U.S. patent application number 11/443300 was filed with the patent office on 2006-09-28 for process for producing chromone compound.
Invention is credited to Hiroaki Hibino, Yasunobu Miyamoto, Susumu Ohtsuka, Itsuo Okumoto, Tomoyasu Yoshida.
Application Number | 20060217565 11/443300 |
Document ID | / |
Family ID | 28457865 |
Filed Date | 2006-09-28 |
United States Patent
Application |
20060217565 |
Kind Code |
A1 |
Hibino; Hiroaki ; et
al. |
September 28, 2006 |
Process for producing chromone compound
Abstract
A process for producing a dicarboxylic acid compound represented
by the formula (4): ##STR1## wherein R.sup.1 and R.sup.2 are the
same or different and each represents lower alkyl and the wavy line
indicates that this compound is the E- or Z-isomer or a mixture of
them, characterized by reacting a compound represented by the
formula (2): ##STR2## wherein R.sup.1, R.sup.2 and the wavy line
have the same meanings as the above, and one of X.sup.2 and X.sup.3
represents hydrogen and the other represents halogen, with
nitrophenol represented by the formula (3): ##STR3## in the
presence of a base; a process for producing a nitrochromone
compound represented by the formula (5): ##STR4## wherein R.sup.1
has the same meaning as the above, characterized by reacting the
dicarboxylic acid compound or carboxylic acid thereof with an acid;
a process for producing an aminochromone compound which comprises
reducing the nitrochromone compound; and a process for producing an
amidochromone compound which comprises acylating the aminochromone
compound are provided.
Inventors: |
Hibino; Hiroaki;
(Toyonaka-shi, JP) ; Ohtsuka; Susumu;
(Ibaraki-shi, JP) ; Miyamoto; Yasunobu;
(Toyonaka-shi, JP) ; Yoshida; Tomoyasu; (Oita-shi,
JP) ; Okumoto; Itsuo; (Sakai-gun, JP) |
Correspondence
Address: |
WENDEROTH, LIND & PONACK, L.L.P.
2033 K STREET N. W.
SUITE 800
WASHINGTON
DC
20006-1021
US
|
Family ID: |
28457865 |
Appl. No.: |
11/443300 |
Filed: |
May 31, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10506119 |
Aug 27, 2004 |
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PCT/JP03/02182 |
Feb 27, 2003 |
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11443300 |
May 31, 2006 |
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Current U.S.
Class: |
549/403 ;
560/20 |
Current CPC
Class: |
C07C 205/37 20130101;
C07C 205/37 20130101; C07D 311/24 20130101; C07C 201/12 20130101;
C07C 201/12 20130101 |
Class at
Publication: |
549/403 ;
560/020 |
International
Class: |
C07D 311/02 20060101
C07D311/02 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 28, 2002 |
JP |
2002-053315 |
Feb 28, 2002 |
JP |
2002-053316 |
Jun 11, 2002 |
JP |
2002-169675 |
Jun 11, 2002 |
JP |
2002-169676 |
Claims
1. A process for producing a dicarboxylic acid compound represented
by the formula (4): ##STR17## wherein R.sup.1 and R.sup.2 and the
wavy line are as defined below; which comprises reacting at least
one compound selected from the group consisting of a dihalosuccinic
acid compound represented by the formula (1): ##STR18## wherein
R.sup.1 and R.sup.2 are the same or different and independently
represent a lower alkyl group and X.sup.1 represents a halogen
atom, and a compound represented by the formula (2): ##STR19##
wherein R.sup.1 and R.sup.2 are as defined above, one of X.sup.2
and X.sup.3 represents a hydrogen atom and the other represents a
halogen atom, and the wavy line indicates that this compound is the
E- or Z-isomer or a mixture of them, with a nitrophenol compound
represented by the formula (3): ##STR20## in the presence of a
base.
2. The process according to claim 1, wherein at least one compound
selected from the group consisting of the dihalosuccinic acid
compound represented by the formula (1) and the compound
represented by the formula (2) is the dihalosuccinic acid compound
represented by the formula (1).
3. The process according to claim 1, wherein at least one compound
selected from the group consisting of the dihalosuccinic acid
compound represented by the formula (1) and the compound
represented by the formula (2) is the compound represented by the
formula (2).
4. The process according to claim 3, wherein the compound
represented by the formula (2) is a compound obtained by reaction
of the dihalosuccinic acid compound represented by the formula (1)
with a base.
5. The process according to claim 3, wherein the compound
represented by the formula (2) is a Z-isomer compound.
6. The process according to claim 1, wherein the dihalosuccinic
acid compound represented by the formula (1) is a composition in
which the proportion of a threo-dihalosuccinic acid compound is
higher than that of an erythro-dihalosuccinic acid compound.
7. The process according to claim 1, wherein the dihalosuccinic
acid compound represented by the formula (1) is a composition in
which the proportion of a threo-dihalosuccinic acid compound is 70%
or higher.
8. The process according to claim 1, wherein the dihalosuccinic
acid compound represented by the formula (1) is a
threo-dihalosuccinic acid compound.
9. The process according to claim 6, wherein the composition is a
composition produced by adding a maleic acid compound represented
by the formula (8): ##STR21## wherein R.sup.10 and R.sup.20 are the
same or different and independently represent a lower alkyl group,
to a halogenating agent.
10. The process according to claim 1, wherein the nitrophenol
represented by the formula (3) is 2-nitrophenol.
11. A dicarboxylic acid compound represented by the formula (4a):
##STR22## wherein R.sup.10 and R.sup.20 are the same or different
and independently represent a hydrogen atom or a lower alkyl group,
and the wavy line indicates that this compound is the E- or
Z-isomer or a mixture of them.
12. A process for producing a dihalosuccinic acid compound in which
the proportion of a threo-dihalosuccinic acid compound is 70% or
higher, which comprises adding a maleic acid compound to a
halogenating agent.
13. The process according to claim 12, wherein the maleic acid
compound is a maleic acid compound represented by the formula (8):
##STR23## wherein R.sup.10 and R.sup.20 are the same or different
and independently represent a hydrogen atom or a lower alkyl group,
the halogenating agent is X.sup.1-X.sup.1 wherein X.sup.1 is a
halogen atom, and the threo-dihalosuccinic acid compound is a
threo-dihalosuccinic acid compound having a relative configuration
represented by the formula (9): ##STR24## wherein R.sup.10,
R.sup.20 and X.sup.1 are as defined above.
14. The process according to claim 13, wherein R.sup.10 and
R.sup.20 independently represent a lower alkyl group.
15. The process according to claim 13, wherein at least one of
R.sup.10 and R.sup.20 in the formulas (8) and (9) represents a
hydrogen atom.
16. The process according to claim 15, which further comprises a
step of reacting the resulting threo-dihalosuccinic acid compound
represented by the formula (9) with lower alkyl alcohol in the
presence of an acid catalyst to obtain a threo-dihalosuccinic acid
compound represented by the formula (9) wherein R.sup.10 and
R.sup.20 independently represent a lower alkyl group.
17. A process for producing a nitrochromone compound represented by
the formula (5): ##STR25## wherein R.sup.10 is as defined below;
which comprises reacting a dicarboxylic acid compound represented
by formula (4'): ##STR26## wherein R.sup.10 and R.sup.20 are the
same or different and independently represent a hydrogen atom or a
lower alkyl group and the wavy line indicates that this compound is
the E- or Z-isomer or a mixture of them, with an acid.
18. The process according to claim 17, wherein R.sup.10 and
R.sup.20 represent a hydrogen atom.
19. The process according to claim 18, wherein the dicarboxylic
acid compound represented by the formula (4') wherein R.sup.10 and
R.sup.20 represent a hydrogen atom is a dicarboxylic acid compound
obtained by hydrolyzing the dicarboxylic acid compound represented
by the formula (4): ##STR27## wherein R.sup.1 and R.sup.2
independently represent a lower alkyl group and the wavy line is as
defined above.
20. The process according to claim 17, wherein R.sup.10 and
R.sup.20 independently represent a lower alkyl group.
21. The process according to claim 17, wherein the acid is fuming
sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid,
chlorosulfonic acid or a mixture of them.
22. The process according to claim 17, wherein the reaction product
nitrochromone compound represented by the formula (5) is
nitrochromone carboxylic acid represented by the formula (5)
wherein R.sup.10 represents a hydrogen atom or a mixture of said
carboxylic acid and a nitrochromone compound represented by the
formula (5) wherein R.sup.10 represents a lower alkyl group, and
which further comprises a step of esterifying the nitrochromone
carboxylic acid represented by the formula (5) in the resulting
reaction product by a reaction of said product with an alkylating
agent having a lower alkyl group in the presence of a base to
obtain the nitrochromone compound represented by the formula (5)
wherein R.sup.10 represents a lower alkyl group.
23-28. (canceled)
29. The process according to claim 2, wherein the dihalosuccinic
acid compound represented by the formula (1) is a composition in
which the proportion of a threo-dihalosuccinic acid compound is
higher than that of an erythro-dihalosuccinic acid compound.
30. The process according to claim 3, wherein the dihalosuccinic
acid compound represented by the formula (1) is a composition in
which the proportion of a threo-dihalosuccinic acid compound is
higher than that of an erythro-dihalosuccinic acid compound.
31. The process according to claim 4, wherein the dihalosuccinic
acid compound represented by the formula (1) is a composition in
which the proportion of a threo-dihalosuccinic acid compound is
higher than that of an erythro-dihalosuccinic acid compound.
32. The process according to claim 5, wherein the dihalosuccinic
acid compound represented by the formula (1) is a composition in
which the proportion of a threo-dihalosuccinic acid compound is
higher than that of an erythro-dihalosuccinic acid compound.
33. The process according to claim 2, wherein the dihalosuccinic
acid compound represented by the formula (1) is a composition in
which the proportion of a threo-dihalosuccinic acid compound is 70%
or higher.
34. The process according to claim 3, wherein the dihalosuccinic
acid compound represented by the formula (1) is a composition in
which the proportion of a threo-dihalosuccinic acid compound is 70%
or higher.
35. The process according to claim 4, wherein the dihalosuccinic
acid compound represented by the formula (1) is a composition in
which the proportion of a threo-dihalosuccinic acid compound is 70%
or higher.
36. The process according to claim 5, wherein the dihalosuccinic
acid compound represented by the formula (1) is a composition in
which the proportion of a threo-dihalosuccinic acid compound is 70%
or higher.
37. The process according to claim 6, wherein the dihalosuccinic
acid compound represented by the formula (1) is a composition in
which the proportion of a threo-dihalosuccinic acid compound is 70%
or higher.
38. The process according to claim 2, wherein the dihalosuccinic
acid compound represented by the formula (1) is a
threo-dihalosuccinic acid compound.
39. The process according to claim 3, wherein the dihalosuccinic
acid compound represented by the formula (1) is a
threo-dihalosuccinic acid compound.
40. The process according to claim 4, wherein the dihalosuccinic
acid compound represented by the formula (1) is a
threo-dihalosuccinic acid compound.
41. The process according to claim 5, wherein the dihalosuccinic
acid compound represented by the formula (1) is a
threo-dihalosuccinic acid compound.
42. The process according to claim 7, wherein the composition is a
composition produced by adding a maleic acid compound represented
by the formula (8): ##STR28## wherein R.sup.10 and R.sup.20 are the
same or different and independently represent a lower alkyl group,
to a halogenating agent.
43. The process according to claim 2, wherein the nitrophenol
represented by the formula (3) is 2-nitrophenol.
44. The process according to claim 3, wherein the nitrophenol
represented by the formula (3) is 2-nitrophenol.
45. The process according to claim 4, wherein the nitrophenol
represented by the formula (3) is 2-nitrophenol.
46. The process according to claim 5, wherein the nitrophenol
represented by the formula (3) is 2-nitrophenol.
47. The process according to claim 6, wherein the nitrophenol
represented by the formula (3) is 2-nitrophenol.
48. The process according to claim 7, wherein the nitrophenol
represented by the formula (3) is 2-nitrophenol.
49. The process according to claim 8, wherein the nitrophenol
represented by the formula (3) is 2-nitrophenol.
50. The process according to claim 9, wherein the nitrophenol
represented by the formula (3) is 2-nitrophenol.
Description
TECHNICAL FIELD
[0001] The present invention relates to a process for producing a
chromone compound, which is a useful compound as a pharmaceutical
intermediate.
BACKGROUND ART
[0002] An aminochromone compound is a useful compound as a
pharmaceutical intermediate (e.g. Eur. J. Med. Chem., 32,
547(1997), JP-A 3-95144, etc.) and a known process for producing
said compound comprises reacting a nitrochromone compound with
hydrogen in the presence of a palladium catalyst (e.g. J. Chem.
Soc. (C), 2230(1970), etc.). However, such a process is
unsatisfactory as an industrial production process because it has a
tendency to produce over-reduced compounds, wherein the
carbon-carbon double bond at the 2-position and/or the carbonyl
group at the 4-position of a nitrochromone compound are also
reduced in addition to the nitro group, as byproducts and therefore
the yield of the aminochromone compound thus obtained is low.
[0003] Another known process of synthesizing a compound having a
chromone skeleton comprises hydrolyzing a dicarboxylic acid
compound obtained by addition reaction of an expensive acetylene
compound and a phenol compound to obtain carboxylic acid and then
cyclizing said carboxylic acid to obtain a chromone compound (Aust.
J. Chem., 48, 677(1995)). However, said process is not necessarily
satisfactory industrially because it requires an expensive
acetylene compound. Further, as a process for producing a
nitrochromone compound, a process involving a use of
nitro-substituted 2-hdyroxyacetophenone as a starting material
(JP-A 3-95144) is known and the nitro-substituted
2-hydoxyacetophenone is produced by nitration of
2-hydroxyacetophenone. However, position-selectivity for the nitro
group-introduction in the nitration is low and as a result, isomers
with nitro groups at different substitution positions are produced
as byproducts. Therefore, a step of removing the isomers is
required and thus said process involving a use of nitro-substituted
2-hydroxyacetophenon as a starting material is not necessarily an
industrially satisfactory process.
DISCLOSURE OF INVENTION
[0004] According to a process of the present invention, a
dicarboxylic acid compound represented by the following formula (4)
can be produced advantageously by using a dihalosuccinic acid
compound obtained from a fumaric acid or maleic acid compound,
which is easily available, and a compound derived from said
dihalosuccinic acid compound, and then a nitrochromone compound can
be easily obtained from said dicarboxylic acid.
[0005] An aminochromone compound can be produced by selective
reduction of the nitrochromone compound thus obtained and
consequently, an amidochromone compound useful as a pharmaceutical
intermediate can be industrially advantageously produced from said
aminochromone compound.
[0006] That is, the present invention provides [0007] 1. a process
for producing a dicarboxylic acid compound represented by the
formula (4): ##STR5## wherein R.sup.1 and R.sup.2 and the wavy line
are as defined below; which comprises reacting a dihalosuccinic
acid compound represented by the formula (1): ##STR6## wherein
R.sup.1 and R.sup.2 are the same or different and independently
represent a lower alkyl group and X.sup.1 represents a halogen
atom, and a compound represented by the formula (2): ##STR7##
wherein R.sup.1 and R.sup.2 are as defined above, one of X.sup.2
and X.sup.3 represents a hydrogen atom and the other represents a
halogen atom, and the wavy line indicates that this compound is the
E- or Z-isomer or a mixture of them, with a nitrophenol compound
represented by the formula (3): ##STR8## in the presence of a base;
[0008] 2. a dicarboxylic acid compound represented by the formula
(4a): ##STR9## wherein R.sup.10 and R.sup.20 independently
represent a hydrogen atom or a lower alkyl group and the wavy line
is as defined above; [0009] 3. a process for producing a
threo-dihalosuccinic acid compound, which comprises adding a maleic
acid compound to a halogenating agent; [0010] 4. a process for
producing a nitrochromone compound represented by the formula (5):
##STR10## wherein R.sup.10 is as defined below; which comprises
reacting a dicarboxylic acid compound represented by formula (4'):
##STR11## wherein R.sup.10 and R.sup.20 are the same or different
and independently represent a hydrogen atom or a lower alkyl group,
with an acid; and [0011] 5. a process for producing an
aminochromone compound represented by the formula (6): ##STR12##
wherein R.sup.10 is as defined above; which comprises reacting the
nitrochromone compound represented by the formula (5) with hydrogen
in the presence of a metal catalyst and a base in an organic
solvent.
MODE FOR CARRYING OUT THE INVENTION
[0012] With respect to the compounds represented by the above
formulas (1) to (6), (4a) and (4') and the compounds represented by
the following formulas (7), (8) and (9), the lower alkyl group
denoted by R.sup.1, R.sup.2, R.sup.10 or R.sup.20 includes
C.sub.1-6 straight chain or branched chain alkyl groups and
specific examples thereof are methyl, ethyl, propyl, butyl, pentyl,
hexyl, and the like.
[0013] The halogen atom denoted by X.sup.1 includes chlorine,
bromine and iodine. When X.sup.2 or X.sup.3 represents a halogen
atom, said halogen atom includes the above-mentioned halogen
atoms.
[0014] First, a process for producing a dicarboxylic acid compound
represented by the formula (4) which comprises reacting at least
one compound selected from the group consisting of a dihalosuccinic
acid compound represented by the formula (1) and a compound
represented by the formula (2) with a nitrophenol compound
represented by the formula (3) in the presence of a base will be
explained.
[0015] The dihalosuccinic acid compound represented by the formula
(1) includes, for example, dimethyl 2,3-dichlorosuccinate, dimethyl
2,3-dibromosuccinate, dimethyl 2,3-diiodosuccinate, diethyl
2,3-dichlorosuccinate, diethyl 2,3-dibromosuccinate, diethyl
2,3-diiodosuccinate, di(n-propyl)2,3-dichlorosuccinate,
di(n-propyl)2,3-dibromosuccinate, di(n-propyl)2,3-diiodosuccinate,
diisopropyl 2,3-dichlorosuccinate, diisopropyl
2,3-dibromosuccinate, diisopropyl 2,3-diiodosuccinate,
di(n-butyl)2,3-dichlorosuccinate, di(n-butyl)2,3-dibromosuccinate,
di(n-butyl)2,3-diiodosuccinate, diisobutyl 2,3-dichlorosuccinate,
diisobutyl 2,3-dibromosuccinate, diisobutyl 2,3-diiodosuccinate,
di(sec-butyl)2,3-dichlorosuccinate,
di(sec-butyl)2,3-dibromosuccinate,
di(sec-butyl)2,3-diiodosuccinate,
di(tert-butyl)2,3-dichlorosuccinate,
di(tert-butyl)2,3-dibromosuccinate,
di(tert-butyl)2,3-diiodosuccinate,
di(n-pentyl)2,3-dichlorosuccinate,
di(n-pentyl)2,3-dibromosuccinate, di(n-pentyl)2,3-diiodosuccinate,
di(n-hexyl)2,3-dichlorosuccinate, di(n-hexyl)2,3-dibromosuccinate
and di(n-hexyl)2,3-diiodosuccinate.
[0016] With respect to the dihalosuccinic acid compound represented
by the formula (1), there are two isomers: erythro-isomer and
threo-isomer. The dihalosuccinic acid compound represented by the
formula (1) may be in the erythro-form or the threo-form or a
composition containing both of them. For the present reaction,
either the erythro-isomer or the threo-isomer may be used, or a
composition containing the erythro-isomer and the threo-isomer in
an optional ratio may be used. The dihalosuccinic acid compound
represented by the formula (1) may be commercially available or may
be prepared, for example, according to a method described in JP-A
56-90017, by reacting a fumaric acid or maleic acid compound
represented by the formula (7): ##STR13## wherein R.sup.10,
R.sup.20 and the wavy line are as defined above, with a
halogenating agent in the presence of halogenated hydracid.
[0017] When at least one of R.sup.10 and R.sup.20 represents a
hydrogen atom, a dihalosuccinic acid or its half-esterified
compound obtained by the above-mentioned halogenation can be
appropriately esterified to obtain the dihalosuccinic acid compound
represented by the formula (1). A method of the esterification is
not particularly limited as long as it is a method of synthesizing
ester from carboxylic acid. Known esterification methods that may
be employed are described, for example, in Jikken Kagaku Koza vol.
22, 4th Ed., the Chemical Society of Japan, p. 43, Shin Jikken
Kagaku Koza 14, the Chemical Society of Japan, p. 1002, and
Comprehensive Organic Functional Group Transformations, PERGAMON
(1995) vol. 5, p. 121.
[0018] For example, the dihalosuccinic acid compound represented by
the formula (1) can be derived by a similar method to the following
esterification of threo-dihalosuccinic acid, for example, by
reaction with an alcohol compound represented by the formula
R.sup.1OH or R.sup.2OH in the presence of an acid catalyst.
[0019] Specific examples of the fumaric acid compound or the maleic
acid compound include, for example, fumaric acid, maleic acid,
monomethyl fumarate, monomethyl maleate, dimethyl fumarate,
dimethyl maleate, diethyl fumarate, diethyl maleate,
di(n-propyl)fumarate, di(n-propyl)maleate, diisopropyl fumarate,
diisopropyl maleate, di(n-butyl)fumarate, di(n-butyl)maleate,
diisobutyl fumarate, diisobutyl maleate, di(sec-butyl)fumarate,
di(sec-butyl)maleate, di(tert-butyl)fumarate,
di(tert-butyl)maleate, di(n-pentyl)fumarate, di(n-pentyl)maleate,
di(n-hexyl)fumarate, and di(n-hexyl)maleate.
[0020] The dihalosuccinic acid compound represented by the formula
(1) may be preferably a composition in which the proportion of a
threo-dihalosuccinic acid compound is higher than that of an
erythro-dihalosuccinic acid compound, specifically a composition in
which the proportion of a threo-dihalosuccinic acid compound is 70%
or higher, more preferably a composition in which the proportion of
a threo-dihalosuccinic acid compound is 85% or higher. Such a
composition can be obtained, for example, by adding a maleic acid
compound to a halogenating agent.
[0021] Specific examples of the maleic acid compound are maleic
acid compounds represented by the formula (8): ##STR14## wherein
R.sup.10 and R.sup.20 are the same or different and independently
represent a hydrogen atom or an alkyl group.
[0022] The halogenating agent includes, for example, halogen such
as chlorine or bromine, and halogen addition compounds such as a
tetramethylammonium bromide-bromine addition compound, a
dioxane-bromine addition compound, a pyridine
hydrobromide-dibromide addition compound or a dibenzo-18-crown-6
bromine complex and among them bromine is preferred. The
halogenating agent may be used as it is or as a solution after
dissolving in an organic solvent inert to the reaction.
[0023] The organic solvent inert to the reaction includes, for
example, halogenated hydrocarbon solvents such as dichloromethane,
dichloroethane, chloroform, carbon tetrachloride, chlorobenzene or
dichlorobenzene.
[0024] The amount used of the halogenating agent is usually 1 mole
or more per 1 mole of the maleic acid compound and there is no
upper limit. However, if the amount used is too much, the unreacted
halogenating agent increases, which results in economical
disadvantage. Therefore, the amount used of the halogenating agent
is practically 2 moles or less, preferably 1.5 moles or less per 1
mole of the maleic acid compound.
[0025] If the reaction temperature is too low, the reaction is
difficult to progress and if it is too high, the halogenating agent
is easy to lose. Therefore, the reaction temperature is usually 0
to 80.degree. C., preferably 20 to 60.degree. C.
[0026] The reaction may be carried out in an organic solvent inert
to the reaction. The organic solvent inert to the reaction
includes, for example, halogenated hydrocarbon solvents such as
dichloromethane, dichloroethane, chloroform, carbon tetrachloride,
chlorobenzene or dichlorobenzene and the amount used thereof is not
particularly limited.
[0027] By such a reaction, the proportion of a threo-dihalosuccinic
acid compound in the resulting dihalosuccinic acid compound can be
increased and the threo-dihalosuccinic acid compound can be
produced selectively and in high yield. Particularly, when a maleic
acid compound represented by the formula (8) is used as the maleic
acid compound, a dihalosuccinic acid compound that contains a
threo-dihalosuccinic acid compound having a relative configuration
represented by the formula (9): ##STR15## wherein R.sup.10,
R.sup.20 and X.sup.1 are as defined above, in a proportion of 85%
or more can be obtained easily.
[0028] For the reaction of the halogenating agent and the maleic
acid compound, a reaction container may be previously charged with
the entire amount of the halogenating agent to be used and the
maleic acid compound may be then added thereto, or a reaction
container may be charged with a portion of the halogenating agent
to be used and the remaining halogenating agent and the maleic acid
compound may be then added in parallel thereto. Although the maleic
acid compound may be added at once to the halogenating agent, it is
preferably added continuously or intermittently.
[0029] After completion of the reaction, the reaction solution is
usually mixed with a reducing agent such as sodium sulfite, sodium
hydrogen sulfite or sodium thiosulfate to remove the unreacted
halogenating agent. Then, the reaction solution can be separated by
addition of water and, if necessary, a water-insoluble organic
solvent to obtain an organic layer containing a
threo-dihalosuccinic acid compound. The organic solvent can be
distilled out of the organic layer to isolate the
threo-dihalosuccinic acid compound. The isolated
threo-dihalosuccinic acid compound may be further purified by a
conventional purification means such as column chromatography,
recrystallization or distillation.
[0030] The reducing agent may be used as it is or in the form of an
aqueous solution. When an aqueous solution of the reducing agent is
used, water need not be added in a step of separating a reaction
solution.
[0031] The water-insoluble organic solvent includes, for example,
halogenated hydrocarbon solvents such as dichloromethane,
dichloroethane, chloroform, carbon tetrachloride, chlorobenzene or
dichlorobenzene; aromatic hydrocarbon solvents such as toluene or
xylene; and aliphatic hydrocarbon solvents such as hexane or
heptane and the amount used thereof is not particularly
limited.
[0032] Specific examples of the threo-dihalosuccinic acid compound
are threo-2,3-dichlorosuccinic acid, threo-2,3-dibromosuccinic
acid, dimethyl threo-2,3-dichlorosuccinate, dimethyl
threo-2,3-dibromosuccinate, diethyl threo-2,3-dichlorosuccinate,
diethyl threo-2,3-dibromosuccinate,
di(n-propyl)threo-2,3-dichlorosuccinate,
di(n-propyl)threo-2,3-dibromosuccinate, diisopropyl
threo-2,3-dichlorosuccinate, diisopropyl
threo-2,3-dibromosuccinate, di(n-butyl)threo-2,3-dichlorosuccinate,
di(n-butyl)threo-2,3-dibromosuccinate, diisobutyl
threo-2,3-dichlorosuccinate, diisobutyl threo-2,3-dibromosuccinate,
di(sec-butyl)threo-2,3-dichlorosuccinate,
di(sec-butyl)threo-2,3-dibromosuccinate,
di(tert-butyl)threo-2,3-dichlorosuccinate,
di(tert-butyl)threo-2,3-dibromosuccinate,
di(n-pentyl)threo-2,3-dichlorosuccinate,
di(n-pentyl)threo-2,3-dibromosuccinate,
di(n-hexyl)threo-2,3-dichlorosuccinate, and
di(n-hexyl)threo-2,3-dibromosuccinate.
[0033] When R.sup.10 and R.sup.20 in the formula (8) independently
represent a lower alkyl group, the resulting product containing the
threo-dihalosuccinic acid compound represented by the formula (9)
can be used as the dihalosuccinic acid compound for reaction with
the nitrophenol compound represented by the formula (3).
[0034] When at least one of R.sup.10 and R.sup.20 in the formula
(8) represents a hydrogen atom, the resulting product containing
dihalosuccinic acid and its half ester compound which are the
threo-dihalosuccinic acid compound represented by the formula (9)
(wherein at least one of R.sup.10 and R.sup.20 represents a
hydrogen atom) can be easily converted into a dihalosuccinic acid
compound containing the threo-dihalosuccinic acid compound
represented by the formula (9) (wherein, R.sup.10 and R.sup.20
independently represent a lower alkyl group) by a known
esterification method, similarly to esterification of the
dihalosuccinic acid compound obtained by halogenation of the
compound represented by the formula (7). For example, such a
esterification method can be performed by using a suitable lower
alkyl alcohol such as R.sup.10OH or R.sup.20OH in the presence of
an acid catalyst or by reacting a reactive derivative of the
threo-dihalosuccinic acid, such as a threo-dihalosuccinic acid
halide, derived from the carboxylic acid and a carboxylic acid
activator such as thionyl chloride with the above-mentioned lower
alkyl alcohol, in the presence of a catalyst such as a base if
necessary.
[0035] The compound (2) can be obtained by, for example, reacting
the above-mentioned compound (1) with a base. The base includes,
for example, organic bases such as triethylamine and inorganic
bases such as sodium carbonate or sodium hydrogen carbonate, and
the amount used thereof is usually 1 to 2 moles per 1 mole of the
dihalosuccinic acid compound (1).
[0036] Depending on reaction conditions, a portion of the
dihalosuccinic acid compound (1) may remain unreacted and a mixture
of the dihalosuccinic acid compound (1) and the compound (2) may be
obtained, which mixture may be also used for the reaction with the
nitrophenol represented by the formula (3).
[0037] The compound (2) includes, for example, dimethyl
2-chlorofumarate, dimethyl 2-chloromaleate, dimethyl
2-bromofumarate, dimethyl 2-bromomaleate, dimethyl 2-iodofumarate,
dimethyl 2-iodomaleate, diethyl 2-chlorofumarate, diethyl
2-chloromaleate, diethyl 2-bromofumarate, diethyl 2-bromomaleate,
diethyl 2-iodofumarate, diethyl 2-iodomaleate,
di(n-propyl)2-chlorofumarate, di(n-propyl)2-chloromaleate,
di(n-propyl)2-bromofumarate, di(n-propyl)2-bromomaleate,
di(n-propyl)2-iodofumarate, di(n-propyl)2-iodomaleate, diisopropyl
2-chlorofumarate, diisopropyl 2-chloromaleate, diisopropyl
2-bromofumarate, diisopropyl 2-bromomaleate, diisopropyl
2-iodofumarate, diisopropyl 2-iodomaleate,
di(n-butyl)2-chlorofumarate, di(n-butyl)2-chloromaleate,
di(n-butyl)2-bromofumarate, di(n-butyl)2-bromomaleate,
di(n-butyl)2-iodofumarate, di(n-butyl)2-iodomaleate, diisobutyl
2-chlorofumarate, diisobutyl 2-chloromaleate, diisobutyl
2-bromofumarate, diisobutyl 2-bromomaleate, diisobutyl
2-iodofumarate, diisobutyl 2-iodomaleate,
di(sec-butyl)2-chlorofumarate, di(sec-butyl)2-chloromaleate,
di(sec-butyl)2-bromofumarate, di(sec-butyl)2-bromomaleate,
di(sec-butyl)2-iodofumarate, di(sec-butyl)2-iodomaleate,
di(sec-butyl)2-chlorofumarate, di(sec-butyl)2-chloromaleate,
di(sec-butyl)2-bromofumarate, di(sec-butyl)2-bromomaleate,
di(sec-butyl)2-iodofumarate, di(sec-butyl)2-iodomaleate,
di(tert-butyl)2-chlorofumarate, di(tert-butyl)2-chloromaleate,
di(tert-butyl)2-bromofumarate, di(tert-butyl)2-bromomaleate,
di(tert-butyl)2-iodofumarate, di(tert-butyl)2-iodomaleate,
di(n-pentyl)2-chlorofumarate, di(n-pentyl)2-chloromaleate,
di(n-pentyl)2-bromofumarate, di(n-pentyl)2-bromomaleate,
di(n-pentyl)2-iodofumarate, di(n-pentyl)2-iodomaleate,
di(n-hexyl)2-chlorofumarate, di(n-hexyl)2-chloromaleate,
di(n-hexyl)2-bromofumarate, di(n-hexyl)2-bromomaleate,
di(n-hexyl)2-iodofumarate, and di(n-hexyl)2-iodomaleate. Preferably
the Z-forms (fumaric acid type) are used.
[0038] The nitrophenol compound represented by the formula (3)
(hereinafter, referred as the nitrophenol compound (3)) includes,
for example, 2-nitrophenol, 3-nitrophenol and 4-nitrophenol.
[0039] The dicarboxylic compound (4) may be produced by reacting
either the dihalosuccinic acid compound (1) or the compound (2)
with the nitrophenol (3) or by reacting a mixture of the
dihalosuccinic acid compound (1) and the compound (2) with the
nitrophenol (3).
[0040] Either one of the nitrophenol compound (3) and at least one
compound selected from the group consisting of the dihalosuccinic
acid compound (1) and the compound (2) may be used in an amount of
1 mole or more per 1 mole of the other.
[0041] The reaction of at least one compound selected from the
group consisting of the dihalosuccinic acid compound (1) and the
compound (2) with the nitrophenol compound (3) is usually carried
out in an organic solvent. The organic solvent includes, for
example, aprotic polar solvents such as N,N-dimethylformamide,
N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, dimethyl
sulfoxide, sulfolane, acetonitrile or propionitrile; alcohol
solvents such as methanol or ethanol; ketone solvents such as
acetone or methyl isobutyl ketone; aromatic hydrocarbon solvents
such as toluene or xylene; halogenated hydrocarbon solvents such as
dichloromethane, dichloroethane, chlorobenzene or dichlorobenzene;
ether solvents such as dimethyl ether, methyl tert-butyl ether or
tetrahydrofuran; ester solvents such as ethyl acetate; and pyridine
solvents such as pyridine or 5-ethyl-2-methylpyridine. These
solvents may be used alone or as a mixture of two or more of these.
Preferred are single solvents or mixtures of aprotic polar
solvents, aromatic hydrocarbon solvents and halogenated hydrocarbon
solvents. The amount used of the solvent is usually 2 to 50 parts
by weight per 1 part by weight of the nitrophenol compound (3).
[0042] The base includes, for example, alkali metal hydrides such
as sodium hydride or potassium hydride; alkaline earth metal
hydrides such as calcium hydride; alkali metal hydroxides such as
lithium hydroxide, sodium hydroxide or potassium hydroxide;
alkaline earth metal hydroxides such as calcium hydroxide or barium
hydroxide; alkali metal carbonates such as lithium carbonate,
sodium carbonate or potassium carbonate; alkaline earth metal
carbonates such as calcium carbonate; alkali metal hydrogen
carbonates such as sodium hydrogen carbonate or potassium hydrogen
carbonate; and organic amines such as triethylamine or pyridine.
These bases may be used alone or as a mixture of two or more of
these. Preferred are alkali metal hydrides and alkali metal
carbonates and more preferred are alkali metal carbonates.
[0043] The amount used of the base may be suitably set based on the
amounts used of the nitrophenol (3) and at least one compound
selected from the group consisting of the dihalosuccinic acid
compound (1) and the compound (2). For example, when the
dihalosuccinic acid compound (1) and the nitrophenol compound (3)
are reacted and the amount used of the nitrophenol compound (3) is
smaller than that of the other, the amount used of the base is
usually 2 moles or more per 1 mole of the nitrophenol compound (3)
and when the amount used of the dihalosuccinic acid compound (1) is
smaller than that of the other, the amount used of the base is
usually 2 moles or more per 1 mole of the dihalosuccinic acid
compound (1). Further, for example, when the dihalosuccinic acid
compound (1) and the nitrophenol (3) are reacted and the amount
used of the nitrophenol compound (3) is smaller than that of the
other, the amount used of the base is usually 1 mole or more per 1
mole of the nitrophenol compound (3) and when the amount used of
the compound (2) is smaller than that of the other, the amount used
of the base is usually 1 mole or more per 1 mole of compound (2).
There is no upper limit of the amount used of the base. However, if
the amount used of the base is too much, it will result in
economical disadvantage and therefore, the amount used of the base
is practically 10 moles or less, preferably 5 moles or less per 1
mol of either one of the nitrophenol compound (3) and at least one
compound selected from the group consisting of the dihalosuccinic
acid compound (1) and the compound (2), wherein the one is used in
a smaller amount than the amount used of the other.
[0044] The reaction temperature is usually 20 to 150.degree. C.
Further, the reaction may be usually carried out by mixing and
contacting at least one compound selected from the group consisting
of the dihalosuccinic acid compound (1) and the compound (2), the
nitrophenol compound (3) and the base in an organic solvent. The
order of mixing them is not particularly limited and however, it is
preferable to mix at least one compound selected from the group
consisting of the dihalosuccinic acid compound (1) and the compound
(2) with a mixture of the nitrophenol compound (3) and the
base.
[0045] Coexistence of a phase transfer catalyst in the reaction
system makes it possible to more smoothly progress the reaction of
at least one compound selected from the group consisting of the
dihalosuccinic acid compound (1) and the compound (2) with the
nitrophenol compound (3) and thereby to obtain the dicarboxylic
acid compound (4) in a higher yield.
[0046] The phase transfer catalyst includes, for example,
quaternary ammonium chlorides such as tetramethylammonium chloride,
tetraethylammonium chloride, tetra(n-propyl)ammonium chloride,
tetraisopropylammonium chloride, tetra(n-butyl)ammonium chloride,
trimethylbenzylammonium chloride, or triethylbenzylammonium
chloride; quaternary ammonium bromides such as tetramethylammonium
bromide, tetraethylammonium bromide, tetra(n-propyl)ammonium
bromide, tetraisopropylammonium bromide, tetra(n-butyl)ammonium
bromide, trimethylbenzylammonium bromide or triethylbenzylammonium
bromide; and quaternary ammonium iodides such as
tetramethylammonium iodide, tetraethylammonium iodide,
tetra(n-propyl)ammonium iodide, tetraisoproyylammonium iodide,
tetra(n-butyl)ammonium iodide, trimethylbenzylammonium iodide or
triethylbenzylammonium iodide.
[0047] The amount used of the phase transfer catalyst is usually
0.005 to 0.5 mole, preferably 0.01 to 0.2 mole per 1 mole of either
one of the nitrophenol compound (3) and at least one compound
selected from the group consisting of the dihalosuccinic acid
compound (1) and the compound (2), wherein the one is used in a
smaller amount than the amount used of the other.
[0048] After completion of the reaction, a reaction solution
containing the dicarboxylic acid compound (4) is obtained. For
example, the reaction solution can be separated by adding water
and, if necessary, a water-insoluble organic solvent to the
reaction solution or by adding the reaction solution to water and,
if necessary, a water-insoluble organic solvent, to obtain an
organic layer. The organic layer thus obtained can be then
concentrated to isolate the dicarboxylic acid compound (4), which
can be used for a reaction with acid. The isolated dicarboxylic
acid compound (4) may be used after further purification by a
conventional purification means. The organic layer containing the
dicarboxylic acid compound (4) obtained by separation of the
reaction solution as described above may be also used as it is or
after washing.
[0049] The above-mentioned reaction solution may be also used as it
is or in the case of containing insoluble matters, after removing
the insoluble matters by filtration or the like if necessary.
[0050] With respect to the dicarboxylic acid compound (4), there
are two geometrical isomers: a maleic acid compound wherein a group
represented by --CO.sub.2R.sup.1 and a group represented by
--CO.sub.2R.sup.2 are positioned on the same side of the
carbon-carbon double bond and a fumaric acid compound wherein these
groups are positioned on the opposite side. In the present
invention, either one of the two geometrical isomers may be used or
a mixture of the two geometrical isomers in an optional ratio may
be used. The carboxylic acid ester group of the dicarboxylic acid
compound (4) may be hydrolyzed with alkali to obtain carboxylic
acid and said carboxylic acid may be then subjected to reaction
with acid. The conversion into carboxylic acid may be carried out
according to a known method (e.g. Aust. J. Chem., 48,
677(1995)).
[0051] Such a dicarboxylic acid compound (4') includes, for
example, 2-(2-nitrophenoxy)fumaric acid, 2-(2-nitrophenoxy)maleic
acid, 2-(3-nitrophenoxy)fumaric acid, 2-(3-nitrophenoxy)maleic
acid, 2-(4-nitrophenoxy)fumaric acid, 2-(4-nitrophenoxy)maleic
acid, dimethyl 2-(2-nitrophenoxy)fumarate, dimethyl
2-(2-nitrophenoxy)maleate, dimethyl 2-(3-nitrophenoxy)fumarate,
dimethyl 2-(3-nitrophenoxy)maleate, dimethyl
2-(4-nitrophenoxy)fumarate, dimethyl 2-(4-nitrophenoxy)maleate,
diethyl 2-(2-nitrophenoxy)fumarate, diethyl
2-(2-nitrophenoxy)maleate, diethyl 2-(3-nitrophenoxy)fumarate,
diethyl 2-(3-nitrophenoxy)maleate, diethyl
2-(4-nitrophenoxy)fumarate, diethyl 2-(4-nitrophenoxy)maleate,
di(n-propyl)2-(2-nitrophenoxy)fumarate,
di(n-propyl)2-(2-nitrophenoxy)maleate,
di(n-propyl)2-(3-nitrophenoxy)fumarate,
di(n-propyl)2-(3-nitrophenoxy)maleate,
di(n-propyl)2-(4-nitrophenoxy)fumarate,
di(n-propyl)2-(4-nitrophenoxy)maleate,
di(n-butyl)2-(2-nitrophenoxy)fumarate,
di(n-butyl)2-(2-nitrophenoxy)maleate,
di(n-butyl)2-(3-nitrophenoxy)fumarate,
di(n-butyl)2-(3-nitrophenoxy)maleate,
di(n-butyl)2-(4-nitrophenoxy)fumarate,
di(n-butyl)2-(4-nitrophenoxy)maleate,
di(tert-butyl)2-(2-nitrophenoxy)fumarate,
di(tert-butyl)2-(2-nitrophenoxy)maleate,
di(tert-butyl)2-(3-nitrophenoxy)fumarate,
di(tert-butyl)2-(3-nitrophenoxy)maleate,
di(tert-butyl)2-(4-nitrophenoxy)fumarate,
di(tert-butyl)2-(4-nitrophenoxy)maleate,
di(n-hexyl)2-(2-nitrophenoxy)fumarate,
di(n-hexyl)2-(2-nitrophenoxy)maleate,
di(n-hexyl)2-(3-nitrophenoxy)fumarate,
di(n-hexyl)2-(3-nitrophenoxy)maleate,
di(n-hexyl)2-(4-nitrophenoxy)fumarate, and
di(n-hexyl)2-(4-nitrophenoxy)maleate, and these may be used alone
or as a mixture of two or more of these.
[0052] Next, the process for producing the nitrochromone compound
represented by the formula (5) (hereinafter, referred as the
nitrochromone compound (5)) by reacting the dicarboxylic acid
compound (4') with an acid will be explained.
[0053] The acid includes, for example, fuming sulfuric acid,
concentrated sulfuric acid, methanesulfonic acid,
trifluoromethanesulfonic acid and chlorosulfonic acid and these
acids may be used alone or as a mixture of two or more of them.
Among them, chlorosulfonic acid is preferred.
[0054] The amount used of such an acid is usually 1 part by weight
or more per 1 part by weight of the dicarboxylic acid compound
(4'). There is no upper limit of the amount and however, in
consideration of volume efficiency or economical efficiency, it is
practically 50 parts by weight or less per 1 part by weight of the
dicarboxylic acid compound (4'). In addition, when the reaction
solution containing the dicarboxylic acid compound (4') obtained by
reaction of at least compound selected from the group consisting of
the compound (1) and the compound (2) with the nitrophenol compound
(3) as described above is used as it is, the amount used of the
acid may be determined in consideration of the amount of an acid to
be used for neutralizing the base remaining in the reaction
solution.
[0055] The reaction of the dicarboxylic acid compound (4') and the
acid may be carried out by mixing and contacting them with each
other and the order of mixing them is not particularly limited.
[0056] The reaction of the dicarboxylic acid compound (4') and the
acid is usually carried out without using a solvent, and however,
the reaction may be also carried out in the presence of an organic
solvent. The organic solvent is not particularly limited as long as
it does not react with an acid.
[0057] The reaction temperature varies depending on the type of the
acid to be used and it is usually 0 to 150.degree. C., preferably
50 to 120.degree. C.
[0058] After completion of the reaction, the resulting reaction
solution containing the nitrochromone compound (5) can be usually
mixed with water to isolate the nitrochromone compound (5) as a
crystal.
[0059] Alternatively, the reaction solution containing the
nitrochromone compound (5) can be mixed with water, and then a
water-insoluble organic solvent if necessary, to carry out
extraction and the organic layer thus obtained can be concentrated
to isolate the nitrochromone compound (5). The water-insoluble
organic solvent includes, for example, aromatic hydrocarbon
solvents such as toluene or xylene; ester solvents such as ethyl
acetate; aliphatic hydrocarbon solvents such as hexane or heptane;
and halogenated hydrocarbon solvents such as dichloromethane or
chlorobenzene.
[0060] Although the amount used of water is not particularly
limited, it is usually 0.5 to 100 parts by weight per 1 part by
weight of the dicarboxylic acid compound. In consideration of the
volume efficiency or economical efficiency, it is practically 1 to
20 parts by weight per 1 part by weight of the dicarboxylic acid
compound.
[0061] A method of mixing the reaction solution containing the
nitrochromone compound (5) with water may be any method capable of
mixing and contacting them with each other. Although the order of
mixing them is not particularly limited, in terms of easy control
of heat generation caused by mixing, it is preferable to add the
reaction solution containing the nitrochromone compound (5) to
water.
[0062] As water to be used, an aqueous salt solution containing an
inorganic salt such as sodium chloride, sodium bromide, potassium
chloride, potassium bromide, lithium chloride, lithium bromide,
calcium chloride or sodium sulfate may be used. The concentration
of the inorganic salt is in the range from 0% by weight to the
saturated solubility and is not particularly limited.
[0063] The temperature for mixing the reaction solution containing
the nitrochromone compound (5) with water is in the range from
above the solidifying point to the reflux temperature of the system
and is not particularly limited. In order to obtain the carboxylic
acid ester of the formula (5), the reaction solution and water are
preferably mixed under cooling, for example, at 0.degree. C. or
lower, so that the compound represented by the formula (5) can be
mainly obtained as carboxylic acid ester.
[0064] The crystal of the reaction product precipitated after the
mixing can be obtained usually as a solid by filtration.
[0065] From the dicarboxylic acid compound represented by the
formula (4') in which R.sup.10 is hydrogen, the nitrochromone
compound represented by the formula (5) in which R.sup.10 is
hydrogen is obtained. From the dicarboxylic acid compound
represented by the formula (4') in which R.sup.10 is a lower alkyl
group, the carboxylic acid ester compound of the nitrochromone
compound represented by the formula (5) in which R.sup.10 is a
lower alkyl group is obtained. Further, the group
--CO.sub.2R.sup.10 at the 2-position of said carboxylic acid ester
compound is hydrolyzed by the above-mentioned treatment to produce
nitrochromone carboxylic acid having the carboxyl group --CO.sub.2H
at the 2-position or a mixture of the above-mentioned carboxylic
acid ester compound and said carboxylic acid. The carboxylic acid
ester compound or carboxylic acid of the nitrochromone compound
thus obtained or a mixture thereof may be subjected to
recrystallization or extraction to purify or isolate the carboxylic
acid eater or carboxylic acid of the nitrochromone compound, if
necessary. By the following method, the carboxylic acid of the
nitrochromone compound of the formula (5) thus obtained or a
mixture of the carboxylic acid compound and the carboxylic acid
ester compound can be reacted with an alkylating agent in the
presence of a base to esterify the carboxyl group of the
nitrochromone compound. A method for the esterification is not
particularly limited as long as it is a method for synthesizing
ester from carboxylic acid. It may be a known method, for example,
described in Jikken Kagaku Koza vol. 22, 4th Ed., the Chemical
Society of Japan, p. 43; Shin Jikken Kagaku Koza vol.14, the
Chemical Society of Japan p.1002; or Comprehensive Organic
Functional Group Transformations, PERGAMON (1995) vol. 5, p.
121.
[0066] Preferred methods are, for example, a method for
esterification by reacting with lower alcohol represented by
R.sup.1OH or R.sup.2OH (wherein R.sup.1 and R.sup.2 are as defined
above) in the presence of an acid catalyst; a method for
esterification by reacting with alcohol via carboxylic acid
chloride; and a method for esterification by using a suitable
alkylating agent [e.g. the formula R.sup.1-L (wherein R.sup.1 is as
defined above, L represents a leaving group such as a halogen atom
or aryl-(phenyl or tosyl), alkyl- or haloalkylsulfonyloxy)] in the
presence of an organic base in an aprotic organic solvent.
[0067] The method for esterification by using an alkylating agent
in the presence of an organic base in an aprotic organic solvent is
preferably employed. This method will be explained in details
below.
[0068] The aprotic organic solvent includes, for example, aprotic
polar solvents such as N,N-dimethylformamide, N-methylpyrrolidone,
1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, sulfolane,
acetonitrile or propionitrile; ketone solvents such as acetone or
methyl isobutyl ketone; aromatic hydrocarbon solvents such as
toluene or xylene; halogenated hydrocarbon solvents such as
dichloromethane, dichloroethane, chlorobenzene or dichlorobenzene;
ether solvents such as dimethyl ether, methyl tert-butyl ether or
tetrahydrofuran; and ester solvents such as ethyl acetate and these
solvents may be used alone or as a mixture of two or more of these.
Preferably, aromatic hydrocarbon solvents or ester solvents are
used alone or as a mixture of two or more of them. The amount used
of the solvent is usually 1 to 50 parts by weight per 1 part by
weight of the nitrochromone carboxylic acid mixture.
[0069] The organic base includes, for example, tertiary amines such
as triethylamine, tributylamine, diisopropylethylamine or
1,8-diazabicyclo[5.4.0]undeca-7-ene; and pyridine compounds such as
pyridine or 5-ethyl-2-methylpyridine, and these bases may be used
alone or as a mixture of two or more of these. Among them,
aliphatic tertiary amines are preferred.
[0070] Although the amount used of the organic base is not
particularly limited, it is usually 0.8 to 5 moles, preferably 0.9
to 3 moles per 1 mole of the nitrochromone compound (5) in which
R.sup.10 is hydrogen because use of too much organic base results
in economic disadvantage and difficulty in purification.
[0071] The alkylating agent includes, for example, alkyl halides
such as methyl chloride, ethyl chloride, propyl chloride, butyl
chloride, methyl bromide, ethyl bromide, propyl bromide, butyl
bromide, isobutyl bromide, isopropyl bromide, pentyl bromide, hexyl
bromide, methyl iodide, ethyl iodide, pentyl iodide, isobutyl
iodide, isopropyl iodide, pentyl iodide, hexyl iodide, butyl
iodide, propyl iodide, heptyl iodide, or hexyl iodide; sulfonic
acid alkyl esters such as methanesulfonic acid alkyl ester,
chloromethanesulfonic acid alkyl ester, p-toluenesulfonic acid
alkyl ester, trifluoromethanesulfonic acid alkyl ester,
nonafluorobutanesulfonic acid alkyl ester (wherein the alkyl group
includes methyl, ethyl, propyl, butyl, isopropyl and isobutyl); and
dialkyl sulfate such as diethyl sulfate or dimethyl sulfate. Among
them, dialkyl sulfate is preferred.
[0072] Although the amount used of the alkylating agent is not
particularly limited, it is usually about 0.8 to 5 moles,
preferably about 0.9 to 3 moles per 1 mole of the nitrochromone
carboxylic acid because use of too much alkylating agent results in
economic disadvantage and difficulty in purification.
[0073] Although the temperature for the esterification is not
particularly limited, it is in the range from above the solidifying
point to the reflux temperature of the system, preferably about 10
to 100.degree. C. By such methods, nitrochromone compound esters
having ester groups suitable to the purposes can be produced.
[0074] The nitrochromone compound (5) thus obtained includes, for
example, 5-nitro-2-carboxy-4-oxo-4H-1-benzopyran,
6-nitro-2-carboxy-4-oxo-4H-1-benzopyran,
7-nitro-2-carboxy-4-oxo-4H-1-benzopyran,
8-nitro-2-carboxy-4-oxo-4H-1-benzopyran,
5-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran,
6-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran,
7-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran,
8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran,
5-nitro-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran,
6-nitro-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran,
7-nitro-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran,
8-nitro-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran,
5-nitro-2-(n-propoxycarbonyl)-4-oxo-4H-1-benzopyran,
6-nitro-2-(n-propoxycarbonyl)-4-oxo-4H-1-benzopyran,
7-nitro-2-(n-propoxycarbonyl)-4-oxo-4H-1-benzopyran,
8-nitro-2-(n-propoxycarbonyl)-4-oxo-4H-1-benzopyran,
5-nitro-2-isopropoxycarbonyl-4-oxo-4H-1-benzopyran,
6-nitro-2-isopropoxycarbonyl-4-oxo-4H-1-benzopyran,
7-nitro-2-isopropoxycarbonyl-4-oxo-4H-1-benzopyran,
8-nitro-2-isopropoxycarbonyl-4-oxo-4H-1-benzopyran,
5-nitro-2-(n-butoxycarbonyl)-4-oxo-4H-1-benzopyran,
6-nitro-2-(n-butoxycarbonyl)-4-oxo-4H-1-benzopyran,
7-nitro-2-(n-butoxycarbonyl)-4-oxo-4H-1-benzopyran,
8-nitro-2-(n-butoxycarbonyl)-4-oxo-4H-1-benzopyran,
5-nitro-2-isobutoxycarbonyl-4-oxo-4H-1-benzopyran,
6-nitro-2-isobutoxycarbonyl-4-oxo-4H-1-benzopyran,
7-nitro-2-isobutoxycarbonyl-4-oxo-4H-1-benzopyran,
8-nitro-2-isobutoxycarbonyl-4-oxo-4H-1-benzopyran,
5-nitro-2-(tert-butoxycarbonyl)-4-oxo-4H-1-benzopyran,
6-nitro-2-(tert-butoxycarbonyl)-4-oxo-4H-1-benzopyran,
7-nitro-2-(tert-butoxycarbonyl)-4-oxo-4H-1-benzopyran,
8-nitro-2-(tert-butoxycarbonyl)-4-oxo-4H-1-benzopyran,
5-nitro-2-(n-pentyloxycarbonyl)-4-oxo-4H-1-benzopyran,
6-nitro-2-(n-pentyloxycarbonyl)-4-oxo-4H-1-benzopyran,
7-nitro-2-(n-pentyloxycarbonyl)-4-oxo-4H-1-benzopyran,
8-nitro-2-(n-pentyloxycarbonyl)-4-oxo-4H-1-benzopyran,
5-nitro-2-(n-hexyloxycarbonyl)-4-oxo-4H-1-benzopyran,
6-nitro-2-(n-hexyloxycarbonyl)-4-oxo-4H-1-benzopyran,
7-nitro-2-(n-hexyloxycarbonyl)-4-oxo-4H-1-benzopyran, and
8-nitro-2-(n-hexyloxycarbonyl)-4-oxo-4H-1-benzopyran.
[0075] Next, a step of reducing the nitrochromone compound to
obtain an aminochromone compound will be explained.
[0076] The metal species of a metal catalyst used in the present
invention includes, for example, late transition metals such as
palladium, platinum., nickel, rhodium, ruthenium, iridium or
cobalt. The metal catalyst includes, for example, heterogeneous
metal catalysts, wherein the metal species is supported on a
carrier such as activated carbon, silica or alumina, such as
palladium/carbon, platinum/carbon, rhodium/carbon,
ruthenium/carbon, palladium/silica or palladium/alumina and
homogeneous metal catalysts such as
chlorotris(triphenylphosphine)rhodium,
tetrakis(triphenylphosphine)palladium, palladium acetate,
dichlorotris(triphenylphosphine)ruthenium,
tetrakis(triphenylphosphine)platinum or
tetrakis(triphenylphosphine)nickel.
[0077] The amount used of such a metal catalyst is usually 0.00001
to 0.01 parts by weight on the basis of metal weight per 1 part by
weight of the nitrochromone compound (5).
[0078] The base includes, for example, alkali metal hydroxide such
as sodium hydroxide; alkaline earth metal hydroxide such as calcium
hydroxide; alkali metal carbonate such as lithium carbonate, sodium
carbonate or potassium carbonate; alkaline earth metal carbonate
such as calcium carbonate; alkali metal hydrogen carbonate such as
sodium hydrogen carbonate or potassium hydrogen carbonate; alkali
metal monohydrogenphosphate such as sodium monohydrogenphosphate;
alkali metal phosphate such as sodium phosphate; alkali metal
carboxylate such as sodium acetate, lithium acetate, potassium
acetate, sodium propionate, sodium benzoate, sodium oxalate, sodium
malonate, or sodium tartrate; tertiary amine such as triethylamine,
tri(n-butyl)amine, dimethylaniline, N-methylpyrrolidine, or
N-methylmorpholine; and pyridine compounds such as pyridine,
2-methylpyridine, 2-methyl-5-ethylpyridine, or
4-dimethylaminopyridine, and among them, preferred are alkali metal
carbonate, alkali metal hydrogen carbonate, alkali metal
carboxylate, tertiary amine and pyridine compounds. Such bases may
be used alone or as a mixture of two or more of them and may be
used as they are or as a mixture with the above-mentioned organic
solvent or water.
[0079] The amount used of the base is usually 0.01 mole or more per
1 mole of the nitrochromone compound (5) and there is no upper
limit thereof. For example, if the base is in the liquid form under
the reaction condition, it may be used both as a base and a
reaction solvent in a considerably excess amount. However, in
consideration of the cost, the amount used of the base is
practically 5 moles or less per 1 mole of the nitrochromone
compound (5).
[0080] The reaction temperature is usually 0 to 100.degree. C. The
amount used of hydrogen is usually 3 moles or more per 1 mole of
the nitrochromone compound (5) and the upper limit is not
particularly limited.
[0081] The reaction may be carried out under the normal pressure or
a pressurized condition. When the reaction is carried out under a
pressurized condition, the pressurized condition is preferably 5
MPa or lower in consideration of a practical aspect.
[0082] The reaction is usually carried out in the presence of an
organic solvent. The organic solvent includes, for example, aprotic
polar solvents such as N,N-dimethylformamide; alcohol solvents such
as methanol or ethanol; aromatic hydrocarbon solvents such as
toluene or xylene; halogenated hydrocarbon solvents such as
dichloromethane, dichloroethane, chlorobenzene or dichlorobenzene;
ether solvents such as dimethyl ether, methyl tert-butyl ether or
tetrahydrofuran; and ester solvents such as ethyl acetate and these
solvents may be used alone or as a mixture of two or more of these.
Further, when the base used is in the liquid form under the
reaction condition, the base may be used as a solvent. The amount
used of the solvent is usually 2 to 50 parts by weight per 1 part
by weight of the nitrochromone compound (5).
[0083] When a heterogeneous metal catalyst is used, the
heterogeneous metal catalyst is usually removed from a reaction
solution by filtration to obtain a solution containing the
aminochromone compound represented by the formula (6) wherein
R.sup.10 represents a hydrogen atom or a C.sub.1-6 alky group
(hereinafter, referred as the aminochromone compound (6)) and the
solution can be concentrated to isolate the aminochromone compound
(6). Alternatively, the aminochromone compound (6) can be
crystallized from the solution. A method for the crystallization
includes, for example, cooling of the above-mentioned solution and
mixing of the above-mentioned solution with an insufficient
solvent.
[0084] In the process of the present invention, byproduction of
over-reduced compounds is suppressed, so that the aminochromone
compound (6) with a high purity can be isolated. The isolated
aminochromone compound (6) may be further purified by a
conventional purification means such as recrystallization. In
addition, in a step of removing the above-mentioned heterogeneous
metal catalyst, acid may be added. The acid includes, for example,
mineral acid such as hydrochloric acid, sulfuric acid or phosphoric
acid and organic acid such as formic acid or acetic acid. The
amount added of the acid is usually 0.1 to 3 moles per 1 mole of
the base used. When acid is added for removal of the heterogeneous
metal catalyst, depending on the amount added of the acid, a
mixture of the aminochromone compound (6) and an acid addition salt
of the aminochromone compound (6), or an acid addition salt of the
aminochromone compound (6) alone may be obtained. When the
homogeneous metal catalyst is used, the aminochromone compound (6)
may be isolated, for example, by crystallization from a reaction
solution, or by flocculation and filtration of the catalyst in a
reaction solution and then concentration or crystallization of the
filtrate.
[0085] The aminochromone compound (6) thus obtained includes, for
example, 5-amino-2-carboxy-4-oxo-4H-1-benzopyran,
6-amino-2-carboxy-4-oxo-4H-1-benzopyran,
7-amino-2-carboxy-4-oxo-4H-1-benzopyran,
8-amino-2-carboxy-4-oxo-4H-1-benzopyran,
5-amino-2-methoxycarbonyl-4-oxo-4H-1-benzopyran,
6-amino-2-methoxycarbonyl-4-oxo-4H-1-benzopyran,
7-amino-2-methoxycarbonyl-4-oxo-4H-1-benzopyran,
8-amino-2-methoxycarbonyl-4-oxo-4H-1-benzopyran,
5-amino-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran,
6-amino-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran,
7-amino-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran,
8-amino-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran,
5-amino-2-(n-propoxycarbonyl)-4-oxo-4H-1-benzopyran,
6-amino-2-(n-propoxycarbonyl)-4-oxo-4H-1-benzopyran,
7-amino-2-(n-propoxycarbonyl)-4-oxo-4H-1-benzopyran,
8-amino-2-(n-propoxycarbonyl)-4-oxo-4H-1-benzopyran,
5-amino-2-isopropoxycarbonyl-4-oxo-4H-1-benzopyran,
6-amino-2-isopropoxycarbonyl-4-oxo-4H-1-benzopyran,
7-amino-2-isopropoxycarbonyl-4-oxo-4H-1-benzopyran,
8-amino-2-isopropoxycarbonyl-4-oxo-4H-1-benzopyran,
5-amino-2-(n-butoxycarbonyl)-4-oxo-4H-1-benzopyran,
6-amino-2-(n-butoxycarbonyl)-4-oxo-4H-1-benzopyran,
7-amino-2-(n-butoxycarbonyl)-4-oxo-4H-1-benzopyran,
8-amino-2-(n-butoxycarbonyl)-4-oxo-4H-1-benzopyran,
5-amino-2-isobutoxycarbonyl-4-oxo-4H-1-benzopyran,
6-amino-2-isobutoxycarbonyl-4-oxo-4H-1-benzopyran,
7-amino-2-isobutoxycarbonyl-4-oxo-4H-1-benzopyran,
8-amino-2-isobutoxycarbonyl-4-oxo-4H-1-benzopyran,
5-amino-2-(tert-butoxycarbonyl)-4-oxo-4H-1-benzopyran,
6-amino-2-(tert-butoxycarbonyl)-4-oxo-4H-1-benzopyran,
7-amino-2-(tert-butoxycarbonyl)-4-oxo-4H-1-benzopyran,
8-amino-2-(tert-butoxycarbonyl)-4-oxo-4H-1-benzopyran,
5-amino-2-(n-pentyloxycarbonyl)-4-oxo-4H-1-benzopyran,
6-amino-2-(n-pentyloxycarbonyl)-4-oxo-4H-1-benzopyran,
7-amino-2-(n-pentyloxycarbonyl)-4-oxo-4H-1-benzopyran,
8-amino-2-(n-pentyloxycarbonyl)-4-oxo-4H-1-benzopyran,
5-amino-2-(n-hexyloxycarbonyl)-4-oxo-4H-1-benzopyran,
6-amino-2-(n-hexyloxycarbonyl)-4-oxo-4H-1-benzopyran,
7-amino-2-(n-hexyloxycarbonyl)-4-oxo-4H-1-benzopyran, and
8-amino-2-(n-hexyloxycarbonyl)-4-oxo-4H-1-benzopyran.
[0086] The aminochromone compound (6) (wherein, preferably,
R.sup.10 represents a lower alkyl group) obtained according to the
present invention can be acylated using a reactive derivative of
carboxylic acid represented by the formula (7): R.sup.11COZ
(wherein R.sup.11 represents a substituted or unsubstituted
aliphatic group or a substituted or unsubstituted aromatic group
and Z represents a leaving group such as a halogen atom or an
acyloxy group) to obtain the corresponding amidochromone
compound.
[0087] The reaction is usually carried out in the presence of an
organic solvent. The organic solvent includes, for example, aprotic
polar solvents such as N,N-dimethylformamide, aromatic hydrocarbon
solvents such as toluene or xylene, halogenated hydrocarbon
solvents such as dichloromethane, dichloroethane, chlorobenzene or
dichlorobenzene, ether solvents such as dimethyl ether, methyl
tert-butyl ether or tetrahydrofuran, nitrile solvents such as
acetonitrile or propionitrile, and ester solvents such as ethyl
acetate, and these solvents may be used alone or as a mixture of
two or more of these. The amount used of the solvent is usually 2
to 50 parts by weight per 1 part by weight of the aminochromone
compound.
[0088] The reactive derivative of carboxylic acid represented by
the formula (7) includes specifically, for example, substituted or
unsubstituted aliphatic or aromatic carboxylic acid halides such as
acetic acid chloride, benzoic acid chloride or
4-(4-phenylbutoxy)benzoic acid chloride and acid anhydrides such as
acetic anhydride or benzoic anhydride. The activated derivative of
carboxylic acid can be also obtained by using aliphatic or aromatic
carboxylic acid and a carboxylic acid activating agent (e.g.
1,3-dicyclohexylcarbodiimide).
[0089] The reaction of the aminochromone compound (6) with the
reactive derivative of carboxylic acid represented by the formula
(7) may be carried out by adding the reactive derivative of
carboxylic acid or a mixture of the reactive derivative and an
organic solvent into a mixture of the aminochromone compound (6)
and an organic solvent, by adding the aminochromone compound (6) or
a mixture of the aminochromone compound (6) and an organic solvent
into the reactive derivative of carboxylic acid or a mixture of the
reactive derivative and an organic solvent, or by adding the
aminochromone compound (6) and the reactive derivative of
carboxylic acid simultaneously.
[0090] In the above-mentioned reaction, addition of a base may be
effective if necessary. The base includes, for example, alkali
metal hydroxide such as lithium hydroxide, sodium hydroxide or
potassium hydroxide; alkaline earth metal hydroxide such as calcium
hydroxide or barium hydroxide; alkali metal carbonate such as
lithium carbonate, sodium carbonate or potassium carbonate;
alkaline earth metal carbonate such as calcium carbonate; alkali
metal hydrogen carbonate such as sodium hydrogen carbonate or
potassium hydrogen carbonate; and organic amines such as
triethylamine, pyridine or 5-ethyl-2-methylpyridine, and these may
be used alone or as a mixture of two or more of these. The base may
be added as it is to a reaction solution or if it is water-soluble,
it may be added to a reaction solution after dissolving. If the
base is in liquid form, it may be used also as a solvent.
[0091] Although the upper limit of the reaction temperature may be
determined depending on the boiling point of a solvent used, it is
usually -50.degree. C. to 150.degree. C., preferably -20.degree. C.
to 100.degree. C.
[0092] After completion of the reaction, the desired amidochromone
compound can be produced by a conventional separation means, for
example, filtration, solvent extraction, or concentration. The
amidochromone compound thus obtained may be further purified by,
for example, recrystallization if necessary.
[0093] Thus, the aminochromone compound (6) can be converted into
the amidochromone compound represented by the formula (8), which is
a pharmaceutical intermediate, for example, as described in JP-A
3-95144.
[0094] The amidochromone compound represented by the formula (8)
which is obtained from the aminochromone compound (6) (wherein
R.sup.10 represents a lower alkyl group) can be subjected to a step
of reacting with ammonia to convert into carbamoyl and then to a
step of dehydrating the resulting compound having carbamoyl to
produce the amidochromonenitrile compound represented by the
formula (10), as described in the following reaction scheme-1. Such
a series of reaction steps can be carried out according to a known
method described in, for example, JP-A 3-95144, JP-A 61-50977 or EP
634409A. For example, the conversion of the compound represented by
the formula (8) into the compound represented by the formula (9)
can be carried out using ammonia in an inert solvent (e.g. lower
alkyl alcohol, the above-mentioned aromatic hydrocarbon solvents,
halogenated hydrocarbon solvents, ether solvents, or aprotic polar
solvents). The step of dehydrating the compound represented by the
formula (9) to obtain the compound represented by the formula (10)
can be carried out using a dehydrating agent such as phosphorus
oxychloride or thionyl chloride. The dehydration step may be
carried out using an inert organic solvent (e.g. aromatic
hydrocarbon, halogenated hydrocarbon solvents, ether solvents, or
aprotic polar solvents) if necessary. ##STR16##
EXAMPLES
[0095] Hereinafter, the present invention will be explained more
specifically with reference to Examples, which are not intended to
limit the scope of the present invention. The yield and the ratio
between stereoisomers were calculated from results of high
performance liquid chromatography.
Example 1
[0096] A reaction container equipped with a stirrer, a cooling tube
and a thermometer was charged with 1,883 parts by weight of bromine
at room temperature and adjusted to an inner temperature of
30.degree. C. At an inner temperature of 30 to 40.degree. C., 1,544
parts by weight of dimethyl maleate was added dropwise over 4 hours
to the content and the mixture was stirred and kept at an inner
temperature of 40.degree. C. for 4 hours to react it. After that,
at room temperature, the reaction solution was added dropwise
slowly to 2,228 parts by weight of a 10% by weight sodium sulfite
aqueous solution. After the mixture was stirred until brown color
showing residual bromine disappeared, 4,884 parts by weight of
toluene was added thereto to separate the solution. The obtained
organic layer was washed with 1,249 parts by weight of a 10% by
weight sodium carbonate aqueous solution and then with 2,228 parts
by weight of water, and then concentrated under reduced pressure to
obtain 3,179 parts by weight of dimethyl dibromosuccinate as white
crystals. The content was 98.4% by weight, the yield was 97%, and
the threo/erythro ratio was 98/2.
Example 2
[0097] A reaction container equipped with a stirrer, a cooling tube
and a thermometer was charged with 36.3 parts by weight of
chlorobenzene at room temperature and 34.3 parts by weight of
bromine was added dropwise thereto. After the container was
adjusted to an inner temperature of 50.degree. C., 28.1 parts by
weight of dimethyl maleate was added dropwise over 1 hour thereto
and the content was stirred and kept at 50.degree. C. for 5 hours
to react it. After that, at room temperature, the reaction solution
was added dropwise slowly to 38 parts by weight of a 10% by weight
sodium sulfite aqueous solution. The mixture was stirred until
brown color showing residual bromine disappeared and then
separated. The obtained organic layer was washed with 30 parts of
10% by weight sodium carbonate aqueous solution and then with 30
parts by weight of water to obtain an organic layer containing 56.3
parts by weight of dimethyl dibromosuccinate. The yield was 95% and
the threo/erythro ratio was 98/2.
Example 3
[0098] A reaction container equipped with a stirrer, a cooling tube
and a thermometer was charged with 25.0 parts by weight of bromine
at room temperature and adjusted to an inner temperature of
40.degree. C. At an inner temperature of 40 to 45.degree. C., 20.5
parts by weight of dimethyl maleate was added dropwise over 10
hours thereto and the content was stirred and kept at an inner
temperature of 40.degree. C. for 2 hours to react it. After that,
at room temperature, the reaction solution was added dropwise
slowly to 24.2 parts by weight of 10% by weight sodium sulfite
aqueous solution. After the mixture was stirred until brown color
showing residual bromine disappeared, 61.7 parts by weight of
toluene was added thereto to separate the solution. The obtained
organic layer was mixed with 20.5 parts by weight of an 18%
solution of sodium chloride in water and adjusted to pH 5.4 with a
10% by weight sodium carbonate aqueous solution. The organic layer
was then washed with 20.5 parts by weight of water and concentrated
under reduced pressure to obtain 51.9 parts by weight of a solution
of dimethyl dibromosuccinate in toluene. The content was 80.0% by
weight, the yield was 96% and the threo/erythro ratio was 99/1.
Comparative Example 1
[0099] A reaction container equipped with a stirrer, a cooling tube
and a thermometer was charged with 28.1 parts by weight of dimethyl
maleate at room temperature and adjusted o an inner temperature of
50.degree. C. After 34.3 parts by weight of bromine was added
dropwise at 50.degree. C. over 2 hours thereto, the content was
stirred and kept at the same temperature for 6 hours to react it.
After that, the reaction solution was added dropwise slowly to 38
parts by weight of a 10% by weight sodium sulfite aqueous solution
at room temperature. After the mixture was stirred until brown
color showing residual bromine disappeared, 90 parts by weight of
toluene was added thereto to separate the solution. The obtained
organic layer was washed with 30 parts by weight of a 10% by weight
sodium carbonate aqueous solution and then with 30 parts by weight
of water to obtain an organic layer containing 56.6 parts by weight
of dimethyl dibromosuccinate. The yield was 96% and the
threo/erythro ratio was 62/38.
Example 4
[0100] A reaction container equipped with a stirrer, a cooling tube
and a thermometer was charged with 60 parts by weight of toluene,
20 parts by weight of sulfolane and then 20 parts by weight of
2-nitrophenol at room temperature, and thereto 60 parts by weight
of potassium carbonate was added in small portions. The inner
temperature was raised to 100.degree. C. and the content was
stirred and kept at the same temperature for 1 hour. After cooled
to an inner temperature of 80.degree. C., to the content, 4.7 parts
by weight of tetra(n-butyl)ammonium bromide was added and a mixture
of 50 parts by weight of dimethyl erythro-2,3-dibromosuccinate and
40 parts by weight of toluene was then added dropwise over 4 hours.
The mixture was stirred and kept at an inner temperature of
80.degree. C. for 7 hours to react it. The reaction solution was
cooled to room temperature and 180 parts by weight of water was
added thereto to separate the solution. The obtained organic layer
was washed with a 5% by weight sodium hydrogen carbonate aqueous
solution and then with a 5% by weight solution of sodium chloride
in water and then concentrated under reduced pressure to obtain
42.4 parts by weight of an oil containing dimethyl
2-(2-nitrophenoxy)fumarate and dimethyl 2-(2-nitrophenoxy)maleate.
The combined content of dimethyl 2-(2-nitrophenoxy)fumarate and
dimethyl 2-(2-nitrophenoxy)maleate was 82.0% by weight, and the
yield based on 2-nitrophenol was 86.1%.
[0101] .sup.1H-NMR spectra for dimethyl 2-(2-nitrophenoxy)fumarate
(DMSO-d.sub.6 solvent, TMS standard, unit: ppm) .delta. 8.16(1H,
d), 7.85(1H, t), 7.55(1H, t), 7.50(1H, d), 5.56(1H, s), 3.82(3H,
s), 3.64(3H, s)
[0102] .sup.1H-NMR spectra for dimethyl 2-(2-nitrophenoxy)maleate
(DMSO-d.sub.6 solvent, TMS standard, unit: ppm) .delta. 8.05(1H,
d), 7.65(1H, t), 7.34(1H, t), 7.20(1H, d), 6.80(1H, s), 3.74(3H,
s), 3.68(3H, s)
Example 5
[0103] A reaction container equipped with a stirrer, a cooling tube
and a thermometer was charged with 9 parts by weight of toluene, 3
parts by weight of N,N-dimethylformamide and then 3 parts by weight
of 2-nitrophenol at room temperature. Thereto, 8.9 parts by weight
of potassium carbonate was added in small portions. The inner
temperature was raised to 100.degree. C. and the content was
stirred and kept at the same temperature for 1 hour. After cooled
to an inner temperature of 80.degree. C., to the content, 0.7 parts
by weight of tetra(n-butyl)ammonium bromide was added and a mixture
of 7 parts by weight of dimethyl erythro-2,3-dibromosuccinate and 6
parts by weight of toluene was then added dropwise over 2 hours.
The mixture was stirred and kept at an inner temperature of
80.degree. C. for 6 hours to react it. After the reaction solution
was cooled to room temperature, 40 parts by weight of water was
added thereto to separate the solution. The obtained organic layer
contained dimethyl 2-(2-nitrophenoxy)fumarate and dimethyl
2-(2-nitrophenoxy)maleate. The combined amount of dimethyl
2-(2-nitrophenoxy)fumarate and dimethyl 2-(2-nitrophenoxy)maleate
was 4.4 parts by weight, and the yield based on 2-nitrophenol was
70.8%.
Example 6
[0104] A reaction container equipped with a stirrer, a cooling tube
and a thermometer was charged with 30 parts by weight of toluene,
2.2 parts by weight of dimethyl erythro-2,3-dibromosuccinate and 1
part by weight of 2-nitrophenol at room temperature. Thereto, 4
parts by weight of potassium carbonate and 0.23 parts by weight of
tetra(n-butyl)ammonium bromide were added. The inner temperature
was raised to 60.degree. C. and the content was stirred and kept at
the same temperature for 5 hours, at an inner temperature of
80.degree. C. for 1 hour and then at an inner temperature of
100.degree. C. for 1 hour to react it. The reaction solution was
cooled to room temperature and 30 parts by weight of water was
added thereto to separate the solution. The obtained organic layer
was washed with a 5% by weight sodium hydrogen carbonate aqueous
solution and a 5% by weight solution of sodium chloride in water,
and then concentrated under reduced pressure to obtain 1.7 parts by
weight of an oil containing dimethyl 2-(2-nitrophenoxy)fumarate and
dimethyl 2-(2-nitrophenoxy)maleate. The combined content of
dimethyl 2-(2-nitrophenoxy)fumarate and dimethyl
2-(2-nitrophenoxy)maleate was 90.4% by weight, and the yield based
on 2-nitrophenol was 74.3%.
Example 7
[0105] A reaction container equipped with a stirrer, a cooling tube
and a thermometer was charged with 15 parts by weight of
N,N-dimethylformamide, 1.1 parts by weight of dimethyl
erythro-2,3-dibromosuccinate and 0.5 parts by weight of
2-nitrophenol at room temperature. Thereto, 2 parts by weight of
potassium carbonate was added. The inner temperature was raised to
60.degree. C. and the content was stirred and kept at the same
temperature for 5 hours to react it. The reaction solution was
cooled to room temperature and 30 parts by weight of water was
added thereto to separate the solution. The obtained organic layer
was washed with a 5% by weight sodium hydrogen carbonate aqueous
solution and then with a 5% by weight solution of sodium chloride
in water and then concentrated under reduced pressure to obtain
0.72 parts by weight of an oil containing dimethyl
2-(2-nitrophenoxy)fumarate and dimethyl 2-(2-nitrophenoxy)maleate.
The combined content of dimethyl 2-(2-nitrophenoxy)fumarate and
dimethyl 2-(2-nitrophenoxy)maleate was 88.9% by weight, and the
yield based on 2-nitrophenol was 63.3%.
Example 8
[0106] A reaction container equipped with a stirrer, a cooling tube
and a thermometer was charged with 10 parts by weight of toluene,
5.3 parts by weight of dimethyl erythro-2,3-dibromosuccinate and 2
parts by weight of 2-nitrophenol at room temperature. Thereto, 4.6
parts by weight of sodium carbonate and 0.47 parts by weight of
tetra(n-butyl)ammonium bromide were added. The inner temperature
was raised to 80.degree. C. and the content was stirred and kept at
the same temperature for 3 hours and then at an inner temperature
of 100.degree. C. for 5 hours to react it. The reaction solution
was cooled to room temperature and 20 parts by weight of water and
20 parts by weight of toluene were added thereto to separate the
solution. The obtained organic layer was washed with a 5% by weight
sodium hydrogen carbonate aqueous solution and then with a 5% by
weight solution of sodium chloride in water and then concentrated
under reduced pressure to obtain 3.8 parts by weight of an oil
containing dimethyl 2-(2-nitrophenoxy)fumarate and dimethyl
2-(2-nitrophenoxy)maleate. The combined content of dimethyl
2-(2-nitrophenoxy)fumarate and dimethyl 2-(2-nitrophenoxy)maleate
was 59.6% by weight, and the yield based on 2-nitrophenol was
55.7%.
Example 9
[0107] A reaction container equipped with a stirrer, a cooling tube
and a thermometer was charged with 10.5 parts by weight of toluene,
3 parts by weight of sulfolane and then 3 parts by weight of
2-nitrophenol at room temperature. Thereto, 6 parts by weight of
potassium carbonate was added in small portions. The inner
temperature was raised to 100.degree. C. and the content was
stirred and kept at the same temperature for 1 hour. After cooled
to an inner temperature of 80.degree. C., to the content, 0.7 parts
by weight of tetra(n-butyl)ammonium bromide was added and then a
mixture of 7.5 parts by weight of toluene and 5.5 parts by weight
of a mixture of dimethyl 2-boromofumarate and dimethyl
2-bromomaleate was added dropwise over 3 hours. The resulting
mixture was stirred and kept at an inner temperature of 80.degree.
C. for 5 hours to react it. The reaction solution was cooled to
room temperature and 21 parts by weight of water was added to
separate the solution. The obtained organic layer was washed with a
5% by weight sodium hydrogen carbonate aqueous solution and then
with a 5% by weight solution of sodium chloride in water and then
concentrated under reduced pressure to obtain 5.8 parts by weight
of an oil containing dimethyl 2-(2-nitrophenoxy)fumarate and
dimethyl 2-(2-nitrophenoxy)maleate. The combined content of
dimethyl 2-(2-nitrophenoxy)fumarate and dimethyl
2-(2-nitrophenoxy)maleate was 81.4% by weight and the yield based
on 2-nitrophenol was 77.7%.
Example 10
[0108] A reaction container equipped with a stirrer, a cooling tube
and a thermometer was charged with 44.1 parts by weight of toluene,
4.2 parts by weight of sulfolane, 21.1 parts by weight of potassium
carbonate and 2.0 parts by weight of tetra(n-butyl)ammonium bromide
at room temperature. After the mixture was warmed to 105.degree.
C., a mixture of 17.0 part by weight of 2-nitrophenol and 17.3
parts by weight of toluene was added dropwise thereto over 2 hours.
The mixture was stirred and kept at 105.degree. C. for 1 hour.
After cooled to an inner temperature of 70.degree. C., a mixture of
7.6 parts by weight of toluene and 40.1 parts by weight of a
mixture (threo-isomer content: 98.0%) of dimethyl
threo-2,3-dibromosuccinate and dimethyl
erythro-2,3-dibromosuccinate was added dropwise over 3 hours
thereto. The mixture was stirred and kept at an inner temperature
of 70.degree. C. for 7 hours to react it. The reaction solution was
cooled to room temperature and 51 parts by weight of water was
added to separate the solution. The obtained organic layer was
washed with a 5% by weight sodium hydrogen carbonate aqueous
solution and then with a 5% by weight solution of sodium chloride
in water and then concentrated under reduced pressure to obtain
37.8 parts by weight of a mixture (oily) of dimethyl
2-(2-nitrophenoxy)fumarate and dimethyl 2-(2-nitrophenoxy)maleate.
The combined content of dimethyl 2-(2-nitrophenoxy)fumarate and
dimethyl 2-(2-nitrophenoxy)maleate was 89.6% by weight and the
yield based on 2-nitrophenol was 98.7%.
Example 11
[0109] A reaction container equipped with a stirrer, a cooling tube
and a thermometer was charged with 100 parts by weight of toluene,
10.0 parts by weight of sulfolane, 49.7 parts by weight of
potassium carbonate and 4.7 parts by weight of
tetra(n-butyl)ammonium bromide at room temperature. After the
mixture was warmed to 95.degree. C., a mixture of 40.1 parts by
weight of 2-nitrophenol and 40.1 parts by weight of toluene was
added dropwise over 2 hours thereto. The resulting mixture was
stirred and kept at 95.degree. C. for 1 hour. After cooled to an
inner temperature of 70.degree. C., a mixture of 20.0 parts by
weight of toluene and 102.8 parts by weight of a mixture
(threo-isomer content: 86.3%) of dimethyl
threo-2,3-dibromosuccinate and dimethyl
erythro-2,3-dibromosuccinate was added dropwise over 4 hours
thereto and the mixture was stirred and kept at the same
temperature for 5 hours to react it. The reaction solution was
cooled to room temperature and 120 parts by weight of water was
added to separate the solution. The obtained organic layer was
washed with a 5% by weight sodium hydrogen carbonate aqueous
solution and then with a 5% by weight solution of sodium chloride
in water and then concentrated under reduced pressure to obtain
93.9 parts by weight of a mixture (oily) of dimethyl
2-(2-nitrophenoxy)fumarate and dimethyl 2-(2-nitrophenoxy)maleate.
The combined content of dimethyl 2-(2-nitrophenoxy)fumarate and
dimethyl 2-(2-nitrophenoxy)maleate was 83.5% by weight and the
yield based on 2-nitrophenol was 96.8%.
Example 12
[0110] A reaction container equipped with a stirrer, a cooling tube
and a thermometer was charged with 101 parts by weight of toluene,
10.1 parts by weight of sulfolane, 24.9 parts by weight of
potassium carbonate, 2.3 parts by weight of tetra(n-butyl)ammonium
bromide and 20.0 parts by weight of 4-nitrophenol at room
temperature. After warmed to 110.degree. C., the mixture was
stirred and kept at the same temperature for 1 hour. After the
mixture was cooled to an inner temperature of 70.degree. C., a
mixture of 20.0 parts by weight of toluene and 47.1 parts by weight
of a mixture (threo-isomer content: 96.0%) of dimethyl
threo-2,3-dibromosuccinate and dimethyl
erythro-2,3-dibromosuccinate was added dropwise thereto over 2
hours. The resulting mixture was stirred and kept at an inner
temperature of 70.degree. C. for 2 hours, at 85.degree. C. for 4
hour, at 95.degree. C. for 3 hour, and then at 105.degree. C. for 3
hours to react it. The reaction solution was cooled to room
temperature and 60 parts by weight of water was added to separate
the solution. The obtained organic layer was washed with a 5% by
weight sodium hydrogen carbonate aqueous solution and then with a
5% by weight solution of sodium chloride in water and then
concentrated under reduced pressure to obtain 41.0 parts by weight
of a mixture (oily) of dimethyl 2-(4-nitrophenoxy)fumarate and
dimethyl 2-(4-nitrophenoxy)maleate. The combined content of
dimethyl 2-(4-nitrophenoxy)fumarate and dimethyl
2-(4-nitrophenoxy)maleate was 55.8% by weight and the yield based
on 2-nitrophenol was 56.9%.
Example 13
[0111] A reaction container equipped with a stirrer, a cooling tube
and a thermometer was charged with 250 parts by weight of
chlorosulfonic acid. Thereto, 50 parts by weight of a mixture
(content: 82.1% by weight, fumaric acid/maleic acid ratio=58/42) of
dimethyl 2-(2-nitrophenoxy)fumarate and dimethyl
2-(2-nitrophenoxy)maleate was added dropwise at an inner
temperature of 50.degree. C. or below. After completion of
addition, the inner temperature was raised to 70.degree. C. and the
mixture was stirred and kept at the same temperature for 6 hours to
obtain a reaction solution containing
8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran (reaction yield:.
92%). After cooled to room temperature, the reaction solution was
gradually added into 300 parts by weight of water. The mixture was
kept at an inner temperature of 60.degree. C. for 1 hour and then
gradually cooled to an inner temperature of 0.degree. C.
Precipitated crystals were filtered and dried to obtain 30 parts by
weight of a crystalline mixture of
8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran and
8-nitro-2-carboxy-4-oxo-4H-1-benzopyran (the content of
8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran: 58.5% by weight;
the content of 8-nitro-2-carboxy-4-oxo-4H-1-benzopyran: 39.8% by
weight). The yield of
8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran was 32% and the
yield of 8-nitro-2-carboxy-4-oxo-4H-1-benzopyran was 50%.
Example 14
[0112] After a reaction container equipped with a stirrer, a
cooling tube and a thermometer was charged with 25 parts by weight
of chlorosulfonic acid, 5 parts by weight of a mixture (content:
65.7% by weight) containing 2-(2-nitrophenoxy)fumaric acid and
2-(2-nitrophenoxy)maleic acid was added. After that, the inner
temperature was raised to 60.degree. C. and the mixture was stirred
and kept at the same temperature for 6 hours to obtain a reaction
solution containing 8-nitro-2-carboxy-4-oxo-4H-1-benzopyran
(reaction yield: 70%). After cooled to room temperature, the
reaction solution was gradually added into 50 parts by weight of
water and the mixture was gradually cooled to an inner temperature
of 0.degree. C. Precipitated crystals were filtered and dried to
obtain 2.2 parts by weight of
8-nitro-2-carboxy-4-oxo-4H-1-benzopyran as crystals (content: 96.9%
by weight, yield: 65%).
Example 15
[0113] After a reaction container equipped with a stirrer, a
cooling tube and a thermometer was charged with 15 parts by weight
of chlorosulfonic acid, 3 parts by weight of a mixture (content:
84.4% by weight, fumaric acid/maleic acid ratio=49/51) containing
diethyl 2-(2-nitrophenoxy)fumarate and diethyl
2-(2-nitrophenoxy)maleate was added dropwise at an inner
temperature of 50.degree. C. or below. After completion of
addition, the inner temperature was raised to 70.degree. C. and the
mixture was stirred and kept at the same temperature for 7 hours to
obtain a reaction solution containing
8-nitro-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran (reaction yield:
70%). After cooled to room temperature, the reaction solution was
gradually added into 24 parts by weight of water. After kept at an
inner temperature of 60.degree. C. for 1 hour, the mixture was
gradually cooled to an inner temperature of 0.degree. C.
Precipitated crystals were filtered and dried to obtain 1.3 parts
by weight of a crystalline mixture containing
8-nitro-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran and
8-nitro-2-carboxy-4-oxo-4H-1-benzopyran (the content of
8-nitro-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran: 0.1% by weight; the
content of 8-nitro-2-carboxy-4-oxo-4H-1-benzopyran: 86.4% by
weight). The yield of
8-nitro-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran was 0.1% and the
yield of 8-nitro-2-carboxy-4-oxo-4H-1-benzopyran was 64%.
Example 16
[0114] After a reaction container equipped with a stirrer, a
cooling tube and a thermometer was charged with 20 parts by weight
of fuming sulfuric acid, 2 parts by weight of a mixture (content:
65.7% by weight) containing 2-(2-nitrophenoxy)fumaric acid and
2-(2-nitrophenoxy)maleic acid was added. After that, the mixture
was stirred and kept at an inner temperature of 25.degree. C. for 2
hours and then at an inner temperature of 50.degree. C. for 2 hours
to obtain a reaction solution containing
8-nitro-2-carboxy-4-oxo-4H-1-benzopyran (reaction yield: 35%).
After cooled to room temperature, the reaction solution was
gradually added into 40 parts by weight of water and the mixture
was gradually cooled to an inner temperature of 0.degree. C.
Precipitated crystals were filtered and dried to obtain 0.28 parts
by weight of 8-nitro-2-carboxy-4-oxo-4H-1-benzopyran as crystals
(content: 95.2% by weight, yield: 20%).
Example 17
[0115] A reaction container equipped with a stirrer, a cooling tube
and a thermometer was charged with 300 parts by weight of
chlorosulfonic acid. Thereto, 60 parts by weight of a mixture
(content: 81.1% by weight, fumaric acid/maleic acid ratio=57/43)
containing dimethyl 2-(2-nitrophenoxy)fumarate and dimethyl
2-(2-nitrophenoxy)maleate was added dropwise at an inner
temperature of 50.degree. C. or below. After completion of
addition, the inner temperature was raised to 60.degree. C. and the
mixture was stirred and kept at the same temperature for 5 hours
and at an inner temperature of 70.degree. C. for 3 hours to obtain
a reaction solution containing
8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran (reaction yield:
86%). After cooled to room temperature, the reaction solution was
poured gradually into 360 parts by weight of water. The mixture was
kept at an inner temperature of 60.degree. C. for 8 hours and then
cooled to an inner temperature of 0.degree. C. gradually.
Precipitated crystals were filtered and dried to obtain 30 parts by
weight of a crystalline mixture of
8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran and
8-nitro-2-carboxy-4-oxo-4H-1-benzopyran (the content of
8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran: 2.5% by weight;
the content of 8-nitro-2-carboxy-4-oxo-4H-1-benzopyran: 96.7% by
weight). The yield of
8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran was 2% and the
yield of 8-nitro-2-carboxy-4-oxo-4H-1-benzopyran was 73%.
Example 18
[0116] A reaction container equipped with a stirrer, a cooling tube
and a thermometer was charged with 200 parts by weight of
chlorosulfonic acid. Thereto, 40 parts by weight of the mixture
containing dimethyl 2-(2-nitrophenoxy)fumarate and dimethyl
2-(2-nitrophenoxy)maleate obtained in Example 4 was added dropwise
at an inner temperature of 50.degree. C. or below. After completion
of addition, the inner temperature was raised to 70.degree. C. and
the mixture was stirred and reacted at the same temperature for 6
hours to obtain a reaction solution containing
8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran (reaction yield
based on 2-nitrophenol: 80%). After cooled to room temperature, the
reaction solution was poured so gradually into 200 parts by weight
of water as to keep an inner temperature of 60.degree. C. or lower.
The inner temperature was adjusted to 60.degree. C. and the
reaction mixture was kept at the same temperature for 1 hour and
then gradually cooled to an inner temperature of 0.degree. C.
Precipitated crystals were filtered and dried to obtain 19.2 parts
by weight of a crystalline mixture of
8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran and
8-nitro-2-carboxy-4-oxo-4H-1-benzopyran (the content of
8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran: 9.5% by weight;
the content of 8-nitro-2-carboxy-4-oxo-4H-1-benzopyran: 85.7% by
weight).
[0117] Based on 2-nitrophenol, the yield of
8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran was 5.4% and the
yield of 8-nitro-2-carboxy-4-oxo-4H-1-benzopyran was 51.4%.
Example 19
[0118] A reaction container equipped with a stirrer, a cooling tube
and a thermometer was charged with 20 parts by weight of
chlorosulfonic acid and 4 parts by weight of the mixture containing
dimethyl 2-(2-nitrophenoxy)fumarate and dimethyl
2-(2-nitrophenoxy)maleate obtained in Example 9 was dropwise added
thereto at an inner temperature of 50.degree. C. or below. After
completion of addition, the inner temperature was raised to
70.degree. C. and the mixture was stirred and reacted at the same
temperature for 6 hours to obtain a reaction solution containing
8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran (reaction yield
based on 2-nitrophenol: 72.7%). After cooled to room temperature,
the reaction solution was poured into 24 parts by weight of water
so gradually as to keep an inner temperature of 60.degree. C. or
lower. The inner temperature was adjusted to 60.degree. C. and the
reaction mixture was kept at the same temperature for 1 hour and
then gradually cooled to an inner temperature of 0.degree. C.
Precipitated crystals were filtered and dried to obtain 2.0 parts
by weight of a crystalline mixture of
8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran and
8-nitro-2-carboxy-4-oxo-4H-1-benzopyran (the content of
8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran: 36.9% by weight;
the content of 8-nitro-2-carboxy-4-oxo-4H-1-benzopyran: 61.2% by
weight).
[0119] Based on 2-nitrophenol, the yield of
8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran was 19.3% and the
yield of 8-nitro-2-carboxy-4-oxo-4H-1-benzopyran was 34.0%.
Example 20
[0120] A reaction container equipped with a stirrer, a cooling tube
and a thermometer was charged with 50.2 parts by weight of
chlorosulfonic acid. Thereto, 25.1 parts by weight of 98% sulfuric
acid was added dropwise over 1 hour and the mixture was then warmed
to 60.degree. C. Thereto, 25.6 parts by weight of a mixture
(content: 89.6% by weight, fumaric acid/maleic acid ratio=54/46)
containing dimethyl 2-(2-nitrophenoxy)fumarate and dimethyl
2-(2-nitrophenoxy)maleate was added dropwise at an inner
temperature of 60.degree. C. over 6 hours. After completion of
addition, the inner temperature was raised to 95.degree. C. and the
mixture was stirred and kept at the same temperature for 4 hours to
obtain a reaction solution containing
8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran (reaction yield:
88%). The reaction solution was poured gradually into 113 parts by
weight of water at 85.degree. C. or below. The mixture was kept at
an inner temperature of 85.degree. C. for 6 hours and then cooled
gradually to an inner temperature of 25.degree. C. Precipitated
crystals were filtered and dried to obtain 16.7 parts by weight of
a crystalline mixture of
8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran and
8-nitro-2-carboxy-4-oxo-4H-1-benzopyran (the content of
8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran: 3.8% by weight;
the content of 8-nitro-2-carboxy-4-oxo-4H-1-benzopyran: 96.0% by
weight). The yield of
8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran was 5.3% and the
yield of 8-nitro-2-carboxy-4-oxo-4H-1-benzopyran was 81.5%.
Example 21
[0121] A reaction container equipped with a stirrer, a cooling tube
and a thermometer was charged with 50.2 parts by weight of
chlorosulfonic acid. Thereto, 25.0 parts by weight of 98% sulfuric
acid was added dropwise over 1 hour and the mixture was then warmed
to 60.degree. C. Thereto, 25.3 parts by weight of the mixture
(content: 89.6% by weight, fumaric acid/maleic acid ratio=54/46)
containing dimethyl 2-(2-nitrophenoxy)fumarate and dimethyl
2-(2-nitrophenoxy)maleate obtained in Example 10 was added dropwise
at an inner temperature of 60.degree. C. over 4 hours. After
completion of addition, the inner temperature was raised to
95.degree. C. and the mixture was stirred and kept at the same
temperature for 4 hours to obtain a reaction solution containing
8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran (reaction yield:
88%). The reaction solution was poured gradually into 113 parts by
weight of water at 85.degree. C. or below. The mixture was kept at
an inner temperature of 85.degree. C. for 6 hours and then cooled
gradually to an inner temperature of 25.degree. C. Precipitated
crystals were filtered and dried to obtain 16.3 parts by weight of
a crystalline mixture of
8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran and
8-nitro-2-carboxy-4-oxo-4H-1-benzopyran (the content of
8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran: 13.8% by weight;
the content of 8-nitro-2-carboxy-4-oxo-4H-1-benzopyran: 84.6% by
weight). The yield of
8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran was 11.5% and the
yield of 8-nitro-2-carboxy-4-oxo-4H-1-benzopyran was 74.0%.
Example 22
[0122] A reaction container equipped with a stirrer, a cooling tube
and a thermometer was charged with 79.3 parts by weight of
chlorosulfonic acid and warmed to 60.degree. C. Thereto 20.2 parts
by weight of a mixture (content: 55.8% by weight, isomer
ratio=52/48) containing dimethyl 2-(4-nitrophenoxy)fumarate and
dimethyl 2-(4-nitrophenoxy)maleate was added at an inner
temperature of 60.degree. C. The inner temperature was raised to
100.degree. C. and the mixture was stirred and kept at the same
temperature for 6 hours to obtain a reaction solution containing
6-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran (reaction yield:
95%). The reaction solution was poured gradually into 120 parts by
weight of water at 60.degree. C. and the mixture was kept at an
inner temperature of 60.degree. C. for 1 hour and then cooled
gradually to an inner temperature of 25.degree. C. Precipitated
crystals were filtered and dried to obtain 10.8 parts by weight of
a crystalline mixture of
6-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran and
6-nitro-2-carboxy-4-oxo-4H-1-benzopyran (the content of
6-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran: 23.0% by weight;
the content of 6-nitro-2-carboxy-4-oxo-4H-1-benzopyran: 58.5% by
weight). The yield of
6-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran was 24.9% and the
yield of 6-nitro-2-carboxy-4-oxo-4H-1-benzopyran was 58.5%.
Example 23
[0123] A reaction container equipped with a stirrer, a cooling tube
and a thermometer was charged with 90 parts by weight of a
nitrochromonecarboxylic acid mixture (a mixture of
8-nitro-2-carboxy-4-oxo-4H-1-benzopyran (content: 47.1%) and
8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran (content: 51.6%)),
540 parts by weight of methanol and 9.78 parts by weight of 96%
sulfuric acid and the mixture was heated to the reflux temperature
and then refluxed for 11 hours under heating. The reaction solution
was then cooled to room temperature to obtain 633 parts by weight
of a methanol solution containing a crystal of
8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran. The yield of
8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran was 98%.
Example 24
[0124] A reaction container equipped with a stirrer, a cooling tube
and a thermometer was charged with 9.97 parts by weight of a
nitrochromonecarboxylic acid mixture (a mixture of
8-nitro-2-carboxy-4-oxo-4H-1-benzopyran (content: 96%) and
6-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran (content: 3.7%)),
29.9 parts by weight of toluene and 0.09 parts by weight of
dimethylformamide and the mixture was warmed to 50.degree. C. After
5.09 parts by weight of thionyl chloride was added dropwise over
0.5 hours, the mixture was kept warm for 9.5 hours. Another 1.0
parts by weight of thionyl chloride was added thereto and the
mixture was kept warm for 2 hours. After cooled to room
temperature, the mixture was concentrated to half volume to remove
excess thionyl chloride. The residue was cooled to 10.degree. C.
and 2.99 parts by weight of ethanol was added dropwise thereto over
0.5 hour at an inner temperature of 15.degree. C. or below. After
completion of addition, the obtained mixture was warmed to room
temperature. After 19.94 parts by weight of water was added,
precipitates were filtered off with Celite and washed thoroughly
with 10 parts by weight of toluene. After the filtrate was allowed
to stand still to separate an aqueous layer, a toluene layer was
mixed with 10 parts by weight of water and adjusted to pH 4.5 with
a 10% sodium carbonate aqueous solution. After an aqueous layer was
separated, a toluene layer was concentrated and dried to obtain
10.63 parts by weight of a nitrochromone ester mixture (a mixture
of 8-nitro-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran (content: 94.5%)
and 8-nitro-2-methoxycarboxy-4-oxo-4H-1-benzopyran (content: 3.5%))
as a pale yellow solid. The yield of
8-nitro-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran was 94%.
Example 25
[0125] A reaction container equipped with a stirrer, a cooling tube
and a thermometer was charged with 8 parts by weight of a
nitrochromonecarboxylic acid mixture (a mixture of
8-nitro-2-carboxy-4-oxo-4H-1-benzopyran (content: 96.8%) and
8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran (content: 3.1%)),
24 parts by weight of ethyl acetate and then 3.7 parts by weight of
triethylamine, and warmed to 70.degree. C. Thereto 5.5 parts by
weight of diethyl sulfate was added dropwise over 1 hour and the
resulting mixture was kept at 70.degree. C. for 5 hours. Thereto
54.8 parts by weight of ethyl acetate and 12 parts by weight of
water were added and the mixture was cooled to room temperature. An
aqueous layer was separated and an ethyl acetate layer was washed
with 9.7 parts by weight of 5% sulfuric acid and 8 parts by weight
of water to obtain 84.74 parts by weight of a solution of
nitrochromone ester mixture in ethyl acetate (a mixture of
8-nitro-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran (content: 9.9%) and
8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran (content: 0.3%)).
The yield of 8-nitro-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran was
98%.
Example 26
[0126] A reaction container equipped with a stirrer, a cooling tube
and a thermometer was charged with 240 parts by weight of
nitrochromonecarboxylic acid mixture (a mixture of
8-nitro-2-carboxy-4-oxo-4H-1-benzopyran (content: 95.9%) and
8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran (content: 3.7%))
and 955 parts by weight of ethyl acetate, and 19.4 parts by weight
of water and 125 parts by weight of triethylamine were further
added. After the mixture was warmed to 70.degree. C., 186.6 parts
by weight of diethyl sulfate was added dropwise over 3 hours and
the resulting mixture was kept at 70.degree. C. for 6 hours.
Thereto 238 parts by weight of ethyl acetate and 152.8 parts by
weight of a 15% solution of sodium chloride in water were added and
the mixture was cooled to 50.degree. C. to separate an aqueous
layer. Then, 179 parts by weight of water and 7.3 parts by weight
of 10% sulfuric acid were added and an aqueous layer was separated
to obtain 1,421.8 parts by weight of a solution of a nitrochromone
ester mixture in ethyl acetate (a mixture of
8-nitro-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran (content: 17.8%) and
8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran (content: 0.5%)).
The yield of 8-nitro-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran was
98%.
Example 27
[0127] A reaction container equipped with a stirrer, a cooling tube
and a thermometer was charged with 10 parts by weight of ethanol, 1
part by weight of 8-nitro-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran
(content: 96.4% by weight), 0.2 part by weight of 5% by weight
palladium/carbon (water content: 50% by weight) and 0.17 parts by
weight of pyridine at room temperature, and purged with nitrogen
and then hydrogen under the normal pressure. The container was kept
at inner temperature of 15 to 25.degree. C. and supplied with
hydrogen for 5 hours under the normal pressure. After that, the
container was purged with nitrogen to stop the reaction. The
reaction solution was filtered to remove insoluble substances such
as palladium/carbon and obtain a solution containing
8-amino-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran.
[0128] The filtered insoluble substances were washed with
acetonitrile and the washing solution was mixed with the previously
obtained filtrate. The mixture was concentrated under reduced
pressure to obtain 0.85 part by weight of
8-amino-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran as yellow crystals.
The crystals were subjected to LC analysis (absolute calibration
method) to find that the content was 91% by weight and the yield
was 89%. It was also found that the yields of over-reduced
compounds in the crystals:
8-amino-2-ethoxycarbonyl-4-hydroxy-3,4-dihydro-2H-1-benzopyran
(hereinafter, referred as the over-reduced compound A),
8-amino-2-ethoxycarbonyl-3,4-dihydro-2H-1-benzopyran (hereinafter,
referred as the over-reduced compound B) and
8-amino-2-ethoxycarbonyl-4-oxochromane (hereinafter, referred as
the over-reduced compound C) were 0.5%, below the detection limit
and 8.2% respectively.
Example 28
[0129] A reaction container equipped with a stirrer, a cooling tube
and a thermometer was charged with 30 parts by weight of ethyl
acetate, 4 parts by weight of
8-nitro-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran (content: 95.4% by
weight), 0.77 part by weight of sodium carbonate and 0.38 part by
weight of 5% by weight palladium/carbon (water content: 50% by
weight) at room temperature, and purged with nitrogen and then
hydrogen under the normal pressure. The container was kept at an
inner temperature of 28 to 32.degree. C. and supplied with hydrogen
for 4 hours under the normal pressure. After that, the container
was purged with nitrogen to stop the reaction. After 30 parts by
weight of tetrahydrofuran was added and the reaction solution was
kept warm for 30 minutes, the solution was filtered to remove
insoluble substances such as palladium/carbon and obtain a solution
containing 8-amino-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran. The
solution was analyzed by LC analysis to find that the yield of
8-amino-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran was 92%. The yields
of the over-reduced compounds A and B were below the detection
limit and the yield of the over-reduced compound C was 4.8%.
Example 29
[0130] A reaction container equipped with a stirrer, a cooling tube
and a thermometer was charged with 30 parts by weight of ethyl
acetate, 4 parts by weight of
8-nitro-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran (content: 95.4% by
weight), 0.61 part by weight of sodium hydrogen carbonate and 0.38
part by weight of 5% by weight palladium/carbon (water content: 50%
by weight) at room temperature, and purged with nitrogen and then
hydrogen under the normal pressure. The container was kept at an
inner temperature of 28 to 32.degree. C. and supplied with hydrogen
for 4 hours under the normal pressure. After that, the container
was purged with nitrogen to stop the reaction. After 30 parts by
weight of tetrahydrofuran was added and the reaction solution was
kept warm for 30 minutes, the solution was filtered to remove
insoluble substances such as palladium/carbon and obtain a solution
containing 8-amino-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran. The
solution was analyzed by LC analysis to find that the yield of
8-amino-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran was 94%. The yields
of the over-reduced compounds A and B were below the detection
limit and the yield of the over-reduced compound C was 5.2%.
Example 30
[0131] A reaction container equipped with a stirrer, a cooling tube
and a thermometer was charged with 30.5 parts by weight of ethyl
acetate, 4 parts by weight of
8-nitro-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran (content: 95.4% by
weight), 0.59 part by weight of sodium acetate and 0.38 part by
weight of 5% by weight palladium/carbon (water content: 50% by
weight) at room temperature, and purged with nitrogen and then
hydrogen under the normal pressure. The container was kept at an
inner temperature of 28 to 32.degree. C. and supplied with hydrogen
for 5 hours under the normal pressure. After that, the container
was purged with nitrogen to stop the reaction. After 30 parts by
weight of tetrahydrofuran was added and the reaction solution was
kept warm for 30 minutes, the solution was filtered to remove
insoluble substances such as palladium/carbon and obtain a solution
containing 8-amino-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran. The
solution was analyzed by LC analysis to find that the yield of
8-amino-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran was 97%. The yields
of the over-reduced compounds A and B were below the detection
limit and the yield of the over-reduced compound C was 2.9%.
Example 31
[0132] A reaction container equipped with a stirrer, a cooling tube
and a thermometer was charged with 20 parts by weight of a solution
(content: 18.0% by weight) of
8-nitro-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran in ethyl acetate,.
13.4 parts by weight of ethyl acetate, a mixture of 0.19 part by
weight of 5% by weight palladium/carbon (water content: 50% by
weight) and 0.56 part by weight of sodium acetate, and 1.1 parts by
weight of water at room temperature, and purged with nitrogen and
then hydrogen under the normal pressure. The container was kept at
an inner temperature of 38 to 42.degree. C. and supplied with
hydrogen for 4 hours under the normal pressure. After that, the
container was purged with nitrogen to stop the reaction. After 33
parts by weight of acetonitrile was added and the reaction solution
was kept warm for 30 minutes, the solution was filtered to remove
insoluble substances such as palladium/carbon and obtain a solution
containing 8-amino-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran. The
solution was analyzed by LC analysis to find that the yield of
8-amino-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran was 94%. The yields
of the over-reduced compounds A and B were below the detection
limit and the yield of the over-reduced compound C was 1.8%.
Example 32
[0133] A pressurized reaction container made of glass and equipped
with a stirrer and a thermometer was charged with 507 parts by
weight of a solution (content: 17.7% by weight) of
8-nitro-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran in ethyl acetate,
122 parts by weight of ethyl acetate, 1.4 parts by weight of sodium
acetate, 1.8 parts by weight of 5% by weight palladium/carbon
(water content: 50% by weight) and 14.4 parts by weight of water
which were mixed previously, and purged with nitrogen under 0.4 MPa
5 times and then hydrogen under 0.66 MPa 5 times. While the
hydrogen pressure was kept at 0.66 MPa and the inner temperature
was kept at 50 to 56.degree. C., the container was supplied with
hydrogen for 9 hours. After that, the container was purged with
nitrogen to stop the reaction. The reaction solution was heated to
70.degree. C. and then hot filtered to remove insoluble substances
such as palladium/carbon. After an aqueous layer was separated, a
solution containing 8-amino-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran
was obtained. The solution was analyzed by LC analysis to find that
the yield of 8-amino-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran was
93%. The yields of the over-reduced compounds A and B were below
the detection limit and the yield of the over-reduced compound C
was 4%.
[0134] The solution thus obtained was loaded into a reaction
container equipped with a stirrer, a cooling tube and a thermometer
and the inner temperature was adjusted to 60.degree. C. Under a
reduced pressure of 60 kPa, 153 parts by weight of ethyl acetate
was distilled off. The pressure in the container was turned back to
the normal pressure and a seed crystal of
8-amino-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran was added to the
solution at an inner temperature of 58.degree. C. After the
solution was cooled to 40.degree. C. in 2 hours, 260 parts by
weight of ethyl acetate was distilled off under a reduced pressure
of 26.6 kPa. The pressure was turned back to the normal pressure
and the solution was cooled to 0.degree. C. in 4 hours, kept for 1
hour, filtered and then dried to obtain 66.5 parts by weight of
8-amino-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran. The obtained
crystals were analyzed by LC analysis to find that the purity was
about 100% by weight and the yield was 94% (total yield: 88%).
Comparative Example 2
[0135] A reaction container equipped with a stirrer, a cooling tube
and a thermometer was charged with 10 parts by weight of ethanol, 1
part by weight of 8-nitro-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran
(content: 96.4% by weight) and 0.2 part by weight of 5% by weight
palladium/carbon (water content: 50% by weight) at room
temperature, and purged with nitrogen and then hydrogen under the
normal pressure. The container was kept at an inner temperature of
15 to 25.degree. C. and supplied with hydrogen for 5 hours under
the normal pressure. The container was further supplied with
hydrogen at an inner temperature of 40.degree. C. for 3 hours and
then purged with nitrogen to stop the reaction. The reaction
solution was filtered to remove insoluble substances such as
palladium/carbon and obtain a solution containing
8-amino-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran.
[0136] The filtered insoluble substances were washed with
acetonitrile and the washing solution was mixed with the previously
obtained filtrate. The mixture was concentrated under reduced
pressure to obtain 0.85 part by weight of
8-amino-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran as golden yellow and
sticky crystals. The crystals were subjected to LC analysis
(absolute calibration method) to find that the content was 67% by
weight and the yield was 64%. It was also found that the yields of
the over-reduced compounds A, B and C in the crystals were 12.2%,
0.1% (LC area percentage value) and 17.7% respectively.
Comparative Example 3
[0137] A reaction container equipped with a stirrer, a cooling tube
and a thermometer was charged with 10 parts by weight of ethanol, 1
part by weight of 8-nitro-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran
(content: 96.4% by weight), 0.13 part by weight of acetic acid and
0.2 part by weight of 5% by weight palladium/carbon (water content:
50% by weight) at room temperature, and purged with nitrogen and
then hydrogen under the normal pressure. The container was kept at
an inner temperature of 15 to 25.degree. C. and supplied with
hydrogen for 4 hours under the normal pressure. The container was
further supplied with hydrogen at an inner temperature of
40.degree. C. for 2 hours and then purged with nitrogen to stop the
reaction. The reaction solution was filtered to remove insoluble
substances such as palladium/carbon and obtain a solution
containing 8-amino-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran.
[0138] The filtered insoluble substances were washed with
acetonitrile and the washing solution was mixed with the previously
obtained filtrate. The mixture was concentrated under reduced
pressure to obtain 0.9 part by weight of
8-amino-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran as brown and sticky
crystals. The crystals were subjected to LC analysis (absolute
calibration method) to find that the content was 60% by weight and
the yield was 62%. It was also found that the yields of the
over-reduced compounds A, B and C in the crystals were 5.5%, 1% (LC
area percentage value) and 11.5% respectively.
Comparative Example 4
[0139] A reaction container equipped with a stirrer, a cooling tube
and a thermometer was charged with 25 parts by weight of a solution
(content: 18.0% by weight) of
8-nitro-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran in ethyl acetate,
7.5 parts by weight of ethyl acetate and a mixture of 0.09 part by
weight of 5% by weight palladium/carbon (water content: 50% by
weight) and 0.4 part by weight of water, and purged with nitrogen
and then hydrogen under the normal pressure. The container was kept
at an inner temperature of 55.degree. C. and supplied with hydrogen
for 4.5 hours under the normal pressure. After that, the container
was purged with nitrogen to stop the reaction. Then, 32 parts by
weight of ethyl acetate was added and the reaction solution was
kept warm for 30 minutes and filtered to remove insoluble
substances such as palladium/carbon and obtain a solution
containing 8-amino-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran. The
solution was subjected to LC analysis to find that the yield of
8-amino-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran was 82%. It was
found that the yields of the over-reduced compounds A, B and C in
the solution were 0.9%, below the detection limit and 13.9%
respectively.
Example 33
[0140] A reaction container equipped with a stirrer, a cooling tube
and a thermometer was charged with 100 parts by weight of crystals
of 8-nitro-2-carboxy-4-oxo-4H-1-benzopyran (content: 96.0% by
weight, containing 3.8% by weight of
8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran) obtained in
Example 20 and 427.9 parts by weight of ethyl acetate, and 25.0
parts by weight of water and 41.69 parts by weight of triethylamine
were further added, warmed to an inner temperature of 60.degree. C.
and kept at the same temperature for 6 hours. Thereafter, the
pressure in the container was reduced to 40 kPa, and the reaction
mixture was refluxed and dehydrated under reduced pressure for 7
hours. After the pressure was turned back, 82.1 parts by weight of
volatile ethyl acetate and 2.1 parts by weight of triethylamine
were added into the container and the mixture was heated to
70.degree. C. Then, 64.8 parts by weight of diethyl sulfate was
added dropwise over 3 hours and the mixture was kept at the same
temperature for 4 hours. Further, 3.9 parts by weight of
triethylamine and 6.1 parts by weight of diethyl sulfate were added
and the mixture was kept warm for 3 hours. After 100 parts by
weight of ethyl acetate and 64 parts by weight of 15% by weight
solution of sodium chloride in water were added, the mixture was
cooled to an inner temperature of 50.degree. C. and then separated.
To the obtained organic layer, 75 parts by weight of water and 2.4
parts by weight of 10% by weight sulfuric acid were added and the
solution was separated to obtain 574.5 parts by weight of an
organic layer containing
8-nitro-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran (content: 18.0% by
weight). The yield: 96%. The organic layer contained
8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran in an amount of
0.5% by weight.
[0141] A reaction container equipped with a stirrer and a
thermometer was charged with 561.7 parts by weight of the above
obtained solution of 8-nitro-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran
in ethyl acetate(content: 18.0% by weight, containing 0.5% by
weight of 8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran), 167.7
parts by weight of ethyl acetate, 1.6 parts by weight of sodium
acetate, 1.6 parts by weight of 5% by weight palladium/carbon
(water content: 50% by weight) and 6.3 parts by weight of water.
The container was purged with nitrogen and then with hydrogen under
the normal pressure. The container was kept at an inner temperature
of 50 to 57.degree. C. and supplied with hydrogen for 4 hours under
the normal pressure. After that, the container was additionally
charged with 0.5 part by weight of 5% by weight palladium/carbon
(water content: 50% by weight) and 2.1 parts by weight of water and
further supplied with hydrogen for 15 hours. After that, the
container was purged with nitrogen to stop the reaction. After the
inner temperature was raised to 70.degree. C., the reaction
solution was filtered at the same temperature and substances
adhered to the container were thoroughly washed with 104 parts by
weight of ethyl acetate to remove insoluble substances such as
palladium/carbon. The filtrate was allowed to stand still and an
aqueous layer was removed to obtain an organic layer containing 800
parts by weight of 8-amino-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran
(content: 10.8% by weight). The yield: 95%. The organic layer
contained 8-amino-2-methoxycarbonyl-4-oxo-4H-1-benzopyran in an
amount of 0.3% by weight. The yields of the over-reduced compounds
A and B were below the detection limit and the over-reduced
compound C was produced in 2% yield.
[0142] A reaction container equipped with a stirrer, a cooling tube
and a thermometer was charged with 765 parts by weight of the above
obtained solution of 8-amino-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran
in ethyl acetate (content: 10.8% by weight, containing 0.3% by
weight of 8-amino-2-methoxycarbonyl-4-oxo-4H-1-benzopyran) and
adjusted to an inner temperature of 48.degree. C. After a seed
crystal was added, the solution was gradually cooled to an inner
temperature of 40.degree. C. and concentrated under a reduced
pressure of 26.6 kPa to remove 492 parts by weight of ethyl
acetate. The pressure in the container was turned back again to the
normal pressure and the inner temperature was decreased to
0.degree. C. The reaction solution was kept at 0.degree. C for 1
hour and then filtered to obtain precipitated crystals, which were
dried to obtain 82.2 parts by weight of
8-amino-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran as crystals (the
yield of the crystals: 95%). The yield based on
8-nitro-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran: 90%. The crystals
contained 8-amino-2-methoxycarbonyl-4-oxo-4H-1-benzopyran in an
amount of 1.7% by weight.
[0143] A reaction container equipped with a stirrer, a cooling tube
and a thermometer was charged with 45 parts by weight of the above
obtained 8-amino-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran (containing
1.7% by weight of 8-amino-2-methoxycarbonyl-4-oxo-4H-1-benzopyran),
29 parts by weight of 5-ethyl-2-methylpyridine and 495 parts by
weight, of toluene. The inner temperature was increased to
60.degree. C. and at the same temperature, 286.8 parts by weight of
a solution (content: 20.4% by weight) of 4-(4-phenylbutoxy)benzoic
acid chloride in toluene was added dropwise over 3 hours. After the
resulting solution was further stirred and kept for 5 hours at the
same temperature, a 20% by weight sulfuric acid aqueous solution
was added and the resulting mixture was warmed to an inner
temperature of 80.degree. C. and then separated. The obtained
organic layer was washed with a 20% by weight sulfuric acid aqueous
solution and then with water and gradually cooled to 50.degree. C.
The organic layer was concentrated under reduced pressure to remove
260 parts by weight of toluene and then cooled gradually to an
inner temperature of 0.degree. C. to precipitate crystals, which
were filtrated. The obtained crystals were washed and dried to
obtain 90.7 parts by weight of
8-[4-(4-phenylbutoxy)benzoyl]amino-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran
(containing 1.8% by weight of
8-[4-(4-phenylbutoxy)benzoyl]amino-2-methoxycarbonyl-4-oxo-4H-1-benzopyra-
n). The yield based on
8-amino-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran: 97%.
[0144] A reaction container equipped with a stirrer, a cooling tube
and a thermometer was charged with 45 parts by weight of the above
obtained
8-[4-(4-phenylbutoxy)benzoyl]amino-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran
(containing 1.8% by weight of
8-[4-(4-phenylbutoxy)benzoyl]amino-2-methoxycarbonyl-4-oxo-4H-1-benzopyra-
n) and 180 parts by weight of monochlorobenzene. At an inner
temperature of 25.degree. C., 58.8 parts by weight of a solution of
ammonia in methanol (content: 16.1% by weight) was added dropwise
over 2 hours and the reaction solution was further stirred and kept
at the same temperature for 6 hours. The obtained reaction mass was
warmed to an inner temperature of 60.degree. C. to remove excess
ammonia gas. Then, in order to remove methanol, the reaction mass
was further warmed to 80.degree. C. and kept at the same
temperature for 30 minutes. Next, the reaction mass was cooled to
50.degree. C. and concentrated under a reduced pressure of 13.3 kPa
so that residual methanol was 0.1% or less. To the concentrated
mass, 6.8 parts by weight of 5-ethyl-2-methylpyridine and 4.4 parts
by weight of methanesulfonic acid were added and the mixture was
heated to 100.degree. C., stirred and kept at the same temperature
for 4 hours. After the reaction mass was cooled to 65.degree. C.,
45 parts by weight of methanol was added dropwise thereto and the
mixture was cooled gradually to 0.degree. C. to precipitate
crystals. The crystals were filtered, washed and then dried to
obtain 41 parts by weight of
8-[4-(4-phenylbutoxy)benzoyl]amino-2-carbamoyl-4-oxo-4H-1-benzo-
pyran. The yield based on
8-[4-(4-phenylbutoxy)benzoyl]amino-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran-
: 96%.
[0145] A reaction container equipped with a stirrer, a cooling tube
and a thermometer was charged with 288 parts by weight of
5-ethyl-2-methylpyridine and 43.7 parts by weight of phosphorus
oxychloride and the inner temperature was increased to 60.degree.
C. The mixture was stirred and kept at the same temperature for 2
hours. After cooled to 40.degree. C., 72 parts by weight of
8-[4-(4-phenylbutoxy)benzoyl]amino-2-carbamoyl-4-oxo-4H-1-benzopyran
obtained as described above and 360 parts by weight of toluene were
charged and the mixture was stirred and kept at the same
temperature for 6 hours. The obtained reaction mass was added to
and mixed with a suspension of 634 parts by weight of toluene and
192 parts by weight of a 50% sulfuric acid aqueous solution. The
mixture was then heated to 84.degree. C., allowed to stand still
and then separated. At the same temperature, the obtained organic
layer was washed successively with brine twice and an aqueous
sodium dihydrogenphosphate, and an activated clay and activated
carbon were added thereto. After stirred for 30 minutes, the
activated clay and activated carbon were removed by filtration to
obtain a solution of
8-[4-(4-phenylbutoxy)benzoyl]amino-2-cyano-4-oxo-4H-benzopyran in
toluene.
[0146] A flask equipped with a stirrer and a thermometer and
connected to a distillation apparatus was charged with 1,236 parts
by weight of water, 1.8 parts by weight of sodium
dihydrogenphosphate and 0.2 part by weight of disodium
hydrogenphosphate, and heated to and kept at 99.degree. C. While
the above obtained solution of
8-[4-(4-phenylbutoxy)benzoyl]amino-2-cyano-4-oxo-4H-benzopyran in
toluene was poured into the separable flask at 95.degree. C. over
about 2.5 hours, toluene-water azeotrope was distilled off under
the normal pressure. Soon after completion of the pouring, the
distillation of toluene was completed and crystals were
precipitated in the solution. The precipitated crystals were
filtered, washed and dried to obtain 64 parts by weight of
8-[4-(4-phenylbutoxy)benzoyl]amino-2-cyano-4-oxo-4H-1-benzopyran.
The yield based on
8-[4-(4-phenylbutoxy)benzoyl]amino-2-carbamoyl-4-oxo-4H-1-benzopyran:
92%.
INDUSTRIAL APPLICABILITY
[0147] According to the present invention, an aminochromone
compound useful as a pharmaceutical intermediate can be produced
industrially advantageously from a dicarboxylic acid compound which
can be easily derived from an easily available nitrophenol.
* * * * *