Environment-friendly preparation method of a substituted oxazole compound

Abstract

N-substituted formyl-alpha-substituted glycine ester is used as the initial raw material, a cyclization reaction is performed under the action of a dehydrating agent (trisubstituted phosphine dihalide, a combination of trisubstituted phosphine dihalide and an acyl halide reagent, or a combination of trisubstituted phosphine oxide and an acyl halide reagent) and an organic amine to obtain the substituted oxazole compound, and the resulting substituted oxazole compound can be further saponified and de-carboxylated to obtain a medical intermediate 4-substituent-5-substituent oxy-oxazole; the reaction process can be carried out in a continuous flow mode to improve the productivity and reduce operations; the byproduct trisubstituted phosphine oxide in the reaction process can be repeatedly used to reduce the cost; dehydrating agents (phosphorus oxychloride and phosphorus pentoxide).

Claims

1. A preparation method of a substituted oxazole compound, comprising the steps as follows: a Compound of Formula II is dissolved in solvent A and cyclized to obtain the substituted oxazole compound (I) in the presence of a dehydrating agent and an organic amine; the dehydrating agent is trisubstituted phosphine dihalide, a combination of trisubstituted phosphine dihalide and an acyl halide reagent, or a combination of trisubstituted phosphine oxide and an acyl halide reagent; ##STR00021## Structural formulas I and II of the compounds, wherein: R.sub.1 can be hydrogen, a C.sub.nH.sub.2n+1 straight-chain or branched-chain group (1≤n≤10), aryl, or substituted aryl; R.sub.2 can be hydrogen, a C.sub.nH.sub.2n+1 straight-chain or branched-chain group (1≤n≤10), aryl, or substituted aryl; R.sub.3 is —COOR, —CH.sub.2COOR, or —CH.sub.2CH.sub.2COOR, wherein R is a C.sub.nH.sub.2n+1 straight-chain or branched-chain group (1≤n≤10).

2. The preparation method of a substituted oxazole compound according to claim 1, characterized in that, in structural formulas I and II of the compounds, R.sub.1 is methyl or ethyl, and R.sub.2 is methyl.

3. The preparation method of a substituted oxazole compound according to claim 1, characterized in that the said solvent A is one selected from among dichloromethane, chloroform, n-hexane, cyclohexane, petroleum ether, n-heptane, dimethylbenzene, chlorobenzene, benzene, methylbenzene, dimethylsulfoxide, trichloromethane, trichloroethane or dichloroethane, or a combination of two or more thereof; preferably, the mass ratio between the solvent A and the Compound of Formula II is (0.5-20.0):1.

4. The preparation method of a substituted oxazole compound according to claim 1, characterized in that the said organic amine is trialkylamine, wherein the general formula of the alkyl is C.sub.nH.sub.2n+1 (1≤n≤10); the alkyl is preferred to be methyl, ethyl, isopropyl, n-propyl, isobutyl, or n-butyl and more preferred to be ethyl, n-propyl, or n-butyl; the organic amine is more preferred to be triethylamine; preferably, the molar ratio between the said organic amine and the Compound of Formula II is (1.8-4.0):1; more preferably, it is (2.0-3.0):1.

5. The preparation method of a substituted oxazole compound according to claim 1, characterized in that the structural formula of the said trisubstituted phosphine oxide is R.sub.aR.sub.bR.sub.cP═O; wherein, R.sub.a, R.sub.b, and R.sub.c can be methyl, ethyl, as well as a C.sub.3-C.sub.10 straight-chain or branched-chain alkyl group, aryl, and substituted aryl and are preferred to be phenyl and isobutyl; R.sub.a, R.sub.b, and R.sub.c can be either the same or different; preferably, when R.sub.a, R.sub.b, and R.sub.c are aryl groups, the trisubstituted phosphine oxide is of a structure as shown in the formula V below: ##STR00022## the structural formula as shown in formula V, wherein m is 0, 1, 2, 3, 4, or 5, R.sub.4 can be hydrogen, a C.sub.nH.sub.2n+1 straight-bran or branched-chain alkyl group (1≤n≤10), or halogen; preferably, R.sub.4 is hydrogen.

6. The preparation method of a substituted oxazole compound according to claim 5, characterized in that the said trisubstituted phosphine oxide is trialkyl phosphine oxide, triphenyl phosphine oxide, or tris(4-methylphenyl) phosphine oxide.

7. The preparation method of a substituted oxazole compound according to claim 1, characterized in that the structural formula of the said trisubstituted phosphine dihalide is as shown in Formula VI: ##STR00023## wherein, R.sub.a, R.sub.b, and R.sub.c can be methyl, ethyl, as well as C.sub.3-C.sub.10 straight-chain or branched-chain alkyl group, aryl, and substituted aryl and are preferred to be phenyl and isobutyl; R.sub.a, R.sub.b, and R.sub.c can be either the same or different; X.sub.1 and X.sub.2 can be fluorine, chlorine, bromine, or iodine, and they can be either the same or different; preferably, when R.sub.a, R.sub.b, and R.sub.c are aryl groups, the trisubstituted phosphine dihalide is of a structure as shown in the formula V below: ##STR00024## the structural formula as shown in formula V, wherein m is 0, 1, 2, 3, 4, or 5, and R.sub.4 can be hydrogen, a C.sub.nH.sub.2n+1 straight-bran or branched-chain alkyl group (1≤n≤10), or halogen.

8. The preparation method of a substituted oxazole compound according to claim 7, characterized in that the said trisubstituted phosphine dihalide is trialkyl phosphine dichloride, triphenyl phosphine dichloride, triphenyl phosphine dibromide, or tris(4-methylphenyl) phosphine dichloride.

9. The preparation method of a substituted oxazole compound according to claim 1, characterized in that: when the said dehydrating agent is trisubstituted phosphine dihalide, the molar ratio between the trisubstituted phosphine dihalide and the Compound of Formula II is (0.01-5.0):1; preferably, it is (0.1-1.5):1; when the said dehydrating agent is a combination of trisubstituted phosphine oxide and an acyl halide reagent, the molar ratio between the acyl halide reagent and the Compound of Formula II is (0.1-2.0):1, and that between the trisubstituted phosphine oxide and the Compound of Formula II is (0.01-5.0):1; preferably, the molar ratio between the said acyl halide reagent and the Compound of Formula II is (0.3-1):1, and that between the trisubstituted phosphine oxide and the Compound of Formula II is (0.1-1.5):1; when the said dehydrating agent is a combination of trisubstituted phosphine dihalide and an acyl halide reagent, the molar ratio between the said acyl halide reagent and the Compound of Formula II is (0.1-2.0):1, and that between the trisubstituted phosphine dihalide and the Compound of Formula II is (0.01-5.0):1; Preferably, the molar ratio between the said acyl halide reagent and the Compound of Formula II is (0.3-1):1, and that between the trisubstituted phosphine dihalide and the Compound of Formula II is (0.1-1.5):1.

10. The preparation method of a substituted oxazole compound according to claim 1, characterized in that the said acyl halide reagent is sulfuryl halide, thionyl halide, oxalyl halide, or carbonyl halide; the said acyl halide reagent is preferred to be an acyl chloride agent, more preferred to be sulfuryl chloride, thionyl chloride, oxalyl chloride, or carbonyl chloride, and still more preferred to be phosgene, diphosgene, or triphosgene. More preferably, it is phosgene or triphosgene.

11. The preparation method of a substituted oxazole compound according to claim 1, characterized in that when the combination of trisubstituted phosphine oxide and an acyl chloride reagent is used as the dehydrating agent, the substituted oxazole compound can be obtained with the batch synthesis process, and the said acyl halide reagent is dropwise added to the reaction system.

12. The preparation method of a substituted oxazole compound according to claim 1, characterized in that when the combination of trisubstituted phosphine oxide and an acyl chloride reagent is used as the dehydrating agent, the substituted oxazole compound can be obtained with the continuous flow process by feeding the dehydrating agent/organic amine/compound II alone or a mixture of any two thereof continuously.

13. The preparation method of a substituted oxazole compound according to claim 1, characterized in that when the trisubstituted phosphine dihalide compound is used as the dehydrating agent, the substituted oxazole compound can be obtained with the continuous flow process by feeding the dehydrating agent/organic amine/compound II alone or a mixture of any two thereof continuously.

14. The preparation method of a substituted oxazole compound according to claim 12, characterized in that the continuous flow process used in the synthesis can be carried out in a tank continuous reactor, a pipeline continuous reactor, a tower continuous reactor, and/or a microchannel reactor.

15. The preparation method of a substituted oxazole compound according to claim 1, characterized in that the Compound of Formula II is N-ethoxalyl glycine ethyl ester, N-ethoxalyl-α-alanine ethyl ester, N-butoxalyl-α-alanine butyl ester, N-ethoxalyl-α-alanine butyl ester, N-ethoxalyl glycine methyl ester, N-methoxalyl-α-alanine methyl ester, N-ethoxalyl-α-phenylglycine ethyl ester, or N-ethoxalyl-α-alanine methyl ester, or a combination of any two or more thereof.

16. The preparation method of a substituted oxazole compound according to claim 1, characterized in that the cyclization reaction temperature is −20° C.-150° C.; preferably, it is 30-95° C.; preferably, the cyclization reaction time is 0.2-10 hours.

17. The preparation method of a substituted oxazole compound according to claim 1, characterized in that the Compound of Formula II is cyclized to obtain a reaction liquid; the resulting reaction liquid is further treated to obtain the substituted oxazole compound (I); the said treatment method comprises steps as follows: water is added to the reaction liquid for stratification; an aqueous phase and an organic phase are obtained by extracting the aqueous layer with solvent A and combining organic phases; the resulting organic phase is distilled under atmospheric pressure to recover the solvent A and then under a reduced pressure to obtain the substituted oxazole compound (I); the resulting aqueous phase or the residue of the reduced pressure distillation contains trisubstituted phosphine oxide; the trisubstituted phosphine oxide can be used together with an acyl halide reagent to prepare trisubstituted phosphine dihalide, which functions as a dehydrating agent, or recycled and used as a dehydrating agent directly; the aqueous phase can be neutralized by sodium hydroxide and distilled to recover organic amine.

18. The preparation method of a substituted oxazole compound according to claim 1, characterized in that the said substituted oxazole compound is 4-R.sub.2 substituent-5-R.sub.1 substituent oxy-2-R.sub.3 substituent oxazole; preferably, it is 4-methyl-5-alkoxy-2-R.sub.3 substituent oxazole; more preferably, it is 4-methyl-5-ethyoxyl-2-R.sub.3 substituent oxazole; preferably, it is 4-methyl-5-ethyoxyl-2-ethoxycarbonyl oxazole, 4-methyl-5-methoxyl-2-methoxycarbonyloxazole, 4-phenyl-5-ethyoxyl-2-ethoxycarbonyl oxazole, or 5-ethyoxyl-2-ethoxycarbonyl oxazole.

19. A preparation method of 4-substituted alkyl-5-substituent oxy oxazole, wherein the said 4-substituted alkyl-5-substituent oxy oxazole is of a structure as shown in formula IV: ##STR00025## the method comprises steps as follows: a Compound of Formula II is dissolved in solvent A and cyclized to obtain the substituted oxazole compound (I) in the presence of a dehydrating agent and an organic amine; the substituted oxazole compound (I) is saponified and de-carboxylated to obtain 4-substituted alkyl-5-substituent oxy oxazole (IV); the dehydrating agent is trisubstituted phosphine dihalide, a combination of trisubstituted phosphine dihalide and an acyl halide reagent, or a combination of trisubstituted phosphine oxide and an acyl halide reagent; ##STR00026## structural formulas I and II of the compounds, wherein: R.sub.1 can be hydrogen, a C.sub.nH.sub.2n+1 straight-chain or branched-chain group (1≤n≤10), aryl, or substituted aryl; R.sub.2 can be hydrogen, a C.sub.nH.sub.2n+1 straight-chain or branched-chain group where (1≤n≤10), aryl, or substituted aryl; R.sub.3 is —COOR, —CH.sub.2COOR, or —CH.sub.2CH.sub.2COOR, where R is a C.sub.nH.sub.2n+1 straight-chain or branched-chain group (1≤n≤10).

20. The preparation method of 4-substituted alkyl-5-substituent oxy oxazole according to claim 19, characterized in that the substituted oxazole compound (I) can be saponified in the presence of alkali to obtain the Compound of Formula III and then decarboxylated under acidic conditions to obtain the Compound of Formula IV; ##STR00027## in the structural formula of the Compound of Formula III, the substituents R.sub.1 and R.sub.2 are the same as those in the structural formula of the Compound of Formula II; M is an alkali metal; x is 0, 1, or 2. In the structural formula of the Compound of Formula IV, the substituents R.sub.1 and R.sub.2 are the same as those in the structural formula of the Compound of Formula II; preferably, the said alkali is the aqueous solution of an alkali metal hydroxide with a mass concentration of 20-30%; the said alkali metal is preferred to be sodium or potassium; the molar ratio between the said alkali and the substituted oxazole compound (I) is 1-1.5:1; the temperature of the said saponification reaction is 20-30° C.; preferably, the said acidic conditions are created by adjusting the reaction system to a pH of 1-2 through the use of aqueous acid (mass concentration 20-35%); the decarboxylation reaction temperature is 50-70° C.; preferably, the preparation method of 4-substituted alkyl-5-substituent oxy oxazole, comprising steps as follows: the Compound of Formula II is cyclized to obtain a reaction liquid; then, water is added to the reaction liquid for stratification; the resulting aqueous layer is extracted with solvent A, and the Compound of Formula I is obtained after combining organic phases and recovering the solvent; alkali is added to the residue for saponification reaction, and stratification is conducted at the end of the reaction; the resulting organic layer is washed with water; the aqueous layers are combined to obtain the resulting solution that contains the Compound of Formula III and decarboxylated by aqueous acid to obtain the Compound of Formula IV; after the Compound of Formula IV is separated, the remaining aqueous phase or organic phase contains trisubstituted phosphine oxide which can be used together with an acyl chloride reagent to prepare trisubstituted phosphine dihalide, which functions as a dehydrating agent, or recycled and used as a dehydrating agent directly.

Description

EMBODIMENTS

[0076] Hereinafter, the present invention will be illustrated in detail with reference to the embodiments; however, the present invention is not limited thereto.

[0077] The percentages in the embodiments all refer to mass percentages, unless otherwise indicated.

[0078] The yields in the embodiments all refer to molar yields.

[0079] The raw materials and reagents in the embodiments are all commercially available. The raw material N-ethoxalyl-α-alanine ethyl ester is supplied by Xinfa Pharmaceutical Co., Ltd.

[0080] Gas-phase detection in the invention uses a Shimadzu gas chromatograph (model GC-1020 PLUS) for reaction monitoring and purity testing. Part of the purity is tested by high performance liquid chromatography (marked as HPLC).

1. Embodiment 1: Preparation of 4-methyl-5-ethyoxyl-2-ethoxycarbonyl oxazole (I.SUB.1.)

[0081] ##STR00009##

[0082] In the mixing tank, 6000 g of well-prepared methylbenzene solution of triphenyl phosphine dichloride (containing 1000 g of triphenyl phosphine dichloride) and 650 g of N-ethoxalyl-α-alanine ethyl ester are added and evenly mixed; then, the reaction mixture is fed into the flow reactor at a rate of 111 g/min to react under a temperature of 35-75° C. with the triethylamine pumped in at a rate of 11 g/min; the solid-liquid mixture flowing out of the reactor is hydrolyzed and stratified by 2000 ml of water; the resulting aqueous phase is extracted by 2000 ml of methylbenzene; the methylbenzene phases are combined and distilled at reduced pressure; after the solvent is recovered, 578.9 g of 4-methyl-5-ethyoxyl-2-ethoxycarbonyl oxazole is obtained through high vacuum distillation in a yield of 96% and a GC purity of 99%.

[0083] The main composition of the residue after the reduced pressure distillation is triphenyl phosphine oxide, which can be used repeatedly to prepare the dehydrating agent.

[0084] Nuclear magnetic resonance data of the resulting product are provided below:

[0085] .sup.1H NMR (CDCl.sub.3, δ, ppm):

[0086] 4.28 (q, 2H), 4.31 (q, 2H), 2.07 (s, 3H), 1.36 (t, 3H), 1.33 (t, 3H).

[0087] 4-methyl-5-ethyoxyl oxazole can be obtained by further reaction following a usual method:

##STR00010##

[0088] In a reaction flask, 201 g of the resulting 4-methyl-5-ethyoxyl-2-ethoxycarbonyl oxazole and 270 g of 15% liquid caustic soda are added; then the reaction mixture is distilled at a reduced pressure to recover ethyl alcohol; then 15% hydrochloric acid is dropwise added to adjust the pH value to 2.5, and the reaction system is heated up to 60-62° C. until no gas escapes; then liquid caustic soda is added to the reaction system, and steam distillation and stratification are conducted; after the resulting oil layer is dried by anhydrous sodium sulfate, 117 g of 4-methyl-5-ethyoxyl oxazole is obtained.

Embodiment 2: Preparation of 4-methyl-5-ethyoxyl-2-ethoxycarbonyl oxazole (I.SUB.1.)

[0089] ##STR00011##

[0090] In the mixing tank, 6000 g of well-prepared methylbenzene solution of triphenyl phosphine dibromide (containing 1300 g of triphenyl phosphine dibromide) and 650 g of N-ethoxalyl-α-alanine ethyl ester are added and evenly mixed; then, the reaction mixture is fed into the flow reactor at a rate of 111 g/min to react under a temperature of 35-75° C. with the triethylamine pumped in at a rate of 11 g/min; the solid-liquid mixture flowing out of the reactor is hydrolyzed and stratified by 2000 ml of water; the resulting aqueous phase is extracted by 2000 ml of methylbenzene; the methylbenzene phases are combined and distilled at reduced pressure; after the solvent is recovered, 572 g of 4-methyl-5-ethyoxyl-2-ethoxycarbonyl oxazole is obtained through high vacuum distillation in a yield of 94.8% and a GC purity of 99%.

[0091] The main composition of the residue after the reduced pressure distillation is triphenyl phosphine oxide, which can be used repeatedly to prepare the dehydrating agent.

1. Comparative Example 1: Preparation of 4-methyl-5-ethyoxyl-2-ethoxycarbonyl oxazole (I.SUB.1.)

[0092] In a 250 ml flask, 100 g of trichloromethane, 10 g of solid phosgene, and 21.7 g (0.1 mol) of N-ethoxalyl-α-alanine ethyl ester are added; then, 25 g of triethylamine is dropwise added within 2 hours under 0-10° C. to have the reaction system react for 1 h under 0-10° C., and 30 g of water is added for stratification; the resulting aqueous layer is extracted twice by trichloromethane (a total consumption of 30 g); the organic phases are combined and distilled under the atmospheric pressure to recover trichloromethane; then after a reduced pressure distillation, 14.5 g of 4-methyl-5-ethyoxyl-2-ethoxycarbonyl oxazole is obtained in a yield of 71.6% and a GC purity of 98.3%.

[0093] It can be seen from the comparative example that the product yield is low when phosgene is used as the dehydrating agent.

Embodiment 3: Preparation of 4-methyl-5-ethyoxyl-2-ethoxycarbonyl oxazole (I.SUB.1.)

[0094] ##STR00012##

[0095] In a 250 ml flask, 100 g of trichloromethane, 33.3 g (0.1 mol) of triphenyl phosphine dichloride, and 21.7 g (0.1 mol) N-ethoxalyl-α-alanine ethyl ester are added; then, 20.2 g (0.2 mol) of triethylamine is dropwise added within 2 hours under 20-25° C. to have the reaction system react for 1 h under 35-40° C., and, after the reaction of raw materials ends, 30 g of water is added for stratification; the resulting aqueous layer is extracted twice by trichloromethane (a total consumption of 30 g); the organic phases are combined and distilled under the atmospheric pressure to recover trichloromethane; then after a reduced pressure distillation, 18.8 g of 4-methyl-5-ethyoxyl-2-ethoxycarbonyl oxazole is obtained in a yield of 94.4% and a GC purity of 99.9%. The main composition of the residue after the reduced pressure distillation is triphenyl phosphine oxide, which can be used repeatedly as the dehydrating agent.

[0096] Nuclear magnetic resonance data of the resulting product are provided below:

[0097] .sup.1H NMR (CDCl.sub.3, δ, ppm):

[0098] 4.28 (q, 2H), 4.31 (q, 2H), 2.07 (s, 3H), 1.36 (t, 3H), 1.33 (t, 3H).

Embodiment 4: Preparation of 4-methyl-5-ethyoxyl-2-ethoxycarbonyl oxazole

[0099] ##STR00013##

[0100] In a 500 ml 4-neck flask, 100 g of methylbenzene, 3.4 g (0.01 mol) of triphenyl phosphine dichloride, 21.7 g (0.1 mol) of N-ethoxalyl-α-alanine ethyl ester, and 20.8 g (0.206 mol) of triethylamine are added; then, the solution of 9.9 g (0.1 mol) of phosgene and 50 g of methylbenzene is dropwise added within 2 hours under 25-30° C. to have the reaction system react for 1 h under 65-70° C., and, after the reaction of raw materials ends, 30 g of water is added for stratification; the resulting aqueous layer is extracted twice by methylbenzene (a total consumption of 30 g); the organic phases are combined and distilled under the atmospheric pressure to recover methylbenzene; then after a reduced pressure distillation, 18.9 g of 4-methyl-5-ethyoxyl-2-ethoxycarbonyl oxazole is obtained in a yield of 94.9% and a GC purity of 99.9%. The main composition of the residue after the reduced pressure distillation is triphenyl phosphine oxide, which can be used repeatedly as the dehydrating agent.

Embodiment 5: Preparation of 4-methyl-5-ethyoxyl-2-ethoxycarbonyl oxazole (I.SUB.1.)

[0101] ##STR00014##

[0102] In a 500 ml 4-neck flask, 100 g of methylbenzene, 27.8 g (0.1 mol) of triphenyl phosphine oxide, and 21.7 g (0.1 mol) of N-ethoxalyl-α-alanine ethyl ester are added; then, the solution of 100 g of methylbenzene and 10.0 g (0.034 mol) of triphosgene and 24.3 g (0.24 mol) of triethylamine are dropwise added within 2 hours under 20-25° C. to have the reaction system react for 1 h under 45-50° C., and, after the reaction of raw materials ends, 30 g of water is added for stratification; the resulting aqueous layer is extracted twice by methylbenzene (a total consumption of 30 g); the organic phases are combined and distilled under the atmospheric pressure to recover methylbenzene; then after a reduced pressure distillation, 19.1 g of 4-methyl-5-ethyoxyl-2-ethoxycarbonyl oxazole is obtained in a yield of 96% and a GC purity of 99.9%. The main composition of the residue after the reduced pressure distillation is triphenyl phosphine oxide, which can be used repeatedly as the dehydrating agent.

Embodiment 6: Preparation of 4-methyl-5-ethyoxyl-2-ethoxycarbonyl oxazole (I.SUB.1.) (Through the Use of the Recovered Triphenyl Phosphine Oxide)

[0103] ##STR00015##

[0104] As described in Embodiment 5, the main composition of the resulting residue after 4-methyl-5-ethyoxyl-2-ethoxycarbonyl oxazole is distilled and recovered is triphenyl phosphine oxide, which can be used repeatedly as the dehydrating agent. In a 500 ml 4-neck flask, 100 g of methylbenzene is dissolved and added and then 21.7 g (0.1 mol) of N-ethoxalyl-α-alanine ethyl ester and 24.4 g (0.24 mol) of triethylamine are added; then, the solution of 100 g of methylbenzene and 9.9 g (0.033 mol) of triphosgene is dropwise added within 2 hours under 25-30° C. to have the reaction system react for 1 h under 45-50° C., and, after the reaction of raw materials ends, 30 g of water is added for stratification; the resulting aqueous layer is extracted twice by methylbenzene (a total consumption of 30 g); the organic phases are combined and distilled under the atmospheric pressure to recover methylbenzene; then after a reduced pressure distillation, 19.3 g of 4-methyl-5-ethyoxyl-2-ethoxycarbonyl oxazole is obtained in a yield of 96.9% and a GC purity of 99.9%. The main composition of the residue after the reduced pressure distillation is triphenyl phosphine oxide, which can be used repeatedly as the dehydrating agent.

1. Embodiment 7: Preparation of 4-methyl-5-methoxyl-2-methoxycarbonyloxazole (I.SUB.2.) and 4-methyl-5-methoxy oxazole (IV.SUB.2.)

[0105] ##STR00016##

[0106] In a 500 ml 4-neck flask, 80 g of dimethylbenzene, 27.8 g (0.1 mol) of triphenyl phosphine oxide, 18.9 g (0.1 mol) of N-methoxalyl-α-alanine methyl ester, and 20.8 g (0.206 mol) of triethylamine are added; then, the mixed solution of 60 g of dimethylbenzene and 9.9 g (0.1 mol) of phosgene is dropwise added within 2 hours under 30-35° C. to have the reaction system react for 1 h under 35-40° C., and, after the reaction of raw materials ends, 30 g of water is added for stratification; the resulting aqueous layer is extracted twice by dimethylbenzene (a total consumption of 30 g); the organic phases are combined; upon GC testing, 16.1 g of 4-methyl-5-methoxyl-2-methoxycarbonyl oxazole is obtained in a yield of 94%.

[0107] To the combined organic phase, 20 g of 25% aqueous solution of sodium hydroxide is added, and then the reaction mixture is stirred and stratified under room temperature for 30 minutes; the resulting organic phase is washed twice by water (30 g each) to obtain triphenyl phosphine oxide, which can be repeatedly used as the dehydrating agent; then the aqueous layers are combined, and 24.7 g of 31% hydrochloric acid is added to adjust the pH to 1.5; the aqueous solution is then heated up to 60° C. and maintained at the temperature for 30 minutes before being neutralized to neutral; after a reduced pressure distillation, 10.1 g of 4-methyl-5-methoxy oxazole is obtained in a yield of 89.3 and a GC purity of 99.9% if calculated by N-methoxalyl-α-alanine methyl ester.

[0108] Nuclear magnetic resonance data of the resulting product 4-methyl-5-methoxy oxazole are provided below:

[0109] .sup.1H NMR (CDCl.sub.3, δ, ppm):

[0110] 7.33 (s, 1H), 3.89 (s, 3H), 1.99 (s, 3H).

Embodiment 8: Preparation of 4-methyl-5-methoxyl-2-methoxycarbonyloxazole (I.SUB.2.) (Through the Use of the Recovered Triphenyl Phosphine Oxide)

[0111] ##STR00017##

[0112] As described in Embodiment 5, the main composition of the resulting residue after 4-methyl-5-ethyoxyl-2-ethoxycarbonyl oxazole is distilled and recovered is triphenyl phosphine oxide, which can be used repeatedly as the dehydrating agent. In a 500 ml 4-neck flask, 100 g of methylbenzene is dissolved and added and then 18.9 g (0.1 mol) of N-methoxalyl-α-alanine methyl ester and 20.8 g (0.206 mol) of triethylamine are added; then, the solution of 60 g of methylbenzene and 9.9 g (0.033 mol) of triphosgene is dropwise added within 2 hours under 20-25° C. to have the reaction system react for 1 h under 35-40° C., and, after the reaction of raw materials ends, 30 g of water is added for stratification; the resulting aqueous layer is extracted twice by methylbenzene (a total consumption of 30 g); the organic phases are combined and distilled under the atmospheric pressure to recover methylbenzene; then after a reduced pressure distillation, 16.5 g of 4-methyl-5-methoxyl-2-methoxycarbonyl oxazole is obtained in a yield of 96.4%.

[0113] Nuclear magnetic resonance data of the resulting product are provided below:

[0114] .sup.1H NMR (CDCl.sub.3, δ, ppm):

[0115] 3.89 (s, 3H), 3.85 (s, 3H), 2.07 (s, 3H)

Embodiment 9: Preparation of 4-methyl-5-methoxyl-2-methoxycarbonyl oxazole (I.SUB.2.)

[0116] ##STR00018##

[0117] In a 500 ml 4-neck flask, 80 g of cyclohexane, 32 g (0.1 mol) of tris(4-methylphenyl)phosphine oxide, 18.9 g (0.1 mol) of N-methoxalyl-α-alanine methyl ester, and 28.9 g (0.202 mol) of tri-n-propylamine are added; then, the mixed solution of 60 g of cyclohexane and 11.9 g (0.1 mol) of thionyl chloride is dropwise added within 2 hours under 20-25° C. to have the reaction system react for 1 h under 60-65° C., and, after the reaction of raw materials ends, 30 g of water is added for stratification; the resulting aqueous layer is extracted twice by cyclohexane (a total consumption of 30 g); the organic phases are combined, washed once with 30 g of water, and stratified to obtain aqueous phase and organic phase; the aqueous phases are combined (this part of water can be used as the aqueous phases contain tris(4-methylphenyl)phosphine oxide); the resulting organic phase is distilled under the atmospheric pressure to recover cyclohexane; after a reduced pressure distillation, 15.6 g of 4-methyl-5-methoxyl-2-methoxycarbonyl oxazole is obtained in a yield of 91.2% and a GC purity of 99.2%.

1. Embodiment 10: Preparation of 4-phenyl-5-ethyoxyl-2-ethoxycarbonyl oxazole (I.SUB.3.)

[0118] ##STR00019##

[0119] In a 500 ml 4-neck flask, 100 g of methylbenzene, 32 g (0.1 mol) of tris(4-methylphenyl)phosphine oxide, 27.9 g (0.1 mol) of N-ethoxalyl-α-phenylglycine ethyl ester, and 25.3 g (0.25 mol) of triethylamine are added; then, the solution of 50 g of methylbenzene and 10.1 g (0.034 mol) of triphosgene is dropwise added within 2 hours under 25-30° C. to have the reaction system react for 1 h under 45-50° C., and, after the reaction of raw materials ends, 30 g of water is added for stratification; the resulting aqueous layer is extracted by methylbenzene (a total consumption of 30 g); the organic phases are combined, washed once with 30 g of water, and stratified to obtain aqueous phase and organic phase; the aqueous phases are combined; the resulting organic phase is distilled under the atmospheric pressure to recover methylbenzene; then after a reduced pressure distillation, 22.3 g of 4-phenyl-5-ethyoxyl-2-ethoxycarbonyl oxazole is obtained in a yield of 85.3%.

[0120] Nuclear magnetic resonance data of the resulting product are provided below:

[0121] .sup.1H NMR (CDCl.sub.3, δ, ppm):

[0122] 7.6 (d, 2H), 7.4-7.5 (m, 3H), 4.27 (q, 2H), 4.31 (q, 2H), 1.35 (t, 3H), 1.33 (t, 3H)

Embodiment 11: Preparation of 5-ethyoxyl-2-ethoxycarbonyl oxazole (I.SUB.4.)

[0123] ##STR00020##

[0124] In a 500 ml 4-neck flask, 80 g of methylbenzene, 27.8 g (0.1 mol) of triphenyl phosphine oxide, 20.3 g (0.1 mol) of N-ethoxalyl glycine ethyl ester, and 22.2 g (0.22 mol) of triethylamine are added; then, the solution of 50 g of methylbenzene and 9.9 g (0.1 mol) of phosgene is dropwise added within 2 hours under 25-30° C. to have the reaction system react for 1 h under 50-55° C., and, after the reaction of raw materials ends, 30 g of water is added for stratification; the resulting aqueous layer is extracted by methylbenzene (a total consumption of 30 g); the organic phases are combined, washed once with 30 g of water, and stratified to obtain aqueous phase and organic phase; the aqueous phases are combined; the resulting organic phase is distilled under reduced pressure to recover methylbenzene; then after a reduced pressure distillation, 17.6 g of 5-ethyoxyl-2-ethoxycarbonyl oxazole is obtained in a yield of 95.1% and a GC purity of 99.9%.

[0125] Nuclear magnetic resonance data of the resulting product are provided below:

[0126] .sup.1H NMR (CDCl.sub.3, δ, ppm):

[0127] 6.81 (s, 1H), 4.29 (q, 2H), 4.32 (q, 2H), 1.35 (t, 3H), 1.32 (t, 3H).

1. Embodiment 12: Preparation of 4-methyl-5-ethyoxyl-2-ethoxycarbonyl oxazole (I.SUB.1.)

[0128] In a 250 ml flask, 100 g of trichloromethane, 33.3 g (0.1 mol) of triphenyl phosphine dichloride, and 21.7 g (0.1 mol) of N-ethoxalyl-α-alanine ethyl ester are added; then, 20.2 g (0.2 mol) of triethylamine is dropwise added within 2 hours under −40° C.-−45° C. to have the reaction system react for 1 h under −40° C.-−45° C.; then 30 g of water is added to quench the reaction for stratification under room temperature; the resulting aqueous layer is extracted twice by trichloromethane (a total consumption of 30 g); the organic phases are combined and distilled under the atmospheric pressure to recover trichloromethane; then after a reduced pressure distillation, 15.3 g of 4-methyl-5-ethyoxyl-2-ethoxycarbonyl oxazole is obtained in a yield of 76.6% and a GC purity of 98.3%.

[0129] As can be seen from the embodiment, the conversion and yield of the product are reduced when the temperature is low.