# US 11,299,499 B2 · Preparation method and application of isoxazinone compounds

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- Number: US 11,299,499 B2
- Document ID: US11299499B2
- Status: Granted
- Kind: B2
- Application number: 16/695,041
- Filed: 2019-11-25
- Published: 2020-04-09
- Granted: 2022-04-12
- Earliest claimed: 2017-05-26
- Assignees: Zhejiang Zhuji United Chemicals Co., Ltd
- Applicants: Zhejiang Zhuji United Chemicals Co., Ltd.
- Inventors: Qiuju Sheng; Baochuan Guan; Tianhao Zhang; Pan Zhang; Jinlong Zhang; Bangchi Chen
- Web page: https://patentgrep.com/patent/US11299499B2

## CPC

- C07D 498/04: Ortho-condensed systems
- C07D 309/34: having three or more double bonds between ring members or between ring members and non-ring members
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- C07D 413/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## 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 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).

## Claims

### Claim 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:
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.

### Claim 2 (depends on 1)

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

### Claim 3 (depends on 1)

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.

### Claim 4 (depends on 3)

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

### Claim 5 (depends on 2)

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

### Claim 6 (depends on 1)

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.

### Claim 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:
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;
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.

### Claim 8 (depends on 7)

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.

### Claim 9 (depends on 7)

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

### Claim 10 (depends on 9)

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.

### Claim 11 (depends on 10)

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

### Claim 12 (depends on 9)

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

### Claim 13 (depends on 7)

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.

### Claim 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 R3OH (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:
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
R3 is alkyl, substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl.

### Claim 15 (depends on 14)

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

### Claim 16 (depends on 14)

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

### Claim 17 (depends on 16)

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.

### Claim 18 (depends on 17)

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

### Claim 19 (depends on 16)

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

### Claim 20 (depends on 14)

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.