KR800001634B1 - Process for preparing oxazoles - Google Patents

Abstract

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Description

Manufacturing method of oxazoles

The present invention relates to 4,5-diaryloxazol-2-ylalkanoic acids of the following structural formula (I) having an anti-inflammatory action and a method for preparing nontoxic salts thereof.

In the above structural formula

Ar and Ar ¹ are the same or different aryl groups selected from phenyl group substituted with phenyl, naphthyl, furyl and halogen, lower alkyl, lower alkoxy, trifluoromethyl, nitro and di (lower alkyl) amino,

R is carboxyethyl or carboxypropyl.

(4,5-Diaryloxazol-2-yl) propionic acids and butyric acids and salts thereof are disclosed in British Patent No. 1,206,403 and show anti-inflammatory effects. One such anti-inflammatory agent is β- (4,5-diphenyloxazol-2-yl) propionic acid.

These compounds are prepared as follows.

a) Benzoin (21.2 g) and succinic anhydride (10.0 g) are heated together at 120 ° C. for 6 hours. It is cooled and the formed glassy solid is dissolved in ether and then exported to a dilute aqueous sodium carbonate solution. This basic extract is washed once with ether and acidified with hydrochloric acid. The oil obtained is extracted with ether, the extract is washed with water, dried over Na ₂ SO ₄ and evaporated to give an oil. When this solidifies, a succinate ester is obtained as a crystal of a square mold.

27g-78% Melting Point: 86-88 ° C

Analytical samples are recrystallized from aqueous acetone:

Melting Point: 88.5-89.5 ℃

b) Benzoin hemisuccinate ester (15 g) and ammonium acetate (30 g) are heated to reflux in glacial acetic acid (100 mL) for 1.5 h. After cooling, the solution is added to water to obtain crystals as a precipitate. This was filtered, washed with water and recrystallized from methanol to give needle- (4,5-diphenyloxazol-2-yl) propionic acid (11.7 g, 83%) as acicular crystals.

Melting Point: 160.5 ~ 161.5 ℃

Total yield: 87% × 83% = 72%

The experiments were carried out on a laboratory scale and are only at the research stage on a large industrial scale. Two drawbacks were found in this study.

First, the yield of oxazole recorded is very low on an industrial scale. However, this disadvantage can be maximized by varying the reaction conditions. Particular preference is given to using pyridine in the ester formation step, in which case the yield of crude β- (4,5-diphenyloxazol-2-yl) propionic acid is increased up to 67%. (Based on benzoin starting material)

Secondly, the purification of the resulting crude β- (4,5-diphenyloxazol-2-yl) propionic acid is very difficult. The crude product must be recrystallized twice to fully purify it. The crude product was found in laboratory experiments to contain impurities that were not effectively removed by methanol, which is used as the recrystallization solvent, and it was found that the impurities were tetraphenylpyrazine. Experimental experiments with various solvents have shown that ethylene dichloride is the most effective solvent for removing these impurities.However, when ethylene dichloride is used as the recrystallization solvent, recrystallized β- (4,5- It has been found that diphenyloxazol-2-yl) propionic acid will contain an unacceptable amount of solvent in the body. For example, one batch of recrystallized oxazole contains 0.3% ethylene dichloride. To remove this solvent, the solvent content was dried at 105 DEG C for 5 hours under reduced pressure (640 mmHg), and the content of the solvent dropped from 0.3% to 0.23%. However, even after drying as above, the above compounds could not be used due to the toxicity of ethylene dichloride to the liver. This toxicity is seen when the drug is administered to patients for a long period of time as an anti-inflammatory agent. As a result, ethylene dichloride could not be used as a final recrystallization solvent. When recrystallized with dichloroethane, the yield of solvent-containing oxazole is 67% x 91.5% = 61.33%, and the secondary recrystallization gives a total yield of 53% pure oxazole. (61.3% x 87%).

The manufacturing method of this compound as an industrial scale is as follows.

A) Preparation of benzoin hyesuccinate

Pyridine (7.0 kg) was added to a clean 20 gallon (91 L) reactor, followed by addition of benzoin (18.80 kg) and succinic anhydride (16.0 kg). Nitrogen is injected into the reactor and the mixture is heated to 90-95 ° C. under a nitrogen atmosphere to maintain this temperature for 2 hours. The reaction mixture is cooled to 35-40 [deg.] C. and after 20 minutes the reaction mixture is transferred in portions over 5 hours to a mixture of water (190 kg) and hydrochloric acid (28 kg) with a specific gravity of 1.18. At this time, the capacity of the reactor is 50 gallons (227 L) and the temperature is 55 to 60 ℃. The temperature of 50-60 ° C. is maintained for 5 hours and washed with dimethylformamide (9.0 kg). The mixture is cooled slowly until the product forms crystals and then cooled to 15-20 ° C. The mixture is stirred overnight at 15-20 ° C. and the product is filtered over a pottery filter and then suction dried. The product is washed 10 times with water (20 kg × 10) and each wash is suction dried. The product is dried in a reflux air oven at a temperature of 50-60 ° C. for 12-18 hours. The yield is 25.5 kg.

B. Preparation of Crude β- (4,5-diphenyloxazol-2-yl) -propionic acid

Glacial acetic acid (92.0 kg) was added to a clean and dried 50 gallon (227 L) reaction tank, and benzoin hemisuccinate (25.3 kg) and ammonium acetate (31 kg) prepared in Preparation (A) were added thereto while stirring. The reaction mixture is heated to 90-95 ° C. and stirred at this temperature for 1.5 hours. Water (44.0 kg) is carefully added to the reaction mixture and reheated to 90 to 95 ° C. The mixture is then loaded into another 50 gallon (227 liter) reactor through a preheated pressure filter. The first reactor and filter were washed with a mixture of glacial acetic acid (13.3 kg) and water (6.2 kg). The reactor is stirred and cooled to 10-15 ° C. and the product is filtered with a pottery filter. The product on the pottery filter is washed with a mixture of glacial acetic acid (25.5 kg) and water (12.5 kg). The product on the filter is suction dried, washed with water (10 kg) containing no inorganics and then suction dried. The product is dried in a Mitchell oven at a temperature of 80 ° C. for 16-18 hours. Crude β- (4,5-diphenyloxazol-2-yl) propionic acid of 17.5 kg (total yield: 67% for A and B) is obtained.

C) Recrystallization of crude β- (4,5-diphenyloxazol-2-yl) propionic acid

To a 50 gallon (227 L) reactor containing ethylene dichloride (20 kg) is added crude β- (4,5-diphenyloxazol-2-yl) propionic acid (130 kg) with stirring. The mixture is refluxed, heated and all the solids dissolved and the solution is cooled to 75 ° C. and charcoal (0.50 kg) is added carefully. The mixture is heated to boiling point and refluxed for 30 minutes. The solution is corrected with another 50 gallon (227 L) reactor through a warm pressure filter, and the initial reactor and filter are washed twice with ethylene dichloride (10 kg x 2). The mixture is again cooled to 0-50 [deg.] C. over 40 minutes and stirred at this temperature for 1 hour. The product is filtered and suction dried with a ceramic filter. The product on the filter is washed with pre-filtered ethylene dichloride (5 kg) followed by suction drying. The product is dried in a Mitchell oven at a temperature of 55-60 ° C. for 6-8 hours. 16 kg of β- (4,5-diphenyloxyzol-2-yl) propionic acid containing a solvent (recrystallized, yield 91.5%) was obtained and the total yield was 61.3%.

Recrystallization of the product from methanol to remove ethylene dichloride impurity yields 13.9 kg pure β- (4,5-diphenyloxazol-2-yl) propionic acid (87% yield when recrystallized from methanol). The total yield is 53%.

The gallon used in the above and the following Example 4 means a unit of British Empire gallons, one unit of British Empire is a gallon of the United States of America 1,2009 units.

The present invention is focused on the fact that the purity of the oxazole obtained prior to recrystallization is enhanced by omitting the operation of separating the ester intermediate. In particular, the oxysol obtained does not contain tetraphenylpyrazine as an impurity and therefore does not need to be recrystallized from toxic solvent ethylene dichloride. Samples of crude β- (4,5-diphenyloxazol-2-yl) propionic acid, when subjected to TLC prior to recrystallization, show only traces of traces of impurities, and the level of impurity can be clearly specified. There is no. An acceptable product that is pure enough can be obtained by recrystallizing once from methanol.

A second advantage of the present invention is that it can be performed effectively on an industrial scale as well as on a laboratory scale without reducing the yield. For example, the yield of crude β- (4,5-diphenyloxazol-2-yl) propionic acid is 67% on the laboratory scale and 69.8% on the industrial scale. Another advantage of the present invention is that the yield on the industrial scale of pure oxazole is higher than when the ester intermediate is separated. For example, the yield on the industrial scale of pure β- (4,5-diphenyloxazol-2-yl) propionic acid is 61.4% as shown in Example 4, which is on the other industrial scales described above. Yield, higher than 53%.

The 4,5-diaryloxazol-2-ylalkanoic acid of the following structural formula (I) according to the present invention may be prepared by converting an aroyl arylcarbol of the following structural formula (II) to an active derivative of butanedioic acid or In the resulting reaction mixture, the oxazole is formed by reacting with a ring closing agent for supplying nitrogen and closing the ring to prepare an oxazole. The acid product may be converted into a non-toxic salt, if necessary.

In the above structural formula

Ar and Ar 'are the same as each other or different aryl groups,

R is carboxyethyl, carboxy propyl.

Ar and Ar 'are the same or different aryl groups, wherein the term "aryl" includes isoaryl groups and is thyethyl or furyl. The aryl group may have a substituent on the aromatic ring, with the convenience that all such aliphatic groups are treated as aryl groups. Iryl groups include phenyl, naphthyl, thienyl and furyl groups. Examples include unsubstituted phenyl, halogen (e.g. fluorine, chlorine, bromine) lower alkyl (methyl, ethyl, n-propyl, isopropyl, n-butyl and iso-butyl), lower alkoxy (e.g. methoxy or ethoxy ), Phenyl substituted with trifluoromethyl, nitro or di (lower alkyl) amino (eg dimethyl amino), or substituted or unsubstituted naphthyl, thienyl or furyl groups (eg 1- or 2-naphthyl) , 2- or 3-thienyl, or 2- or 3-furyl) group. Ar and Ar 'groups are preferably phenyl and a phenyl group substituted once or twice with halogen, lower alkyl, lower alkoxy. R is preferably carboxyethyl as carboxyethyl or carboxypropyl group. As used herein, the terms "lower alkyl" and "lower alkoxy" are alkyl or alkoxy groups having up to 6 carbon atoms (preferably up to 4 carbon atoms).

As the esterifying agent in the present invention, succinic anhydride and glutaric anhydride are preferable, and succinic anhydride is particularly convenient. When pyridine is added to the reaction mixture, pyridine acts as a catalyst in forming the ester and is convenient because the temperature can be adjusted appropriately. In order to obtain the best results it is advisable to carry out the ester formation under anhydrous inert atmosphere, for example nitrogen atmosphere.

The ring closure reaction is carried out directly without separating the ketoester of formula (I) from the reaction mixture, except that the reaction mixture is adjusted to conditions suitable for the ring closure step, and the ring mixture is added to the reaction mixture. Since the ring closure reaction is carried out under acidic conditions, it is preferable to add the ring closure agent with an acid. However, the acid may be added at any time, either before or after adding the ring closure agent. It is preferable to use urea or an ammonium salt as a ring-closure, and to use ammonium acetate as a ring-closure with acetic acid as a solvent.

The present invention is carried out as follows. Succinic anhydride or glutaric anhydride and ketoalcohol are added to a suitable organic solvent such as pyridine and the mixture is heated to a temperature of 90 to 120 ° C. while stirring under nitrogen atmosphere. The esterification reaction takes from 1 hour to several hours, particularly importantly, the hemisuccinate or hemiglutarate as esterified product must remain in the reaction mixture prior to performing the ring closure step. Ammonium acetate and acetic acid are added to the reaction mixture as a solution containing ammonium acetate in acetic acid, and the temperature is maintained so that the ring-closure reaction can proceed. The ring closure reaction takes from one hour to several hours. The product is filtered off and washed with acetic acid and water to give crude oxazole. An advantage of the present invention is that it has a very high purity on its own even without recrystallization of the crude product from the organic solvent.

The following examples illustrate the invention.

Example 1

The 5 L flask is equipped with a stirrer, thermometer, reflux condenser and nitrogen introducer. Succinic anhydride (373g), benzoin (531g) and pyridine (300ml: 296g) were added thereto, and nitrogen was injected, followed by heating to 90 to 95 ° C. At this temperature the mixture is stirred for 1.5 hours, acetic acid (1300 mL) and ammonium acetate (385 g) are added and the mixture is reheated to 90-95 ° C. Stirring is continued for 2 hours while maintaining this temperature. The mixture is filtered and washed with acetic acid (150 mL). Distilled water (750 mL) was added, reheated at 90-95 ° C. and cooled with stirring at 15 ° C. for 1 hour. After filtration, the mixture was washed with a mixture of acetic acid / distilled water (2: 1) (600 mL) and then immersed in distilled water (1000 mL). After filtration and washing with distilled water (2 x 400 mL) the product is dried under vacuum at 90-100 ° C. 702 g (67%) of β- (4,5-diphenyloxazol-2-yl) propionic acid is obtained as a white crystalline powder. Melting Point: 163 ~ 165 ℃

Qualitative analysis with TLC shows that the product is a very high purity material.

Example 2

β- (4,5-diphenyloxazol-2-yl) butyric acid

The title compound (melting point: 125-126 ° C.) is prepared according to the method of Example 1 using glutaric anhydride instead of succinic anhydride.

Example 3

The oxazoles in the table below are prepared from substituted benzoins according to the method of Example 1 using urea instead of ammonium acetate.

Example 4

A. Preparation of Crude β- (4,5-diphenyloxazol-2-yl) propionic acid

Pyridine (9.25 kg), benzoin (16.5 kg) and succinic anhydride (11.7 kg) were put in a clean dry reaction tank (20 gallons, 91 L) to maintain nitrogen atmosphere throughout the reaction. The mixture is heated without stirring until the temperature reaches 85 ° C. Stirring is started and the mixture is heated at 90-95 ° C. for 1.5 h. A glacial acetic acid solution (35.0 kg) containing ammonium acetate (12.0 kg) is placed in a header of the reactor and added to the reaction mixture over 15 minutes. The container and header containing the solution are washed with acetic acid (4.0 kg) and the wash solution is added to the reaction mixture. The reaction mixture is left at 90 to 95 ° C. for 2 hours. The reaction mixture is cooled to 50 ° C. and transferred to a 50 gallon (227 L) reactor via a line filter. The reactor and line filters are washed with acetic acid (4.0 kg) and then combined with the reaction mixture. The reaction mixture is heated to 90-95 ° C. for 30 minutes with stirring. Water (21.0 kg) is added while maintaining a temperature of 90 to 95 ° C. and the reaction mixture is cooled to 20 to 25 ° C. over 55 minutes. The reaction mixture is cooled back to 10-15 ° C. with brine and left overnight. The product is filtered with a pottery filter and suction filtered and dried. The product on the filter is washed with a mixture of prefiltered glacial acetic acid (25.5 kg) and water (12.5 kg), suction filtered and dried. Pre-filtered water (50.0 kg) and the filter cake are placed in a 50 gallon (227 L) reactor.

The mixture is stirred for 30 minutes at room temperature, the filtration of the ceramic filter is carried out and the product is suction dried. The filter phase is washed twice with pre-filtered water (10 kg) and suction dried. It is then dried for 16-18 hours at 80 ° C. in a Mitchell oven. 15.9 kg (69.8%) of crude β- (4,5-diphenyloxazol-2-yl) propionic acid is obtained. Even if a very small amount of impurities are found in the TLC analysis, this substance can not accurately calculate the toxic purity in a considerable amount.

B) Recrystallization of crude β- (4,5-diphenyloxazol-2-yl) propionic acid

Methanol (63.0 kg) was put into a 50 gallon (227 L) reaction tank, and 15.9 kg of the oxazole prepared in Production Process (A) was added with stirring. This mixture is refluxed-heated. Once all solids are dissolved, the mixture is cooled to 50 ° C. and transferred to a 20 gallon (91 L) reactor. The reactor and tube are washed twice with methanol at 40 ° C. (3 kg × 2) and the mixture is cooled gradually to 15-20 ° C. for 1 hour and 50 minutes with stirring. The product is filtered with a pottery filter (using water in the reaction vessel), and aspirated and dried. The product on the filter is washed twice with methanol (5 kg × 2), suctioned and dried. The washings are combined with the filtrate and left to stand. The product from the filtrate is dried in an air oven at a temperature of 55-60 ° C. for 18 hours. 12.1 kg of β- (4,5-diphenyloxazol-2-yl) propionic acid are obtained. TLC showed that the product was pure.

Another product is obtained from the methanol solution as follows. The solution is placed in a 20 gallon (91 L) reactor and the solvent is distilled off for 9 hours until a solid appears. The mixture is cooled to 15-20 ° C. for 1.3 / 4 hours with cooling water in the reactor, cooled to 10 ° C. with brine and then stirred at this temperature for 30 minutes. The product is filtered through a ceramic filter, suctioned and dried. The product on the filter is washed twice with methanol (5 kg × 2) and dried by suction. The product is dried for 18 hours at a temperature of 55-60 ° C. in an air oven. 2.14 kg is obtained. This product is pure enough to be accepted by the body, but its purity cannot be measured. The crude product therefore has to be recrystallized from methanol.

Recrystallization from 13.76 kg of crude product yielded 12.1 kg (88%) of material with a total yield of 69.8% × 88% = 61.4% of pure product.

Claims (1)

Aroylaryl carbinol of the following formula (II) is esterified with an active derivative of butanedioic acid or pentanedioic acid to produce a keto ester of the following formula (II), which is used as a nitrogen donor ring closure agent in the reaction mixture. A method for producing 4,5-diaryloxazol-2-ylalkanoic acids of the following structural formula (I) and their non-toxic salts, characterized in that oxazole is produced by ring closure.

Ar and Ar ¹ in the above formula are the same or different aryl selected from phenyl group substituted with phenyl, naphthyl, thienyl, furyl and halogen, lower alkyl, lower alkoxy, trifluoromethyl, nitro, di (lower alkyl) amino And R is carboxyethyl or carboxypropyl.