Preparation method of 7-fluorobenzoxazinone compound and intermediates thereof

Abstract

The application discloses a preparation method of 7-fluorobenzoxazinone compounds and intermediates thereof. The method is easy in raw material acquisition, simple in operation, low in waste and suitable for industrial production.

Description

A preparation method of 7-fluorobenzoxazinone compounds and intermediates thereof Technical Field

[0001] The present invention belongs to the field of organic synthesis, and specifically relates to a preparation method of 7-fluorobenzoxazinone compounds and intermediates thereof. Background Art

[0002] 7-Fluorobenzoxazinones are important chemical intermediates widely used in the preparation of pharmaceuticals and pesticides. For example, 7-Fluorobenzoxazinones are used to prepare AZD 9977 (CN106536491B), a drug for heart failure and chronic kidney disease; antiparasitic drugs (CN105164124B); and STK4 inhibitors for the treatment of hematological malignancies (US10710978B2). Furthermore, 7-Fluorobenzoxazinones are used to prepare highly effective herbicides such as fluazifop (US4792605A), thiadiazole (DE4008691A1), and trifluoperazine (CN102459205B).

[0003] There are three strategies for the preparation of 7-fluorobenzoxazinones:

[0004] The first strategy is to use 2-nitro-5-fluorophenol as the raw material, and generate the corresponding intermediate through a condensation reaction with a haloacetic acid or its ester, and then the intermediate is reduced and cyclized to obtain a 7-fluorobenzoxazinone compound.

[0005] Patent CN108727367A discloses a method for using 2-nitro-5-fluorophenol as a raw material, reacting it with ethyl bromoacetate in the presence of a base to produce an intermediate ethyl 2-nitro-5-fluoro-phenoxyacetate. This intermediate is then hydrogenated using a metal reduction system or hydrogen / palladium-on-carbon catalysis to produce 7-fluorobenzoxazinone. This method uses a metal reducing agent, generating a large amount of waste, waste gas, and expensive palladium-on-carbon catalysis, making it uneconomical.

[0006] The Journal of Advanced Chemistry (2006), 27(11), 2117-2119 reported that 2-nitro-5-fluorophenol and chloroacetic acid were used as starting materials. In the presence of a base, chloroacetic acid resin was reacted with 2-nitro-5-fluorophenol to produce 7-fluorobenzoxazinone through condensation reaction, followed by zinc chloride reduction and cleavage ring closure. The resin compound used in this method is not available in large quantities, making it difficult to industrialize.

[0007] The second strategy is to use 2-nitro-5-fluorophenol as the raw material, generate the corresponding intermediate through condensation reaction with halogenated acetonitrile, and then the intermediate is reduced, cyclized and hydrolyzed to obtain 7-fluorobenzoxazinone compound.

[0008] Tetrahedron (2011), 67(6), 1187-1192 reported a method for synthesizing 7-fluorobenzoxazinone. 2-Nitro-5-fluorophenol and chloro / bromoacetonitrile are used as the raw materials. Under the action of a base, 2-nitro-5-fluorophenoxyacetonitrile is generated, which is then reduced with iron powder to yield 7-fluorobenzoxazinone. The chloro / bromoacetonitrile raw materials used in this method are relatively expensive, making it uneconomical. The iron powder reduction process also produces a large amount of iron sludge, a waste product, and serious pollution.

[0009] The third strategy is to use 2-nitro-5-fluorophenol as the raw material to prepare 2-amino-5-fluorophenol by reduction, which then undergoes condensation and cyclization reaction with haloacetyl chloride to generate the corresponding 7-fluorobenzoxazinone compound.

[0010] Molecules (2020), 25 (20), 4614 reported a method for preparing a 2-amino-5-fluorophenol intermediate by reducing 2-nitro-5-fluorophenol with iron powder, which then reacts with chloroacetyl chloride under the action of a base and simultaneously closes the ring to obtain a 7-fluorobenzoxazinone compound. The 2-nitro-5-fluorophenol raw material used in this method is prepared by hydrolysis of 2,4-difluoronitrobenzene (CN106045861B). The hydrolysis reaction has low chemical selectivity and produces a large amount of 3-fluoro-4-nitrophenol by-product. This nitrophenol by-product has a high explosion risk during separation and purification. The hydrolysis reaction also produces a large amount of corrosive fluoride ions, which places high demands on the material of engineering equipment. In addition, the iron powder reducing agent used in this method will lead to the production of a large amount of iron sludge, which is difficult to post-process, seriously pollutes the three wastes, and is difficult to industrialize.

[0011] Summary of the Invention

[0012] In view of the shortcomings of the existing technology, the present invention provides a preparation method of 7-fluorobenzoxazinone compounds and intermediates thereof, which have readily available raw materials, simple operation, less three wastes, and are suitable for industrial production.

[0013] The first object of the present invention is to provide a method for preparing a 7-fluorobenzoxazinone compound (I), the method comprising the following steps:

[0014] Step 1: In the presence of a base 1, the compound of formula (II) reacts with the compound of formula (III) to produce a compound of formula (IV);

[0015] Step 2: reacting the compound of formula (IV) with the compound of formula (V) to produce the compound of formula (VI);

[0016] Step 3: Rearrange the compound of formula (VI) to obtain the compound of formula (VII);

[0017] Step 4: In the presence of base 2, the compound of formula (VII) is cyclized to obtain the compound of formula (I);

[0018] The reaction formula is as follows:

[0019] in,

[0020] The R1 is any one of hydrogen, halogen, unsubstituted or substituted C1-C8 alkyl, unsubstituted or substituted C6-C12 aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted acyl, cyano, substituted hydroxyl, substituted thiol, substituted sulfoxide, substituted sulfone, nitro, and substituted amino; preferably hydrogen, halogen, unsubstituted or substituted C1-C3 alkyl, unsubstituted or substituted C6-C12 aryl, unsubstituted or substituted heteroaryl, cyano, nitro, and substituted amino; more preferably hydrogen, nitro, and substituted amino.

[0021] R2 and R3 are independently any one of hydrogen, halogen, unsubstituted or substituted C1-C8 alkyl, unsubstituted or substituted C1-C8 alkoxy, unsubstituted or substituted C6-C12 aryl, unsubstituted or substituted C6-C12 aryloxy, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroaryloxy, preferably hydrogen, halogen, unsubstituted or substituted C1-C3 alkyl, unsubstituted or substituted C1-C3 alkoxy, and more preferably hydrogen, F, Cl, and Br.

[0022] The R4 is any one of hydrogen, halogen, unsubstituted or substituted C1-C8 alkyl, unsubstituted or substituted C1-C8 alkoxy, C1-C8 acyloxy, unsubstituted or substituted C6-C12 aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted C1-C8 alkylsulfonyloxy, and unsubstituted or substituted C6-C12 arylsulfonyloxy, preferably hydrogen, halogen, unsubstituted or substituted C1-C3 alkylsulfonyloxy, and unsubstituted or substituted C6-C12 arylsulfonyloxy, and more preferably hydrogen, Cl, Br, methanesulfonyloxy, and benzenesulfonyloxy.

[0023] The A is C or S,

[0024] When A is C, m is 0;

[0025] When A is S, m is 0 or 1.

[0026] The R5 is any one of hydrogen, unsubstituted or substituted C1-C8 alkyl, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted C1-C8 alkoxy, unsubstituted or substituted C6-C12 aryl, and unsubstituted or substituted heteroaryl; preferably unsubstituted or substituted C1-C3 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C1-C3 alkoxy, unsubstituted or substituted C6-C12 aryl, and unsubstituted or substituted heteroaryl; more preferably methyl, chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, tribromomethyl, methoxy, ethoxy, chlorodifluoromethyl, bromodifluoromethyl, bromodichloromethyl, cyclopropyl, and unsubstituted or substituted phenyl.

[0027] The unsubstituted or substituted heteroaryl group is a heteroaryl group containing 1-4 atoms selected from nitrogen, oxygen, and sulfur atoms, such as pyrazolyl, thiazolyl, thienyl, pyridinyl, pyrimidinyl, and the like.

[0028] The L1 and L2 are each independently a leaving group; the leaving group is preferably R6C(=O)O-, halogen; more preferably Cl, CH3C(=O)O-, CCl3C(=O)O-, ClCH2C(=O)O-.

[0029] The R6 is any one of hydrogen, unsubstituted or substituted C1-C8 alkyl, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted C1-C8 alkoxy, unsubstituted or substituted C6-C12 aryl, and unsubstituted or substituted heteroaryl; preferably unsubstituted or substituted C1-C3 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C1-C3 alkoxy, unsubstituted or substituted C6-C12 aryl, and unsubstituted or substituted heteroaryl; more preferably methyl, chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, tribromomethyl, methoxy, ethoxy, chlorodifluoromethyl, bromodifluoromethyl, bromodichloromethyl, cyclopropyl, and unsubstituted or substituted phenyl.

[0030] Said n is 0, 1, 2, 3 or 4; when n>1, multiple R1s may be the same or different.

[0031] Step 2 is optionally carried out under the action of base 3.

[0032] The base 1, base 2, and base 3 are independently one or more inorganic bases or organic bases. The inorganic bases include carbonates, bicarbonates, phosphates, hydroxides, hydrides, and amides of alkali metals; carbonates, bicarbonates, phosphates, hydroxides, oxides, hydrides, and amides of alkaline earth metals; the inorganic bases are preferably carbonates, bicarbonates, and hydroxides of alkali metals, and carbonates, bicarbonates, and hydroxides of alkaline earth metals; and more preferably sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, and potassium hydroxide.

[0033] The organic base includes an organic salt or an organic amine. The organic salt includes alkyl carboxylates and aryl carboxylates, alkoxy salts, metal alkyls, and metal aryls. The organic amine includes alkylamine and arylamine compounds. The alkylamine is preferably a tertiary amine, more preferably triethylamine. The arylamine is preferably pyridinamine, more preferably pyridine or picoline.

[0034] In step 1, the compound of formula (III) is an acyl halide or an acid anhydride, wherein the acyl halide is an unsubstituted or substituted C1-C8 alkyl acyl halide, an unsubstituted or substituted C3-C10 cycloalkyl acyl halide, an unsubstituted or substituted C6-C12 aryl acyl halide, or an unsubstituted or substituted heteroaryl acyl halide, preferably acetyl chloride, chloroacetyl chloride, bromoacetyl chloride, dichloroacetyl chloride, trichloroacetyl chloride, tribromoacetyl chloride, acetic anhydride, chloroacetic anhydride, dichloroacetic anhydride, trichloroacetic anhydride, bromoacetic anhydride, 2-chloro-2,2-difluoroacetyl chloride, 2-bromo-2,2-difluoroacetyl chloride, or 2-bromo-2,2-dichloroacetyl chloride.

[0035] The solvent used is an organic solvent or a mixture thereof with water, wherein the organic solvent is one or more of an aromatic hydrocarbon solvent, an amide solvent, a (sub)sulfone solvent, a halogenated hydrocarbon solvent, an ether solvent, and an ester solvent: an aromatic hydrocarbon solvent such as a C6-C12 aromatic hydrocarbon solvent, specifically toluene, xylene, and trimethylbenzene; an amide solvent such as a C1-C6 amide solvent, specifically dimethylformamide and dimethylacetamide; a (sub)sulfone solvent such as a C1-C6 (sub)sulfone solvent, specifically dimethyl sulfoxide and sulfolane; a halogenated hydrocarbon solvent such as dichloromethane, chloroform, carbon tetrachloride, and dichloroethane; an ether solvent such as methyl tert-butyl ether, tetrahydrofuran, and methyltetrahydrofuran; an ester solvent such as ethyl acetate; preferably toluene, tetrahydrofuran, methyltetrahydrofuran, and ethyl acetate.

[0036] In step 2, the compound of formula (V) is an acid halide or an acid anhydride, wherein the acid halide is an unsubstituted or substituted C1-C8 alkyl acid halide, an unsubstituted or substituted C3-C10 cycloalkyl acid halide, an unsubstituted or substituted C6-C12 aryl acid halide, or an unsubstituted or substituted heteroaryl acid halide, preferably acetyl chloride, chloroacetyl chloride, bromoacetyl chloride, dichloroacetyl chloride, trichloroacetyl chloride, tribromoacetyl chloride, cyclopropanoyl chloride, acetic anhydride, chloroacetic anhydride, dichloroacetic anhydride, trichloroacetic anhydride, bromoacetic anhydride, 2-chloro-2,2-difluoroacetyl chloride, 2-bromo-2,2-difluoroacetyl chloride, 2-bromo-2,2-dichloroacetyl chloride, benzoyl chloride, thiopheneyl chloride, methanesulfonyl chloride, or benzenesulfonyl chloride.

[0037] Step 2 selectively uses a solvent, and the solvent is one or more of an aromatic hydrocarbon solvent, an amide solvent, a (sub)sulfone solvent, a halogenated hydrocarbon solvent, an ether solvent, and an ester solvent: an aromatic hydrocarbon solvent such as a C6-C12 aromatic hydrocarbon solvent, specifically toluene, xylene, and trimethylbenzene; an amide solvent such as a C1-C6 amide solvent, specifically dimethylformamide and dimethylacetamide; a (sub)sulfone solvent such as a C1-C6 (sub)sulfone solvent, specifically dimethyl sulfoxide and sulfolane; a halogenated hydrocarbon solvent such as dichloromethane, chloroform, carbon tetrachloride, and dichloroethane; an ether solvent such as methyl tert-butyl ether, tetrahydrofuran, and methyltetrahydrofuran; an ester solvent such as ethyl acetate; preferably toluene, tetrahydrofuran, methyltetrahydrofuran, and ethyl acetate.

[0038] The solvent used in step 3 and step 4 can be one or more of aromatic hydrocarbon solvents, amide solvents, (sub)sulfone solvents, halogenated hydrocarbon solvents, ether solvents, and ester solvents: aromatic hydrocarbon solvents such as C6-C12 aromatic hydrocarbon solvents, specifically toluene, xylene, and trimethylbenzene; amide solvents such as C1-C6 amide solvents, specifically dimethylformamide and dimethylacetamide; (sub)sulfone solvents such as C1-C6 (sub)sulfone solvents, specifically dimethyl sulfoxide and sulfolane; halogenated hydrocarbon solvents such as dichloromethane, chloroform, carbon tetrachloride, and dichloroethane; ether solvents such as methyl tert-butyl ether, tetrahydrofuran, and methyltetrahydrofuran; ester solvents such as ethyl acetate; preferably toluene, tetrahydrofuran, methyltetrahydrofuran, and ethyl acetate.

[0039] Benzoxazinone compound (I) can be prepared in one pot from compound (II) in the presence of base 1.

[0040] Benzoxazinone compound (I) can be prepared from compound (IV) or compound (VI) in one pot.

[0041] Compound (VII) can be prepared in one pot by reacting a compound of formula (IV) with a compound of formula (VI), necessarily in the presence of a base 2.

[0042] The second object of the present invention is to provide an intermediate compound (IV) for preparing 7-fluorobenzoxazinone compound (I), the structural formula of which is as follows:

[0043] in,

[0044] The R1 is any one of hydrogen, halogen, unsubstituted or substituted C1-C8 alkyl, unsubstituted or substituted C6-C12 aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted acyl, cyano, substituted hydroxyl, substituted thiol, substituted sulfoxide, substituted sulfone, nitro, and substituted amino; preferably hydrogen, halogen, unsubstituted or substituted C1-C3 alkyl, unsubstituted or substituted C6-C12 aryl, unsubstituted or substituted heteroaryl, cyano, nitro, and substituted amino; more preferably hydrogen, nitro, and substituted amino.

[0045] R2 and R3 are independently any one of hydrogen, halogen, unsubstituted or substituted C1-C8 alkyl, unsubstituted or substituted C1-C8 alkoxy, unsubstituted or substituted C6-C12 aryl, unsubstituted or substituted C6-C12 aryloxy, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroaryloxy, preferably hydrogen, halogen, unsubstituted or substituted C1-C3 alkyl, unsubstituted or substituted C1-C3 alkoxy, and more preferably hydrogen, F, Cl, and Br.

[0046] The R4 is any one of hydrogen, halogen, unsubstituted or substituted C1-C8 alkyl, unsubstituted or substituted C1-C8 alkoxy, C1-C8 acyloxy, unsubstituted or substituted C6-C12 aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted C1-C8 alkylsulfonyloxy, and unsubstituted or substituted C6-C12 arylsulfonyloxy, preferably halogen, unsubstituted or substituted C1-C3 alkylsulfonyloxy, and unsubstituted or substituted C6-C12 arylsulfonyloxy, and more preferably Cl, Br, methanesulfonyloxy, and benzenesulfonyloxy.

[0047] The third object of the present invention is to provide an intermediate compound (VI) for preparing a 7-fluorobenzoxazinone compound (I), the structural formula of which is as follows:

[0048] in,

[0049] R1, R2, R3, R4, R5, A, m, and n are as defined above;

[0050] Preferably, when R1 is hydrogen:

[0051] R2 and R3 are independently hydrogen or halogen; more preferably hydrogen, F, Cl, or Br;

[0052] R4 is any one of hydrogen, halogen, unsubstituted or substituted C1-C8 alkyl, unsubstituted or substituted C1-C8 alkoxy, unsubstituted or substituted C6-C12 aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted C1-C8 alkylsulfonyloxy, and unsubstituted or substituted C6-C12 arylsulfonyloxy, preferably halogen, unsubstituted or substituted C1-C3 alkylsulfonyloxy, and unsubstituted or substituted C6-C12 arylsulfonyloxy, and more preferably Cl, Br, methanesulfonyloxy, and benzenesulfonyloxy;

[0053] R5 is any one of unsubstituted or substituted C1-C8 alkyl, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted C1-C8 alkoxy, unsubstituted or substituted C6-C12 aryl, and unsubstituted or substituted heteroaryl; preferably unsubstituted or substituted C1-C3 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C1-C3 alkoxy, unsubstituted or substituted C6-C12 aryl, and unsubstituted or substituted heteroaryl; more preferably methyl, chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, tribromomethyl, methoxy, ethoxy, chlorodifluoromethyl, bromodifluoromethyl, bromodichloromethyl, cyclopropyl, phenyl, and substituted phenyl.

[0054] The unsubstituted or substituted heteroaryl group is a heteroaryl group containing 1-4 atoms selected from nitrogen, oxygen, and sulfur atoms, such as pyrazolyl, thiazolyl, thienyl, pyridinyl, pyrimidinyl, and the like.

[0055] The fourth object of the present invention is to provide an intermediate compound (VII) for preparing 7-fluorobenzoxazinone compound (I), the structural formula of which is as follows:

[0056] in,

[0057] R1, R2, R3, R4, R5, A, m, and n are as defined above;

[0058] Preferably, when R1 is hydrogen:

[0059] R2 and R3 are independently hydrogen or halogen; more preferably hydrogen, F, Cl, or Br;

[0060] R4 is any one of hydrogen, halogen, unsubstituted or substituted C1-C8 alkyl, unsubstituted or substituted C1-C8 alkoxy, unsubstituted or substituted C6-C12 aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted C1-C8 alkylsulfonyloxy, and unsubstituted or substituted C6-C12 arylsulfonyloxy, preferably halogen, unsubstituted or substituted C1-C3 alkylsulfonyloxy, and unsubstituted or substituted C6-C12 arylsulfonyloxy, and more preferably Cl, Br, methanesulfonyloxy, and benzenesulfonyloxy;

[0061] R5 is any one of unsubstituted or substituted C1-C8 alkyl, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted C1-C8 alkoxy, unsubstituted or substituted C6-C12 aryl, and unsubstituted or substituted heteroaryl; preferably unsubstituted or substituted C1-C3 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C1-C3 alkoxy, unsubstituted or substituted C6-C12 aryl, and unsubstituted or substituted heteroaryl; more preferably methyl, chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, tribromomethyl, methoxy, ethoxy, chlorodifluoromethyl, bromodifluoromethyl, bromodichloromethyl, cyclopropyl, phenyl, and substituted phenyl.

[0062] The unsubstituted or substituted heteroaryl group is a heteroaryl group containing 1-4 atoms selected from nitrogen, oxygen, and sulfur atoms, such as pyrazolyl, thiazolyl, thienyl, pyridinyl, pyrimidinyl, and the like.

[0063] Compared with the prior art, the present invention has the following significant features and advantages:

[0064] (1) The present invention provides a new strategy and new intermediate compounds for preparing 7-fluorobenzoxazinones;

[0065] (2) The reaction raw materials are cheap and readily available, and no special reagents such as expensive catalysts or special reaction equipment are required;

[0066] (3) Mild reaction conditions and easy operation;

[0067] (4) Safe process, less waste;

[0068] (5) Suitable for industrial production.

[0069] Group Definition

[0070] The halogen mentioned herein means fluorine, chlorine, bromine and iodine.

[0071] The substitution in the term "non-substituted" or "substituted" herein means that one or more hydrogen atoms on a carbon atom or a nitrogen atom are independently replaced by halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C9 cycloalkyl, C3-C9 halocycloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C 1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C2-C7 alkylcarbonyl, C2-C7 haloalkylcarbonyl, C2-C7 alkylcarbonyloxy, C2-C7 haloalkylcarbonyloxy, C1-C6 alkylsulfonyloxy, C1-C6 haloalkylsulfonyloxy, C2-C7 alkoxycarbonyl, C2-C7 haloalkoxycarbonyl, C2-C7 alkylcarbonylamino, C2-C C2-C7 haloalkylcarbonylamino, C2-C7 alkoxycarbonylamino, C2-C7 haloalkoxycarbonylamino, C2-C7 alkylaminocarbonyl, C2-C7 haloalkylaminocarbonyl, C1-C6 alkylamino, C1-C6 haloalkylamino, C2-C6 alkenylamino, C2-C6 haloalkenylamino, C2-C6 alkynylamino, C2-C6 haloalkynylamino, C3-C9 cycloalkylamino, C3-C9 halocycloalkylamino, C3-C7 alkenylamino substituted groups, such as phenyl, which may have a substituent group, phenylcarbonyl, which may have a substituent group, phenylamino, which may have a substituent group, and phenylamino, which may have a substituent group. DETAILED DESCRIPTION

[0072] Example 1

[0073] 18.45 g of p-fluorohydroxylamine was dissolved in 40 mL of tetrahydrofuran and cooled to -15°C to -20°C. Then, 19 g of triethylamine and 17 g of chloroacetyl chloride were added, and the internal temperature was controlled at about -15°C. After the reaction was completed, conventional post-treatment was performed to obtain 29.5 g of the product 2-chloro-N-(4-fluorophenyl)-N-hydroxyacetamide with a yield of 97%.

[0074] 1 H NMR (CDCl3, 500MHz, TMS) δ10.73 (s, 1H), 6.90-6.87 (m, 2H), 6.82-6.78 (m, 2H), 4.59 (s, 2H).

[0075] Example 2

[0076] 17 g of p-fluorohydroxylamine was dissolved in 40 mL of ethyl acetate and cooled to -5 to 0°C. 16.8 g of chloroacetyl chloride and 145.6 g of a 10% aqueous sodium bicarbonate solution were then added dropwise. After the addition was complete, the mixture was kept warm until the reaction was complete. Conventional post-treatment gave 26.2 g of 2-chloro-N-(4-fluorophenyl)-N-hydroxyacetamide in a yield of 98%.

[0077] Example 3

[0078] 12 g of p-fluorohydroxylamine was dissolved in 30 mL of methyltetrahydrofuran, and the temperature was lowered to -15°C to -20°C. Then, 10.5 g of triethylamine and 7.9 g of acetyl chloride were added, and the internal temperature was controlled at about -15°C. After the reaction was completed, conventional post-treatment was performed to obtain 16.2 g of the product N-(4-fluorophenyl)-N-hydroxyacetamide with a yield of 96%.

[0079] Example 4

[0080] Dissolve 17g of p-fluorohydroxylamine in 40mL of toluene, cool to -20 to -15°C, then dropwise add 13.6g of acetyl chloride and 17.04g of triethylamine. After the addition is complete, incubate and allow to react until the reaction is complete. Conventional post-processing yields 22g of N-(4-fluorophenyl)-N-hydroxyacetamide in a 97% yield.

[0081] 1 H NMR (CDCl3, 500MHz, TMS) δ10.47 (s, 1H), 7.68-7.60 (m, 2H), 7.25-7.16 (m, 2H), 2.18 (s, 3H).

[0082] Example 5

[0083] 5 g of 2-chloro-N-(4-fluorophenyl)-N-hydroxyacetamide prepared in Example 1 or 2 was added to 20 g of acetic anhydride, and the mixture was reacted in an oil bath at 55° C. After the intermediate control reaction was completed, conventional post-treatment was performed to obtain 6 g of the product N-acetoxy-2-chloro-N-(4-fluorophenyl)acetamide in a yield of 99%.

[0084] 1 H NMR (CDCl3, 500MHz, TMS) δ7.60 (s, 2H), 7.34 (s, 2H), 4.49 (br, 2H), 2.26 (s, 3H).

[0085] Example 6

[0086] 4 g of 2-chloro-N-(4-fluorophenyl)-N-hydroxyacetamide prepared in Example 1 or 2 was dissolved in 20 mL of chloroform, and 3.2 g of ethyl chloroformate and 2.5 g of pyridine were added dropwise at room temperature. After the addition was complete, the reaction was kept warm and the reaction was controlled by HPLC to be complete. After conventional post-treatment, 5.4 g of the product 2-chloro-N-((ethoxycarbonyl)oxy)-N-(4-fluorophenyl)acetamide was obtained in a yield of 99%.

[0087] 1 H NMR (CDCl3, 500MHz, TMS) δ7.62 (s, 2H), 7.39-7.36 (m, 2H), 4.44 (br, 2H), 4.31 (q, J = 7.0Hz, 2H), 1.27 (t, J = 7.0Hz, 3H).

[0088] Example 7

[0089] 4 g of 2-chloro-N-(4-fluorophenyl)-N-hydroxyacetamide prepared in Example 1 or 2 was dissolved in 20 mL of chloroform, and 3.2 g of p-nitrobenzoyl chloride and 2.5 g of pyridine were added dropwise at room temperature. The mixture was kept warm and the reaction was controlled to be complete by HPLC. After conventional post-treatment, 5.4 g of the product 2-chloro-N-(4-fluorophenyl)-N-(4-nitrobenzoyloxy)acetamide was obtained in a yield of 99%.

[0090] 1 H NMR (CDCl3, 500MHz, TMS) δ 8.39-8.41 (d, 2H), 8.28-8.32 (d, 2H), 7.72 (m, 2H), 7.72 (m, 2H), 7.38 (m, 2H), 4.58 (s, 2H).

[0091] Example 8

[0092] 20.0 g of 2-chloro-N-(4-fluorophenyl)-N-hydroxyacetamide prepared in Example 1 was dissolved in 40 mL of chloroform, and 19.6 g of trichloroacetyl chloride was added dropwise at room temperature. After the addition was complete, stirring was continued until the reaction was complete. After completion of the reaction, conventional post-processing was performed to obtain 25.6 g of 2-(2-chloroacetylamino)-5-fluorophenyl 2,2,2-trichloroacetate in a yield of 75%.

[0093] 1 H NMR (500MHz, CDCl3) δ8.44(s,1H),8.22(dd,J=9.2,5.7Hz,1H),7.18(dd,J=8.4,2.8Hz,1H),7.09(ddd,J=9.3,7.9,2.8Hz,1H),4.21(s,2H)

[0094] Example 9

[0095] 2-(2-Chloroacetylamino)-5-fluorophenyl benzoate

[0096] 19.3 g of N-benzoyloxy-2-chloro-N-(4-fluorophenyl)acetamide, prepared in Example 5, was dissolved in 40 mL of toluene and the mixture was heated to reflux until the reaction was complete. After completion of the reaction, conventional post-processing was performed to obtain 22.5 g of 2-(2-chloroacetylamino)-5-fluorophenyl benzoate in a yield of 72%.

[0097] 1 H NMR (CDCl3, 500MHz, TMS) δ9.97(s,1H),8.16-8.15(m,2H),7.80-7.75(m,2H),7.61(s,2H),7.39-7.37(m,1H),7.20(m,1H),4.24(s,2H).

[0098] Example 10

[0099] 2-(2-Bromoacetylamino)-5-fluorophenylbenzenesulfonate

[0100] 20.0 g of N-benzenesulfonyloxy-2-bromo-N-(4-fluorophenyl)acetamide, prepared in Example 5, was dissolved in 40 mL of ethyl acetate and stirred under reflux until the reaction was complete. After completion of the reaction, conventional post-treatment afforded 23.9 g of 2-(2-bromoacetylamino)-5-fluorophenylbenzenesulfonate in a yield of 71%.

[0101] 1 H NMR (CDCl3, 500MHz, TMS) δ9.88 (s, 1H), 7.87-7.85 (m, 2H), 7.82-7.74 (m, 2H), 7.66-7.63 (m, 2H), 7.23-7.20 (m, 2H), 3.91 (s, 2H).

[0102] Example 11

[0103] 2-(2-Chloroacetylamino)-5-fluorophenylthiophene-2-carboxylate

[0104] 15.7 g of N-thiophene-2-yloxy-2-chloro-N-(4-fluorophenyl)acetamide, prepared in Example 5, was dissolved in 40 mL of toluene. 7.0 g of potassium carbonate was added with stirring, and the mixture was refluxed until the reaction was complete. After completion of the reaction, conventional post-processing was performed to obtain 23.9 g of 2-(2-chloroacetylamino)-5-fluorophenylthiophene-2-carboxylate, in a yield of 76%.

[0105] 1H NMR(CDCl3,500MHz,TMS)δ9.92(s,1H),8.11-8.10(m,1H),8.03-8.02(m,1H),7.76- 7.73(m,1H),7.40-7.38(m,1H),7.32-7.31(m,1H),7.22-7.18(m,1H),4.23(s,2H).

[0106] Example 12

[0107] 2-(2-bromo-2,2-difluoroacetylamino)-5-fluorophenyl acetate was prepared with a yield of 67%.

[0108] 1 H NMR(500MHz,DMSO)δ9.81(s,1H),7.70(dd,J=8.7,6.1Hz,1H),7.18(dd,J=9.3,2.6Hz,1H),7. 13(td,J=8.6,2.7Hz,1H),4.29(s,2H),1.94–1.86(m,1H),1.08(d,J=6.4Hz,2H),1.06(s,2H)

[0109] Example 13

[0110] 2-(2-chloroacetylamino)-5-fluorophenylcyclopropanecarboxylate was prepared in reference to Example 9 with a yield of 70%.

[0111] 1 H NMR(500MHz,DMSO)δ9.81(s,1H),7.70(dd,J=8.7,6.1Hz,1H),7.18(dd,J=9.3,2.6Hz,1H ),7.13(td,J=8.6,2.7Hz,1H),4.29(s,2H),1.94–1.86(m,1H),1.08(s,2H),1.06(s,2H)

[0112] Example 14

[0113] 4.2 g of 2-(2-chloroacetylamino)-5-fluorophenyl 2,2,2-trichloroacetate prepared in Example 8 was dissolved in 40 mL of ethanol, and 28.8 g of a NaOH aqueous solution was slowly added dropwise with stirring. After the addition was complete, stirring was continued until the reaction was complete. After the reaction was completed, conventional post-treatment was performed to obtain 14.8 g of the product, 7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one, with a yield of 97%.

[0114] Example 15 One-pot preparation of compound

[0115] 26.0 g of 2-chloro-N-(4-fluorophenyl)-N-hydroxyacetamide prepared in Example 1 was dissolved in 40 mL of toluene, the temperature was raised to 50° C., and 24.2 g of trichloroacetyl chloride was slowly added dropwise. After the addition was complete, the mixture was incubated for reaction. After the reaction was completed, the layers were washed with water, and 51.4 g of a NaOH aqueous solution was added dropwise to the reaction solution. After the addition was complete, the reaction was continued until the reaction was complete. After the reaction was completed, conventional post-processing was performed to obtain 20.1 g of the product in a yield of 94%.

[0116] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the above embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing a 7-fluorobenzoxazinone compound (I), comprising the following steps: Step 1: In the presence of a base 1, the compound of formula (II) reacts with the compound of formula (III) to produce a compound of formula (IV); Step 2: reacting the compound of formula (IV) with the compound of formula (V) to produce the compound of formula (VI); Step 3: Rearrange the compound of formula (VI) to obtain the compound of formula (VII); Step 4: In the presence of base 2, the compound of formula (VII) is cyclized to obtain the compound of formula (I); The reaction formula is as follows: in, R1 is any one of hydrogen, halogen, unsubstituted or substituted C1-C8 alkyl, unsubstituted or substituted C6-C12 aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted acyl, cyano, substituted hydroxy, substituted thiol, substituted sulfoxide, substituted sulfone, nitro, and substituted amino; R2 and R3 are independently any one of hydrogen, halogen, unsubstituted or substituted C1-C8 alkyl, unsubstituted or substituted C1-C8 alkoxy, unsubstituted or substituted C6-C12 aryl, unsubstituted or substituted C6-C12 aryloxy, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroaryloxy; R4 is any one of hydrogen, halogen, unsubstituted or substituted C1-C8 alkyl, unsubstituted or substituted C1-C8 alkoxy, C1-C8 acyloxy, unsubstituted or substituted C6-C12 aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted C1-C8 alkylsulfonyloxy, and unsubstituted or substituted C6-C12 arylsulfonyloxy; The A is C or S, When A is C, m is 0; When A is S, m is 0 or 1; R5 is any one of hydrogen, unsubstituted or substituted C1-C8 alkyl, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted C1-C8 alkoxy, unsubstituted or substituted C6-C12 aryl, and unsubstituted or substituted heteroaryl; The L1 and L2 are independently a leaving group; Said n is 0, 1, 2, 3 or 4; when n>1, multiple R1 may be the same or different; The base 1 and base 2 are independently one or more inorganic bases or organic bases.

2. The method according to claim 1, characterized in that R1 is hydrogen, halogen, unsubstituted or substituted C1-C3 alkyl, unsubstituted or substituted C6-C12 aryl, unsubstituted or substituted heteroaryl, cyano, nitro, or substituted amino; R2 and R3 are independently hydrogen, halogen, unsubstituted or substituted C1-C3 alkyl, or unsubstituted or substituted C1-C3 alkoxy; R4 is hydrogen, halogen, unsubstituted or substituted C1-C3 alkoxy, unsubstituted or substituted C1-C3 alkylsulfonyloxy, unsubstituted or substituted C6-C12 arylsulfonyloxy; R5 is unsubstituted or substituted C1-C3 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C1-C3 alkoxy, unsubstituted or substituted C6-C12 aryl, or unsubstituted or substituted heteroaryl; L1 and L2 are each independently halogen or R6C(=O)O-; R6 is any one of hydrogen, unsubstituted or substituted C1-C8 alkyl, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted C1-C8 alkoxy, unsubstituted or substituted C6-C12 aryl, and unsubstituted or substituted heteroaryl; The inorganic base includes carbonates, bicarbonates, phosphates, hydroxides, hydrides, and amides of alkali metals; carbonates, bicarbonates, phosphates, hydroxides, oxides, hydrides, and amides of alkaline earth metals; and the organic base includes organic salts or organic amines.

3. The method according to claim 2, characterized in that R1 is hydrogen, nitro, or substituted amino; R2 and R3 are independently hydrogen, F, Cl, or Br; R4 is hydrogen, Cl, Br, methanesulfonyloxy, or benzenesulfonyloxy; R5 is methyl, chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, tribromomethyl, methoxy, ethoxy, chlorodifluoromethyl, bromodifluoromethyl, bromodichloromethyl, cyclopropyl, unsubstituted or substituted phenyl, pyrazolyl, thiazolyl, thienyl, pyridyl, or pyrimidinyl; R6 is methyl, chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, tribromomethyl, methoxy, ethoxy, chlorodifluoromethyl, bromodifluoromethyl, bromodichloromethyl, cyclopropyl, or unsubstituted or substituted phenyl; The inorganic base is preferably alkali metal carbonate, bicarbonate, hydroxide, alkaline earth metal carbonate, bicarbonate, hydroxide; the organic salt includes alkyl carboxylates and aryl carboxylates, alkoxy salts, metal alkyls, metal aryls; the organic amine includes alkylamine and arylamine compounds.

4. The method according to claim 3, characterized in that The inorganic base is preferably sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide; the alkylamine is a tertiary amine, preferably triethylamine; the arylamine is a pyridylamine, preferably pyridine or picoline.

5. The method according to claim 1, wherein The benzoxazinone compound (I) can be prepared in one pot from compound (II) in the presence of a base 1; or from compound (IV) or compound (VI) in one pot.

6. The method according to claim 1, characterized in that The compound (VII) can be prepared by reacting a compound of formula (IV) with a compound of formula (VI) in one pot.

7. The compound represented by formula (IV) has the following structural formula: in, The R1 is any one of hydrogen, halogen, unsubstituted or substituted C1-C8 alkyl, unsubstituted or substituted C6-C12 aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted acyl, cyano, substituted hydroxyl, substituted thiol, substituted sulfoxide, substituted sulfone, nitro, and substituted amino; preferably hydrogen, halogen, unsubstituted or substituted C1-C3 alkyl, unsubstituted or substituted C6-C12 aryl, unsubstituted or substituted heteroaryl, cyano, nitro, and substituted amino, more preferably hydrogen, nitro, and substituted amino; R2 and R3 are each independently any one of hydrogen, halogen, unsubstituted or substituted C1-C8 alkyl, unsubstituted or substituted C1-C8 alkoxy, unsubstituted or substituted C6-C12 aryl, unsubstituted or substituted C6-C12 aryloxy, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroaryloxy, preferably hydrogen, Halogen, unsubstituted or substituted C1-C3 alkyl, unsubstituted or substituted C1-C3 alkoxy, more preferably hydrogen, F, Cl, Br; R4 is any one of hydrogen, halogen, unsubstituted or substituted C1-C8 alkyl, unsubstituted or substituted C1-C8 alkoxy, C1-C8 acyloxy, unsubstituted or substituted C6-C12 aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted C1-C8 alkylsulfonyloxy, and unsubstituted or substituted C6-C12 arylsulfonyloxy, preferably halogen, unsubstituted or substituted C1-C3 alkylsulfonyloxy, and unsubstituted or substituted C6-C12 arylsulfonyloxy, and more preferably Cl, Br, methanesulfonyloxy, and benzenesulfonyloxy.

8. The compound represented by formula (VI) has the following structural formula: in, R1, R2, R3, R4, R5, A, m, and n are as defined above; Preferably, when R1 is hydrogen, R2 and R3 are independently hydrogen or halogen; R4 is any one of hydrogen, halogen, unsubstituted or substituted C1-C8 alkyl, unsubstituted or substituted C1-C8 alkoxy, unsubstituted or substituted C6-C12 aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted C1-C8 alkylsulfonyloxy, and unsubstituted or substituted C6-C12 arylsulfonyloxy; R5 is any one of unsubstituted or substituted C1-C8 alkyl, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted C1-C8 alkoxy, unsubstituted or substituted C6-C12 aryl, and unsubstituted or substituted heteroaryl.

9. The compound according to claim 8, characterized in that R2 and R3 are independently hydrogen, F, Cl, or Br; R4 is halogen, unsubstituted or substituted C1-C3 alkylsulfonyloxy, unsubstituted or substituted C6-C12 arylsulfonyloxy, preferably Cl, Br, methanesulfonyloxy, benzenesulfonyloxy; R5 is an unsubstituted or substituted C1-C3 alkyl group, an unsubstituted or substituted C3-C6 cycloalkyl group, an unsubstituted or substituted C1-C3 alkoxy group, an unsubstituted or substituted C6-C12 aryl group, an unsubstituted or substituted heteroaryl group, more preferably a methyl group, a chloromethyl group, a bromomethyl group, a dichloromethyl group, a trichloromethyl group, a tribromomethyl group, a methoxy group, Ethoxy, chlorodifluoromethyl, bromodifluoromethyl, bromodichloromethyl, cyclopropyl, phenyl, substituted phenyl.

10. The compound represented by formula (VII) has the following structural formula: in, Said R1, R2, R3, R4, R5, A, m, and n are as defined in claim 9.