Technical Field

The present invention is related to a new process for producing oxazole compounds.

Background of the Invention

Oxazole compounds represent a vast class of heterocyclic aromatic organic compounds. Oxazole compounds have become increasingly important because of biological activities and their use as intermediates for the preparation of new biological materials. The wide range of biological activities of oxazole compounds includes anti-inflammatory, analgesic, antibacterial, antifungal, hypoglycemic, antiproliferative, anti-tuberculosis, muscle relaxant and HIV inhibitor activity.

4-methyl-5-cyanooxazole is an important intermediate for producing vitamin Bg. In industry, it is mainly produced by the process comprising the steps: a) ethyl acetoacetate is chlorinated to chloroethyl acetoacetate, b) chloroethyl acetoacetate is reacted with formamide to give 4- methyl-5-oxazolecarboxylic acid ethyl ester, and c) the obtained ester is dehydrated to 4-methyl-

5-cyanooxazole via 4-methyl-5-oxazole carboxamide, (see H. Pauling, B. Weimann, Ullmann, VCH, (2012) 248; Werner Bonrath; Kun Peng, Qiong-Mei Zhang, Horst Pauling, Bernd-Jurgen Weimann, Ullmann's Encyclopedia of Industrial Chemistry (7th Edition) (2020)).

The above process has several disadvantages. For example, the chlorination step uses chlorine and the dehydration reaction uses phosphorus pentoxide, which are toxic or corrosive. In addition, the process produces many salts which cause environment problem.

Therefore, there is still demand of new processes for producing oxazole compounds.

Summary of the Invention The present invention provides a new process for producing an oxazole compound of formula (I), which can avoid toxic reagents and reduce salts by-products with high efficiency, wherein Ri is H, or lower alkyl or aryl optionally substituted by one or more substituents; and E is C N, or C(=O)R' wherein R' is H, lower alkyl, aryl or lower alkoxyl.

Detailed Description of the Invention

Particularly, the present invention provides a process for producing a compound of formula (I), comprising treating a compound of formula (II) with a first acid followed by a treatment with a second acid and an anhydride in the presence of a solvent to obtain the compound of formula (I),

Wherein Ri is H, or lower alkyl or aryl optionally substituted by one or more substituents; R2 is one or more substituents selected from the group consisting of H, NO2, hydroxyl, lower alkyl, lower alkoxyl and halo; and E is be C=N, or C(=O)R' wherein R' may be H, lower alkyl, aryl or lower alkoxy I.

In the present invention, the term "lower alkyl" as used refers to C1-C10 alkyl, i.e., branched or unbranched, cyclic or non-cyclic, saturated hydrocarbon comprising 1-10 carbon atoms. Preferably, the "lower alkyl" is Ci-Cs alkyl, including but not limited to methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, pentyl, iso-pentyl, tert-pentyl, cyclopentyl, hexyl, isohexyl, tert-hexyl, cyclohexyl, octyl, isooctyl, tert-octyl, cyclooctyl, nonyl, isononyl, tert-nonyl, cyclononyl, decyl, isodecyl, tert-decyl, cyclodecyl. More preferably, the "lower alkyl" is methyl or ethyl. In the present invention, the term "aryl" as used refers to aromatic hydrocarbon such as phenyl, benzyl, xylyl and naphthalenyl.

In the present invention, the term "lower alkoxyl" as used refers to the structure represented by (lower alkyl)-O-, wherein the lower alkyl is as defined above.

In the present invention, the term "substituent" or "substituents" as used refers to lower alkyl, lower alkoxyl, hydroxyl, halo, -NH2, -NO2, cyano and/or isocyano.

In the present invention, the term "halo" or "halogen" as used refers to a group of elements including fluorine (F), chlorine (Cl), bromine (Br) and iodine (I), preferably refers to Cl or Br.

In the present invention, Ri is preferably H, or lower alkyl or phenyl optionally substituted by one or more substituents. More preferably, Ri is H or Ci-Cs alkyl or phenyl optionally substituted by one or more substituents. More preferably, Ri is H, methyl, ethyl or phenyl optionally substituted by one or more substituents. The most preferably, Ri is H, CH3 or phenyl.

In the present invention, R2 is preferably one or more substituents selected from the group consisting of H, NO2, hydroxyl, Ci-Cs alkyl, Ci-Cs alkoxyl or halo. More preferably, R2 is H, halo, methyl, ethyl, methoxy, ethoxy and/or -NO2.

In the present invention, E is preferably C N, or C(=O)R' wherein R' is lower alkoxyl such as methoxy and ethoxy.

In one embodiment of the present invention, Ri is H or methyl; R2 is H or NO2; and E is C=N.

In another embodiment of the present invention, Ri is H or methyl; R2 is H or NO2; and E is C(=O)R' wherein R' is lower alkoxyl such as methoxy and ethoxy. In the process of the present invention, the first acid and the second acid may be same or different, independently selected from any organic acid or inorganic acid. Example of the organic acid includes but is not limited to formic acid, acetic acid, glycolic acid, propanoic acid, 3- hydroxypropanic acid, butanoic acid, succinic acid, pentatonic acid, trimethylacetic acid, methanesulfonic acid, trifloroacetic acid, p-toluenesulfonic acid, ascorbic acid and citric acid. Example of the inorganic acid includes but is not limited to hydrochloric acid, sulfuric acid and nitric acid. Preferably, the first acid and the second acid are same and selected from formic acid, acetic acid, glycolic acid, propanoic acid, 3-hydroxypropanic acid, butanoic acid, succinic acid, pentatonic acid, trimethylacetic acid, ascorbic acid, and citric acid. The most preferably, the first acid and the second acid are formic acid.

In the process of the present invention, the first acid may be used in an amount of from 0.01 mole to 10 moles, preferably from 0.05 moles to 5 moles, more preferably from 0.1 moles to 1 moles such as 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 and 1.0 mole, per 1 mole of the compound of formula (II).

In the process of the present invention, the second acid may be used in an amount of from 0.01 moles to 30 moles, more preferably from 0.05 moles to 25 moles, further preferably from 0.08 mole to 20 moles, the most preferably from 0.1 moles to 18 moles such as 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, 10.0, 11.0, 12.0, 13.0, 14.0, 15.0, 16.0, 17.0 and 18.0 moles, per 1 mole of the compound of formula (II).

In the process of the present invention, the solvent may be any aprotic solvent or mixture thereof. Example of the aprotic solvent includes but is not limited to tetra hydrofuran (THF), ethyl acetate, acetone, dimethylformamide (DMF), acetonitrile, dimethyl sulfoxide (DMSO), dichloromethane (DCM), dimethyl carbonate, butyl acetate, methyl tert-butyl ether (MTBE), nitromethane, and nitroethane; and cyclic carbonates such as ethylene carbonate (EC), propylene carbonate (PC), and butylene carbonate (BC), and mixture thereof. Preferably, the solvent is DCM or PC. The solvent may be added in an amount of from 20 L to 80 L, preferably from 30 L to 60 L, more preferably from 45 L to 55 L, per 1 mole of the compound of formula (II).

In the present invention, the anhydride may be acetic anhydride, propionic anhydride or o- phthalic anhydride. It may be added into the reaction in an amount of from 0.01 moles to 10 moles, preferably from 0.05 moles to 5 moles, more preferably from 0.1 mole to 1 moles such as 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1 mole, per 1 mole of the compound of formula (II).

The treatment with the first acid according to the present invention may be carried out at room temperature. The treatment with the second acid according to the present invention may be carried out at the temperature from 20°C to 120°C, preferably from 50°C to 100°C, more preferably from 80°C to 90°C.

The treatments with the first acid and the second acid may be carried out in one pot or in separate pots. Preferably, the treatments with the first acid and the second acid is carried out in one pot.

The obtained compound of formula (I) may be easily isolated and purified by any known process, such as distillation, rectification and column chromatography.

Starting from the compound of formula (II), the process for producing oxazole compounds according to the present invention is easily to operate at a mild temperature. In addition, the process avoids producing any salt which is not good for environment and provide a high yield of the oxazole compounds.

The present invention and advantage thereof will be further illustrated by the following examples.

Examples

Example 1

In a 20 mL round-bottomed flask phenyliodine(lll) diacetate (332 mg, 1.030 mmol) was added in TFE (5 ml) to give a colorless solution. Formic acid (120 mg, 2.5 mmol) was added. The mixture was stirred at room temperature for 10 mins. 3-aminobut-2-enenitrile (90 mg, 1.030 mmol) was added. The resulting yellow mixture was stirred at room temperature for lh to obtain compound 1 (yield 90%)

^X H NMR (400 MHz, Deuterium Oxide) 6 8.38 (s, 1H), 8.02 - 7.92 (m, 2H), 7.67 (t, J = 7.4 Hz, 1H),

7.51 (t, J = 7.9 Hz, 2H), 2.31 (s, 2H). MS: 285.0

Example 2

Into a 100 mL round-bottomed flask, compound 1 (10 g) obtained according to Example 1 was added into the solution of formic acid (400 ul) in propylene carbonate (50 ml) at 60°C in one portion. The reaction mixture was cooled down to room temperature after stirred at 60°C for 15 min. The resulting solution was added dropwise to the solution of formic acid (20 ml) and acetic anhydride (3.8 ml) at 90°C. the reaction mixture was stirred at same temperature for additional 2 hours to afford 5-cyano-4-methyloxazole (2) in 80% yield.

Example 3

Into a 10 mL round-bottomed flask, compound 1 (1 g) obtained according to Example 1 was added into the solution of formic acid (40 ul) in propylene carbonate (5 ml) at 60°C in one portion. The reaction mixture was cooled down to room temperature after stirred at 60°C for 15 min. The resulting solution was added dropwise to the solution of methanesulfonic acid (MSA) (100 ul) and acetic anhydride (200 ul) in propylene carbonate (5 ml) at 90°C. the reaction mixture was stirred at same temperature for additional 2 hours to afford 5-cyano-4-methyloxazole (2) in 60% yield.

Example 4

Into a 10 mL round-bottomed flask, compound 1 (1 g) obtained according to Example 1 was added into the solution of formic acid (40 ul) in propylene carbonate (5 ml) at 60°C in one portion. The reaction mixture was cooled down to room temperature after stirred at 60°C for 15 min. The resulting solution was added dropwise to the solution of trifloroacetic acid (TFA) (2 ml) and acetic anhydride (200 ul) in propylene carbonate (5 ml) at 90°C. the reaction mixture was stirred at same temperature for additional 2 hours to afford 5-cyano-4-methyloxazole (2) in 30% yield.

Example 5 Into a 10 mL round-bottomed flask, compound 1 (1 g) obtained according to Example 1 was added into the solution of formic acid (40 ul) in propylene carbonate (5 ml) at 60°C in one portion. The reaction mixture was cooled down to room temperature after stirred at 60°C for 15 min. The resulting solution was added dropwise to the solution of p-toluenesulfonic acid monohydrate (p- TSA) (50 mg) and acetic anhydride (400 ul) in propylene carbonate (5 ml) at 90°C. the reaction mixture was stirred at same temperature for additional 2 hours to afford 5-cyano-4- methyloxazole (2) in 35% yield.

Example 6

Into a 10 mL round-bottomed flask, compound 1 (1 g) obtained according to Example 1 was added into the solution of formic acid (40 ul) in propylene carbonate (5 ml) at 60°C in one portion. The reaction mixture was cooled down to room temperature after stirred at 60°C for 15 min. The resulting solution was added dropwise to the solution of sulfuric acid (50 ul) and acetic anhydride (100 ul) in propylene carbonate (5 ml) at 90°C. the reaction mixture was stirred at same temperature for additional 2 hours to afford 5-cyano-4-methyloxazole (2) in 30% yield.