A method for preparing substituted isothiazole derivatives

Abstract

The present invention relates to a method for preparing substituted isothiazole derivatives. The present invention belongs to the field of chemical synthesis, and specifically relates to a method for preparing substituted isothiazole derivatives represented by a compound of formula I, wherein each group is as defined in the specification.

Description

[0001] This application claims the priority of Chinese application 202311866376.6 filed on December 29, 2023. The entire text of the priority document is incorporated into this application by reference. Technical Field

[0002] The invention belongs to the field of chemical synthesis, and in particular relates to a method for preparing substituted isothiazole derivatives. Background Art

[0003] Thiazole derivatives are an important class of five-membered heterocyclic compounds containing nitrogen and sulfur atoms. Because they are rich in electrons, they are easy to form various non-covalent interactions such as hydrogen bonding, electrostatics and hydrophobic interactions, which makes thiazole compounds have many special properties. They have broad application prospects in the fields of chemistry, pharmacy and biology, showing great development value. Among them, isothiazole is a common biological electronic isostere, a common structure in active compounds, and has potential biological activity. Therefore, its synthesis and derivative research have received extensive attention from scientists. The development of simple and efficient new methods for the synthesis of isothiazole compounds has important academic significance and potential application value.

[0004] Currently, the most common method for synthesizing isothiazole compounds is the cycloaddition reaction.For example, in 1978, Robert K. Howe et al. synthesized substituted isothiazole compounds through the cycloaddition reaction of nitrile sulfides with acetylenic esters / olefins (Cycloaddition reactions of nitrile sulfides with acetylenic esters.Synthesis of isothiazolecarboxylates, Robert K. Howe, Terry A. Gruner, Linda G. Carter, Linda L. Black, and John E. Franz, J. Org. Chem., 1978, 43, 19,3736–3742; Cycloaddition reactions of nitrile sulfides with olefins, Robert K. Howe and John E. Franz, J. Org. Chem., 1978, 43, 19, 3742–3745); in 1979, Michael J. Sanders et al. synthesized substituted isothiazoles through the 1,3-dipolar cycloaddition reactions of benzonitrile N-sulfide (1,3-Dipolar cycloaddition reactions of benzonitrile N-sulfide,Michael J. Sanders, Sandra L. Dye, Alan G. Miller, and John R. Grunwell, J.Org. Chem., 1979, 44, 4, 510–513); in 2010, Euan AF Fordyce et al. synthesized substituted isothiazoles through the cycloaddition reaction of nitrile sulfides generated by microwave-assisted decarboxylation of 1,3, 4-thiazol-2-one with dimethylacetylene dicarboxylate (Microwave-induced generation and reactions of nitrilesulfides: an improved method for the synthesis of isothiazoles and 1,2,4-thiadiazoles, Euan AF Fordyce, Angus J. Morrison, Robert D. Sharp and R.Michael Paton, Tetrahedron., 2010, 66, 35, 7192-7197).

[0005] These methods are essentially cycloaddition reactions of 1, 3, 4-oxathiazole-2-one to generate nitrile sulfides after decarboxylation with alkynyl esters / olefins. The reaction is subject to some limitations, including, for example, severe reaction conditions, the need for high temperature or microwave reaction equipment, expensive raw materials and difficult preparation, which makes the reaction cost high. Moreover, the purification of the product is more difficult. These all limit the use of existing technical reactions. Therefore, it is still of great significance to study how to synthesize isothiazole compounds simply and efficiently. Summary of the invention

[0006] The present invention provides a novel method for preparing a substituted isothiazole derivative compound of formula I. The overall preparation method is shown in the following formula:

[0007]

[0008] Wherein, each group is as defined below.

[0009] More specifically, in one embodiment, the molar ratio of the compound of formula II to the compound of formula III is 10:1 to 1:10. Specifically, the molar ratio of the compound of formula II to the compound of formula III is 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1 or 10:1, including a range consisting of any two different ratios therebetween. More preferably, the molar ratio of the compound of formula II to the compound of formula III is 10:1 to 1:1. More preferably, the molar ratio of the compound of formula II to the compound of formula III is 2:1 to 1:1. More preferably, the molar ratio of the compound of formula II to the compound of formula III is 1.5:1 to 1.2:1, for example 1.3:1.

[0010] Furthermore, the present invention provides a novel method for preparing a substituted isothiazole derivative compound of formula I, wherein a compound of formula II reacts with a compound of formula III in the presence of a base to obtain a compound of formula I.

[0011] More specifically, in one embodiment, the base is an inorganic base or an organic base.

[0012] More specifically, the molar ratio of the compound of formula III to the base is 10:1 to 1:10. Specifically, the molar ratio of the compound of formula III to the base is 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:8.5, 1:9, 1:9.5 or 1:10, including ranges consisting of any two different ratios therebetween. Preferably, the molar ratio of the compound of formula III to the base is 1:1 to 1:10; more preferably, the molar ratio of the compound of formula III to the base is 1:3 to 1:7, and further preferably, the molar ratio of the compound of formula III to the base is 1:4 to 1:6, for example 1:5.

[0013] More specifically, the present invention provides a novel method for preparing a substituted isothiazole derivative compound of formula I, wherein a compound of formula II reacts with a compound of formula III in the presence of a base and a solvent to obtain a compound of formula I.

[0014] More specifically, in one embodiment, the solvent is a polar solvent selected from a polar protic solvent or a polar aprotic solvent.

[0015] More specifically, the solvent is selected from acetonitrile, acetone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, chloroform, diethyl ether, toluene, dichloromethane and 1,2-dichloroethane.

[0016] More specifically, in one embodiment, the solvent is an alcohol R 4 OH, and the product formed is of formula Ia:

[0017]

[0018] Wherein, each group is as defined below.

[0019] More specifically, in one embodiment, the alcohol R 4 OH is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, pentanol and hexanol, preferably n-butanol or isopropanol, for example isopropanol.

[0020] More specifically, in one embodiment, the alcohol R 4 OH is used in solvent amounts, more specifically, the molar ratio of the compound of formula III to the alcohol is 1:20 to 1:1000, more preferably 1:50 to 1:300, for example 1:100 to 1:200.

[0021] Further, the reaction temperature of the compound of formula II and the compound of formula III is from room temperature to the reflux temperature of the solvent, preferably, the reaction temperature is 35 To the solvent reflux temperature. Specifically, the reaction temperature is 35 , 45 , 50 , 55 , 60 , 65 , 70 , 75 , 80 ,82.5 , 85 or 117 , including the range consisting of any two different values ​​therebetween. For example, the reaction temperature is 35-45 , 45-55 , 55-65 , 65-75 , 75-82.5 ,82.5-85 or 85-117 .

[0022] The present invention relates to a method of simultaneously using a type of sulfur-containing internal Salt and α-halogenated ketone oxime are used as reactants to react to obtain substituted isothiazole derivatives. In the method of the present invention, no metal catalyst needs to be added, and no additional oxidant needs to be added, and the isothiazole ring can be synthesized quickly and simply. In addition, the reaction raw materials are easily available, the reaction conditions are mild, no inert gas protection is required, the operation is simple, and the post-treatment is simple. Based on this, the reaction of the present invention is helpful for application in the synthesis of drug molecules, and it can easily prepare substituted isothiazole derivatives. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 For compound Ⅰ-1 1 H NMR spectrum.

[0024] Figure 2 For compound Ⅰ-1 13 C NMR spectrum.

[0025] Figure 3 For compound Ⅰ-5 1 H NMR spectrum.

[0026] Figure 4 For compound Ⅰ-5 13 C NMR spectrum.

[0027] Figure 5 For compound Ⅰ-6 1 H NMR spectrum.

[0028] Figure 6For compound Ⅰ-6 13 C NMR spectrum.

[0029] Figure 7 For compound Ⅰ-11 1 H NMR spectrum.

[0030] Figure 8 For compound Ⅰ-11 13 C NMR spectrum. DETAILED DESCRIPTION OF THE INVENTION

[0032] definition

[0033] Chemical Definition

[0034] Definitions of specific functional groups and chemical terms are described in more detail below.

[0035] When a numerical range is listed, it is intended to include every value and sub-range within the stated range. For example, "C 1-6 "Alkyl" includes C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 and C 5-6 alkyl.

[0036] “C 1-8 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 8 carbon atoms, also referred to herein as "lower alkyl". In some embodiments, C 1-6 Alkyl, C 1-4 Alkyl and C 1-3 Alkyl is particularly preferred. Examples of the alkyl include, but are not limited to, methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5) and n-hexyl (C6). Regardless of whether the alkyl is modified with "substituted", each of the alkyl groups is independently optionally substituted, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent, and suitable substituents are defined as follows.

[0037] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). In some embodiments, the halogen group is F, Cl, or Br. In some embodiments, the halogen group is Cl or Br. In some embodiments, the halogen group is Br.

[0038] Therefore, “C 1-8 "Haloalkyl" refers to the above-mentioned "C 1-8 "alkyl", which is substituted by one or more halogen groups. In some embodiments, C 1-6 Haloalkyl is particularly preferred, more preferably C 1-4 Haloalkyl, C 1-3 Haloalkyl and C 1-2 Haloalkyl. Exemplary haloalkyl groups include, but are not limited to, -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like.

[0039] “C 3-6 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 6 ring carbon atoms and zero heteroatoms. In some embodiments, C 5-6 Cycloalkyl is particularly preferred.Cycloalkyl also includes a ring system in which the above-mentioned cycloalkyl ring is fused with one or more aryl or heteroaryl groups, wherein the connection point is on the cycloalkyl ring, and in such a case, the number of carbons continues to represent the number of carbons in the cycloalkyl system. Exemplary cycloalkyls include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), etc. Regardless of whether the cycloalkyl is modified with "substituted", each of the cycloalkyls is independently optionally substituted, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent, and suitable substituents are defined as follows.

[0040] "3-10 membered heterocyclyl" refers to a group of a 3-10 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon. In heterocyclyls containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as long as the valence permits. In some embodiments, a 5-6 membered heterocyclyl is preferred, which is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms. Heterocyclyl also includes a ring system in which the above-mentioned heterocyclyl ring is fused with one or more cycloalkyl, aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring; and in such a case, the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Regardless of whether the heterocyclyl is modified with "substituted" before, each of the heterocyclyl groups is independently optionally substituted, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent, and suitable substituents are defined as follows.

[0041] “C 6-10 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) group having 6-10 ring carbon atoms and zero heteroatoms. In some embodiments, aryl has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, aryl has ten ring carbon atoms ("C 10 "Aryl"; for example, naphthyl, for example, 1-naphthyl and 2-naphthyl). In some embodiments, phenyl is particularly preferred. Aryl also includes a ring system in which the above-mentioned aryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. Regardless of whether the aryl group is preceded by "substituted", each of the aryl groups is independently optionally substituted, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent, and suitable substituents are defined as follows.

[0042] "5-10 membered heteroaryl" refers to a group of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as long as the valence permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings. Heteroaryl also includes a ring system in which the above-mentioned heteroaryl ring is fused to one or more cycloalkyl or heterocyclic groups, and the point of attachment is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5-6 membered heteroaryl groups are particularly preferred, which are 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. In some embodiments, 5-membered heteroaryl is particularly preferred, which is a 5-membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. In some embodiments, 6-membered heteroaryl is particularly preferred, which is a 6-membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. Regardless of whether the heteroaryl is modified with "substituted", each of the heteroaryl groups is independently optionally substituted, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent, and suitable substituents are defined as follows.

[0043] Exemplary substituents on carbon atoms include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa 、-ON(R bb )2、-N(R bb )2、-N(R bb )3 + X - 、-N(OR cc )R bb , -SH, -SR aa 、-SSR cc 、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc 2. -CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2.-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(Rbb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2R aa 、-OP(=O)2R aa 、-P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb )2、-P(=O)(NR bb )2、-OP(=O)(NR bb )2、-NR bb P(=O)(OR cc )2、-NR bbP(=O)(NR bb )2. -P(R cc )2. -P(R cc )3.-OP(R cc )2.-OP(R cc )3. -B(R aa )2、-B(OR cc )2. -BR aa (OR cc ), alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R dd Group substitution;

[0044] Or the two geminal hydrogen atoms on the carbon atom are replaced by groups =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa 、=NNR bb C(=O)OR aa 、=NNR bb S(=O)2R aa 、=NR bb =NOR cc replace;

[0045] R aa Each of R is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R aa The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R dd Group substitution;

[0046] R bb Each of the following is independently selected from: hydrogen, -OH, -OR aa 、-N(R cc )2, -CN, -C(=O)R aa 、-C(=O)N(R cc 2. -CO2R aa 、-SO2R aa 、-C(=NR cc )OR aa 、-C(=NR cc )N(R cc )2、-SO2N(R cc 2. -SO2R cc 、-SO2OR cc 、-SOR aa、-C(=S)N(R cc )2. -C(=O)SR cc 、-C(=S)SR cc 、-P(=O)2R aa 、-P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl, or two R bb The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R dd Group substitution;

[0047] R cc Each of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R cc The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R dd Group substitution;

[0048] R dd Each of is independently selected from: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee 、-ON(R ff )2、-N(R ff )2, 、-N(R ff )3 + X - 、-N(OR ee )R ff , -SH, -SR ee 、-SSR ee 、-C(=O)R ee 、-CO2H、-CO2R ee 、-OC(=O)R ee 、-OCO2R ee 、-C(=O)N(R ff )2、-OC(=O)N(R ff )2.-NR ff C(=O)R ee 、-NR ff CO2R ee 、-NR ff C(=O)N(R ff )2、-C(=NR ff )ORee 、-OC(=NR ff )R ee 、-OC(=NR ff )OR ee 、-C(=NR ff )N(R ff )2. -OC(=NR ff )N(R ff )2.-NR ff C(=NR ff )N(R ff )2.-NR ff S02R ee 、-SO2N(R ff 2. -SO2R ee 、-SO2OR ee 、-OSO2R ee 、-S(=O)R ee 、-Si(R ee )3.-OSi(R ee )3. -C(=S)N(R ff )2. -C(=O)SR ee 、-C(=S)SR ee 、-SC(=S)SR ee 、-P(=O)2R ee 、-P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(OR ee )2, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R gg Group substitution, or two geminal R dd Substituents may combine to form =O or =S;

[0049] R ee Each of R is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R gg Group substitution;

[0050] R ff Each of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R ffThe groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R gg Group substitution;

[0051] R gg Each of is independently: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)3 + X - 、-NH(C 1-6 Alkyl)2 + X - 、-NH2(C 1-6 alkyl) + X - 、-NH3 + X - 、-N(OC 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 Alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 Alkyl), -OC(=O)(C 1-6 Alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 Alkyl)2, -OC(=O)NH(C 1-6 Alkyl), -NHC(=O)(C 1-6 Alkyl), -N(C 1-6 Alkyl)C(=O)(C 1-6 Alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 Alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 Alkyl), -OC(=NH)(C 1-6 Alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 Alkyl)2, -C(=NH)NH(C 1-6alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2, -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 Alkyl), -SO2N(C 1-6 Alkyl)2, -SO2NH(C 1-6 Alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 Alkyl)3, -OSi(C 1-6 Alkyl)3, -C(=S)N(C 1-6 Alkyl)2, C(=S)NH(C 1-6 alkyl), C(=S)NH2, -C(=O)S(C 1-6 Alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O)2(C 1-6 Alkyl), -P(=O)(C 1-6 Alkyl)2, -OP(=O)(C 1-6 Alkyl)2, -OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 carbocyclic group, C6-C 10 Aryl, C3-C7 heterocyclic, C5-C 10 heteroaryl; or two geminal R gg Substituents may combine to form =O or =S; where X - For the counter ion.

[0052] Exemplary substituents on nitrogen atoms include, but are not limited to, hydrogen, -OH, -OR aa 、-N(R cc )2, -CN, -C(=O)R aa 、-C(=O)N(R cc 2. -CO2R aa 、-SO2R aa 、-C(=NR bb )R aa 、-C(=NR cc )OR aa、-C(=NR cc )N(R cc )2、-SO2N(R cc 2. -SO2R cc 、-SO2OR cc 、-SOR aa 、-C(=S)N(R cc )2. -C(=O)SR cc 、-C(=S)SR cc 、-P(=O)2R aa 、-P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R attached to the nitrogen atom cc The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R dd substituted with a group, and wherein R aa , R bb , R cc and R dd As mentioned above.

[0053] Other definitions

[0054] "Polar solvent" refers to a molecule in which the centers of gravity of positive and negative charges do not coincide in the spatial structure of the solvent molecule.

[0055] The term "protic solvent" refers to a solvent having OH bonds or NH bonds in the solvent molecules that can serve as hydrogen bond donors.

[0056] "Aprotic solvents" are also called non-protic solvents and protonic solvents. Such solvents have very weak or no proton self-transfer reaction.

[0057] Therefore, "polar protic solvent" refers to a solvent that satisfies the concepts of both "polar solvent" and "protic solvent", including water; alcohols such as ethanol, isopropanol, butanol; acids such as acetic acid; amines such as ammonia.

[0058] "Polar aprotic solvent" refers to a solvent that meets the concepts of both "polar solvent" and "aprotic solvent", including ethers such as diethyl ether, tetrahydrofuran, and dioxane; halogen compounds such as methyl chloride, chloroform, dichloromethane, 1, 2-dichloroethane, and carbon tetrachloride; ketones such as acetone and methyl ethyl ketone; nitrogen-containing hydrocarbons such as nitromethane, N,N-dimethylformamide, N,N-dimethylacetamide, nitrobenzene, pyridine, acetonitrile, and quinoline; sulfoxides such as dimethyl sulfoxide; and aromatics such as toluene.

[0059] The "solvent reflux temperature" refers to the temperature at which the solvent gas condenses and refluxes in the condensation part of the device to form an equilibrium between the liquid vaporization and the liquid phase during experimental operation.

[0060] The "amount of solvent" refers to the amount of solvent required to ensure the normal progress of the reaction, which can be determined by those skilled in the art.

[0061] Specifically, the present invention relates to the following technical solutions:

[0062] In one embodiment, the present invention relates to a process for preparing a compound of formula I,

[0063]

[0064] The method comprises reacting a compound of formula II with a compound of formula III to obtain a compound of formula I,

[0065]

[0066] in,

[0067] X is a halogen;

[0068] R 1 Selected from C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally selected from C 1-8 Alkyl, C 1-8 Substitution by haloalkyl, halogen, OR' and NR'R'';

[0069] R 2 Each occurrence is independently selected from C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl and 3-7 membered heterocyclic group;

[0070] R 3 Selected from H, C 1-8 Alkyl, C1-8 haloalkyl, halogen, OR' and NR'R'';

[0071] R' and R'' are each independently selected from H, C 1-8 Alkyl and C 1-8 Halogenated alkyl.

[0072] In a more specific embodiment, the present invention provides a method for preparing a compound of formula I as described above, wherein:

[0073] X is selected from Cl and Br;

[0074] R 1 Selected from C 1-6 Alkyl, C 1-6 haloalkyl and phenyl, wherein the alkyl, haloalkyl and phenyl are optionally selected from C 1-6 Alkyl, C 1-6 Substitution by haloalkyl, OR' and halogen;

[0075] R 2 Each occurrence is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-5 Cycloalkyl and 3-6 membered heterocyclic group;

[0076] R 3 Selected from H, C 1-6 Alkyl, C 1-6 haloalkyl, halogen, OR' and NR'R'';

[0077] R' and R'' are each independently selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0078] In a more specific embodiment, the present invention provides a method for preparing a compound of formula I as described above, wherein:

[0079] X is selected from Cl and Br;

[0080] R 1 Selected from C 1-6 Alkyl and phenyl, wherein the phenyl is optionally selected from C 1-6 Substitution by substituents of alkyl, OR' and halogen;

[0081] R 2 Each occurrence is independently C 1-6 Alkyl and C 1-6 Haloalkyl;

[0082] R 3 Selected from H and OR';

[0083] R' is C1-6 Alkyl or C 1-6 Halogenated alkyl.

[0084] In a more specific embodiment, the present invention provides the above-mentioned method for preparing a compound of formula I, wherein the molar ratio of the compound of formula II to the compound of formula III is 10:1 to 1:1, preferably, the molar ratio of the compound of formula II to the compound of formula III is 2:1 to 1:1, preferably, the molar ratio of the compound of formula II to the compound of formula III is 1.2:1 to 1.5:1, for example, the molar ratio of the compound of formula II to the compound of formula III is 1.3:1.

[0085] In a more specific embodiment, the present invention provides the above-mentioned method for preparing the compound of formula I, wherein the reaction is carried out in the presence of a base, preferably, the base is an inorganic base or an organic base, preferably, the base is a basic salt or an amine, preferably, the base is selected from sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, lithium bicarbonate, triethylamine and N, N-diisopropylethylamine, preferably, the base is selected from potassium carbonate, sodium carbonate and triethylamine, preferably potassium carbonate or sodium carbonate.

[0086] In a more specific embodiment, the present invention provides the above-mentioned method for preparing a compound of formula I, wherein the molar ratio of the compound of formula III to the base is 1:1 to 1:10, preferably, the molar ratio of the compound of formula III to the base is 1:3 to 1:7, preferably, the molar ratio of the compound of formula III to the base is 1:4 to 1:6, for example, 1:5.

[0087] In a more specific embodiment, the present invention provides the above-mentioned method for preparing the compound of formula I, wherein the reaction is carried out in the presence of a solvent, preferably, the solvent is a polar solvent selected from polar protic solvents and polar aprotic solvents, preferably, the solvent is selected from acetonitrile, acetone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, chloroform, diethyl ether, toluene, dichloromethane and 1,2-dichloroethane, preferably acetonitrile.

[0088] In a more specific embodiment, the present invention provides the above method for preparing the compound of formula I, wherein the solvent is an alcohol R 4 OH, and the product formed is of formula Ia:

[0089]

[0090] in,

[0091] R 4 Selected from C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl and 3-7 membered heterocyclic group; preferably selected from C1-6 Alkyl, C 1-6 Haloalkyl, C 3-5 Cycloalkyl and 3-6 membered heterocyclic group; more preferably C 1-6 Alkyl or C 1-6 Haloalkyl; more preferably isopropyl;

[0092] R 1 As defined above.

[0093] In a more specific embodiment, the present invention provides the above-mentioned method for preparing the compound of formula I, wherein the alcohol R 4 OH is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, pentanol and hexanol, preferably n-butanol or isopropanol, for example isopropanol.

[0094] In a more specific embodiment, the present invention provides the above method for preparing the compound of formula I, wherein the reaction temperature is from room temperature to the reflux temperature of the solvent, preferably, the reaction temperature is 35 To the solvent reflux temperature, for example 35-45 , 45-55 , 55-65 , 65-75 , 75-82.5 ,82.5-85 or 85-117 . DETAILED DESCRIPTION

[0095] The technical solution of the present invention is further described below with reference to the accompanying drawings and through specific embodiments:

[0096] The following are some examples of the compounds prepared by the present invention. In all the following examples, the NMR spectra were obtained by BRUKER 400M AV III NMR instrument in CDCl3. Values ​​are relative to internal standard (CHCl3 calibration 7.27 1 H NMR and 77.06 13 C NMR. Mass spectrometry was obtained using HPLC Waters ACQUITY Arc, ESI MS mass spectrometer.

[0097] Example 1

[0098]

[0099] 543 mg (2.54 mmol, 1.3 equivalents) of compound II-1 and 494 mg (1.95 mmol, 1.0 equivalents) of compound III-1 were dissolved in 24 mL of acetonitrile, and 1610 mg (11.7 mmol, 5.0 equivalents) of potassium carbonate were added. The mixture was refluxed for 12 h, and both reactants II-1 and III-1 disappeared completely. The reaction mixture was evaporated under reduced pressure by a water pump to remove the solvent. The residue was chromatographed on a silica gel column to obtain 210 mg of compound I-1, which was identified by nuclear magnetic resonance (hydrogen spectrum, carbon spectrum) and mass spectrometry.

[0100] The product Ⅰ-1 was a light yellow solid with a yield of 47%. 1 H NMR (400 MHz, CDCl3) 7.98–7.91(m, 2H), 7.75 (s, 1H), 7.47–7.41 (m, 2H), 7.40–7.34 (m, 1H), 4.03 (s, 3H); 13 CNMR (101 MHz, CDCl3) 160.61, 157.85, 157.78, 133.43, 128.86, 128.85,126.71, 118.92, 53.29; MS (ESI) m / z(%)[M+H] + :219.98.

[0101] The same reactants as in Example 1 were used to carry out each batch of reactions, but the reaction conditions were adjusted, including the molar ratio between the reactants, the types of base and solvent, temperature and reaction time, as summarized in the following table:

[0102]

[0103] Example 2

[0104]

[0105] 543 mg (2.54 mmol, 1.3 equivalents) of compound II-1 and 548 mg (1.95 mmol, 1.0 equivalents) of compound III-2 were dissolved in 24 mL of acetonitrile, and 1610 mg (11.7 mmol, 5.0 equivalents) of potassium carbonate were added. The reaction mixture was refluxed for 12 h, and both reactants II-1 and III-2 disappeared completely. The reaction mixture was rotary evaporated under reduced pressure of a water pump to remove the solvent. The residue was subjected to silica gel column chromatography to obtain 210 mg of compound I-6, and the product was identified by nuclear magnetic resonance (hydrogen spectrum, carbon spectrum) and mass spectrometry.

[0106] Product Ⅰ-6 was a light yellow solid with a yield of 46%. 1 H NMR (400 MHz, CDCl3) 7.99–7.93(m, 2H), 7.74 (s, 1H), 7.47–7.41 (m, 2H), 7.40–7.35 (m, 1H), 4.51 (q, J = 7.1Hz, 2H), 1.46 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDCl3) 160.13, 158.21,157.81, 133.53, 128.82, 128.81, 126.73, 118.69, 62.65, 14.30; MS (ESI) m / z(%)[M+H] + :233.98.

[0107] Example 3

[0108]

[0109] 493 mg (2.54 mmol, 1.3 equivalents) of compound II-5 and 494 mg (1.95 mmol, 1.0 equivalents) of compound III-1 were dissolved in 24 mL of acetonitrile, and 1610 mg (11.7 mmol, 5.0 equivalents) of potassium carbonate were added. The mixture was refluxed for 12 h, and both reactants II-5 and III-1 disappeared completely. The reaction mixture was rotary evaporated under reduced pressure of a water pump to remove the solvent. The residue was subjected to silica gel column chromatography to obtain 210 mg of compound I-5, and the product was identified by nuclear magnetic resonance (hydrogen spectrum, carbon spectrum) and mass spectrometry.

[0110] The product I-5 was a white solid with a yield of 46%. 1H NMR (400 MHz, CDCl3) 7.23 (s,1H), 4.00 (s, 3H), 1.40 (s, 9H); 13 C NMR (101 MHz, CDCl3) 169.34, 160.81,157.06, 117.18, 53.12, 35.09, 30.11; MS (ESI) m / z(%)[M+H] + :200.01.

[0111] Example 4

[0112]

[0113] 543 mg (2.54 mmol, 1.3 equivalents) of compound II-1 and 494 mg (1.95 mmol, 1.0 equivalents) of compound III-1 were dissolved in 24 mL of isopropanol, and 1610 mg (11.7 mmol, 5.0 equivalents) of potassium carbonate were added, and the mixture was refluxed for 12 h. Both reactants II-1 and III-1 disappeared completely. The reaction mixture was rotary evaporated under reduced pressure by a water pump to remove the solvent. The residue was subjected to silica gel column chromatography to obtain 210 mg of compound I-11, which was identified by nuclear magnetic resonance (hydrogen spectrum, carbon spectrum) and mass spectrometry.

[0114] Product Ⅰ-11 is a light yellow liquid with a yield of 41%. 1 H NMR (400 MHz, CDCl3) 7.99–7.94(m, 2H), 7.72 (s, 1H), 7.47–7.40 (m, 2H), 7.39–7.34 (m, 1H), 5.35 (sep, J =6.3 Hz, 1H), 1.44 (d, J = 6.3 Hz, 6H); 13 C NMR (101 MHz, CDCl3) 159.58,158.51, 157.72, 133.60, 128.80, 128.75, 126.73, 118.48, 70.68, 21.83; MS(ESI) m / z(%)[M+H] + :248.01.

[0115] Example 5

[0116] The same operation as in Example 1 was used to prepare other compounds of the present invention.

[0117] The structures of the raw materials used to prepare compounds Ⅰ-1 to Ⅰ-11 are as follows:

[0118]

[0119] Among them, compounds ⅠⅠ-1 to ⅠⅠ-6 are from reference (Nitrimines as Reagents for Metal-Free Formal C (sp 2 )–C(sp 2 ) Cross-Coupling Reactions. Veronica V. Angeles-Dunham, David M. Nickerson, Devin M. Ray, and Anita E. Mattson., Angew. Chem.Int. Ed., 2014, 53, 14538 –14541); compounds ⅠⅠⅠ-1 to ⅠⅠⅠ-3 were obtained by the preparation method of reference (Visible-Light-Induced [1+5] Annulation of PhosphorylDiazomethylarenes and Pyridinium 1,4-Zwitterionic Thiolates. Simin Sun,Yuliang Wei, and Jiaxi Xu., Org. Lett., 2022, 24, 6024−6030).

[0120] The structures and data characterizations of each product are as follows:

[0121]

[0122] The NMR and mass spectrometry data of the products are summarized as follows:

[0123] The product Ⅰ-1 was a light yellow solid with a yield of 47%. 1 H NMR (400 MHz, CDCl3) 7.98–7.91(m, 2H), 7.75 (s, 1H), 7.47–7.41 (m, 2H), 7.40–7.34 (m, 1H), 4.03 (s, 3H); 13 CNMR (101 MHz, CDCl3) 160.61, 157.85, 157.78, 133.43, 128.86, 128.85,126.71, 118.92, 53.29; MS (ESI) m / z(%)[M+H] + :219.98.

[0124] The product Ⅰ-2 was an off-white solid with a yield of 46%. 1 H NMR (400 MHz, CDCl3) 7.87–7.80(m, 2H), 7.69 (s, 1H), 7.28–7.21 (m, 2H), 4.03 (s, 3H), 2.39 (s, 3H); 13 C NMR (101 MHz, CDCl3) 160.67, 157.98, 157.62, 138.83, 130.73, 129.53, 126.60,118.20, 53.27, 21.31; MS (ESI) m / z(%)[M+H] + :233.99.

[0125] The product I-3 was a light yellow solid with a yield of 44%. 1 H NMR (400 MHz, CDCl3) 7.96–7.89 (m, 2H), 7.69 (s, 1H), 7.16–7.09 (m, 2H), 4.04 (s, 3H); 13 C NMR (101 MHz,CDCl3) 164.39 (F atom directly connected to benzene ring carbon), 161.92 (F atom directly connected to benzene ring carbon), 160.50, 157.88,156.82, 129.75 (F atom para-benzene ring carbon), 129.72 (F atom para-benzene ring carbon), 128.58 (F atom meta-benzene ring carbon), 128.50 (F atom meta-benzene ring carbon), 118.52, 115.92 (F atom ortho-benzene ring carbon), 115.71 (F atom ortho-benzene ring carbon), 53.31; MS (ESI) m / z(%)[M+H] + :237.98.

[0126] The product I-4 was an off-white solid with a yield of 42%. 1 H NMR (400 MHz, CDCl3) 7.91–7.85(m, 2H), 7.62 (s, 1H), 6.99–6.93 (m, 2H), 4.03 (s, 3H), 3.85 (s, 3H); 13 C NMR (101 MHz, CDCl3) 160.67, 160.18, 157.75, 157.56, 128.06, 126.35, 117.27,114.18, 55.36, 53.25; MS (ESI) m / z(%)[M+H] + :249.98.

[0127] The product I-5 was a white solid with a yield of 46%. 1 H NMR (400 MHz, CDCl3) 7.23 (s,1H), 4.00 (s, 3H), 1.40 (s, 9H); 13C NMR (101 MHz, CDCl3) 169.34, 160.81,157.06, 117.18, 53.12, 35.09, 30.11; MS (ESI) m / z(%)[M+H] + :200.01.

[0128] Product Ⅰ-6 was a light yellow solid with a yield of 46%. 1 H NMR (400 MHz, CDCl3) 7.99–7.93(m, 2H), 7.74 (s, 1H), 7.47–7.41 (m, 2H), 7.40–7.35 (m, 1H), 4.51 (q, J = 7.1Hz, 2H), 1.46 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDCl3) 160.13, 158.21,157.81, 133.53, 128.82, 128.81, 126.73, 118.69, 62.65, 14.30; MS (ESI) m / z(%)[M+H] + :233.98.

[0129] The product I-7 was a light yellow solid with a yield of 42%. 1 H NMR (400 MHz, CDCl3) 7.87–7.82(m, 2H), 7.67 (s, 1H), 7.28–7.20 (m, 2H), 4.50 (q, J = 7.1 Hz, 2H), 2.38 (s,3H), 1.45 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDCl3) 160.16, 158.01,157.89, 138.74, 130.82, 129.50, 126.61, 118.01, 62.60, 21.31, 14.30; MS (ESI)m / z(%)[M+H] + :247.98.

[0130] The product I-8 was a light yellow solid with a yield of 43%. 1 H NMR (400 MHz, CDCl3) 7.98–7.89(m, 2H), 7.68 (s, 1H), 7.17–7.09 (m, 2H), 4.51 (q, J = 7.1 Hz, 2H), 1.46 (t,J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDCl3) 164.36 (F atom directly connected to benzene ring carbon), 161.89 (F atom directly connected to benzene ring carbon), 160.02, 158.31, 156.76, 129.83 (F atom para-benzene ring carbon), 129.80 (F atom para-benzene ring carbon), 128.59 (F atom meta-benzene ring carbon), 128.50 (F atom meta-benzene ring carbon), 118.31, 115.89 (F atom ortho-benzene ring carbon), 115.68 (F atom ortho-benzene ring carbon), 62.69, 14.28; MS (ESI) m / z (%) [M+H] + :251.99.

[0131] The product I-9 was a light yellow solid with a yield of 44%. 1 H NMR (400 MHz, CDCl3) 7.93–7.85(m, 2H), 7.61 (s, 1H), 6.99–6.92 (m, 2H), 4.50 (q, J = 7.1 Hz, 2H), 3.84 (s,3H), 1.46 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) 160.16, 160.13,157.94, 157.65, 128.06, 126.44, 117.08, 114.15, 62.57, 55.34, 14.29; MS (ESI)m / z(%)[M+H] + :263.99.

[0132] The product I-10 was a white solid with a yield of 44%. 1 H NMR (400 MHz, CDCl3) 7.21 (s,1H), 4.47 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H), 1.39 (s, 9H); 13 C NMR (101 MHz, CDCl3) 169.25, 160.21, 157.29, 116.85, 62.32, 35.10, 30.12,14.29; MS (ESI) m / z(%)[M+H] + :214.02.

[0133] Product Ⅰ-11 is a light yellow liquid with a yield of 41%. 1 H NMR (400 MHz, CDCl3) 7.99–7.94(m, 2H), 7.72 (s, 1H), 7.47–7.40 (m, 2H), 7.39–7.34 (m, 1H), 5.35 (sep, J =6.3 Hz, 1H), 1.44 (d, J = 6.3 Hz, 6H); 13 C NMR (101 MHz, CDCl3) 159.58,158.51, 157.72, 133.60, 128.80, 128.75, 126.73, 118.48, 70.68, 21.83; MS(ESI) m / z(%)[M+H] + :248.01.

[0134] It will be apparent to those skilled in the art that the invention is not limited to the details of the exemplary embodiments described above and that the invention can be implemented in other specific forms without departing from the spirit or essential features of the invention. Therefore, the embodiments should be considered exemplary and non-limiting in all respects, and the scope of the invention is defined by the appended claims rather than the foregoing description, and it is intended that all variations falling within the meaning and scope of the equivalent elements of the claims be included in the invention. Any reference numeral in a claim should not be considered as limiting the claim to which it relates.

[0135] In addition, it should be understood that although the present specification is described according to implementation modes, not every implementation mode contains only one independent technical solution. This description of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment may also be appropriately combined to form other implementation modes that can be understood by those skilled in the art.

Claims

1. A method for preparing a compound of formula I, The method comprises reacting a compound of formula II with a compound of formula III to obtain a compound of formula I, in, X is a halogen; R 1 Selected from C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally selected from C 1-8 Alkyl, C 1-8 Substitution by haloalkyl, halogen, OR' and NR'R''; R 2 Each occurrence is independently selected from C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl and 3-7 membered heterocyclic group; R 3 Selected from H, C 1-8 Alkyl, C 1-8 haloalkyl, halogen, OR' and NR'R''; R' and R'' are each independently selected from H, C 1-8 Alkyl and C 1-8 Halogenated alkyl.

2. The method according to claim 1, wherein: X is selected from Cl and Br; R 1 Selected from C 1-6 Alkyl, C 1-6 haloalkyl and phenyl, wherein the alkyl, haloalkyl and phenyl are optionally selected from C 1-6 Alkyl, C 1-6 Substitution by haloalkyl, OR' and halogen; R 2 Each occurrence is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-5 Cycloalkyl and 3-6 membered heterocyclic group; R 3 Selected from H, C 1-6 Alkyl, C 1-6 haloalkyl, halogen, OR' and NR'R''; R' and R'' are each independently selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

3. The method according to claim 1, wherein: X is selected from Cl and Br; R 1 Selected from C 1-6 Alkyl and phenyl, wherein the phenyl is optionally selected from C 1-6 Substitution by substituents of alkyl, OR' and halogen; R 2 Each occurrence is independently C 1-6 Alkyl and C 1-6 Haloalkyl; R 3 Selected from H and OR'; R' is C 1-6 Alkyl or C 1-6 Halogenated alkyl.

4. The method according to any one of claims 1 to 3, wherein the molar ratio of the compound of formula II to the compound of formula III is 10:1 to 1:1, preferably, the molar ratio of the compound of formula II to the compound of formula III is 2:1 to 1:1, preferably, the molar ratio of the compound of formula II to the compound of formula III is 1.2:1 to 1.5:1, for example, the molar ratio of the compound of formula II to the compound of formula III is 1.3:

1.

5. The method according to any one of the preceding claims, wherein the reaction is carried out in the presence of a base, preferably, the base is an inorganic base or an organic base, preferably, the base is a basic salt or an amine, preferably, the base is selected from sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, lithium bicarbonate, triethylamine and N, N-diisopropylethylamine, preferably, the base is selected from potassium carbonate, sodium carbonate and triethylamine, preferably potassium carbonate or sodium carbonate.

6. The method according to claim 5, wherein the molar ratio of the compound of formula III to the base is 1:1 to 1:10, preferably, the molar ratio of the compound of formula III to the base is 1:3 to 1:7, preferably, the molar ratio of the compound of formula III to the base is 1:4 to 1:6, for example 1:

5.

7. The method according to any one of the preceding claims, wherein the reaction is carried out in the presence of a solvent, preferably a polar solvent selected from polar protic solvents and polar aprotic solvents, preferably selected from acetonitrile, acetone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, chloroform, diethyl ether, toluene, dichloromethane and 1,2-dichloroethane, preferably acetonitrile.

8. The method according to claim 7, wherein the solvent is an alcohol R 4 OH, and the product formed is of formula Ia: in, R 4 Selected from C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl and 3-7 membered heterocyclic group; preferably selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-5 Cycloalkyl and 3-6 membered heterocyclic group; more preferably C 1-6 Alkyl or C 1-6 Haloalkyl; more preferably isopropyl; R 1 As defined in any one of claims 1 to 3.

9. The process according to claim 8, wherein the alcohol R 4 OH is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, pentanol and hexanol, preferably n-butanol or isopropanol, for example isopropanol.

10. The method according to any one of the preceding claims, wherein the reaction temperature is from room temperature to the reflux temperature of the solvent, preferably, the reaction temperature is 35 To the solvent reflux temperature, for example 35-45 , 45-55 , 55-65 , 65-75 , 75-82.5 ,82.5-85 or 85-117 .

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