Production of diethyl (3S)-2-benzoylamino-2-[4-chloro-3-tertbutyloxy-
butyl]malonate ester (a compound of the formula (6), wherein X = Cl, P =
tert-butyl group, R3 = ethyl group, and A = phenyl group)
In a 50-mL reactor, 1.12 g (4.00 mmol) of diethyl benzoylaminomalonate
ester (a compound of the formula (5), wherein R3 = ethyl group and A = phenyl
group) and 4.4 mL of N,N-dimethylformamide were placed, and 0.38 g (3.92 mmol)
of sodium tert-butoxide was added thereto and the mixture was stirred for 1 hour at
40°C. To this mixture, 2 mL of the toluene solution containing 1.25 g (pure
content: 0.94 g, 3.64 mmol) of the crude (3S)methanesulfonic acid 4-chloro-3-tertbutyloxy-
butyl ester (a compound of the formula (4), wherein X = Cl, P = tert-butyl
group, and R2 = methyl group) obtained in Example 4-4 and 0.12 g (0.73 mmol) of
potassium iodide were added at 40°C and the mixture was stirred for 2 hours at 80°C.
Toluene was added to this reaction liquid and the resulting reaction liquid was
washed with water, dried, then concentrated, and purified by silica gel
chromatography to obtain 1.24 g of diethyl (3S)-2-benzoylamino-2-[4-chloro-3-tertbutyloxy-
butyl]malonate ester (a compound of the formula (6), wherein X = Cl, P =
tert-butyl group, R3 = ethyl group, and A = phenyl group) (pure content: 1.10 g;
yield: 69%).
[0165]
1H-NMR (400MHz, CDCl3) δ1.16 (9H, s), 1.25-1.29 (7H, m), 1.31-1.42 (1H, m),
2.48-2.57 (2H, m), 3.34-3.49 (2H, m), 3.65 (1H, m), 4.28 (4H, q, J=6.8Hz), 7.44-7.53
(4H, m), 7.81 (2H, m).
[0166]
[Example 9] Production of diethyl (5S)-1-acetyl-5-(tetrahydropyran-2-yloxy)-
piperidine-2,2-dicarboxylate ester (a compound of the formula (7), wherein P =
tetrahydropyranyl group, R3 = ethyl group, and A = methyl group)
76
In a 100-mL reactor, 5.08 g (pure content: 4.35 g, 10.68 mmol) of the crude
diethyl (3S)-2-acetylamino-2-[4-chloro-3-(tetrahydropyran-2-yloxy)-butyl]malonate
ester (a compound of the formula (6), wherein X = Cl, P = tetrahydropyranyl group,
R3 = ethyl group, and A = methyl group) obtained in Example 5, 40 mL of
dimethylformamide and 10.44 g (32.04 mmol) of cesium carbonate were placed and
the mixture was stirred for 7 hours at 100°C. Toluene was added to this reaction
liquid and the resulting reaction liquid was washed with water, dried, and then
concentrated to obtain 4.18 g of crude diethyl (5S)-1-acetyl-5-(tetrahydropyran-2-
yloxy)-piperidine-2,2-dicarboxylate ester (a compound of the formula (7), wherein P
= tetrahydropyranyl group, R3 = ethyl group, and A = methyl group) (yield: 94%).
[0167]
1H-NMR (400MHz, CDCl3) δ1.15-1.25 (6H, m), 1.32-1.95 (8H, m), 1.95-2.10 (1H,
m), 2.10 (3H, s), 2.40-2.50 (1H, m), 3.02 and 3.22 (1H, m), 3.43 (1H, m), 3.55-3.70
(1H, m), 3.72-3.88 (2H, m), 4.10-4.25 (4H, m), 4.65 (1H, m).
[0168]
[Example 10] Production of diethyl (5S)-1-acetyl-5-(tetrahydropyran-2-yloxy)-
piperidine-2,2-dicarboxylate ester (a compound of the formula (7), wherein P =
tetrahydropyranyl group, R3 = ethyl group, and A = methyl group)
In a 100-mL reactor, 5.77 g (pure content: 4.95 g, 12.14 mmol) of the crude
diethyl (3S)-2-acetylamino-2-[4-chloro-3-(tetrahydropyran-2-yloxy)-butyl]malonate
ester (a compound of the formula (6), wherein X = Cl, P = tetrahydropyranyl group,
R3 = ethyl group, and A = methyl group) obtained in Example 5 and 58 mL of
dimethylformamide were placed and 1.52 g (15.78 mmol) of sodium tert-butoxide
were placed therein in three portions over 3 hours at 15°C and the mixture was
stirred for 2 hours at 15°C. An excess amount of the base was neutralized by
adding 0.22 mL of acetic acid to this reaction liquid, toluene was added thereto, and
the resulting mixture was washed with water, dried, and then concentrated to obtain
77
3.85 g (pure content: 2.77 g; yield: 62%) of crude diethyl (5S)-1-acetyl-5-
(tetrahydropyran-2-yloxy)-piperidine-2,2-dicarboxylate ester (a compound of the
formula (7), wherein P = tetrahydropyranyl group, R3 = ethyl group, and A = methyl
group).
[0169]
[Example 11-1] Production of diethyl (5S)-1-acetyl-5-(tetrahydropyran-2-yloxy)-
piperidine-2,2-dicarboxylate ester (a compound of the formula (7), wherein P =
tetrahydropyranyl group, R3 = ethyl group, and A = methyl group)
In a 10-mL reactor, 0.53 g (pure content: 0.5 g, 1.23 mmol) of the crude
diethyl (3S)-2-acetylamino-2-[4-chloro-3-(tetrahydropyran-2-yloxy)-butyl]malonate
ester (a compound of the formula (6), wherein X = Cl, P = tetrahydropyranyl group,
R3 = ethyl group, and A = methyl group) obtained in Example 5 and 2.7 mL of
dimethylformamide were placed, and potassium carbonate (1.23 mmol) and
tetrabutylammonium bromide (hereinafter referred to as “TBAB”) (1.227 mmol)
were placed therein and the mixture was stirred for 15 hours at 100°C.
Toluene was added to the mixture and the resulting mixture was washed
with brine, dried, and then concentrated to obtain 0.61 g (pure content: 0.37 g; yield:
80%) of diethyl (5S)-1-acetyl-5-(tetrahydropyran-2-yloxy)-piperidine-2,2-
dicarboxylate ester (a compound of the formula (7), wherein P = tetrahydropyranyl
group, R3 = ethyl group, and A = methyl group).
[0170]
[Example 11-2] Production of diethyl (5S)-1-acetyl-5-methoxymethyloxy-piperidine-
2,2-dicarboxylate ester (a compound of the formula (7), wherein P = methoxymethyl
group, R3 = ethyl group, and A = methyl group)
In a 50-mL reactor, 1.41 g (pure content: 1.12 g, 3.04 mmol) of the crude
diethyl (3S)-2-acetylamino-2-[4-chloro-3-methoxymethyloxy-butyl]malonate ester (a
compound of the formula (6), wherein X = Cl, P = methoxymethyl group, R3 = ethyl
78
group, and A = methyl group) obtained in accordance with Example 7, 5.3 mL of
dimethylformamide and 2.97 g (9.12 mmol) of cesium carbonate were placed and the
mixture was stirred for 3 hours at 100°C. Toluene was added to this reaction liquid
and the resulting reaction liquid was washed with water, dried, and then concentrated
to obtain 0.95 g (pure content: 0.87 g; yield: 87%) of crude diethyl (5S)-1-acetyl-5-
methoxymethyloxy-piperidine-2,2-dicarboxylate ester (a compound of the formula
(7), wherein P = methoxymethyl group, R3 = ethyl group, and A = methyl group).
[0171]
1H-NMR (400MHz, CDCl3) δ1.27-1.31 (6H, m), 1.50-1.59 (1H, m), 1.80-1.90 (1H,
m), 2.08-2.17 (1H, m), 2.17 (3H, s), 2.48-2.55 (1H, m), 3.28-3.40 (1H, m), 3.40 (3H,
s), 3.63 (1H, m), 3.76 (1H, m), 4.18-4.30 (4H, m), 4.71 (2H, m).
[0172]
[Example 11-3] Production of diethyl (5S)-1-acetyl-5-(1-ethoxyethyloxy)-piperidine-
2,2-dicarboxylate ester (a compound of the formula (7), wherein P = ethoxyethyl
group, R3 = ethyl group, and A = methyl group)
In a 100-mL reactor, 7.64 g (pure content: 7.14 g, 18.06 mmol) of the crude
diethyl (3S)-2-acetylamino-2-[4-chloro-3-(1-ethoxyethyloxy)-butyl]malonate ester (a
compound of the formula (6), wherein X = Cl, P = ethoxyethyl group, R3 = ethyl
group, and A = methyl group) obtained in Example 7-2 and 17.1 mL of
dimethylformamide were placed, and 853 mg (21.40 mmol) of 60% sodium hydride
was added portion-wise over 5 hours at 40°C. To this reaction liquid, 0.43 mL of
acetic acid and toluene were added, and the resulting mixture was washed with water
and aqueous 2% potassium carbonate, dried, and then concentrated to obtain 5.64 g
(pure content: 5.31 g; yield: 77%) of crude diethyl (5S)-1-acetyl-5-(1-
ethoxyethyloxy)-piperidine-2,2-dicarboxylate ester (a compound of the formula (7),
wherein P = ethoxyethyl group, R3 = ethyl group, and A = methyl group).
[0173]
79
1H-NMR (400MHz, CDCl3) δ1.20-1.35 (12H, m), 1.35-1.50 (1H, m), 1.90 (1H, m),
2.03-2.12 (1H, m), 2.14 (3H, s), 2.47-2.55 (1H, m), 3.02-3.15 and 3.44-3.86 (5H, m),
4.20-4.35 (4H, m), 4.81 (1H, m).
[0174]
[Example 11-4] Production of diethyl (5S)-1-acetyl-5-tert-butyldimethylsilyloxypiperidine-
2,2-dicarboxylate ester (a compound of the formula (7), wherein P = tertbutyldimethylsilyl
group, R3 = ethyl group, and A = methyl group)
In a 50-mL reactor, 2.10 g (pure content: 1.77 g, 4.05 mmol) of the crude
diethyl (3S)-2-acetylamino-2-[4-chloro-3-tert-butyldimethylsilyloxy-butyl]malonate
ester (a compound of the formula (6), wherein X = Cl, P = tert-butyldimethylsilyl
group, R3 = ethyl group, and A = methyl group) obtained in Example 7-3, 8.4 mL of
dimethylformamide and 3.96 g (12.15 mmol) of cesium carbonate were placed and
the mixture was stirred for 3 hours at 100°C. Toluene was added to this reaction
liquid and the resulting reaction liquid was washed with water, dried, then
concentrated, and purified by silica gel chromatography to obtain 1.18 g (pure
content: 1.13 g; yield: 70%) of diethyl (5S)-1-acetyl-5-tert-butyldimethylsilyloxypiperidine-
2,2-dicarboxylate ester (a compound of the formula (7), wherein P = tertbutyldimethylsilyl
group, R3 = ethyl group, and A = methyl group).
[0175]
1H-NMR (400MHz, CDCl3) δ0.09 (3H, s), 0.10 (3H, s), 0.90 (9H, s), 1.25-1.30 (6H,
m), 1.30-1.40 (1H, m), 1.75-1.85 (1H, m), 2.03-2.10 (1H, m), 2.15 (3H, s), 2.49-2.58
(1H, m), 3.02 (1H, dd, J=10.6, 12.1Hz), 3.58 (1H, dd, J=3.0, 12.1Hz), 3.83 (1H, m),
4.17-4.31 (4H, m).
[0176]
[Example 11-5] Production of diethyl (5S)-1-acetyl-5-tert-butyloxy-piperidine-2,2-
dicarboxylate ester (a compound of the formula (7), wherein P = tert-butyl group, R3
= ethyl group, and A = methyl group)
80
In a 50-mL reactor, 1.06 g (pure content: 0.95 g, 2.50 mmol) of the crude
(3S)-2-acetylamino-2-[4-chloro-3-tert-butyloxy-butyl]malonate diethyl ester (a
compound of the formula (6), wherein X = Cl, P = tert-butyl group, R3 = ethyl group,
and A = methyl group) obtained in Example 7-4, 4 mL of dimethylformamide and
2.44 g (7.50 mmol) of cesium carbonate were placed and the mixture was stirred for
4 hours at 100°C. Toluene was added to this reaction liquid and the resulting
reaction liquid was washed with water, dried, and then concentrated to obtain 0.73 g
(pure content: 0.64 g; yield: 75%) of diethyl (5S)-1-acetyl-5-tert-butyloxypiperidine-
2,2-dicarboxylate ester (a compound of the formula (7), wherein P = tertbutyl
group, R3 = ethyl group, and A = methyl group).
[0177]
1H-NMR (400MHz, CDCl3) δ1.22 (9H, s), 1.25-1.32 (6H, m), 1.35 (1H, m), 1.83-
1.87 (1H, m), 2.00-2.07 (1H, m), 2.15 (3H, s), 2.50-2.56 (1H, m), 2.85-2.91 (1H, m),
3.63-3.66 (2H, m), 4.20-4.27 (4H, m).
[0178]
[Example 11-6] Production of diethyl (5S)-1-benzoyl-5-(tetrahydropyran-2-yloxy)-
piperidine-2,2-dicarboxylate ester (a compound of the formula (7), wherein P =
tetrahydropyranyl group, R3 = ethyl group, and A = phenyl group)
In a 50-mL reactor, 3.09 g (6.57 mmol) of the crude diethyl (3S)-2-
benzoylamino-2-[4-chloro-3-(tetrahydropyran-2-yloxy)-butyl]malonate ester (a
compound of the formula (6), wherein X = Cl, P = tetrahydropyranyl group, and R3 =
ethyl group, and A = phenyl group) obtained in accordance with Example 8, 12 mL
of dimethylformamide and 6.42 g (19.71 mmol) of cesium carbonate were placed
and the mixture was stirred for 4.5 hours at 100°C. Toluene was added to this
reaction liquid and the resulting reaction liquid was washed with water, dried, then
concentrated, and purified by silica gel chromatography to obtain 2.08 g (pure
content: 1.88 g; yield: 66%) of diethyl (5S)-1-benzoyl-5-(tetrahydropyran-2-yloxy)-
81
piperidine-2,2-dicarboxylate ester (a compound of the formula (7), wherein P =
tetrahydropyranyl group, R3 = ethyl group, and A = phenyl group).
[0179]
1H-NMR (400MHz, CDCl3) δ1.23-1.35 (6H, m), 1.43-1.95 (8H, m), 2.20-2.31 (1H,
m), 2.57-2.69 (1H, m), 3.22-3.89 (5H, m), 4.22-4.32 (4H, m), 4.50 and 4.69 (1H, m)
7.40 (3H, m), 7.53-7.61 (2H, m).
[0180]
[Example 11-7] Production of diethyl (5S)-1-benzoyl-5-methoxymethyloxypiperidine-
2,2-dicarboxylate ester (a compound of the formula (7), wherein P =
methoxymethyl group, R3 = ethyl group, and A = phenyl group)
In a 50-mL reactor, 1.42 g (pure content: 1.10 g, 2.56 mmol) of the crude
diethyl (3S)-2-benzoylamino-2-[4-chloro-3-methoxymethyloxy)-butyl]malonate
ester (a compound of the formula (6), wherein X = Cl, P = methoxymethyl group, R3
= ethyl group, and A = phenyl group) obtained in accordance with Example 8-2, 5.2
mL of dimethylformamide and 2.50 g (7.68 mmol) of cesium carbonate were placed
and the mixture was stirred for 3 hours at 100°C. Toluene was added to this
reaction liquid and the resulting reaction liquid was washed with water, dried, and
then concentrated to obtain 0.99 g (pure content: 0.93 g; yield: 92%) of diethyl (5S)-
1-benzoyl-5-methoxymethyloxy-piperidine-2,2-dicarboxylate ester (a compound of
the formula (7), wherein P = methoxymethyl group, R3 = ethyl group, and A =
phenyl group).
[0181]
1H-NMR (400MHz, CDCl3) δ1.29-1.34 (6H, m), 1.58-1.68 (1H, m), 1.81-1.90 (1H,
m), 2.21-2.30 (1H, m), 2.55-2.65 (1H, m), 3.20-3.30 (1H, m), 3.28 (3H, s), 3.40 (1H,
m), 3.58 (1H, dd, J=3.2, 14.0Hz), 3.75 (1H, m), 4.20-4.39 (4H, m), 4.54 and 4.63
(1H, d, J=7.2Hz), 7.42 (3H, m), 7.55 (2H, m).
[0182]
82
[Example 11-8] Production of diethyl (5S)-1-benzoyl-5-(1-ethoxyethyloxy)-
piperidine-2,2-dicarboxylate ester (a compound of the formula (7), wherein P =
ethoxyethyl group, R3 = ethyl group, and A = phenyl group)
In a 50-mL reactor, 2.31 g (5.04 mmol) of the diethyl (3S)-2-
benzoylamino-2-[4-chloro-3-(1-ethoxyethyloxy)-butyl]malonate ester (a compound
of the formula (6), wherein X = Cl, P = ethoxyethyl group, R3 = ethyl group, and A =
phenyl group) obtained in Example 8-3, 9.2 mL of dimethylformamide and 4.93 g
(15.12 mmol) of cesium carbonate were placed and the mixture was stirred for 5
hours at 100°C. Toluene was added to this reaction liquid and the resulting reaction
liquid was washed with water, dried, and then concentrated to obtain 0.92 g of
diethyl (5S)-1-benzoyl-5-(1-ethoxyethyloxy)-piperidine-2,2-dicarboxylate ester (a
compound of the formula (7), wherein P = ethoxyethyl group, R3 = ethyl group, and
A = phenyl group) (yield: 43%).
[0183]
1H-NMR (400MHz, CDCl3) δ0.99-1.10 (3H, m), 1.17-1.35 (9H, m), 1.45-1.60 (1H,
m), 1.83-1.92 (1H, m), 2.18-2.26 (1H, m), 2.57-2.65 (1H, m), 3.11 (1H, m), 4.20-
4.33 (4H, m), 4.61 and 4.73 (1H, m), 7.40 (3H, m), 7.52 (2H, m).
[0184]
[Example 11-9] Production of diethyl (5S)-1-benzoyl-5-tert-butyldimethylsilyloxypiperidine-
2,2-dicarboxylate ester (a compound of the formula (7), wherein P = tertbutyldimethylsilyl
group, R3 = ethyl group, and A = phenyl group)
In a 50-mL reactor, 2.68 g (pure content: 1.95 g, 3.91 mmol) of the diethyl
(3S)-2-benzoylamino-2-[4-chloro-3-tert-butyldimethylsilyloxy-butyl]malonate ester
(a compound of the formula (6), wherein X = Cl, P = tert-butyldimethylsilyl group,
R3 = ethyl group, and A = phenyl group) obtained in Example 8-4, 10.7 mL of
dimethylformamide, 3.82 g of cesium carbonate (11.73 mmol) were placed and the
mixture was stirred for 3 hours at 100°C. Toluene was added to this reaction liquid
83
and the resulting reaction liquid was washed with water, dried, then concentrated,
and purified by silica gel chromatography to obtain 1.70 g (pure content: 1.45 g;
yield: 80%) of diethyl (5S)-1-benzoyl-5-tert-butyldimethylsilyloxy-piperidine-2,2-
dicarboxylate ester (a compound of the formula (7), wherein P = tertbutyldimethylsilyl
group, R3 = ethyl group, and A = phenyl group).
[0185]
1H-NMR (400MHz, CDCl3) δ0.02 (3H, s), 0.03 (3H, s), 0.90 (9H, s), 1.32 (6H, m),
1.50-1.59 (1H, m), 1.77-1.85 (1H, m), 2.20-2.30 (1H, m), 2.62-2.70 (1H, m), 3.16
(1H, dd, J=6.9, 12.0Hz), 3.50 (1H,dd, J=1.7, 13.7Hz), 3.83 (1H, m), 4.23-4.37 (4H,
m), 4.65 (1H, m), 7.42 (3H, m), 7.58 (2H, m).
[0186]
[Example 11-10] Production of diethyl (5S)-1-benzoyl-5-tert-butyloxy-piperidine-
2,2-dicarboxylate ester (a compound of the formula (7), wherein P = tert-butyl group,
R3 = ethyl group, and A = phenyl group)
In a 50-mL reactor, 1.24 g (pure content: 1.10 g, 2.50 mmol)of the diethyl
(3S)-2-benzoylamino-2-[4-chloro-3-tert-butyloxy-butyl]malonate ester (a compound
of the formula (6), wherein X = Cl, P = tert-butyl group, R3 = ethyl group, and A =
phenyl group) obtained in Example 8-5, 5 mL of dimethylformamide and 2.44 g
(7.50 mmol) of cesium carbonate were placed and the mixture was stirred for 4 hours
at 100°C. Toluene was added to this reaction liquid and the resulting reaction
liquid was washed with water, dried, and then concentrated to obtain 1.06 g (pure
content: 0.84 g; yield: 83%) of diethyl (5S)-1-benzoyl-5-tert-butyloxy-piperidine-
2,2-dicarboxylate ester (a compound of the formula (7), wherein P = tert-butyl group,
R3 = ethyl group, and A = phenyl group).
[0187]
84
1H-NMR (400MHz, CDCl3) δ1.11 (9H, s), 1.28-1.33 (6H, m), 1.42 (1H, m), 1.80-
1.86 (1H, m), 2.17-2.24 (1H, m), 2.60-2.66 (1H, m), 2.94-2.99 (1H, m), 3.56-3.63
(2H, m), 4.26-4.31 (4H, m), 7.38-7.43 (3H, m), 7.54 (2H, m).
[0188]
[Example 12-1] Production of diethyl (5S)-1-acetyl-5-hydroxy-piperidine-2,2-
dicarboxylate ester (a compound of the formula (8), wherein R3 = ethyl group and A
= methyl group)
In a 100-mL reactor, 4.18 g (10.68 mmol) of the crude diethyl (5S)-1-
acetyl-5-(tetrahydropyran-2-yloxy)-piperidine-2,2-dicarboxylate ester (a compound
of the formula (7), wherein P = tetrahydropyranyl group, R3 = ethyl group, and A =
methyl group) obtained in Example 10, 20 mL of methanol and 19 μL of
concentrated hydrochloric acid were placed and the mixture was stirred for 4 hours at
room temperature. The reaction was stopped by adding 45 μL of triethylamine to
this reaction liquid and methanol was concentrated under vacuum to obtain 3.7 g of
an oily substance. Next, this oily substance was dissolved in 20 mL of toluene, 10
mL of n-heptane was added thereto at room temperature for crystallization and
another 10 mL of n-heptane was added thereto to allow crystallization to proceed
aging at room temperature, and then the crystals were filtered, washed with nheptane,
and dried to obtain 2.30 g of diethyl (5S)-1-acetyl-5-hydroxy-piperidine-
2,2-dicarboxylate ester (a compound of the formula (8), wherein R3 = ethyl group
and A = methyl group) (yield: 75%).
[0189]
1H-NMR (400MHz, CDCl3) δ1.20-1.30 (6H, m), 1.40-1.52 (1H, m), 1.80-1.90 (1H,
m), 2.09-2.15 (1H, m), 2.15 (3H, s), 2.40-2.50 (1H, m), 3.23 (1H, dd, J=7.6, 14.4Hz),
3.57 (1H, dd, J=4.8, 12.8Hz), 3.92 (1H, m), 4.17-4.32 (4H, m).
[0190]
85
[Example 12-2] Production of diethyl (5S)-1-acetyl-5-hydroxy-piperidine-2,2-
dicarboxylate ester (a compound of the formula (8), wherein R3 = ethyl group and A
= methyl group)
In a 50-mL reactor, 1.45 g (pure content: 1.28 g, 3.57 mmol) of the crude
diethyl (5S)-1-acetyl-5-(1-ethoxyethyloxy)-piperidine-2,2-dicarboxylate ester (a
compound of the formula (7), wherein P = ethoxyethyl group, R3 = ethyl group, and
A = methyl group) obtained in Example 11-3, 7.25 mL of methanol and 10 μL of
concentrated hydrochloric acid were placed and the mixture was stirred for 4 hours at
room temperature. This reaction liquid was concentrated under vacuum and
purified by silica gel chromatography to obtain 0.79 g of diethyl (5S)-1-acetyl-5-
hydroxy-piperidine-2,2-dicarboxylate ester (a compound of the formula (8), wherein
R3 = ethyl group and A = methyl group) (yield: 77%).
[0191]
[Example 12-3] Production of diethyl (5S)-1-acetyl-5-hydroxy-piperidine-2,2-
dicarboxylate ester (a compound of the formula (8), wherein R3 = ethyl group and A
= methyl group)
In a 10-mL reactor, 355 mg (pure content: 342 mg, 0.85 mmol) of the crude
(5S)-1-acetyl-5-tert- butyldimethylsilyloxy-piperidine-2,2-dicarboxylate diethyl ester
(a compound of the formula (7), wherein P = tert-butyldimethylsilyl group, R3 =
ethyl group, and A = methyl group) obtained in Example 11-4, 2 mL of methanol
and 20 μL of 20% hydrochloric acid were placed and the mixture was stirred for 28.5
hours at room temperature. This reaction liquid was concentrated under vacuum
and purified by silica gel chromatography to obtain 171 mg of diethyl (5S)-1-acetyl-
5-hydroxy-piperidine-2,2-dicarboxylate ester (a compound of the formula (8),
wherein R3 = ethyl group and A = methyl group) (yield: 70%).
[0192]
86
[Example 12-4] Production of diethyl (5S)-1-acetyl-5-hydroxy-piperidine-2,2-
dicarboxylate ester (a compound of the formula (8), wherein R3 = ethyl group and A
= methyl group)
In a 10-mL reactor, 0.30 mg (pure content: 0.26 g, 0.77 mmol) of the crude
diethyl (5S)-1-acetyl-5-tert-butyloxy-piperidine-2,2-dicarboxylate ester (a compound
of the formula (7), wherein P = tert-butyl group, R3 = ethyl group, and A = methyl
group) obtained in Example 11-5, 1 mL of toluene and 0.5 mL of trifluoroacetic acid
were placed and the mixture was stirred for 48.5 hours at room temperature. To this
reaction liquid, 1 mL of triethylamine was added, and the resulting reaction liquid
was purified by silica gel chromatography to obtain 0.14 g of diethyl (5S)-1-acetyl-5-
hydroxy-piperidine-2,2-dicarboxylate ester (a compound of the formula (8), wherein
R3 = ethyl group and A = methyl group) (yield: 64%).
[0193]
[Example 12-5] Production of diethyl (5S)-1-benzoyl-5-hydroxy-piperidine-2,2-
dicarboxylate ester (a compound of the formula (8), wherein R3 = ethyl group and A
= phenyl group)
In a 50-mL reactor, 2.08 g (pure content: 1.88 g, 4.33 mmol) of the crude
diethyl (5S)-1-benzoyl-5-(tetrahydropyran-2-yloxy)-piperidine-2,2-dicarboxylate
ester (a compound of the formula (7), wherein P = tetrahydropyranyl group, R3 =
ethyl group, and A = phenyl group) obtained in Example 11-6, 10 mL of methanol
and 20 μL of concentrated hydrochloric acid were placed and the mixture was stirred
for 6 hours at room temperature. The reaction was stopped by adding 100 μL of
triethylamine to this reaction liquid, and methanol was concentrated under vacuum,
and the resulting mixture was purified by silica gel chromatography to obtain 1.59 g
(pure content: 1.46 g; yield: 97%) of diethyl (5S)-1-benzoyl-5-hydroxy-piperidine-
2,2-dicarboxylate ester (a compound of the formula (8), wherein R3 = ethyl group
and A = phenyl group).
87
[0194]
1H-NMR (400MHz, CDCl3) δ1.29-1.35 (6H, m), 1.50-1.65 (1H, m), 1.82-1.90 (1H,
m), 2.05 (1H, brs), 2.25-2.33 (1H, m), 2.56-2.62 (1H, m), 3.30 (1H, dd, J=6.8,
13.6Hz), 3.50 (1H, dd, J=3.2, 14.0Hz), 3.89 (1H, m), 4.21-4.38 (4H, m), 7.42 (3H,
m), 7.52 (2H, m).
[0195]
[Example 12-6] Production of diethyl (5S)-1-benzoyl-5-hydroxy-piperidine-2,2-
dicarboxylate ester (a compound of the formula (8), wherein R3 = ethyl group and A
= phenyl group)
In a 50-mL reactor, 0.38 g (pure content: 0.36 g, 0.92 mmol) of the crude
diethyl (5S)-1-benzoyl-5-methoxymethyloxy-piperidine-2,2-dicarboxylate ester (a
compound of the formula (7), wherein P = methoxymethyl group, R3 = ethyl group,
and A = phenyl group) obtained in Example 11-7, 5 mL of methanol and 50 μL of
concentrated hydrochloric acid were placed and the mixture was stirred for 4.5 hours
at 70°C. This reaction liquid was concentrated under vacuum to obtain 0.30 g (pure
content: 0.29 g; yield: 91%) of diethyl (5S)-1-benzoyl-5-hydroxy-piperidine-2,2-
dicarboxylate ester (a compound of the formula (8), wherein R3 = ethyl group and A
= phenyl group).
[0196]
[Example 12-7] Production of diethyl (5S)-1-benzoyl-5-hydroxy-piperidine-2,2-
dicarboxylate ester (a compound of the formula (8), wherein R3 = ethyl group and A
= phenyl group)
In a 50-mL reactor, 0.86 g (2.03 mmol) of the crude diethyl (5S)-1-
benzoyl-5-(1-ethoxyethyloxy)-piperidine-2,2-dicarboxylate ester (a compound of the
formula (7), wherein P = ethoxyethyl group, R3 = ethyl group, and A = phenyl group)
obtained in Example 11-8, 4 mL of methanol and 10 μL of concentrated hydrochloric
acid were placed and the mixture was stirred for 4 hours at room temperature. The
88
reaction was stopped by adding 100 μL of triethylamine to this reaction liquid, and
methanol was concentrated under vacuum, and the resulting mixture was purified by
silica gel chromatography to obtain 0.68 g (pure content: 0.60 g; yield: 85%) of
diethyl (5S)-1-benzoyl-5-hydroxy-piperidine-2,2-dicarboxylate ester (a compound of
the formula (8), wherein R3 = ethyl group and A = phenyl group).
[0197]
[Example 12-8] Production of diethyl (5S)-1-benzoyl-5-hydroxy-piperidine-2,2-
dicarboxylate ester (a compound of the formula (8), wherein R3 = ethyl group and A
= phenyl group)
In a 50-mL reactor, 383 mg (pure content: 327 mg, 0.71 mmol) of the crude
(5S)1-benzoyl-5-tert-butyldimethylsilyloxy-piperidine-2,2-dicarboxylate diethyl
ester (a compound of the formula (7), wherein P = tert-butyldimethylsilyl group, R3
= ethyl group, and A = phenyl group) obtained in Example 11-9, 2 mL of methanol
and 50 μL of 20% hydrochloric acid were placed and the mixture was stirred for 28.5
hours at room temperature. Then, methanol was concentrated under vacuum and
the resulting mixture was purified by silica gel chromatography to obtain 269 mg
(pure content: 226 mg; yield: 91%) of diethyl (5S)-1-benzoyl-5-hydroxy-piperidine-
2,2-dicarboxylate ester (a compound of the formula (8), wherein R3 = ethyl group
and A = phenyl group).
[0198]
[Example 12-9] Production of diethyl (5S)-1-benzoyl-5-hydroxy-piperidine-2,2-
dicarboxylate ester (a compound of the formula (8), wherein R3 = ethyl group and A
= phenyl group)
In a 50-mL reactor, 0.29 g (pure content: 0.23 g, 0.57 mmol) of the crude
diethyl (5S)-1-benzoyl-5-tert-butyloxy-piperidine-2,2-dicarboxylate ester (a
compound of the formula (7), wherein P = tert-butyl group, R3 = ethyl group, and A
= phenyl group) obtained in Example 11-10, 1 mL of toluene and 0.5 mL of
89
trifluoroacetic acid were placed and the mixture was stirred for 48.5 hours at room
temperature. Then, ethyl acetate was added thereto and the resulting mixture was
washed with saturated aqueous sodium bicarbonate solution, concentrated, and
purified by silica gel chromatography to obtain 0.03 g of diethyl (5S)-1-benzoyl-5-
hydroxy-piperidine-2,2-dicarboxylate ester (a compound of the formula (8), wherein
R3 = ethyl group and A = phenyl group) (yield: 15%).
[0199]
[Example 13] Production of (2S,5S)-5-acetyl-2-oxa-5-azabicyclo[2.2.2]octan-3-one
(a compound of the formula (9), wherein A = methyl group)
In a 200-mL reactor, 8.7 g (23.45 mmol) of the crude diethyl (5S)-1-acetyl-
5-(tetrahydropyran-2-yloxy)-piperidine-2,2-dicarboxylate ester (a compound of the
formula (7), wherein P = tetrahydropyranyl group, R3 = ethyl group, and A = methyl
group) obtained in Example 10, 44 mL of methanol, 43.5 mL of toluene and 0.24 g
of 35% hydrochloric acid were placed and the mixture was stirred for 3 hours at
room temperature to obtain a solution of diethyl (5S)-1-acetyl-5-hydroxypiperidine-
2,2-dicarboxylate ester (a compound of the formula (8), wherein R3 = ethyl group
and A = methyl group) in methanol and toluene. To this reaction liquid, 3.75 g of
sodium hydroxide was added and the mixture was stirred for 3 hours, and methanol
was evaporated under vacuum to obtain a toluene solution. Next, 21.1 g of acetic
acid and 12.0 g of acetic anhydride were added to this solution and the mixture was
stirred for 1 hour at 50°C, 0.47 g of triethylamine was further added thereto, and the
mixture was heated to 70°C and stirred for 5 hours. This reaction liquid was cooled
down to 30°C and 15 mL of toluene was added thereto for deposition and the
deposited sodium acetate was removed by filtration, and the filtrate was concentrated
to obtain 2.83 g of (2S,5S)-5-acetyl-2-oxa-5-azabicyclo[2.2.2]octan-3-one (a
compound of the formula (9), wherein A = methyl group) (yield: 96%).
[0200]
90
1H-NMR (400MHz, CDCl3) δ1.78-2.23 (4H, m), 2.06 and 2.12 (3H, s), 3.55 (1H, t,
J=12.4Hz), 3.65-3.77 (1H, m), 4.38 and 5.19 (1H, m), 4.83-4.90 (1H, m).
[0201]
[Example 14-1] Production of (2S,5S)-5-acetyl-2-oxa-5-azabicyclo[2.2.2]octan-3-one
(a compound of the formula (9), wherein A = methyl group)
In a 500-mL reactor, 38.1 g (132.8 mmol) of the diethyl (5S)-1-acetyl-5-
hydroxypiperidine-2,2-dicarboxylate ester (a compound of the formula (8), wherein
R3 = ethyl group and A = methyl group) obtained in Example 12, 190 mL of
methanol and 21.2 g of sodium hydroxide were placed and the mixture was stirred
for 3 hours at 50°C to obtain a solution of (5S)-1-acetyl-5-hydroxypiperidine-2,2-
dicarboxylic acid disodium salt (compound (8) (a compound with R3 = Na and A =
methyl group) in methanol. To this reaction liquid, 119.5 g of acetic acid and 1.3 g
of triethylamine were added and the mixture was stirred for 1 hour at 95°C to obtain
a mixture of diastereomers of (5S)-1-acetyl-5-hydroxypiperidine-2-carboxylic acid
(compounds (11c, 11d)) in a mixed solution of acetic acid and methanol.
[0202]
(2R,5S)-1-acetyl-5-hydroxypiperidine-2-carboxylic acid
1H-NMR (400MHz, D2O) δ1.50-1.70 (2H, m), 1.85-2.10 (2H, m) 2.03 and 2.10 (3H,
s), 2.81 (0.3H, d, J=8.9Hz), 3.35 (0.7H, d, J=8.9Hz), 3.75 (0.7H, d, J=8.9Hz), 3.98
(1H, m), 4.26 (0.3H, d, J=8.9Hz), 4.66 (0.3H, m), 5.08 (0.7H, m)
[0203]
(2S,5S)-1-acetyl-5-hydroxypiperidine-2-carboxylic acid
1H-NMR (400MHz, D2O) δ1.23-1.36 (1H, m), 1.59-1.81 (1H, m), 1.98 (1H, m), 2.10
and 2.19 (3H, s), 2.24-2.36 (1H, m), 2.54 (0.4H, t, J=12.6Hz), 3.03 (0.6H, dd, J=10.7
and 13.3Hz), 3.55-3.65 (0.6H, m), 3.67-3.76 (0.8H, m), 3.92 (0.6H, dd, J=5.3 and
13.3Hz), 4.44 (0.6H, m), 4.47 (0.4H, m), 4.94 (0.6H, m)
[0204]
91
Next, methanol was evaporated under vacuum from the solution and 108 g
of acetic anhydride was added thereto and the mixture was stirred for 3 hours at
100°C. This reaction liquid was cooled down to 30°C and 190 mL of toluene was
added thereto. The deposited sodium acetate was removed by filtration and the
filtrate was concentrated to obtain 2.83 g of crude (2S,5S)-5-acetyl-2-oxa-5-
azabicyclo[2.2.2]octan-3-one (a compound of the formula (9), wherein A = methyl
group) (yield: 72%).
[0205]
[Example 14-2] Production of (2S,5S)-5-benzoyl-2-oxa-5-azabicyclo[2.2.2]octan-3-
one (a compound of the formula (9), wherein A = phenyl group)
In a 30-mL reactor, 1.29 g (3.68 mmol) of the diethyl (5S)1-benzoyl-5-
hydroxypiperidine-2,2-dicarboxylate ester (a compound of the formula (8), wherein
R3 = ethyl group and A = phenyl group) obtained in accordance with Example 12-5,
6.5 mL of methanol and 0.29 g (7.36 mmol) of sodium hydroxide were placed and
the mixture was heated to reflux for 2 hours and further heated for 14.5 hours after
the addition of 0.15 g (3.68 mmol) of sodium hydroxide. Then, the mixture was
adjusted on ice to pH 1 with aqueous sulfuric acid solution and the produced
inorganic salt was removed by filtration. The mixture was adjusted to pH 2 by
addition of sodium acetate and subsequently methanol and water were concentrated
to obtain a mixture of diastereomers of (5S)-1-benzoyl-5-hydroxypiperidine-2-
carboxylic acid (compounds (11e, 11f)) in a white solid.
[0206]
(2R,5S)-1-benzoyl-5-hydroxypiperidine-2-carboxylic acid
1H-NMR (400MHz, D2O) δ1.33-1.85 (2H, m), 2.20 (2H, m), 3.12 (0.5H, d,
J=15.0Hz), 3.40 (0.5H, m), 3.50-3.90 (1H, m), 4.09 (0.5H, brs), 4.47 (0.5H, m), 4.60
(0.5H, d, J=15.0Hz), 5.46 (0.5H, m), 7.40-7.50 (5H, m).
[0207]
92
(2S,5S)-1-benzoyl-5-hydroxypiperidine-2-carboxylic acid
1H-NMR (400MHz, D2O) δ1.33-1.46 (1H, m), 1.65 (0.4H, m), 1.81 (0.6H, m), 2.02
(1H, m), 2.30 (0.4H, m), 2.43 (0.6H, m), 2.72 (0.4H, t, J=12.0Hz), 3.03 (0.6H, t,
J=12.0Hz), 3.58 (0.6H, m), 3.65 (0.4H, m), 3.80 (0.6H, m), 4.40 (0.4H, m), 4.65
(0.4H, m), 5.40 (0.6H, m), 7.40 (5H, m).
[0208]
Next, 1.32 mL of acetic acid (22.08 mmol), 5.2 mL of toluene, 0.04 g (0.37
mmol) of triethylamine and 0.57 g (6.38 mmol) of acetic anhydride were added to
the white solid and the mixture was stirred for 2.5 hours at 90°C. This reaction
liquid was concentrated and toluene was added thereto. The deposited sodium
acetate was removed by filtration, and the filtrate was concentrated and purified by
silica gel chromatography to obtain 0.76 g (pure content: 0.65 g; yield: 76%) of
(2S,5S)-5-benzoyl-2-oxa-5-azabicyclo[2.2.2]octan-3-one (a compound of the formula
(9), wherein A = phenyl group).
[0209]
1H-NMR (400MHz, CDCl3) δ1.88-2.30 (4H, m), 3.70 (1H, m), 3.90 (1H, m), 4.45
and 4.79 (1H, brs), 4.98 and 5.27 (1H, brs), 7.45 (5H, m).
[0210]
[Example 15] Production of (2S,5S)-5-hydroxypiperidine-2-carboxylic acid (the
compound (10))
In a 200-mL reactor, 6.36 g (37.59 mmol) of the crude (2S,5S)-5-acetyl-2-
oxa-5-azabicyclo[2.2.2]octan-3-one (a compound of the formula (9), wherein A =
methyl group) obtained in Example 13 and 93.98 mL (187.97 mmol) of 2 mol/L
hydrochloric acid were placed and the mixture was stirred for 3 hours at 90°C. This
reaction liquid was concentrated and then dissolved again in water (42.9 mL) and
allowed to be adsorbed on strong acidic cation exchange resin (88.69 mL). The
resin was washed with water and then elution was performed with ammonia water
93
and the eluted fraction was concentrated to obtain crude (2S,5S)-5-hydroxypiperidine-
2-carboxylic acid (the compound (10)).
[0211]
The obtained crude (2S,5S)-5-hydroxy-piperidine-2-carboxylic acid (the
compound (10)) was dissolved in water (10 mL) and 0.26 g of activated charcoal was
added thereto and the mixture was stirred for 2 hours at 40°C. The reaction liquid
was filtered and then concentrated, and ethanol was added to the residue to obtain
crude crystals, and the obtained crystals were further recrystallized with
water/ethanol/acetone to obtain 1.61 g of (2S,5S)-5-hydroxy-piperidine-2-carboxylic
acid (the compound (10)) (purity: 96%; yield: 28%).
[0212]
1H-NMR (400MHz, CD3OD) δ1.73-1.90 (2H, m), 2.03-2.10 (2H, m), 3.09 (1H, dd,
J=2.4, 12.8Hz), 3.17-3.23 (1H, m), 3.45 (1H, m), 4.02 (1H, m).
[0213]
[Example 16-1] Production of (2S,5S)-5-hydroxypiperidine-2-carboxylic acid (the
compound (10))
In a 1000-mL reactor, 18 g of an aqueous acetic acid solution containing
11.31 g (66.90 mmol) of the crude (2S,5S)-5-acetyl-2-oxa-5-azabicyclo[2.2.2]octan-
3-one (in the formula (9), A = methyl group) prepared in accordance with Example
13 and 121 mL of 2 mol/L hydrochloric acid were placed and the mixture was stirred
for 3 hours at 90°C. To this reaction liquid, 1.2 g of activated charcoal was added
and the mixture was stirred for 1 hour at 45°C, and then the activated charcoal was
filtered and the filtrate was concentrated to obtain 20.5 g of a residue. Then, this
residue was dissolved in 50 mL of water and 175 mL of DIAION®SAT10L (acetate
anion type) resin was added thereto and the mixture was stirred for 30 minutes at
room temperature and then filtered, and the filtrate was concentrated to obtain 16.5 g
of a residue. Then, 2.1 mL of water and 70 mL of ethanol were added to this
94
residue for crystallization at 60°C and the crystals were filtered at room temperature
and dried to obtain 8.0 g of crude crystals of (2S,5S)-5-hydroxy-piperidine-2-
carboxylic acid (the compound (10)) (purity: 93%; yield: 77%).
[0214]
[Example 16-2] Production of (2S,5S)-5-hydroxypiperidine-2-carboxylic acid
hydrochloride (a hydrochloride of the compound (10))
In a 10-mL reactor, 0.43 g (pure content: 0.36 g, 1.58 mmol) of the (2S,5S)-5-
benzoyl-2-oxa-5-azabicyclo[2.2.2]octan-3-one (in the formula (9), A = phenyl group)
obtained in Example 14-2, 1.5 mL of water and 0.50 g of 35% hydrochloric acid
were placed and the mixture was stirred for 15 hours at 100°C. The deposited
benzoic acid was removed by filtration and 11.38 g of the obtained filtrate was
subjected to the quantification by HPLC. Consequently, it was indicated that the
filtrate contained 1.50 mmol of (2S,5S)-5-hydroxypiperidine-2-carboxylic acid
hydrochloride (yield: 95%).
95
CLAIMS
1. A method for producing (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic
acid represented by the formula (10) below:
the method comprising (i) the step 4 of:
removing the protecting group from the hydroxyl group in a compound
represented by the formula (7) below:
(wherein P represents a protecting group, R3 represents an alkyl group containing 1
to 4 carbon atoms, and A represents an alkyl group containing 1 to 10 carbon atoms,
an aryl group containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to 4
carbon atoms, or an aralkyloxy group containing 7 to 20 carbon atoms)
to synthesize a compound represented by the formula (8) below:
96
(wherein R3 represents an alkyl group containing 1 to 4 carbon atoms, and A
represents an alkyl group containing 1 to 10 carbon atoms, an aryl group containing 6
to 12 carbon atoms, an alkyloxy group containing 1 to 4 carbon atoms, or an
aralkyloxy group containing 7 to 20 carbon atoms).
2. The method for producing (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-
carboxylic acid according to claim 1, the method further comprising (ii) the step 5 of:
(a) in the compound (8), hydrolyzing the ester groups, allowing one of the carboxyl
groups to react with the hydroxyl group to allow the lactonization, and further
decarboxylating the other carboxyl group; or
(b) in the compound (8), hydrolyzing the ester groups, decarboxylating one of the
carboxyl groups to form a stereoisomeric mixture of a 2-monocarboxylic acid, and
then isomerizing and lactonizing the stereoisomeric mixture;
to synthesize a compound represented by the formula (9) below:
(wherein A represents an alkyl group containing 1 to 10 carbon atoms, an aryl group
containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to 4 carbon atoms,
or an aralkyloxy group containing 7 to 20 carbon atoms).
3. The method for producing (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-
carboxylic acid according to claim 1 or 2, further comprising (iii) the step 6 of:
97
cleaving the amide bond in the compound (9) and hydrolyzing the lactone
in the compound (9) to synthesize (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic
acid.
4. The method for producing (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-
carboxylic acid according to claim 2 or 3, wherein the step of decarboxylating the
carboxyl group in the step 5(a) or the step 5(b) is performed in the presence of an
organic base.
5. A method for producing the compound represented by the formula (7)
below:
(wherein P represents a protecting group, R3 represents an alkyl group containing 1
to 4 carbon atoms, and A represents an alkyl group containing 1 to 10 carbon atoms,
an aryl group containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to 4
carbon atoms, or an aralkyloxy group containing 7 to 20 carbon atoms),
the method comprising the step 1 of:
protecting the hydroxyl group with a protecting group in a compound
represented by the formula (1) below:
98
(wherein X represents Cl, Br, or I, and R1 represents a hydrogen atom or an
optionally substituted alkyl group containing 1 to 4 carbon atoms)
to synthesize a compound represented by the formula (2) below:
(wherein X represents Cl, Br, or I, R1 represents a hydrogen atom or an optionally
substituted alkyl group containing 1 to 4 carbon atoms, and P represents a protecting
group)
and then reducing the ester group in the compound (2) to synthesize a
compound represented by the formula (3) below:
(wherein X represents Cl, Br, or I, and P represents a protecting group).
6. The method for producing the compound (7) according to claim 5, wherein
the method comprises (i) the step 2 of:
esterifying the hydroxyl group in the compound (3) with a sulfonate group
to synthesize a compound represented by the formula (4) below:
(wherein X represents Cl, Br, or I, R2 represents an aryl group containing 6 to 12
carbon atoms, an alkyl group containing 1 to 10 carbon atoms, or an aralkyl group
containing 7 to 20 carbon atoms)
99
and allowing the compound (4) to react with a compound represented by the formula
(5) below:
(wherein R3 represents an alkyl group containing 1 to 4 carbon atoms, and A
represents an alkyl group containing 1 to 10 carbon atoms, an aryl group containing 6
to 12 carbon atoms, an alkyloxy group containing 1 to 4 carbon atoms, or an
aralkyloxy group containing 7 to 20 carbon atoms)
to synthesize a compound represented by the formula (6) below:
(wherein X represents Cl, Br, or I, P represents a protecting group, R3 represents an
alkyl group containing 1 to 4 carbon atoms, and A represents an alkyl group
containing 1 to 10 carbon atoms, an aryl group containing 6 to 12 carbon atoms, an
alkyloxy group containing 1 to 4 carbon atoms, or an aralkyloxy group containing 7
to 20 carbon atoms);
and
(ii) the step 3 of:
cyclizing the compound (6) to synthesize the compound represented by the
formula (7) below:
100
(wherein P represents a protecting group, R3 represents an alkyl group containing 1
to 4 carbon atoms, and A represents an alkyl group containing 1 to 10 carbon atoms,
an aryl group containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to 4
carbon atoms, or an aralkyloxy group containing 7 to 20 carbon atoms).
7. The method for producing the compound (7) according to claim 6, wherein
the reaction of the compound (4) with the compound (5) in the step 2 is performed in
the presence of an iodide salt.
8. The method for producing the compound (7) according to claim 6 or 7,
wherein the cyclizing reaction of the compound (6) in the step 3 is performed in the
presence of a quaternary ammonium salt.
9. The method for producing (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-
carboxylic acid according to any one of claims 1 to 4, wherein the compound (7) is
synthesized by the method according to any one of claims 5 to 8.
10. A method for producing the compound represented by the formula (8), the
method comprising (i) the step 4 of:
removing the protecting group from the hydroxyl group in the compound
represented by the formula (7) below:
101
(wherein P represents a protecting group, R3 represents an alkyl group containing 1
to 4 carbon atoms, and A represents an alkyl group containing 1 to 10 carbon atoms,
an aryl group containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to 4
carbon atoms, or an aralkyloxy group containing 7 to 20 carbon atoms)
to synthesize the compound represented by the formula (8) below:
(wherein R3 represents an alkyl group containing 1 to 4 carbon atoms, and A
represents an alkyl group containing 1 to 10 carbon atoms, an aryl group containing 6
to 12 carbon atoms, an alkyloxy group containing 1 to 4 carbon atoms, or an
aralkyloxy group containing 7 to 20 carbon atoms).
11. A method for producing the compound represented by the formula (9), the
method comprising
(i) the step 4 of:
removing the protecting group from the hydroxyl group in the compound represented
by the formula (7) below:
102
(wherein P represents a protecting group, R3 represents an alkyl group containing 1
to 4 carbon atoms, and A represents an alkyl group containing 1 to 10 carbon atoms,
an aryl group containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to 4
carbon atoms, or an aralkyloxy group containing 7 to 20 carbon atoms)
to synthesize the compound represented by the formula (8) below:
(wherein R3 represents an alkyl group containing 1 to 4 carbon atoms, and A
represents an alkyl group containing 1 to 10 carbon atoms, an aryl group containing 6
to 12 carbon atoms, an alkyloxy group containing 1 to 4 carbon atoms, or an
aralkyloxy group containing 7 to 20 carbon atoms)
and (ii) the step 5 of:
(a) in the compound (8), hydrolyzing the ester groups, allowing one of the carboxyl
groups to react with the hydroxyl group to allow the lactonization, and further
decarboxylating the other carboxyl group; or
(b) in the compound (8), hydrolyzing the ester groups, decarboxylating one of the
carboxyl groups to form a stereoisomeric mixture of a 2-monocarboxylic acid, and
then isomerizing and lactonizing the stereoisomeric mixture;
to synthesize the compound represented by the formula (9) below:
103
(wherein A represents an alkyl group containing 1 to 10 carbon atoms, an aryl group
containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to 4 carbon atoms,
or an aralkyloxy group containing 7 to 20 carbon atoms).
12. A compound represented by the formula (9a) below:
(wherein A’ represents an alkyl group containing 1 to 10 carbon atoms or an aryl
group containing 6 to 12 carbon atoms).
13. A compound or a salt thereof, the compound represented by the formula
(11a) below:
(wherein A’ represents an alkyl group containing 1 to 10 carbon atoms or an aryl
group containing 6 to 12 carbon atoms)
or the formula (11b) below:
104
(wherein A’ represents an alkyl group containing 1 to 10 carbon atoms or an aryl
group containing 6 to 12 carbon atoms).
14. A compound represented by the formula (8) below or a dicarboxylic acid
salt thereof:
(wherein R3 represents an alkyl group containing 1 to 4 carbon atoms, and A
represents an alkyl group containing 1 to 10 carbon atoms, an aryl group containing 6
to 12 carbon atoms, an alkyloxy group containing 1 to 4 carbon atoms, or an
aralkyloxy group containing 7 to 20 carbon atoms).
15. A compound represented by the formula (7) below:
(wherein P represents a protecting group, R3 represents an alkyl group containing 1
to 4 carbon atoms, and A represents an alkyl group containing 1 to 10 carbon atoms,
105
an aryl group containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to 4
carbon atoms, or an aralkyloxy group containing 7 to 20 carbon atoms).
16. A compound represented by the formula (6a) below:
(wherein X represents Cl, Br, or I, P’ represents a tetrahydropyranyl group,
methoxymethyl group, ethoxyethyl group, tert-butyl group, or tert-butyldimethylsilyl
group, and R3 represents an alkyl group containing 1 to 4 carbon atoms, and A
represents an alkyl group containing 1 to 10 carbon atoms, an aryl group containing 6
to 12 carbon atoms, an alkyloxy group containing 1 to 4 carbon atoms, or an
aralkyloxy group containing 7 to 20 carbon atoms).
17. A compound represented by the formula (4a) below:
(wherein X represents Cl, Br, or I, P’ represents a tetrahydropyranyl group,
methoxymethyl group, ethoxyethyl group, tert-butyl group, or tert-butyldimethylsilyl
group, and R2 represents an alkyl group containing 1 to 10 carbon atoms, an aryl
group containing 6 to 12 carbon atoms, or an aralkyl group containing 7 to 20 carbon
atoms).
18. A compound represented by the formula (3a) below:
106
(wherein X represents Cl, Br, or I, and P’ represents a tetrahydropyranyl group,
methoxymethyl group, ethoxyethyl group, tert-butyl group, or tert-butyldimethylsilyl
group).
19. A compound represented by the formula (2a) below:
(wherein X represents Cl, Br, or I, R1 represents a hydrogen atom or an optionally
substituted alkyl group containing 1 to 4 carbon atoms, P’’ represents a
tetrahydropyranyl group or ethoxyethyl group).