TECHNICAL FIELD
[0001] The present invention relates to a method for producing a high-purity
nitrogen-containing heterocyclic compound of Formula (A):
(where R1 and R2 are each independently a hydrogen atom, a Ci-6 alkyl group, or a C7-12
aralkyl group; R3 is a hydrogen atom, a Ci-6 alkyl group, a C7-12 aralkyl group, or a C1-6
acyloxy group; and X is a hydrogen atom, a halogen atom, a Ci-6 alkyl group, a C3-6
cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group, a Ci-6 alkoxy group, a Ci-6
15 acyloxy group, or a cyano group).
BACKGROUND ART
[0002]
20 (3R*,4S*)-7-hydroxymethyl-2,2,9-triinethyL4-(phenetylamino)-3,4-dihydro-2H-pyr
ano[2,3-g]quinolin-3-ol of Formula (3) [compound (3)] exmbits an anti-arrhythmic action
and possibility of the compound (3) for using as a medicine is known (for example, see
Patent Document I).
2
[0003] For synthesizing the compound (3), a reaction path is shown below in
which: 2,2,7,9-tetramethyl-2H-pyrano[2,3-g]quiiioline [compound (4)] is reacted with
m-chloroperoxybenzoic acid and the resultant reaction product is reacted with acetic
5 anhydride to obtain (2,2,9-trimethyl-2H-pyrano[2)3-g]quinolin-7-yl)-methyl acetate
[compound (1)]; and the compound (1) is subjected to an asymmetric epoxidation
reaction using as a catalyst} an optically active manganese complex (for example, see
Patent Document 1) or an optically active titanium complex (for example, see Patent
Document 2) to obtain (3R*,4R*)-(3,4-epoxy-2,2,9-trimethyI-3,4-dihydro
10 -2H-pyrano[2,3-g]quinolin-7~yl)-methylacetate [compound (5)].
[0004] Here, in a reaction using a small amount of a metal complex as a catalyst,
there is a probability that the reaction is largely inliibited by a small amount of impurities.
Accordingly, in a reaction leading the compound (1) to the compound (5), it is
15 particularly desired that the compound (1) as the reaction substrate is obtained in high
purity. As the production method of the compound (1), however, only a method has
been known in which after the completion of the reaction, a crude product is purified
through silica gel column chromatography, and thus another new production method of
the compound (1) available in an industrial scale has been desired.
3
Prior Art Documents
Patent Documents
[0005] Patent Document 1: WO 2005/090357
Patent Document 2: WO 2007/105658
5
SUMMARY OF THE INVENTION
Problem to be Solved by the Invention
[0006] It is an object of the present invention to provide a method for producing a
10 high-purity nitrogen-containing heterocyclic compound.
Means for Solving the Problem
[0007] As a result of assiduous research, the inventors of the present invention
have found that when the compound (4) is oxidized and further, the oxidized compound
is reacted with an acid anhydride or an acid halide to be led to the compound (1),
15 5-hydroxy-2,2,7,9-tetramethyI-2H-pyrano[2,3-g]quinoline [compound (2)] in which a
quinoline ring part is oxidized is generated as a by-product, and that when the compound
(2) and the compound (1) are in a mixed state, in a process in which the compound (1) is
led to the compound (5), the compound (2) decomposes a metal complex catalyst used
for the reaction to inhibit the reaction progress,
o
20
[0008] Further, the inventors of the present invention have found a production
process capable of removing the compound (2) simply and effectively from the mixture
containing the compound (1) and the compound (2) and have completed a production
method of the compound (1) having high purity.
4
[0009] Specifically, the present invention is characterized by the following
methods:
(i)
a production method of a compound (A) having high purity, comprising: a process
5 (a) and a process (b):
(a) a process of mixing a mixture containing a compound (A):
(where Rl and R2 are each independently a hydrogen atom, a Ci-6 alkyl group, or a Ci-n
aralkyl group; R3 is a hydrogen atom, a Ci-6 alkyl group, a C7-12 aralkyl group, or a C1-6
10 acyloxy group; and X is a hydrogen atom, a halogen atom, a Ci-6 alkyl group, a C3-6
cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group, a Ci-6 alkoxy group, a Cue
acyloxy group, or a cyano group) and
as an impurity, a compound (B):
15 (where R1, R2, R3, and X are the same as defined above) with a solvent and a metal salt,
and
(b) a process of obtaining a mixture in a solution state in which the content of the
compound (B) has decreased compared to that in the mixture in the process (a) by
filtering a mixed solution obtained in the process (a), or a process of obtaining a mixture
20 in which the content of the compound (B) has decreased compared to that in the mixture
in the process (a) by further evaporating the solvent or crystallizing following the
filtering;
(II)
the production method according to (I), in which the compound (A) is a compound
and
the compound (B) is a compound (2):
(III)
the production method according to (I) or (II), in which the process (b) is a process
(bl) below,
(bl) a process of obtaining a mixture in a solution state in which the content of the
10 compound (B) has decreased compared to that in the mixture in the process (a) by
filtering the mixed solution obtained in the process (a) using a filtration auxiliary, or a
process of obtaining a mixture in which the content of the compound (B) has decreased
compared to that in the mixture in the process (a) by further evaporating the solvent or
crystallizing following the filtering;
15 (IV)
the production method according to (III), in which the filtration auxiliary is silica
gel;
(V)
the production method according to any one of (I) to (IV), further comprising: a
20 process (c); and a process (d), after the process (b);
(c) a process of mixing the mixture obtained in the process (b) with a solvent and a
porous adsorbent, and
6
(d) a process of obtaining a mixture in a solution state in which the content of the
compound (B) has decreased compared to that in the mixture in the process (b) by
filtering a mixed solution obtained in the process (c), or a process of obtaining a mixture
in which the content of the compound (B) has decreased compared to that in the mixture
5 in the process (b) by further evaporating the solvent or crystallizing following the
filtering;
(VI)
the production method according to (V), in which the porous adsorbent is active
carbon;
10 (VII)
the production method according to any one of (I) to (VI), further comprising: a
process (e); to a process (g), after the process (d):
(e) a process of mixing the mixture obtained in the process (d) with a solvent and an acid,
(f) a process of recovering an acid salt generated in the process (e) by filtration, and
15 (g) a process of obtaining a mixture in a solution state in which the content of the
compound (B) has decreased compared to that in the mixture in the process (d) by adding
the acid salt obtained in the process (f) to a solvent, further adding an alkaline aqueous
solution to neutralize the acid salt, and by removing an aqueous phase containing an
alkaline salt of an acid by a phase separation operation, or a process of obtaining a
20 mixture in which the content of the compound (B) has decreased compared to that in the
mixture in the process (d) by further evaporating the solvent or crystallizing following the
above phase separation operation;
(VIII)
the production method according to (VII), in which the acid is hydrogen chloride,
25 methanesulfonic acid, or oxalic acid;
(IX)
the production method according to any one of (I) to (VIII), in which the metal salt
is a copper salt;
(X)
7
the production method according to (IX), in which the copper salt is copper sulfate;
(XI)
the production method according to any one of (I) to (X), in which the solvent
contains at least one solvent selected from the group consisting of an acetic acid ester, an
5 aliphatic hydrocarbon, an aromatic hydrocarbon, an alcohol, and an ether; and
(XII)
a production method of a compound (1), comprising: a process (a); to a process (g):
(a) a process of: mixing a solvent mixture of ethyl acetate, hexane, and methanol with a
mixture obtained by oxidizing a compound (4):
10
using m-chloroperoxybenzoic acid or Oxone (registered trademark) and by causing the
oxidized compound (4) to react with acetic anhydride or acetic acid halide, the mixture
containing a compound (1):
15 and
as an impurity, a compound (2):
in a content of 3% or more, determined by absorbance analysis at a wavelength of 230
nm; and adding a copper sulfate aqueous solution or copper sulfate anhydride to the
20 resultant mixture to stir the resultant mixture,
8
(b) a process of obtaining a mixture in which the content of the compound (2) has
decreased compared to that in the mixture in the process (a) by adding silica gel to the
mixed solution obtained in the process (a) to stir the resultant mixture and filtering the
mixture, or by passing the mixed solution obtained in the process (a) through a silica gel
5 layer to filter the mixed solution and evaporating a solvent from the mixed solution
filtered,
(c) a process of mixing the mixture obtained in the process (b) with ethyl acetate and
active carbon to stir the resultant mixture,
(d) a process of obtaining a mixture in a solution state in which the content of the
10 compound (2) has decreased compared to that in the mixture in the process (b) by
filtering a mixed solution obtained in the process (c),
(e) a process of adding a solution obtained in the process (d), or a solution obtained by
concentrating the solution obtained in the process (d) followed by adding ethyl acetate, to
a solution obtained by adding 1-propanol and t-butyl methyl ether to oxalic acid
15 dihydrate and stirring the resultant solution,
(f) a process of recovering a salt of oxalic acid generated in the process (e) by filtration,
and
(g) a process of obtaining a mixture in a solution state in which the content of the
compound (2) has decreased compared to that in the mixture in the process (d), by adding
20 the salt of oxalic acid obtained in the process (f) to toluene, further adding a potassium
carbonate aqueous solution to neutralize the salt of oxalic acid, and removing an aqueous
phase containing potassium oxalate salt by a phase separation operation.
MODES FOR CARRYING OUT THE INVENTION
25
[0010] Hereinafter, the present invention is described more in detail.
The high purity mentioned in the present invention means a state in which the
content of the impurity contained in the mixture has decreased compared to that in the
mixture before the treatment process.
9
In the present specification, "n-" means "normal-", "i-" means "iso-", "s-" and
"sec-" mean "secondary-", and "t-" and "tert-" mean "tertiary-".
[0011] The compound (1) as a raw material of the present invention can be
synthesized, for example, by a method described in WO 2005/090357 (Patent Document
5 1).
[0012] The compound (A):
(where R1 and R2 are each independently a hydrogen atom, a Ci-6 alkyl group, or a C7.12
aralkyl group; R3 is a hydrogen atom, a Ci-e alkyl group, a C7.12 aralkyl group, or a Ci-e
10 acyloxy group; and X is a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C3.6
cycloalkyl group, a C6-IG aryl group, a C7-12 aralkyl group, a Ci-e alkoxy group, a Cue
acyloxy group, or a cyano group)
as a raw material of the present invention can be also synthesized by the method
described in Patent Document 1.
15 [0013] The substituent in the present invention is described.
The halogen atom means fluorine, chlorine, bromine, or iodine.
In the concept of the alkyl group in the present invention, the linear alkyl group and
the branched alkyl group are included.
The C1-6 alkyl group means an alkyl group having a carbon atom number of 1 to 6
20 and examples thereof include a methyl group, an ethyl group, a n-propyl group, an
i-propyl group, a n-butyl group, an i-butyl group, a s-butyl group, a t-butyl group, a
n-pentyl group, and a n-hexyl group. Among them, as the Ci-g alkyl group, a C4-3 alkyl
group, that is, an alkyl group having a carbon atom number of 1 to 3 is preferred and a
methyl group is more preferred.
25 The C3-6 cycloalkyl group means a cycloalkyl group having a carbon atom number
of 3 to 6 and examples thereof include a cyclopropyl group, a cyclobutyl group, and a
cyclohexyl group. Among them, as the C3-6 cycloalkyl group, a cyclopropyl group is
10
preferred.
The Cg-io aryl group means an aryl group having a carbon atom number of 6 to 10
and examples thereof include a phenyl group and a naphthyl group. Among them, as
the C6-10 aryl group, a phenyl group is preferred.
5 The C7-12 aralkyl group means a group formed by substituting the above-described
C1-6 alkyl group with one phenyl group. The phenyl group may be substituted at any
position on the Ci-g alkyl group. Examples of the C7.12 aralkyl group include a benzyl
group, a phenylethyl group, a phenylpropyl group, and a phenylbutyl group. Among
them, as the C7-12 aralkyl group, a benzyl group is preferred.
10 The C1-6 alkoxy group means an oxy group substituted with the above-described C1-6
alkyl group. Examples thereof include a methoxy group, an ethoxy group, an i-propoxy
group, and at-butoxy group. Among them, as the Ci-e alkoxy group, a C1-3 alkoxy
group, that is, an oxy group substituted with a C1-3 alkyl group is preferred and a methoxy
group is more preferred.
15 The Ci-6 acyloxy group means a carbonyloxy group substituted with the
above-described Ci_6 alkyl group. Examples thereof include an acetoxy group [a
CH3C(=0)0- group]. Among them, as the C1-6 acyloxy group, an acetoxy group is
preferred,
[0014] One aspect of the present invention is, as described above, a production
20 method of the compound (A) having high purity including a process (a) below and a
process (b) below,
(a) a process of mixing a mixture containing a compound (A) and a compound (B) or a
mixture containing a compound (1) and a compound (2) with a solvent and a metal salt,
and
25 (b) a process of obtaining a mixture in a solution state in which the content of the
compound (B) or the compound (2) has decreased compared to that of the compound (B)
or the compound (2) in the mixture in the process (a) by filtering the mixed solution
obtained in the process (a), or a process of obtaining a mixture in which the content of the
compound (B) or the compound (2) has decreased compared to that of the compound (B)
11
or the compound (2) in the mixture in the process (a) by further evaporating the solvent
or crystallizing after the filtering.
In the present specification, if necessary,
• "The mixture containing the compound (A) and the compound (B)" or "the mixture
5 containing the compound (1) and the compound (2)" described in the process (a) is
described as "the mixture before the purification",
* The process (a) and the process (b) are described as "the metal salt treatment process",
and
* The mixture containing the compound (A) and the compound (B) or the mixture
10 containing the compound (1) and the compound (2) after the metal salt treatment process
is described as "the purified product after the metal salt treatment".
[0015] The metal salt treatment process can be performed by dissolving or
dispersing the mixture before the purification in a solvent.
[0016] As the metal salt used, a salt containing copper (monovalent or divalent),
15 cobalt (divalent), manganese (trivalent), or titanium (tetravaient) can be used. Preferred
examples thereof include a copper salt and more preferred examples thereof include an
anhydride or a hydrate of a halogenide of copper (for example, a chloride, a bromide, and
an iodide), a nitrate, a carbonate, a sulfate, a phosphate, an acetate, and the like. Further
preferred examples thereof include copper sulfate anhydride, copper sulfate pentahydrate,
20 cupric chloride, cupric bromide, cupric nitrate, cuprous chloride, cuprous bromide, and
cupric acetate and particularly preferred examples thereof include copper sulfate
anhydride and copper sulfate pentahydrate.
These metal salts may be used individually or in combination of two or more types
thereof.
25 [0017] These metal salts may be used either in a solid state or as a solution (for
example, an aqueous solution or a methanol solution) thereof.
In terms of the efficiency as the production method, it is desired to dissolve the
metal salt before using the metal salt as a solution.
[0018] Although the amount of the metal salt used is not limited so long as the
12
effects of the object of the present invention can be achieved, the metal salt is used in an
amount of preferably 0.001 molar equivalent to 1.5 molar equivalent, more preferably
0.005 molar equivalent to 1.0 molar equivalent, and further preferably 0.01 molar
equivalent to 0.5 molar equivalent, based on the number of moles of the mixture before
5 the purification.
[0019] Although the solvent capable of being used in the metal salt treatment
process is not limited so long as the effects of the object of the present invention can be
achieved,
water,
10 alcohol solvents (for example, methanol, ethanol, 1-propanol, and isopropanol),
halogen-containing hydrocarbon solvents (for example, methylene chloride),
ketone solvents (for example, acetone and methyl ethyl ketone),
ester solvents (for example, methyl formate, ethyl formate, methyl acetate, ethyl
acetate, propyl acetate, and isopropyl acetate),
15 aromatic hydrocarbon solvents (for example, benzene, toluene, and xylene),
aliphatic hydrocarbon solvents (for example, hexane and heptane), and
ether solvents (for example, tetrahydrofuran, 1,4-dioxane, and t-butyl methyl ether)
are preferably used in terms of effectively performing the purification.
[0020] These solvents may be used individually or in combination of two or more
20 types thereof.
In particular, an aliphatic hydrocarbon solvent and an organic solvent miscible with
the aliphatic hydrocarbon solvent are used. Specifically, an aliphatic hydrocarbon
solvent and an alcohol solvent, an aliphatic hydrocarbon solvent and a
halogen-containing hydrocarbon solvent, an aliphatic hydrocarbon solvent and a ketone
25 solvent, an aliphatic hydrocarbon solvent and an ester solvent, an aliphatic hydrocarbon
solvent and an aromatic hydrocarbon solvent, an aliphatic hydrocarbon solvent and an
ether solvent, or an aliphatic hydrocarbon solvent and an ester solvent and an alcohol
solvent are used. More preferably, a single solvent of an ester solvent, a solvent mixture
of an aliphatic hydrocarbon solvent and an ester solvent, and a solvent mixture of an
13
aliphatic hydrocarbon solvent, an ester solvent, and an alcohol solvent is used.
Particularly preferably, a solvent mixture of hexane, ethyl acetate, and methanol is used.
[0021] Although the amount of the solvent used is not particularly limited, it is
0.1 parts by mass to 1,000 parts by mass, more preferably 0.5 parts by mass to 100 parts
5 by mass, and further preferably 1 part by mass to 50 parts by mass, based on the mass of
the mixture before the purification.
[0022] Although the treatment temperature for the metal salt treatment process is
not particularly limited, it is an arbitrary temperature preferably in a range of from 0°C to
a boiling point of the solvent used and more preferably in a range of from 1°C to 40°C.
10 [0023] Although the treatment time for the metal salt treatment process is not
particularly limited, from the viewpoint of the production efficiency, it is preferably up to
24 hours from immediately after the mixture containing the compound (A) and the
compound (B) or the mixture containing the compound (1) and the compound (2) is
mixed with the metal salt. The treatment time is more preferably from 10 minutes to 10
15 hours and further preferably from 30 minutes to 3 hours.
[0024] In the present invention, for the filtration in the process (b) of the metal
salt treatment process, a filtration auxiliary can be used. A representative example of
the filtration auxiliary is silica gel.
In the present specification, if necessary, the filtration operation using the filtration
20 auxiliary in the metal salt treatment process is described as "silica gel treatment
operation".
[0025] After the process (a), when a complex of the mixture before the
purification with the metal is filtered, the filtration auxiliary is preferably used.
[0026] Although the filtration auxiliary is not limited so long as the effects of the
25 object of the present invention can be achieved, as the filtration auxiliary, preferably used
is a granular substance that is not dissolved in each component of the mixture before the
filtration, is not chemically reacted with each component of the mixture before the
filtration, and can be filtered with a filter medium used for the filtration.
Preferred specific examples of the filtration auxiliary include a particle containing
14
silicon dioxide, a particle containing a silicate, asbestos, and active carbon. More
preferred specific examples include silica gel, diatomaceous earth, Celite (registered
trademark), talc, zeolite, and active carbon. Further preferred examples thereof include
silica gel, diatomaceous earth, and Celite (registered trademark). Particularly preferred
5 is silica gel.
[0027] The amount of the filtration auxiliary used is 0.1 part by mass to 5 parts by
mass, more preferably 0.5 part by mass to 2 parts by mass, and further preferably 0.5 part
by mass to 1 part by mass, based on the mass of the mixture before the purification.
[0028] The filtration can be performed either by laying the filtration auxiliary in a
10 filtration apparatus beforehand or by charging the filtration auxiliary into a solution to be
filtered.
[0029] As described above, although a representative example of the filtration
auxiliary is silica gel, the silica gel treatment operation of the present invention differs
from the column chromatography in the essential principle, which can be judged from
15 such facts as (i) also by filtering a solution to be filtered after the filtration auxiliary is
charged into the solution, a desired effect can be obtained, and (ii) even when filtration is
performed after the filtration auxiliary is laid in a filtration apparatus, the filtrate is not
fractionated.
[0030] Although the treatment temperature for charging the filtration auxiliary
20 into a solution to be filtered is not particularly limited, it is an arbitraiy temperature in a
range of preferably from 0°C to a boiling point of the solvent used and more preferably
froml°Cto40°C.
[0031] Although the treatment time for charging the filtration auxiliary into the
solution to be filtered is not particularly limited, from the viewpoint of the production
25 efficiency, the treatment time is preferably up to 24 hours from immediately after the
mixed solution obtained in the process (a) and the filtration auxiliary are mixed with each
other, more preferably from 1 hour to 10 hours.
[0032] Although the treatment temperature for the treatment of filtration by
laying the filtration auxiliary in a filtration apparatus beforehand is not particularly
15
limited, from the viewpoint of the production efficiency, it is an arbitrary temperature in a
range of preferably from 0°C to a boiling point of the used solvent, more preferably from
0°C to 50°C, and further preferably from 10°C to 40°C.
[0033] Although the treatment time for the treatment of filtration by laying the
5 filtration auxiliary in a filtration apparatus beforehand is not particularly limited, fi-om the
viewpoint of the production efficiency, the treatment time is preferably up to 24 hours
from immediately after the mixed solution obtained in the process (a) and the filtration
auxiliary are mixed with each other, more preferably from 1 hour to 10 hours.
[0034] In the present invention, the purified product after the metal salt treatment
10 can be further treated with a porous adsorbent.
In the present specification, if necessary, the present process is described as "porous
adsorbent treatment process", and the mixture containing the compound (A) and the
compound (B) or the mixture containing the compound (1) and the compound (2) after
the porous adsorbent treatment process, is described as "purified product after porous
15 adsorbent treatment".
[0035] The porous adsorbent treatment process can be performed by dissolving or
dispersing the purified product after the metal salt treatment in a solvent.
[0036] Examples of the porous adsorbent include zeolite, silica gel, alumina, and
active carbon and among them, active carbon is preferred.
20 [0037] The amount of the porous adsorbent used is 0.001 part by mass to 1 part
by mass, more preferably 0.01 part by mass to 0.5 part by mass, and further preferably
0.05 part by mass to 0.2 part by mass, based on the mass of the mixture before the
purification.
[0038] Although the solvent capable of being used in the porous adsorbent
25 treatment process is not limited so long as the effects of the object of the present
invention can be achieved,
water,
alcohol solvents (for example, methanol, ethanol, 1-propanol, and isopropanol),
halogen-containing hydrocarbon solvents (for example, methylene chloride),
16
ketone solvents (for example, acetone and methyl ethyl ketone),
ester solvents (for example, methyl formate, ethyl formate, methyl acetate, ethyl
acetate, propyl acetate, and isopropyl acetate),
aromatic hydrocarbon solvents (for example, benzene, toluene, and xylene),
5 aliphatic hydrocarbon solvents (for example, hexane and heptane), and
ether solvents (for example, tetrahydrofuran, l,4~dioxane, and t-butyl methyl ether)
are preferably used in terms of effectively performing the purification.
[0039] These solvents may be used individually or in combination of two or more
types thereof.
10 In particular, an ester solvent and an organic solvent miscible with the ester solvent
are used. Specifically, an ester solvent and an alcohol solvent, an ester solvent and a
halogen-containing hydrocarbon solvent, an ester solvent and a ketone solvent, an ester
solvent and an aromatic hydrocarbon solvent, an ester solvent and an aliphatic
hydrocarbon solvent, or an ester solvent and an ether solvent are used. More preferably,
15 a single solvent of an ester solvent and a solvent mixture of an ester solvent and an
aliphatic hydrocarbon solvent are used. Particularly preferably, ethyl acetate is used.
[0040] Although the amount of the solvent used is not particularly limited, it is
0.1 part by mass to 1,000 parts by mass, more preferably 0.5 part by mass to 100 parts by
mass, and further preferably 1 part by mass to 50 parts by mass, based on the mass of the
20 mixture before the purification.
[0041] Although the treatment temperature for the porous adsorbent treatment
process is not particularly limited, it is an arbitrary temperature in a range of preferably
from 0°C to a boiling point of the solvent used and more preferably from 1°C to 40°C.
[0042] Although the treatment time for the porous adsorbent treatment process is
25 not particularly limited, from the viewpoint of the production efficiency, the treatment
time is preferably up to 24 hours from immediately after the purified product after the
metal salt treatment and the porous adsorbent are mixed with each other, more preferably
from 1 hour to 10 hours.
[0043] In the present invention, the purified product after the porous adsorbent
17
treatment can be further purified by recrystallizing the purified product as an acid salt.
In the present specification, if necessary, the present process is described as "acid
treatment process" and an acid salt of the compound (A) or an acid salt of the compound
(1) after the acid treatment is described as "purified product after acid treatment".
5 [0044] The acid treatment process can be performed by dissolving or dispersing
the purified product after the porous adsorbent treatment in a solvent.
[0045] Although the acid capable of being used for the present invention is not
limited so long as the effects of the object of the present invention can be achieved, the
acid used is hydrochloric acid, methanesulfonic acid, oxalic anhydride, or oxalic acid
10 dihydrate. More preferably, oxalic anhydride or oxalic acid dihydrate is used, and
particularly preferably, oxalic acid dihydrate is used.
[0046] The amount of the acid used is 1 molar equivalent to 5 molar equivalent
and more preferably 1 molar equivalent to 3 molar equivalent, based on the number of
moles of the mixture before the purification.
15 [0047] Although the solvent capable of being used in the acid treatment process is
not limited so long as the effects of the object of the present invention can be achieved,
water,
alcohol solvents (for example, methanol, ethanol, 1-propanol, and isopropanol),
halogen-containing hydrocarbon solvents (for example, methylene chloride),
20 ketone solvents (for example, acetone and methyl ethyl ketone),
ester solvents (for example, methyl formate, ethyl formate, methyl acetate, ethyl
acetate, propyl acetate, and isopropyl acetate),
aromatic hydrocarbon solvents (for example, benzene, toluene, and xylene),
aliphatic hydrocarbon solvents (for example, hexane and heptane), and
25 ether solvents (for example, tetrahydrofuran, 1,4-dioxane, and t-butyl methyl ether)
are preferably used in terms of effective performance the purification.
[0048] These solvents may be used individually or in combination of two or more
types thereof.
In particular, an ester solvent and an organic solvent miscible with the ester solvent
18
are used. Specifically, an ester solvent and an alcohol solvent, an ester solvent and a
halogen-containing hydrocarbon solvent, an ester solvent and a ketone solvent, an ester
solvent and an aromatic hydrocarbon solvent, an ester solvent and an aliphatic
hydrocarbon solvent, an ester solvent and an ether solvent, or an ester solvent and an
5 ether solvent and an alcohol solvent are used. More preferably, a solvent mixture of an
ester solvent and an ether solvent and an alcohol solvent are used. Particularly
preferably, a solvent mixture of ethyl acetate and t-butyl methyl ether and 1-propanol is
used.
[0049] Although the amount of the solvent used is not particularly limited, it is
10 0.1 part by mass to 1,000 parts by mass, more preferably 0.5 part by mass to 100 parts by
mass, and further preferably 1 part by mass to 50 parts by mass, based on the mass of the
mixture before the purification.
[0050] Although the treatment temperature for the acid treatment process is not
particularly limited, it is an arbitrary temperature in a range of preferably from -10°C to a
15 boiling point of the solvent used and preferably from -10°C to 40°C.
[0051] Although the treatment time for the acid treatment process is not
particularly limited, from the viewpoint of the production efficiency, the treatment time is
preferably up to 48 hours from immediately after the purified product after the porous
adsorbent treatment and the acid are mixed with each other, and more preferably from 1
20 hour to 20 hours.
[0052] In the present invention, the purified product after the acid treatment is
further neutralized and can be converted back into a free form of the compound (A) or the
compound (1).
In the present specification, if necessary, the present process is described as
25 "neutralization process" and the compound (A) or the compound (1) after the
neutralization process is described as "final purified product".
[0053] The neutralization process can be performed by dissolving or dispersing
the purified product after the acid treatment in a solvent.
[0054] Although the base capable of being used in the present invention is not
19
particularly limited so long as the effects of the object of the present invention can be
achieved, an alkali metal salt is used. Particularly preferably, potassium carbonate is
used.
[0055] The amount of the base used is 1 molar equivalent to 10 molar equivalent
5 and more preferably 1 molar equivalent to 5 molar equivalent, based on the number of
moles of the mixture before the purification.
[0056] Although the solvent capable of being used in the neutralization process is
not limited so long as the effects of the object of the present invention can be achieved,
water,
10 alcohol solvents (for example, methanol, ethanol, 1-propanol, and isopropanol),
halogen-containing hydrocarbon solvents (for example, methylene chloride),
ketone solvents (for example, acetone and methyl ethyl ketone),
ester solvents (for example, methyl formate, ethyl formate, methyl acetate, ethyl
acetate, propyl acetate, and isopropyl acetate),
15 aromatic hydrocarbon solvents (for example, benzene, toluene, and xylene),
aliphatic hydrocarbon solvents (for example, hexane and heptane), and
ether solvents (for example, tetrahydrofuran, 1,4-dioxane, and t-butyl methyl ether)
are preferably used in terms of effective performance the purification.
[0057] These solvents may be used individually or in combination of two or more
20 types thereof.
In particular, an aromatic hydrocarbon solvent and an organic solvent miscible with
the aromatic hydrocarbon solvent are used. Specifically, an aromatic hydrocarbon
solvent and an alcohol solvent, an aromatic hydrocarbon solvent and a
halogen-containing hydrocarbon solvent, an aromatic hydrocarbon solvent and a ketone
25 solvent, an aromatic hydrocarbon solvent and an ester solvent, an aromatic hydrocarbon
solvent and an aliphatic hydrocarbon solvent, or an aromatic hydrocarbon solvent and an
ether solvent are used. Preferably, a single solvent of an aromatic hydrocarbon solvent
and a solvent mixture of an aromatic hydrocarbon solvent and an ester solvent are used.
Particularly preferably, toluene is used.
20
[0058] Although the amount of the solvent used is not particularly limited, it is
0.1 part by mass to 1,000 parts by mass, more preferably 0.5 part by mass to 100 parts by
mass, and further preferably 1 part by mass to 50 parts by mass, based on the mass of the
mixture before the purification.
5 [0059] Although the treatment temperature for the neutralization process is not
particularly limited, it is an arbitrary temperature in a range of preferably from 0°C to a
boiling point of the used solvent and more preferably from 1°C to 40°C.
[0060] Although the treatment time for the neutralization process is not
particularly limited, from the viewpoint of the production efficiency, the treatment time is
10 preferably up to 24 hours from immediately after the purified product after the acid
treatment is neutralized, and more preferably from 1 hour to 10 hours.
Examples
[0061] Hereinafter, the present invention will be further specifically described,
15 referring to Examples, which should not be constmed as limiting the scope of the present
invention.
In Examples, NMR means nuclear magnetic resonance, HPLC means high
performance liquid chromatography, and V/V means volume vs volume.
The purity (content ratio in the case of the impurity) of each compound in the HPLC
20 analysis is expressed by an area percentage method by which a ratio of the object peak
area in the total peak area is expressed in percentage.
In Examples, the NMR analysis was performed using ECP300 manufactured by
JEOL Ltd. and the melting point measurement was performed using B-545 manufactured
by Shibata Scientific Technology Ltd. The HPLC analysis was performed using
25 LC-20A manufactured by Shimadzu Corporation under the conditions below.
Column: CAPCELLPAK C18-UG80 [manufactured by Shiseido Co., Ltd.; diameter: 4.6
mm, length: 150 mm, particle diameter: 5 pm]
Eluent: acetonitrile-0.02 M phosphoric acid buffer solution (pH 2.9), 40:60, V/V
Flow rate: l.OmL/min
21
Column temperature: 40°C
Detector wavelength: 230 nm and 254 nm
The compound (1) is detected at around 17.9 minutes and the compound (2) is
detected at around 10.2 minutes. It was confirmed by a change in an area ratio of a peak
5 of the compound (2) detected at 230 nm whether the compound (2) was removed. In
addition, the quantitative recovery percentage calculation analysis of the compound (1)
was performed at 254 nm using an internal standard calibration curve prepared by using
the preparation of the compound (1) and using diethyl phthalate as an internal standard
substance.
10 [0062] [Synthesis Example]
Synthesis of Compound (1)
((2,2,9-trimethyl-2H-pyrano[2,3-g]quinoiin-7-yl)-methyl acetate)
Acetic anhydride (138 g, 1.35 mol) and chloroform (400 g) were mixed and the
resultant mixture was heated to 40°C to 55°C. Into the mixture, a chloroform (360 g)
15 solution of 2,2,7,9-tetramethyl-2H-pyrano[2,3-g]quinoline 6-oxide (124 g, 0.486 mol)
was added dropwise and the resultant mixture was stirred at 40°C to 55°C for 30 minutes.
The mixture was cooled down to 30°C and thereto, methanol (200 g) was added,
followed by stirring the resultant mixture for 30 minutes. Then, into the mixture, a 10%
sodium hydroxide aqueous solution (649 g) was added dropwise and the resultant mixture
20 was stirred for 3 hours, followed by leaving the mixture at rest to subject the mixture to
phase separation. To the resultant organic phase, a 2.5% sodium bicarbonate aqueous
solution (600 g) and methanol (200 g) were added and the resultant mixture was stirred
for 1 hour, followed by leaving the mixture at rest to subject the mixture to phase
separation. To the resultant organic phase, water (600 g) and methanol (100 g) were
25 added and the resultant mixture was stirred for 30 minutes, followed by leaving the
mixture at rest to subject the mixture to phase separation. The resultant organic phase
was filtered through a funnel in which silica gel (200 g) was laid and the filtration cake of
silica gel was washed with ethyl acetate. From the obtained filtrate, the solvent was
evaporated under reduced pressure to obtain 298 g of an ethyl acetate solution of the
22
compound (1). As a result of the HPLC quantitative analysis, it was confirmed that the
ethyl acetate solution of the compound (1) contained 117 g of the compound (1).
The solution was concentrated to dryness, and then, purified by silica gel
chromatography to obtain a reference standard of the compound (1) for the HPLC
5 quantitative analysis and a compound (2)
(5-hydroxy-2,2,7,9-tetramethyi-2H-pyrano[2,3-g]quinoIine). The analysis data of each
compound are shown below.
[0063] Compound (1)
Appearance: yellow solid
10 !H-NMR (CDCb, TMS):
8 (ppm): 1.50 (6H, s), 2.17 (3H, s), 2.60 (3H, s), 5.27 (2H, s), 5.90 (1H, d, J-9.9 Hz),
6.57 (1H, d, J-9.9 Hz), 7.18 (1H, s), 7.23 (1H, s), 7.66 (1H, s)
Melting point: 72°C
[0064] Compound (2)
15 Appearance: gray solid
^-NMR (CDCb, TMS):
8 (ppm): 1.49 (6H, s), 2.52 (3H, s), 2.59 (3H, s), 5.80 (1H, d, J-9.9 Hz), 6.74 (1H, s),
6.91 (1H, d, J=10.9 Hz), 7.02 (1H, s)
Melting point: 120°C
20 [0065] In the following Example 1 to Example 3 and Comparative Example 1,
using, the mixture of the compound (1) and the compound (2) [in the mixture, the content
of the compound (2) was 3.61%, which was found as a result of the HPLC analysis] as a
raw material, the purification effect of the compound (2) and a recovery percentage of the
compound (1) were studied. The recovery percentage was calculated by dividing the
25 mass of the compound (1) after the treatment by the mass of the compound (1) before the
treatment. The mass may be a mass quantified by HPLC. In Example 1 to Example 3
and Comparative Example 1, as silica gel, Silica gel 60 (particle diameter: 0.063 to 0.100
mm) manufactured by Merck KGaA was used.
[0066] [Example 1]
23
To a 25% ethyl acetate solution (8.02 g, 6.73 mmol) containing the compound (1)
and the compound (2), methanol (2.00 g) was added and thereto, as a metal salt, a 10%
copper sulfate aqueous solution (0.54 g, 0.34 mmol) was added, followed by stirring the
resultant mixture at 20°C for 1 hour. To the mixture, n-hexane (8.03 g) was added and
5 the resultant mixture was stirred for 30 minutes. The mixture was then filtered tlirough
a funnel in which silica gel (2.00 g) was laid and a filtration cake of silica gel was washed
with a mixed liquid of n-hexane (4.00 g) and ethyl acetate (2.00 g) to obtain a solution
containing the compound (1).
The content ratio of the compound (2) measured by the HPLC analysis was before
10 the treatment, 3,61% and after the treatment, 0.23%. The mass of the compound (1) was
before the treatment, 2.00 g and after the treatment, 1.98 g. The recovery percentage of
the compound (1) was 99.0%.
By the present treatment, with losing little amount of the compound (1), the content
of the compound (2) was able to be reduced.
15 [0067] In the same manner as in Example 1, a 25% ethyl acetate solution
containing the compound (1) and the compound (2) was treated with each metal salt
aqueous solution. The obtained results are shown in Table 1. From the results in Table
1, for each metal salt aqueous solution, the effects of removing the compound (2) was
confirmed, and particularly, for a copper salt compound aqueous solution, a cobalt salt
20 compound aqueous solution, and a manganese salt compound aqueous solution, a large
effect of removing the compound (2) was confirmed.
[0068] Table 1
[0069] [Example 2]
To a 25% ethyl acetate solution (8.01 g, 6.73 mmol) containing the compound (1)
and the compound (2), methanol (2.01 g) was added and thereto, a copper sulfate
5 anhydride (0.22 g, 1.35 mmol) in a solid state was added, followed by dispersing and
stirring the resultant mixture at 20°C for 1 hour. To the mixture, n-hexane (8.02 g) was
added and the resultant mixture was stirred for 30 minutes. The mixture was then
filtered through a funnel in which silica gel (2.03 g) was laid and a filtration cake of silica
gel was washed with a mixed liquid of n-hexane (4.00 g) and ethyl acetate (2.01 g) to
10 obtain a solution containing the compound (1).
The content ratio of the compound (2) measured by the HPLC analysis was before
the treatment, 3.61% and after the treatment, 0.26%. The mass of the compound (1) was
before the treatment, 2.00 g and after the treatment, 1.99 g. The recovery percentage of
the compound (1) was 99.3%.
15 By the present treatment, with losing little amount of the compound (1), the content
of the compound (2) was able to be reduced.
[0070] In the same manner as in Example 2, a 25% ethyl acetate solution
containing the compound (1) and the compound (2) was subjected to a dispersing-stirring
treatment using each metal salt (solid or liquid). The obtained results are shown in
20 Table 2. From the results in Table 2, for almost all metal salt compounds, the effects of
removing the compound (2) was confirmed, and particularly, for a manganese salt
compound (solid dispersing treatment), a copper salt compound (solid dispersing
treatment), and a titanium salt compound (liquid dispersing treatment), a large effect of
removing the compound (2) was confirmed.
[0072] [Example 3]
To a 25% ethyl acetate solution (80.0 g, 67.3 mmol) containing the compound (1)
5 and the compound (2), methanol (20.0 g) was added and thereto, a 10% copper sulfate
aqueous solution (5.37 g, 3.36 mmol) was added, followed by stirring the resultant
mixture at 20°C for 1 hour. To the mixture, n-hexane (80.0 g) was added and the
resultant mixture was stirred for 30 minutes. The mixture was then filtered through a
funnel in which silica gel (20.1 g) was laid and a filtration cake of silica gel was washed
10 with a mixed liquid of n-hexane (40.0 g) and ethyl acetate (20.0 g) to obtain a solution
containing the compound (1).
The content ratio of the compound (2) measured by the HPLC analysis was before
the treatment, 3.61% and after the treatment, 0.21%. The mass of the compound (1) was
before the treatment, 20.00 g and after the treatment, 19.80 g. The recovery percentage
15 of the compound (1) was 99.0%.
[0073] From this solution, the solvent was evaporated under reduced pressure and
thereto, ethyl acetate (140 g) was added, followed by evaporating the solvent again and
the resultant solution mass became 120 g. Thereto, active carbon (2.02 g) was added
26
and the resultant solution was stirred at 19°C for 1 hour. Active carbon was filtered and
further, a filtration cake of active carbon was washed with ethyl acetate (60.0 g) to obtain
a solution containing the compound (1).
The content ratio of the compound (2) measured by the HPLC analysis after the
5 treatment was 0.07%.
From the solution, the solvent was evaporated under reduced pressure so that the
total amount became 60 g. Into another flask, t-butyl methyl ether (80.1 g), 1 -propanol
(40.1 g), and oxalic acid dihydrate (17.0 g, 135 mmol) were charged and into the resultant
mixture, the concentrate after the above evaporation of the solvent was added dropwise at
10 26°C. The resultant mixture was stirred at the same temperature for 1 hour, cooled
down to 5°C or lower, and stirred at 5°C or lower for 4 hours. The precipitated crystal
was recovered by filtration and the filtration cake was washed with ethyl acetate (40.0 g)
twice.
The obtained crystal was suspended in toluene (100 g) and thereto, a 10% potassium
15 carbonate aqueous solution (139 g) was added and the resultant mixture was stirred, left
at rest, and separated. To the resultant organic phase, water (100 g) was added and the
resultant mixture was stirred, left at rest, and separated. From the resultant organic
phase, the solvent was evaporated under reduced pressure to obtain 60.11 g of a toluene
solution containing the compound (1).
20 The content ratio of the compound (2) measured by the HPLC analysis was after the
treatment, 0.02%. The mass of the compound (1) was after the treatment, 17.46 g.
The recovery percentage of the compound (1) was 87.3%.
By the present treatment, while most of the amount of the compound (1) was able to
be recovered, the content of the compound (2) was able to be reduced to about 1/180.
25 [0074] [Comparative Example 1]
To a 25% ethyl acetate solution (80.0 g, 67.3 mmol) containing the compound (1)
and the compound (2), methanol (20.0 g) was added and the resultant mixture as it was
was stirred at 20°C for 1 hour. To the mixture, n-hexane (80.0 g) was added and the
resultant mixture was stirred for 30 minutes, followed by filtering the mixture through a
27
funnel in which silica gel (20.0 g) was laid. Further, the filtration cake of silica gel was
washed with a liquid mixture of n-hexane (40.0 g) and ethyl acetate (20.0 g) to obtain a
solution containing the compound (1).
The content of the compound (2) measured by the HPLC analysis was before the
5 treatment, 3.61% and after the treatment, 3.42%. The mass of the compound (1) was
before the treatment, 20.00 g and after the treatment, 19.68 g. The recovery percentage
of the compound (1) was 98.4%.
From this solution, the solvent was evaporated under reduced pressure and thereto,
ethyl acetate (140.0 g) was added, followed by evaporating the solvent again under
10 reduced pressure so that the solution mass became 120 g. Thereto, active carbon (2.00
g) was added and the resultant solution was stirred at 21°C for 1 hour. Active carbon
was removed by filteration and further, a filtration cake of active carbon was washed with
ethyl acetate (60.0 g) to obtain a solution containing the compound (1).
The content ratio of the compound (2) measured by the HPLC analysis was after the
15 treatment, 3.42%. The mass of the compound (1) was after the treatment, 19.68 g.
The recovery percentage of the compound (1) was 98.4%.
From the solution, the solvent was evaporated under reduced pressure so that the
total amount became 60.0 g. Into another flask, t-butyl methyl ether (80.0 g),
1-propanol (40.0 g), and oxalic acid dihydrate (17.0 g, 135 mmol) were charged and into
20 the resultant mixture, the concentrate after the above evaporation of the solvent was
added dropwise at 25°C. The resultant mixture was stirred at the same temperature for 1
hour, cooled down to 5°C or lower, and stirred at 5°C or lower for 4 hours. The
precipitated crystal was filtered and the crystal was washed with ethyl acetate (40.0 g)
twice.
25 The obtained crystal was suspended in toluene (100 g) and thereto, a 10% potassium
carbonate aqueous solution (139 g) was added and the resultant mixture was stirred, left
at rest, and separated. To the resultant organic phase, water (100 g) was added and the
resultant mixture was stirred, left at rest, and separated. From the resultant organic
phase, the solvent was evaporated under reduced pressure to obtain 60.11 g of a toluene
28
solution containing the purified compound (1).
The content ratio of the compound (2) measured by the HPLC analysis was after the
treatment, 1.79%. The mass of the compound (1) was after the treatment, 17.82 g.
The recovery percentage of the compound (1) was 89.1%.
5 [0075] [Test Example]
Using the compound (1) obtained in Example 3 and the compound (1) obtained in
Comparative Example 1 as a raw material, an asymmetric epoxidation reaction with an
optically active titanium-salan complex described in Patent Document 2 was performed,
so that the reactivities of these two compounds (1) were compared with each other.
10 The optically active titanium-salan complex was prepared, for example, by a method
described in WO 2007/105658 (Patent Document 2) from 3-{([{(lS,
2S)-2-[{2-hydroxy-2'-methoxy(l,r-biphenyl)-3-yi}methyl]amino}cyclohexyl]amino)me
thyl}-2'-methoxy-(l,r-biphenyl)-2-ol and titanium tetraisopropoxide.
The evaluation of the reactivity was performed by comparing the reaction
15 conversion rates obtained by dividing a peak area of (3R*,
4R*)-(3,4-epoxy-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinolin-7-yl)-methylacet
ate as a reaction product detected by the HPLC analysis performed during the reaction,
by the sum of a peak area of the compound (1) as a raw material and a peak area of the
reaction product.
20 [0076] (1) To the 20% toluene solution (50.0 g, 33.6 mmoi) of the compound (1)
obtained in Example 3, a solution of an optically active titanium-salan complex (in an
amount corresponding to 0.37 mmol) was added and into the resultant mixture, a 30%
hydrogen peroxide water (7.64 g, 67.3 mmol) to which sodium acetate (0.28 g) was
added was added dropwise at 26°C to 27°C and was reacted at 25°C to 26°C for 7 hours.
25 The changes of the reaction conversion rate obtained as a result of the above
reaction are summarized in Table 3. The reaction progression was good and the reaction
conversion rate exceeded 90%.
[0077] Table 3
Reaction time
(hourCs))
Reaction conversion rate (%)
[0078] (2) To the 20% toluene solution (50.0 g, 33.6 mmol) of compound (1)
obtained in Comparative Example 1, a solution of an optically active titanium-salan
complex (in an amount corresponding to 0.37 mmol) was added and into the resultant
mixture, a 30% hydrogen peroxide water (7.64 g, 67.4 mmol) to which sodium acetate
(0.28 g) was added was added dropwise at 26°C and was reacted at 25°C to 26°C for 23
hours.
The changes of the reaction conversion rate obtained as a result of the above
reaction are summarized in Table 4. For the reaction, the reaction conversion rate did
not reach even 70% and the reaction progression was poor.
INDUSTRIAL APPLICABILITY
5 [0080] The present invention provides a method for producing a high-purity
nitrogen-containing heterocyclic compound.

CLAIMS
1. A production method of a compound (A) having high purity, comprising:
a process (a); and
5 a process (b):
(a) a process of mixing a mixture containing a compound (A);
(where Rl and R2 are each independently a hydrogen atom, a Ci-e alkyl group, or a C7.12
aralkyl group; R3 is a hydrogen atom, a C1-6 alkyl group, a C7-12 aralkyl group, or a Ci-6
10 acyloxy group; and X is a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C3-6
cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group, a C1-6 alkoxy group, a C1-6
acyloxy group, or a cyano group) and
as an impurity, a compound (B):
15 (where R1, R2, R3, and X are the same as defined above) with a solvent and a metal salt,
and
(b) a process of obtaining a mixture in a solution state in which the content of the
compound (B) has decreased compared to that in the mixture in the process (a) by
filtering a mixed solution obtained in the process (a), or a process of obtaining a mixture
20 in which the content of the compound (B) has decreased compared to that in the mixture
in the process (a) by farther evaporating the solvent or crystallizing following the
filtering.
2. The production method according to claim 1, wherein
32
tV»p» r>r»mr»rM 1 n rl (A\ io Q c n m n n n n r l / ' lA
and
the compound (B) is a compound (2)
OH
3. The production method according to claim 1 or 2, wherein
the process (b) is a process (bi):
(bl) a process of obtaining a mixture in a solution state in which the content of the
10 compound (B) has decreased compared to that in the mixture in the process (a) by
filtering the mixed solution obtained in the process (a) using a filtration auxiliary, or a
process of obtaining a mixture in which the content of the compound (B) has decreased
compared to that in the mixture in the process (a) by flu-ther evaporating the solvent or
crystallizing following the filtering.
15
4. The production method according to claim 3, wherein
the filtration auxiliary is silica gel.
5. the production method according to any one of claims 1 to 4, further
20 comprising:
a process (c); and
a process (d),
33
after the process (b):
(c) a process of mixing the mixture obtained in the process (b) with a solvent and a
porous adsorbent, and
(d) a process of obtaining a mixture in a solution state in which the content of the
5 compound (B) has decreased compared to that in the mixture in the process (b) by
filtering a mixed solution obtained in the process (c), or a process of obtaining a mixture
in which the content of the compound (B) has decreased compared to that in the mixture
in the process (b) by further evaporating the solvent or crystallizing following the
filtering.
10
6. The production method according to claim 5, wherein
the porous adsorbent is active carbon.
7. The production method according to any one of claims 1 to 6, further
15 comprising:
a process (e); to a process (g),
after the process (d):
(e) a process of mixing the mixture obtained in the process (d) with a solvent and an acid,
(f) a process of recovering an acid salt generated in the process (e) by filtration, and
20 (g) a process of obtaining a mixture in a solution state in which the content of the
compound (B) has decreased compared to that in the mixture in the process (d) by adding
the acid salt obtained in the process (f) to a solvent, further adding an alkaline aqueous
solution to neutralize the acid salt, and removing an aqueous phase containing an alkaline
salt of an acid by a phase separation operation, or a process of obtaining a mixture in
25 which the content of the compound (B) has decreased compared to that in the mixture in
the process (d) by further evaporating the solvent or crystallizing following the above
phase separation operation.
8. The production method according to claim 7, wherein
5
34
the acid is hydrogen chloride, methanesulfonic acid, or oxalic acid.
9. The production method according to any one of claims 1 to 8, wherein
the metal salt is a copper salt.
10. The production method according to claim 9, wherein
the copper salt is copper sulfate.
11. The production method according to any one of claims 1 to 10, wherein
10 the solvent contains at least one solvent selected from the group consisting of an
acetic acid ester, an aliphatic hydrocarbon, an aromatic hydrocarbon, an alcohol, and an
ether.
12. A production method of a compound (1), comprising:
15 a process (a); to
a process (g):
(a) a process of: mixing a solvent mixture of ethyl acetate, hexane, and methanol with a
mixture obtained by oxidizing a compound (4):
20 using m-chloroperoxybenzoic acid or Oxone (registered trademark) and by causing the
oxidized compound (4) to react with acetic anhydride or acetic acid halide, the mixture
containing a compound (1):
and
as an impurity, a compound (2):
5 in a content of 3% or more, determined by absorbance analysis at a wavelength of 230
nm; and adding a copper sulfate aqueous solution or copper sulfate anhydride to the
resultant mixture to stir the resultant mixture,
(b) a process of obtaining a mixture in which the content of the compound (2) has
decreased compared to that in the mixture in the process (a) by adding silica gel to the
10 mixed solution obtained in the process (a) to stir the resultant mixture and filtering the
mixture, or by passing the mixed solution obtained in the process (a) through a silica gel
layer to filter the mixed solution and evaporating a solvent from the mixed solution
filtered,
(c) a process of mixing the mixture obtained in the process (b) with ethyl acetate and
15 active carbon to stir the resultant mixture,
(d) a process of obtaining a mixture in a solution state in which the content of the
compound (2) has decreased compared to that in the mixture in the process (b) by
filtering a mixed solution obtamed in the process (c),
(e) a process of adding a solution obtained in the process (d), or a solution obtained by
20 concentrating the solution obtained in the process (d) followed by adding ethyl acetate, to
a solution obtained by adding 1-propanol and t-butyl methyl ether to oxalic acid
dihydrate and stirring the resultant solution,
36
(f) a process of recovering a salt of oxalic acid generated in the process (e) by filtration,
and
(g) a process of obtaining a mixture in a solution state in which the content of the
compound (2) has decreased compared to that in the mixture in the process (d), by adding
5 the salt of oxalic acid obtained in the process (f) to toluene, further adding a potassium
carbonate aqueous solution to neutralize the salt of oxalic acid, and removing an aqueous
phase containing potassium oxalate salt by a phase separation operation.