Preparation method and application of isoxazinone compounds

Abstract

Disclosed herein are a preparation method and an application of an isoxazinone compound (I), where the preparation method includes: reacting compound (II) with a carboxylic acid (III) in the presence of a dehydrating agent and a base to produce the isoxazinone compound (I); and subjecting the isoxazinone compound (I) and a protonic acid salt of an amino compound (IV) or R.sub.3OH (VII) to ring-opening reaction in the presence of a base to produce a bisamide compound (V) or an N-acyl benzoate compound (VI).

Claims

1. A method for preparing an isoxazinone compound (I), comprising: reacting compound (II) with a carboxylic acid (III) in the presence of a dehydrating agent and a base to produce the isoxazinone compound (I), as shown in the following reaction scheme: ##STR00009## wherein: Q is N or C—Z; each R is independently alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cyano, carbonyl, alkoxycarbonyl, halogen, alkoxy, alkylthio, sulfonyl, sulfinyl, alkylamino or nitro; each Z is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cyano, carbonyl, alkoxycarbonyl, halogen, alkoxy, alkylthio, sulfonyl, sulfinyl, alkylamino or nitro; n is 0, 1, 2 or 3; and R′ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; and the dehydrating agent is a phosphorus reagent.

2. The method of claim 1, wherein the base is an organic base.

3. The method of claim 1, wherein the phosphorus reagent is selected from the group consisting of phosphorus pentoxide, phosphorus oxychloride, phosphorus oxybromide, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride and phosphorus pentabromide.

4. The method of claim 3, wherein the phosphorus reagent is phosphorus oxychloride or phosphorus oxybromide.

5. The method of claim 2, wherein the organic base is selected from the group consisting of pyridine, 3-methylpyridine, N,N-dimethylaminopyridine and triethylamine.

6. The method of claim 1, wherein a molar ratio of the compound (II) to the carboxylic acid (III) is 1:0.5-1.5; a molar ratio of the compound (II) to the dehydrating agent is 1:1-2; and a molar ratio of the compound (II) to the base is 1:2-5.

7. A method for preparing a bisamide compound (V), comprising: reacting compound (II) with a carboxylic acid (III) in the presence of a dehydrating agent and a first base to produce the isoxazinone compound (I); and subjecting the isoxazinone compound (I) and a protonic acid salt of an amino compound (IV) to ring-opening reaction in the presence of a second base to produce the bisamide compound (V), as shown in the following reaction scheme: ##STR00010## wherein: Q is N or C—Z; each R is independently alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cyano, carbonyl, alkoxycarbonyl, halogen, alkoxy, alkylthio, sulfonyl, sulftnyl, alkylamino or nitro; each Z is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cyano, carbonyl, alkoxycarbonyl, halogen, alkoxy, alkylthio, sulfonyl, sulfinyl, alkylamino or nitro; n is 0, 1, 2 or 3; R′ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; R.sub.1 and R.sub.2 are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, but are not simultaneously hydrogen; and HY is hydrohalic acid, sulfuric acid, phosphoric acid or carboxylic acid.

8. The method of claim 7, wherein HY is hydrochloric acid or sulfuric acid; and the second base used in the ring-opening reaction is triethylamine, pyridine, 3-methylpyridine or N,N-dimethylaminopyridine.

9. The method of claim 7, wherein the dehydrating agent is a phosphorus reagent and the first base is an organic base.

10. The method of claim 9, wherein the phosphorus reagent is selected from the group consisting of phosphorus pentoxide, phosphorus oxychloride, phosphorus oxybromide, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride and phosphorus pentabromide.

11. The method of claim 10, wherein the phosphorus reagent is phosphorus oxychloride or phosphorus oxybromide.

12. The method of claim 9, wherein the organic base is selected from the group consisting of pyridine, 3-methylpyridine, N,N-dimethylaminopyridine and triethylamine.

13. The method of claim 7, wherein a molar ratio of the compound (II) to the carboxylic acid (III) is 1:0.5-1.5; a molar ratio of the compound (II) to the dehydrating agent is 1:1-2; and a molar ratio of the compound (II) to the first base is 1:2-5.

14. A method for preparing an N-acyl benzoate compound (VI), comprising: reacting compound (II) with a carboxylic acid (III) in the presence of a dehydrating agent and a first base to produce the isoxazinone compound (I); and subjecting the isoxazinone compound (I) and R.sub.3OH (VII) to ring-opening reaction in the presence of a second base to produce the N-acyl benzoate compound (VI), as shown in the following reaction scheme: ##STR00011## wherein: Q is N or C—Z; each R is independently alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cyano, carbonyl, alkoxycarbonyl, halogen, alkoxy, alkylthio, sulfonyl, sulftnyl, alkylamino or nitro; each Z is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cyano, carbonyl, alkoxycarbonyl, halogen, alkoxy, alkylthio, sulfonyl, sulfinyl, alkylamino or nitro; n is 0, 1, 2 or 3; R′ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; and R.sub.3 is alkyl, substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl.

15. The method of claim 14, wherein the second base used in the ring-opening reaction is an alkoxide of an alkali metal.

16. The method of claim 14, wherein the dehydrating agent is a phosphorus reagent and the first base is an organic base.

17. The method of claim 16, wherein the phosphorus reagent is selected from the group consisting of phosphorus pentoxide, phosphorus oxychloride, phosphorus oxybromide, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride and phosphorus pentabromide.

18. The method of claim 17, wherein the phosphorus reagent is phosphorus oxychloride or phosphorus oxybromide.

19. The method of claim 16, wherein the organic base is selected from the group consisting of pyridine, 3-methylpyridine, N,N-dimethylaminopyridine and triethylamine.

20. The method of claim 14, wherein a molar ratio of the compound (II) to the carboxylic acid (III) is 1:0.5-1.5; a molar ratio of the compound (II) to the dehydrating agent is 1:1-2; and a molar ratio of the compound (II) to the first base is 1:2-5.

Description

DETAILED DESCRIPTION OF EMBODIMENTS

(1) The features of the invention will be further illustrated below with reference to the embodiments, but these embodiments are not intended to limit the invention.

Example 1 Preparation of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-chloro-8-methyl-4H-3,1-benzoxazin-4-one

(2) 3.02 g of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid, 1.95 g of 3-methylpyridine and 15 mL of acetonitrile were added to a 100 mL three-necked flask, to which 5.73 g of POBr.sub.3 was dropwise added at −5° C. The reaction mixture was stirred for half an hour with the temperature kept, and then 1.86 g of 2-amino-3-methyl-5-chlorobenzoic acid was added. The reaction mixture was reacted at room temperature for 1 h. After the reaction was complete, the reaction mixture was added with 20 mL of water, stirred for 0.5 h and filtered. The filter cake was washed with a mixture of acetonitrile and water in a ratio of 3:2 and dried to give 4.16 g of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-chloro-8-methyl-4H-3,1-benzoxazin-4-one, and the yield was 92%.

Example 2 Preparation of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-cyano-8-methyl-4H-3,1-benzoxazin-4-one

(3) 3.02 g of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid, 1.95 g of 3-methylpyridine and 15 mL of acetonitrile were added to a 100 mL three-necked flask, to which 3.23 g of POCl.sub.3 was dropwise added at −5° C. The reaction mixture was stirred for half an hour with the temperature kept, and then 1.94 g of 2-amino-3-methyl-5-cyanobenzoic acid was added. The reaction mixture was reacted at room temperature for 1 h. After the reaction was complete, the reaction mixture was added with 20 mL of water, stirred for 0.5 h and filtered. The filter cake was washed with a mixture of acetonitrile and water in a ratio of 3:2 and dried to give 3.82 g of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-cyano-8-methyl-4H-3,1-ben zoxazin-4-one, and the yield was 86%.

(4) .sup.1H NMR (500 MHz, DMSO): δ 8.63 (dd, 1H), 8.40-8.33 (m, 2H), 8.10 (s, 1H), 7.77 (dd, 1H), 7.60 (s, 1H), 1.73 (s, 3H).

Example 3 Preparation of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazin-4-one

(5) 3.02 g of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid, 2.02 g of triethylamine and 15 mL of acetonitrile were added to a 100 mL three-necked flask, to which 3.23 g of POCl.sub.3 was dropwise added at −5° C. The reaction mixture was stirred for half an hour with the temperature kept, and then 3.02 g of 2-amino-3-methylbenzoic acid was added. The reaction mixture was reacted at room temperature for 2 h. After the reaction was complete, the reaction mixture was added with 20 mL of water, stirred for 0.5 h and filtered. The filter cake was washed with a mixture of acetonitrile and water in a ratio of 3:2 and dried to give 3.76 g of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazin-4-one, and the yield was 90%.

(6) .sup.1HNMR (500 MHz, DMSO): δ8.63 (dd, 1H), 8.35 (dd, 1H), 7.93 (d, 1H), 7.76 (dd, 1H), 7.68 (d, 1H), 7.49 (dd, 2H), 1.74 (s, 3H).

Example 4 Preparation of 2-[3,4-Dibromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-cyano-8-methyl-4H-3,1-benzoxazin-4-one

(7) 3.81 g of 3,4-Dibromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid, 2.46 g of N,N-dimethylaminopyridine and 15 mL of acetonitrile were added to a 100 mL three-necked flask, to which 3.23 g of POCl.sub.3 was dropwise added at −5° C. The reaction mixture was stirred for half an hour with the temperature kept, and then 1.86 g of 2-amino-3-methyl-5-chlorobenzoic acid was added. The reaction mixture was reacted at room temperature for 3 h. After the reaction was complete, the reaction mixture was added with 20 mL of water, stirred for 0.5 h and filtered. The filter cake was washed with a mixture of acetonitrile and water in a ratio of 3:2 and dried to give 5.04 g of 2-[3,4-Dibromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-cyano-8-methyl-4H-3,1-benzoxazin-4-one, and the yield was 95%.

(8) .sup.1H NMR (400 MHz, DMSO): δ8.60 (d, 1H), 8.36 (d, 1H), 7.97-7.88 (m, 1H), 7.83 (s, 1H), 7.76 (dd, 1H), 1.88 (S, 3H).

Example 5 Preparation of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-bromo-8-methyl-4H-3,1-benzoxazin-4-one

(9) 3.02 g of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid, 3.95 g of pyridine and 15 mL of acetonitrile were added to a 100 mL three-necked flask, to which 3.23 g of PCl.sub.3 was dropwise added at −5° C. The reaction mixture was stirred for half an hour with the temperature kept, and then 2.3 g of 2-amino-3-methyl-5-bromobenzoic acid was added. The reaction mixture was reacted at room temperature for 1 h. After the reaction was complete, the reaction mixture was added with 20 mL of water, stirred for 0.5 h and filtered. The filter cake was washed with a mixture of acetonitrile and water in a ratio of 3:2 and dried to give 4.42 g of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-bromo-8-methyl-4H-3,1-ben zoxazin-4-one, and the yield was 89%.

(10) .sup.1H NMR (500 MHz, DMSO): δ8.63 (dd, 1H), 8.35 (dd, 1H), 8.02 (d, 1H), 7.95-7.87 (m, 1H), 7.77 (dd, 1H), 7.54 (s, 1H), 1.71 (s, 3H).

Example 6 Preparation of 2-[pyridin-4-yl]-6-chloro-8-methyl-4H-3,1-benzoxazin-4-one

(11) 1.84 g of isonicotinic acid, 2.02 g of triethylamine and 15 mL of acetonitrile were added to a 100 mL three-necked flask, to which 4.59 g of POCl.sub.3 was dropwise added at −5° C. The reaction mixture was stirred for half an hour with the temperature kept, and then 1.86 g of 2-amino-3-methyl-5-chloromobenzoic acid was added. The reaction mixture was reacted at room temperature for 2.5 h. After the reaction was complete, the reaction mixture was added with 20 mL of water, stirred for 0.5 h and filtered. The filter cake was washed with a mixture of acetonitrile and water in a ratio of 3:2 and dried to give 2.5 g of 2-[pyridin-4-yl]-6-chloro-8-methyl-4H-3,1-benzoxazin-4-one, and the yield was 92%.

(12) .sup.1H NMR (400 MHz, DMSO): δ 8.86 (d, 2H), 8.09 (dd, 2H), 8.01-7.92 (m, 2H), 2.62 (s, 3H).

Example 7 Preparation of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-4H-pyrido[2,3-d][3,1]oxazin-4-one

(13) 3.02 g of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid, 2.02 g of triethylamine and 15 mL of acetonitrile were added to a 100 mL three-necked flask, to which 4.59 g of POCl.sub.3 was dropwise added at −5° C. The reaction mixture was stirred for half an hour with the temperature kept, and then 1.86 g of 2-amino-3-picolinic acid was added. The reaction mixture was reacted at room temperature for 2 h. After the reaction was complete, the reaction mixture was added with 20 mL of water, stirred for 0.5 h and filtered. The filter cake was washed with a mixture of acetonitrile and water in a ratio of 3:2 and dried to give 3.67 g of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-4H-pyrido[2,3-d][3,1]oxazin-4-one, and the yield was 91%.

(14) .sup.1H NMR (400 MHz, DMSO): δ8.88 (dd, 1H), 8.63-8.56 (m, 1H), 8.52-8.43 (m, 1H), 8.33 (dd, 1H), 7.77 (dd, 1H), 7.65-7.56 (m, 2H).

Example 8 Preparation of 3-bromo-N-(2-methyl-4-cyano-6-(carbamoyl)phenyl)-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide

(15) 4.17 g of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-cyano-8-methyl-4H-3,1-benzoxazin-4-one was dissolved in 20 mL of acetonitrile, to which 1.78 g of triethylamine and 2.82 g of methylamine sulfate were added. The reaction mixture was stirred at room temperature for 2.5 h, desolventizied under vacuum, washed with water and dried to give 4.08 g of 3-bromo-N-(2-methyl-4-cyano-6-(carbamoyl)phenyl)-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide, and the yield was 98%.

Example 9 Preparation of 3-bromo-N-(2-methyl-4-chloro-6-(carbamoyl)phenyl)-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide

(16) 4.2 g of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-chloro-8-methyl-4H-3,1-benzoxazin-4-one was dissolved in 20 mL of acetonitrile, to which 1.23 g of 4-dimethylaminopyridine and 2.18 g of methylamine sulfate were added. The reaction mixture was stirred at room temperature for 2.5 h, desolventizied under vacuum, washed with water and dried to give 4.27 g of 3-bromo-N-(2-methyl-4-chloro-6-(carbamoyl)phenyl)-1-(3-chloro-2-pyridinyl)-1H-py razole-5-carboxamide, and the yield was 95%.

Example 10 Preparation of 3-bromo-N-(2-methyl-4-chloro-6-(methoxycarbonyl)phenyl)-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide

(17) 10 g of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-chloro-8-methyl-4H-3,1-benzoxazin-4-one was dissolved in 100 mL of methanol, to which 10 g of sodium methoxide was added at room temperature. The reaction mixture was reacted under stirring for 1 h, and then desolventizied under vacuum, washed with water and dried to give 9.74 g of 3-bromo-N-(2-methyl-4-chloro-6-(methoxycarbonyl)phenyl)-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide, and the yield was 91%.