Preparation method of 2-amino-3-bromobenzotrifluoride

Abstract

The invention discloses a preparation method of 2-amino-3-bromobenzotrifluoride. The method comprises the following steps: carrying out deprotection on a compound shown in a formula V to obtain 2-amino-3-bromobenzotrifluoride (shown in a formula VI). The synthesis route is as follows: # imgabs0 #, wherein the definitions of R3 and R4 are as defined in the specification. The invention also discloses a novel intermediate compound for synthesizing the 2-amino-3-bromobenzotrifluoride, the total yield of the synthesized 2-amino-3-bromobenzotrifluoride is high due to the use of the compounds, the production cost of the 2-amino-3-bromobenzotrifluoride is reduced, and the 2-amino-3-bromobenzotrifluoride has relatively strong competitiveness.

Description

Technical Field

[0001] The invention relates to the field of chemical synthesis, and in particular to a novel preparation method of 2-amino-3-bromotrifluorotoluene. Background Art

[0002] 3-Bromo-2-aminotrifluorotoluene is an important chemical intermediate and has broad development prospects in the fields of chemical materials, pesticides, and medicines.

[0003] Since trifluoromethyl does not exist in natural products, it is particularly important to develop a new, simple and practical method for introducing trifluoromethyl. In 1987, Wakselman and his colleagues first reported the trifluoromethylation reaction of aromatic amines under certain pressure using trifluoromethyl bromide under the action of zinc and sulfur dioxide (J.Chem.Soc., Chem.Commun.1987,1701-1703). Subsequently, some electrophilic trifluoromethyl reagents were used to synthesize trifluoromethyl aromatic amines, but amino substrates were limited (E.Eur.J.Org.Chem.2009,1390–1397). In recent years, there has been a method for introducing trifluoromethyl with aromatic amines with protecting groups to obtain the corresponding trifluoromethyl aromatic amines, but this method should consider the tolerance of other groups in the molecule during the deprotection process (Chem.Commun.2013,49,4552-4554). In 2014, a method for introducing trifluoromethyl groups by photocatalysis to form trifluoromethyl aromatic amines was developed (Org. Lett. 2014, 16, 1768-1771).

[0004] The methods for synthesizing 3-bromo-2-aminobenzotrifluoride at present mainly include:

[0005] Method 1: CN103553857A reports that aromatic amine and trivalent iodine reagent compound are used as raw materials, under the protection of argon or nitrogen, tri(2-phenylpyridine)iridium [Ir(ppy)3] is used as a catalyst, and reacts under light conditions to obtain o-trifluoroaniline or its derivatives. The synthesis route of this method is as follows:

[0006]

[0007] The typical reaction is disclosed in the patent:

[0008]

[0009] , wherein R may be halogen.

[0010] This patent does not disclose the preparation of 3-bromo-2-aminobenzotrifluoride, but according to the examples disclosed, it can be known that the yield of the main product in the reaction process is not high, and the maximum is only about 80%. When there is bromine substitution on the benzene ring, the yield is only 61% at best, and even the yield of the two products is close (see Example 12). If this method is used to synthesize 3-bromo-2-aminobenzotrifluoride, not only the raw material trivalent iodine reagent compound is costly and difficult, but also its catalyst is very expensive, and the reaction conditions are also harsh, especially the yield is low. The above factors will increase the cost of synthesizing 3-bromo-2-aminobenzotrifluoride.

[0011] Method 2: CN108503552A discloses a method for preparing trifluoromethyl aromatic amine, and its synthetic route is as follows: The method still has expensive catalysts in large-scale production, and the trifluoromethylation reagent is difficult to prepare, making large-scale industrialization difficult. The patent discloses the preparation of 3-bromo-2-aminotrifluorotoluene, in which o-bromoaniline is used as a raw material to react and obtain two products: Product 1: The yield is 37%, product 2: and the reaction yield is low at only 37%. The yield is 33%. The yield of 3-bromo-2-aminotrifluorotoluene obtained from m-bromoaniline is only 29%.

[0012] The prior art for synthesizing 3-bromo-2-aminobenzotrifluoride has the defects of high raw material cost and low reaction yield, which results in a relatively high cost for synthesizing 3-bromo-2-aminobenzotrifluoride. Summary of the invention

[0013] Aiming at the problems of high raw material cost and low product yield in the prior art for synthesizing 3-bromo-2-aminobenzotrifluoride, the present invention provides a method for preparing 3-bromo-2-aminobenzotrifluoride with low raw material cost and high yield.

[0014] Specifically, the present invention adopts the following technical scheme: the compound of formula V is deprotected under the action of a deprotecting agent to obtain 2-amino-3-bromotrifluorotoluene (formula VI), and its synthesis route is as follows:

[0015] wherein R3 and R4 are independently selected from hydrogen, optionally substituted alkyl, acyl, sulfonyl, alkylsilyl, cyano, and allyl, preferably hydrogen, benzyl, acetyl, propionyl, trifluoroacetyl, formyl, benzenesulfonyl, p-toluenesulfonyl, methylsulfonyl, trifluoromethanesulfonyl, trimethylsilyl, cyano, 1,1-diphenylmethyl, and tert-butyl;

[0016] or R3 and R4 form a cyclic imide structure with the central N atom, preferably one of phthalimide, succinimide, tetrahydrophthalimide, 1,2-cyclohexanediamide, and butenediimide;

[0017] Provided that R3 and R4 are not H at the same time.

[0018] Preferably, the present invention provides a method for preparing a compound of formula V, and the synthetic route thereof is as follows:

[0019] wherein R3 and R4 are independently selected from hydrogen, optionally substituted alkyl, acyl, sulfonyl, alkylsilyl, cyano, and allyl, preferably hydrogen, benzyl, acetyl, propionyl, trifluoroacetyl, formyl, benzenesulfonyl, p-toluenesulfonyl, methylsulfonyl, trifluoromethanesulfonyl, trimethylsilyl, cyano, 1,1-diphenylmethyl, and tert-butyl;

[0020] or R3 and R4 form a cyclic imide structure with the central N atom, preferably one of phthalimide, succinimide, tetrahydrophthalimide, 1,2-cyclohexanediamide, and butenediimide;

[0021] Provided that R3 and R4 are not H at the same time.

[0022] Preferably, the present invention also provides a method for preparing a compound of formula IV, and its synthetic route is as follows: Wherein, R1 is selected from fluorine, chlorine, bromine or iodine;

[0023] R3, R4 are independently selected from hydrogen, optionally substituted alkyl, acyl, sulfonyl, alkylsilyl, cyano, allyl, preferably hydrogen, benzyl, acetyl, propionyl, trifluoroacetyl, formyl, benzenesulfonyl, p-toluenesulfonyl, methylsulfonyl, trifluoromethanesulfonyl, trimethylsilyl, cyano, 1,1-diphenylmethyl, tert-butyl;

[0024] or R3 and R4 form a cyclic imide structure with the central N atom, preferably one of phthalimide, succinimide, tetrahydrophthalimide, 1,2-cyclohexanediamide, and butenediimide;

[0025] Provided that R3 and R4 are not H at the same time.

[0026] Preferably, the present invention also provides a method for preparing a compound of formula III, the synthesis route of which is as follows: wherein R1 is selected from chlorine, bromine and iodine, and R2 is selected from fluorine, chlorine, bromine or iodine;

[0027] R3, R4 are independently selected from hydrogen, optionally substituted alkyl, acyl, sulfonyl, alkylsilyl, cyano, allyl, preferably hydrogen, benzyl, acetyl, propionyl, trifluoroacetyl, formyl, benzenesulfonyl, p-toluenesulfonyl, methylsulfonyl, trifluoromethanesulfonyl, trimethylsilyl, cyano, 1,1-diphenylmethyl, tert-butyl;

[0028] or R3 and R4 form a cyclic imide structure with the central N atom, preferably one of phthalimide, succinimide, tetrahydrophthalimide, 1,2-cyclohexanediamide, and butenediimide;

[0029] Provided that R3 and R4 are not H at the same time.

[0030] Particularly preferably, the present invention provides compounds of formula III, formula IV and formula V, wherein R1 is selected from chlorine, bromine and iodine, and R2 is selected from fluorine, chlorine, bromine or iodine;

[0031] R3, R4 are independently selected from hydrogen, optionally substituted alkyl, acyl, sulfonyl, alkylsilyl, cyano, allyl, preferably H, benzyl, acetyl, propionyl, trifluoroacetyl, formyl, benzenesulfonyl, p-toluenesulfonyl, methylsulfonyl, trifluoromethanesulfonyl, trimethylsilyl, cyano, 1,1-diphenylmethyl, tert-butyl;

[0032] or R3 and R4 form a cyclic imide structure with the central N atom, preferably one of phthalimide, succinimide, tetrahydrophthalimide, 1,2-cyclohexanediamide, and butenediimide;

[0033] Provided that R3 and R4 are not H at the same time.

[0034] Beneficial Effects

[0035] 1. The present invention uses the compound of formula V as a raw material for deprotection to obtain 2-amino-3-bromotrifluorotoluene (formula VI), with high yield. At the same time, the compound of formula V is easy to synthesize. In the process of synthesizing the raw material of formula V, a relatively low-priced raw material is used, and a relatively high-yield reaction is used to prepare the compound of formula V with relatively low cost.

[0036] 2. The reaction conditions of the present invention are simple and mild, and are more suitable for industrial production. In particular, the use of the new intermediates III, compounds of formula IV and compounds of formula V in the synthesis process makes the synthesis process of the compound 3-bromo-2-aminotrifluorotoluene simple, and the production cost is greatly reduced, which is more suitable for industrial production. DETAILED DESCRIPTION

[0037] The endpoints and any values ​​of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article.

[0038] The specific embodiments of the present invention are described in detail below. It should be understood that the specific embodiments described herein are only used to illustrate and explain the present invention, and are not used to limit the present invention.

[0039] The percentage content in the present invention generally refers to the weight percentage content.

[0040] In the present invention, halogen means fluorine, chlorine, bromine and iodine.

[0041] In the present invention, aryl refers to a monovalent monocyclic or bicyclic aromatic hydrocarbon group of 6 to 10 ring atoms, such as phenyl, but not limited thereto. The aryl may be substituted by alkyl, halogen, cyano, nitro, cycloalkyl, heterocyclic, acylamino, ester, etc., but not limited thereto.

[0042] Alkyl in the present invention is in each case a straight-chain or branched alkyl radical having usually 1 to 20 carbon atoms, frequently 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms and in particular 1 to 3 carbon atoms. Examples of C1-C4-alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl). Examples of C1-C6 alkyl groups include, in addition to the groups mentioned for C1-C4 alkyl groups, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl or 1-ethyl-2-methylpropyl. 10 Examples of the alkyl group include, but are not limited to, n-heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 1-ethylhexyl, 2-ethylhexyl, 1,2-dimethylhexyl, 1-propylpentyl, 2-propylpentyl, nonyl, decyl, 2-propylheptyl, and 3-propylheptyl in addition to the groups mentioned for the C1-C6 alkyl group. The alkyl group may be substituted with, but not limited to, halogen, cyano, nitro, aryl, cycloalkyl, heterocyclic, acylamino, ester, and the like.

[0043] In the present context, an alkyl radical substituted by a halogen to form a "haloalkyl radical" generally refers to a radical having 1 to 10 carbon atoms ("C1-C 10The term "haloalkyl" refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms ("C1-C6 haloalkyl"), more commonly 1 to 4 carbon atoms ("C1-C4 haloalkyl"), wherein the hydrogen atoms of the group are partially or completely replaced by halogen. Preferred haloalkyl moieties are selected from C1-C4 haloalkyl, more preferably C1-C2 haloalkyl, further preferably halomethyl, especially C1-C2 fluoroalkyl. Halomethyl is a methyl group in which 1, 2 or 3 hydrogen atoms are replaced by halogen, such as bromomethyl, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichloromonofluoromethyl, chlorodifluoromethyl, etc. Examples of C1-C2 fluoroalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2 Examples of C1-C2 haloalkyl groups include, in addition to the groups mentioned for C1-C2 fluoroalkyl groups, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, chlorofluoromethyl, dichloromonofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 2-chloroethyl, 2,2-dichloroethyl, 2,2,2-trichloroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 1-bromoethyl, and the like. Examples of C1-C4 haloalkyl groups include, in addition to the groups mentioned for C1-C2 haloalkyl groups, 1-fluoropropyl, 2-fluoropropyl, 3-fluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, heptafluoropropyl, 1,1,1-trifluoroprop-2-yl, 3-chloropropyl, 4-chlorobutyl, and the like.

[0044] The term "optionally substituted" means that the relevant group may be substituted by a substituent or may not be substituted.

[0045] When a group is substituted, the substituent may be halogen, cyano, nitro, cycloalkyl, heterocyclic, acylamino, ester, alkoxy and aryl, but is not limited thereto. For example, when an alkyl group is substituted with a halogen, a haloalkyl group is formed, but is not limited thereto.

[0046] In the present invention, acyl refers to a group containing R-CO2-, wherein R is an optionally substituted alkyl group, and R-CO2- is preferably one of formyl, acetyl, propionyl, trifluoroacetyl and benzyl.

[0047] In the present invention, the sulfonyl group refers to a group containing R'-SO2-, wherein R' is an optionally substituted aryl group or an optionally substituted alkyl group.

[0048] R'-SO2- is preferably a benzenesulfonyl group, a p-toluenesulfonyl group, a methanesulfonyl group or a trifluoromethanesulfonyl group.

[0049] R3, R4 are independently selected from hydrogen, optionally substituted alkyl, acyl, sulfonyl, alkylsilyl, cyano, allyl, preferably H, benzyl, acetyl, propionyl, trifluoroacetyl, formyl, benzenesulfonyl, p-toluenesulfonyl, methylsulfonyl, trifluoromethanesulfonyl, trimethylsilyl, cyano, 1,1-diphenylmethyl, tert-butyl;

[0050] or R3 and R4 form a cyclic imide structure with the central N atom, preferably one of phthalimide, succinimide, tetrahydrophthalimide, 1,2-cyclohexanediamide, and butenediimide;

[0051] Provided that R3 and R4 are not H at the same time.

[0052] The present invention provides a method for preparing 2-amino-3-bromobenzotrifluoromethane, characterized in that the method comprises the following steps: deprotecting a compound of formula V under the action of a protecting agent to obtain 2-amino-3-bromobenzotrifluoromethane (formula VI), and the synthesis route thereof is as follows:

[0053]

[0054] wherein R3 and R4 are independently selected from hydrogen, optionally substituted alkyl, acyl, sulfonyl, alkylsilyl, cyano, and allyl, preferably hydrogen, benzyl, acetyl, propionyl, trifluoroacetyl, formyl, benzenesulfonyl, p-toluenesulfonyl, methylsulfonyl, trifluoromethanesulfonyl, trimethylsilyl, cyano, 1,1-diphenylmethyl, and tert-butyl;

[0055] or R3 and R4 form a cyclic imide structure with the central N atom, preferably one of phthalimide, succinimide, tetrahydrophthalimide, 1,2-cyclohexanediamide, and butenediimide;

[0056] Provided that R3 and R4 are not H at the same time.

[0057] In the above method, the deprotection reagent is an aqueous acid solution or an aqueous base solution, the acid is an organic acid or an inorganic acid, and the base is selected from an organic base or an inorganic base.

[0058] In a preferred embodiment, R3 and R4 are independently selected from hydrogen, benzyl, acetyl, propionyl, trifluoroacetyl, formyl, benzenesulfonyl, p-toluenesulfonyl, methanesulfonyl, trifluoromethanesulfonyl, trimethylsilyl, cyano, 1,1-diphenylmethyl, tert-butyl, phthalimide, succinimide, tetrahydrophthalimide, 1,2-cyclohexanediamide, and butenediimide.

[0059] In the above preparation method, the deprotection of the compound of formula V is carried out under the action of a deprotection agent, the deprotection agent is an aqueous solution of an acid or a base, and the base is selected from an organic base or an inorganic base. The organic base is at least one of triethylamine, pyridine, sodium methoxide, and sodium ethoxide, and the inorganic base is one of potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, and sodium hydrogen; preferably sodium hydroxide and potassium hydroxide; the acid is selected from trifluoroacetic acid, hydrobromic acid, phosphoric acid, sulfuric acid, and hydrochloric acid, preferably hydrochloric acid or / and hydrobromic acid. The molar ratio of the compound of formula V to the deprotection agent is 1:1.0-3.0, preferably 1:2.1-2.4.

[0060] In a preferred embodiment, the acid is hydrochloric acid and hydrobromic acid. When the acid is hydrochloric acid, the solubility of the acid in the aqueous solution is 1-37%, preferably 10-37%, and particularly preferably 30-37%. When the acid is hydrobromic acid, the concentration of the acid in the aqueous solution is 1-68.85%, preferably 10-60%, and particularly preferably 30-50%. The dosage of the concentrated hydrochloric acid and hydrobromic acid aqueous solutions described in the embodiments is calculated according to the conventional understanding in the art.

[0061] In a preferred embodiment, the alkali is sodium hydroxide or potassium hydroxide, and the concentration of the aqueous solution of the alkali is 1-40%, preferably 10-40%.

[0062] The reaction in the deprotection step of the compound of formula V is carried out in an organic solvent, and the organic solvent is preferably one of methanol, acetonitrile, dichloromethane, dichloroethane, water, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methylpyrrolidone.

[0063] The present invention also provides a method for preparing a compound of formula V, comprising subjecting a compound of formula IV to diazotization and bromination to obtain a compound of formula V,

[0064] Its synthetic route is as follows:

[0065] Wherein, R3 and R4 are independently selected from hydrogen, tert-butyl, an alkyl group, an acyl group, a sulfonyl group, an alkylsilyl group, a cyano group, and an allyl group, preferably hydrogen, benzyl, acetyl, propionyl, trifluoroacetyl, formyl, benzenesulfonyl, p-toluenesulfonyl, methanesulfonyl, trifluoromethanesulfonyl, trimethylsilyl, cyano group, 1,1-diphenylmethyl, and tert-butyl;

[0066] or R3 and R4 form a cyclic imide structure with the central N atom, preferably one of phthalimide, succinimide, tetrahydrophthalimide, 1,2-cyclohexanediamide, and butenediimide;

[0067] Provided that R3 and R4 are not H at the same time.

[0068] In a preferred embodiment, R3 and R4 are independently selected from benzyl, acetyl, propionyl, trifluoroacetyl, formyl, benzenesulfonyl, p-toluenesulfonyl, methanesulfonyl, trifluoromethanesulfonyl, trimethylsilyl, cyano, 1,1-diphenylmethyl, tert-butyl, phthalimide, succinimide, tetrahydrophthalimide, 1,2-cyclohexanediamide, and butenediimide.

[0069] The compound of formula IV is subjected to a diazotization reaction with a diazotizing agent in an aqueous acid solution, wherein the acid is selected from hydrochloric acid, sulfuric acid and hydrogen bromide, the diazotizing agent is a nitrite or a nitrite ester, the nitrous acid is preferably potassium nitrite and sodium nitrite, the nitrous acid ester is preferably methyl nitrite and ethyl nitrite, the diazotization reaction temperature is -10-10°C, preferably -5-5°C, and the molar ratio of the compound of formula IV to the acid is 1:1.0-3.0.

[0070] Preferably, formula IV is added to acid water for salt formation reaction, the temperature is lowered to -5-0°C, sodium nitrite aqueous solution is added dropwise for diazotization reaction, and a bromination reagent is added after the diazotization reaction for bromination reaction; the acid in the acid water includes hydrochloric acid, sulfuric acid, and hydrogen bromide, and the bromination reagent is cuprous bromide; the bromination reaction temperature is 30-100°C, and the molar ratio of formula IV, acid and bromination reagent is 1:1.0-3.0:1.0-2.0, preferably 1:1.2-2.2:1.2-1.5.

[0071] The present invention also provides a method for preparing compound IV, which comprises synthesizing the compound of formula III by reduction reaction, and the synthesis route is as follows:

[0072] wherein R1 is selected from chlorine, bromine and iodine;

[0073] R3, R4 are independently selected from hydrogen, optionally substituted alkyl, acyl, sulfonyl, alkylsilyl, cyano, allyl, preferably hydrogen, benzyl, acetyl, propionyl, trifluoroacetyl, formyl, benzenesulfonyl, p-toluenesulfonyl, methylsulfonyl, trifluoromethanesulfonyl, trimethylsilyl, cyano, 1,1-diphenylmethyl, tert-butyl;

[0074] or R3 and R4 form a cyclic imide structure with the central N atom, preferably one of phthalimide, succinimide, tetrahydrophthalimide, 1,2-cyclohexanediamide, and butenediimide;

[0075] Provided that R3 and R4 are not H at the same time.

[0076] In a preferred embodiment, R3 and R4 are independently selected from hydrogen, benzyl, acetyl, propionyl, trifluoroacetyl, formyl, benzenesulfonyl, p-toluenesulfonyl, methanesulfonyl, trifluoromethanesulfonyl, trimethylsilyl, cyano, 1,1-diphenylmethyl, tert-butyl, phthalimide, succinimide, tetrahydrophthalimide, 1,2-cyclohexanediamide, and butenediimide.

[0077] Compound IV is hydrogenated and reduced under the condition of an acid binding agent. In the reaction, the acid binding agent is selected from an organic base or an inorganic base. The organic base is at least one of triethylamine, pyridine, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen, sodium methoxide, and sodium ethoxide; preferably triethylamine and / or potassium carbonate; the reaction reducing agent is hydrogen, and the conditions of the hydrogenation reaction include: the hydrogenation temperature is 30-100°C, preferably 40-60°C; the hydrogen pressure is 1-3MPa, preferably 1.5-1.8MPa, the hydrogenation catalyst is selected from palladium carbon or Raney nickel, preferably palladium carbon, and the molar ratio of formula III, palladium and acid binding agent is 1:0.02-0.05:1.0-1.5. The reaction in the above steps is carried out in an organic polar solvent, and the organic solvent is preferably a polar solvent, which is one of methanol, acetonitrile, dichloromethane, dichloroethane, water, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methylpyrrolidone.

[0078] The present invention also provides a method for preparing a compound of formula III, which comprises amination and protective amination of a compound of formula I, and the synthetic route is as follows:

[0079] wherein R1 is selected from chlorine, bromine and iodine, and R2 is selected from fluorine, chlorine, bromine and iodine;

[0080] R3, R4 are independently selected from hydrogen, optionally substituted alkyl, acyl, sulfonyl, alkylsilyl, cyano, allyl, preferably hydrogen, benzyl, acetyl, propionyl, trifluoroacetyl, formyl, benzenesulfonyl, p-toluenesulfonyl, methylsulfonyl, trifluoromethanesulfonyl, trimethylsilyl, cyano, 1,1-diphenylmethyl, tert-butyl;

[0081] or R3 and R4 form a cyclic imide structure with the central N atom, preferably one of phthalimide, succinimide, tetrahydrophthalimide, 1,2-cyclohexanediamide, and butenediimide;

[0082] Provided that R3 and R4 are not H at the same time.

[0083] In a preferred embodiment, R3 and R4 are independently selected from benzyl, acetyl, propionyl, trifluoroacetyl, formyl, benzenesulfonyl, p-toluenesulfonyl, methanesulfonyl, trifluoromethanesulfonyl, trimethylsilyl, cyano, 1,1-diphenylmethyl, tert-butyl, phthalimide, succinimide, tetrahydrophthalimide, 1,2-cyclohexanediamide, and butenediimide.

[0084] The present invention also provides a method for preparing the compound of formula III, and the synthesis route thereof is as follows:

[0085] Wherein, R1, R2 are selected from fluorine, chlorine, bromine or iodine;

[0086] R3, R4 are independently selected from hydrogen, optionally substituted alkyl, acyl, sulfonyl, alkylsilyl, cyano, allyl, preferably hydrogen, benzyl, acetyl, propionyl, trifluoroacetyl, formyl, benzenesulfonyl, p-toluenesulfonyl, methylsulfonyl, trifluoromethanesulfonyl, trimethylsilyl, cyano, 1,1-diphenylmethyl, tert-butyl;

[0087] or R3 and R4 form a cyclic imide structure with the central N atom, preferably one of phthalimide, succinimide, tetrahydrophthalimide, 1,2-cyclohexanediamide, and butenediimide;

[0088] Provided that R3 and R4 are not H at the same time.

[0089] Compound I is subjected to an amination reaction in a solvent to synthesize compound II, the reaction temperature is 10-180°C, preferably 70-100°C; the time is 2-6h, preferably 3-4h. The amination reagent is ammonia water or an alcohol solution of ammonia, and the molar ratio of compound I to the amination reagent is 1:1.0-4.5, preferably 1:2-2.2.

[0090] The reaction for synthesizing compound III is amino protection, and the protecting agents include acetyl chloride, acetic anhydride, trifluoroacetyl chloride, trifluoroacetic anhydride, benzyl bromide, benzyl chloride; preferably acetyl chloride and or acetic anhydride; the protecting temperature is -10-70°C, preferably 40-60°C, and the molar ratio of compound II to the protecting agent is 1:1.0-3.0, preferably 1:2.0-2.2. In the above steps, the reaction is carried out in an organic polar solvent, and the organic solvent is preferably a polar solvent, which refers to one of methanol, acetonitrile, dichloromethane, dichloroethane, water, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methylpyrrolidone.

[0091] The present invention also discloses a compound of formula III, wherein R3 and R4 are independently selected from hydrogen, optionally substituted alkyl, acyl, sulfonyl, alkylsilyl, cyano, and allyl, preferably benzyl, acetyl, propionyl, trifluoroacetyl, formyl, benzenesulfonyl, p-toluenesulfonyl, methylsulfonyl, trifluoromethanesulfonyl, trimethylsilyl, cyano, 1,1-diphenylmethyl, and tert-butyl;

[0092] or R3 and R4 form a cyclic imide structure with the central N atom, preferably one of phthalimide, succinimide, tetrahydrophthalimide, 1,2-cyclohexanediamide, and butenediimide;

[0093] Provided that R3 and R4 are not H at the same time.

[0094] Particularly preferred compounds are:

[0095] The present invention also discloses formula IV,

[0096] wherein R3 and R4 are independently selected from hydrogen, optionally substituted alkyl, acyl, sulfonyl, alkylsilyl, cyano, and allyl, preferably hydrogen, benzyl, acetyl, propionyl, trifluoroacetyl, formyl, benzenesulfonyl, p-toluenesulfonyl, methylsulfonyl, trifluoromethanesulfonyl, trimethylsilyl, cyano, 1,1-diphenylmethyl, and tert-butyl;

[0097] or R3 and R4 form a cyclic imide structure with the central N atom, preferably one of phthalimide, succinimide, tetrahydrophthalimide, 1,2-cyclohexanediamide, and butenediimide;

[0098] Provided that R3 and R4 are not H at the same time.

[0099] Particularly preferred compounds are:

[0100] The present invention also discloses a compound of formula V, wherein R3 and R4 are independently selected from hydrogen, optionally substituted alkyl, acyl, sulfonyl, alkylsilyl, cyano, and allyl, preferably hydrogen, benzyl, acetyl, propionyl, trifluoroacetyl, formyl, benzenesulfonyl, p-toluenesulfonyl, methylsulfonyl, trifluoromethanesulfonyl, trimethylsilyl, cyano, 1,1-diphenylmethyl, and tert-butyl;

[0101] or R3 and R4 form a cyclic imide structure with the central N atom, preferably one of phthalimide, succinimide, tetrahydrophthalimide, 1,2-cyclohexanediamide, and butenediimide;

[0102] Provided that R3 and R4 are not H at the same time.

[0104] Particularly preferred compounds are,

[0105] The above-mentioned compound can be prepared by the method disclosed in the present invention. At the same time, the above-mentioned intermediate compound disclosed in the present invention can be used to prepare the intermediate compound of the 2-amino-3-bromotrifluorotoluene of the present invention, so that the preparation process is simpler, the yield is greatly improved, the production cost of 2-amino-3-bromotrifluorotoluene is greatly reduced, and unexpected technical effects are brought about.

[0106] The present invention will be described in detail below by way of examples. The raw materials in the following examples are not particularly limited and can all be purchased from the market.

[0107] The amounts of reactants and products were determined by liquid chromatography (Agilent HPLC 1260).

[0108] The conversion and selectivity of the reaction were calculated by the following formula:

[0109] Yield = actual mass of target product / theoretical mass of target product × 100%

[0110] Unless otherwise specified, all raw materials used are commercially available products. In this embodiment, unless otherwise specified, the percentage by weight is generally understood in the art.

[0111] Example 1 Preparation of 2-(N,N-diacetyl)amino-3-nitro-5-chlorobenzotrifluoride

[0112]

[0113] 1.1 2-Amino-5-chloro-3-nitrobenzotrifluoride

[0114] 26.0 g (0.1 mol, 99%, purchased from Aladdin) of 2,5-dichloro-3-nitrobenzotrifluoride, 15.0 g (0.22 mol, 25%, purchased from Aladdin) of ammonia water and 78 g of dioxane were added into an autoclave, the temperature was raised to 100°C, and the reaction was stirred for 4 hours. HPLC detected that the raw materials had reacted completely, the reaction mother liquor was desolvated, and ethyl acetate was added for extraction and desolvation to obtain 22.8 g of the compound 2-amino-5-chloro-3-nitrobenzotrifluoride, with a yield of 95%.

[0115] 1.2 2-(N,N-diacetyl)amino-3-nitro-5-chlorobenzotrifluoride

[0116] The 2-amino-5-chloro-3-nitrobenzotrifluoride prepared in 1.1 was added to a four-necked bottle, and 64 g of ethylene dichloride was added. The temperature was kept at 50°C, and 16.6 g of acetyl chloride was added. The reaction was stirred for 3 h, and 29.3 g of 2-(N,N-diacetyl)amino-3-nitro-5-chlorobenzotrifluoride was obtained after desolventizing. The yield was 95%. The NMR data of 2-(N,N-diacetyl)amino-3-nitro-5-chlorobenzotrifluoride are as follows: 1 H NMR(500MHz,DMSO-d6)δ8.05(1H,s,ArH),7.92(1H,s,ArH),2.40(6H,s,2C H 3);

[0117] Example 2 2-(N,N-ditrifluoroacetyl)amino-3-nitro-5-chlorobenzotrifluoride

[0118]

[0119] The difference between Example 2 and Example 1 is that trifluoroacetic anhydride replaces acetyl chloride, and other conditions remain unchanged.

[0120] The reaction yielded 37.0 g of 2-(N,N-ditrifluoroacetyl)amino-3-nitro-5-chlorobenzotrifluoride, with a yield of 90%. The NMR data of 2-(N,N-ditrifluoroacetyl)amino-3-nitro-5-chlorobenzotrifluoride are as follows: 1 H NMR(500MHz,DMSO-d6)δ8.09(1H,s,ArH),7.95(1H,s,ArH);

[0121] Example 3 Preparation of 2-(N,N-diacetyl)amino-3-nitro-5-bromotrifluorotoluene

[0122]

[0123] The difference between Example 3 and Example 1 is that 2-chloro-5-bromo-3-nitrobenzotrifluoride is substituted for 2,5-dichloro-3-nitrobenzotrifluoride, and other conditions remain unchanged.

[0124] The reaction yielded 32.3 g of 2-(N,N-diacetyl)amino-3-nitro-5-bromobenzotrifluoride, with a yield of 87%. The NMR data of 2-(N,N-diacetyl)amino-3-nitro-5-bromobenzotrifluoride are as follows: 1 H NMR(500MHz,DMSO-d6)δ8.01(1H,s,ArH),7.98(1H,s,ArH),2.35(6H,s,2C H 3);

[0125] Example 4 Preparation of 2-(N,N-diacetyl)amino-3-aminotrifluorotoluene

[0126]

[0127] 0.1 mol of compound 2-(N,N-diacetyl)-amino-3-nitro-5-chlorobenzotrifluoride and 50 g of methanol were added to an autoclave in sequence, and then 1.0 g of palladium carbon and 14.6 g of potassium carbonate were added, and then hydrogen gas of 1.8 MPa was introduced, and the mixture was stirred at 60°C for 6 h. HPLC detected that the raw material reaction was complete, and the reaction mother liquor was filtered and desolvated to obtain 24.2 g of 2-(N,N-diacetyl)amino-3-aminobenzotrifluoride, with a yield of 93%. The NMR data of 2-(N,N-diacetyl)amino-3-aminobenzotrifluoride are as follows: 1 H NMR(500MHz,DMSO-d6)δ8.02(2H,m,ArH),7.90(1H,dd,J=7.9Hz,1.4Hz,ArH),4.97(2H,s,N H 2), 2.30(6H,s,2C H 3);

[0128] Example 5 Preparation of 2-benzylamino-3-aminobenzotrifluoride

[0129]

[0130] The difference between Example 5 and Example 4 is that 2-benzyl-3-nitro-5-chlorobenzotrifluoride is substituted for 2-(N,N-diacetyl)-amino-3-nitro-5-chlorobenzotrifluoride. Other conditions remain unchanged. 21.3 g of 2-benzylamino-3-aminobenzotrifluoride is obtained with a yield of 80%. The NMR data of 2-benzylamino-3-aminobenzotrifluoride are as follows: 1 H NMR(500MHz,DMSO-d6)δ7.42–7.36(2H,m,ArH),7.33(2H,dd,J=8.1,6.7Hz,ArH),7.30–7. 22(2H,m,ArH),6.60(1H,t,J=7.4Hz,ArH),6.53(1H,dd,J=7.5,2.0Hz,ArH),4.37(2H,s,N H 2),4.30(2H,m,C H 2),3.03(1H,s,N H );

[0131] Example 6 Preparation of 2-N-succinimidyl-3-aminobenzotrifluoromethane

[0132]

[0133] The difference between Example 6 and Example 5 is that 2-N-succinimidyl-3-aminobenzotrifluoride replaces 2-(N,N-diacetyl)-amino-3-nitro-5-chlorobenzotrifluoride. Other conditions remain unchanged. The reaction yields 22.2 g of 2-N-succinimidyl-3-aminobenzotrifluoride with a yield of 86%. The NMR data of 2-N-succinimidyl-3-aminobenzotrifluoride are as follows: 1 H NMR(500MHz,DMSO-d6)δ7.09–6.98(2H,m,ArH),6.76(1H,dd,J=7.3,2.2Hz,ArH),4.36(2H,s,N H 2),2.90(2H,m,C H 2),2.84(2H,m,C H 2);

[0134] Example 7 Preparation of 2-(N,N-diacetyl)amino-3-bromotrifluorotoluene

[0135]

[0136] Add 0.1mol 2-(N,N-diacetyl)amino-3-aminotrifluorotoluene to a four-necked flask, add 20.3g hydrobromic acid, stir at room temperature for 1h, place in an ice bath and keep warm at 0°C, start to dropwise add 22.4g 30% sodium nitrite, HPLC detection, after complete reaction, add diazo liquid dropwise to an aqueous solution of 15.5g cuprous bromide, slowly heat to 50°C, keep warm for 2h, HPLC detection shows that the raw material has reacted completely, then add ethyl acetate for extraction, desolventize to obtain 28.9g 2-(N,N-diacetyl)amino-3-bromotrifluorotoluene, yield 89%, 2-(N,N-diacetyl)amino-3-bromotrifluorotoluene NMR data are as follows: 1 H NMR(500MHz,DMSO-d6)δ7.72(2H,m,ArH),7.25(1H,dd,J=7.9Hz,1.4Hz,ArH),2.31(6H,s,2C H 3);

[0137] Example 8 Preparation of 2-benzyl-3-bromotrifluorotoluene

[0138]

[0139] The difference between Example 8 and Example 7 is that 2-benzylamino-3-aminobenzotrifluoride replaces 2-(N,N-diacetyl)amino-3-bromobenzotrifluoride, and other conditions remain unchanged. The reaction produces 9.4 g of 2-benzyl-3-bromobenzotrifluoride with a yield of 42%. The NMR data of 2-benzyl-3-bromobenzotrifluoride are as follows: 1H NMR (500MHz, CDCl3, ppm): δ7.51–7.39(4H,m,ArH),7.33(2H,t,J=7.4Hz,ArH),7.30–7.22(1H,m,ArH),6.80(1H,t,J=7.4Hz,ArH),4.30(2H,m,C H 2),2.25(1H,s,N H );

[0140] Example 9 Preparation of 2-N-succinimidyl-3-bromotrifluorotoluene

[0141]

[0142] The difference between Example 9 and Example 8 is that 2-N-succinimidyl-3-bromobenzotrifluoride is used instead of 2-(N,N-diacetyl)amino-3-bromobenzotrifluoride, and other conditions remain unchanged. The reaction produces 28.1 g of 2-N-succinimidyl-3-bromobenzotrifluoride with a yield of 87%. The NMR data of 2-N-succinimidyl-3-bromobenzotrifluoride are as follows: 1 H NMR (500MHz, CDCl3, ppm): δ7.66 (1H, dd, J = 7.5, 2.0 Hz, ArH), 7.59 (1H, dd, J = 7.4, 1.9 Hz, ArH), 6.99 (1H, t, J = 7.4 Hz, ArH), 2.91 (2H, m, C H 2),2.80(2H,m,C H 2);

[0143] Example 10 Preparation of 2-amino-3-bromotrifluorotoluene

[0144] Add 0.1 mol 2-(N,N-diacetyl)amino-3-bromobenzotrifluoride, 22 ml concentrated hydrochloric acid and 100 ml water into a four-necked flask, reflux for 8 hours, and complete the reaction of the raw materials by HPLC. Add ethyl acetate for extraction and desolventization to obtain 23.5 g of the compound 2-amino-3-bromobenzotrifluoride, with a yield of 98%;

[0145] Embodiment 11

[0146] The difference from Example 10 is that 10% sodium hydroxide replaces hydrochloric acid, and other conditions remain unchanged, to obtain 22.8 g of the compound 2-amino-3-bromotrifluorotoluene, with a yield of 95%.

[0147] Example 12

[0148] The difference from Example 10 is that 2-N-succinimidyl-3-bromobenzotrifluoride is used instead of 2-(N,N-diacetyl)amino-3-bromobenzotrifluoride. Other conditions remain unchanged, and 23.2 g of the compound 2-amino-3-bromobenzotrifluoride is obtained with a yield of 97%.

[0149] The preferred embodiments of the present invention are described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, the technical solution of the present invention can be subjected to a variety of simple modifications, including the combination of various technical features in any other suitable manner, and these simple modifications and combinations should also be regarded as the contents disclosed by the present invention and belong to the protection scope of the present invention.

Claims

1. A method for preparing 2-amino-3-bromotrifluorotoluene, characterized in that: The method comprises the following steps: deprotecting the compound of formula V under the action of a deprotecting agent to obtain 2-amino-3-bromotrifluorotoluene (formula VI), and the synthesis route thereof is as follows: in, R3 and R4 are independently selected from hydrogen, optionally substituted alkyl, acyl, sulfonyl, alkylsilyl, cyano, and allyl, preferably hydrogen, benzyl, acetyl, propionyl, trifluoroacetyl, formyl, benzenesulfonyl, p-toluenesulfonyl, methylsulfonyl, trifluoromethanesulfonyl, trimethylsilyl, cyano, 1,1-diphenylmethyl, and tert-butyl; or R3 and R4 form a cyclic imide structure with the central N atom, preferably one of phthalimide, succinimide, tetrahydrophthalimide, 1,2-cyclohexanediamide, and butenediimide; Provided that R3 and R4 are not H at the same time.

2. The preparation method according to claim 1, characterized in that: The deprotection reagent is an aqueous solution of an acid or an aqueous solution of a base, the acid is an organic acid or an inorganic acid, and the base is selected from an organic base or an inorganic base.

3. The preparation method according to claim 2, characterized in that: The acid is selected from trifluoroacetic acid, hydrobromic acid, phosphoric acid, sulfuric acid, and hydrochloric acid, preferably one of hydrochloric acid, hydrobromic acid and sulfuric acid; the organic base is at least one of triethylamine, pyridine, sodium methoxide, and sodium ethoxide; the inorganic base is selected from at least one of potassium hydroxide, sodium hydroxide, sodium carbonate, and potassium carbonate; preferably one of potassium hydroxide and sodium hydroxide.

4. The preparation method according to claim 3, characterized in that: The molar ratio of the compound of formula V to the deprotection agent is 1:1.0-3.0, preferably 1:2.1-2.

4.

5. The preparation method according to any one of claims 1 to 4, characterized in that: The compound of formula IV is subjected to diazotization reaction and bromination reaction to obtain the compound of formula V, Its synthetic route is as follows: Wherein, the definitions of R3 and R4 are as defined in claims 1-4.

6. The preparation method according to claim 5, characterized in that: The compound of formula IV is subjected to a diazotization reaction with a diazotizing agent in an acid aqueous solution, wherein the acid is selected from one of hydrochloric acid, sulfuric acid and hydrogen bromide, and the diazotizing agent is preferably one of nitrite and nitrite ester. The diazotization reaction temperature is -10-10°C, and the molar ratio of the compound of formula IV to the acid is 1:1.0-3.

0.

7. The preparation method according to claim 5 or 6, characterized in that: The product obtained after the diazotization reaction reacts with a brominating agent to obtain a compound of formula V, wherein the brominating agent is cuprous bromide; the molar ratio of formula IV to the brominating agent is 1:1.0-2.

0.

8. The preparation method according to claim 7, characterized in that: Compound IV is synthesized by reduction reaction of compound III, and its synthesis route is as follows: wherein R1 is selected from chlorine, bromine and iodine; The definitions of R3 and R4 are as defined in any one of claims 1 to 4.

9. The preparation method according to claim 8, characterized in that: The compound of formula III is obtained by amination and protective amination of the compound of formula I, and its synthesis route is as follows: wherein R1 is selected from chlorine, bromine and iodine, and R2 is selected from fluorine, chlorine, bromine and iodine; The definitions of R3 and R4 are as defined in any one of claims 1 to 4.

10. Formula III, in, R3 and R4 are independently selected from hydrogen, optionally substituted alkyl, acyl, sulfonyl, alkylsilyl, cyano, and allyl, preferably hydrogen, benzyl, acetyl, propionyl, trifluoroacetyl, formyl, benzenesulfonyl, p-toluenesulfonyl, methylsulfonyl, trifluoromethanesulfonyl, trimethylsilyl, cyano, 1,1-diphenylmethyl, and tert-butyl; or R3 and R4 form a cyclic imide structure with the central N atom, preferably one of phthalimide, succinimide, tetrahydrophthalimide, 1,2-cyclohexanediamide, and butenediimide; Provided that R3 and R4 are not H at the same time.

11. Formula IV, in, R3 and R4 are independently selected from hydrogen, optionally substituted alkyl, acyl, sulfonyl, alkylsilyl, cyano, and allyl, preferably hydrogen, benzyl, acetyl, propionyl, trifluoroacetyl, formyl, benzenesulfonyl, p-toluenesulfonyl, methylsulfonyl, trifluoromethanesulfonyl, trimethylsilyl, cyano, 1,1-diphenylmethyl, and tert-butyl; or R3 and R4 form a cyclic imide structure with the central N atom, preferably one of phthalimide, succinimide, tetrahydrophthalimide, 1,2-cyclohexanediamide, and butenediimide; Provided that R3 and R4 are not H at the same time.

12. A compound of formula V, in, R3 and R4 are independently selected from hydrogen, optionally substituted alkyl, acyl, sulfonyl, alkylsilyl, cyano, and allyl, preferably hydrogen, benzyl, acetyl, propionyl, trifluoroacetyl, formyl, benzenesulfonyl, p-toluenesulfonyl, methylsulfonyl, trifluoromethanesulfonyl, trimethylsilyl, cyano, 1,1-diphenylmethyl, and tert-butyl; or R3 and R4 form a cyclic imide structure with the central N atom, preferably one of phthalimide, succinimide, tetrahydrophthalimide, 1,2-cyclohexanediamide, and butenediimide; Provided that R3 and R4 are not H at the same time.

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