JP3258992B2 - Process for producing oxazolyl methanol compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a compound of the following formula [11] useful as a therapeutic agent for diabetes:

[0002]

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(Wherein, R is an optionally substituted aromatic hydrocarbon group, an optionally substituted cycloaliphatic hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted fused heterocyclic group. And a method for producing an intermediate for producing the compound [11].

[0004]

2. Description of the Related Art Compounds useful as therapeutic agents for diabetes [1]
1] and intermediates and methods for producing them have already been disclosed in International Publication No. WO95 / 18125, and the intermediate compound [6 ′]

[0005]

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[0006] A method for producing the same is also specifically disclosed (Journal of Medicinal Chemistry, 1992, Vol. 35, No. 1, 1992, 35, No. 14, p. 2625).
4,2625)).

However, in these conventional production methods, the yield of final products and their intermediates has not been sufficiently satisfactory due to many steps. Solvents, bases, catalysts, etc. used in each process can be used at the laboratory level, but when industrial production is considered, there are many difficult-to-use substances and lack in practicality. There was a point.

[0008]

SUMMARY OF THE INVENTION In order to solve the above problems, the present inventors have studied and improved each step in detail. Specifically, the most similar manufacturing method, Journal of Medicin
al Chemistry, 1992, Vol. 35, No. 14, 2625 (hereinafter referred to as "method A") were compared and studied in the first to fourth steps. For example, in the method A, the compound [6 ′] (R
Is a phenyl group).

[0009]

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Step 1 In method A, compound [1] is reacted with compound [2 '] in dichloromethane in the presence of triethylamine to obtain compound [3']. Here, when dichloromethane used as a solvent is used in a large amount, there is a problem that it is impractical in industrial production due to great restrictions on its drainage and the like. The present inventors have found that this reaction can be sufficiently performed by using a safe and inexpensive aqueous solvent (particularly water), and have solved this problem. Moreover,
More surprisingly, it was also found that the use of an inorganic base such as potassium carbonate or sodium carbonate as the base used at this time resulted in a yield of 92 to 97%. As a result, the yield was higher than that of the conventional method. Was increased by 10% or more.

Step 2 and Step 3 In the method A, the compound [3 '] is dissolved in 10 equivalents of
Compound [4 '] is obtained using dimethylaminopyridine in the presence of 7 equivalents of triethylamine. But,
In order to obtain the compound [4 '], a further post-treatment step was required, that is, post-treatment was required in which acetic anhydride was used as a solvent to obtain acetic acid while adding water, followed by isolation and purification. . This treatment step requires a long time, and there is a problem that a part of the obtained compound [4 '] is decomposed. The present inventors have intensively studied to improve the yield and to solve the problem of the post-treatment step. as a result,
The necessary amount of acetic anhydride (about 4 equivalents) is added in advance in the next step,
It was found that compound [4 '] was obtained by using dimethylaminopyridine in the presence of 0.25 equivalent of N-methylmorpholine in toluene solvent. Moreover,
The obtained compound [4 '] can be used as it is in the next step without isolation and purification. By cyclizing compound [4'] using p-toluenesulfonic acid monohydrate, And the compound [5 '] could be obtained in a high yield (95 to 97%). As a result, the yield of compound [5 '] was able to be increased by about 40% as compared with Method A. Also A
Oxychloride (POCl) used in the third step of the method
3) is a highly corrosive poison, its use is considerably restricted, and it is a major problem in terms of industrial use. The present inventors have found safety and ease of use by using p-toluenesulfonic acid monohydrate, and found a production method that can be used industrially.

[0012] to obtain compound [5 '] is the fourth step A method diethyl ether, compound by reaction with lithium aluminum hydride (LiAlH ₄₎ [6' a]. Both LiAlH ₄ and diethyl ether used here are highly ignitable, and have a problem in terms of safety when used industrially. The present inventors have solved this problem by using sodium borohydride (NaBH ₄ ) and tetrahydrofuran and methanol as an accelerator (activator) for reduction, whereby the compound [6 ′] can be industrially produced without any problem. The way to get it was established. Also surprisingly,
It has been found that by using the same method, not only the safety but also the yield becomes 85 to 95%, and the yield is improved as compared with the method A.

Next, from the compound [6 '] to the final compound [1
As the method most similar to the present method, the production method described in International Publication No. WO95 / 18125 (hereinafter referred to as "method B") can be mentioned. The present inventors have specifically studied the method B.

[0014]

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(Wherein R ¹ is a lower alkyl group)

Fifth Step In the method B, the compound [6 '] is treated with p-toluenesulfonyl chloride (TsC) in dichloromethane in the presence of pyridine.
Compound [7 '] is obtained by reacting with [1]. Here, as described in the first step of Method A, dichloromethane used as a solvent is subject to great restrictions on its drainage and the like when used in large quantities, and is not practical in industrial production. there were. The present inventors have found that the reaction can be sufficiently carried out in safe toluene, and have solved this problem. Further, in terms of yield, when the method B is used, in addition to the target compound [7 '], the compound [1]
5]

[0017]

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It was also found that the yield of the desired compound [7 '] was reduced by-product at the same time. In order to solve this problem, a method which is generally disclosed in the specification of International Publication No. WO95 / 18125 but not disclosed as a specific example has been adopted. Specifically, a mesyl group was used instead of a tosyl group as a leaving group. That is, TsC
Methanesulfonyl chloride (MsCl) instead of l
Is reacted with the compound [6 ′] to surprisingly obtain a target compound [7 ″] in a yield of 99 to 100%.

[0019]

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Was obtained.

Steps 6 and 7 In method B, 4-hydroxybenzaldehyde [12] is reacted with compound [7 '] to give compound [13].
Further, the compound [13] is reacted with a malonic acid derivative [14] to obtain a compound [9 ']. In this step,
Since the compound [13] was slightly unstable, the yield of [9 '] from the compound [7'] was 65%, which was not satisfactory. In order to increase the yield, the present inventors have previously prepared compound [8] from compound [12] and compound [14].

[0022]

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(Wherein R ¹ is the same as described above), and the compound [7 ′] is reacted with the compound [7 ′] to obtain the compound [9 ′] in high yield (80-85%). Was found to be.

Steps 8 and 9 In the method B, the compound [9 '] is reduced under a hydrogen atmosphere using a catalyst to give the compound [10'], and the compound [10 '] is further dissolved in anhydrous alcohol. To give the final target compound [1
1 ']. Also in this step, the yield of the final compound (about 40%) was not yet satisfactory. In order to increase the yield, the present inventors did not isolate the compound [10 '], and prepared a hydroxyl group in a mixed solvent of tetrahydrofuran, water and alcohol in the presence of a base (potassium carbonate, sodium carbonate or sodium methoxide). It was found that the target compound [11 '] was obtained in good yield (80%) by reacting with an amine. In addition, the above is from compound [6 '] to compound [1].
Although the method for producing 1 ′] has been described, it goes without saying that compound [6 ′] is also useful for producing compound [16] as described below, for example.

[0025]

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(Where X is an oxygen atom or a sulfur atom)

[0027]

Means for Solving the Problems The present inventor described above,
For the purpose of improving the yield of the target compound and establishing a method that can be industrially produced, the problems in each step were examined in detail, and the solvents, bases, catalysts, etc. used in each step were determined as described above. By the selection, the target compound can be obtained in good yield, and a production method that is industrially practical has been found, and the present invention has been completed. That is, the present invention is as shown in the following (1) to (7).

(1) Compound [1]

[0029]

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Or a salt thereof in an aqueous solvent in the presence of an inorganic base, represented by the general formula [2]:

[0031]

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(Wherein R is an optionally substituted aromatic hydrocarbon group, an optionally substituted cycloaliphatic hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted fused heterocyclic group. A compound represented by the general formula [3]:

[0033]

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Wherein R is the same as defined above, which is reacted with acetic anhydride in the presence of a base using dimethylaminopyridine as a catalyst, and then heated. Decarboxylation by the general formula [4]

[0035]

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(Wherein R is as defined above), followed by adding p-toluenesulfonic acid without isolation of the compound to obtain a compound of the general formula [5]

[0037]

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(Wherein R is as defined above), which is prepared in tetrahydrofuran in the presence of NaBH ₄ as a reducing agent and methanol as an activating agent. Reduce to the general formula [6]

[0039]

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(Wherein R is as defined above), which is reacted with mesyl chloride in toluene in the presence of triethylamine as a base catalyst. General formula [7]

[0041]

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(Wherein R is as defined above), which is converted to potassium carbonate and a quaternary ammonium salt or tris [2- (2-methoxyethoxy) ethyl] as a catalyst. Formula [8] in the presence of an amine

[0043]

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(Wherein R ¹ is a lower alkyl group) to give a compound of the general formula

[9]

[0045]

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(Wherein R and R ¹ are the same as described above)
Is reduced under a hydrogen atmosphere to obtain a benzylidene derivative represented by the general formula [10]:

[0047]

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(Wherein R and R ¹ are the same as described above)
A malonic acid derivative represented by the general formula [11], which is further reacted with hydroxylamine in the presence of a base.

[0049]

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(Wherein R is as defined above) or a method for producing an isoxazolidinedione compound or a salt thereof.

(2) Compound [1]

[0052]

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Or a salt thereof in an aqueous solvent in the presence of an inorganic base, represented by the general formula [2]:

[0054]

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(Wherein R is the same as defined in the above (1)) to give a compound of the general formula [3]

[0056]

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(Wherein R is the same as defined above), which is reacted with acetic anhydride in the presence of a base using dimethylaminopyridine as a catalyst, and then heated. Decarboxylation by the general formula [4]

[0058]

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(Wherein R is as defined above), followed by adding p-toluenesulfonic acid without isolation of the compound to obtain a compound of the general formula [5]

[0060]

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(Wherein R is the same as defined above), which is further treated in tetrahydrofuran in the presence of NaBH ₄ as a reducing agent and methanol as an activating agent. General formula [6] characterized by being reduced to

[0062]

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Wherein R is the same as defined above, or a salt thereof.

(3) Compound [1]

[0065]

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Or a salt thereof in an aqueous solvent in the presence of an inorganic base by the general formula [2]

[0067]

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(Wherein R is the same as defined in the above (1)) to give a compound of the general formula [3]

[0069]

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(Wherein R is as defined above) or a method for producing an aspartic acid ester derivative or a salt thereof.

(4) General formula [3]

[0072]

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(Wherein R is the same as in (1)). The aspartate derivative represented by the formula (1) is reacted with acetic anhydride in the presence of a base using dimethylaminopyridine as a catalyst, followed by heating to remove the aspartic acid ester derivative. Carbonated, general formula [4]

[0074]

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(Wherein R is as defined above), followed by adding p-toluenesulfonic acid without isolation of the compound to obtain a compound of the general formula [5]

[0076]

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(Wherein R is as defined above) or a method for producing the oxazolyl acetate derivative or a salt thereof.

(5) General formula [5]

[0079]

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Wherein the oxazolyl acetate derivative represented by the formula (1) is reduced in tetrahydrofuran in the presence of NaBH ₄ as a reducing agent and methanol as an activating agent. By doing, the general formula [6]

[0081]

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(Wherein R is as defined above) or a method for producing the oxazolylethanol derivative or a salt thereof.

(6) General formula [6]

[0084]

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(Wherein R is the same as in (1)), by reacting the oxazolylethanol derivative with mesyl chloride in toluene in the presence of triethylamine as a base catalyst to obtain a compound represented by the general formula [ 7]

[0086]

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(Wherein R is as defined above) or a method for producing a methanesulfonate derivative or a salt thereof.

(7) General formula [7]

[0089]

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(Wherein R is the same as defined in (1)), by adding potassium carbonate and a quaternary ammonium salt or tris [2-
(2-methoxyethoxy) ethyl] amine in the presence of
General formula [8]

[0091]

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(Wherein R ¹ is the same as defined in (1)).

[9]

[0093]

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(Wherein R and R ¹ are the same as described above)
A method for producing a benzylidene derivative or a salt thereof represented by the formula: Next, terms used in this specification will be described.

"Aromatic hydrocarbon group" means a phenyl group,
It means a biphenylyl group, a naphthyl group or the like, but may be an aralkyl group such as a benzyl group. Preferably it is a phenyl group.

The "cycloaliphatic hydrocarbon group" means a cycloaliphatic hydrocarbon group having 3 to 7 carbon atoms, specifically, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group. , Cycloheptyl group, cyclopropenyl group, cyclobutenyl group, cyclobutadienyl group,
A cyclopentenyl group, a cyclopentadienyl group, a cyclohexenyl group, a cyclohexadienyl group, a cycloheptenyl group, a cycloheptadienyl group and the like, preferably a cycloaliphatic hydrocarbon group having 5 to 7 carbon atoms. Specifically, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclopentenyl group, a cyclopentadienyl group, a cyclohexenyl group, a cyclohexadienyl group,
A cycloheptenyl group, a cycloheptadienyl group,
Particularly preferred are a cyclopentyl group and a cyclohexyl group.

The term "heterocyclic group" refers to a ring containing 5 to 3 or more, preferably 1 or 2, hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms. A 6-membered heterocycle, preferably an aromatic heterocycle, specifically, a thienyl group, a furyl group, a pyrrolyl group,
Imidazolyl group, pyrazolyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, oxadiazolyl group, thiadiazolyl group, triazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, triazinyl group, dithiazolyl group, dioxolanyl group, dithiolyl group , Pyrrolidinyl group, dithiadiazinyl group, thiadiazinyl group, morpholinyl group, oxazinyl group, thiazinyl group, piperazinyl group, piperidinyl group, pyranyl group, thiopyranyl group, preferably thienyl group, furyl group, pyrrolyl group, imidazolyl group, pyridyl group, It is a pyrimidinyl group, particularly preferably a pyridyl group, a pyrimidinyl group or an imidazolyl group.

The term "condensed heterocyclic group" refers to a ring containing 1 to 3, preferably 1 or 2 hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms. Or a 6-membered heterocyclic ring, preferably a ring in which aromatic heterocyclic rings are fused together, or a heterocyclic ring, preferably an aromatic heterocyclic ring, and a 4- to 6-membered aromatic hydrocarbon ring, preferably a benzene ring, condensed Ring, specifically, furisoxazolyl group, imidazothiazolyl group, thienoisothiazolyl group, thienothiazolyl group, imidazopyrazolyl group, cyclopentapyrazolyl group, pyrrolopyrrolyl group, cyclopentathienyl group, thienothienyl group , Oxadiazolopyrazinyl group, benzofurazanyl group, thiadiazolopyridinyl group, triazolothiazinyl group, triazolopyrimidinyl group, Azolopyridinyl, benzotriazolyl, oxazolopyrimidinyl, oxazolopyridinyl, benzoxazolyl, thiazolopyridazinyl, thiazolopyrimidinyl, benzoisothiazolyl, benzothiazolyl, pyra Zolotriazinyl group, pyrazolothiazinyl group, imidazopyrazinyl group, purinyl group, pyrazolopyridazinyl group, pyrazolopyrimidinyl group, imidazopyridinyl group, pyranopyrazolyl group, benzimidazolyl group, indazolyl Group, benzooxathiolyl group, benzodioxalyl group, dithiolopyrimidinyl group, benzodithiolyl group, indolizinyl group, indolyl group, isoindolyl group, flopyrimidinyl group, flopyridinyl group, benzofuranyl group, isobenzofuranyl group, thienopyrazinyl group, thienopyrimidyl group Nyl, thienodioxynyl, thienopyridinyl, benzothienyl, isobenzothienyl, cyclopentaoxazinyl, cyclopentafuranyl, benzothiadiazinyl, benzotriazinyl, pyridoxazinyl Benzoxazinyl group, pyrimidothiazinyl group, benzothiazinyl group, pyrimidopyridazinyl group, pyrimidopyrimidinyl group, pyridopyridazinyl group, pyridopyrimidinyl group, cinnolinyl group, quinazolinyl group, Quinoxalinyl group, benzoxathynyl group, benzodioxinyl group,
A benzodithiynyl group, a naphthyridinyl group, an isoquinolyl group, a quinolyl group, a benzopyranyl group, a benzothiopyranyl group, a chromanyl group, an isochromanyl group, an indolinyl group, and the like, preferably a benzooxazolyl group, a benzoisothiazolyl group, a benzothiazolyl group, a benzimidazolyl group. , Indazolyl group, benzooxathiolyl group,
Benzodioxolyl, benzodithiolyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzothiadiazinyl, benzotriazinyl,
Benzoxazinyl group, benzothiazinyl group, cinnolinyl group, quinazolinyl group, quinoxalinyl group, benzoxathinyl group, benzodioxinyl group, benzodithiynyl group, isoquinolyl group, quinolyl group, benzopyranyl group, benzothiopyranyl group, chromanyl Group, isochromanyl group and indolinyl group, particularly preferably indolyl group, isoindolyl group, benzofuranyl group, isobenzofuranyl group, benzothienyl group, isobenzothienyl group, isoquinolyl group and quinolyl group.

"Lower alkyl group" means an alkyl group having 1 to 6 carbon atoms which may be branched, and specifically, a methyl group, an ethyl group, a propyl group, an isopropyl group,
Butyl group, isoptyl group, sec-butyl group, tert
-Butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, hexyl group, isohexyl group, 3,3-dimethylbutyl group, 2,2-dimethylbutyl group and the like, preferably having 1 to 1 carbon atoms. Four alkyl groups, specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec
-Butyl group and tert-butyl group, and particularly preferably a methyl group.

The expression "may be substituted" means that the substituent may be substituted with 1 to 3 substituents, which may be the same or different. Specifically, lower alkyl groups such as methyl group, ethyl group, propyl group, butyl group and tert-butyl group; lower alkoxy groups such as methoxy group, ethoxy group, propoxy group, butoxy group and tert-butoxy group; halogen atom A nitro group; a cyano group; a hydroxyl group;
Acyl groups (eg, formyl group, acetyl group, propionyl group, butyryl group, lower alkanoyl group such as isobutyryl group, or benzoyl group, aroyl group such as naphthoyl group, etc.); formyloxy group, acetyloxy group, propionyloxy group, Acyloxy groups such as butyryloxy group, isobutyryloxy group and benzoyloxy group (the acyl part is the same as above); aralkyloxy groups such as benzyloxy group, phenethyloxy group and phenylpropyloxy group; mercapto group; methylthio group and ethylthio Group, propylthio group, butylthio group, isobutylthio group, ter
alkylthio group such as t-butylthio group; amino group; lower alkylamino group such as methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group; dimethylamino group, diethylamino group, dipropylamino group; Di-lower alkylamino groups such as diisopropylamino group and dibutylamino group; carboxy group; lower alkoxycarbonyl groups such as methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group and tert-butoxycarbonyl group. Acylamino group (acyl moiety is the same as above); trifluoromethyl group; phosphoryl group; sulfonyl group; sulfonyloxy group; carbamoyl group; sulfamoyl group; methylphosphonamide group, ethylphosphonamide group; Methylenedioxy group; methoxy phosphoryl group, propyl phosphonic amide group, a lower alkyl phosphonic amide group such as isopropyl phosphonic amide group
Lower alkoxyphosphoryl groups such as ethoxyphosphoryl group, propoxyphosphoryl group, isopropoxyphosphoryl group; lower alkylsulfonyl groups such as methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, butylsulfonyl group, tert-butylsulfonyl group; methylsulfonylamino Group, ethylsulfonylamino group, propylsulfonylamino group, butylsulfonylamino group,
a lower alkylsulfonylamino group such as a tert-butylsulfonylamino group, preferably a hydroxyl group, a lower alkyl group, a lower alkoxy group, an aralkyloxy group,
Mercapto group, lower alkylthio group, nitro group, halogen atom, trifluoromethyl group, amino group, di-lower alkylamino group, lower alkylamino group, acyl group, cyano group, carbamoyl group, acyloxy group, sulfonyl group, carboxy group, It is a lower alkoxycarbonyl group, particularly preferably a hydroxyl group, a lower alkyl group or a lower alkoxy group. Here, the term “lower” means that the number of carbon atoms is preferably 1
The number is preferably from 6 to 6, more preferably from 1 to 4.

General formulas [3], [5] to [7],

The salt of the compound represented by [9] or [11] refers to the above general formulas [3], [5] to [7],

Any compound that forms a nontoxic salt with the compound represented by [9] or [11] may be used, for example, an alkali metal salt such as a sodium salt and a potassium salt; a magnesium salt and a calcium salt; Alkaline earth metal salts; ammonium salts; organic base salts such as trimethylamine salts, triethylamine salts, pyridine salts, picoline salts, dicyclohexylamine salts, N, N'-dibenzylethylenediamine salts; amino acid salts such as lysine salts and arginine salts. Can be mentioned.

The salt of compound [1] may be any salt, for example, an inorganic acid addition salt such as hydrochloride, sulfate, phosphate, hydrobromide; oxalic acid, malonic acid, citric acid Organic acid addition salts such as acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, ascorbic acid, methanesulfonic acid and benzylsulfonic acid; alkali metal salts such as sodium flame and potassium salt; magnesium salt and calcium salt Alkaline earth metal salts such as; ammonium salts; trimethylamine salts, triethylamine salts, pyridine salts, picoline salts,
Organic base salts such as dicyclohexylamine salt and N, N'-dibenzylethylenediamine salt are exemplified.

Next, the method for producing the compound [11] and the intermediate compound will be described in detail.

[0104]

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(Wherein, R and R ¹ are the same as described above)

[0106]

[General Production Method] Step 1 Compound [3] can be obtained by reacting compound [1] or a salt thereof with compound [2] in an aqueous solvent in the presence of an inorganic base. The aqueous solvent used for the reaction is specifically water, but a polar solvent such as methanol, ethanol, or acetic acid may be mixed with the aqueous solvent in an amount that does not hinder the reaction. Examples of the inorganic base include potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, and the like, and preferably potassium carbonate. The reaction temperature is -20C to 50C, preferably 0C to 30C. The reaction time is 2 to 24 hours, preferably 2 to 5 hours.

Second Step The compound [4] can be obtained by reacting the compound [3] with acetic anhydride in an organic solvent in the presence of a base using a catalyst and further heating. Without isolating the obtained compound, the compound [5] can be obtained by subsequently cyclizing it by adding an acid such as p-toluenesulfonic acid. Preferably, toluene can be used as the organic solvent used in the reaction. Here, in order to carry out the next reaction without isolating the compound [4], acetic anhydride in an amount necessary for the next reaction, preferably about 4 equivalents, is used in advance. Examples of the base include tertiary amines, preferably N-methylmorpholine or pyridine, and more preferably N-methylmorpholine. The base can suitably be used in an amount of 0.25 to 1.0 equivalent. Dimethylaminopyridine is preferred as the catalyst. Also,
The acid necessary for obtaining [5] from compound [4] includes p
-Toluenesulfonic acid monohydrate is preferred. The heating temperature during decarboxylation is 40 ° C to 70 ° C, preferably 55 ° C to 60 ° C.
° C. The reaction time for decarboxylation is 4 to 48 hours, preferably 4 to 24 hours. The reaction temperature of the reduction reaction is 7
0 ° C to 100 ° C, preferably 85 ° C to 90 ° C. The reaction time of the reduction reaction is 2 to 24 hours, preferably 4 hours.
~ 6 hours.

Step 3 Compound [6] can be obtained by reducing compound [5] in a solvent using a reducing agent. At this time, the reaction can proceed smoothly by using the activator of the reducing agent. Tetrahydrofuran is preferred as the solvent used in the reaction. As the reducing agent, sodium borohydride (NaBH ₄ ) is preferable. As the activator of the reducing agent, methyl alcohol is preferable. The reaction temperature is 30 ° C to 100 ° C, preferably 40 ° C to 80 ° C. The reaction time is 1 to 10 hours, preferably 1 to 2 hours.
Time.

Fourth Step Compound [7] can be obtained by reacting compound [6] with methanesulfonyl chloride (mesyl chloride) in a solvent in the presence of a base. Examples of the solvent used for the reaction include an organic solvent such as toluene or dichloromethane, and toluene is preferable. Examples of the base include tertiary amines, preferably triethylamine or N-methylmorpholine, and particularly preferably triethylamine. Reaction temperature is 0 ° C
To 100 ° C, preferably 0 ° C to 50 ° C. The reaction time is 0.5 to 24 hours, preferably 1 to 10 hours.

Step 5 Compound [7] is reacted with compound [8] using a catalyst in the presence of a base in a solvent to give compound [7].

[9] can be obtained. As a solvent used for the reaction, toluene is preferable. Preferred as the base is potassium carbonate. As the catalyst, a quaternary ammonium salt such as tetrabutylammonium bromide, tetramethylammonium bromide, tetraethylammonium bromide, tetraethylammonium chloride, benzyltrimethylammonium chloride, benzyltriethylammonium chloride, benzyltriethylammonium bromide, or tris [2- (2- Methoxyethoxy)
[Ethyl] amine. Preferred is tetramethylammonium bromide or tris [2- (2-methoxyethoxy) ethyl] amine. Reaction temperature is 0 ° C. to 150
° C, preferably 10 ° C to 120 ° C. Reaction time is 5
２４24 hours, preferably 6-10 hours.

Step 6 Compound

Compound [10] can be obtained by reducing [9] in a solvent using a reducing catalyst under a hydrogen atmosphere. Subsequently, the compound [11] can be obtained by reacting with hydroxylamine in a solvent in the presence of a base under cooling to warming without isolation.
Solvents used in the reaction include methanol, ethanol, propanol, isopropanol, tetrahydrofuran,
Organic solvents such as dioxane, dichloromethane, acetic acid and the like or a mixed solvent thereof. Preferred is tetrahydrofuran. Examples of the reduction catalyst include palladium carbon and palladium black, and preferably palladium carbon. The reaction time of the reduction reaction is 4 to 24 hours, preferably 6 to 24 hours.
10 hours. As a solvent in the reaction of the compound [10] to the compound [11], methanol, ethanol,
It is propanol, isopropanol, tetrahydrofuran, dioxane, dichloromethane, acetic acid, water or the like, or a mixed solvent thereof. Preferred is a mixed solution of methanol, tetrahydrofuran and water. The base is potassium carbonate, sodium carbonate, sodium methoxide or sodium ethoxide. Preferably, it is potassium carbonate. The reaction temperature is 0 ° C to 50 ° C, preferably 20 ° C to 30 ° C. The reaction time is 4 to 24 hours, preferably 6 to 10 hours.

[0112]

Example 1 N-benzoyl-L-aspartic acid-β-methyl ester (Production of compound [3] (R = phenyl group)) L-aspartic acid-β-methyl ester hydrochloride (compound [1] 183.6 g) was dissolved in water (800 mL). The solution was cooled to 5 ° C. while stirring, and a solution of sodium carbonate (265 g) in water (1 L) was added. Benzoyl chloride (121.9 mL) was added to the reaction solution.
Was added at 5 ° C. over 1 hour and 20 minutes. 10 to 18
After stirring at 2 ° C. for 2 hours, water (1.2 L) was added to the reaction solution to form a uniform solution. Here dichloromethane (0.5
L) was added and the mixture was separated, and the organic layer was removed. Concentrated hydrochloric acid was added to the aqueous layer to adjust the pH to 2, and ethyl acetate (1.5 L) was added for extraction. The aqueous layer was further extracted with ethyl acetate (0.5 L), and the organic layers were combined. The organic layer was sequentially washed with water (1 L) and saturated saline (1 L), and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to about half the volume,
The precipitated crystals were collected by filtration. The filtrate was further concentrated under reduced pressure to about half the volume, and the precipitated crystals were collected by filtration. The obtained crystals were dried to give the title compound (Compound [3]; 229.9 g, yield 91.5%). mp.124-125 ° C 1H-NMR (300MHz, DMSO-d6, TMS) δ 2.80 (1H, dd, J = 16.2, 8.1Hz), 2.94 (1H, dd, J =
16.2, 6.3Hz), 3.61 (3H, s), 4.79 (1H, m), 7.45-7.
58 (3H, m), 7.83 to 7.86 (2H, m), 8.77 (1H, d, J = 7.8
Hz), 12.82 (1H, br-s) FAB-MS: 252.1 (M + H) +

Example 2 Methyl 2- (5-methyl-2-phenyl-4-oxazolyl) acetate (compound [5] (R = phenyl group)
Production of N-benzoyl-L-aspartic acid-β-methyl ester obtained in Example 1 (compound [3]; 229.9)
g) in toluene (1.2 L) and acetic anhydride (346 m
L), N-methylmorpholine (4.7 mL) and 4-dimethylaminopyridine (1.04 g) were sequentially added, and the mixture was stirred at an internal temperature of 55 to 60 ° C. for 4 hours, and methyl 3-benzoylamino-4-oxopentane was added. Noart (compound [4])
A toluene solution of was obtained. Subsequently, without isolating compound [4], methyl 3-benzoylamino-4
-To a solution of oxopentanoate in toluene was added p-toluenesulfonic acid monohydrate (31.8 g),
After stirring at 0 ° C. for 5 hours, the mixture was cooled to room temperature. While stirring the reaction solution, sodium carbonate (75.6 g) was added to water (303 m).
The aqueous solution dissolved in L) was added to adjust the pH to 7 to 7.5. After standing, the aqueous layer was removed, the organic layer was concentrated, and the title compound (compound [5]; 206.7 g, yield 97.7%)
I got

Example 3 2- (5-methyl-2-phenyl-4-oxazolyl)
Ethanol (Production of compound [6] (R = phenyl group)) Methyl 2- (5-methyl-2-phenyl-4-oxazolyl) acetate (Compound [5]; 170 g) obtained in Example 2 was added to tetrahydrofuran ( 935m
L), and sodium borohydride (27.81 g) was added thereto at room temperature. This suspension was heated and stirred at 60 ° C., and methyl alcohol (57.9 mL) was added dropwise thereto over 1 hour. After the dropwise addition, the mixture was cooled to room temperature, and water (3
(5 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction solution was filtered to remove solid components. This solid component was washed with tetrahydrofuran, and the washing was combined with the previous filtrate and concentrated under reduced pressure. Ethyl acetate (1 L) was added to the residue, and after dissolution,
Water (1 L) was added and the mixture was separated. The aqueous layer was extracted again with ethyl acetate (0.5 L), and the organic layers were combined, washed successively with saturated aqueous sodium bicarbonate (1 L) and saturated brine (1 L), and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude crystal (compound [6]; 149 g). This was recrystallized from a mixed solvent of n-hexane (1 L) and ethyl acetate (0.2 L) to give the title compound (Compound [6];
g, yield 89.7%). mp.73.0〜73.8 ℃ 1H-NMR (300MHz, CDCl3, TMS) δ 2.34 (3H, s), 2.72 (2H, t, J = 5.4Hz), 3.27 (1H,
br-s), 3.92 (2H, t, J = 5.4Hz), 7.38 to 7.47 (3H, m),
7.95 to 7.99 (2H, m) IR (KBr): 3294, 1647, 1556, 1447, 1338, 1056, 77
8, 715, 691 cm-1 FAB-MS: 204.1 (M + H) +

Example 4 2- (5-methyl-2-phenyl-4-oxazolyl)
Ethyl methanesulfonate (Production of compound [7] (R = phenyl group)) 2- (5-methyl-2-phenyl- obtained in Example 3
4-oxazolyl) ethanol (compound [6]; 10
8.6 g) was dissolved in toluene (600 mL), methanesulfonyl chloride (45.4 mL) was added, and the mixture was stirred under ice-cooling. To this solution was added triethylamine (8
(1.7 mL) was added dropwise. After stirring for 1 hour, toluene (1
L), 1N hydrochloric acid (1 L) was added, and the mixture was separated. The aqueous layer was extracted again with toluene (0.5 L). The combined organic layers were sequentially washed with water (1 L), saturated aqueous sodium bicarbonate (1 L), and saturated saline (1 L), and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure to give the title compound (compound [7]; 150 g, yield 100%) as crystals. mp.88.2 ~ 89.0 ℃ 1H-NMR (300MHz, CDCl3, TMS) δ 2.36 (3H, s), 2.96 (3H, s), 2.96 (2H, t, J = 6.6
Hz), 4.53 (2H, t, J = 6.6Hz), 7.39 to 7.47 (3H, m), 7.
94〜7.99 (2H, m) IR (KBr): 1637, 1340, 1160, 981, 961, 869, 692 cm
-1 FAB-MS: 282.1 (M + H) +

Production Example 1 2- (4-hydroxybenzylidene) malonic acid dimethyl ester (Production of compound [8]) 4-Hydroxybenzaldehyde (280.9 g), dimethyl malonate (289.2 mL) and toluene (1.1)
Acetic acid (13.2 mL) and piperidine (11.4 mL) were sequentially added to the mixture (2 mL). Next, internal temperature 70 ° C
After dehydrating and refluxing at ~ 75 ° C for about 4 hours, the internal temperature is 10 ° C.
It was cooled below and stirring was continued for another hour. The precipitated crystals were collected by filtration and washed with toluene (350 mL) to give the title compound (compound [8]; 523.7 g, yield 96.4%). mp. 157.4-158.0 ° C 1H-NMR (300MHz, CDCl3, TMS) δ 3.84 (3H, s), 3.87 (3H, s), 5.71 (1H, m),
6.81 to 6.84 (2H, m), 7.26 to 7.34 (2H, m), 7.70 (1H
, s) IR (KBr): 3340, 1740, 1670, 1320, 1070,840 cm-1

Example 5 Dimethyl [4- [2- (5-methyl-2-phenyl-
4-oxazolyl) ethoxy] benzylidene] malonate (compound

[9] (R = phenyl group, R ¹ = methyl group)
Production of 2- (5-methyl-2-phenyl-) obtained in Example 4.
4-oxazoyl) ethyl methanesulfonate (compound [7]; 24.4 g) and 2- (4
-Hydroxybenzylidene) malonic acid dimethyl ester (compound [8]; 20.5 g) was added to tetrabutylammonium bromide (1.4 g) and toluene (210 m2).
L), heated to 90 ° C. and dissolved by heating. Then, potassium carbonate (13.2 g) was added, and the mixture was stirred at 110 ° C for 6 hours. The reaction solution was cooled on ice and water (210 mL)
Was added and stirred. After standing, the aqueous layer was removed, and a 10% aqueous solution of sodium chloride (210 mL) was added to the organic layer with stirring, and the mixture was left standing to remove the aqueous layer. The organic layer was concentrated, and the concentrated residue was dissolved by heating in methanol (150 mL), then cooled to 10 ° C. or lower and stirred for 1 hour. The obtained crystals were collected by filtration and washed with methanol (65 mL) to give the title compound (compound

[9]; 31.1 g, yield 85.0%). mp. 104.0 ~ 105.0 ℃ 1H-NMR (300MHz, CDCl3, TMS) δ 2.37 (3H, s), 2.99 (2H, t, J = 6.7Hz), 3.82 (3
H, s), 3.85 (3H, s), 4.28 (2H, t, J = 6.7Hz), 6.89
(2H, d, J = 6.8Hz), 7.35 to 7.43 (5H, m), 7.70 (1H,
s), 7.97 (2H, m) IR (KBr): 1729, 1706, 1606, 1252, 1066 cm-1 FAB-MS: (M + H) +

Example 6 4- [4- [2- (5-Methyl-2-phenyl-4-oxazolyl) ethoxy] benzyl] -3,5-isoxazolidinedione (Compound [11] (R = phenyl group)
Production of dimethyl [4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] benzylidene] malonate (compound

[9]; 2.5 g)
Dissolve in tetrahydrofuran (20 ml) and add 5% Pd-
C, 150 mg was added, and the mixture was vigorously stirred under a hydrogen atmosphere at normal temperature and normal pressure. After 8 hours, the catalyst was removed by filtration, and hydroxylamine (360 mg), methanol (4 ml) and potassium carbonate (574 mg) were added to the filtrate, and water (4 m
l) was added dropwise and stirred at room temperature for 6 hours. Evaporate the solvent,
1N HCl aqueous solution (50 ml) was added to the residue to make it acidic. After extracting twice with ether, drying over magnesium sulfate and distilling off the solvent, the obtained solid was repeatedly recrystallized twice from methanol to give the title compound (compound [11];
(50 mg, 80%).

[0119]

As is apparent from the above, according to the method of the present invention, the general formula [11] which is extremely efficient as compared with the conventional method, and which is useful as a therapeutic drug for diabetes at a high yield.
And its intermediate compounds can be produced. Further, the production method of the present invention is a highly practical and industrially very useful production method.

──────────────────────────────────────────────────続 き Continuation of the front page (56) References International Publication 95/18125 (WO, A1) , Et al. , Synthesis and Hydrolipidic Activities of 5-Thienyl-4 -oxazoleacetic Acid Derivatives, J. et al. Med. Chem. , Vol. 29, pp. 333-341 (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 263/00-263/62 A61K 31/00-31/80 A61P 1/00-43/00 C07D 413 / 00-413/14 CA (STN) REGISTRY (STN) WPI (DIALOG) CASREACT (STN)

Claims (1)

(57) [Claims] 1. A compound of the general formula [5] (In the formula, R is an optionally substituted aromatic hydrocarbon group, an optionally substituted cycloaliphatic hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted fused heterocyclic group. Is reduced in a tetrahydrofuran solvent in the presence of NaBH4 as a reducing agent and methanol as an activator,
General formula [6] Wherein R is the same as defined above, or a method for producing an oxazolylmethanol derivative or a salt thereof.