BR112019024928B1 - METHOD FOR PREPARING ISOXAZINONE, BISAMIDE AND N-ACYL BENZOATE COMPOUNDS - Google Patents

Abstract

This is about a method of preparation and an application of an isoxazinone compound (I), wherein the method of preparation 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 salt (IV) formed by a proton acid and an amino compound or R3OH (VII) to ring opening reaction in the presence of a base to produce a bisamide compound (V) or an N-acyl benzoate compound (VI). This method has available and low-priced raw materials, low cost, simple operation and mild reaction. Furthermore, this method is free of methanesulfonyl chloride, avoiding the production of waste water containing organic sulfur, and it generates less waste which can be easily treated, and thus it is suitable for industrial production.

Description

FIELD OF TECHNIQUE

[001] This application relates to organic synthesis and, more specifically, to a method of preparation and application of isoxazinone compounds.

BACKGROUND

[002] Isoxazinones(I) are an important class of compounds or intermediates in organic synthesis, and are widely used in chemical, pharmaceutical, pesticide, and material engineering fields. For example, such compounds can be used respectively as a UV absorber in various UV blocking materials (Document No. US4446262A), as a serine hydrolase inhibitor in the treatment, prevention and improvement of serine hydrolase mediated diseases (Document No. CN101535304A), and also as an important intermediate in the preparation of anthranilamide insecticides (such as chlorantraniliprole and cyantraniliprole) (WO2003/015519 and WO2004/067528).

[003] Currently, there are mainly three methods to synthesize isoxazinone compounds, which are specifically described below.

[004] In method 1 (document No. US 4832897 A), a carboxylic acid (III) is converted into an acyl chloride (IV) in the presence of thionyl chloride and pyridine, and then the acyl chloride (IV) is reacted with a substituted anthranilic acid (II') in the presence of a base to produce benzoxazinone (I'), where the specific reaction scheme is shown below:

[005] It is necessary that this method be carried out in two steps, and there are many by-products formed in the reaction (document No. U.S. 8927559 B2), in addition, this method also has a low yield, and therefore, it is inappropriate for industrial production.

[006] As for method 2, a substituted anthranilic acid (II') is reacted with a carboxylic acid (III) in the presence of sulfonyl chloride and a base to directly produce benzoxazinone (I') (document No. WO 2003/ 015519), where the reaction scheme is shown below:

[007] Although method 2 is simpler than method 1 and can be implemented in a “one-pot” mode, this method requires the excessive use of sulfonyl chloride, in which sulfonyl chloride may not react directly with the compound of anthranilic acid to produce a large amount of sulfonamide by-product, but it can also result in the generation of a considerable number of sulfur-containing organic acids in the waste water, which poses serious problems with triple waste. Therefore method 2 is also not conducive to industrial production.

[008] Regarding method 3, a carboxylic acid (III) is first activated in the presence of an activator N,N'-carbonyldiimidazole (CDI), and then reacted with a substituted anthranilic acid (II') to produce benzoxazinone (I ') (document No. CN 101535304 A), in which the reaction scheme is shown below:

[009] Although this method is also performed in a "one-pot" mode, an equivalent amount of the costly activator N, N'-carbonyldiimidazole (CDI) is required, which causes a high cost. Additionally, the 2 imidazole equivalents formed are not easy to recover, which will cause triple waste problems, making this method not conducive to industrial production.

SUMMARY

[010] This application provides a method for preparing isoxazinone compounds (I) to overcome the defects in the prior art, which has simple operation, environmentally friendly process, low cost, high yield and good product quality.

[011] In a first aspect, this application provides a method for preparing an isoxazinone compound (I), comprising:

em que:[012] React 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:

on what:

[013] Q is N or C-Z;

[014] each R and Z are, independently, hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cyano, carbonyl, alkoxycarbonyl, halogen, alkoxy, alkylthio, sulfonyl, sulfinyl, alkylamino or nitro;

[015] n is 0, 1, 2 or 3; It is

[016] R' is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl.

[017] In one embodiment, Q is CZ, and compound (II) has the following structural formula:

[018] Substituted alkyl, aryl and heteroaryl are formed by replacing one or more hydrogen atoms in the corresponding alkyl, aryl and heteroaryl, each independently with alkyl, alkenyl, alkynyl, aryl, alkoxy, halogen, nitro, cyano, sulfonyl or sulfinyl.

[019] The alkyl is a linear alkyl, a branched alkyl or a cycloalkyl.

[020] The dehydrating agent is preferably a phosphorous reagent, wherein the phosphorous reagent refers to a phosphorus-containing compound and is preferably phosphorus pentoxide, phosphorus oxychloride, phosphorus oxybromide, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride or phosphorus pentabromide, and most preferably phosphorous oxychloride or phosphorus oxybromide.

[021] The base is an inorganic base or an organic base, preferably the organic base, and more preferably a tertiary amine base, such as pyridine, 3-methylpyridine, N,N-dimethylaminopyridine and triethylamine.

[022] A molar ratio of compound (II) to carboxylic acid (III) is 1:0.5 to 1.5; a molar ratio of compound (II) to dehydrating agent is 1:1 to 2; and a molar ratio of compound (II) to base is 1:2 to 5.

[023] In a second aspect, this application provides a method for preparing a bisamide compound (V), comprising:

[024] Submitting the isoxazinone compound (I) prepared by the above method and a salt (IV) formed by a proton acid and an amino compound to ring opening reaction in the presence of a base to produce the bisamide compound (V ), as shown in the following reaction scheme:

[025] in which:

[026] Q, n, R and R' are defined as above;

[027] R1 and R2 are, independently, hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, but are not simultaneously hydrogen;

[028] the alkyl is a linear alkyl, a branched alkyl or a cycloalkyl; It is

[029] HY is hydrohalic acid, sulfuric acid, phosphoric acid or carboxylic acid, preferably hydrochloric acid or sulfuric acid.

[030] The base used in the ring opening reaction is an organic base or an inorganic base, preferably the organic base, and more preferably triethylamine, pyridine, 3-methylpyridine or N,N-dimethylaminopyridine.

[031] In a third aspect, this application provides a method for preparing an N-acyl benzoate (VI) compound, comprising:

[032] Subject the isoxazinone compound (I) prepared by the above method and R3OH (VII) to the ring opening reaction in the presence of a base to produce the N-acyl benzoate compound (VI), as shown in the following scheme of reaction:

[033] in which:

[034] Q, n, R and R' are defined as above; It is

[035] R3 is alkyl, substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl.

[036] The base used in the ring opening reaction is an inorganic base or an organic base, such as an alkali metal carbonate, an alkali metal hydroxide, an alkali metal alkoxide, triethylamine and pyridine, preferably the alkali metal alkoxide , and more preferably a salt formed by R3OH and an alkali metal, such as R3ONa and R3OK.

[037] Compared with the prior art, the method provided herein for preparing an isoxazinone compound has the following beneficial effects.

[038] (1) This method has readily available raw materials and low cost.

[039] (2) This method is free of methanesulfonyl chloride, avoiding the production of waste water that contains organic sulfur, and it generates less waste that can be easily treated.

[040] (3) This method is carried out in a "one-pot" mode, and has simple operation, mild reaction and high yield, and thus, it is suitable for industrial production.

DETAILED DESCRIPTION OF MODALITIES

[041] Features of the invention will be further illustrated below with reference to 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- ONA

[042] 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 POBr3 was added dropwise at -5 °C. The reaction mixture was stirred for half an hour with the temperature maintained, 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 completed, the reaction mixture was added with 20 ml of water, stirred for 0.5 h and filtered. The filter residue was washed with a mixture of acetonitrile and water in a 3:2 ratio 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- ONA

[043] 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 POCl3 was added dropwise at -5 °C. The reaction mixture was stirred for half an hour with the temperature maintained, 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 completed, the reaction mixture was added with 20 ml of water, stirred for 0.5 h and filtered. The filter residue was washed with a mixture of acetonitrile and water in a 3:2 ratio 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-benzoxazin-4-one, and the yield was 86%.

[044] 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

[045] 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 vial of three 100 ml bottlenecks to which 3.23 g of POCl3 was added dropwise at -5 °C. The reaction mixture was stirred for half an hour with the temperature maintained, 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 completed, the reaction mixture was added with 20 ml of water, stirred for 0.5 h and filtered. The filter residue was washed with a mixture of acetonitrile and water in a 3:2 ratio 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%.

[046] 1H NMR (500 MHz, DMSO): δ 8.63 (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

[047] 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 POCl3 was added dropwise at -5 °C. The reaction mixture was stirred for half an hour with the temperature maintained, 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 completed, the reaction mixture was added with 20 ml of water, stirred for 0.5 h and filtered. The filter residue was washed with a mixture of acetonitrile and water in a 3:2 ratio 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%.

[048] 1H NMR (400 MHz, DMSO): δ 8.60(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-IL]-6-BROMO-8-METHYL-4H-3,1-BENZOXAZIN-4- ONA

[049] 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 vial of three 100 ml bottlenecks to which 3.23 g of PCl3 was added dropwise at -5 °C. The reaction mixture was stirred for half an hour with the temperature maintained, 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 completed, the reaction mixture was added with 20 ml of water, stirred for 0.5 h and filtered. The filter residue was washed with a mixture of acetonitrile and water in a 3:2 ratio 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-benzoxazin-4-one, and the yield was 89%.

[050] 1H NMR (500 MHz, DMSO): δ 8.63(dd,1H), 8.35 (dd,1H), 8.02 (d,1H), 7.95 to 7.87(m ,1H), 7.77(dd,1H), 7.54(s,1H), 1.71(s,3H).

EXAMPLE 6 PREPARATION OF 2-[PYRIDIN-4-IL]-6-CHLORO-8-METHYL-4H-3,1-BENZOXAZIN-4-ONE

[051] 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 POCl3 was added dropwise at -5 °C . The reaction mixture was stirred for half an hour with the temperature maintained, 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 completed, the reaction mixture was added with 20 ml of water, stirred for 0.5 h and filtered. The filter residue was washed with a mixture of acetonitrile and water in a 3:2 ratio 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%.

[052] 1H NMR (400 MHz, DMSO): δ 8.86 (d,2H), 8.09(dd,2H), 8.01 to 7.92 (m,2H), 2.62 (s ,3H).

EXAMPLE 7 PREPARATION OF 2-[3-BROMO-1-(3-CHLORO-2-PYRIDINYL)-1H-PYRAZOL-5-IL]-4H-PYRIDO[2,3-D][3,1]OXAZIN-4 -ONA

[053] 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 vial of three 100 ml bottlenecks to which 4.59 g of POCl3 was added dropwise at -5 °C. The reaction mixture was stirred for half an hour with the temperature maintained, 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 completed, the reaction mixture was added with 20 ml of water, stirred for 0.5 h and filtered. The filter residue was washed with a mixture of acetonitrile and water in a 3:2 ratio 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%.

[054] 1H NMR (400 MHz, DMSO): δ 8.88 (dd,1H), 8.63-8.56 (m,1H), 8.52 to 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-PYRAZOL-5-CARBOXAMIDE

[055] 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, desolventized 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-PYRAZOL-5-CARBOXAMIDE

[056] 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, desolventized 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-pyrazole-5-carboxamide, and the yield was 95%.

EXAMPLE 10 PREPARATION OF 3-BROMO-N-(2-METHYL-4-CHLORO-6-(METHOXICARBONYL)PHENYL)-1-(3-CHLORO-2-PYRIDINYL)-1H-PYRAZOL-5-CARBOXAMIDE

[057] 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 stirred for 1 h, then desolventized 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%.

Claims (9)

1. METHOD FOR PREPARING AN ISOXAZINONE COMPOUND (I) characterized in that it comprises: 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:

where: Q is N or CZ; each R and Z are 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; wherein the dehydrating agent is a phosphorus reagent selected from the group consisting of phosphorus pentoxide, phosphorus oxychloride, phosphorus oxybromide, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride or phosphorus pentabromide. 2. METHOD, according to claim 1, characterized in that the base is an organic base. 3. METHOD, according to claim 1, characterized in that the phosphorous reagent is phosphorus oxychloride or phosphorous oxybromide. 4. METHOD, according to claim 2, characterized in that the organic base is selected from the group consisting of pyridine, 3-methylpyridine, N,N-dimethylaminopyridine or triethylamine. 5. METHOD, according to claim 1, characterized by the fact that a molar ratio of compound (II) to carboxylic acid (III) is 1:0.5-1.5; a molar ratio of compound (II) to dehydrating agent is 1:1-2; and a molar ratio of compound (II) to base is 1:2-5. 6. METHOD FOR PREPARING A BISAMIDE COMPOUND (V) characterized in that it comprises: submitting the isoxazinone compound (I) prepared by the method as defined in any one of claims 1 to 5 and a salt (IV) formed by an acid of a proton and an amino compound for ring opening reaction in the presence of a base to produce the bisamide compound (V) as shown in the following reaction scheme:

where: Q is N or CZ; each R and Z are 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; R1 and R2 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. 7. METHOD, according to claim 6, characterized by the fact that HY is hydrochloric acid or sulfuric acid; and the base used in the ring opening reaction is triethylamine, pyridine, 3-methylpyridine or N,N-dimethylaminopyridine. 8. METHOD FOR PREPARING A N-ACYL BENZOATE COMPOUND (VI) characterized in that it comprises: subjecting the isoxazinone compound (I) prepared by the method as defined in any one of claims 1 to 5 and R3OH (VII) to benzoate compound opening reaction reaction scheme:

where: Q is N or CZ; each R and Z are 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 R3 is alkyl, substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl. 9. METHOD, according to claim 8, characterized by the fact that the base used in the ring opening reaction is an alkoxide of an alkali metal.