U.S. patent application number 09/767669 was filed with the patent office on 2001-11-15 for process for producing 2-substituted propionic acid.
Invention is credited to Suyama, Kazuharu, Watanabe, Saisuke.
Application Number | 20010041742 09/767669 |
Document ID | / |
Family ID | 26585178 |
Filed Date | 2001-11-15 |
United States Patent
Application |
20010041742 |
Kind Code |
A1 |
Watanabe, Saisuke ; et
al. |
November 15, 2001 |
Process for producing 2-substituted propionic acid
Abstract
Adipic acid diester is caused to react with alkoxide
M(OR).sub.n, wherein R is an alkyl group and M is an alkali metal
or alkaline earth metal, the reaction product is successively
subjected either to coupling with halomethylstyrene followed by
carbonylation, or to coupling with 2-(halomethylphenyl)propionic
acid or its ester followed by decarboxylation and hydrolysis. With
this process, it is possible to produce more efficiently a specific
2-substituted propionic acid, loxoprofen.
Inventors: |
Watanabe, Saisuke;
(Kawasaki-shi, JP) ; Suyama, Kazuharu; (Tokyo,
JP) |
Correspondence
Address: |
HOLLANDER LAW FIRM, P.L.C.
SUITE 305
10300 EATON PLACE
FAIRFAX
VA
22030
|
Family ID: |
26585178 |
Appl. No.: |
09/767669 |
Filed: |
January 23, 2001 |
Current U.S.
Class: |
514/568 ;
562/459 |
Current CPC
Class: |
C07C 67/343 20130101;
C07C 51/14 20130101; C07C 2601/08 20170501; C07C 67/38 20130101;
C07C 51/14 20130101; C07C 59/86 20130101; C07C 67/343 20130101;
C07C 69/757 20130101; C07C 67/38 20130101; C07C 69/757
20130101 |
Class at
Publication: |
514/568 ;
562/459 |
International
Class: |
A61K 031/19; A01N
037/10 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 10, 2000 |
JP |
2000-033231 |
Jun 21, 2000 |
JP |
2000-185993 |
Claims
What is claimed is:
1. A process for producing a compound as represented by the
following general formula II (hereinafter referred to as "compound
II"): 15wherein R' represents an alkyl group having 4 or less
carbon atoms, R" represents hydrogen atom or an alkyl group having
4 or less carbon atoms, and R' and R" can be either the same or
different, which process comprises the steps of: causing adipic
acid diester to react with alkoxide as represented by the following
general formula: M(OR).sub.n wherein R represents an alkyl group
having 5 or less carbon atoms, M represents alkali metal or
alkaline earth metal, and n represents the number corresponding to
the valence of M, and (OR)'s of n in number can be either the same
or different, successively subjecting the product obtained above to
coupling with halomethylstyrene to obtain a compound as represented
by the following general formula I (hereinafter referred to as
"compound I"): 16wherein R' represents an alkyl group having 4 or
less carbon atoms, and causing said compound I to react with carbon
monoxide and water or alcohol in the presence of metal catalyst to
obtain said compound II.
2. A process for producing 2-substituted propionic acid as
represented by the following general formula III (hereinafter
referred to as "compound III"): 17which process comprises the steps
of (1-1) to (1-3): step (1-1) to cause adipic acid diester to react
with alkoxide as represented by the following general formula:
M(OR).sub.n wherein R represents an alkyl group having 5 or less
carbon atoms, M represents alkali metal or alkaline earth metal,
and n represents the number corresponding to the valence of M and
(OR)'s of n in number can be either the same or different,
successively subjecting the product obtained above to coupling with
halomethylstyrene to obtain the compound I as represented by the
following general formula I: 18wherein R' represents an alkyl group
having 4 or less carbon atoms, step (1-2) to cause said compound I
to react with carbon monoxide and water or alcohol in the presence
of metal catalyst to obtain the compound II as represented by the
following general formula II: 19wherein R' represents an alkyl
group having 4 or less carbon atoms, R" represents hydrogen atom or
an alkyl group having 4 or less carbon atoms, and R' and R" can be
either the same or different, step (1-3) to subject said compound
II to decarboxylation and hydrolysis to obtain said compound
III.
3. A process for the production as claimed in claim 1 or 2, wherein
halomethylstyrene is chloromethylstyrene.
4. A process for producing a compound II as represented by the
following general formula II: 20wherein R' represents an alkyl
group having 4 or less carbon atoms, R" represents hydrogen atom or
an alkyl group having 4 or less carbon atoms, and R' and R" can be
either the same or different, which process comprises the steps of:
causing adipic acid diester to react with alkoxide as represented
by the following general formula: M(OR).sub.n wherein R represents
an alkyl group having 5 or less carbon atoms, M represents alkali
metal or alkaline earth metal, and n represents the number
corresponding to the valence of M and (OR)'s of n in number can be
either the same or different, successively subjecting the product
obtained above to coupling with a compound as represented by the
following general formula IV (hereinafter referred to as "compound
IV") to obtain said compound II. 21wherein X represents halogen
atom, and R" represents hydrogen atom or an alkyl group having 4 or
less carbon atoms.
5. A process for producing 2-substituted propionic acid as
represented by the following formula III (compound III): 22which
process comprises the steps of (2-1) and (2-2): step (2-1) to cause
adipic acid diester to react with alkoxide as represented by the
following general formula: M(OR).sub.n wherein R represents an
alkyl group having 5 or less carbon atoms, M represents alkali
metal or alkaline earth metal, and n represents the number
corresponding to the valence of M and (OR)'s of n in number can be
either the same or different, successively subjecting the product
obtained above to coupling with a compound IV as represented by the
following general formula IV to obtain the compound II as
represented by the general formula II: 23wherein X represents
halogen atom, and R" represents hydrogen atom or an alkyl group
having 4 or less carbon atoms, and 24wherein R' represents an alkyl
group having 4 or less carbon atoms, R" represents hydrogen atom or
an alkyl group having 4 or less carbon atoms. R' and R" can be
either the same or different, and step (2-2) to subject said
compound II to decarboxylation and hydrolysis to obtain said
compound III.
6. A process for the production as claimed in claim 4 or 5, wherein
halogen atom X in said general formula IV is chlorine or
bromine.
7. A process for the production as claimed in any one of claims 4
to 6, wherein R" in said general formula IV is hydrogen atom, or
methyl or ethyl group.
8. A process for the production as claimed in any one of claims 1
to 7, wherein the effective amount of alkoxide M(OR).sub.n is 0.7
to 1 equivalent relative to 1 mole of adipic acid diester in said
reaction.
9. A process for the production as claimed in any one of claims 1
to 8, wherein adipic acid diester is dimethyl adipate or diethyl
adipate.
10. A process for the production as claimed in any one of claims 1
to 9, wherein alkoxide M(OR).sub.n is sodium methoxide or sodium
ethoxide.
Description
BACKGROUND OF THE INVENTION
[0001] (1) Field of the Invention
[0002] The present invention relates to a process for producing
2-substituted propionic acid having effects as anti-inflammatory
agent, analgesic, antipyretic and so forth.
[0003] (2) Prior Art
[0004] As disclosed in Japanese Patent Publication No. S58-004699,
compounds of 2-substituted propionic acid have effects as
anti-inflammatory agent, analgesic and antipyretic. Especially,
2-[4-(2-oxocyclopentan-1-yl methyl)phenyl]propionic acid,
"loxoprofen", is commercially available as an excellent analgesic
drug.
[0005] In addition to the above disclosure, as disclosed in
Japanese Laid-Open Patent Publication No. S62-161740, the
conventional preparation process includes the steps of (1) coupling
reaction of 2-(p-halomethylphenyl)propionic acid ester with
2-cyclopentanone carboxylic acid ester in the presence of a base,
and (2) decarboxylation and hydrolysis of ester with an acid.
[0006] In the above first coupling step, the hydrogen atom at
.alpha.-position of 2-cyclopentanone carboxylic acid ester, is
taken off to give 2-(alkoxycarbonyl)cyclopentenolate anion, which
attacks the halomethyl group of 2-(p-halomethylphenyl)propionic
acid ester to generate carbon-carbon bond so that the fundamental
skeletal structure of loxoprofen is formed.
[0007] Although above 2-(p-halomethylphenyl)propionic acid ester is
relatively inexpensive, 2-cyclopentanone carboxylic acid ester is
an expensive reagent.
[0008] Furthermore, the reaction in the presence of a base, the
base likely causes side reaction with halomethyl group of
2-(p-halomethylphenyl)propionic acid ester.
[0009] Proposed in PCT International Publication No. WO 97/47581 is
a method that loxoprofen is produced through carbonylation of
p-chloromethylstyrene in the presence of a transition metal complex
catalyst. That is, the method comprises (i) carbonylation of
p-chloromethylstyrene, (ii) coupling with cyclopentanone carboxylic
acid ester, and (iii) decarboxylation and hydrolysis.
[0010] The above method of utilizing carbonylation is advantageous
in industrial working because the structure of substituted styrene
can easily be converted into the structure of substituted propionic
acid ester.
[0011] However, p-chloromethylstyrene has a high polymerization
activity in the presence of heat, light and pressure owing to the
existence of substituted chloromethyl groups bonded to the benzene
ring. Particularly in the carbonylation with a transition metal
complex catalyst, p-chloromethylstyrene is liable to polymerize.
This fact may be apprehended in view of the fact that commercially
available p-chloromethylstyrene usually contains polymerization
inhibitor and that polymerization inhibitor may be added in
carbonylation as described on page 6 of the foregoing International
Publication.
[0012] As described above, p-chloromethylstyrene is liable to cause
self-polymerization, so that, according to the above International
Publication, polymerization inhibitor is added during the
carbonylation as above. In addition, it is required to use solvents
as much as several times to several tens times, mostly over ten
times the volume of p-chloromethylstyrene as substrate in all the
examples on carbonylation.
[0013] However, the necessity for large quantity of solvent
relative to the substrate substance of p-chloromethylstyrene is not
advantageous in industrial practice.
[0014] In the method as described in the above International
Publication, highly reactive vinyl groups are reacted to convert
into other less reactive substituents in the first step among
plurality of steps. This method cannot always be regarded as
reasonable in industrial scale process in view of the fact that the
high reactivity of vinyl group is not taken into consideration
sufficiently.
[0015] Moreover, the method disclosed in the above International
Publication cannot be said as inexpensive because expensive
cyclopentanone carboxylic acid alkyl ester is used as a starting
material. In addition, the yield is not always satisfactory
either.
[0016] As mentioned above, the most suitable method for producing
loxoprofen has not yet been proposed, and a more efficient method
is wanted.
BRIEF SUMMARY OF THE INVENTION
[0017] It is the object of the present invention to provide a
process for producing loxoprofen using adipic acid diester as one
of starting materials, which is more effective as compared with
conventional methods.
[0018] More particularly, a first aspect of the present invention
relates to a process for producing a compound as represented by the
following general formula II (hereinafter referred to as "compound
II"): 1
[0019] wherein R' represents an alkyl group having 4 or less carbon
atoms, R" represents hydrogen atom or an alkyl group having 4 or
less carbon atoms, and R' and R" can be either the same or
different, which process comprises the steps of:
[0020] to cause adipic acid diester to react with alkoxide as
represented by the following general formula:
M(OR).sub.n
[0021] wherein R represents an alkyl group having 5 or less carbon
atoms, M represents alkali metal or alkaline earth metal, n
represents the number corresponding to the valence of M and (OR)'s
of n in number can be either the same or different,
[0022] to subject successively the above product to coupling with
halomethylstyrene to obtain the compound as represented by the
following general formula I (hereinafter referred to as "compound
I"): 2
[0023] wherein R' represents an alkyl group having 4 or less carbon
atoms,
[0024] and to cause the above compound I to react with carbon
monoxide and water or alcohol in the presence of a metal catalyst
to obtain the above compound II.
[0025] A second aspect of the present invention relates to a
process for producing 2-substituted propionic acid as represented
by the following general formula III (hereinafter referred to as
"compound III"): 3
[0026] which process comprises the steps of (1-1) to (1-3):
[0027] step (1-1) to cause adipic acid diester to react with
alkoxide as represented by the following general formula:
M(OR).sub.n
[0028] wherein R represents an alkyl group having 5 or less carbon
atoms, M represents alkali metal or alkaline earth metal, n
represents the number corresponding to the valence of M, and (OR)'s
of n in number can be either the same or different, and
successively subjecting the above product to coupling with
halomethylstyrene to obtain the compound I as represented by the
following general formula I: 4
[0029] wherein R' represents an alkyl group having 4 or less carbon
atoms,
[0030] step (1-2) to cause the above compound I to react with
carbon monoxide and water or alcohol in the presence of metal
catalyst to obtain a compound II as represented by the following
general formula II: 5
[0031] wherein R' represents an alkyl group having 4 or less carbon
atoms, R" represents hydrogen atom or an alkyl group having 4 or
less carbon atoms, and R' and R" can be either the same or
different, and
[0032] step (1-3) to subject the above compound II to
decarboxylation and hydrolysis to obtain the above compound
III.
[0033] A third aspect of the present invention relates to a process
for the production as described in the first or second aspect,
wherein halomethylstyrene is chloromethylstyrene.
[0034] According to the above methods, the halomethyl group of
halomethylstyrene is converted into a particular substituent, so
that the liability for self-polymerization of vinyl group is
reduced. Therefore, a large quantity of solvent is not required in
carbonylation. Furthermore, it is possible to produce 2-substituted
propionic acid effectively using an inexpensive starting
material.
[0035] A fourth aspect of the present invention relates to a
process for producing a compound II as represented by the following
general formula II: 6
[0036] wherein R' represents an alkyl group having 4 or less carbon
atoms, R" represents hydrogen atom or an alkyl group having 4 or
less carbon atoms, and R' and R" can be either the same or
different, which process comprises the steps of:
[0037] causing adipic acid diester to react with alkoxide as
represented by the following general formula:
M(OR).sub.n
[0038] wherein R represents an alkyl group having 5 or less carbon
atoms, M represents alkali metal or alkaline earth metal, n
represents the number corresponding to the valence of M, and (OR)'s
of n in number can be either the same or different,
[0039] successively subjecting the product obtained above to
coupling with a compound as represented by the following general
formula IV (hereinafter referred to as "compound IV") to obtain the
above compound II, 7
[0040] wherein X represents halogen atom, and R" represents
hydrogen atom or an alkyl group having 4 or less carbon atoms.
[0041] A fifth aspect of the present invention relates to a process
for producing 2-substituted propionic acid as represented by the
following formula III (compound III): 8
[0042] which process comprises the steps of (2-1) and (2-2):
[0043] step (2-1) to cause adipic acid diester to react with
alkoxide as represented by the following general formula:
M(OR).sub.n
[0044] wherein R represents an alkyl group having 5 or less carbon
atoms, M represents alkali metal or alkaline earth metal, n
represents the number corresponding to the valence of M, and (OR)'s
of n in number can be either the same or different,
[0045] and successively subjecting the product obtained above to
coupling with a compound IV as represented by the following general
formula IV to obtain a compound II as represented by the general
formula II: 9
[0046] wherein X represents halogen atom, and R" represents
hydrogen atom or an alkyl group having 4 or less carbon atoms, and
10
[0047] wherein R' represents an alkyl group having 4 or less carbon
atoms, R" represents hydrogen atom or an alkyl group having 4 or
less carbon atoms, and R' and R" can be either the same or
different,
[0048] step (2-2) to subject the above compound II to
decarboxylation and hydrolysis to obtain the above compound
III.
[0049] A sixth aspect of the present invention relates to a process
for the production as described in the fourth or fifth aspect,
wherein halogen atom X in the general formula IV is chlorine or
bromine.
[0050] A seventh aspect of the present invention relates to a
process for the production as described in any one of fourth to
sixth aspects, wherein R" in the general formula IV is hydrogen
atom, or methyl or ethyl group.
[0051] An eighth aspect of the present invention relates to a
production process as described in any one of first to seventh
aspects, wherein the effective amount of alkoxide, M(OR).sub.n, is
0.7 to 1 equivalent relative to 1 mole of adipic acid diester
during the reaction.
[0052] A ninth aspect of the present invention relates to a
production process as described in any one of first to eighth
aspects, wherein adipic acid diester is dimethyl adipate or diethyl
adipate.
[0053] A tenth aspect of the present invention relates to a
production process as described in any of first to ninth aspects,
wherein alkoxide, M(OR).sub.n, is sodium methoxide or sodium
ethoxide.
DETAILED DESCRIPTION OF THE INVENTION
[0054] In all the processes for production according to the present
invention, adipic acid diester is used as a starting material. One
process comprises the step (1-1): [coupling], step (1-2):
[carbonylation] and step (1-3): [decarboxylation and hydrolysis].
The other process comprises the step (2-1): [coupling] and step
(2-2) [decarboxylation and hydrolysis].
[0055] In the first place, the production process comprising steps
of (1-1) to (1-3) will be described in the order of steps.
[0056] Step (1-1): [Coupling]
[0057] In step (1-1), after Dieckmann condensation of dimethyl
adipate with the above alkoxide M(OR).sub.n is carried out to
produce 2-(alkoxycarbonyl)cyclopentenolate anion, the above
obtained compound is successively subjected to the coupling with
halomethylstyrene to obtain a compound I.
[0058] In the present step, 2-(alkoxycarbonyl)cyclopentenolate
anion is produced as an intermediate product, which is then
subjected to coupling with halomethylstyrene without isolation.
Although both the compounds are unsaturated ones, it is
advantageous because the carbon-carbon double bonds in
halomethylstyrene are almost inactive in this reaction. Because
2-(alkoxycarbonyl)cyclopentenolate anion is not isolated as ester
or acid, the operation of reaction is simple and the yield is
higher than that in the case with effecting isolation.
[0059] Among adipic acid diesters, adipic acid dialkyl esters are
preferable. Exemplified as the alkyl groups for the above dialkyl
esters are those having 4 or less carbon atoms such as Me (methyl),
Et (ethyl), n-Pr (propyl), iso-Pr, n-Bu (butyl), iso-Bu, sec-Bu and
tert-Bu. Two alkyl groups contained in the adipic acid dialkyl
ester can be either the same or different. They have preferably the
same alkyl groups of Me, Et, n-Pr or iso-Bu, more preferably they
are dimethyl adipate and diethyl adipate.
[0060] As the alkoxide, M(OR).sub.n, commercially available common
ones can be used. The alkali metals and alkaline earth metals of
"M" are exemplified by sodium, potassium, lithium, calcium and
magnesium. Exemplified as "R" are alkyl groups having 5 or less
carbon atoms such as Me, Et, n-Pr, iso-Pr, n-Bu, iso-Bu, sec-Bu,
tert-Bu, 1-pentyl, 2-pentyl, 3-pentyl, neopentyl and tert-amyl. The
symbol "n" represents the number corresponding to the valence of M,
and (OR)'s of n in number can be either the same or different.
Preferably, it has the same alkoxyl groups, wherein R is an alkyl
group such as Me, Et, n-Pr or iso-Pr.
[0061] Exemplified as the foregoing alkoxides are lithium
methoxide, sodium methoxide, potassium methoxide, calcium methoxide
and magnesium methoxide; lithium ethoxide, sodium ethoxide,
potassium ethoxide, calcium ethoxide and magnesium ethoxide;
lithium n-propoxide, sodium n-propoxide, potassium n-propoxide,
calcium n-propoxide and magnesium n-propoxide; lithium
iso-propoxide, sodium iso-propoxide, potassium iso-propoxide,
calcium iso-propoxide and magnesium iso-propoxide; lithium
n-butoxide, sodium n-butoxide, potassium n-butoxide, calcium
n-butoxide and magnesium n-butoxide; lithium iso-butoxide, sodium
iso-butoxide, potassium iso-butoxide, calcium iso-butoxide and
magnesium iso-butoxide; lithium sec-butoxide, sodium sec-butoxide,
potassium sec-butoxide, calcium sec-butoxide and magnesium
sec-butoxide; lithium tert-butoxide, sodium tert-butoxide,
potassium tert-butoxide, calcium tert-butoxide and magnesium
tert-butoxide; lithium 1-pentoxide, sodium 1-pentoxide, potassium
1-pentoxide, calcium 1-pentoxide and magnesium 1-pentoxide; lithium
2-pentoxide, sodium 2-pentoxide, potassium 2-pentoxide, calcium
2-pentoxide and magnesium 2-pentoxide; lithium 3-pentoxide sodium
3-pentoxide, potassium 3-pentoxide, calcium 3-pentoxide and
magnesium 3-pentoxide; lithium tert-amyloxide, sodium
tert-amyloxide, potassium tert-amyloxide, calcium tert-amyloxide
and magnesium tert-amyloxide; lithium neopentoxide, sodium
neopentoxide, potassium neopentoxide, calcium neopentoxide and
magnesium neopentoxide; and so forth. Exemplified as particularly
suitable ones are lithium methoxide, sodium methoxide and potassium
methoxide, lithium ethoxide, sodium ethoxide and potassium
ethoxide, lithium iso-propoxide, sodium iso-propoxide and potassium
iso-propoxide, and lithium tert-butoxide, sodium tert-butoxide and
potassium tert-butoxide.
[0062] As for the halomethylstyrene, styrene having fluoromethyl-,
chloromethyl-, bromomethyl- or iodomethyl group is used. Preferable
ones are chloromethylstyrene and bromomethylstyrene. Among them,
chloromethylstyrene is desirable, particularly
p-chloromethylstyrene is preferable.
[0063] In the present step, reaction solvents are preferably used.
The solvents can vary depending on the kinds of adipic acid
diesters.
[0064] In the initial condensation reaction of adipic acid diester
with alkoxide, 1 equivalent of alcohol is produced as a by-product.
By means of continuous or intermittent removal of the alcohol, the
reaction proceeds to produce the above-mentioned
2-(alkoxycarbonyl)cyclopentenolat- e anion. Therefore, the
procedure for removing selectively the produced alcohol from the
reaction system is inevitable for the purpose of acceleration of
reaction. As the removal operation, it is convenient to distill off
with heating under atmospheric pressure or reduced pressure.
Therefore, when a solvent is used for the reaction, its boiling
point must be the same as or higher than that of the by-product
alcohol.
[0065] For example, when dimethyl adipate is used as adipic acid
diester, a solvent having a boiling point higher than that of
methanol (about 65.degree. C.) is used. The solvents are
exemplified by nitrogen-containing compounds such as dimethyl
formamide and acetonitrile; ether such as tetrahydrofuran; ketones
such as acetone and methyl ethyl ketone; ester such as ethyl
acetate; aromatic hydrocarbons such as benzene, toluene and xylene;
aliphatic hydrocarbons such as octane, nonane, decane and
isododecane; and the mixed solvents of them. Among them, toluene
and benzene are preferable, and toluene is more preferable.
[0066] When adipic acid diester other than dimethyl adipate is
used, solvents conforming to the above description can be used.
[0067] Concerning the use quantity of solvent for reaction, for
example, 500 to 5,000 ml of solvent is used relative to 1 mole of
adipic acid diester. The amount is preferably 800 to 3,000 ml,
particularly 1,000 to 2,000 ml.
[0068] The above M(OR).sub.n and adipic acid diester are allowed to
react together, preferably in a solvent, in a temperature range of
0 to 300.degree. C., preferably 10 to 250.degree. C., more
preferably 20 to 200.degree. C., within 24 hours, preferably for 6
hours, and more preferably for one hour.
[0069] During the reaction, the produced alcohol is distilled off
under atmospheric pressure or reduced pressure. In order to remove
the alcohol completely, it is preferable to remove simultaneously a
part of solvent. In the case when a reaction solvent is distilled
off, the solvent can be newly supplemented.
[0070] When alkoxide is reacted with adipic acid ester, the
alkoxide can be used in the form of solid, for example, it is dried
and preferably as fine powder, or as a solution of alkoxide in
alcohol. Preferably, alcoholic solution containing dissolved
alkoxide is used. The alcohol content is distilled off before the
reaction with adipic acid ester starts substantially. By carrying
out this procedure, suspension containing alkoxide finely dispersed
in a reaction mixture is obtained, which can produce a desirable
result.
[0071] As to the amount of alkoxide, for example, 0.1 to 10
equivalents of alkoxide can be used for 1 mole of adipic acid
diester. When M is an alkali metal, 1 mole of alkoxide corresponds
to 1 equivalent, and when M is an alkaline earth metal, 1 mole of
alkoxide corresponds to 2 equivalents. It is preferable that 0.5 to
2 equivalents of alkoxide is used relative to 1 mole of adipic acid
diester. It is particularly desirable that the effective amount of
alkoxide is 0.7 to 1 equivalent during reaction.
[0072] When alcohol remains after the reaction, the alcohol can be
distilled off.
[0073] By the above reaction of adipic acid diester with alkoxide,
the above 2-(alkoxycarbonyl)cyclopentenolate anion can be obtained,
the latter of which is successively subjected to coupling with
halomethylstyrene without isolation. Although the by-product
alcohol is distilled off in order to accelerate reaction as
described above, it is not always necessary that the reaction
mixture is completely free from the by-product alcohol. The
reaction mixture containing a certain amount of alcohol as
by-product can be fed into the next step of coupling reaction
without any treatment. If unreacted substances coexist, it is
rather favorable for the next coupling reaction. Therefore, the
reaction mixture containing unreacted substances can be fed
directly to the next coupling reaction.
[0074] Thus, halomethylstyrene is added to the obtained reaction
mixture to carry out coupling reaction. The amount of
halomethylstyrene is 0.1 to 20 moles, preferably 0.5 to 2 moles,
more preferably 0.7 to 1.5 moles, relative to 1 mole of previously
added adipic acid diester.
[0075] The temperature of reaction is in the range of 0 to
150.degree. C., preferably 20 to 150.degree. C., more preferably
room temperature to 80.degree. C.
[0076] The time length of reaction is 24 hours or less, preferably
0.1 to 20 hours, more preferably 1 to 10 hours.
[0077] Though the coupling reaction can be carried without reaction
solvent, it is also possible to use a solvent. In the like manner
as the foregoing, usable solvents are exemplified by
nitrogen-containing compounds such as dimethyl formamide and
acetonitrile; ether such as tetrahydrofuran; acetals; ketones such
as acetone and methyl ethyl ketone; ester such as ethyl acetate;
aromatic hydrocarbons such as benzene, toluene and xylene;
aliphatic hydrocarbons such as octane, nonane, decane and
isododecane; and the mixed solvents of them. Among them, toluene
and benzene are preferable, and toluene is more preferable.
[0078] As to the amount of reaction solvents, for example, 500 to
5,000 ml, preferably 800 to 3,000 ml, more preferably 1,000 to
2,000 ml, can be used relative to 1 mole of adipic acid diester
that is added previously.
[0079] After the reaction, residual base is neutralized with acid,
which is followed by extraction and water washing, and then
extraction solvent is removed. When the reaction solvent is water
soluble one, it is removed under reduced pressure. After that, an
extraction solvent is added and extraction and water washing are
carried out, and further, the extraction solvent is removed. As the
extraction solvents, appropriate ones can be used, while toluene is
usually employed. It is not always necessary to remove completely
the extraction solvents remaining after extraction, as long as they
do not have influence on the next step. They can be used as
dilution solvents in the next step (1-2).
[0080] Compound I can be obtained according to the above method,
and it is used in the next step (1-2). Compound I can be supplied
to step (1-2) after refined further by methods of distillation or
others, but additional refining is not necessary.
[0081] In the obtained product, the compound as represented by the
formula V (hereinafter referred to as "compound V") is sometimes
present in a small amount. However, it is converted finally into
the intended compound III, therefore its mixing does not cause any
trouble. 11
[0082] Halomethylstyrene used in step (1-1) is liable to polymerize
by itself. The polymerization is further accelerated particularly
when it is handled in a heated and pressurized system. Therefore,
when halomethylstyrene is directly subjected to carbonylation, it
is necessary to dilute the reaction system with a large amount of
solvent as mentioned above, which is industrially costly. However,
a compound I, which is obtained by coupling halomethylstyrene with
cyclopentanone carboxylic acid ester, is difficult to polymerize by
itself. As shown by the examples of the present invention, the
dilution solvent required in carbonylation of compound I is only
several times or less the amount of substrate.
[0083] Further, in the method of the present invention, the amount
of by-product resulting from the polymerization of
halomethylstyrene is small, which is favorable also from the
viewpoint of waste disposal. Accordingly, the present invention is
superior by far in efficiency to the conventional method comprising
(i) carbonylation of p-chloromethylstyrene, (ii) coupling with
cyclopentanone carboxylic acid ester, and (iii) decarboxylation and
hydrolysis.
[0084] Step (1-2): [Carbonylation]
[0085] In the present step (1-2), the compound I resulting from the
above step (1-1) is caused to react with carbon monoxide and water
or alcohol, in the presence of catalyst and dilution solvents, or
with addition of polymerization inhibitor if necessary, to obtain a
compound II. The catalysts used in the present step is any selected
from the group of (i) metal complex itself, (ii) substance
comprising metal complex and ligand, and (iii) substance comprising
metal complex, ligand and additive.
[0086] When a catalyst corresponding to (ii) or (iii) is used, it
is desirable to use the procedure for developing catalyst activity
by mixing metal complex, or metal complex and additive, with
alcohol to be used in the reaction, then adding ligand.
[0087] As metal complexes, transition metal complexes, preferably
complexes of transition metal of group VIII, more preferably those
of cobalt, rhodium, platinum and palladium can be used. As the
examples, there are Co.sub.2(CO).sub.8, RhCl(PPh.sub.3).sub.3,
wherein "Ph" represents phenyl group, RhCl(CO)(PPh.sub.3).sub.2,
H.sub.2PtCl.sub.6, Pd carbon, Pd black, Pd(PPh.sub.3).sub.4,
Pd(PPhBu.sub.2).sub.2, Pd(P Bu.sub.3).sub.2,
Pd(P(OPh).sub.3).sub.4, Pd(P(OEt).sub.3).sub.4,
Pd(C.sub.2H.sub.4)(PPh.sub.3).sub.2,
Pd(PhCN).sub.2(BF.sub.4).sub.2, Pd(MeCN).sub.4(BF.sub.4).sub.2,
Pd(PhCN).sub.2(PPh.sub.3).sub.2(BF.sub.4)- .sub.2,
Pd(MeCN).sub.2(PPh.sub.3).sub.2(BF.sub.4).sub.2, Pd(acac).sub.2,
wherein "acac" represents acetylacetonato group,
Pd.sub.2(dba).sub.3CHCl.- sub.3, Pd(dba).sub.2, wherein "dba"
represents dibenzylideneacetone, PdO, PdS, Pd(NO.sub.3).sub.2,
PdSO.sub.4, PdX.sub.2, wherein "X" represents Cl, Br, I,
OCOCF.sub.3 or OCOMe, PdX.sub.2(PhCN).sub.2, PdX.sub.2(MeCN).sub.2,
PdX.sub.2(CO).sub.2, wherein "X" represents Cl, Br, or I,
Pd(COD).sub.2, PdX.sub.2(COD).sub.2, wherein "X" represents Cl, Br
or I and "COD" represents 1,5-cyclo-octadiene,
Pd(MA)(PPh.sub.3).sub.2- , wherein "MA" represents maleic
anhydride, M.sub.2PdX.sub.4, wherein "X" represents Cl, Br, I or
OCOMe and "M" represents H, NH.sub.4, Li, Na or K,
PdX.sub.2(PArAr'Ar").sub.2, wherein "X" represents Cl, Br or I and
Ar, Ar' or Ar" represents the same or different aryl group,
PdX.sub.2(PPh.sub.3).sub.2, PdX.sub.2(PRPh.sub.2).sub.2,
PdX.sub.2(PR.sub.2Ph).sub.2, PdX.sub.2(PR.sub.3).sub.2,
Pd.sub.2X.sub.4(PR.sub.3).sub.2, wherein "X" represents Cl, Br or I
and "R" represents Me, Et, Pr, Bu, OPh, menthyl group or cyclohexyl
group, PdX.sub.2(dppf, wherein "X" represents Cl, Br or I and
"dppf" represents bis(di-phenylphosphino)ferrocene,
PdX.sub.2(Ph.sub.2P(CH.sub.2).sub.nPPh.- sub.2), wherein "X"
represents Cl, Br or I and "n" represents an integer from 1 to 4,
PdR.sub.2(PR'.sub.3).sub.2, wherein R and R' represents Me, Et, Pr,
Bu, OPh or Ph, PdXR(PR'.sub.3).sub.2, wherein "X" represents Cl, Br
or I, "R" represents H, Me, Et, Pr, Bu, Ph, CH.sub.2Ph or COMe and
R' represents Me, Et, Pr, Bu, OPh, Ph or cyclohexyl group,
[Pd(.eta..sup.3-CH.sub.2CHCH.sub.2)X].sub.2,
[Pd(.eta..sup.3-CH.sub.2CHCH- .sub.2)X(PPh.sub.3)],
[Pd(.eta..sup.3-CH.sub.2CHCHCH.sub.2X)X].sub.2, wherein "X"
represents Cl, Br or I, Pd(.eta..sup.3-CH.sub.2CHCH.sub.2).su- b.2,
Pd(.eta..sup.3-CH.sub.2CHCH.sub.2)(.eta..sup.5-C.sub.5H.sub.5) and
so forth, but the metal complexes used in the present step are not
limited to these.
[0088] The amounts of metal complex is 1 mole or less relative to 1
mole of compound I, preferably in the range of 0.00001 to 0.1 mole,
more preferably 0.0001 to 0.01 mole.
[0089] Ligands are compounds that have the property to produce
coordination compounds, and phosphines or phosphites are favorably
used, and more favorably triarylphosphines. As the examples, there
are PPh.sub.3, PArAr'Ar" (Ar, Ar' and Ar" are the same or different
aryl groups), PRPh.sub.2, PR.sub.2Ph, PR.sub.3, wherein "R"
represents Me, Et, n-Pr, iso-Pr, n-Bu, menthyl group or cyclohexyl
group, Ph.sub.2P(CH.sub.2).sub.nPPh.sub.2, wherein "n" represents
an integer from 1 to 4, bis(diphenylphosphino)ferrocene,
P(OPh).sub.3 and so forth, but the ligands used in the present step
are not limited to these.
[0090] The amount of ligand is 10 equivalent or less relative to 1
equivalent of metal complex, preferably 5 equivalent or less, more
preferably 2 to 4 equivalent.
[0091] As additives, inorganic substances are used, preferably tin
chloride, copper oxide, and alkali metal salts or alkaline earth
metal salts. Among them, alkali metal salts are favorable. As the
examples, there are SnCl.sub.2, CuCl.sub.2, MgCl.sub.2, CaCl.sub.2,
NaCl, NaBr, LiCl, LiBr, KCl, KBr and so forth, but the additives
used in the present step are not limited to these.
[0092] The additive can be Br.phi.nsted acid and Lewis acid
depending on the metal complexes to be used. As Br.phi.nsted acids,
it is preferable to use the ones, which counter anions coordinate
weakly or do not coordinate at all with metal atoms. As the
examples, there are p-toluenesulfonic acid,
trifluoromethanesulfonic acid, trifluoroacetic acid, HBF.sub.4,
HBAr.sub.4, wherein "Ar" represents aryl group, HPF.sub.6 and so
forth, but Br.phi.nsted acids used in the present step are not
limited to these. From the viewpoint of easy handling,
p-toluenesulfonic acid is particularly favorable.
[0093] As Lewis acids, general compounds can be used, preferably
those comprising B, Al, Ti, Zn, Sn, Sb and so forth. Among them,
those comprising B, Al or Ti are favorable. As substances to be
connected with these elements, there are alkoxyl group, halogen
atom, oxygen atom, hydrogen atom and so forth. Among theme, halogen
is favorable. As the examples of Lewis acids, there are TX.sub.4,
BX.sub.3, AlX.sub.3, ZnX.sub.2, SnX.sub.4, SbX.sub.5, wherein "X"
represents halogen atom, Ti(OR).sub.nX.sub.4-n, wherein "R"
represents methyl group, ethyl group, isopropyl group or butyl
group, "X" represents halogen atom, and "n" represents an integer
from 1 to 4, TiH.sub.nCl.sub.4-n, wherein "n" represents an integer
from 1 to 3, Al(OR).sub.3, Zn(OR).sub.2, wherein "R" represents
methyl group, ethyl group or isopropyl group, TiO.sub.2,
Al.sub.2O.sub.3, ZnO.sub.2, SnO.sub.2, SbO.sub.5 and so forth, but
Lewis acids used in the present step are not limited to these.
[0094] These Lewis acids in themselves are difficult to handle.
Therefore, it is preferable to use them in the form of complexes
containing water, ether, alcohol, ester, carboxylic acid or THF
(tetrahydrofuran) as ligand. As the examples, there are
BF.sub.3-OEt.sub.2, BF.sub.3-OH.sub.2, BF.sub.3-(THF).sub.2,
TiCl.sub.4-(THF).sub.2, AlCl.sub.3-(H.sub.2O).sub.n and so
forth.
[0095] The amount of additive is 20 equivalents or less relative to
1 equivalent of metal complex, preferably 0.1 to 10 equivalents,
more preferably 1 to 4 equivalents.
[0096] As dilution solvents, commonly available organic solvents
can be used. As the examples, there are benzene, toluene, xylene,
tetrahydrofuran, acetone, methyl ethyl ketone, ethyl acetate and so
forth, but the dilution solvents used in the present step are not
limited to these.
[0097] As to the amount of dilution solvent, solvent is 20 times or
less the volume of compound I, preferably 10 times or less, more
preferably 0.5 to 3 times.
[0098] As polymerization inhibitors, it is possible to use the
compounds that do not hinder carbonylation and reactions
thereafter. As the examples, there are nitromethane, nitrobenzene,
hydroquinone, CuCl.sub.2, FeCl.sub.2, 4-tert-butylcatechol,
nitrophenol, nitrocresol, 2,6-di-tert-butyl-4-methylphenol,
4-methoxyphenol and so forth, but the polymerization inhibitors
used in the present step are not limited particularly. Any mixture
comprising two or more kinds of polymerization inhibitors may be
used.
[0099] The amount of polymerization inhibitor is 10% or less
relative to the mass of compound I, preferably 1% or less, more
preferably 0.1% or less.
[0100] As carbon monoxide, the one having the purity of 20% or
more, preferably 50% or more, more preferably 80% or more is
used.
[0101] Carbon monoxide is prepared in such an amount that 1 mole or
more can be supplied to 1 mole of compound I. When hydrogen is
present together with carbon monoxide, the partial pressure of
carbon monoxide is reduced depending on the amount of coexisting
hydrogen. That affects the reaction of the present step somewhat,
but the reaction proceeds without any trouble.
[0102] Exemplified as alcohols are methyl alcohol, ethyl alcohol,
n-propyl alcohol, iso-propyl alcohol, n-butyl alcohol, sec-butyl
alcohol, tert-butyl alcohol and iso-butyl alcohol. Methyl alcohol,
ethyl alcohol, n-propyl alcohol and iso-propyl alcohol are
preferably used, and particularly methyl alcohol and ethyl alcohol
are favorable.
[0103] The amount of alcohol is 1 mole or more relative to 1 mole
of compound I, preferably 1 to 30 moles, more preferably 1 to 3
moles.
[0104] An autoclave is charged with the above catalyst, a compound
I, water or alcohol, and dilution solvent. Then, at the reaction
temperature of 40 to 200.degree. C., preferably 50 to 140.degree.
C., more preferably 70 to 100.degree. C., carbon monoxide is
pressurized to 0.1 to 30 MPa, preferably 0.2 to 10 MPa, more
preferably 2.5 to 7 MPa, and stirring is carried out for 0.1 to 100
hours, preferably 6 to 30 hours, more preferably 8 to 24 hours.
[0105] Otherwise, it is also possible to mix catalyst, alcohol and
dilution solvent in an autoclave, and then add a compound I
successively into the reaction system under the above conditions.
In this case, it is preferable to supply a compound I over 0.1 to
100 hours, preferably for 5 to 20 hours, more preferably for 7 to
20 hours.
[0106] After the reaction is over, carbon monoxide is removed and
the condition is set at normal temperature and pressure. When
catalysts are precipitated in a reaction mixture, they can be
recovered by filtration and reused. After appropriate filtration of
catalysts, separation by distillation can be carried out under
reduced pressure to obtain a compound II in high purity. The
meta-isomer and para-isomer of compound II have different boiling
points, therefore it is possible to separate the mixture of them by
rectification. By this method, the pare-isomer can be obtained as a
precursor of loxoprofen in high purity.
[0107] In the carbonylation carried out in the present step, the
temperature is relatively high, and moreover metal catalysts are
present. However, a specific substituent group is substituted for
halomethyl group of halomethylstyrene such as chloromethyl group of
chloromethylstyrene, therefore the polymerization activity of vinyl
group is suppressed, so that the reaction of high efficiency can be
accomplished.
[0108] In the present carbonylation, the compound as represented by
the general formula VI (hereinafter referred to as "compound VI")
is produced as an isomer of compound II in a small amount, 12
[0109] wherein R' represents an alkyl group having 4 or less carbon
atoms, and R" represents hydrogen atom or an alkyl group having 4
or less carbon atoms.
[0110] Further, the compound as represented by the general formula
VII resulting from carbonylation of compound V is produced in a
trace, 13
[0111] wherein R" represents hydrogen atom or an alkyl group having
4 or less carbon atoms.
[0112] However, they are converted finally into the intended
compound III, therefore their mixing does not cause any
trouble.
[0113] Step (1-3): [Decarboxylation and Hydrolysis]
[0114] In the present step, for example, according to the method of
the above International Publication, hydrolysis and decarboxylation
are carried out using acids such as sulfuric acid and hydrochloric
acid.
[0115] Otherwise, it is possible to obtain a compound III by
heating the compound II obtained in the above step (1-2) together
with water and acid in the presence of solvent so as to carry out
decarboxylation and hydrolysis step by step. In the present step of
decarboxylation and hydrolysis, although the compound II has two
ester groups, both groups can be treated at the same time, which is
advantageous. The ester group of compound I can be subjected to
decarboxylation and hydrolysis before carbonylation of the step
(1-2). However, with the hydrolysis and decarboxylation according
to the present step, it is possible to treat two ester groups at
the same time, even if a compound has two ester groups like
compound II.
[0116] As acids, commonly available mineral acids can be used. As
the examples, there are hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid and so forth, but the acids used in the
present step are not limited to these.
[0117] The amount of acids is 20 times or less the mass of compound
II, preferably 0.001 to 10 times, more preferably 0.001 to 5
times.
[0118] As solvents, hydrophilic organic solvents are preferable.
When the reaction is carried out in the presence of hydrophilic
organic solvent, the time of reaction can be shortened preferably.
Exemplified as hydrophilic organic solvents are tetrahydrofuran,
ethyl acetate, acetonitrile, acetic acid and so forth, but the
solvents used in the present step are not limited to these. Acetic
acid is particularly favorable.
[0119] Hydrophilic organic solvents are used in the amount of 20
times or less the mass of compound II, preferably 0.5 to 10 times,
more preferably 1 to 5 times.
[0120] A reaction vessel is charged with the above acid, solvent
and a compound II. Then, at room temperature to 150.degree. C.,
preferably 50.degree. C. to 120.degree. C., more preferably
90.degree. C. to 110.degree. C., stirring is carried out for 1 to
100 hours, preferably 2 to 24 hours, more preferably 6 to 12 hours.
The time of reaction is shortened by removing alcohol produced as
by-product from the reaction zone with Dean-Stark apparatus or the
like.
[0121] After the reaction, extraction is carried out with a
hydrophilic organic solvent such as toluene and the solvent is
removed to obtain a raw product of compound III. Further,
recrystallization can be carried out using good solvent such as
ether and bad solvent such as hexane to obtain a compound III in
high purity.
[0122] In the following, the process for production comprising the
steps (2-1) and (2-2) will be described in serial order of the
steps.
[0123] Step (2-1): [Coupling]
[0124] In step (2-1), after the reaction of dimethyl adipate with
the above alkoxide M(OR).sub.n is carried out to produce
2-(alkoxycarbonyl)cyclopentenolate anion, the obtained product is
successively subjected to coupling with a compound IV to obtain a
compound II.
[0125] In the present step, 2-(alkoxycarbonyl)cyclopentenolate
anion obtained as an intermediate product, its ester, the
corresponding acid and the like, without isolation, can be
successively subjected to reaction with a compound IV. Therefore,
the operation of reaction is simple, and the yield is higher than
in the case with isolation.
[0126] As above, it is important to cause
2-(alkoxycarbonyl)cyclopentenola- te anion to react with a compound
IV without isolation. As long as isolation is excluded, the other
simple refining is allowed. In the reaction of alkoxide M(OR).sub.n
as base and adipic acid diester, if only excess of base is avoided,
there is no need for apprehension that the base might react with a
compound IV as a side reaction.
[0127] Adipic acid diester and alkoxide M(OR).sub.n used in step
(2-1) are the same as those described in the above-mentioned step
(1-1).
[0128] Exemplified as compound IV of 2-(halomethylphenyl)propionic
acids or their esters are 2-(fluoromethylphenyl)propionic acid or
its ester, 2-(chloromethylphenyl)propionic acid or its ester,
2-(bromomethylphenyl)propionic acid or its ester, and
2-(iodomethylphenyl)propionic acid or its ester. Preferable ones
are 2-(chloromethylphenyl)propionic acid, methyl
2-(chloromethylphenyl)propio- nate, ethyl
2-(chloromethylphenyl)propionate, 2-(bromomethylphenyl)propion- ic
acid, methyl 2-(bromomethylphenyl)propionate and ethyl
2-(bromomethylphenyl)propionate. Among them, methyl
2-(chloromethylphenyl)propionate, ethyl 2-
(chloromethylphenyl)propionate- , methyl
2-(bromomethylphenyl)propionate and ethyl 2-(bromomethylphenyl)pr-
opionate are favorable. Further, methyl
2-(p-chloromethylphenyl)propionate- , ethyl
2-(p-chloromethylphenyl)propionate, methyl 2-(p-bromomethylphenyl)-
propionate and ethyl 2-(p-bromomethylphenyl)propionate are
particularly favorable. These acids and esters, especially acids
are commercially available at a low price.
[0129] When 2-(halomethylphenyl)propionic acid is caused to react
with lower alcohol using acid catalyst, it can be easily converted
into 2-(halomethylphenyl)propionic acid ester. Accordingly, raw
products of the above reaction containing these esters can be used
for coupling advantageously.
[0130] In the present step, reaction solvents are used preferably.
The kinds and the amount of solvent in the condensation reaction of
adipic acid diester and alkoxide are the same as those in the above
step (1-1).
[0131] Further, various conditions in the reaction of adipic acid
diester and alkoxide are also the same as those in the above step
(1-1). When alcohol remains after the reaction, the alcohol can be
distilled off later.
[0132] By the above reaction of adipic acid diester with alkoxide,
the above 2-(alkoxycarbonyl)cyclopentenolate anion can be obtained,
the latter of which is successively subjected to coupling with a
compound IV without isolation.
[0133] In this case, the by-product of alcohol is distilled off
from the viewpoint of accelerating reaction as above-mentioned.
However, the reaction mixture does not need to be completely free
from by-product of alcohol. The reaction mixture containing a
certain amount of alcohol as by-product can be fed into the next
step of coupling reaction without any treatment. The reaction
mixture containing unreacted substances can also be fed directly to
the coupling reaction.
[0134] Thus, a compound IV is added to the obtained reaction
mixture to carry out coupling reaction. The amount of compound IV
is 0.1 to 20 moles relative to 1 mole of adipic acid diester added
previously, preferably 0.5 to 2 moles, more preferably 0.7 to 1.5
moles.
[0135] The temperature of reaction is in the range of 0 to
150.degree. C., preferably 20 to 150.degree. C., more preferably
room temperature to 80.degree. C.
[0136] The time of reaction is 24 hours or less, preferably 0.1 to
20 hours, more preferably 1 to 10 hours.
[0137] Although coupling reaction can be carried out without
reaction solvent, solvents may be used. As to the solvents, the
kinds and the amount can be determined in the same way as in the
case of the coupling reaction of the above step (1-1).
[0138] After the reaction, residual base is neutralized with acid,
extraction and water washing are carried out, and then extraction
solvent is removed. When reaction solvent is water soluble, the
solvent is removed under reduced pressure. Then, extraction solvent
is added, extraction and water washing are carried out, and
extraction solvent is removed. It is not necessary to remove
completely the extraction solvents remaining after extraction, as
long as they do not influence the next step.
[0139] Compound II can be obtained according to the above method,
and it is used in the next step (2-2). Compound II can be refined
further by methods such as distillation and then supplied to step
(2-2), but the additional refining is not necessary.
[0140] In the obtained product, the compound as represented by the
formula VII is sometimes present in a trace. However, it is
converted finally into the intended compound III, therefore its
mixing does not cause any trouble. 14
[0141] wherein R" is hydrogen atom or an alkyl group having 4 or
less carbon atoms,
[0142] Step (2-2): [Carbonylation and Hydrolysis]
[0143] The present step can be carried out in the same way as the
above-mentioned step (1-3). That is, acid catalysts, solvents and
reaction conditions are all the same as those of the above.
EXAMPLE
[0144] In the following, the present invention will be described in
more detail referring to examples.
Example 1
[0145] [Step (1-1)]
[0146] Into a reaction vessel of 15 liters were put 7.2 liters of
toluene, 243 g (4.27 mol) of sodium methoxide (purity 95%) and 900
g (5.11 mol) of dimethyl adipate (purity 99%), and the mixture was
heated with stirring. After the temperature in the vessel reached
60.degree. C., removal of the solvent of toluene was started under
reduced pressure (9.3 kPa (70 mmHg) or less). At the same time, a
by-product of methanol was also distilled off. The reaction was
carried out for 40 minutes. As the result of measurement after the
reaction, the total volume of mixed solvents of toluene and
methanol was 6 liters. After that, 5.5 liters of acetone was added
to the mixture. Further, 612 g (3.81 mol) of chloromethylstyrene
(purity 95%; containing 500 ppm of nitrocresol, nitrophenol and
4-tert-butylcatechol in total; para-isomer:meta-isomer ratio=96:4)
was added at room temperature, then the mixture was heated with
refluxing for 8 hours.
[0147] At the temperature of 60.degree. C. in the vessel, acetone
started to be distilled off under reduced pressure. In the middle
of that, 2.5 liters of toluene was added. Distilled acetone
amounted to 5.5 liters in total.
[0148] To the reaction mixture was added 2.7 liters of water and
100 ml of concentrated hydrochloric acid, and extraction was
conducted by separation of liquids. Then, the organic phase was
washed twice with 1.8 liters of water.
[0149] With the removal of toluene under reduced pressure, 1,857.3
g of a liquid in pale yellow was obtained. The purity by gas
chromatography of compound I (R' in the general formula I=methyl
group (Me)) was 50.3% (para-isomer:meta-isomer ratio=96:4, toluene
40.6%).
[0150] Then, 100 mg of the obtained oily substance was treated with
thin layer chromatography (developing solvent:ethyl
acetate/hexane=30/70, Rf=0.75) to isolate 70 mg of para-isomer of
compound I (R'=Me) as a colorless, oily substance. The structure
was confirmed with the following spectroscopic data and mass
spectrum:
[0151] .sup.1H NMR (CDCl.sub.3, 400 MHz): .delta.1.62 (m, 1H),
1.82-2.10 (m, 3H), 2.33-2.45 (m, 2H), 3.10 (d, J=13.7 Hz, 1H), 3.19
(d, J=13.7 Hz, 1H), 3.72 (s, 3H), 5.22 (dd, J=10.8, 1.0 Hz, 1H),
5.71 (dd, J=17.6, 1.0 Hz, 1H), 6.67 (dd, J=17.6, 10.8 Hz, 1H), 7.08
(d, J=8.3 Hz, 2H), 7.30 (d, J=8.3 Hz, 2H).
[0152] .sup.13C NMR (CDCl.sub.3, 100 MHz): .delta.19.47, 31.69,
38.36, 38.85, 52.64, 61.48, 113.68, 126.23, 130.33, 136.17, 136.22,
136.67, 171.34, 214.74.
[0153] Mass spectrum: 258 (M.sup.+), 199, 198, 141, 128, 117
(100%), 115, 104, 91.
[0154] [Step (1-2)]
[0155] In an autoclave of 5 liters, 1.28 g (7.2 mmol) of PdCl.sub.2
and 0.89 g (15.2 mmol) of NaCl were dissolved in 93.0 g (2.90 mol)
of methanol, and 3.99 g (15.2 mmol) of PPh.sub.3 dissolved in 120 g
of toluene was added to the solution. To this mixture were added
186.0 g (5.81 mol) of methanol and 310 g of toluene. Then, 1,857 g
of the solution of compound I (R'=Me) synthesized in step (1-1) was
added successively with a pump over 18 hours at 90.degree. C. under
the pressure of 4.0 MPa of carbon monoxide, and further, reaction
was carried out for 3 hours. The above solution of compound I had
the purity of 50.3%, substantially 3.62 moles of compound I (R'=Me)
and para-isomer:meta-isomer ratio of 96:4, and had 1,000 ppm of
4-tert-butylcatechol added.
[0156] After the reaction, the reaction product was analyzed with
gas chromatography and gel permeation chromatography. As a result,
the conversion was 99.9% and the formation ratio of para-isomer of
compound II (R'=R"=Me) and para-isomer of compound VI (R'=R"=Me)
was 95:5.
[0157] The obtained mixture was subjected to vacuum flash
distillation to obtain 460.3 g of a liquid having the melting point
of 224.degree. C. (533 Pa (4 mmHg)). The purity of compound II
(R'=R"=Me) was 75.6% (para-isomer:meta-isomer ratio=96:4) by means
of gas chromatography.
[0158] [Step (1-3)]
[0159] In this step, 100.0 g of the compound II (R'=R"=Me) obtained
in step (1-2) was subjected to refluxing for 5 hours in a solution
containing 144 ml of acetic acid/96 ml of 25% aqueous sulfuric
acid. In the middle of the reaction, 72 ml of 33% aqueous solution
of acetic acid was added. The solvent was distilled off under
normal pressure to remove 190 ml of the solvent in total. The
contents were cooled, extracted with a solution containing 280 ml
of toluene/300 ml of water, and washed thrice with 100 ml of water
each time. The solvent was distilled off under reduced pressure to
obtain a yellow, oily substance.
[0160] The oily substance was recrystallized twice with a mixed
solvent of ethyl acetate/hexane to obtain 36.5 g of white,
crystalline loxoprofen. The purity by liquid chromatography was
99.9%. The NMR data and the retention time of liquid chromatography
coincided completely with those of specimen.
Example 2
[0161] [Step (2-1)]
[0162] Into a reaction vessel of 300 ml were put 65 ml of toluene,
2.2 g (0.039 mol) of sodium methoxide (purity 95%) and 8.0 g (0.046
mol) of dimethyl adipate (purity 95%), and the mixture was heated
with stirring, then the solvent was removed under reduced pressure.
After that, 50 ml of acetone was added, then 30 ml of a toluene
solution of methyl 2-(bromomethylphenyl)propionate (purity 92.7%;
prepared from 9.09 g of 2-(bromomethylphenyl)propionic acid (purity
99.25%) was added at room temperature, and the mixture was heated
with refluxing for 4 hours.
[0163] Acetone was distilled off under reduced pressure, then 50 ml
of toluene, 30 ml of water and 1 ml of concentrated hydrochloric
acid were added, and extraction was conducted by separation of
liquids. After the organic phase was washed twice with 30 ml of
water, filtration was carried out. With the removal of toluene
under reduced pressure, 12.9 g of compound II (R'=R"=Me) in pale
yellow was obtained as a raw product.
[0164] [Step (2-2)]
[0165] A solution containing 12 ml of acetic acid/18 ml of 25%
aqueous sulfuric acid was added to 12.9 g of compound II (R'=R"=Me)
obtained in step (2-1), and refluxing was conducted for 5 hours.
The solvent was distilled off under normal pressure, in the middle
of which 9 ml of 33% aqueous solution of acetic acid was added.
After the distilled solvent amounted to 19 ml, extraction was
carried out by separation with 50 ml of toluene and 30 ml of water,
and the organic phase was washed with 50 ml of water. With the
removal of the solvent under reduced pressure, 8.16 g of a yellow,
crystalline substance of raw loxoprofen was obtained.
[0166] The obtained raw loxoprofen was dissolved in a mixed solvent
of 10 ml of ethyl acetate/10 ml of hexane, then recrystallized at
0.degree. C. to obtain 4.92 g of a white, crystalline substance of
loxoprofen. The purity by liquid chromatography was 99%. The NMR
data and the retention time of liquid chromatography coincided
completely with those of specimen.
[0167] According to the present invention, an industrial process
can be provided which produces loxoprofen effectively using an
inexpensive starting material. That is, adipic acid diester is used
as a starting material, by which 2-substituted propionic acid can
be produced more effectively than with conventional methods.
Further, according to the present method, there is no need for
apprehension about side reaction and the yield is higher.
* * * * *