JP3445191B2 - Method for producing oxazole compound - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to the following general formula [7] having a selective inhibitory action on cyclooxygenase-2 (COX-2).

[0002]

[Chemical 16]

(Wherein R ¹ is an optionally substituted cycloalkyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group, and R ² is a lower alkyl group or a halogenated lower alkyl group. And R ³ is a halogen atom or a hydrogen atom). The present invention also relates to a method for producing an intermediate for producing the compound represented by the above general formula [7].

[0004]

PRIOR ART Cyclooxygenase-2 (COX-
The compound [7] which selectively inhibits 2) is, for example,
It is useful as an anti-inflammatory agent. The method for producing the compound [7] has already been specifically disclosed in WO96 / 19463. However, the conventional production method has not been sufficiently satisfactory in terms of yields of final products and their intermediates due to many processing steps. In addition, reagents, solvents, etc. used in each step can be used at the laboratory level, but when industrial production is considered, there are some substances that are difficult to use and lack practicality. .

[0005]

DISCLOSURE OF THE INVENTION The present inventor has studied and improved each step in detail in order to solve the above problems. Specifically, a comparison was made with the most similar manufacturing method described in WO96 / 19463 (hereinafter referred to as "method A"). For example, in method A, compound [7 ′], which is one of the target compounds of the present invention, is produced through the following first to fourth steps.

[0006]

[Chemical 17]

In the first step, Method A, compound [1 '] is reacted with ethyl chlorocarbonate in ethyl acetate in the presence of triethylamine to give compound [2']. In this step, when ethyl chlorocarbonate is used as a reagent, ethanol is produced as a by-product, which decomposes the compound [2 ']. Therefore, after the cyclization reaction, which is the main reaction, a complicated post-treatment process such as desalting filtration and concentration was required. There is a problem that the yield of the compound [2 ′] is lowered due to such complicated post-treatment process and formation of by-products. In order to solve this problem, the present inventors examined the use of inexpensive thionyl chloride instead of ethyl chlorocarbonate. As a result, it was found that, by using thionyl chloride, surprisingly, the above-mentioned complicated post-treatment step is not required and by-products are not produced, and the yield can be improved. It was also found that the unstable compound [2 ′] can be directly used in the next step without isolation and purification. With these, the yield could be increased.

In the second step A, the compound [2 '] is reacted with the compound [3'] in the suspension of magnesium chloride in tetrahydrofuran in the presence of triethylamine to obtain the compound [4 ']. . Tetrahydrofuran, which is used as a reagent and a solvent in this step, was not the optimum solvent in terms of cost when used in large quantities in industrial production. Therefore, the present inventors have studied a solvent that is inexpensive and suitable for industrial production, and also a solvent from the viewpoint of improving the yield.
As a result, this reaction can be carried out in the same manner by using ethyl acetate, which is mentioned as a general example in WO96 / 19463, but is not disclosed as a specific example. I found it. Such a change of the solvent not only has a merit of cost reduction, but also makes it possible to omit the reaction solvent concentration step before extraction in the next step (third step). As a result, the problems of cost reduction and yield improvement could be solved all at once. Together, they found that the unstable compound [4 ^′ ] was used in the next step without isolation and purification. With these improvements, improved yields were achieved.

In the third step A method, hydrochloric acid is added to the compound [4 '] in tetrahydrofuran to carry out hydrolysis and decarboxylation reaction. Subsequently, as a post-treatment, the reaction solvent (tetrahydrofuran)
Compound [5 ′] is obtained through steps such as concentration, extraction, concentration of extraction solvent and the like. The present inventors can carry out the third step in ethyl acetate by replacing the tetrahydrofuran used as the solvent in the previous step (second step) with ethyl acetate, and the tetrahydrofuran before the extraction operation It succeeded in omitting the concentration step. This led to improvement in the yield of compound [5 ′]. Comparing the yields of the compound [1 ′] to the compound [5 ′], it was 67.7% in the method A, but was 84.7% in the method of the present invention, and a yield improvement of 17% was achieved. I was able to.

In the fourth step, Method A, compound [5 '] is reacted with chlorosulfonic acid in chloroform to obtain compound [6']. Further, the target compound [7 ′] is obtained by reacting it with aqueous ammonia in tetrahydrofuran without isolation. Here, chloroform used as a solvent is highly toxic and has a problem in terms of industrial use. The present inventors have solved this problem by using a method not generally disclosed in WO96 / 19463 but not disclosed as a specific example. Specifically, it was surprisingly found that the reaction proceeded smoothly without solvent as in the case of using chloroform. Further, Method A has not yet been satisfactory in terms of yield of the target compound [7 ']. In Method A, as a post-treatment, the compound [7 ′] is obtained through steps such as concentration of the reaction solvent (tetrahydrofuran), extraction, concentration of the extraction solvent. Similar to the second step, the present inventors succeeded in omitting the step of concentrating tetrahydrofuran before the extraction operation by changing the solvent in the amidation reaction from tetrahydrofuran to ethyl acetate. Thereby, the yield of the compound [7 ′] from the compound [5 ′] was improved from 77.2% to 82.0% by about 5%,
The problems of the conventional method can be solved, and the invention has been completed.

[0011]

As described above, the present inventors have studied in detail the problems in each step for the purpose of improving the yield of the target compound and establishing a method that can be industrially manufactured. As a result, by selecting the solvent, reagents, etc. used in each step as described above, it is possible to obtain the target compound in good yield, and to find a production method that is industrially practical, and to complete the present invention. Arrived That is, the present invention is as shown in the following (1) to (9).

(1) General formula [1]

[0013]

[Chemical 18]

(In the formula, R ¹ is an optionally substituted cycloalkyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group, and R ² is a lower alkyl group or a halogenated lower alkyl group. The compound represented by the general formula [2] is reacted with thionyl chloride in the presence of a base in an inert solvent.

[0015]

[Chemical 19]

An oxazolone compound represented by the formula (wherein R ¹ and R ² are the same as those described above), and then the compound is represented by the general formula [3] in ethyl acetate in the presence of a magnesium salt and a base.

[0017]

[Chemical 20]

(Wherein R ³ is a halogen atom or a hydrogen atom, and X is a halogen atom) is reacted with a compound represented by the general formula [4]

[0019]

[Chemical 21]

A compound represented by the formula (wherein R ¹ , R ² and R ³ are the same as above) is obtained, and the compound is subjected to hydrolysis and decarboxylation reaction with an acid to give a compound of the general formula [5].

[0021]

[Chemical formula 22]

(Wherein R ¹ , R ² and R ³ are the same as above), the compound is cyclized and sulfonated with a sulfonating agent, and then chlorinated with thionyl chloride. Then, the general formula [6]

[0023]

[Chemical formula 23]

(Wherein R ¹ , R ² and R ³ are the same as defined above), and the compound is subsequently amidated with aqueous ammonia in ethyl acetate. , General formula [7]

[0025]

[Chemical formula 24]

A process for producing an oxazole compound represented by the formula (wherein R ¹ , R ² and R ³ are the same as above).

(2) R ¹ is a cycloalkyl group,
The production method according to (1), wherein R ² is a lower alkyl group and R ³ is a halogen atom.

(3) R ¹ is a cyclohexyl group,
R ² is a methyl group and R ³ is a fluorine atom (1)
The manufacturing method described.

(4) General formula [1]

[0030]

[Chemical 25]

(In the formula, R ¹ is an optionally substituted cycloalkyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group, and R ² is a lower alkyl group or a halogenated lower alkyl group. The compound represented by the general formula [2] is reacted with thionyl chloride in the presence of a base in an inert solvent.

[0032]

[Chemical formula 26]

(Wherein R ¹ and R ² are the same as above), and then this compound is prepared by reacting this compound in ethyl acetate in the presence of a magnesium salt and a base with the general formula [3].

[0034]

[Chemical 27]

(Wherein R ³ is a halogen atom or a hydrogen atom, and X is a halogen atom), and reacted with a compound represented by the general formula [4]

[0036]

[Chemical 28]

A compound represented by the formula (wherein R ¹ , R ² and R ³ are the same as described above), and the compound is subjected to hydrolysis and decarboxylation with an acid, Formula [5]

[0038]

[Chemical 29]

A method for producing an acetophenone compound represented by the formula (wherein R ¹ , R ² and R ³ are the same as above).

(5) R ¹ is a cycloalkyl group,
The production method according to (4), wherein R ² is a lower alkyl group and R ³ is a halogen atom.

(6) R ¹ is a cyclohexyl group,
R ² is a methyl group and R ³ is a fluorine atom (4)
The manufacturing method described.

(7) General formula [5]

[0043]

[Chemical 30]

(In the formula, R ¹ is an optionally substituted cycloalkyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group, and R ² is a lower alkyl group or a halogenated lower alkyl group. And R ³ is a halogen atom or a hydrogen atom) is cyclized and sulfonated with a sulfonating agent, and then chlorinated with thionyl chloride to give a compound of the general formula [6]

[0045]

[Chemical 31]

(Wherein R ¹ , R ² and R ³ are the same as above), and the compound is subsequently amidated with aqueous ammonia in ethyl acetate. , General formula [7]

[0047]

[Chemical 32]

A process for producing an oxazole compound represented by the formula (wherein R ¹ , R ² and R ³ are the same as above).

(8) R ¹ is a cycloalkyl group,
The production method according to (7), wherein R ² is a lower alkyl group and R ³ is a halogen atom.

(9) R ¹ is a cyclohexyl group,
R ² is a methyl group and R ³ is a fluorine atom (7)
Manufacturing method described

The definition of each substituent used in the present specification is as follows.

The "cycloalkyl group" has 3 to 8 carbon atoms.
Means a cycloalkyl group, specifically, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group. Preferred is a cycloalkyl group having 5 to 7 carbon atoms, and specifically, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group. Particularly preferred is a cyclohexyl group.

The "heterocyclic group" is a 5- to 6-membered aromatic heterocycle containing 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom in addition to carbon atoms as ring-constituting atoms. , A saturated heterocycle, an unsaturated heterocycle, or a condensed heterocycle in which these heterocycles are condensed with a benzene ring or a cyclohexane ring. Group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, morpholino group, morpholinyl group, piperazinyl group, piperidyl group, pyranyl group, thiopyranyl group, pyridyl group, benzothienyl group, benzofuranyl group, indolyl group, 4, 5, 6 , 7-Tetrahydroindolyl group, 4,5,6,7-tetrahydrobenzothienyl group, 4,5,6, - tetrahydronaphthyl benzofuranyl group. Preferably thienyl group, furyl group, pyrrolyl group, morpholino group, morpholinyl group, piperazinyl group,
It is a piperidyl group. A thienyl group is particularly preferred.

The "aryl group" is, for example, a phenyl group, a naphthyl group, a biphenylyl group or the like, preferably a phenyl group.

The term "may be substituted" means that it may be substituted with 1 to 3 substituents, which may be the same or different. The position of the substituent is arbitrary and is not particularly limited. In particular,
Lower alkyl group such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, tert-butyl group; hydroxyl group; lower alkoxy group such as methoxy group, ethoxy group, propoxy group, butoxy group; fluorine, chlorine, bromine, etc. A halogen atom; a nitro group; a cyano group; an acyl group (eg, a lower alkylcarbonyl group such as a formyl group or an acetyl group, a propionyl group); Are the same as above); mercapto group; methylthio group,
Lower alkylthio groups such as ethylthio group, propylthio group, butylthio group, isobutylthio group; amino groups; lower alkylamino groups such as methylamino group, ethylamino group, propylamino group, butylamino group; dimethylamino group, diethylamino group, A di-lower alkylamino group such as a dipropylamino group and a dibutylamino group; a carboxy group;
Lower alkoxycarbonyl group such as methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group; amide group; trifluoromethyl group; methylsulfonyl group,
Lower alkylsulfonyl group such as ethylsulfonyl group; aminosulfonyl group; lower cycloalkyl group such as cyclopentyl group, cyclohexyl group; phenyl group; acylamino group such as acetamido group, propionamide group (acyl moiety is the same as above) Of these, a hydroxyl group, a lower alkyl group, a lower chalcoxy group, a mercapto group, a lower alkylthio group, a halogen atom, a trifluoromethyl group, a lower alkylcarbonyl group, a lower alkoxycarbonyl group and an acylamino group are preferable. Here, the term “lower” means preferably having 1 to 6 carbon atoms, and more preferably 1 to 4 carbon atoms.

More specifically, the "aryl group which may be substituted" means an aryl which may be substituted with a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a lower alkylsulfonyl group, an aminosulfonyl group or the like. Group, especially a phenyl group, and examples thereof include a phenyl group, a fluorophenyl group, a methylphenyl group, a methoxyphenyl group, a methylsulfonylphenyl group, an aminosulfonylphenyl group and the like, preferably a phenyl group and a 4-fluorophenyl group. it can.

The “heterocyclic group which may be substituted” is a heterocyclic group which may be substituted with a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a lower alkylsulfonyl group, an aminosulfonyl group or the like, Preferred are thienyl group, furyl group, 5-methylthienyl group, and 5-chlorothienyl group.

The "optionally substituted cycloalkyl group" is a cycloalkyl group which may be substituted with a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a lower alkylsulfonyl group, an aminosulfonyl group or the like. ,
A cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a 4-methylcyclohexyl group, a 4-hydroxycyclohexyl group, a 4-fluorocyclohexyl group and the like are preferable, and a cyclohexyl group is particularly preferable.

The "lower alkyl group" is a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec. -Butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group,
A 1-ethylpropyl group, a tert-pentyl group, a hexyl group or the like is preferable, and a methyl group is preferable.

The "halogen atom" is a chlorine atom, a bromine atom, a fluorine atom or the like, preferably a chlorine atom or a fluorine atom. R ³ is preferably a fluorine atom, and X is preferably a chlorine atom.

The "halogenated lower alkyl group" is the above-defined lower alkyl group substituted with a halogen atom as defined above, and specifically includes fluoromethyl group, chloromethyl group, bromomethyl group, iodomethyl group. , Difluoromethyl group, dichloromethyl group, trifluoromethyl group, trichloromethyl group, fluoroethyl group, chloroethyl group, difluoroethyl group, dichloroethyl group, trifluoroethyl group, trichloroethyl group, tetrachloroethyl group, pentafluoroethyl group , A fluoropropyl group and the like, preferably a fluoromethyl group, a chloromethyl group, a dichloromethyl group, a difluoromethyl group, a trichloromethyl group and a trifluoromethyl group.

The "inert solvent" is ethyl acetate, tetrahydrofuran, toluene, dichloromethane or the like, preferably ethyl acetate.

The "base" is a tertiary amine such as triethylamine, pyridine or N-methylmorpholine; a secondary amine such as diethylamine or diisopropylamine; an inorganic base such as potassium carbonate or sodium carbonate, preferably a tertiary amine. Yes, and more preferably triethylamine.

The "magnesium salt" is anhydrous magnesium chloride, anhydrous magnesium bromide or the like, and preferably anhydrous magnesium chloride.

The "acid" is hydrochloric acid, oxalic acid, dilute sulfuric acid, phosphoric acid or the like, preferably hydrochloric acid.

The "sulfonating agent" is chlorosulfonic acid, sulfuric anhydride, concentrated sulfuric acid, fuming sulfuric acid or the like, preferably chlorosulfonic acid.

Next, the method for producing the oxazole compound represented by the general formula [7] will be described in detail.

[0068]

[Chemical 33]

(In the formula, R ¹ , R ² , R ³ and X are the same as above)

[0070]

[General production method] Step 1 Compound [2] can be obtained by reacting compound [1] with thionyl chloride in the presence of a base in an inert solvent. The inert solvent used in the reaction is ethyl acetate, tetrahydrofuran, toluene, dichloromethane or the like, preferably ethyl acetate. As a base,
Tertiary amines such as triethylamine, pyridine and N-methylmorpholine; secondary amines such as diethylamine and diisopropylamine; inorganic bases such as potassium carbonate and sodium carbonate; preferably tertiary amines, more preferably triethylamine. is there. Reaction temperature is -20 ℃
To 20 ° C, preferably -10 ° C to 0 ° C. The reaction time is 0.5 to 10 hours, preferably 0.5 to 2 hours. When carrying out this reaction, it is desirable to carry out the reaction in an atmosphere of an inert gas such as nitrogen in order to prevent a decrease in yield due to mixing of water. Further, the obtained compound [2] can be used for the next reaction without isolation.

Step 2 Compound [4] can be obtained by reacting compound [2] with compound [3] in ethyl acetate in the presence of a magnesium salt and a base. The magnesium salt is anhydrous magnesium chloride, anhydrous magnesium bromide, or the like, and preferably anhydrous magnesium chloride. Examples of the base include tertiary amines such as triethylamine, pyridine and N-methylmorpholine; secondary amines such as diethylamine and diisopropylamine; inorganic bases such as potassium carbonate and sodium carbonate; preferably tertiary amines, and Preferred is triethylamine. The reaction temperature is -20 ° C to 20 ° C, preferably 0 ° C to 10 ° C. The reaction time is 1 to 20 hours, preferably 6
Hours to 15 hours. Also in the case of carrying out this reaction, it is desirable to carry out the reaction under an atmosphere of an inert gas such as nitrogen in order to prevent a decrease in yield due to mixing of water, as in Step 1. In this step, the reaction can be smoothly progressed by using ethers such as tetrahydrofuran or diethyl ether, preferably tetrahydrofuran, as a reagent. The ethers are used in an amount of 2 to 5 equivalents, preferably about 2 equivalents, relative to compound [2]. Further, the obtained compound [4] can be used for the next reaction without isolation.

Step 3 Compound [5] can be obtained by subjecting compound [4] to acid hydrolysis and decarboxylation. This reaction can be preferably carried out in a mixed solvent of ethyl acetate and water. Acids used include hydrochloric acid, oxalic acid,
Examples thereof include dilute sulfuric acid and phosphoric acid, and hydrochloric acid is preferable. The reaction temperature is -20 ° C to 100 ° C, preferably 35
C. to 45.degree. The reaction time is 1 hour to 20 hours, preferably 1 hour to 3 hours.

Step 4 The compound [5] can be obtained by cyclizing and sulfonating the compound [5] with a sulfonating agent and then chlorinating with thionyl chloride. Then, the target compound [7] can be obtained by reacting with ammonia water in ethyl acetate without isolating the product. The cyclization and sulfonation reactions are preferably carried out without solvent.
The sulfonating agent used is chlorosulfonic acid, sulfuric anhydride, concentrated sulfuric acid, fuming sulfuric acid, or the like, and preferably chlorosulfonic acid. The reaction temperature of the reaction for obtaining the compound [6] from the compound [5] is 0 ° C to 200 ° C, preferably 75 ° C to 95 ° C. The reaction time of the cyclization and sulfonation reaction is 1 hour to 10 hours, preferably 2 hours to 5 hours. The reaction time for chlorination is 0.5 to 10 hours, preferably 0.5 to 5 hours. In addition, in the reaction for obtaining the compound [6] from the compound [5], it is desirable to carry out the reaction in an atmosphere of an inert gas such as nitrogen in order to prevent a decrease in yield due to mixing of water as in the first step. The reaction temperature of the reaction for obtaining the compound [7] from the compound [6] is −20 ° C. to 200 ° C., preferably −10 ° C. to 10 ° C. Reaction time is 1 to 2 hours
It is 4 hours, preferably 1 to 3 hours.

[0074]

[Example] Example 1 2-N-acetylamino-2-cyclohexyl-3'-
Fluoroacetophenone (Compound [5] (R¹= Cyclo
Hexyl group, R²= Methyl group, R³= 3-fluoro)
(Building method) DL-N-acetyl-2-cyclohexyl under nitrogen atmosphere
Luglycine (60.0 g) with ethyl acetate (420 mL)
And triethylamine (45.7 g) added
Dissolved. Thionyl chloride (37.6 g) under ice salt cooling,
Next, add triethylamine (106.6 g) to an internal temperature of 0 ° C.
It was dropped so that it would not exceed. After completion of dropping, -10 to 0 ° C
Stir for 30 minutes or more at 4-cyclohexyl-2-methyl
A mixed solution of -5-oxazolone in ethyl acetate was obtained. This 4
-Cyclohexyl-2-methyl-5-oxazolone vinegar
The ethyl acetate mixed solution was previously mixed with ethyl acetate (1
20 mL) and tetrahydrofuran (43.4 g)
Prepared by adding anhydrous magnesium chloride (28.7g)
Add the prepared mixture and stir at 0-10 ° C for over 1 hour.
did. Furthermore, at 0-10 ° C, 3-fluorobenzoyl chloride
Loride (47.7 g) was added dropwise and the mixture was stirred at the same temperature for 6 hours or more.
4-cyclohexyl-4- (3-fluorobenzo) with stirring
Il) -2-methyl-5-oxazolone mixed with ethyl acetate
A combined solution was obtained. This 4-cyclohexyl-4- (3-full
Orobenzoyl) -2-methyl-5-oxazolone vinegar
35% hydrochloric acid (72.1 g) and water were added to the ethyl acid mixture.
(173 mL) was added dropwise so that the internal temperature did not exceed 45 ° C.
It was After stirring this reaction solution at 35 to 45 ° C. for 1 hour or more, 1
The mixture was cooled to 0 to 30 ° C., and allowed to stand to separate the water layer. Profit
The obtained organic layer was water (420 mL), 20% potassium carbonate
Aqueous solution (420g), then 10% saline (420g)
Washed with. 198 g of organic layer obtained by stationary separation
After concentrating with, the residue was dissolved by heating and heptane (212 m
L) was added. The internal temperature is gradually cooled to 55 to 65 ° C, and 55
Crystallization aging at ~ 65 ° C for 1 hour or more, and -10 ° C or less.
It was then cooled at -10 ° C. and aged at -10 ° C. or lower for crystallization for 1 hour or longer. This
The crystallization solution of is filtered, and the crystals collected by filtration are cooled to -10 ° C or lower.
Rejected ethyl acetate (54 mL) and heptane (162 m
L), and then dried under reduced pressure to give the title compound (compound
[5]; 70.7 g, yield: 84.7%) to give a pale yellowish white color.
Obtained as crystals. mp .: 116-118 ℃ 1H-NMR (300MHz, CDCl3, TMS): δ 0.9 ~ 1.3 (5H, m),
1.5 (1H, m) 1.6 to 1.9 (4H, m), 2.07 (3H, s), 5.52 (1
H, dd), 6.27 (1H, br-d), 7.31 (1H, td), 7.49 (1H, td), 7.67 (1
H, td), 7.79 (1H, br-d) IR (KBr): 3282, 2920, 1681, 1637, 1588, 1297 cm^-1 MS (FAB +): 278 (MH⁺)

Example 2 5- (4-aminosulfonyl-3-fluorophenyl)
-4-cyclohexyl-2-methyloxazole (compound
Object [7] (R¹= Cyclohexyl group, R²= Methyl group, R
³= 3-fluoro) production method) 2 in chlorosulfonic acid (126.1 g) under nitrogen atmosphere
-N-acetylamino-2-cyclohexyl-3'-f
Luoroacetophenone (60.0g) with an internal temperature of 20 ° C
I put it in separately so as not to exceed it. 2 hours at an internal temperature of 75-95 ° C
After stirring for a while or more, thionyl chloride (77.2
g) was added dropwise, and the mixture was stirred at 75 to 95 ° C for 30 minutes or longer.
While the reaction solution was cooled to 5 ° C or lower, ethyl acetate (180
(mL) so that the internal temperature does not exceed 10 ° C,
It was cooled to below 5 ° C. The reaction solution was cooled with ethyl acetate.
Chill-water mixture (120 mL-480 mL; 5 ° C or less)
The solution was added dropwise to the inside so that the internal temperature did not exceed 10 ° C. Dripping volume
Wash the vessel with ethyl acetate (60 mL) and water (60 mL)
After cleaning and combining the reaction solution and the washing solution, leave the solution in a stationary layer to remove the water layer.
I was there. Wash the resulting organic layer with water (300 mL) and
-(4-chlorosulfonyl-3-fluorophenyl)-
4-Cyclohexyl-2-methyloxazole acetate
A chill solution was obtained. This 5- (4-chlorosulfonyl-3
-Fluorophenyl) -4-cyclohexyl-2-methyl
After cooling the ethyl acetate solution of luoxazole to below 0 ° C,
25% aqueous ammonia (73.7
g) and ethyl acetate (180 mL) to a mixture,
Drop it so that it does not exceed ℃, and keep it at -10 to 10 ℃ for 1 hour or more.
Stir over. 25% saline (226 g) was added to this reaction solution.
In addition, the stationary layer was separated to remove the aqueous layer, and the organic layer was washed with 25% saline solution.
It was washed with (226 g). Acetate obtained by stationary separation
Chill extract is concentrated to isopropyl alcohol crystallization solution
The solvent was replaced. After heating and dissolving this slurry, 30 to 50 ° C
Slowly cool down to the same temperature, crystallize and ripen at the same temperature for 1 hour or more, and further 10 ℃
After cooling to the following, crystallization and aging was carried out for 2 hours or more at the same temperature. Crystallization
The liquid is filtered and isopropyl alcohol (180 mL) is added.
Wash with a solution cooled to 10 ° C or lower, dry under reduced pressure, and
Compound (Compound [7]; 60.0 g, yield: 82.0
%) As white crystals. mp .: 166-167 ℃ 1H-NMR (300MHz, CDCl3, TMS): δ 1.3 ~ 1.5 (3H, m),
1.7 to 1.9 (7H, m), 2.51 (3H, s), 2.79 (1H, tt, J = 3.
7, 11.3Hz), 5.19 (2H, br-s), 7.36 ~ 7.43 (2H, m), 7.94 (1H, t) IR (KBr): 3342, 3244, 2932, 1612, 1344, 1168 cm^-1 MS (FAB +): 339 (MH⁺)

[0076]

As is apparent from the above, according to the present invention, a compound [7] which selectively inhibits desired cyclooxygenase-2 (COX-2) in a highly efficient manner and in a high yield as compared with conventional methods [7] ] Can be manufactured.
Further, the production method of the present invention is highly practical and industrially very useful.

─────────────────────────────────────────────────── ─── Continuation of the front page (56) Reference JP-A-10-120566 (JP, A) JP-A-5-70425 (JP, A) International Publication 96/019463 (WO, A1) (58) Fields investigated (Int.Cl. ⁷ , DB name) C07D 263/32 CA (STN) CASREAT (STN) REGISTRY (STN)

Claims (9)

(57) [Claims] 1. A general formula [1]: (In the formula, R ¹ is an optionally substituted cycloalkyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group, and R ² is a lower alkyl group or a halogenated lower alkyl group) By reacting the represented compound with thionyl chloride in the presence of a base in an inert solvent,
General formula [2] (Wherein R ¹ and R ² are the same as above), and this compound is subsequently prepared in the presence of a magnesium salt and a base in ethyl acetate and tetrahydrofuran to give a compound of the general formula [3] 3] (In the formula, R ³ is a halogen atom or a hydrogen atom, and X is a halogen atom), and reacted with a compound represented by the general formula [4] (Wherein R ¹ , R ² and R ³ are the same as above), the compound is subjected to hydrolysis and decarboxylation with an acid to give a compound of the general formula [5] ] (Wherein R ¹ , R ² and R ³ are the same as above), the compound is cyclized and sulfonated with a sulfonating agent, and further chlorinated with thionyl chloride. General formula [6] (Wherein R ¹ , R ² and R ³ are the same as defined above), and the compound is then amidated with aqueous ammonia in ethyl acetate. [7] [Chemical 7] (In the formula, R ¹ , R ² and R ³ are the same as the above), and a method for producing the oxazole compound. 2. The production method according to claim 1, wherein R ¹ is a cycloalkyl group, R ² is a lower alkyl group, and R ³ is a halogen atom. 3. R¹Is a cyclohexyl group, R^TwoBut
A methyl group, R ^ThreeIs a fluorine atom.
Manufacturing method. 4. A compound represented by the general formula [1]: (In the formula, R ¹ is an optionally substituted cycloalkyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group, and R ² is a lower alkyl group or a halogenated lower alkyl group) By reacting the represented compound with thionyl chloride in the presence of a base in an inert solvent,
General formula [2] (Wherein R ¹ and R ² are the same as above), and this compound is subsequently prepared in the presence of a magnesium salt and a base in ethyl acetate and tetrahydrofuran to give a compound of the general formula [3] 10] (In the formula, R ³ is a halogen atom or a hydrogen atom, and X is a halogen atom), and the compound represented by the general formula [4] (Wherein R ¹ , R ² and R ³ are the same as described above), and the compound is subjected to hydrolysis and decarboxylation reaction with an acid, and the compound of the general formula [5 ] [Chemical formula 12] (In the formula, R ¹ , R ² and R ³ are the same as the above), and a method for producing the acetophenone compound. 5. The production method according to claim 4, wherein R ¹ is a cycloalkyl group, R ² is a lower alkyl group, and R ³ is a halogen atom. 6. R¹Is a cyclohexyl group, R^TwoBut
A methyl group, R ^ThreeIs a fluorine atom.
Manufacturing method. 7. A compound represented by the general formula [5]: (In the formula, R ¹ is an optionally substituted cycloalkyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group, R ² is a lower alkyl group or a halogenated lower alkyl group, and R 2 ³ is a halogen atom or a hydrogen atom) is cyclized and sulfonated with a sulfonating agent, and further chlorinated with thionyl chloride,
General formula [6] (Wherein R ¹ , R ² and R ³ are the same as defined above), and the compound is then amidated with aqueous ammonia in ethyl acetate. [7] [Chemical 15] (In the formula, R ¹ , R ² and R ³ are the same as the above), and a method for producing the oxazole compound. 8. The production method according to claim 7, wherein R ¹ is a cycloalkyl group, R ² is a lower alkyl group, and R ³ is a halogen atom. 9. R¹Is a cyclohexyl group, R^TwoBut
A methyl group, R ^ThreeIs a fluorine atom.
Manufacturing method.