JP2001226322A - Method for 2-substituted propionic acid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a 2-substituted propionic acid by converting a halomethyl styrene into a styrene derivative, by which the 2-substituted propionic acid can effectively be produced and which can reduce the self polymerization of the styrene compound on a carbonylation process. SOLUTION: This method for producing the 2-substituted propionic acid (loxoprofen) of the general formula III, characterized by (1) reacting an adipic acid dieter with an alkoxide; M(OR)n (R is a <=5C alkyl; M is an alkali metal or an alkaline earth metal), coupling the reaction product with a halomethylstyene, (2) reacting the obtained intermediate with water or an alcohol in the presence of a metal catalyst to produce the compound of the general formula (II) (R' is a <=4C alkyl; R" is H or a <=4C alkyl; R' and R" may be the same or different), and then (3) subjecting the produced compound of the general formula (II) to decarbonation and hydrolysis reactions.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a 2-substituted propionic acid having an action such as anti-inflammatory, analgesic and antipyretic.

[0002]

BACKGROUND OF THE INVENTION 2-Substituted propionic acids are disclosed in
It exhibits anti-inflammatory, analgesic and antipyretic effects as seen in US Pat. Particularly, 2- [4- (2-oxocyclopentan-1-ylmethyl) phenyl] propionic acid (so-called loxoprofen) is commercially available as an excellent analgesic, and various production methods have been conventionally developed. For example, WO 97/47581 proposes a method for producing loxoprofen via carbonylation of p-chloromethylstyrene in the presence of a transition metal complex catalyst. The method utilizing this carbonylation reaction is industrially advantageous because a substituted styrene structure can be easily converted to a substituted propionate structure.

[0003] However, p-chloromethylstyrene has a chloromethyl group substituted on the benzene ring,
High polymerization activity due to heat, light, pressure, etc. Particularly in carbonylation in the presence of a transition metal complex catalyst, p
-Chloromethylstyrene is easy to polymerize. This means that a polymerization inhibitor is often added to commercially available p-chloromethylstyrene, and the International Publication, page 6, states that a polymerization inhibitor may be added during carbonylation. It is also understood by. Since p-chloromethylstyrene is easily self-polymerized,
According to the international publication, in addition to the addition of a polymerization inhibitor during the carbonylation reaction as described above, in the examples of carbonylation, each is several times the volume ratio of p-chloromethylstyrene as a substrate. It is necessary to use from 10 to several times, and in many cases ten and several times, the solvent. However, it is industrially disadvantageous to use a large amount of solvent as described above for the substrate p-chloromethylstyrene.

[0004] As described above, the method described in the above-mentioned International Publication in which a highly reactive vinyl group is reacted in the first step of a plurality of steps to convert it into another substituent having lower reactivity is disclosed in the above-mentioned International Publication. It is not necessarily rational on an industrial scale because the reactivity is not sufficiently considered. Further, the method described in the above-mentioned International Publication is not inexpensive in that an expensive cyclopetenone carboxylic acid alkyl ester is used as a starting material, and the yield is not always satisfactory. As described above, an optimal method for producing loxoprofen has not yet been found,
There is a need for more efficient methods.

[0005]

SUMMARY OF THE INVENTION The present invention provides a method for converting halomethylstyrene into another styrene derivative.
It is an object of the present invention to provide a method for producing a 2-substituted propionic acid which is less efficient than the conventional method by reducing the self-polymerization property in the subsequent carbonylation.

[0006]

The method of the present invention comprises the steps of (i)
Coupling of the first adipic diester with the reaction product
-Polymerization activity of halomethylstyrene in the aging reaction
And (ii) the resulting halome
The styrene derivative in which the tyl group is substituted with a specific substituent
It is based on the finding that self-polymerization is also low.
You. This allows particularly large amounts of solvent in the carbonylation
Eliminates the need for more efficient 2-substituted propion than conventional methods
It has become possible to produce acids. A cheaper starting point
To produce 2-substituted propionic acid efficiently from raw materials
it can. That is, the first aspect of the present invention is that
Is converted to an alkoxide M (OR) represented by the following formula:_n  (Wherein, R is an alkyl group having 5 or less carbon atoms, M is
Li metal or alkaline earth metal, n is the valence of M
The corresponding numbers are indicated. And n (OR) are the same
May also be different. ), And then
By coupling with styrene, the following general
Formula (I)

Embedded image (Wherein R ′ represents an alkyl group having 4 or less carbon atoms) (hereinafter referred to as “compound (I)”), and then compound (I) is added in the presence of a metal catalyst. By reacting with carbon monoxide and water or alcohol, the following general formula (II)

Embedded image (In the formula, R ′ represents an alkyl group having 4 or less carbon atoms, R ″ represents a hydrogen atom or an alkyl group having 4 or less carbon atoms. R ′ and R ″ may be the same or different.) (Hereinafter, referred to as “compound (II)”).

A second aspect of the present invention is the following steps (1) to (3):
Wherein the following general formula [III]

Embedded image2-substituted propionic acid (hereinafter referred to as “compound
(III))). Step (1): Adipic acid diester is represented by the following formula
Alkoxide M (OR)_n  (Wherein, R is an alkyl group having 5 or less carbon atoms, M is
Li metal or alkaline earth metal, n is the valence of M
The corresponding numbers are indicated. And n (OR) are the same
May also be different. ), And then
By coupling with styrene, the following general
Formula (I)

Embedded image (Wherein, R ′ represents an alkyl group having 4 or less carbon atoms). Step (2): The above compound (I) is treated with carbon monoxide in the presence of a metal catalyst. And by reacting with water or alcohol, the following general formula (II)

Embedded image (In the formula, R ′ represents an alkyl group having 4 or less carbon atoms, R ″ represents a hydrogen atom or an alkyl group having 4 or less carbon atoms. R ′ and R ″ may be the same or different.) Step of obtaining (II), and Step (3): step of obtaining compound (III) by performing decarboxylation and hydrolysis of compound (II).

A third aspect of the present invention is the first or second aspect of the present invention.
Wherein the adipic acid diester is dimethyl adipate or diethyl adipate.
A fourth aspect of the present invention relates to the method according to any one of the first to third aspects, wherein the halomethylstyrene is chloromethylstyrene. The fifth aspect of the present invention is the first aspect of the present invention.
To the fourth, the alkoxide M (O
R) _n relates to a production process wherein _n is sodium methoxide or sodium ethoxide.

According to the method of the present invention, by converting the halomethyl group of halomethylstyrene to a specific substituent to reduce the self-polymerization property of the vinyl group, carbonylation does not require a particularly large amount of solvent, Further, 2-substituted propionic acid can be efficiently produced from inexpensive raw materials.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION In the method of the present invention, starting from adipic diester, step (1): [coupling reaction], step (2): [carbonylation], and step (3):
[Decarboxylation / hydrolysis]. Hereinafter, each step will be sequentially described. Step (1): [Coupling] In the step (1), the cyclopentanone carboxylate anion is generated by Deckman condensation of dimethyl adipate and the alkoxide M (OR) _n, and then the cyclopentanone carboxylate is produced. Compound (I) is obtained by coupling halomethylstyrene to the rate anion. In this step, a cyclopentanone carboxylate anion is generated in the middle, and the coupling reaction is continuously performed with halomethylstyrene without isolation. Although both components are unsaturated compounds, the carbon-carbon double bond of halomethylstyrene is advantageous because it is almost inert in this reaction. The cyclopentanone carboxylate anion is
Since it is not isolated as an ester or an acid, the reaction operation is simple, and the yield is improved as compared with the case of isolation.

As the adipic acid diester, dialkyl adipate is preferable. Specific examples of the alkyl group of the above ester include Me (methyl), Et (ethyl), n-Pr (propyl), iso-Pr, n- 4 carbon atoms such as Bu (butyl), iso-Bu, sec-Bu or tert-Bu
The following are exemplified. The two alkyl groups of the dialkyl adipate may be the same or different. Me, Et, n- which are preferably the same alkyl group
It is a compound having Pr or iso-Pr, and more preferably a dialkyl adipate having an alkyl group of Me or Et, such as dimethyl adipate and diethyl adipate.

As the alkoxide M (OR) _n , commercially available general ones can be used. The alkali metal or alkaline earth metal M is specifically sodium,
Potassium, lithium, calcium or magnesium. R is Me, Et, n-Pr, iso-Pr, n-B
Examples thereof include alkyl groups having 5 or less carbon atoms, such as u, iso-Bu, sec-Bu, tert-Bu, 1-pentyl, 2-pentyl, 3-pentyl, neopentyl, and tert-amyl. n is a number corresponding to the valence of M, and n (OR) s may be the same or different. Preferably, they have the same alkoxy group, and R is an alkyl group such as Me, Et, n-Pr, iso-Pr.

Specific examples of the alkoxide include 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 i
so-butoxide, sodium iso-butoxide, potassium i
so-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
Butoxide, potassium tert-butoxide, calcium ter
t-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 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 the like. Particularly preferred 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.

As the halomethylstyrene, a styrene having a fluoro-, chloro-, bromo- or iodomethyl group is used, preferably chloro or bromomethylstyrene, more preferably chloromethylstyrene. Particularly preferred is p-chloromethylstyrene.

In this step, a reaction solvent is preferably used. A different reaction solvent may be used depending on the type of adipic acid diester. In the first condensation reaction, one equivalent of alcohol is by-produced, but the reaction proceeds by continuously or intermittently removing the alcohol from the reaction system,
The cyclopentanone carboxylate anion is formed. Therefore, an operation for selectively removing the generated alcohol is indispensable for promoting the reaction. As a removal operation, a method of distilling off by heating under normal pressure or reduced pressure is simple. Therefore, when a reaction solvent is used, it is necessary that the boiling point of the solvent is equal to or higher than the boiling point of the generated alcohol.

For example, when dimethyl adipate is used as the adipic acid diester, a solvent having a boiling point higher than that of methanol (about 65 ° C.) is used. Examples of such a solvent include nitrogen-containing compound solvents such as dimethylformamide and acetonitrile; ethers and acetal solvents such as tetrahydrofuran; ketone solvents such as acetone and methyl ethyl ketone; ester solvents such as ethyl acetate; benzene, toluene; Examples thereof include aromatic hydrocarbon solvents such as xylene; aliphatic hydrocarbon solvents such as octane, nonane, decane, and isododecane; and mixed solvents thereof. Of these, toluene and benzene are preferred, and toluene is more preferred. When an adipic acid diester other than dimethyl adipate is used, a solvent according to the above can be used. The amount of the reaction solvent is, for example, 5 mol per mol of adipic acid diester.
00-5,000 ml can be used. Preferably from 800 to 3,000 ml, especially from 1,000 to 2,000 ml.
0 ml.

The above M (OR) _n and adipic acid diester are preferably used in a solvent at 0 to 300 ° C., preferably 10 to 250 ° C., more preferably 20 to 200 ° C.
Within 24 hours, preferably within 6 hours, at a temperature range of
The reaction is more preferably performed within one hour. During the reaction,
The alcohol formed is distilled off under normal pressure or under reduced pressure. In order to completely remove the alcohol, it is preferable to partially remove the reaction solvent. When the reaction solvent is distilled off, a new solvent can be added. When reacting with an adipic ester, the alkoxide can be used, for example, as a dry, preferably finely divided solid, or as an alcoholic solution in which the alkoxide is dissolved. Preferably, an alcohol solution of an alkoxide is used, the alcohol being distilled off before the reaction with the adipic ester has substantially started. By performing in this manner, a suspension in which the alkoxide is finely dispersed in the reaction mixture is formed, so that good results can be obtained.

Regarding the amount of alkoxide to be used, for example, 0.1 to 10 equivalents of alkoxide can be used per 1 mol of adipic acid diester. Here, 1 mol of alkoxide in which M is an alkali metal corresponds to 1 equivalent, and 1 mol of alkoxide in which M is an alkaline earth metal corresponds to 2 equivalents. Preferably adipic acid diester 1
It is preferred to use from 0.5 to 2 equivalents of alkoxide per mole, especially from 0.95 to 1.05 equivalents of alkoxide.

If alcohol remains after the reaction, the alcohol can be distilled off. The cyclopentanone carboxylate anion is obtained by the reaction of the above-mentioned adipic acid diester. The cyclopentanone carboxylate anion is successively reacted with halomethylstyrene without isolation, and the coupling reaction is carried out. The by-product alcohol is distilled off from the viewpoint of accelerating the reaction as described above, but it is not necessary to completely remove the by-product alcohol from the reaction mixture after the reaction, and the reaction containing a certain amount of by-product alcohol is not necessary. Even a mixture can be directly used for the next coupling reaction. Further, even if unreacted substances coexist, it is rather convenient for the next coupling reaction. Therefore, the mixture after the reaction including the unreacted substances and the like can be continuously subjected to the coupling reaction.

That is, a coupling reaction is carried out by adding halomethylstyrene to the obtained reaction mixture. The amount of halomethylstyrene is 0.1 to 20 equivalents, preferably, 20 equivalents to the previously added adipic diester. It is 0.5 to 2 equivalents, more preferably 0.7 to 1.5 equivalents. The reaction temperature ranges from 0 to 150 ° C, preferably from 20 to 150 ° C, more preferably from room temperature to 80 ° C. The reaction time is 24 hours or less, preferably 0.1 to 20 hours, more preferably 1 to 10 hours.

The coupling reaction can be carried out in the absence of a reaction solvent, but a solvent can also be used. Examples of such a reaction solvent include, as described above, nitrogen-containing compound solvents such as dimethylformamide and acetonitrile; ethers and acetal solvents such as tetrahydrofuran; ketone solvents such as acetone and methyl ethyl ketone;
Ester solvents such as ethyl acetate; benzene, toluene,
Examples thereof include aromatic hydrocarbon solvents such as xylene; aliphatic hydrocarbon solvents such as octane, nonane, decane, and isododecane; and mixed solvents thereof. Of these, ketone solvents are preferred, and acetone is more preferred. The solvent can be used in an amount of, for example, 500 to 5,000 ml based on 1 mol of the adipic acid diester introduced earlier. Preferably 800-3,000m
l, especially 1,000 to 2,000 ml.

After the reaction, the remaining base is neutralized with an acid, followed by extraction and washing with water to remove the extraction solvent. When a reaction solvent which is easily soluble in water is used, the solvent is removed under reduced pressure, then an extraction solvent is added, extraction and washing are performed, and the extraction solvent is removed. As the extraction solvent, an appropriate solvent can be used, but usually, water is used. It is not always necessary to remove all the extraction solvent remaining after the extraction as long as it does not affect the next step, and it can be used as a diluting solvent in the next step (2).

Compound (I) can be obtained by the above-mentioned method, and this is used in the next carbonylation step (2). In addition, after further refine | purifying by distillation or other methods, it can also be provided to process (2), but does not need to specifically purify. The product obtained has the general formula (IV)

Embedded image (Hereinafter, referred to as “compound (IV)”)
Although trace amounts may be produced, they eventually become the target compound (III), so that they may be mixed.

The halomethylstyrene used in the step (1) has a property of self-polymerization. In particular, when the heating and pressurizing system is used, self-polymerization tends to be further accelerated.
For this reason, when carbonylating halomethylstyrene as it is, it is necessary to dilute the reaction system using a large amount of solvent as described above, but this involves an industrially large economic burden. However, the compound (I) obtained by coupling halomethylstyrene with cyclopentanone carboxylate has a property that self-polymerization is difficult, and as shown in the examples of the present invention, the compound (I)
The diluting solvent used in the carbonylation of is a small amount of several times or less with respect to the substrate. In the method of the present invention, a by-product of a self-polymerized product of halomethylstyrene is small, which is preferable in terms of waste treatment. Therefore, the method of the present invention is more efficient than the conventional method comprising (i) carbonylation of p-chloromethylstyrene, (ii) coupling with cyclopentanone carboxylate, and (iii) decarboxylation / hydrolysis. It is much better in that respect.

Step (2): [Carbonylation] In this step (2), the compound (I) obtained in the above step (1) is treated with a polymerization inhibitor in the presence of a catalyst and a diluting solvent, if necessary. In addition, the compound (II) is obtained by reacting with carbon monoxide and water or an alcohol. The catalyst used in this step includes (i) the metal complex itself, (i)
(i) one consisting of a metal complex and a ligand; and (iii) one consisting of a metal complex and a ligand and an additive. When the catalyst of (ii) or (iii) is used, a method of generating catalytic activity by mixing a metal complex or a metal complex and an additive with an alcohol used for the reaction and then adding a ligand is used. desirable.

As the metal complex, a transition metal complex, preferably
Or a Group VIII transition metal complex, more preferably cobalt,
Rhodium, platinum or palladium complexes are used. Ingredient
As an example, Co₂(CO)₈, RhCl (PPh₃)₃(P
h represents a phenyl group), RhCl (CO) (PPh₃)₂,
H₂PtCl₆, Pd carbon, Pd black, Pd (PPh
₃)₄, Pd (PPhBu₂)₂, Pd (PBu₃)₂, Pd (P
(OPh)₃)₄, Pd (P (OEt)₃)₄, Pd (C₂H₄) (P
Ph₃)₂, Pd (PhCN)₂(BF₄)₂, Pd (MeCN)₄
(BF₄)₂, Pd (PhCN)₂(PPh₃)₂(BF₄)₂,
Pd (MeCN)₂(PPh₃)₂(BF₄)₂, Pd (acac)
₂(Acac represents an acetylacetonate group), Pd₂(db
a)₃CHCl₃, Pd (dba)₂(The above is dba dibenzylide
Represents acetone), PdO, PdS, Pd (N
O₃)₂, PdSO₄, PdX₂(X is Cl, Br, I, O
COCF₃Or OCOMe), PdX₂(PhC
N)₂, PdX₂(MeCN)₂, PdX₂(CO)₂(that's all,
X represents Cl, Br or I), Pd (COD)₂, Pd
X₂(COD)₂(X is Cl, Br or I, CO is
D represents 1,5-cyclooctadiene), Pd (MA)
(PPh₃)₂(MA represents maleic anhydride), M₂
PdX₄(X is Cl, Br, I or OCOMe, M is
H, NH₄, Li, Na or K), PdX₂(P
ArAr'Ar ")₂(X represents Cl, Br or I, Ar, A
r 'and Ar "represent the same or different aryl groups),
PdX₂(PPh₃)₂, PdX₂(PRPh₂)₂, PdX
₂(PR₂Ph)₂, PdX ₂(PR₃)₂, Pd₂X₄(PR
₃)₂(X is Cl, Br or I, R is Me, E
t, Pr, Bu, OPh, menthyl group or cyclohexyl
Represents a group), PdX₂(dppf) (X is Cl, Br or I
And dppf stands for bis (diphenylphosphino) ferrocene.
I say), PdX₂(Ph₂P (CH₂)_nPPh₂) (X is C
l, Br or I, n represents an integer of 1 to 4), P
dR₂(PR '₃)₂(R and R 'are Me, Et, Pr, B
u, OPh or Ph), PdXR (PR ′₃)
₂(X is Cl, Br or I, R is H, Me, Et, P
r, Bu, Ph, CH₂Ph or COMe, R 'is Me,
Et, Pr, Bu, OPh, Ph or cyclohexyl groups
), [Pd (η³-CH₂CHCH₂) X]₂, [Pd
(η³-CH₂CHCH₂) X (PPh₃)], [Pd (η³-C
H₂CHCHCH₂X) X]₂(X is Cl, Br or
Represents I), Pd (η³-CH₂CHCH₂)₂, Pd
(η³-CH₂CHCH₂) (η⁵-C₅H₅)
However, the present invention is not limited to these. Metal complex
The amount to be used is 1 equivalent or less, preferably 0.1 equivalent, relative to compound (I).
00001 to 0.1 equivalent, more preferably 0.0001
~ 0.01 equivalents.

The ligand is a coordinating compound, preferably a phosphine or phosphite compound, more preferably a triarylphosphine. As a specific example, PPh ₃ , PArAr′Ar ″ (Ar, Ar ′,
Ar ″ represents the same or different aryl groups), PR
_{Ph 2, PR 2 Ph, PR} 3 ( or more, R represents Me, Et, n-
Pr, iso-Pr, n- Bu, represents a menthyl group or a cyclohexyl _{group), Ph 2 P (CH 2} ) n PPh 2 (n is 1 to
4), bis (diphenylphosphino) ferrocene, P (OPh) _{3 and the} like, but are not limited thereto. The amount of the ligand to be used is 10 equivalents or less, preferably 5 equivalents or less, more preferably 2 to 4 equivalents to 1 equivalent of the metal complex.

As the additive, an inorganic substance is used, preferably tin chloride, copper oxide, an alkali metal or alkaline earth metal salt, and more preferably an alkali metal salt. Specific examples include SnCl ₂ , CuCl ₂ , MgCl ₂ , and CaCl ₂ .
₂ , NaCl, NaBr, LiCl, LiBr, KCl, KBr, etc., but are not limited thereto.
The additive may be a Bronsted acid or a Lewis acid, depending on the metal complex used. The Brönsted acid is preferably one in which the counter anion is weakly coordinated with the metal atom or not at all. Specific examples include, but are not limited to, paratoluenesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, HBF ₄ , HBAr ₄ (Ar represents an aryl group), HPF _{6 and the} like. Para-toluenesulfonic acid is particularly preferred in terms of ease of handling.

As the Lewis acid, a general Lewis acid can be used.
But compounds containing B, Al, Ti, Zn, Sn, Sb, etc.
Are preferred, and compounds containing B, Al, Ti and the like are further preferred.
preferable. What binds to these elements is alkoxy
Group, halogen, oxygen, hydrogen, etc.
Logens are preferred. Specific examples of Lewis acids include TiX
₄, BX₃, AlX₃, ZnX₂, SnX₄, SbX₅(After
X above represents a halogen atom), Ti (OR)_nX
_4-n(R represents a methyl group, an ethyl group, an isopropyl group,
X represents a halogen atom, and n represents 1 to 4
Represents an integer), TiH_nCl_4-n(N is an integer from 1 to 3
Represents a number), Al (OR)₃, Zn (OR)₂(R is
Tyl group, ethyl group, isopropyl group), TiO
₂, Al₂O₃, ZnO₂, SnO₂, Sb₂O₅Etc.
However, the present invention is not limited to these. these
Is difficult to handle on its own,
Water, ether, alcohol, ester, carboxylic acid, T
HF (THF represents tetrahydrofuran)
It is preferable to use it as a complex. Specifically, B
F₃・ OEt ₂, BF₃・ OH₂, BF₃・ (THF)₂, T
iCl₄・ (THF)₂, AlCl₃・ (H ₂O)_nIs an example
It is. The amount of the additive used is 20 per equivalent of the metal complex.
Equivalent or less, preferably 0.1 to 10 equivalents, more preferably
Or 1 to 4 equivalents.

As the diluting solvent, commercially available organic solvents can be used. Specific examples include, but are not limited to, benzene, toluene, xylene, tetrahydrofuran, acetone, methyl ethyl ketone, ethyl acetate, and the like. The amount of the diluting solvent to be used is 20 times or less, preferably 10 times or less, more preferably 0.5 to 3 times, by volume, relative to compound (I).

As the polymerization inhibitor, a compound which does not hinder the carbonylation and the subsequent reaction can be used. Specifically, nitromethane, nitrobenzene, _{hydroquinone, CuCl 2, FeCl 2, 4} -tert- butylcatechol, nitrophenol, nitro cresol, 2,6
-Di-tert-butyl-4-methylphenol, 4-methoxyphenol and the like, but are not particularly limited. Further, two or more kinds of optional polymerization inhibitors may be used as a mixture. The amount of the polymerization inhibitor to be added is 10% or less, preferably 1% or less, more preferably 0.1% or less, based on the weight of the compound (I).

As carbon monoxide, one having a purity of 20% or more, preferably 50% or more, more preferably 80% or more is used. The amount of carbon monoxide is prepared so that it can be supplied in an amount of 1 equivalent or more based on the compound (I). When hydrogen coexists with carbon monoxide, the partial pressure of carbon monoxide decreases in accordance with the amount of coexisting hydrogen, which is affected, but the reaction in this step does not hinder any problem. proceed.

As the alcohol, methyl alcohol,
Ethyl alcohol, n-propyl alcohol, iso-propyl alcohol, n-butyl alcohol, sec-butyl alcohol, tert-butyl alcohol and iso-butyl alcohol are used, preferably methyl alcohol, ethyl alcohol, n-propyl alcohol or
iso-Propyl alcohol, more preferably methyl alcohol or ethyl alcohol. The amount of the alcohol to be used is 1 equivalent or more, preferably 1 to 30 equivalents, more preferably 1 to 3 equivalents, relative to compound (I).

The above-mentioned catalyst, compound (I), water or alcohol, and a diluting solvent are charged into an autoclave, and carbon monoxide is added at a reaction temperature of 40 to 200 ° C., preferably 50 to 140 ° C., more preferably 70 to 100 ° C. Is pressurized to 0.1 to 30 MPa, preferably 0.2 to 10 MPa, more preferably 2.5 to 7 MPa, and 0.1 to 100 MPa.
Time, preferably 6 to 30 hours, more preferably 8 to
Stir for 24 hours. Alternatively, the reaction may be carried out by mixing a catalyst, an alcohol and a diluting solvent in an autoclave, and then sequentially adding the compound (I) to the reaction system under the above conditions. In this case, compound (I) was used for 0.1 to 100 hours,
A method of supplying over 5 to 20 hours, more preferably 7 to 20 hours is desirable. After the completion of the reaction, carbon monoxide is removed and the state is set to normal temperature and normal pressure. If the catalyst has precipitated in the reaction mixture, it can be recovered by filtration and reused. After appropriately filtering the catalyst, high-purity compound (II) can be obtained by distillation under reduced pressure. Particularly, the mixture of the m-form and the p-form of the compound (II) has a difference in boiling point, and therefore, it is possible to separate them by precision distillation. As a result, a p-form which is a loxoprofen precursor is obtained with high purity.

In the carbonylation reaction performed in this step, the chloromethyl group of halomethylstyrene, for example, chloromethylstyrene, is substituted with a specific substituent even at a relatively high temperature and despite the presence of a metal catalyst. As a result, the polymerization activity of the vinyl group is suppressed, and as a result, a highly efficient reaction is achieved. In the present carbonylation reaction, the compound represented by the general formula [V] which is an isomer of compound (II)

Embedded image (Wherein, R ′ represents an alkyl group having 4 or less carbon atoms, and R ″ represents a hydrogen atom or an alkyl group having 4 or less carbon atoms) (hereinafter, referred to as “compound (V)”). . Also, a compound of the general formula [VI] in which the compound (IV) is carbonylated

Embedded image (R represents a hydrogen atom or an alkyl group having a carbon number of 4 or less), etc., but is ultimately converted into the target compound (III). Absent.

Step (3): [Decarboxylation / Hydrolysis] In this step, hydrolysis and decarboxylation are carried out using an acid such as sulfuric acid or hydrochloric acid, for example, according to the method described in the aforementioned International Publication. In addition, the compound (II) obtained in the above step (2)
Can be heated together with water and an acid in the presence of a solvent to progress the decarboxylation and hydrolysis stepwise to obtain compound (III). The decarboxylation / hydrolysis in this step is carried out with the compound (I
Even when I) has two ester groups, it is advantageous because both can be treated simultaneously. That is, it is possible to hydrolyze and decarboxylate the ester group of the compound (1) before the carbonylation reaction in the step (2). Even when it has two ester groups as in (II), both can be treated simultaneously. As the acid, a commercially available mineral acid can be used. Specific examples include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and the like. As the solvent, a hydrophilic organic solvent is preferable. When the reaction is performed in the presence of a hydrophilic organic solvent,
This is preferable because the reaction time can be shortened. Specific examples of the hydrophilic organic solvent include tetrahydrofuran,
Examples include, but are not limited to, ethyl acetate, acetonitrile, acetic acid, and the like. Acetic acid is particularly preferred. The amount of the acid to be used is 20 times or less, preferably 0.001 to 10 times, more preferably 0.001 to 5 times, by weight, relative to compound (II). The hydrophilic organic solvent is used at a weight ratio of 20 times or less, preferably 0.5 to 10 times, more preferably 1 to 5 times, relative to the compound (II).

As described above, the acid, the solvent and the compound (II) are charged into the reaction vessel, and the reaction is carried out at room temperature to 150 ° C., preferably 50 ° C.
° C to 120 ° C, more preferably 90 ° C to 110 ° C
In 1 to 100 hours, preferably 2 to 24 hours,
More preferably, stirring is performed for 6 to 12 hours. During the heating and stirring, the reaction time is shortened by removing the alcohol by-produced from the system using a Dean-Stark apparatus or the like. After the reaction, the crude compound (III) is extracted by extracting with a lipophilic organic solvent such as toluene and removing the solvent.
Is obtained. Further, by recrystallization using a good solvent such as ether and a poor solvent such as hexane, a highly pure compound (III) can be obtained.

[0038]

The present invention will be described in more detail with reference to the following examples. <Example 1> [Step (1)] Toluene was placed in a 15-liter reactor.
2 liters, sodium methoxide (purity 95%) 24
3 g (4.27 mol), dimethyl adipate (purity 9
(9%) 900 g (5.11 mol) was charged and heated with stirring. After the temperature in the vessel reached 60 ° C., the removal of the toluene solvent was started under reduced pressure (70 mmHg or less). At this time, by-product methanol was also distilled off at the same time. The reaction was carried out for 40 minutes and weighed after the completion of the reaction. The total amount of the mixed solvent of toluene and methanol was 6 liters. Thereafter, 5.5 liters of acetone was added, and chloromethylstyrene (purity: 95%; nitrocresol, nitrophenol and 4-tert-butylcatechol were contained in the mixture at a total of 500 ppm);
6: 4) 612 g (3.81 mol) was added at room temperature to give 8
The mixture was heated under reflux for an hour. At an internal temperature of 60 ° C., acetone distillation was started under reduced pressure. In the middle 2.5 l of toluene were added. A total of 5.5 liters of acetone was distilled off. 2.7 l of water and 100 ml of concentrated hydrochloric acid were added to the reaction mixture to carry out liquid separation extraction, and the organic layer was washed twice with 1.8 l of water. The toluene was removed under reduced pressure to obtain 1,857.3 g of a pale yellow liquid. The gas chromatographic purity of the compound (I) (compound of the general formula [I] where R '= Me) was 50.3% (para-meta-form ratio = 96: 4, toluene 40.6%). .

The obtained oily substance (100 mg) was treated by thin layer chromatography (developing solvent: ethyl acetate / hexane = 30/70, Rf = 0.75) to obtain a colorless oily compound (I). 70 mg of the para-form of (compound of the general formula [I] where R '= Me) was isolated. The structure was confirmed by the following spectroscopic data and mass spectrum: ¹ H NMR (CDCl ₃ , 400 MHz): δ 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, 1
H), 5.71 (dd, J = 17.6, 1.0 Hz, 1H),
6.67 (dd, J = 17.6, 10.8 Hz, 1H), 7.0
8 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.3 H)
z, 2H). ¹³ C NMR (CDCl ₃ , 100 MHz): δ 19.
47, 31.69, 38.36, 38.85, 52.6
4, 61.48, 113.68, 126.23, 130.3
3, 136.17, 136.22, 136.67, 171.
34, 214.74. Mass spectrum: 258 (M ⁺ ), 199, 198, 1
41, 128, 117 (100%), 115, 104,
91.

[Step (2)] In a 5-liter autoclave, 1.28 g (7.2 mmol) of PdCl ₂ and NaC
10.89 g (15.2 mmol) of methanol 93.0
g (2.90 mol), and toluene 120
dissolved PPh ₃ 3.99 g of (15.2 mmol) was added to g. To this mixture was added 186.0 g of methanol (5.8 g).
1 mol) and 310 g of toluene, and the temperature was 90 ° C.
Step (1) under a pressure of 4.0 MPa of carbon monoxide
(I) (in the general formula [I], R ′ = M
1,857 g (purity: 50.3%; substantial molar amount of compound (I) (compound of general formula [I], R '= Me) 3.62 mol, para: meta ratio = 96 :
(4,4-tert-butylcatechol added at 1,000 ppm)) was sequentially added by a pump over 18 hours, and the reaction was further performed for 3 hours. After completion of the reaction, the reaction product was analyzed by gas chromatography and gel permeation chromatography. As a result, the reaction rate was 99.9%.
Met. Compound (II) (in the general formula [II], R ′ =
The formation ratio between the para-form of R ″ = Me and the para-form of compound (V) (compound of general formula [V], R ′ = R ″ = Me) was 95: 5. The obtained mixture was subjected to vacuum flash distillation, and the boiling point was 224 ° C. (667 Pa, 4 mmH
460.3 g of liquid g) were obtained. The gas chromatographic purity of the compound (II) (compound of the general formula [II] where R ′ = R ″ = Me) is 75.6% (para-meta-form ratio =
96: 4).

[Step (3)] 100.0 g of the compound (II) obtained in the step (2) (compound of the general formula [II] in which R ′ = R ″ = Me) was added to 144 ml of acetic acid / 9% aqueous 25% sulfuric acid.
Reflux in 6 ml for 5 hours. During the reaction,
72 ml of 33% acetic acid aqueous solution was added. The solvent was distilled off at normal pressure, and a total of 190 ml of the solvent was removed. The content was cooled, extracted with 280 ml of toluene / 300 ml of water, and washed three times with 100 ml of water. The solvent was distilled off under reduced pressure to obtain a yellow oily substance. This oily substance was recrystallized twice with a mixed solvent of ethyl acetate / hexane to obtain 36.5 g of loxoprofen as white crystals. Its liquid chromatography purity was 99.9%. The NMR data of the obtained loxoprofen and the retention time of liquid chromatography were completely consistent with those of the standard.

[0042]

Industrial Applicability The present invention can provide an industrial production method for efficiently obtaining loxoprofen from inexpensive starting materials.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (reference) // C07B 61/00 300 C07B 61/00 300 C07C 67/32 C07C 67/32 67/343 67 / 343F Term (reference) 4H006 AA02 AB21 AC21 AC48 BA02 BA05 BA06 BA11 BA20 BA23 BA24 BA25 BA26 BA40 BA45 BA46 BA48 BE40 BE60 BJ20 BJ50 BR70 BS10 KA60 4H039 CA66 CF10

Claims (5)

[Claims] An adipic acid diester represented by the following formula:
Alkoxide M (OR)_n (Where R is 5 or less carbon atoms)
And M is an alkali metal or alkaline earth
A metal and n is a number corresponding to the valence of M.
The n (OR) s may be the same or different. ) And anti
After reaction, the halomethylstyrene and
The following general formula [I](Wherein R ′ represents an alkyl group having 4 or less carbon atoms).
The compound represented (hereinafter, referred to as “compound (I)”)
And then compound (I) is reacted with monoacid in the presence of a metal catalyst.
Reaction with carbonized water and water or alcohol
And the following general formula [II](Wherein R ′ represents an alkyl group having 4 or less carbon atoms, and R ″ represents water
Represents an atom or an alkyl group having 4 or less carbon atoms. R 'and
R ″ may be the same or different.)
(Hereinafter referred to as “compound (II)”).
For producing compound (II). 2. The method comprising the following steps (1) to (3):
A 2-substituted compound represented by the following general formula [III]:
Production of ropionic acid (hereinafter referred to as "compound [III]")
Method,Step (1): Adipic acid diester is represented by the following formula
Alkoxide M (OR)_n  (Wherein, R is an alkyl group having 5 or less carbon atoms, M is
Li metal or alkaline earth metal, n is the valence of M
The corresponding numbers are indicated. And n (OR) are the same
May also be different. ), And then
By coupling with styrene, the following general
Formula [I](Wherein R ′ represents an alkyl group having 4 or less carbon atoms).
Step of obtaining a compound (I) represented by the following step: Step (2): The above compound (I) is reacted in the presence of a metal catalyst.
Reacting with carbon monoxide and water or alcohol
By the following general formula [II](Wherein R ′ represents an alkyl group having 4 or less carbon atoms, and R ″ represents water
Represents an atom or an alkyl group having 4 or less carbon atoms. R 'and
R ″ may be the same or different.)
Step of obtaining (II), and Step (3): decarboxylation and hydrolysis of compound (II)
To obtain a compound (III). 3. The method according to claim 1, wherein the diester adipate is dimethyl adipate or diethyl adipate. 4. The method according to claim 1, wherein the halomethylstyrene is chloromethylstyrene. 5. The method according to claim 1, wherein said alkoxide M (OR) _n is sodium methoxide or sodium ethoxide.