METHOD FOR PREPARING INTERMEDIATE OF URACIL COMPOUND CONTAINING ISOXAZOLINE

Abstract

A method for preparing an intermediate of a uracil compound containing isooxazoline includes the steps of: making 3-amino-4,4,4-trifluorocrotonic acid methyl ester react with substituted aryl carbamate; in a reaction process, continuously evaporating water and byproduct alcohol in the system; and conducting processing to obtain the intermediate of the uracil compound containing isooxazoline. Using this method the selectivity of the reaction and the utilization rate of raw materials are improved; the hydrolysis products, impurities and tar are reduced; the reaction time is greatly shortened; and the productivity is improved. After one recrystallization of crude products, an intermediate product with purity of more than 97% can be obtained, and quantitative yield can be more than 85%.

Claims

1. A method for preparing an intermediate of a uracil compound containing isooxazoline, characterized by comprising: making 3-amino-4,4,4-trifluorocrotonic acid methyl ester react with substituted aryl carbamate; in a reaction process, continuously evaporating water and byproduct alcohol in the system; and conducting processing to obtain the intermediate of the uracil compound containing isooxazoline; or, making 3-amino-4,4,4-trifluorocrotonic acid methyl ester react with substituted aryl carbamate in the presence of a catalyst; in a reaction process, continuously evaporating water and byproduct alcohol in the system; and conducting processing to obtain the intermediate of the uracil compound containing isooxazoline.

2. The method for preparing the intermediate of the uracil compound containing isooxazoline according to claim 1, characterized in that a reaction formula is: ##STR00006## R.sub.1 and R.sub.2 can be the same or different, and are respectively selected from hydrogen, fluorine or chlorine; R.sub.3 is selected from hydrogen or C.sub.1-C.sub.4 alkyl; R.sub.4 is selected from hydrogen, CO.sub.2R.sub.7 or CH.sub.2OR.sub.8; R.sub.5 is selected from hydrogen, CO.sub.2R.sub.7 or CH.sub.2OR.sub.8; R.sub.6 is selected from hydrogen, C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 haloalkyl; R.sub.7 is selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, allyl or propargyl; R.sub.8 is selected from hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl or C.sub.1-C.sub.4 alkyl carbonyl; R.sub.9 is selected from C.sub.1-C.sub.4 alkyl; R.sub.10 is selected from C.sub.1-C.sub.4 alkyl.

3. The method for preparing the intermediate of the uracil compound containing isooxazoline according to claim 1, characterized in that in the reaction formula, R.sub.1 and R.sub.2 can be the same or different, and are respectively selected from hydrogen, fluorine or chlorine; R.sub.3 is selected from hydrogen or C.sub.1-C.sub.4 alkyl; R.sub.4 is selected from hydrogen; R.sub.5 is selected from CO.sub.2R.sub.7; R.sub.6 is selected from hydrogen, C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 haloalkyl; R.sub.7 is selected from methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, tert-butyl, trifluoroethyl, allyl and propargyl; R.sub.9 is selected from methyl or ethyl; R.sub.10 is selected from methyl or ethyl.

4. The method for preparing the intermediate of the uracil compound containing isooxazoline according to claim 1, characterized in that the compound shown in formula III and the compound shown in formula IV react in the presence of a water carrying agent or a mixed solvent; in the reaction process, the water and byproduct alcohol in the system are continuously evaporated, and the intermediate of the uracil compound containing isooxazoline is obtained after treatment; or, the reaction process is carried out under the action of a catalyst.

5. The method for preparing the intermediate of the uracil compound containing isooxazoline according to claim 4, characterized in that alkali is added in the reaction process, wherein the molar ratio of the alkali to the compound shown in formula III is 0.5:1-3:1.

6. The method for preparing the intermediate of the uracil compound containing isooxazoline according to claim 4, characterized in that the catalyst is 1,8-diazabicyclo[5.4.0]undec-7-ene, salt of 1,8-diazabicyclo[5.4.0]undec-7-ene or solution of 1,8-diazabicyclo[5.4.0]undec-7-ene, wherein the use amount of the catalyst is 0.001%-10% of the weight of the compound shown in formula III.

7. The method for preparing the intermediate of the uracil compound containing isooxazoline according to claim 6, characterized in that the use amount of the catalyst is 0.1%-5% of the weight of the compound shown in formula III.

8. The method for preparing the intermediate of the uracil compound containing isooxazoline according to claim 5, characterized in that the alkali is one or two of potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate or cesium bicarbonate.

9. The method for preparing the intermediate of the uracil compound containing isooxazoline according to claim 8, characterized in that the alkali is one or two of potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate, wherein the molar ratio of the alkali to the compound shown in formula III is 0.5:1-2:1.

10. The method for preparing the intermediate of the uracil compound containing isooxazoline according to claim 4, characterized in that the amount of the water carrying agent or mixed solvent is 2-20 times the weight of the compound shown in formula III; the mixed solvent comprises the water carrying agent and a polar aprotic solvent, wherein the weight of the polar aprotic solvent in the mixed solvent is 20%-70%.

11. The method for preparing the intermediate of the uracil compound containing isooxazoline according to claim 10, characterized in that the water carrying agent is one of n-propyl acetate, isopropyl acetate, n-butyl acetate, methyl isopropyl ketone, methyl isobutyl ketone, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, 2-methyl tetrahydrofuran and acetonitrile; the water carrying agent in the mixed solvent is one of toluene, chlorobenzene, n-propyl acetate, isopropyl acetate, methyl isopropyl ketone, methyl isobutyl ketone, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, 2-methyltetrahydrofuran and acetonitrile; and the polar aprotic solvent in the mixed solvent is N,N-dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidone.

12. A method for production of compound of formula I, comprising: producing compound of formula II using a method according to claim 2, and converting compound of formula II for obtain compound of formula I.

Description

DETAILED DESCRIPTION

[0049] The preparation method of the compound shown in formula II is further detailed below by enumerating embodiments, but the present invention is not limited to these embodiments. Various changes and variations may be made to the present invention for those skilled in the art. Any modification, equivalent substitution, improvement, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

[0050] In the method of the present invention, the selectivity of the reaction and the utilization rate of raw materials are improved; the hydrolysis products, impurities and tar are reduced; the reaction time is greatly shortened; and the productivity is improved. Moreover, after one recrystallization of crude products, an intermediate product with purity of more than 97% can be obtained, and quantitative yield can be more than 85%, which is suitable for industrial production.

Embodiment 1 Synthesis of Compound II-1

[0051] 39.3 g (100 mmol) of 3-(2-chloro-5-((ethoxycarbonyl)amino)-4-fluorophenyl)-5-methyl-4,5-dihydroisoxazole-5-carboxylate ethyl, 19.2 g (103 mmol) of 3-amino-4,4,4-trifluorocrotonate, 10.4 g (75 mmol) of potassium carbonate, 80 g of isopropyl acetate, 80 g of N,N-dimethylformamide and 1.0 g of 1,8-diazabicyclo[5.4.0]undec-7-ene were added to a reaction flask with a rectification device, stirred, heated and subjected to reflux reaction for 5 hours; in this period, a small amount of low-boiling-point substances below 78° C. were separated from the top of the tower; HPLC was used for tracking until the reaction was ended; most solvents were evaporated under reduced pressure; residues were acidified with hydrochloric acid; pH was adjusted to 2-4; isopropyl acetate was added for extraction; after stirring for 20 minutes, the lower water layer was removed; the organic layer was washed with water once; after the water layer was removed, isopropyl acetate was evaporated under reduced pressure; residues were normalized by HPLC and the content was 96.1%; the mixture was recrystallized with ethanol water, and filtered at 0-5° C.; a filter cake was drip-washed with cold ethanol water and dried to obtain 41.3 g; HPLC quantitative content was 98.3%; and quantitative yield was 87.5%.

Embodiment 2 Synthesis of Compound II-1

[0052] 39.3 g (100 mmol) of 3-(2-chloro-5-((ethoxycarbonyl)amino)-4-fluorophenyl)-5-methyl-4,5-dihydroisoxazole-5-carboxylate ethyl, 19.2 g (103 mmol) of 3-amino-4,4,4-trifluorocrotonate, 10.4 g (75 mmol) of potassium carbonate, 120 g of methyl isobutyl ketone and 1.0 g of 1,8-diazabicyclo[5.4.0]undec-7-ene were added to a reaction flask with a rectification device, stirred, heated and subjected to reflux reaction for 10 hours; in this period, a small amount of low-boiling-point substances below 78° C. were separated from the top of the tower; HPLC was used for tracking until the reaction was ended; most solvents were evaporated under reduced pressure; residues were acidified with hydrochloric acid; pH was adjusted to 2-4; methyl isobutyl ketone was added for extraction; after stirring for 20 minutes, the lower water layer was removed; the organic layer was washed with water once; after the water layer was removed, methyl isobutyl ketone was evaporated under reduced pressure; residues were normalized by HPLC and the content was 95.0%; the mixture was recrystallized with ethanol water, and filtered at 0-5° C.; a filter cake was drip-washed with cold ethanol water and dried to obtain 41.7 g; HPLC quantitative content was 96.0%; and quantitative yield was 86.3%.

Embodiment 3 Synthesis of Compound II-2

[0053] 39.3 g (100 mmol) of (3-(2-chloro-4-fluoro-5-((methoxycarbony)amino)phenyl)-5-methyl-4,5-dihydroisoxazole-5-yl) methylacetate, 19.2 g (103 mmol) of 3-amino-4,4,4-trifluorocrotonate, 9.1 g (65 mmol) of potassium carbonate, 80 g of isopropyl acetate, 80 g of N-methylpyrrolidone and 1.0 g of 1,8-diazabicyclo[5.4.0]undec-7-ene were added to a reaction flask with a rectification device, stirred, heated and subjected to reflux reaction for 5 hours; in this period, a small amount of low-boiling-point substances below 78° C. were separated from the top of the tower; HPLC was used for tracking until the reaction was ended; most solvents were evaporated under reduced pressure; residues were acidified with hydrochloric acid; pH was adjusted to 2-4; isopropyl acetate was added for extraction; after stirring for 20 minutes, the lower water layer was removed; the organic layer was washed with water once; after the water layer was removed, isopropyl acetate was evaporated under reduced pressure; residues were normalized by HPLC and the content was 95.1%; the mixture was recrystallized with ethanol water, and filtered at 0-5° C.; a filter cake was drip-washed with cold ethanol water and dried to obtain 42.0 g; HPLC quantitative content was 97.1%; and quantitative yield was 87.9%.

Embodiment 4 Synthesis of Compound II-2

[0054] 39.0 g (100 mmol) of (3-(2-chloro-5-((methoxycarbony)amino)-4-fluorophenyl)-5-methyl-4,5-dihydroisoxazole-5-yl) methylacetate, 19.2 g (103 mmol) of 3-amino-4,4,4-trifluorocrotonate, 3.0 g of tetrabutylammonium bromide, 9.1 g (65 mmol) of potassium carbonate, 80 g of toluene and 80 g of N,N-dimethylformamide were added to a reaction flask with a rectification device, stirred, heated and subjected to reflux reaction for 25 hours; in this period, a small amount of low-boiling-point substances below 80° C. were separated from the top of the tower; HPLC was used for tracking until the reaction was ended; most solvents were evaporated under reduced pressure; residues were acidified with hydrochloric acid; pH was adjusted to 2-4; toluene was added for extraction; after stirring for 20 minutes, the lower water layer was removed; the organic layer was washed with water once; after the water layer was removed, toluene was evaporated under reduced pressure; residues were normalized by HPLC and the content was 86%; the mixture was recrystallized with ethanol water for three times, and filtered at 0-5° C.; a filter cake was drip-washed with cold ethanol water and dried to obtain 24.2 g; HPLC quantitative content was 96.1%; and quantitative yield was 50.1%.

Embodiment 5 Synthesis of Compound II-2

[0055] 3.1 Kg (8 mol) of (3-(2-chloro-4-fluoro-5-((methoxycarbony)amino)phenyl)-5-methyl-4,5-dihydroisoxazole-5-yl) methylacetate, 1.5 Kg (8.1 mol) of 3-amino-4,4,4-trifluorocrotonate, 0.75 Kg (5.5 mol) of potassium carbonate, 70 Kg of isopropyl acetate, 60 Kg of N,N-dimethylformamide and 0.06 Kg of 1,8-diazabicyclo[5.4.0]undec-7-ene were added to a reaction flask with a rectification device, stirred, heated and subjected to reflux reaction for 5 hours; in this period, a small amount of low-boiling-point substances below 78° C. were separated from the top of the tower; HPLC was used for tracking until the reaction was ended; most solvents were evaporated under reduced pressure; residues were acidified with hydrochloric acid; pH was adjusted to 2-4; isopropyl acetate was added for extraction; after stirring for 20 minutes, the lower water layer was removed; the organic layer was washed with water once; after the water layer was removed, isopropyl acetate was evaporated under reduced pressure; residues were normalized by HPLC and the content was 94.5%; the mixture was recrystallized with ethanol water, and filtered at 0-5° C.; a filter cake was drip-washed with cold ethanol water and dried to obtain 3.3 Kg; HPLC quantitative content was 97.0%; and quantitative yield was 86.3%.

Embodiment 6 Synthesis of Compound I-3

[0056] 33.4 g (0.07 mol, quantitative content of 97.2%) of above compound II-2 (3-(2-chloro-5-(2,6-dioxy-4-trifluoromethyl-3,6-dihydropyrimidine-1(2H)-yl)-4-fluorophenyl)-5-methyl-4,5-dihydroisoxazole-5-yl) methylacetate, 7.10 g (0.084 mol) of sodium bicarbonate, 150 g of dichloromethane and 3.0 g of 1, 4-diazadicyclic [2.2.2] octane were added to an autoclave; 5.0 g of methyl chloride was measured and introduced; the mixture was stirred and heated to 70-80° C.; a pressure gauge showed 0.4 Mpa; and the reaction lasted for 11 hours. The temperature was lowered to 20° C., the pressure in the autoclave was discharged, and the excess methyl chloride was recovered. 50 g of water was added to the autoclave and stirred for 10 minutes; after that, the mixture was layered and the water layer was removed; the organic layer was washed with 50 g of water once; the organic layer was filtered to remove a small amount of undissolved substances; the desolvent was decompressed to obtain 33.9 g of oil, with quantitative content of 93.5% and yield of 94.5%.

[0057] The specific structures of the compounds obtained in embodiments 1, 2, 3 and 4:

TABLE-US-00001 Nuclear magnetic data (.sup.1HNMR, 300 MHz, internal standard No. Structure TMS, solvent CDC1.sub.3) II-1 [00003] 1.33(t, 3H), 1.71(s, 3H), 3.34(d, 1H), 3.60(d, 1H), 4.27(m, 2H), 6.21(s, 1H), 7.36(d, 1H), 7.71(d, 1H), 10.13(s, 1H). II-2 [00004] 1.40(s, 3H), 2.02(s, 3H), 3.24(d, 1H), 3.49(d, 1H), 3.86(m, 2H), 6.21(s, 1H), 7.50(d, 1H), 7.69(d, 1H), 10.01(s, 1H). I-3 [00005] 1.41(s, 3H), 2.03(s, 3H), 3.25(d, 1H), 3.50(d, 1H), 3.62(s, 3H), 3.88(m, 2H), 6.22(s, 1H), 7.51(d, 1H), 7.69(d, 1H).

Reference Embodiment 1 Synthesis of Compound II-2

[0058] 39.0 g (100 mmol) of (3-(2-chloro-5-(methoxycarbonyl)amino)-4-fluorophenyl)-5-methyl-4,5-dihydroisoxazole-5-yl) methylacetate, 19.2 g (103 mmol) of 3-amino-4,4,4-trifluorocrotonate, 9.1 g (65 mmol) of potassium carbonate and 100 g of N,N-dimethylformamide were added to a reaction flask with a rectification device, stirred, heated and subjected to reaction for 4 hours at 130° C.; HPLC was used for tracking until the reaction was ended; most solvents were evaporated under reduced pressure; residues were acidified with hydrochloric acid; pH was adjusted to 2-4; methyl isobutyl ketone was used for extraction; after stirring for 20 minutes, the lower water layer was removed; the organic layer was washed with water once; after the water layer was removed, methyl isobutyl ketone was evaporated under reduced pressure; residues were normalized by HPLC and the content was 42.2%;

Reference Embodiment 2 Synthesis of Compound II-2

[0059] 39.0 g (100 mmol) of (3-(2-chloro-5-(methoxycarbonyl)amino)-4-fluorophenyl)-5-methyl-4,5-dihydroisoxazole-5-yl) methylacetate, 19.2 g (103 mmol) of 3-amino-4,4,4-trifluorocrotonate, 9.1 g (65 mmol) of potassium carbonate and 100 g of N,N-dimethylformamide were added to a reaction flask with a rectification device, stirred and heated; micro negative pressure was applied to the reaction system through the top of the tower; water and byproduct ethanol were removed from the reaction system, and the reaction was carried out at 105° C. for 18 hours; most solvents were evaporated under reduced pressure; residues were acidified with hydrochloric acid; pH was adjusted to 2-4; methyl isobutyl ketone was used for extraction; after stirring for 20 minutes, the lower water layer was removed; the organic layer was washed with water once; after the water layer was removed, methyl isobutyl ketone was evaporated under reduced pressure; residues were normalized by HPLC and the content was 64.3%;

[0060] It can be seen from the above embodiments and reference embodiments that the method for preparing the intermediate of the uracil compound containing isooxazoline is available in raw materials and mild in conditions; through the water carrying agent or the mixed solvent, the water and the alcohol in the system can be continuously removed, the hydrolysis of raw materials and products is reduced, and the selectivity of the reaction is improved. The addition of the catalyst greatly reduces the reaction time. Under the combined action of the two, the utilization rate of raw materials is improved; the hydrolysis products, impurities and tar are reduced; the reaction time is greatly shortened; and the productivity is greatly improved, which is convenient for industrial production.