DESCRIPTION
TITLE OF INVENTION: NOVEL METHOD FOR PRODUCING 1,3-DI-SUBSTITUTEDCYCLOBUTANE-
1,2,3,4-TETRACARBOXYLIC ACID AND DIANHYDRIDE OF SAID
ACID
5
TECHNICAL FIELD
The present invention relates to a novel method for producing a 1,3-di-substitutedcyclobutane-
1,2,3,4-tetracarboxylic acid and a dianhydride of said acid, with high
selectivity and high yield.
10
BACKGROUND ART
A 1,3-di-substituted-cyclobutane-1,2,3,4-tetracarboxylic acid dianhydride is useful
as a raw material for various industrial applications. Further, a 1,3-di-substitutedcyclobutane-
1,2,3,4-tetracarboxylic acid as a raw material for such a 1,3-di-substitutedcyclobutane-
1,2,3,4-tetracarboxylic acid dianhydride is also a useful compound15 .
In particular, 1,3-dimethylcyclobutane-1,2,3,4-tetracarboxylic acid dianhydride
represented by the formula (12a) and 1,3-dimethylcyclobutane-1,2,3,4-tetracarboxylic
acid represented by the formula (13a) as a raw material for said acid dianhydride, are a
main raw material or synthetic intermediate for polyimide being widely used as a
20 protective material, an insulating material, a color filter, a liquid alignment film or an
optical waveguide material in liquid crystal display devices or semiconductors (Patent
Document 1 and Non-Patent Document 1).
1,3-Dimethylcyclobutane-1,2,3,4-tetracarboxylic acid dianhydride represented by
the formula (12a) and 1,3-dimethylcyclobutane-1,2,3,4-tetracarboxylic acid represented
25 by the formula (13a), have such structural features that two methyl groups in the
cyclobutane ring are present at the 1-position and the 3-position, and further that the
relative configuration of the methyl groups is trans.
Heretofore, the following production methods have been known as methods for
producing a 1,3-di-substituted-cyclobutane-1,2,3,4-tetracarboxylic acid dianhydride.
30 According to Non-Patent Document 2, citraconic anhydride and benzophenone as
a photosensitizer, are dissolved in 1,4-dioxane, and the resulting solution is irradiated
with light so as to carry out a cyclization reaction, thereby to synthesize dimethyl
cyclobutane tetracarboxylic dianhydride having two methyl groups as substituents in the
cyclobutane ring. Further, the dimethyl cyclobutane tetracarboxylic acid dianhydride
35 thus obtained is subjected to hydrolysis and methyl-esterification in this order, thereby
to synthesize dimethyl cyclobutane-1,2,3,4-tetracarboxylic acid tetramethyl ester.
However, the position and the relative configuration of the methyl groups on the
cyclobutane ring have not yet been determined.
According to Non-Patent Document 3 and Non-Patent Document 4,
O
O
O
Me
Me H
O
O
O
H
HO2C
HO2C
Me
Me H CO2H
CO2H
H
( 12a ) ( 13a )
2
dimethylcyclobutane-1,2,3,4-tetracarboxylic acid dianhydride is synthesized from
citraconic anhydride, and then dimethyl cyclobutane-1,2,3,4-tetracarboxylic acid
tetramethyl ester is synthesized, in accordance with the method of Non-Patent
Document 2. Further, Non-Patent Document 3 and Non-Patent Document 4 disclose a
possibility of production of four types of dimethyl cyclobutane-1,2,3,4-tetracarboxyli5 c
acid dianhydride diastereomers attributed to the position and the relative configuration
of the methyl groups on the cyclobutane ring.
According to Patent Document 2, 1,000 g of citraconic anhydride is dissolved in
ethyl acetate, and the resulting solution is irradiated with light so as to carry out a
10 cyclization reaction, whereby a dimer of citraconic anhydride is synthesized with a yield
of 695 g. However, determination of the structure and a formation ratio of
diastereomers, of such a citraconic anhydride dimer, are not described therein.
Patent Document 3 has reported that it is possible to obtain a mixture of 1,3-
diethylcyclobutane-1,2,3,4-tetracarboxylic acid 1,2:3,4-dianhydride and 1,2-
15 diethylcyclobutane-1,2,3,4-tetracarboxylic acid 1,4:2,3-dianhydride by dissolving ethyl
maleic anhydride in ethyl acetate and irradiating the resulting solution with light so as to
carry out a cyclization reaction. In Patent Document 3, the mixture has been subjected
to purification operation such as distillation to remove the solvent, filtration or
crystallization, but isolated purification of the respective dianhydrides has not yet been
20 achieved. Further, the yield calculated by both the amount of the obtained mixture and
NMR is at a medium level.
PRIOR ART DOCUMENTS
PATENT DOCUMENTS
25 Patent Document 1: WO2010/092989
Patent Document 2: JP-A-4-106127
Patent Document 3: JP-A-2006-347931
NON-PATENT DOCUMENTS
Non-Patent Document 1: New Revised Latest Polyimide Fundamentals and
30 Applications (ISBN 978-4-86043-273-7), 2010, NTS Inc., pp. 344 to 354.
Non-Patent Document 2: Chemische Berichte 1962, vol. 95, pp. 1,642 to 1,647.
Non-Patent Document 3: Journal of Organic Chemistry 1968, vol. 33, pp. 920 to
921.
Non-Patent Document 4: Chemische Berichte 1998, vol. 121, pp. 295 to 297.
35
DISCLOSURE OF INVENTION
TECHNICAL PROBLEM
Heretofore, no method for highly selectively producing a 1,3-di-substitutedcyclobutane-
1,2,3,4-tetracarboxylic acid and a dianhydride of said acid, which is
40 capable of controlling the position and the relative configuration of substituents in the
cyclobutane ring at the same time in the reaction of constructing the cyclobutane ring
has been known. Accordingly, in order to obtain the aimed compound, it was
necessary to carry out purification operation, specifically, purification by sublimation,
crystallization using a large amount of an organic solvent, suspension washing, or
45 further cumbersome purification operation such as filtration, and therefore a large
amount of waste liquid or waste was produced, an excessive load was applied onto
environments in view of green chemistry, and the productivity was poor.
It is an object of the present invention to provide a novel method for producing a
3
1,3-di-substituted cyclobutane-1,2,3,4-tetracarboxylic acid or a dianhydride of said acid
with high selectivity and high yield, which is useful as a raw material for various
industrial applications and which satisfies such a desirable stereostructure that two
substituents in the cyclobutane ring are present at the 1-position and 3-position and
further that the relative configuration of the substituents is trans, at the same time5 .
SOLUTION TO PROBLEM
The present inventors have conducted extensive studies to solve the above
problems and as a result, have found that it is possible to obtain a 1,3-di-substituted10
cyclobutane-1,2,3,4-tetracarboxylic acid having a desirable stereostructure with high
selectively and high yield, by producing a crystal composed of an ethylene dicarboxylic
acid derivative and a nitrogen-containing organic compound, and applying light to the
crystal so as to carry out a cyclization reaction. The present invention has been made
based on the above discovery and provides the following.
15
[1] A method for producing a 1,3-di-substituted-cyclobutane-1,2,3,4-tetracarboxylic
acid represented by the formula (2),
wherein R1 is a C1-4 alkyl group, a phenyl group or a halogen atom,
said method comprising the following step (a) and step (b):
20 Step (a): a step of producing a crystal (1) composed of an ethylene dicarboxylic
acid derivative represented by the formula (4C) or (4M) and a nitrogen-containing
organic compound (5), in the presence or absence of a solvent,
wherein R1 has the same meaning as the above,
Step (b): a step of applying light to the crystal (1) obtained in step (a) so as to
25 carry out a cyclization reaction.
[2] The production method according to the above [1], wherein the nitrogencontaining
organic compound (5) is an aliphatic amine, an aromatic amine, an amine
oxide, an amide, an imide or a nitrogen-containing heterocyclic compound.
[3] The production method according to the above [2], wherein the nitrogen30
containing organic compound (5) is a nitrogen-containing heterocyclic compound.
[4] The production method according to the above [3], wherein the nitrogen-
HO2C
HO2C
R1
H
( 4C )
HO2C R1
H CO2H
( 4M )
4
containing heterocyclic compound is nicotinamide or pyridine.
[5] The production method according to any one of the above [1] to [4], wherein the
light to be applied has a wavelength of from 290 nm to 600 nm, in step (b).
[6] The production method according to any one of the above [1] to [4], wherein the
light to be applied has a wavelength of from 300 nm to 580 nm, in step (b)5 .
[7] The production method according to any one of the above [1] to [6], wherein the
light is applied in the presence of a photosensitizer, in step (b).
[8] The production method according to any one of the above [1] to [7], wherein R1 in
the formula (4C) or (4M) is a methyl group or an ethyl group.
10 [9] The production method according to any one of the above [1] to [8], wherein the
compound represented by the formula (4C) is used.
[10] A method for producing a 1,3-di-substituted-cyclobutane-1,2,3,4- tetracarboxylic
acid dianhydride represented by the formula (3), comprising subjecting the 1,3-disubstituted-
cyclobutane-1,2,3,4-tetracarboxylic acid represented by the formula (2)
15 obtained by the production method as defined in the above [1], to dehydration
condensation reaction,
wherein R1 is a C1-4 alkyl group, a phenyl group or a halogen atom,
wherein R1 has the same meaning as the above.
[11] The production method according to the above [10], wherein the dehydration
20 condensation reaction is carried out in the presence of acetic anhydride.
[12] A crystal composed of pyridine and citraconic acid, which has, in powder X-ray
diffraction measured by Cu-K rays, peaks at diffraction angles 2=(12.58±0.2,
15.05±0.2, 16.08±0.2, 17.60±0.2, 19.20±0.2, 21.57±0.2, 23.02±0.2, 24.50±0.2,
26.45±0.2, 27.06±0.2, 28.10±0.2, 32.49±0.2, 35.90±0.2, 36.46±0.2 and 38.43±0.2).
25 [13] The crystal according to the above [12], which has, in powder X-ray diffraction
measured by Cu-K rays, peaks at diffraction angles 2=(12.58±0.2, 15.05±0.2,
16.08±0.2, 17.60±0.2, 18.34±0.2, 19.20±0.2, 21.57±0.2, 23.02±0.2, 24.50±0.2,
26.45±0.2, 27.06±0.2, 28.10±0.2, 30.39±0.2, 32.49±0.2, 34.71±0.2, 35.90±0.2,
5
36.46±0.2 and 38.43±0.2).
ADVANTAGEOUS EFFECTS OF INVENTION
According to the present invention, it is possible to produce a 1,3-di-substitutedcyclobutane-
1,2,3,4-tetracarboxylic acid and a dianhydride of said acid having desirabl5 e
stereostructures with high selectivity and high yield, by producing a crystal composed of
an ethylene dicarboxylic acid derivative and a nitrogen-containing organic compound
and then applying light to the crystal so as to carry out a cyclization reaction. Further,
according to the production method of the present invention, by-products are hardly
10 produced during the production of the 1,3-di-substituted-cyclobutane-1,2,3,4-
tetracarboxylic acid and dianhydride of said acid, whereby it is possible to remarkably
reduce purification operation for obtaining such a compound having a desirable
stereostructure, and therefore such a method is useful as an industrial production
method considering the environmental load.
15
BRIEF DESCRIPTION OF DRAWINGS
Fig. 1 is a FT-IR chart of the crystal (8) composed of pyridine and citraconic acid,
produced in Examples.
Fig. 2 is a powder X-ray diffraction chart of the crystal (8) composed of pyridine
20 and citraconic acid, produced in Examples.
Fig. 3 is a view illustrating a packing structure of pyridinium and citraconic acid
anion as a cylinder model together with a unit cell, from the result of X-ray structural
analysis of a single crystal of the crystal (8) produced in Examples.
Fig. 4 is a view illustrating an ORTEP diagram of only a configuration of citraconic
25 acid anions, from the result of X-ray structural analysis of a single crystal of the crystal
(8) produced in Examples.
Fig. 5 is a view illustrating an ORTEP diagram of a molecular structure of a
compound (13a), from the result of X-ray structural analysis of a single crystal of the
compound (13a) produced in Examples.
30 Fig. 6 is a view illustrating an ORTEP diagram of a molecular structure of a
compound (12a), from the result of X-ray structural analysis of a single crystal of the
compound (12a) produced in Examples.
Fig. 7 is a view schematically illustrating a flow reactor used in Example 9.
Fig. 8 is a cross-sectional view illustrating a T-shaped mixer (mixer 2) having a
35 double tube structure in the flow reactor used in Example 9.
DESCRIPTION OF EMBODIMENTS
In this specification, the following symbols respectively represent the following
meanings.
40 "n-" represents normal, "s-" represents secondary, "t-" represents tertiary, "o-"
represents ortho, "m-" represents meta, and "p-" represents para. Further, "trans" and
"cis" represent the relative configuration of substituents in a cyclic compound, in which
trans represents a case where corresponding substituents are present on the opposite
side in the annular plane, and cis represents a case where they are present on the
45 same side in the annular plane. Moreover, (E) and (Z) represent a stereochemistry in
which (E) is a case where, among groups bonded to atoms forming a double bond in an
intramolecular plane having the double bond, prior groups in a priority rule are present
on the opposite side, and (Z) is a case where they are present on the same side.
6
The symbol "Me" means a methyl group. A Ca-b alkyl group represents a
monovalent group obtained by removing one hydrogen atom from a linear or branched
aliphatic hydrocarbon having a number of carbon atoms being from a to b. As a
specific example, a methyl group, an ethyl group, a n-propyl group, an isopropyl group,
a n-butyl group, an isobutyl group, a s-butyl group, a t-butyl group, a n-pentyl group, a5 n
isopentyl group, a neopentyl group, a t-pentyl group, a 1,1-dimethylpropyl group, a nhexyl
group or an isohexyl group may be mentioned.
A halogen atom may, for example, be a fluorine atom, a chlorine atom, a bromine
atom or an iodine atom. Further, the symbol of halo represents a halogen atom.
10 Now, the steps (a) to (c) in the method for producing a 1,3-di-substituted
cyclobutane-1,2,3,4-tetracarboxylic acid and a dianhydride of said acid, will be
described.
Step (a): Production of crystal composed of ethylene dicarboxylic acid derivative
and nitrogen-containing organic compound
15 In this step, a crystal (1) composed of an ethylene dicarboxylic acid derivative
represented by the formula (4C) or (4M) and a nitrogen-containing organic compound
(5) is obtained. In the formula, R1 is a C1-4 alkyl group, a phenyl group or a halogen
atom, but among them, R1 is preferably a methyl group, an ethyl group or a phenyl
group, more preferably a methyl group or an ethyl group.
20
In this specification, the crystal (1) composed of the ethylene dicarboxylic acid
derivative represented by the formula (4C) or (4M) and the nitrogen-containing organic
compound (5) is a crystal which is solid at room temperature, has distinctive powder Xray
diffraction peaks, and is composed of at least two compounds in a constant
25 stoichiometric ratio. The crystal (1) has such a structure that at least two compounds
as constituting elements are three-dimensionally and periodically arranged in the form
of molecules or ions. Further, it is also said that the crystal (1) is a so-called
multicomponent crystal since it is composed of at least two components. Here, the
room temperature is a temperature of from 1 to 40 C.
30 On the other hand, in this crystal (1), destruction of the periodic arrangement may
occur on e.g. the crystal surface or the ethylene dicarboxylic acid derivative and the
nitrogen-containing organic compound may gather without having a periodic structure in
the form of molecules or ions. However, a crystal containing a structure which has a
three-dimensional and periodic arrangement, even though such a structure is partially
35 lost, is included in the crystal (1) of the present invention in a case where it is possible
7
to produce a 1,3-di-substituted-cyclobutane-1,2,3,4-tetracarboxylic acid having a
desirable stereostructure with high selectivity, by applying light to the crystal so as to
carry out a cyclization reaction.
In the present invention, the structure of the crystal (1) composed of an ethylene
dicarboxylic acid derivative and a nitrogen-containing compound in step (a), is 5 s a
determinant of stereoselectivity of a 1,3-di-substituted-cyclobutane-1,2,3,4-
tetracarboxylic acid in the subsequent step (b) and further a dianhydride of the 1,3-disubstituted-
cyclobutane-1,2,3,4-tetracarboxylic acid in step (c), and therefore alignment
of molecules of the ethylene dicarboxylic acid derivative in the crystal (1) is important.
10 The crystal (1) in the present invention is preferably such that, in the photocyclization
reaction in step (b) as a subsequent step, two ethylene dicarboxylic acid derivatives are
aligned so as to construct a cyclobutane ring in which the two methyl groups are
present at 1-position and 3-position and further the relative configuration of the methyl
groups becomes trans.
15 The ethylene dicarboxylic acid derivative to be used in the present invention may
be a known compound, and some of them are available as a commercial product. For
example, citraconic acid is available from Tokyo Chemical Industry Co., Ltd., Sigma-
Aldrich Co., LLC., etc. Further, phenyl maleic acid is available from Hydrus Chemical
Inc. Moreover, mesaconic acid is available from Tokyo Chemical Industry Co., Ltd.,
20 Sigma-Aldrich Co., LLC., etc.
Further, some of the ethylene dicarboxylic acid derivative to be used in the
present invention may be synthesized in accordance with a known method described in
documents. For example, 2-isopropyl maleic acid can be synthesized with reference to
e.g. Synthetic Communications, 2013, vol. 43(10), pp. 1,455 to 1,459, and phenyl
25 fumaric acid can be synthesized with reference to Journal of the American Chemical
Society, 1954, vol. 76, pp. 1,872 to 1,873.
As a specific example of the ethylene dicarboxylic acid derivative represented by
the formula (4C) to be used in the present invention, citraconic acid, 2-ethyl maleic acid,
2-isopropyl maleic acid, 2-propyl maleic acid, 2-n-butyl maleic acid, 2-isobutyl maleic
30 acid, 2-(t-butyl) maleic acid, 2-phenyl maleic acid, 2-fluoromaleic acid, 2-chloromaleic
acid, 2-bromomaleic acid or 2-iodomaleic acid may be mentioned.
Among them, citraconic acid, 2-ethyl maleic acid, 2-isopropyl maleic acid or 2-
phenyl maleic acid is preferred, and citraconic acid or 2-ethyl maleic acid is particularly
preferred.
35 As a specific example of the ethylene dicarboxylic acid derivative represented by
the formula (4M) to be used in the present invention, mesaconic acid, 2-ethyl fumaric
acid, 2-isopropyl fumaric acid, 2-propyl fumaric acid, 2-n-butyl fumaric acid, 2-isobutyl
fumaric acid, 2-(t-butyl) fumaric acid, 2-phenyl fumaric acid, 2-fluorofumaric acid, 2-
chlorofumaric acid, 2-bromofumaric acid or 2-iodofumaric acid may be mentioned.
40 Among them, mesaconic acid, 2-ethyl fumaric acid, 2-phenyl fumaric acid or 2-
fluorofumaric acid is preferred, and mesaconic acid or 2-ethyl fumaric acid is particularly
preferred.
As the nitrogen-containing organic compound (5), various compounds may be
used. For example, in production of the above crystal (1), proton may transfer
45 between the nitrogen-containing organic compound (5) and the ethylene dicarboxylic
acid derivative represented by the formula (4C) or (4M) which is acidic in the crystal
structure, whereby a crystal may be produced through an ionic bond formed.
Accordingly, a lot of nitrogen-containing organic compounds having a basicity which
8
allows it to undergo neutralization reaction with the ethylene dicarboxylic acid derivative
having an acidity are possible to use.
Further, in production of the crystal (1), a lot of nitrogen-containing organic
compounds having a substituent or a partial skeleton capable of forming intermolecular
interaction such as a hydrogen bond or a van der Waals force with the ethylen5 e
dicarboxylic acid dianhydride are possible to use. The substituent may, for example,
be an amino group, an amido group, an imino group, an ether group, a hydroxy group, a
carbonyl group or a carboxy group, and the partial skeleton may, for example, be a
pyrrole skeleton, a pyrroline skeleton, a pyrrolidine skeleton, an indole skeleton, an
10 indoline skeleton, an isoindole skeleton, an imidazoline skeleton, an imidazolidine
skeleton, a pyridine skeleton, a piperidine skeleton, a quinoline skeleton, an acridine
skeleton or a triazine skeleton.
In the present invention, in the subsequent step (b), the double bond of the
ethylene dicarboxylic acid derivative in the crystal (1) composed of the ethylene
15 dicarboxylic acid derivative represented by the formula (4C) or (4M) and the nitrogencontaining
organic compound (5), undergoes a cyclization reaction by irradiation with
light, and therefore the nitrogen-containing organic compound is preferably one which
does not inhibit the photocyclization reaction. Therefore, preferred is a compound
which produces no by-products by the reaction with the ethylene dicarboxylic acid
20 derivative, a compound having a structure that can prevent e.g. an isomization reaction
to destruct the crystal (1) before producing an aimed compound, or a compound having
a structure which has a resistance to the light irradiation. As a preferred example of
such a nitrogen-containing organic compound, an aliphatic amine, an aromatic amine,
an amine oxide, an amide, an imide or a nitrogen-containing heterocyclic compound
25 may be mentioned.
The above aliphatic amine may, for example, be methylamine, ethylamine,
isopropylamine, butylamine, isobutylamine, s-butylamine, t-butylamine, pentylamine,
isopentylamine, 2-pentanamine, t-pentylamine, hexylamine, heptylamine, octylamine, 2-
octanamine, 2-ethylhexylamine, nonylamine, decylamine, benzylamine,
30 phenethylamine, -methylbenylzmine, mescaline, dopamine, dipropylamine,
diisopropylamine, N-methylethylamine, N-ethylisobutylamine, dibutylamine,
diisobutylamine, dipentylamine, N,N-dimethylpropylamine, tripropylamine, N-ethyl-Nmethylbutylamine,
tributylamine, N,N-dimethylbenzylamine, N,N-diethylbenzylamine,
tribenzylamine, cyclopropylamine, cyclobutylamine, cyclohexylamine,
35 dicyclohexylamine, N,N-dimethylcyclohexylamine, cyclohexane-1,2-diamine,
(1R,2R)-1,2-cyclohexanediamine or (1S,2S)-1,2-cyclohexanediamine. Among them,
methylamine, ethylamine, cyclohexane-1,2-diamine, (1R,2R)-1,2-
cyclohexanediamine or (1S,2S)-1,2-cyclohexanediamine is preferred.
The above aromatic amine may, for example, be o-toluidine, m-toluidine, p40
toluidine, o-ethylaniline, m-ethylaniline, p-ethylaniline, p-isopropylaniline, p-tpentylaniline,
xylidine, 2,3-xylidine, 2,4-xylidine, 2,6-xylidine, 3,4-xylidine, 3,5-xylidine,
thymylamine, 2,4,5-trimethylaniline, 2,4,6-trimethylaniline, pentamethylaniline, 1-
naphtylamine, 2-naphthylamine, 1-anthrylamine, 2-anthrylamine, 9-anthrylamine, Nbutylaniline,
N-isopentylaniline, N-benzylaniline, N-benzyl-N-ethylaniline, N,N45
diphenylbenzylamine, N-methyl-o-toluidine, N-methyl-p-toluidine, N,N-dimethylaniline,
N,N-diethylaniline, N,N-dibutylaniline, N,N-dipentylaniline, N,N-methyl-o-toluidine, N,Nmethyl-
m-toluidine, N,N-methyl-p-toluidine, diphenylamine, di-p-tolylamine, Nmethyldiphenylamine,
N-ethyldiphenylamine, triphenylamine, N,N-dibenzylaniline, N9
benzyl-N-ethylaniline, o-phenylenediamine, m-phenylenediamine or pphenylenediamine.
Among them, o-toluidine, m-toluidine, p-toluidine, o-ethylaniline,
m-ethylaniline or p-ethylaniline is preferred.
The above amine oxide may, for example, be trimethylamine oxide, pyridine 1-
oxide, 2,2’-bipyridine 1,1’-dioxide, 4,4’-dimethyl-2,2’-bipyridine 1,1’-dioxide or 3,3’5 -
dimethyl-2,2’- bipyridine 1,1’-dioxide. Among them, trimethylamine oxide, pyridine 1-
oxide or 3,3’-dimethyl-2,2’-bipyridine 1,1’-dioxide is preferred.
The above amide may, for example, be formamide, N,N-dimethylformamide, N,Ndiisopropylformamide,
acetamide, N-ethylacetamide, N,N-dimethylacetamide, N10
chloroacetamide, N-bromoacetamide, diacetamide, triacetamide, propionamide,
butylamide, isobutylamide, valeramide, isovaleramide, capronamide, heptanamide,
octanamide, acrylamide, chloroacetamide, dichloroacetamide, trichloroacetamide,
glycolamide, lactamide, pyruvamide, cyanoacetamide, fulminuric acid, oxamide,
malonamide, succinic amide, adipamide, L-malamide or (R,R)-tartaramide. Among
15 them, formamide, N,N-dimethylformamide, N,N-diisopropylformamide or acetamide is
preferred.
The above imide may, for example, be succinimide, N-bromosuccinimide or Nchlorosuccinimide.
Among them, succinimide is preferred.
The above nitrogen-containing heterocyclic compound may, for example, be a
20 pyrrole compound, a pyrroline compound, a pyrrolidine compound, an indole compound,
an indoline compound, an isoindole compound, a carbazole compound, a diazole
compound, an imidazoline compound, an imidazolidine compound, a pyridine
compound, a substituted derivative of pyridine, a piperidine compound, a quinoline
compound, a hydroquinoline compound, an isoquinoline compound, an acridine
25 compound, a phenanthridine compound, a diazine compound, a sulfadiazine
compound, a hydropyrimidine compound, a piperazine compound, a benzodiazine
compound, a triazole compound, a benzotriazole compound, a triazine compound,
purine, hypoxanthine, xanthine, theobromine, theophylline, caffeine, uric acid, adenine,
guanine, 3-methyl uric acid or 7-methyl uric acid.
30 The above pyrrole compound may, for example, be pyrrole, methyl pyrrole,
dimethyl pyrrole, 3-ethyl-4 methyl pyrrole, ethyl dimethyl pyrrole, 3-ethyl-2,4,5-trimethyl
pyrrole, 2,3,4,5-tetramethyl pyrrole or acetyl pyrrole. The above pyrroline compound
may, for example, be pyrroline. The above pyrrolidine compound may, for example, be
pyrrolidine. The above indole compound may, for example, be indole, indolenine,
35 methylindole, 2,3-dimethylindole or 2-phenylindole. The above indoline compound
may, for example, be indoline, isatin, O-methylisatin, N-methylisatin or 2-chloro-3-
indolone.
The above isoindole compound may, for example, be isoindole, isoindoline or
phthalimidine. The above carbazole compound may, for example, be carbazole,
40 indigo, leuco indigo or indirubin. The above diazole compound may, for example, be
pyrazole, 3,5-dimethyl pyrazole, 2-pyrazoline, pyrazolidine, pyrazolone, 3-methyl-1-
phenyl-5-pyrazolone, 2,3-dimethyl-1-phenyl-5-pyrazolone, aminopyrine or indazole.
The above imidazoline compound may, for example, be imidazoline, amaline or
naphazoline. The above imidazolidine compound may, for example, be ethylene urea,
45 hydantoin, 1-methyl hydantoin, 5-methyl hydantoin, diphenyl hydantoin or creatinine.
The above pyridine compound may, for example, be pyridine, 2-methylpyridine, 3-
methylpyridine, 4-methylpyridine, 2-ethylpyridine, 3-ethylpyridine, 4-ethylpyridine, 2-
propylpyridine, 2,3-dimethylpyridine, 2,4-dimethylpyridine, 2,5-dimethylpyridine, 2,6-
10
dimethylpyridine, 3,4-dimethylpyridine, 3,5-dimethylpyridine, 4-ethyl-2-methylpyridine, 3-
ethyl-4-methylpyridine, 5-ethyl-2-methylpyridine, 6-ethyl-2-methylpyridine, 2,4,6-
trimethylpyridine, 2,3,4-trimethylpyridine, 4-ethyl-2,6-dimethylpyridine, 2-phenylpyridine,
3-phenylpyridine, 4-phenylpyridine, 2-benzylpyridine, 3-benzylpyridine, 4-
benzylpyridine, 2,2’-bipyridyl, 3,3’-bipyridyl or 4,4’-bipyridyl5 .
The above substituted derivative of pyridine may, for example, be 2-
chloropyridine, 3-chloropyridine, 4-chloropyridine, 2-pyridone, 3-pyridinol, 4-pyridone, 2-
methoxypyridine, 3-methoxypyridine, 4-methoxypyridine, 2-pyridine carbaldehyde, 3-
pyridine carbaldehyde, 4-pyridine carbaldehyde, 2-acetylpyridine, 3-acetylpyridine, 4-
10 acetylpyridine, 2-ethoxypyridine 1-oxide, 2-pyridine carboxylic acid, nicotinic acid,
isonicotinic acid, nicotinamide, nikethamide, isonicotinic acid hydrazide, 2-
ethylisonicotinthioamide, 2,3-pyridine dicarboxylic acid, 2,4-pyridine dicarboxylic acid,
2,5-pyridine dicarboxylic acid, 2,6-pyridine dicarboxylic acid, 3,4-pyridine dicarboxylic
acid, 3,5-pyridine dicarboxylic acid, 3-nitropyridine, 2-pyridylamine, 3-pyridylamine, 4-
15 pyridylamine or N,N-dimethyl-4-pyridylamine.
The above piperidine compound may, for example, be piperidine, 2-
methylpiperidine, coniine, 3-methylpiperidine, 4-methylpiperidine, N-methylpiperidine, 1-
phenylpiperidine, 2,6-dimethylpiperidine, N-benzoylpiperidine or 4-piperidone. The
above quinoline compound may, for example, be quinoline, 2-methylquinoline, 3-
20 methylquinoline, 4-methylquinoline, 6-methylquinoline, 8-methylquinoline, 2,3-
dimethylquinoline, 2,4-dimethylquinoline, 2.6-dimethylquinoline, 2-phenylquinoline, 6-
phenylquinoline, 8-phenylquinoline, 2-chloroquinoline, 2-quinolone, 4-quinolone, 5-
quinolinol, 6-quinolinol, 7-quinolinol, 8-quinolinol, -naphthoquinoline, -
naphthoquinoline, 2-methyl-4-quinolinol, 4-mehtyl-2-quinolinol, 6-methoxyquinoline, 2,4-
25 quinolinediol, 2-quinoline carboxylic acid, 3-quinoline carboxylic acid, 4-quinoline
carboxylic acid, 5-quinoline carboxylic acid, 5-nitroquinoline, 6-nitroquinoline, 7-
nitroquinoline, 8-nitroquinoline, 2-quinolylamine, 3-quinolylamine, 4-quinolylamine,
flavaniline, 2,2’-biquinolyl, 3,3’-biquinolyl, 5,5’-biquinolyl, 6,6’-biquinolyl or 2,3’-biquinolyl.
The above hydroquinoline compound may, for example, be 1,2,3,4-
30 tetrahydroquinoline, 1-methyl-1,2,3,4-tetrahydroquinoline, 6-methoxy-1,2,3,4-
tetrahydroquinoline, 3,4-dihydro-2-quinolinone or cis-decahydroquinoline. The above
isoquinoline compound may, for example, be isoquinoline, 1-methylisoquinoline, 1-
isoquinoline, 1,2,3,4-tetrahydroisoquinoline or 1-benzylisoquinoline. The above
acridine compound may, for example, be acridine, 2-methylacridine, 3-methylacridine,
35 9-methylacridine, 9-phenylacridine, 3-amino-9-(p-aminophenyl)acridine, 3,6-diamino-10-
methylacridinium chloride, acridane, acridone or acrinol.
The above phenanthridine compound may, for example, be phenanthridine,
benzo[f]quinoline, benzo[g]quinoline, benzo[h]quinoline, benzo[g]isoquinoline, 1,10-
phenanthroline, 2,9-dimethyl-1,10-phenanthroline, 4,7-diphenyl-1,10-phenanthroline or
40 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline. The above diazine compound may, for
example, be pyridazine, pyrimidine, pyrazine, 2,5-dimethylpyrazine or
tetraphenylpyrazine.
The above sulfadiazine compound may, for example, be sulfadiazine,
sulfadimethoxine, sulfaphenazole, sulfamethizole, sulfamethoxypyridazine,
45 sulfaisoxazole or sulfisomidine. The above hydropyrimidine compound may, for
example, be uracil, thymine, primidone, 2-thiouracil, cytosine, barbituric acid, 5,5-
diethylbarbituric acid, 5,5-dipropylbarbituric acid, allobarbital, 5-ethyl-5-phenylbarbituric
acid, cyclobarbital, hexobarbital, dialluric acid, dilituric acid, uramil, amobarbital, violuric
11
acid, alloxan, alloxanthin, purpuric acid, murexide or amalic acid. The above
piperazine compound may, for example, be piperazine, 2,5-dimethylpiperazine or 2,5-
piperazinedione. The above benzodiazine compound may, for example, be cinnoline,
phthalazine, quinazoline or quinoxaline. The above triazole compound may, for
example, be 1,2,3-triazole, 1,2,4-triazole or 4-amino-1,2,4-triazole5 .
The above benzotriazole compound may, for example, be benzotriazole or 5-
methylbenzotriazole. The above triazine compound may, for example, be 1,2,3-
triazine, 4-methyl-1,2,3-triazine, 4,6-dimethyl-1,2,3-triazine, 4,5,6-trimethyl-1,2,3-
triazine, 1,2,3-benzotriazine, 4-methyl-1,2,3-benzotriazine, 1,3,5-triazine, cyanuric
10 chloride, cyanuric acid, trimethyl cyanurate, methyl isocyanurate, ethyl isocyanurate,
melanin, ammeline or ammelide.
In the present invention, a preferred nitrogen-containing heterocyclic compound
may be a pyridine compound or a substituted derivative of pyridine. The pyridine
compound is preferably pyridine, 2,3-dimethylpyridine or 3,5-dimethylpyridine, more
15 preferably pyridine. The substituted derivative of pyridine is preferably nicotinic acid,
isonicotinic acid, nicotinamide or nikethamide, more preferably nicotinamide.
The above nitrogen-containing organic compound may be used alone or two or
more of them may be used in combination.
In the present invention, it is possible to produce the crystal (1) composed of the
20 ethylene dicarboxylic acid derivative represented by the formula (4C) or (4M) and the
nitrogen-containing organic compound (5) by mixing both of them so as to sufficiently
contact them. The amount of the nitrogen-containing organic compound used in
production of the crystal (1) is preferably from 0.1 to 50 equivalents, more preferably
from 0.2 to 15 equivalents, particularly preferably from 0.5 to 3 equivalents to 1
25 equivalent of the ethylene dicarboxylic acid derivative.
Particularly in a case where the nitrogen-containing organic compound is in the
form of liquid, it may be used as a solvent to the ethylene dicarboxylic acid derivative,
and in a case where the ethylene dicarboxylic acid derivative is in the form of liquid, it
may be used as a solvent to the nitrogen-containing organic compound.
30 The temperature at the time of producing the crystal (1) is not particularly limited,
but may be optionally set to a range of from -78 C to a reflux temperature of the
reaction mixture. The temperature is preferably from -30 to 70 C, more preferably from
-20 to 40 C.
The pressure at the time of producing the crystal (1) may be elevated pressure,
35 normal pressure or reduced pressure, but is preferably from 0.5 to 10 atm, more
preferably from 0.9 to 2 atm.
The method of mixing the ethylene dicarboxylic acid derivative represented by the
formula (4C) or (4M) with the nitrogen-containing organic compound (5) at the time of
producing the crystal (1) may, for example, be a method of directly mixing both of them
40 or a method of mixing them by using a solvent.
As the method of directly mixing both of them, a kneading method or a mixing and
pulverizing method may, for example, be employed. The kneading method is
applicable to mixing when one is a solid and the other is a liquid, wherein a mortar can
be used in the case of a small amount, and a kneader, a reactor for organic synthesis or
45 a stirrer may, for example, be used in the case of a large amount.
In a case where both of the ethylene dicarboxylic acid derivative and the nitrogencontaining
organic compound are in the form of a solid, the mixing and pulverizing
method is applicable, wherein a mortar can be used in the case of a small amount, and
12
e.g. a pulverizer can be used in the case of a large amount. The mixing by means of a
kneading method or a mixing and pulverizing method, may sometimes be accompanied
by heat generation due to e.g. neutralization reaction, and therefore the mixing may be
carried out while e.g. a mortar or a reactor is cooled.
As the method of mixing the ethylene dicarboxylic acid derivative and the nitrogen5 -
containing organic compound by using a solvent, a temperature control method using a
solvent, a solvent evaporation method, a solvent distillation method, a poor solvent
addition method, a solution-solution mixing method, a suspension-solution mixing
method or a suspension-suspension mixing method may, for example, be used.
10 Further, the mixing of these compounds may sometimes be accompanied by heat
generation due to e.g. dissolution or neutralization reaction, and therefore they may be
mixed while e.g. a reactor is cooled.
The method for producing the crystal (1) by the temperature control method using
a solvent is a method wherein, first a reaction mixture of the ethylene dicarboxylic acid
15 derivative and the nitrogen-containing organic compound is dissolved in a solvent, and
then a crystal is obtained by utilizing the difference in solubility between at a high
temperature and at a low temperature.
The method for producing the crystal (1) by the solvent evaporation method or the
solvent distillation method using a solvent is a method wherein, first a reaction mixture
20 of the ethylene dicarboxylic acid derivative and the nitrogen-containing organic
compound is dissolved in the solvent, followed by evaporating or distilling the solvent, in
which a preferred crystal is more likely to be obtained in a case where the solvent is
slowly evaporated. In the case of distilling the solvent, e.g. a rotary evaporator may be
used. If crystallization cannot desirably be carried out from one type of the solvent, a
25 mixed solvent may be used.
The method for producing the crystal (1) by the poor solvent addition method
using a solvent is a method, wherein, first a reaction mixture of the ethylene dicarboxylic
acid derivative and the nitrogen-containing organic compound is dissolved in the
solvent, and then a poor solvent is added thereto so as to obtain the crystal.
30 Depending on a solvent used, the reaction mixture of the ethylene dicarboxylic acid
derivative and the nitrogen-containing organic compound may not partly be dissolved
therein, whereby a slurry having solid particles dispersed in liquid may be formed.
The method for producing the crystal (1) by a solution and a suspension using a
solvent will be described below. First, a solution A having the ethylene dicarboxylic
35 acid derivative is dissolved in a solvent is prepared. A solution B of the nitrogencontaining
organic compound is prepared in the same manner. Further, a suspension
A having the ethylene dicarboxylic acid derivative suspended in a solvent is prepared,
and a suspension B of the nitrogen-containing organic compound is prepared in the
same manner. From the above solutions and the suspensions, the solution or the
40 suspension of the ethylene dicarboxylic acid derivative and the nitrogen-containing
organic compound are respectively selected and mixed to obtain the crystal. The
mixing may be carried out by a method wherein these liquids are dropwise added at the
same time, in order or in the opposite order. As the solvent to be used at that time,
one type may be used or a plurality of solvents may be used as a mixture.
45 The concentration of the solution A and the suspension A of the ethylene
dicarboxylic acid derivative is not particularly limited so long as the reaction of producing
the crystal (1) is not inhibited, but is preferably from 0.01 to 100 mol/L, more preferably
from 0.05 to 10 mol/L, particularly preferably from 0.2 to 3 mol/L.
13
The concentration of the solution B and the suspension B of the nitrogencontaining
organic compound is not particularly limited so long as the reaction of
producing the crystal (1) is not inhibited, but is preferably from 0.01 to 100 mol/L, more
preferably from 0.05 to 10 mol/L, particularly preferably from 0.2 to 3 mol/L.
The solution-solution mixing method is a method for obtaining the crystal (1) b5 y
mixing the above solution A and the solution B. As the mixing at that time, a method of
dropwise adding the solution A and the solution B at the same time is regarded as
simultaneous dropwise addition, a method of dropwise adding the solution A to the
solution B is regarded as order dropwise addition, and a method of dropwise adding the
10 solution B to the solution A is regarded as reverse dropwise addition.
The suspension-solution mixing method is a method for obtaining the crystal (1)
by mixing the above solution A and suspension B or mixing the above suspension A
and solution B. The mixing at that time can be selected from the simultaneous
dropwise addition, the order dropwise addition or the reverse dropwise addition.
15 The suspension-suspension mixing method is a method for obtaining the crystal
(1) by mixing the above suspension A and suspension B. The mixing at that time can
be selected from the simultaneous dropwise addition, the order dropwise addition or the
reverse dropwise addition.
In the present invention, the above methods may be carried out in combination in
20 an optional order. For example, such a poor solvent addition method may be carried
out in combination with the solvent distillation method or the temperature control method
using a solvent in an optional order, whereby conditions for producing the crystal (1) can
be constructed.
In the method for producing the crystal (1) using a solvent, the stirring efficiency of
25 the solution or the suspension is preferably high. The stirring apparatus which can be
used therein will be described below, but is not limited to the following description. The
apparatus may, for example, be a kneader, a reactor for organic synthesis, a stirrer, an
ultrasonic generator or a mixer for a flow reactor. Specifically, stirring with a magnetic
stirrer bar and a magnetic stirrer, stirring with stirring vanes, stirring by bubbling of inert
30 gas, stirring with a centrifugal stirring device or a baffle which can be arranged in a
reactor may be mentioned. The stirring vanes may, for example, be propeller vanes,
paddle vanes, MAXBLEND vanes (registered trademark), disk turbine vanes or
FULLZONE vanes (registered trademark), preferably MAXBLEND vanes (registered
trademark), disk turbine vanes or FULLZONE vanes (registered trademark).
35 The crystal (1) produced in step (a) may be isolated by e.g. filtration, or may be
subjected to a cyclization reaction continuously by applying light in the subsequent step
(b) without isolation, depending upon its property. In this specification, the latter is
called continuity of step (a) and step (b).
The solvent to be used in the method of mixing the above ethylene dicarboxylic
40 acid derivative and the nitrogen-containing organic compound by using a solvent, is not
particularly limited so long as the reaction for producing the crystal (1) is not inhibited.
The solvent to be used in such mixing may, for example, be an aromatic hydrocarbon
solvent such as toluene or o-xylene, an aliphatic hydrocarbon solvent such as hexane,
heptane or petroleum ether, an alicyclic hydrocarbon solvent such as cyclohexane, an
45 aromatic halogenated hydrocarbon solvent such as chlorobenzene or odichlorobenzene,
an aliphatic halogenated hydrocarbon solvent such as
dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1,1-
trichloroethane, trichloroethylene or tetrachloroethylene, an ether solvent such as
14
diethyl ether, diisopropyl ether, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane or
cyclopentyl methyl ether, an amine solvent such as triethylamine, tributylamine or N,Ndimethylaniline,
a pyridine solvent such as pyridine or picoline, an ester solvent such as
ethyl acetate, n-butyl acetate or ethyl propionate, an alcohol solvent such as methanol,
ethanol, n-propanol, 2-propanol or ethylene glycol, a ketone solvent such as acetone o5 r
methyl isobutyl ketone, a carbonic acid ester solvent such as dimethyl carbonate or
diethyl carbonate, acetonitrile, dimethyl sulfoxide, sulfolane, 1,3-dimethyl-2-
imidazolidinone, ethylene glycol diacetate, acetic acid or water.
Among them, the solvent is preferably toluene, o-xylene, hexane, heptane,
10 petroleum ether, o-dichlorobenzene, dichloromethane, diethylether, tetrahydrofuran,
1,4-dioxane, pyridine, ethyl acetate, n-butyl acetate, methanol, ethanol, 2-propanol,
acetone, methyl isobutyl ketone, dimethyl carbonate, diethyl carbonate, acetonitrile,
ethylene glycol diacetate or acetic acid. The solvent is more preferably hexane,
heptane, tetrahydrofuran, pyridine, ethyl acetate, n-butyl acetate, methanol, ethanol,
15 dimethyl carbonate or acetic acid. Such a solvent may be used alone or two or more
of them may be used as a mixture.
As a typical example of the crystal (1) produced in step (a), the values at
diffraction angles 2 showing peak values (simply referred to also as peak values) in a
powder X-ray diffraction using Cu-K radiation, of the crystal (8) composed of pyridine
20 and citraconic acid, obtained in the after-mentioned Example 1, are shown in [Table 1].
[Table 1]
---------------------------------------------------------------------------------------------------------------------
2 = 12.58, 15.05, 16.08, 17.60, 18.34, 19.20, 21.57, 23.02, 24.50, 26.45, 27.06, 28.10,
30.39, 32.49, 34.71, 35.90, 36.46, 38.43
25 ---------------------------------------------------------------------------------------------------------------------
The peak values of the crystal (8) described in [Table 1] are an average value of
peak values of three lots of the crystal (8) obtained in accordance with the method
described in the following Example 1.
Here, any peak in the powder X-ray diffraction usually has an error of ±0.2. The
30 peak values of the crystal (8) where the above error is taken into account, are shown in
[Table 2].
[Table 2]
---------------------------------------------------------------------------------------------------------------------
2 = 12.58±0.2, 15.05±0.2, 16.08±0.2, 17.60±0.2, 18.34±0.2, 19.20±0.2, 21.57±0.2,
35 23.02±0.2, 24.50±0.2, 26.45±0.2, 27.06±0.2, 28.10±0.2, 30.39±0.2, 32.49±0.2,
34.71±0.2, 35.90±0.2, 36.46±0.2, 38.43±0.2
---------------------------------------------------------------------------------------------------------------------
Then, especially characteristic peak values among powder X-ray diffraction peaks
of the crystals (8) are shown in [Table 3].
40 [Table 3]
---------------------------------------------------------------------------------------------------------------------
2= 12.58, 15.05, 16.08, 17.60, 19.20, 21.57, 23.02, 24.50, 26.45, 27.06, 28.10, 32.49,
35.90, 36.46, 38.43
---------------------------------------------------------------------------------------------------------------------
45 The characteristic peak values of the crystal (8) where errors are taken into
account, are shown in [Table 4].
15
[Table 4]
---------------------------------------------------------------------------------------------------------------------
2= 12.58±0.2, 15.05±0.2, 16.08±0.2, 17.60±0.2, 19.20±0.2, 21.57±0.2, 23.02±0.2,
24.50±0.2, 26.45±0.2, 27.06±0.2, 28.10±0.2, 32.49±0.2, 35.90±0.2, 36.46±0.2,
38.43±0.5 2
---------------------------------------------------------------------------------------------------------------------
Step (b): Production of 1,3-di-substituted-cyclobutane-1,2,3,4-tetracarboxylic acid
by applying light to the crystal (1) composed of the ethylene dicarboxylic acid derivative
and the nitrogen-containing organic compound so as to carry out a cyclization reaction.
10
In this step (b), light is applied to the crystal (1) composed of the ethylene
dicarboxylic acid derivative and the nitrogen-containing organic compound so that the
double bond of the ethylene dicarboxylic acid derivative in the crystal undergoes a
cyclization reaction, whereby 1,3-di-substituted-cyclobutane-1,2,3,4-tetracarboxylic acid
15 represented by the formula (2) is produced. In the formula, R1 has the same meaning
as above.
The cyclization reaction carried out by applying light in the present invention is a
reaction in the crystal, that is in a solid phase, and the starting materials are in a solid
state, and therefore the reaction is characterized by proceeding in an environment
20 where moving of atoms or molecules is remarkably restricted.
The wavelength of a light source in the cyclization reaction carried out by applying
light to the crystal (1) in the present invention is preferably from 280 to 600 nm, more
preferably from 290 to 600 nm, furthermore preferably from 300 to 580 nm.
As the light source, a high-pressure mercury lamp, a low-pressure mercury lamp,
25 an ultrahigh-pressure mercury lamp, a xenon lamp, a sodium lamp, a halogen lamp, a
gas laser light, a liquid laser light, a solid laser light, a solar light or a light emitting diode
may, for example, be mentioned. Among them, a high-pressure mercury lamp or a
light emitting diode is preferred, and a high-pressure mercury lamp is particularly
preferred.
30 The light source is preferably stored in a jacket for cooling, and the material of the
jacket may, for example, be quartz glass, Pyrex (registered trademark), hario glass,
molybdenum glass, soda glass, lead glass, tungsten glass, VYCOR (registered
trademark) or synthetic quartz glass (SUPRA SIL). The material of the jacket is
preferably quartz glass, Pyrex, hario glass or molybdenum glass, more preferably
35 Pyrex.
In the present invention, as a method of applying a light source in the cyclization
reaction carried out by applying light to the crystal (1), for example, interior radiation by
which a light source is provided on inside of a reactor or exterior radiation by which a
light source is provided on outside of a reactor may be employed.
40 As a specific method for applying a light source, a method of directly applying light
16
to the crystal (1) or a method of applying light to a slurry having the crystal (1) dispersed
in a solvent, may, for example, be mentioned. In the case of applying light to the
slurry, both of the interior radiation by which a light source is provided on inside of a
reactor and the exterior radiation by which a light source is provided on outside of a
reactor, may be employed5 .
The atmosphere in the cyclization reaction carried out by applying light to the
crystal (1) may, for example, be atmosphere, normal air, nitrogen, helium or argon.
Among them, atmosphere, air, nitrogen or argon is preferred, and atmosphere or
nitrogen is particularly preferred.
10 The reaction temperature at the time of carrying out the cyclization reaction by
applying light to the crystal (1) is not particularly limited, but may be set to a range of
from -78 C to a reflux temperature of the reaction mixture, preferably from -40 to 90 C,
more preferably from -20 to 50 C.
The reaction apparatus at the time of carrying out the cyclization reaction by
15 applying light to the crystal (1) is not particularly limited, but a tank or a pipe may, for
example, be used in view of the shape, and a batch type, a continuous type or a
semibatch type may, for example, be used in view of the operation method. For
example, a batch reactor, a continuous stirred tank reactor, a piston flow reactor or a
flow reactor may be mentioned.
20 In step (b), at the time of applying light to the slurry having the crystal (1)
dispersed in a solvent, the stirring efficiency of the slurry is preferably high. The
stirring apparatus which can be used at that time will be described below, but is not
limited to them. The apparatus may, for example, be a reactor for organic synthesis, a
stirrer, an ultrasonic generator or a mixer for a flow reactor. Specifically, stirring with a
25 magnetic stirrer bar and a magnetic stirrer, stirring with stirring vanes, stirring by
bubbling of inert gas, stirring with a centrifugal stirrer or a baffle which can be disposed
in a reactor may, for example, be mentioned. The stirring vanes may, for example, be
propeller vanes, paddle vanes, MAXBLEND vanes (registered trademark), disk turbine
vanes or FULLZONE vanes (registered trademark), preferably stirring vanes having
30 good stirring efficiency to the slurry, more preferably MAXBLEND vanes (registered
trademark), disk turbine vanes or FULLZONE vanes (registered trademark).
The cyclization reaction carried out by applying light to the crystal (1) in the
present invention can be carried out in the presence of a photosensitizer. The
photosensitizer may, for example, be benzene, toluene, acetone, butane-2,3-dione,
35 durene, benzonitrile, butyrophenone, propiophenone, acetophenone, xanthone, 4-
methoxyacetophenone, 4’-acetylacetophenone, anthrone, benzaldehyde, 4,4’-
dimethoxybenzophenone, benzophenone, fluorene, triphenylene, biphenyl,
thioxanthone, anthraquinone, 4,4’-bis(dimethylamino)benzophenone, phenanthrene,
naphthalene, 4-phenylacetophenone, 4-phenylbenzophenone, 2-iodonaphthalene, 1,2-
40 didehydroacenaphthylene, 2-napthonitrile, 1-iodonaphthalene, 1-naphthonitrile,
chrysene, coronene, benzyl, fluoranthene, pyrene, 1,2-benzanthracene, acridine,
anthracene, perylene, tetracene, 2-methoxynaphthalene, 2-acetylnaphthalene, 1,4’-
dicyanonaphthalene, 9-cyanoanthracene, 9,10-dicyanoanthracene, 9,10-
dibromoanthracene or 2,6,9,10-tetracyanoanthracene.
45 Among them, a preferred photosensitizer is benzene, toluene, acetone, butane-
2,3-dione, benzonitrile, butyrophenone, propiophenone, acetophenone, xanthone, 4-
methoxyacetophenone, 4’-acetylacetophenone, anthrone, benzaldehyde, 4,4’-
dimethoxybenzophenone, benzophenone, fluorene, triphenylene, biphenyl,
17
thioxanthone, anthraquinone, 4,4’-bis(dimethylamino)benzophenone, phenanthrene,
naphthalene, 4-phenylacetophenone, 4-phenylbenzophenone, 1,2-
didehydroacenaphthylene, benzyl, pyrene, acridine, anthracene, perylene, 2-
acetylnaphthalene or 9,10-dibromoanthracene.
In the cyclization reaction carried out by applying light to the crystal (1) in th5 e
present invention, the solvent for preparing the crystal (1) in the form of a slurry may, for
example, be an aromatic hydrocarbon solvent such as toluene or o-xylene, an aliphatic
hydrocarbon solvent such as hexane, heptane, 2-methylpentane, octane or petroleum
ether, an alicyclic hydrocarbon solvent such as cyclohexane, an aromatic halogenated
10 hydrocarbon solvent such as chlorobenzene or o-dichlorobenzene, an aliphatic
halogenated hydrocarbon solvent such as dichloromethane, chloroform, carbon
tetrachloride, 1,2-dichloroethane, 1,1,1-trifluoroethane, trichloroethylene or
tetrachloroethylene, an ether solvent such as diethyl ether, diisopropyl ether, 1,2-
dimethoxyethane, tetrahydrofuran, 1,4-dioxane or cyclopentyl methyl ether, an amine
15 solvent such as triethylamine, tributylamine or N,N-dimethylaniline, a pyridine solvent
such as pyridine or picoline, an ester solvent such as ethyl acetate, n-butyl acetate or
ethyl propionate, an alcohol solvent such as methanol, ethanol, n-propanol, 2-propanol,
n-butanol, 2-butanol, isobutyl alcohol, t-butyl alcohol, 1-pentanol, 2-pentanol, 3-
pentanol, 1-octanol, 2-octanol or ethylene glycol, a ketone solvent such as acetone or
20 methyl isobutyl ketone, a carbonic acid ester solvent such as dimethyl carbonate or
diethyl carbonate, acetonitrile, dimethyl sulfoxide, sulforane, 1,3-dimethyl-2-
imidazolidinone, ethylene glycol diacetate, acetic acid, acetic anhydride or water.
Among them, a preferred solvent to be used for preparing the crystal (1) in the
form of a slurry, is toluene, o-xylene, hexane, heptane, petroleum ether, o25
dichlorobenzene, diethyl ether, diisopropyl ether, pyridine, ethyl acetate, n-butyl acetate,
methyl isobutyl ketone or dimethyl carbonate. The solvents may be used alone, or two
or more of them may be used as a mixture.
In the present invention, when the cyclization reaction is carried out by applying
light to the crystal (1) in the form of a slurry, it is advantageous in that the crystal
30 dispersed in a solution can be efficiently irradiated with light or that a reaction
temperature during the photoreaction can easily be controlled. In such a case, the
concentration at the time of preparing a slurry of the crystal (1) is preferably from 0.001
to 100 mol/L, more preferably from 0.01 to 10 mol/L, particularly preferably from 0.05 to
3 mol/L.
35 Step (c): Production of 1,3-di-substituted-cyclobutane-1,2,3,4-tetracarboxylic acid
dianhydride
In step (c), the 1,3-di-substituted-cyclobutane-1,2,3,4-tetracarboxylic acid
dianhydride represented by the formula (3) is produced by subjecting, as a starting
40 material, the 1,3-di-substituted-cyclobutane-1,2,3,4-tetracarboxylic acid represented by
18
the formula (2) to dehydration condensation reaction. In the formula, R1 has the same
meaning as above.
The reaction of step (c) may be carried out in accordance with a known method,
such as a method disclosed in Synthetic Communications, 1989, vol. 19 (3-4), pp. 679-
688, Synthetic Communications, 1987, vol. 17 (3), pp. 355-368 or Syntheti5 c
Communications, 2003, vol. 33 (8), pp. 1,275-1,283.
The condensation agent to be used in the dehydration condensation reaction of
step (c) in the present invention may, for example, be acetic anhydride, thionyl chloride
or acetyl chloride. Further, the condensation agent may be used as a solvent.
10 The solvent to be used in the dehydration condensation reaction of step (c) is not
particularly limited so long as the progress of the reaction is not inhibited, and it may, for
example, be toluene, ethyl acetate, acetic anhydride, thionyl chloride, acetyl chloride or
pyridine. Such a solvent may be used alone or two or more of them may be used in
combination. Further, the dehydration condensation reaction can be carried out
15 without using a solvent.
The reaction temperature of the dehydration condensation reaction of step (c) can
be set to an optional temperature within a range of from -60 C to the reflux temperature
of the reaction mixture, preferably from -20 to 230 C, more preferably from 0 to 150 C.
The reaction temperature of the dehydration condensation reaction without using
20 a solvent in step (c) can be set to an optional temperature within a range of from 100 C
to the thermal decomposition temperature of the starting material. A preferred reaction
temperature is from 100 to 230 C.
EXAMPLES
25 Now, the present invention will be described in detail with reference to Examples
of the present invention, but it should be understood that the present invention is by no
means restricted thereto. Analyzers and light sources for photoreaction used in
Examples are as follows.
NMR:
30 ECX 300 (manufactured by JEOL Ltd.): 1H-NMR, 13C-NMR
The chemical shift was measured by using Me4Si (tetramethylsilane) as an
internal standard substance in a deuterated dimethylsulfoxide (DMSO-d6) solvent.
JNM-ECA 500 (manufactured by JEOL Ltd.): quantitative 1H-NMR (13C decupling
1H measurement)
35 Measurement was carried out by using maleic acid as a standard substance in a
deuterated dimethylsulfoxide (DMSO-d6) solvent.
AVANCE III 500 (manufactured by Bruker Corporation): solid phase 13C-NMR
Measurement was carried out by using adamantane as a standard substance.
Gas chromatograph (GC):
40 GC: 6890 series GC (manufactured by Hewlett Packard)
Gas chromatograph-high resolution mass spectrometry (GC-MRMS):
GC: 7890A (manufactured by Agilent Technologies), MS: GCT Premier
(manufactured by Waters)
Single crystal X-ray structural analysis:
45 SMART APEX II ULTRA (manufactured by Bruker Corporation)
Powder X-ray diffraction:
MiniFlex 600 (manufactured by Rigaku Corporation)
Infrared absorption (IR):
19
FT-IR ALPHA (manufactured by Bruker Optics)
Light source: As a 100 W high-pressure mercury lamp, a power source: HB100P-1
(5/6), and a light source: HL100CH-4, manufactured by Sen Lights Corporation, were
used and, as a 400 W high-pressure mercury lamp, a power source: HB400P-1, and a
light source: HL400B (L/H/S)-8, manufactured by Sen Lights Corporation, were used5 ,
and as a 450 W high-pressure mercury lamp, UM-452 manufactured by Ushio Inc. was
used. As a xenon lamp, UV-XEFL (dominant wavelengths peak 290 nm, 4.5 W [using
3 cm in length of one having 1.5 W/cm]) and UV-XEFL (dominant wavelength peak 320
nm, 4.5 W [using 3 cm in length of one having 1.5 W/cm]) manufactured by Ushio Inc.,
10 were used.
Ultrasonic cleaner:
US-18KS (manufactured by SND Co., Ltd.)
Karl Fischer moisture titrator:
MKC-510 (manufactured by Kyoto Electronics Manufacturing Co., Ltd.)
15 Liquid chromatograph (HPLC):
HPLC: Prominence (manufactured by Shimadzu Corporation)
EXAMPLE 1-1: Production of crystal (8) composed of pyridine and citraconic acid (Part
1)
20 Citraconic acid (3.11 g, 23.90 mmol) and pyridine (1.89 g, 23.89 mmol) were
added to a mortar in this order, and the solid produced was sufficiently mixed while
grinding with a pestle for 5 minutes, whereby the crystal (8) composed of pyridine and
citraconic acid was obtained as a white solid (4.79 g) (yield: 96%).
The crystal (8) composed of pyridine and citraconic acid was analyzed as follows.
25 Solid phase 13C-NMR:
4 mm CP/MAS probe, 13C, CP/TOSS method, contact time 4 ms, number of
revolutions 8 kHz, external standard sample adamantane (29.472 ppm)
172.4, 168.4, 144.4, 144.4, 142.5, 140.1, 134.2, 129.8, 127.9, 25.8 ppm
FT-IR:
30 Fig. 1 is a FT-IR chart of the crystal (8).
Powder X-ray diffraction:

X-ray: Cu-K
Voltage: 40 kV
35 Current: 15 mA
Step width: 0.020 deg.
Scanning range: 2=3 to 40 deg.
Fig. 2 is a powder X-ray diffraction chart of the crystal (8). The peak values of
the powder X-ray diffraction read from the chart of the powder X-ray diffraction are as
40 follows.
2=12.56, 15.03, 16.06, 17.58, 18.29, 19.21, 21.55, 22.99, 24.50, 26.43, 27.04,
28.08, 30.33, 32.48, 34.69, 35.87, 36.44, 38.43
20
EXAMPLE 1-2: Production of crystal (8) (Part 2)
Citraconic acid (130.1 mg, 1.00 mmol), pyridine (80.6 µL, 1.00 mmol) and
methanol (2 mL) were added to a screw-top bottle (a screw tube manufactured by
Maruemu Corporation) in this order, and the reaction mixture was mixed so as to be
dissolved. Then, the opening of the screw-top bottle containing the reaction mixtur5 e
was covered with a gauze, the screw-top bottle was left at rest at a temperature of from
20 to 25 C for 64 hours in a draft chamber operated so as to evaporate methanol,
whereby the crystal (8) composed of pyridine and citraconic acid was obtained as a
white solid (197.2 mg). (yield: 94%)
10 The crystal (8) composed of pyridine and citraconic acid was analyzed as follows.
Powder X-ray diffraction:
were the same as the
conditions described in Example 1-1. The peak values of the powder X-ray diffraction
of the crystal (8) are shown below.
15 2=12.56, 15.04, 16.08, 17.58, 18.33, 19.14, 21.55, 23.01, 24.43, 26.42, 27.03,
28.07, 30.40, 32.48, 34.70, 35.88, 36.44, 38.42
Single crystal X-ray structural analysis:
Using a single crystal X-ray diffractometer SMART APEX II ULTRA, manufactured
by Bruker Corporation, measurement was carried out by Cu-K rays (wavelength:
20 1.54178 Å) while cooling to -50 C. A SAINT software was used for integration
processing of the X-ray diffraction data, and a SHELXTL-97 program was used for
determination of space group and crystal structural analysis, whereby the single crystal
X-ray structural analysis of the crystal (8) as the above white solid was carried out.
Table 5 shows crystal data and refinement of structure of the crystal (8).
25
X-ray: Cu-K
Voltage: 50 kV
Current: 24 mA
Measurement temperature: -50 C
30
21
[Table 5]
Empirical formula C10H11NO4
Formula weight 209.20
Temperature 223(2) K
Wavelength 1.54178 Å
Crystal system Triclinic system
Space group P1
Unit cell dimensions a=7.0204(8) Å =76.922(7)
b=7.3592(9) Å =85.012(7)
c=9.8865(12) Å =86.106(7)
Volume 495.04(10) Å3
Z 2
Density (calculated value) 1.403 Mg/m3
Absorption coefficient 0.927 mm-1
F(000) 220
Theta range for data collection 4.60 to 69.77
Index ranges -7<=h<=8, -8<=k<=8, -11<=1<=11
Reflections collected 5008
Independent reflections 1543 [R(int)=0.0311]
Completeness to theta = 69.77 82.9%
Absorption correction None
Refinement method Full matrix least-squares on F2
Date / restraints / parameters 1543/ 0/ 181
Goodness-of-fit on F2 1.104
Final R indices [I>2sigma(I)] R1=0.0344, wR2=0.1049
R indices (all data) R1=0.0372, wR2=0.1115
Extinction coefficient 0.026(4)
Largest diff. peak and hole 0.169 and -0.175 e.Å-3
On the basis of the result of crystal X-ray structural analysis of a single crystal of
the crystal (8), a packing structure of citraconic acid anion and pyridinium are shown, as
a cylinder model, in Fig. 3, together with a unit cell5 .
In Fig. 3, carbon atoms are shown in black, hydrogen atoms are shown in white,
nitrogen atoms and oxygen atoms are represented by symbols of element, and two
dotted lines in Fig. 3 show the closest double bonds.
Further, on the basis of the result of crystal X-ray structural analysis of a single
10 crystal of the crystal (8), only the configuration of citraconic acid anions in the crystal (8)
is shown, as ORTEP diagram, in Fig. 4.
From the result of the above single crystal X-ray structural analysis, the crystal (8)
was found to be a crystal made of only two kinds of constituting elements of the
citraconic acid anion and pyridinium in a molar ratio of 1:1.
15 Further, from the result of Fig. 4, it is found that, in the crystal structure of the
crystal (8), the closest double bonds are positioned in parallel with each other, and the
distance L1 between the parallel double bonds shown in the following formula (8A) was
4.12 Å.
22
Example 1-3: Production of crystal (8) (Part 3)
Heptane (28 mL) and pyridine (1.87 mL, 23.25 mmol) were added to a reactor,
and the resulting solution was kept at a temperature of from 20 to 25 C. Then,
citraconic acid (2.75 g, 21.14 mmol) dissolved in ethyl acetate (28 mL) was dropwise
added to the solution over a period of 10 minutes, followed by stirring for 20 minutes a5 t
a temperature of from 20 to 25 C, whereby a slurry of the crystal (8) composed of
pyridine and citraconic acid was prepared. After termination of the stirring, a solid
collected by filtration was washed with a mixed solvent of heptane (15 mL) and ethyl
acetate (15 mL), and then washed with hexane (30 mL), followed by vacuum drying,
10 whereby the crystal (8) composed of pyridine and citraconic acid was obtained as a
white solid (4.14 g) (yield: 94%).
The crystal (8) composed of pyridine and citraconic acid was analyzed as follows.
Powder X-ray diffraction:
are the same as the conditions
15 described in Example 1-1. The peak values of the powder X-ray diffraction of the
crystal (8) are shown below.
2q=12.61, 15.08, 16.11, 17.64, 18.39, 19.26, 21.61, 23.05, 24.57, 26.51, 27.12,
28.15, 30.43, 32.53, 34.74, 35.94, 36.50, 38.44
From the result of the above powder X-ray diffraction, the crystals obtained in
20 Examples 1-1 to 1-3 were found to be the same. Further, the above formula (8)
represents a crystal of pyridine citraconic acid (1:1) composed of pyridine and citraconic
acid.
EXAMPLE 2-1: Production of (1R, 2R, 3S, 4S)-1,3-dimethylcyclobutane-1,2,3,4-
tetracarboxylic acid (13a) (Part 1)
25
The crystal (8) (100.0 mg, 0.478 mmol) composed of pyridine and citraconic acid
23
was spread on a petri dish, and was covered with a lid. The petri dish was put on a
cooled plate set to 25 C, and was irradiated with light for 50 hours by using a 100 W
high-pressure mercury lamp so as to carry out a cyclization reaction. The distance
between the petri dish and the light source was 1 cm. After termination of the reaction,
a reaction mixture was recovered as a pale yellow solid (80.2 mg). According to th5 e
analysis of the reaction mixture, of the aimed compound (13a), the yield was 83%, the
conversion rate was 94% and the selectivity was >99%. The yield was determined by
means of uantitative 1H-NMR using maleic acid as a standard sample. Further, the
conversion rate and the selectivity were calculated from a relative area ratio of peaks
10 derived from the aimed compound, an unnecessary diastereomer and starting
materials, in GC analysis.
Preparation of GC sample for determining the conversion rate and the selectivity
in the above cyclization reaction is summarized in (Formula A).
15 In order to determine the conversion rate and the selectivity, a part of the reaction
mixture was collected after a photocyclization reaction using the crystal (8), the sample
was subjected to the after-mentioned GC sample preparation method B, whereby the
aimed compound (13a) and the diastereomers were induced to the compound (14a)
and the diastereomers, and then GC analysis and GC-HRMS analysis were conducted.
20 Then, in order to trace the by-products corresponding to diastereomers of the
aimed compound (13a) by GC analysis, a photocyclization reaction using the citraconic
anhydride (11) as a starting material in a solution was carried out as step (z) by a
method different from the photocyclization reaction using the crystal (8), whereby the
compound (12a) and the diastereomers were synthesized. According to the after24
mentioned GC sample preparation method A, the compound (12a) and the
diastereomers were led to the compound (14a) and the diastereomers via the aimed
compound (13a) and the diastereomers, by hydrolysis and then methyl esterification
reaction, and then GC analysis and GC-HRMS were conducted. Here, details of the
cyclization reaction by applying light in a solution of citraconic anhydride, will b5 e
mentioned in Reference Examples.
GC analytical conditions and GC-HRMS analytical conditions are described below.

Column: TC-5 (0.53 mm × 30 m, film thickness 1.5 µm)
10 Carrier gas: helium
Flow rate: 3.3 mL/min (constant flow rate)
Split ratio: 1/10, injection amount of sample: 3 µL
Column temperature: 80 C (maintained for 2 minutes), temperature-raising rate:
10 C/min, 250 C (maintained for 11 minutes)
15 Inlet temperature: 280 C
Detector temperature: 280 C

Column: DB-5 (0.25 mm × 30 m, film thickness 0.25 µm)
Carrier gas: helium
20 Flow rate: 1 mL/min (constant flow rate)
Split ratio: 1/50, injection amount of sample: 0.2 µL
Column temperature: 80 C (maintained for 3 minutes), temperature-raising rate:
25 C/min, 250 C (maintained for 7.2 minutes)
Inlet temperature: 280 C
25 Ionization method: El, Cl+
GC sample preparation methods and analytical results are described below.

This preparation method comprises preparation step I and subseuent preparation
step II described in (Formula A). After a cyclization reaction by light irradiation, a
30 reaction mixture (20 mg) having a solvent distilled off was collected in a screw-top
bottle, methanol (3 mL) and a 0.05 mol/L sodium hydroxide aueous solution (2 mL)
were added thereto, and the resulting solution was stirred at a temperature of from 20 to
25 C for 20 minutes. A part of the reaction mixture (1 mL) was charged into a screw
tube, toluene (0.2 mL) was added thereto, and then trimethylsilyl diazomethane (0.2 mL,
35 about 0.6 mol/L, a commercial product manufactured by Tokyo Chemical Industry Co.,
Ltd.) of a hexane solution was added thereto, followed by stirring at a temperature of
from 20 to 25 C for 20 minutes. A part of the organic layer (0.4 mL) of the reaction
mixture was taken out, and was diluted with methanol (1 mL) so as to obtain a GC
analysis sample.
40 As shown in (Formula A), the compound (12a) was led to the compound (14a)
by the GC sample preparation method A. The analytical results are described below.
GC analysis: retention time = 18.62 minutes
GC-HRMS analysis: m/z calcd for C16H25O8 [M+C2H5]+:345.1549, found 345.1577
The diastereomer of the compound (12a), which is any one of the compound
45 (12b), the compound (12c) and the compound (12d), is led to any one of the compound
(14b), the compound (14c) and the compound (14d) by the GC sample preparation
method A. The analytical results are described below.
GC analysis: retention time = 18.97 minutes
25
GC-HRMS analysis: m/z calcd for C16H25O8 [M+C2H5]+:345.1549, found 345.1561
From the result of mass number by GC-HRMS, the diastereomer having the same
molecular weight but differing in GC retention time from the compound (14a) could be
confirmed.

This preparation method comprises preparation step II described in (Formula A).
After a cyclization reaction by light irradiation, a reaction mixture (25 mg) taken out by
e.g. filtration operation was collected, and methanol (0.5 mL) and toluene (0.5 mL) were
added thereto so as to prepare a solution. Then, trimethylsilyl diazomethane (0.8 mL,
10 about 0.6 mol/L, a commercial product manufactured by Tokyo Chemical Industry Co.,
Ltd.) of a hexane solution was added to the above solution, followed by stirring at a
temperature of from 20 to 25 C for 20 minutes. A part of this reaction mixture (0.12
mL) was taken out, and diluted with methanol (1.5 mL) so as to obtain a GC analysis
sample.
15 The compound (13a) was led to the compound (14a) by a GC sample preparation
method B. The analytical results are described below.
GC analysis: retention time = 18.62 minutes
GC-HRMS analysis: m/z calcd for C16H25O8 [M+C2H5]+:345.1549, found 345.1542
Unreacted citraconic acid is led to dimethyl (Z)-2-methyl-2-butenedioate by the CG
20 sample preparation method B. The analytical results are described below.
GC analysis: retention time = 9.68 minutes
GC-HRMS analysis: m/z calcd for C9H15O4 [M+C2H5]+:187.0970, found 187.0972
The conversion rate was calculated from a relative area ratio of dimethyl (Z)-2-
methyl-2-butenedioate, the compound (14a) and the diastereomers based on the GC
25 analytical results.
The selectively was calculated from the relative area ratio of the compound (14a)
and the diastereomers based on the GC analytical results.
EXAMPLE 2-2: Production of (1R, 2R, 3S, 4S)-1,3-dimethylcyclobutane-1,2,3,4-
tetracarboxylic acid (13a) (Part 2)
30 The crystal (8) (5.00 g, 23.90 mmol) composed of pyridine and citraconic acid and
hexane (100 mL) as a solvent were added to a photochemical reaction experimental
apparatus (manufactured by Sen Lights Corporation) capable of stirring with a magnetic
stirrer, and a light source was disposed at the center in the inside. The slurry was
stirred at a reaction temperature of from 20 to 25 C, and a cyclization reaction was
35 carried out by applying light by using a 100 W high-pressure mercury lamp for 20 hours.
After termination of the reaction, filtration was carried out to recover a reaction mixture
(4.33 g) as a white solid. According to the analysis of the reaction mixture, of the
aimed compound (13a), the yield was 94%, the conversion rate was 95% and the
selectivity was >99%. The yield was determined by a uantitative 1H-NMR using
40 maleic acid as a standard sample. The conversion rate and the selectivity were
analyzed in accordance with the method as described in Example 2-1, and were
calculated from the relative area ratio of each peak in GC analysis.
EXAMPLE 2-3: Production of (1R, 2R, 3S, 4S)-1,3-dimethylcyclobutane-1,2,3,4-
tetracarboxylic acid (13a) (Part 3)
45 The crystal (8) (25.00 g, 119.50 mmol) composed of pyridine and citraconic acid,
heptane (200 mL) and n-butyl acetate (200 mL) were added to a photochemical reaction
experimental apparatus (manufactured by Sen Lights Corporation) capable of stirring
with a magnetic stirrer, and a light source was disposed at the center in the inside.
26
The slurry was stirred at a reaction temperature of from 20 to 25 C, and a cyclization
reaction was carried out by applying light by using a 400 W high-pressure mercury lamp
for 12 hours. After termination of the reaction, filtration was carried out to recover a
reaction mixture (19.64 g) as a white solid. According to the analysis of the reaction
mixture of the aimed compound (13a), the yield was 93%, the conversion rate was 955 %
and the selectivity was >99%. The yield was calculated from the amount of the
reaction mixture obtained and 1H-NMR. The conversion rate and the selectivity were
analyzed in accordance with the method described in Example 2-1, and were calculated
from the relative area ratio of each peak in GC analysis.
10 The white solid reaction mixture obtained in the above photoreaction was isolated
and purified. In the purification, 10.00 g of the reaction mixture was taken out
therefrom and dissolved in methanol (70 mL), followed by filtration, and then the solvent
was distilled off. Thereafter, the resultant was dissolved in acetic acid (45 mL), then
the solution was stirred at 60 C for two and a half hours, and then cooled to a
15 temperature of from 20 to 25 C, followed by filtration. Then, the solvent contained in
the resulting solid was distilled off, followed by vacuum drying using a vacuum pump,
whereby an aimed compound (6.12 g) was obtained as a white solid. The yield
calculated by 1H-NMR was 83%.
A part of the aimed compound thus obtained was collected, and dissolved until
20 saturation in acetonitrile heated to 70 C so as to prepare a solution. Then, the solution
was cooled to a temperature of from 20 to 25 C, and was left at rest so as to carry out
recrystallization, and the resulting single crystal was subjected to single crystal X-ray
structural analysis.
Analysis of compound (13a)
25 1H NMR(DMSO-d6):
12.46(br), 3.30(s,2H), 1.42(s,6H) ppm
13C-NMR (DMSO-d6):
175.9, 175.9, 171.5, 171.5, 51.7, 51.7, 44.2, 44.2, 20.7, 20.7 ppm
Single crystal X-ray structural analysis:
30 On the basis of the results of X-ray structural analysis of a single crystal of the
compound (13a), the molecular structure of the compound (13a) was shown, as an
ORTEP diagram, in Fig. 5.
EXAMPLE 2-4: Production of (1R, 2R, 3S, 4S)-1,3-dimethylcyclobutane-1,2,3,4-
tetracarboxylic acid (13a) (Part 4)
35 To a photochemical reaction experimental apparatus (manufactured by Sen Lights
Corporation) capable of stirring with a magnetic stirrer, ethyl acetate (110 mL) and
pyridine (7.49 mL, 93.01 mmol) were added and cooled to 5 C. Then, citraconic acid
(11.00 g, 84.55 mmol) dissolved in ethyl acetate (110 mL) was dropwise added to the
reaction mixture over a period of 30 minutes. Then, the reaction mixture was stirred at
40 5 C for 20 minutes to prepare a slurry of the crystal (8) composed of pyridine and
citraconic acid. A 100 W high-pressure mercury lamp was inserted to the reactor, and
a cyclization reaction was carried out by applying light for 22 hours with stirring at 5 C.
Then, a solid was filtrated by a Kiriyama funnel, washed with ethyl acetate (30 mL),
followed by vacuum drying, whereby a white solid reaction mixture (12.82 g) was
45 obtained. According to the analysis of the reaction mixture, of the aimed compound
(13a), the yield was 93%, the conversion rate was 95% and the selectivity was >99%.
The yield was calculated from the amount of the reaction mixture obtained and 1H-NMR.
The conversion rate and the selectivity were analyzed in accordance with the method
27
described in Example 2-1, and were calculated from the relative area ratio of each peak
in GC analysis.
EXAMPLE 3-1: Production of (1R, 2R, 3S, 4S)-1,3-dimethylcyclobutane-1,2,3,4-
tetracarboxylic acid (13a)
The crystal (8) (200.0 mg, 0.956 mmol) composed of pyridine and citraconic acid5 ,
and ethyl acetate (4 mL) as a solvent, were added to a screw-top bottle (a screw tube
manufactured by Maruemu Corporation) so as to prepare a slurry. Then, a light source
was disposed on outside of the screw-top bottle so that it is possible to carry out stirring
with a magnetic stirrer. The distance between the screw-top bottle and the light source
10 was 4.5 cm. A cyclization reaction was carried out by applying light by using a 100 W
high-pressure mercury lamp for 20 hours at a temperature of from 20 to 25 C. After
termination of the reaction, filtration was carried out to obtain a white solid reaction
mixture (116.0 mg). According to the analysis of the reaction mixture, of the aimed
compound (13a), the yield was 69%, the conversion rate of 97% and the selectivity was
15 >99%. The yield was calculated from the amount of the reaction mixture obtained and
1H-NMR. The conversion rate and the selectivity were analyzed in accordance with
the method described in Example 2-1, and were calculated from the relative area ratio
of each peak in GC analysis.
The reaction was carried out in the same conditions as in the reaction described in
20 Example 3-1 except that ethyl acetate as a solvent was changed to solvents described
in Table 6. The solvent used, and the experimental results regarding the conversion
rate, selectivity, the yield and appearance at the time of recovery, are shown as
Examples 3-2 to 3-8 in Table 6.
In Table 6, AcOn-Bu represents n-butyl acetate, hexane/AcOn-Bu (v/v=1/1)
25 represents a mixed solvent of hexane (2 mL) and n-butyl acetate (2 mL), and
heptane/AcOn-Bu (v/v=1/1) represents a mixed solvent of heptane (2 mL) and n-butyl
acetate (2mL).
[Table 6]
30 EXAMPLE 4: Production of (3aR, 3bR, 6aS, 6bS)-3a,6a-dimethylcyclobuta[1,2-c:3,4-
c’]difuran-1,3,4,6(3aH, 3bH, 6aH, 6bH)-tetraone (12a)
28
[Continuity of step (a) and step (b)]
As step (a), pyridine (60 mL) and then citraconic acid (15.55 g, 119.52 mmol) were
added in this order to a photochemical reaction experimental apparatus (manufactured
by Sen Lights Corporation) capable of stirring with a magnetic stirrer, followed by stirrin5 g
for 10 minutes at a temperature of from 20 to 25 C. After completion of the stirring,
heptane (175 mL) and n-butylacetate (175 mL) were added as solvents, followed by
stirring for 30 minutes so as to prepare a slurry of the crystal (8) composed of pyridine
and citraconic acid. Then, a light source was disposed at the center in the inside of the
10 reactor, and as step (b), the slurry of the crystal (8) obtained in step (a) was stirred while
applying light by using a 400 W high-pressure mercury lamp for 8 hours at a
temperature of from 20 to 25 C. After termination of the reaction by stopping the
application of light, the resulting slurry was filtrated to obtain a white solid reaction
mixture. According to the analysis of the reaction mixture, of the aimed compound
15 (13a), the conversion rate was 97% and the selectivity was >99%. The conversion
rate and the selectivity were analyzed in accordance with the method described in
Example 2-1, and were calculated from the relative area ratio of each peak in GC
analysis.
In order to carry out purification of the compound (13a) from the crude product
20 obtained after the photoreaction, the reaction mixture was dissolved in tetrahydrofuran
(250 mL), followed by filtration, and then the solvents were distilled off. Then,
suspension washing was carried out by using a mixed solvent of acetic acid (40 mL)
and n-butyl acetate (40 mL), followed by filtration again. Then, vacuum drying was
carried out by a vacuum pump to obtain the compound (13a) purified.
25 [Step (c)]
The compound (13a) after the above purification, toluene (60 mL) and acetic
anhydride (31.8 mL, 336.4 mmol) were added to a reactor, followed by stirring at 100 C
for 3 hours. After completion of the stirring, the reactor was cooled to a temperature of
from 20 to 25 C, whereby the reaction was terminated. The resulting reaction mixture
30 was filtrated, then the resulting solid was washed with an ether solvent, and vacuum
drying was carried out by a vacuum pump, whereby the aimed compound (12a) (11.36
g) was obtained as a white solid. The total yield from citraconic acid as a starting
material was 85% as calculated by 1H-NMR. A part of the aimed compound obtained
29
was collected and subjected to single crystal X-ray structural analysis.
The analytical results of the compound (12a) are as follows.
1H NMR(DMSO-d6):
3.88(s,2H), 1.38(s,6H) ppm
13C-NMR (DMSO-d6)5 :
173.5, 173.5, 168.1, 168.1, 49.0, 49.0, 44.1, 44.1, 15.7, 15.7 ppm
Single crystal X-ray structural analysis:
On the basis of the results of single crystal X-ray structural analysis of the
compound (12a), the molecular structure of the compound (12a) was shown, as an
10 ORTEP diagram, in Fig. 6.
EXAMPLE 5: Production of (1R, 2R, 3S, 4S)-1,3-dimethylcyclobutane-1,2,3,4-
tetracarboxylic acid (13a) using a photosensitizer
Benzophenone (21.78 g, 0.12 mmol) as a photosensitizer and heptane (10 mL) as
15 a solvent were added to a screw-top bottle (a screw tube manufactured by Maruemu
Corporation). Benzophenone was confirmed to be dissolved, and then the crystal (8)
(500.0 mg, 2.39 mmol) composed of pyridine and citraconic acid was added to the
screw-top bottle so as to prepare a slurry. After completion of the preparation, a light
source was disposed on outside of the screw-top bottle while a magnetic stirrer was set
20 to carry out stirring. The distance between the screw-top bottle and the light source
was 4.5 cm. A cyclization reaction was carried out by applying light at a temperature of
from 20 to 25 C by using a 100 W high-pressure mercury lamp for 5 hours and 30
minutes. The application of light was terminated so as to terminate the reaction, and
then the resulting slurry was filtrated to obtain a white solid reaction mixture (471.9 mg).
25 According to the analysis of the reaction mixture, of the aimed compound (13a), the
conversion rate was 34% and the selectivity was >99%. The conversion rate and the
selectivity were analyzed in accordance with the method described in Example 2-1, and
were calculated from the relative area ratio of each peak in GC analysis.
EXAMPLE 6: Production of (1R, 2R, 3S, 4S)-1,3-dimethylcyclobutane-1,2,3,4-
30 tetracarboxylic acid (13a)
Step (a)
Mesaconic acid (6M) (130.1 mg, 1.00 mmol), methanol (2 mL) and nicotinamide
(9) (122.1 mg, 1.00 mmol) were added in this order to a screw-top bottle (a screw tube
30
manufactured by Maruemu Corporation) and the resulting reaction mixture was mixed
so as to be dissolved. Then, the opening of the screw-top bottle containing the
reaction mixture was covered with a gauze, and the screw-top bottle was left at rest in a
draft chamber operated for 64 hours at a temperature of from 20 to 25 C so as to
evaporate methanol, whereby the crystal (10) composed of nicotinamide and mesaconi5 c
acid was obtained as a white solid. The above formula (10) represents a nicotinamidemesaconic
acid crystal composed of nicotinamide and mesaconic acid.
Step (b)
The crystal (10) (100.0 mg, 0.396 mmol) composed of nicotinamide and
10 mesaconic acid was spread on a glass-made petri dish. The petri dish was covered
with a lid and then put on a cooled plate set to a temperature of 25 C, the distance
between the petri dish and the light source was set to 3 cm, and then light was applied
for 20 hours by using a 100 W high-pressure mercury lamp. After application of light
was terminated so as to terminate the reaction, a reaction mixture was recovered as a
15 white solid. According to the analysis of the reaction mixture, of the aimed compound
(13a), the conversion rate was 23% and the selectivity was >99%. The conversion
rate and the selectivity was analyzed in accordance with the method described in
Example 2-1, and were calculated from the relative area ratio of each peak in GC
analysis. Mesaconic acid was used as a raw material, and in GC sample preparation,
20 unreacted mesaconic acid was led to dimethyl (E)-2-methyl-2-butenedioate.
Therefore, peaks of dimethyl (E)-2-methyl-2-butenedioate was treated as peaks derived
of the raw material.
EXAMPLE 7-1: Production of (1R, 2R, 3S, 4S)-1,3-dimethylcyclobutane-1,2,3,4-
tetracarboxylic acid (13a) (Part 1)
25
[Continuity of step (a) and step (b)]
A photochemical reaction experimental apparatus (manufactured by Sen Lights
Corporation) using a magnetic stirrer as a stirring device, was used. Dimethyl
carbonate (110 mL) and pyridine (7.49 mL, 93.01 mmol) were added in this order to a
30 reactor of the apparatus, followed by cooling to 10 C. After completion of the cooling,
citraconic acid (11.00 g, 84.55 mmol) dissolved in dimethyl carbonate (110 mL) was
dropwise added to the resulting reaction solution over a period of 30 minutes. After
completion of the dropwise addition, the reaction mixture was stirred at 10 C for 20
hours. After completion of the stirring, a slurry of the crystal (8) composed of pyridine
35 and citraconic acid was obtained. The resulting crystal (8) was used as it was in the
subseuent step without carrying out isolation and purification. The slurry was stirred
at 10 C, and was irradiated with light by using a 100 W high-pressure mercury lamp for
17 hours. After completion of the reaction, a solid in the reaction mixture was collected
by filtration with a funnel, and then washed with dimethyl carbonate (30 mL). The
40 resulting solid was subjected to vacuum drying, whereby 14.23 g of an aimed product
was obtained as a white solid. According to the analysis of the white solid, of the
aimed compound (13a), the yield was 88%, the conversion rate was 94% and the
selectivity was >99%. The yield was calculated from the amount of the reaction
31
mixture obtained and 1H-NMR analysis. The conversion rate and the selectivity were
calculated in accordance with the method described in Example 2-1 from the relative
area ratio of each peak in GC analysis.
EXAMPLE 7-2: Production of (1R, 2R, 3S, 4S)-1,3-dimethylcyclobutane-1,2,3,4-
tetracarboxylic acid (13a) (Part 25 )
[Continuity of step (a) and step (b)]
A photochemical reaction experimental apparatus (manufactured by Sen Lights
Corporation) using a magnetic stirrer as a stirring device, was used. Ethyl acetate (110
mL) and pyridine (14.98 mL, 186.02 mmol) were added to the reactor of the apparatus,
10 followed by cooling to 5 C. After completion of the cooling, citraconic acid (22.00 g,
169.10 mmol) dissolved in ethyl acetate (110 mL) was dropwise added to the reaction
solution over a period of 30 minutes. After completion of the dropwise addition, the
reaction mixture was stirred at 5 C for 20 minutes. After completion of the stirring, a
slurry of the crystal (8) composed of pyridine and citraconic acid was obtained. The
15 resulting crystal (8) was used as it was in the subseuent step without carrying out
isolation and purification. The slurry was stirred at 5 C, and was irradiated with light by
using a 100 W high-pressure mercury lamp for 33 hours. The moisture content in the
reaction mixture after the irradiation with light, was measured by a Karl Fischer moisture
titrator (MKC-510, manufactured by Kyoto Electronics Manufacturing Co., Ltd.), and as
20 a result, the moisture content was 1,570 ppm. After completion of the reaction, the
solid in the reaction mixture was collected by filtration with a funnel, and then washed
with ethyl acetate (40 mL). The resulting solid was subjected to vacuum drying,
whereby 26.03 g of an aimed product was obtained as a white solid. According to the
analysis of the white solid, of the aimed compound (13a), the yield was 93%, the
25 conversion rate was 94% and the selectivity was >99%. The yield was calculated from
the amount of the reaction mixture obtained and 1H-NMR analysis. The conversion
rate and the selectivity were analyzed in accordance with the method described in
Example 2-1, and were calculated from the relative area ratio of each peak in GC
analysis.
30 EXAMPLE 8-1: Production of (1R, 2R, 3S, 4S)-1,3-dimethylcyclobutane-1,2,3,4-
tetracarboxylic acid (13a) (Part 1)
The crystal (8) (100.0 mg, 0.478 mmol) composed of pyridine and citraconic acid
and ethyl acetate (2 mL) were added to a screw-top bottle (a screw tube manufactured
by Maruemu Corporation) so as to prepare a slurry. After completion of the
35 preparation, the screw-top bottle containing the slurry was disposed so that the distance
from the light source would be 5 cm. After completion of the disposition, light was
applied for 2 hours by using a xenon lamp (dominant wavelength peak 290 nm, 4.5 W)
as a light source, so that the temperature of the slurry would be kept at from 20 to 25 C.
Here, a magnetic stirrer was used for stirring. After completion of the stirring, the slurry
40 was subjected to HPLC analysis, whereby the conversion rate of the aimed compound
(13a) was 3%.

Detector: differential refractive index detector
Column: Develosil C30-UG5 (inner diameter 4.6 mm, length 150 mm, particle size
45 5 µm)
Eluent: a 0.2% weight concentration trifluoroacetic acid aueous solution:
acetonitrile = 95:5 (volume ratio)
Flow rate: 1.5 mL/min
32
Column temperature: 35 C
Retention time: 3.06 minutes [aimed product (13a)], 3.39 minutes [citraconic acid
(6C)]
EXAMPLE 8-2: Production of (1R, 2R, 3S, 4S)-1,3-dimethylcyclobutane-1,2,3,4-
tetracarboxylic acid (13a) (Part 25 )
The crystal (8) (300.0 mg, 1.434 mmol) composed of pyridine and citraconic acid,
and ethyl acetate (6 mL), were added to a screw-top bottle (a screw tube manufactured
by Maruemu Corporation) so as to prepare a slurry. After completion of the
preparation, the screw-top bottle containing the slurry was disposed so that the distance
10 from the light source would be 5 cm. After completion of the disposition, light was
applied for 77 hours by using a xenon lamp (dominant wavelength peak 320 nm, 4.5 W)
as a light source, so that the temperature of the slurry would be kept at from 20 to 25 C.
Here, a magnetic stirrer was used for stirring. After completion of the stirring, the slurry
was subjected to HPLC analysis (analytical conditions are the same as in Example 8-1),
15 whereby the conversion rate of the aimed compound (13a) was 74%.
EXAMPLE 9: Production of (1R, 2R, 3S, 4S)-1,3-dimethylcyclobutane-1,2,3,4-
tetracarboxylic acid (13a)
Step (a) and step (b) were carried out by using a flow reactor. A view
20 schematically illustrating the flow reactor is shown in Fig. 7, and a cross-sectional view
illustrating a T-shaped mixer (mixer 2) having a double tube structure in the flow reactor
is shown in Fig. 8. As the flow reactor, an apparatus having a FEP tube (a tube made
of a fluororesin composed of a tetrafluoroethylene/hexafluoropropylene copolymer)
having an inner diameter of 2 mm, an outer diameter of 3 mm and a length of 10 m,
25 wound on a lamp jacket of a light source, was used, and the apparatus was disposed in
an ultrasonic cleaner.
Step (a):
An ethyl acetate solution of citraconic acid (437.9 mg, 3.366 mmol) having a
concentration of 0.34 mol/L was prepared. Further, an ethyl acetate solution of
30 pyridine (266.3 mg, 3.366 mmol) having a concentration of 0.34 mol/L was prepared.
The ethyl acetate solution of citraconic acid and the ethyl acetate solution of pyridine
were respectively transferred at a rate of 0.9 mL/min by using a syringe pump, and
mixed in a mixer 1 (21 in Fig. 7). Thereafter, the mixture was mixed with nitrogen gas
in a mixer 2 (32 in Fig. 7) so as to form a slug flow (a flow where slurry and nitrogen gas
35 were alternately arranged) by the slurry of the crystal (8) and the nitrogen gas.
Further, in order to avoid clogging of a tube in the mixer 2, the mixer 2 had a double
tube structure as shown in Fig. 8 and was disposed in a thermostatic bath having a
temperature of 50 C.
Step (b):
40 A cyclization reaction was carried out under irradiation with light by using a 450 W
high-pressure mercury lamp and further under irradiation with ultrasonic wave. The
reaction was carried out by adjusting the slug flow by a mass flow controller so as to
allow the slug flow to pass through the portion irradiated with light and the ultrasonic
33
wave over 11 minutes. According to the HPLC analysis of effluent recovered, the
conversion rate of the aimed compound (13a) was 34%.
REFERENCE EXAMPLE 1
In accordance with the above Non-Patent Document 2, a cyclization reaction was
carried out by applying light to citraconic anhydride (11) in a solution5 .
Citraconic anhydride (11) (1.38 g, 12.31 mmol), 1,4-dioxane (10 mL) as a solvent
and benzophenone (93.0 mg, 0.51 mmol) as a photosensitizer, were added to a screwtop
bottle (a screw tube manufactured by Maruemu Corporation), and a light source was
10 disposed on outside of the screw-top bottle while a magnetic stirrer was set to carry out
stirring. The distance between the screw-top bottle and the light source was 4.5 cm.
A cyclization reaction by applying light by a 100 W high-pressure mercury lamp was
carried out at a temperature of from 20 to 25 C for 18 hours. After termination of the
reaction, the reaction mixture was analyzed, whereby of the aimed compound (12a), the
15 conversion rate was 68% and the selectivity was 50%. The conversion rate and the
selectivity were calculated from the relative area ratio of each peak in GC analysis. As
a raw material, citraconic anhydride was used, and peaks of the citraconic anhydride
was treated as peaks of the raw material in GC analysis.
The method for preparing a sample for GC analysis and GC-HRMS analysis, and
20 analytical results, will be described below. From the reaction mixture suspended, a
suspension (100 µL) was sampled, and diluted with dimethylsulfoxide (1.5 mL) so as to
obtain a sample for analysis.
Analytical results of the aimed compound (12a) are as follows.
GC analysis: retention time = 15.60 minutes
25 GC-HRMS analysis: m/z calcd for C10H9O6 [M+H]+:225.0399, found 225.0386
The analytical results of the diastereomer of the aimed compound (12a) are as
follows.
GC analysis: retention time = 15.81 minutes
GC-HRMS analysis: m/z calcd for C10H9O6 [M+H]+:225.0399, found 225.0403
30 From the result of mass number by GC-HRMS, the diastereomer having the same
molecular weight as the compound (12a) but differing in the GC retention time therefrom
could be confirmed. However, it was impossible to determine a stereostructure of the
diastereomer of the compound (12a). The diastereomer of the aimed compound (12a)
was assumed to be one of the compound (12b), the compound (12c) and the compound
35 (12d).
REFERENCE EXAMPLE 2
In accordance with the method as described in the above Patent Document 2, a
cyclization reaction was carried out by applying light to citraconic anhydride (11) in a
34
solution.
Citraconic anhydride (11) (1.42 g, 12.67 mmol) and ethyl acetate (10 mL) as a
solvent were added to a screw-top bottle (a screw tube manufactured by Maruemu
Corporation), and a light source was disposed on outside of the screw-top bottle while 5 a
magnetic stirrer was set to carry out stirring. No photosensitizer was added thereto,
and the distance between the screw-top bottle and the light source was adjusted to 4.5
cm. A cyclization reaction by applying light by a 100 W high-pressure mercury lamp
was carried out for 60 hours at a temperature of from 20 to 25 C. After termination of
10 the reaction, the solvent in the reaction mixture was distilled off, and vacuum drying was
carried out by using a vacuum pump, whereby a reaction mixture (1.36 g) was obtained
as a white solid. According to the analysis of the reaction mixture, of the aimed
compound (12a), the conversion rate was 88% and the selectivity was 41%. As a
method of preparing a GC sample, the above GC sample preparation method A was
15 employed. The conversion rate and the selectivity were analyzed in accordance with
the method described in Example 2-1, and were calculated from the relative area ratio
of each peak in GC analysis.
The above Patent Document 2 and Non-Patent Document 2 failed to disclose the
selectivity of the aimed compound and unnecessary diastereomers immediately after
20 the cyclization reaction by light irradiation, that is before carrying out purification
operation. From the results of the above Reference Examples, it was confirmed that
unnecessary diastereomers were produced by approximately 1 to 1.4 times to the 1,3-
dimethylcyclobutane-1,2,3,4-tetracarboxylic acid dianhydride as the aimed compound.
35
Accordingly, it is assumed that conventional production methods adversely affect the
production efficiency since cumbersome purification operations are needed due to such
a low selectivity.
INDUSTRIAL APPLICABILIT5 Y
1,3-di-substituted-cyclobutane-1,2,3,4-tetracarboxylic acid and dianhydride of said
acid obtained by the present invention, which have two substituents present at 1-
position and 3-position in the cyclobutane ring, and further satisfy that the relative
configuration of the substituents is trans, are used in a wide range of fields as a raw
10 material or a synthetic intermediate for various industries such as polyimide, and thus
are useful compounds.
The entire disclosure of Japanese Patent Application No. 2014-098037 filed on
May 9, 2014 including specification, claims, drawings and summary is incorporated
15 herein by reference in its entirety.
REFERENCE SYMBOLS
11: Syringe pump containing ethyl acetate solution of compound (6C)
12: Syringe pump containing ethyl acetate solution of compound (7)
20 21: T-shaped mixer (mixer 1)
31: Thermostatic bath
32: T-shaped mixer (mixer 2) having dual tube structure
33: Mass flow controller
34: Nitrogen gas cylinder
25 41: Ultrasonic cleaner
42: Lamp jacket
43: Light source
44: Container for recovering aimed product
36
CLAIMS
1. A method for producing a 1,3-di-substituted-cyclobutane-1,2,3,4-tetracarboxylic
acid represented by the formula (2),
wherein R1 is a C1-4 alkyl group, a phenyl group or a halogen atom,
said method comprising the following step (a) and step (b)5 :
Step (a): a step of producing a crystal (1) composed of an ethylene dicarboxylic
acid derivative represented by the formula (4C) or (4M) and a nitrogen-containing
organic compound (5), in the presence or absence of a solvent,
wherein R1 has the same meaning as above,
10 Step (b): a step of applying light to the crystal (1) obtained in step (a) so as to
carry out a cyclization reaction.
2. The production method according to Claim 1, wherein the nitrogen-containing
organic compound (5) is an aliphatic amine, an aromatic amine, an amine oxide, an
amide, an imide or a nitrogen-containing heterocyclic compound.
15 3. The production method according to Claim 2, wherein the nitrogen-containing
organic compound (5) is a nitrogen-containing heterocyclic compound.
4. The production method according to Claim 3, wherein the nitrogen-containing
heterocyclic compound is nicotinamide or pyridine.
5. The production method according to any one of Claims 1 to 4, wherein the light to
20 be applied has a wavelength of from 290 nm to 600 nm, in step (b).
6. The production method according to any one of Claims 1 to 4, wherein the light to
be applied has a wavelength of from 300 nm to 580 nm, in step (b).
7. The production method according to any one of Claims 1 to 6, wherein the light is
applied in the presence of a photosensitizer, in step (b).
25 8. The production method according to any one of Claims 1 to 7, wherein R1 in the
formula (4C) or (4M) is a methyl group or an ethyl group.
9. The production method according to any one of Claims 1 to 8, wherein the
compound represented by the formula (4C) is used.
10. A method for producing a 1,3-di-substituted-cyclobutane-1,2,3,4- tetracarboxylic
30 acid dianhydride represented by the formula (3), comprising subjecting the 1,3-disubstituted-
cyclobutane-1,2,3,4-tetracarboxylic acid represented by the formula (2)
37
obtained by the production method as defined in Claim 1, to dehydration condensation
reaction,
wherein R1 is a C-M alkyl group, a phenyl group or a halogen atom.
wherein R1 has the same meaning as above.
11. The production method according to Claim 10, wherein the dehydration
condensation reaction is carried out in the presence of acetic anhydride.
12. A crystal composed of pyridine and citraconic acid, which has, in powder X-ray
diffraction measured by Cu-Ka rays, peaks at diffraction angles 29=(12.58±0.2,
15.05±0.2, 16.08±0.2, 17.60±0.2, 19.20±0.2, 21.57±0.2, 23.02±0.2, 24.50±0.2,
26.45±0.2, 27.06±0.2, 28.10±0.2, 32.49±0.2, 35.90±0.2, 36.46±0.2 and 38.43±0.2).
13. The crystal according to Claim 12, which has, in powder X-ray diffraction
measured by Cu-Ka rays, peaks at diffraction angles 29=(12.58±0.2, 15.05±0.2,
16.08±0.2, 17.60±0.2, 18.34±0.2, 19.20±0.2, 21.57*0.2, 23.02±0.2, 24.50±0.2,
26.45±0.2, 27.06±0.2, 28.10±0.2, 30.39±0.2, 32.49±0.2, 34.71 ±0.2, 35.90±0.2,
36.46±0.2 and 38.43±0.2).