A method for preparing a benzylamine compound

Abstract

The application relates to a preparation method of a benzylamine compound and belongs to the field of organic synthesis. The preparation method of the benzylamine compound is as follows: a reaction formula is shown in the description. The application also provides a preparation method of the compound of the above formula (VI). Compared with methyl o-bromomethylbenzoate used in the prior art, methyl o-chloromethylbenzoate used in the application is cheaper, has lower preparation cost, less pollution and is more environment-friendly. Compared with the prior art, the benzylization reaction of the application has higher reaction conversion rate, less dibenzyl impurities, is convenient for product post-treatment and purification, has higher yield, and has better product quality.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for preparing benzylamine compounds. Background Technology

[0002] Patent CN111825585B discloses a class of aryl sulfides containing a benzylamine structure that exhibit good acaricidal activity and has potential application value in the control of agricultural mites. The patent also discloses a preparation method, which involves alkylating a disulfide to obtain a thioether compound, and then reacting it with a substituted benzyl bromide to prepare the aryl sulfide containing the benzylamine structure. However, due to the poor selectivity of the benzylation reaction using substituted benzyl bromide, it easily generates dibenzylated impurities (byproducts), as shown in the following reaction formula:

[0003]

[0004] Meanwhile, the cost of substitute benzyl bromide compounds is high, and their preparation causes significant pollution. Therefore, this method is unsuitable for large-scale industrial production. There is still an urgent need to develop a novel preparation method that uses inexpensive raw materials, is environmentally friendly, and exhibits high reaction selectivity. Summary of the Invention

[0005] To address the problems of expensive raw materials, heavy pollution, poor reaction selectivity, low yield, and high production cost in the preparation of aryl sulfides containing benzylamine structures using existing technologies, this invention provides a method for preparing benzylamine compounds.

[0006] The technical solution of this invention is as follows:

[0007] In a first aspect, the present invention provides a method for preparing benzylamine compounds, wherein the reaction formula is as follows:

[0008]

[0009] Where n is 0, 1, or 2;

[0010] X and Y are each independently a halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or C1-C3 haloalkoxy;

[0011] L2 is a leaving group, but it is not bromine;

[0012] R1 is a C1-C6 haloalkyl, C2-C6 alkynyl, C2-C6 alkenyl, C1-C6 alkyl, C3-C6 cycloalkyl, or C3-C6 epoxyalkyl;

[0013] R3 is C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Alkoxy, C1-C10 Halogenated alkyl groups, C1-C 10 Alkoxy C1-C 10 Alkyl, C1-C 10 Halogenated alkyl C1-C 10 Alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl, C1-C5 alkyl, C3-C7 cycloalkyloxy, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C6 cycloalkyl;

[0014] R4, R5, R6, and R7 are each independently hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxymethyl, carboxyl, hydroxyl, mercapto, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkoxy groups, C1-C 10 alkoxycarbonyl, C1-C 10 Haloalkoxycarbonyl;

[0015] The preparation method involves adding a base to compound (VI) and compound (VII) in a solvent and at a certain temperature to carry out a substitution reaction, thereby preparing compound (I).

[0016] Furthermore, n can be 0 or 1;

[0017] X and Y can be independently halogen, cyano, methyl, or trifluoromethyl.

[0018] L2 represents chlorine, iodine, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, and benzenesulfonyloxy.

[0019] R1 is 1,1,1-trifluoroethyl, 1,1-difluoroethyl, or n-propyl;

[0020] R3 is a C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 halooxyalkyl, C1-C3 alkoxyC1-C3 alkyl, C1-C3 halooxyalkylC1-C3 alkyl, C3-C6 cycloalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, or C2-C4 alkynyl.

[0021] R4, R6, and R7 are each independently hydrogen;

[0022] R5 can be hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, amino, trifluoromethyl, or trifluoromethoxy.

[0023] Furthermore, n can be 0 or 1;

[0024] X represents methyl or chlorine;

[0025] Y represents fluorine, chlorine, methyl, or trifluoromethyl.

[0026] L2 is chlorine;

[0027] R1 is 1,1,1-trifluoroethyl;

[0028] R3 can be methyl, ethyl, propyl, isopropyl, or trifluoromethyl.

[0029] R4, R5, R6, and R7 are each hydrogen atoms.

[0030] Furthermore, the solvent is selected from organic solvents and / or water;

[0031] The temperature is selected from -10°C to the solvent boiling point;

[0032] The alkali is selected from inorganic alkalis or organic alkalis.

[0033] Furthermore, the solvent is at least one of methanol, ethanol, isopropanol, propanol, butanol, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, ethyl acetate, toluene, xylene, acetonitrile, tetrahydrofuran, acetone, N,N-dimethylformamide, N-methylpyrrolidone, dioxane, or water.

[0034] The base is at least one of triethylamine, diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, morpholine, or pyridine.

[0035] Furthermore, the solvent is at least one of methanol, ethanol, dichloromethane, dichloroethane, toluene, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, or water;

[0036] The alkali is selected from at least one of sodium carbonate, potassium carbonate, lithium carbonate, or sodium bicarbonate.

[0037] Secondly, the present invention provides a method for preparing an aniline compound, wherein the aniline compound has the structure shown in formula (VI):

[0038]

[0039] The reaction formula is as follows:

[0040]

[0041] Where n is 0, 1, or 2;

[0042] X and Y are each independently a halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or C1-C3 haloalkoxy;

[0043] R1 is a C1-C6 haloalkyl, C2-C6 alkynyl, C2-C6 alkenyl, C1-C6 alkyl, C3-C6 cycloalkyl, or C3-C6 epoxyalkyl;

[0044] R2 is C1-C 10 Alkyl, C2-C 10 Halogenated alkyl, chloromethyl, trichloromethyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkyl groups, C1-C 10 Alkoxy C1-C 10 Alkyl, C1-C 10 Halogenated alkyl C1-C 10 Alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkylC1-C5 alkyl, C3-C7 cycloalkyloxy, C1-C6 alkyl-substituted phenyl, halogen-substituted phenyl, haloalkyl-substituted phenyl, C1-C6 alkyl-substituted aromatic heterocycle, halogen-substituted aromatic heterocycle, haloalkyl-substituted aromatic heterocycle;

[0045] Compounds of formula (V) are prepared by adding acid or base to a solvent and at a certain temperature to obtain compounds of general formula (VI) or their salts.

[0046] Furthermore, n can be 0 or 1;

[0047] X and Y can be independently halogen, cyano, methyl, or trifluoromethyl.

[0048] R1 is trifluoroethyl, difluoroethyl, or n-propyl;

[0049] R2 is a C1-C6 alkyl, C2-C4 haloalkyl, chloromethyl, trichloromethyl, C1-C4 alkoxy, C1-C4 halooxyalkyl, C1-C4 alkoxy-C1-C4 alkyl, C1-C4 halooxyalkyl-C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C4 alkyl, C3-C6 cycloalkyloxy, C1-C3 alkyl-substituted phenyl, halogen-substituted phenyl, trifluoromethyl-substituted phenyl, C1-C3 alkyl-substituted aromatic heterocycle, halogen-substituted aromatic heterocycle, or trifluoromethyl-substituted aromatic heterocycle.

[0050] Furthermore, n is 0;

[0051] X represents methyl or chlorine;

[0052] Y represents fluorine, chlorine, methyl, or trifluoromethyl.

[0053] R1 is trifluoroethyl;

[0054] R2 is methyl, ethyl, propyl, chloromethyl, trichloromethyl, methoxymethyl, ethoxymethyl, phenyl, p-tolyl, p-chlorophenyl, 2-furanyl, 3-furanyl, 2-thienyl, or 3-thienyl.

[0055] Furthermore, the solvent is selected from water and / or organic solvents;

[0056] The alkali is selected from organic or inorganic alkalis;

[0057] The acid is selected from organic acids or inorganic acids.

[0058] Thirdly, the present invention provides a method for preparing a sulfur-containing amide compound, wherein the sulfur-containing amide compound is shown in formula (V):

[0059]

[0060] The reaction formula is as follows:

[0061]

[0062] Wherein, X and Y are each independently a halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or C1-C3 haloalkoxy;

[0063] L1 is a leaving group;

[0064] R1 is a C1-C6 haloalkyl, C2-C6 alkynyl, C2-C6 alkenyl, C1-C6 alkyl, C3-C6 cycloalkyl, or C3-C6 epoxyalkyl;

[0065] R2 is C1-C 10 Alkyl, C2-C 10 Halogenated alkyl, chloromethyl, trichloromethyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkyl groups, C1-C 10 Alkoxy, C1-C 10 Halogenated alkyl C1-C 10 Alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkylC1-C5 alkyl, C3-C7 cycloalkyloxy, C1-C6 alkyl-substituted phenyl, halogen-substituted phenyl, haloalkyl-substituted phenyl, C1-C6 alkyl-substituted aromatic heterocycle, halogen-substituted aromatic heterocycle, haloalkyl-substituted aromatic heterocycle;

[0066] The preparation method involves reacting compound (II) with compound (III) in a solvent and at a certain temperature, with or without the addition of a alkali, to obtain compound (V).

[0067] Furthermore, X and Y are each independently halogen, cyano, methyl, or trifluoromethyl;

[0068] L1 represents chlorine, bromine, iodine, methanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, and p-toluenesulfonyloxy.

[0069] R1 is trifluoroethyl, difluoroethyl, or n-propyl;

[0070] R2 is a C1-C6 alkyl, C2-C4 haloalkyl, chloromethyl, trichloromethyl, C1-C4 alkoxy, C1-C4 halooxyalkyl, C1-C4 alkoxy-C1-C4 alkyl, C1-C4 halooxyalkyl-C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C4 alkyl, C3-C6 cycloalkyloxy, C1-C3 alkyl-substituted phenyl, halogen-substituted phenyl, trifluoromethyl-substituted phenyl, C1-C3 alkyl-substituted aromatic heterocycle, halogen-substituted aromatic heterocycle, or trifluoromethyl-substituted aromatic heterocycle.

[0071] Furthermore, X can be methyl or chlorine;

[0072] Y represents fluorine, chlorine, methyl, or trifluoromethyl.

[0073] L1 represents bromine, iodine, methanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, and p-toluenesulfonyloxy.

[0074] R1 is trifluoroethyl;

[0075] R2 is methyl, ethyl, propyl, chloromethyl, trichloromethyl, methoxymethyl, ethoxymethyl, phenyl, p-tolyl, p-chlorophenyl, 2-furanyl, 3-furanyl, 2-thienyl, or 3-thienyl.

[0076] Fourthly, the present invention provides a method for preparing a sulfur-containing amide compound, wherein the sulfur-containing amide compound is shown in formula (V):

[0077]

[0078] The reaction formula is as follows:

[0079]

[0080] Wherein, X and Y are each independently a halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or C1-C3 haloalkoxy;

[0081] L1 is a leaving group;

[0082] R1 is a C1-C6 haloalkyl, C2-C6 alkynyl, C2-C6 alkenyl, C1-C6 alkyl, C3-C6 cycloalkyl, or C3-C6 epoxyalkyl;

[0083] R2 is C1-C10 Alkyl, C2-C 10 Halogenated alkyl, chloromethyl, trichloromethyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkyl groups, C1-C 10 Alkoxy, C1-C 10 Halogenated alkyl C1-C 10 Alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkylC1-C5 alkyl, C3-C7 cycloalkyloxy, C1-C6 alkyl-substituted phenyl, halogen-substituted phenyl, haloalkyl-substituted phenyl, C1-C6 alkyl-substituted aromatic heterocycle, halogen-substituted aromatic heterocycle, haloalkyl-substituted aromatic heterocycle;

[0084] The preparation method involves reacting compound (VII) with compound (III) in a solvent and at a certain temperature, with or without the addition of a reducing agent, to obtain compound (V).

[0085] Furthermore, X and Y are each independently halogen, cyano, methyl, or trifluoromethyl;

[0086] L1 represents chlorine, bromine, iodine, methanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, and p-toluenesulfonyloxy.

[0087] R1 is trifluoroethyl, difluoroethyl, or n-propyl;

[0088] R2 is a C1-C6 alkyl, C2-C4 haloalkyl, chloromethyl, trichloromethyl, C1-C4 alkoxy, C1-C4 halooxyalkyl, C1-C4 alkoxy-C1-C4 alkyl, C1-C4 halooxyalkyl-C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C4 alkyl, C3-C6 cycloalkyloxy, C1-C3 alkyl-substituted phenyl, halogen-substituted phenyl, trifluoromethyl-substituted phenyl, C1-C3 alkyl-substituted aromatic heterocycle, halogen-substituted aromatic heterocycle, or trifluoromethyl-substituted aromatic heterocycle.

[0089] Furthermore, X can be methyl or chlorine;

[0090] Y represents fluorine, chlorine, methyl, or trifluoromethyl.

[0091] L1 represents bromine, iodine, methanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, and p-toluenesulfonyloxy.

[0092] R1 is trifluoroethyl;

[0093] R2 is methyl, ethyl, propyl, chloromethyl, trichloromethyl, methoxymethyl, ethoxymethyl, phenyl, p-tolyl, p-chlorophenyl, 2-furanyl, 3-furanyl, 2-thienyl, or 3-thienyl.

[0094] Furthermore, the solvent is selected from organic solvents and / or water;

[0095] The temperature is selected from -10°C to the solvent boiling point;

[0096] The alkali is selected from inorganic alkalis or organic alkalis.

[0097] Fifthly, the present invention provides a compound of formula (V):

[0098]

[0099] Where n is 0, 1, or 2;

[0100] X and Y are each independently a halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or C1-C3 haloalkoxy;

[0101] R1 is a C1-C6 haloalkyl, C2-C6 alkynyl, C2-C6 alkenyl, C1-C6 alkyl, C3-C6 cycloalkyl, or C3-C6 epoxyalkyl;

[0102] R2 is C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkyl groups, C1-C 10 Alkoxy C1-C 10 Alkyl, C1-C 10 Halogenated alkyl C1-C 10 Alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkylC1-C5 alkyl, C3-C7 cycloalkyloxy, C1-C6 alkyl-substituted phenyl, halogen-substituted phenyl, trifluoromethyl-substituted phenyl, C1-C6 alkoxycarbonyl-substituted phenyl, C1-C6 alkylsulfonyl-substituted phenyl, C1-C6 alkylamino-substituted phenyl, C1-C6 alkylcarbonylamino-substituted phenyl, C1-C6 alkyl-substituted aromatic heterocycle, halogen-substituted aromatic heterocycle, haloalkyl-substituted aromatic heterocycle.

[0103] Furthermore, n can be 0 or 1;

[0104] X and Y can be independently halogen, cyano, methyl, or trifluoromethyl.

[0105] R1 is CF3CH2, CHF2CH2, or n-propyl;

[0106] R2 is a C1-C6 alkyl, C1-C4 alkoxy, C1-C4 halooxyalkyl, C1-C4 alkoxyC1-C4 alkyl, C1-C4 halooxyalkylC1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylC1-C4 alkyl, C3-C6 cycloalkyloxy, C1-C3 alkyl-substituted phenyl, halogen-substituted phenyl, trifluoromethyl-substituted phenyl, C1-C3 alkoxycarbonyl-substituted phenyl, C1-C3 alkyl-substituted aromatic heterocycle, halogen-substituted aromatic heterocycle, or trifluoromethyl-substituted aromatic heterocycle.

[0107] Furthermore, n can be 0 or 1;

[0108] X represents methyl or chlorine;

[0109] Y represents fluorine, chlorine, methyl, or trifluoromethyl.

[0110] R1 is CF3CH2;

[0111] R2 is methyl, ethyl, propyl, trifluoromethyl, chloromethyl, trichloromethyl, methoxymethyl, ethoxymethyl, phenyl, p-tolyl, p-chlorophenyl, 2-furanyl, 3-furanyl, 2-thienyl, or 3-thienyl.

[0112] The compounds of formula (V) are shown in Table 1, but are by no means limited to these compounds. In addition, the compound numbers in the table are as described below.

[0113] Table 1 shows compounds of formula (V).

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128] In a sixth aspect, the present invention also provides the use of the above-described compound (V) in the preparation of the above-described compound (I).

[0129] The beneficial effects of this invention are as follows:

[0130] (1) The raw material methyl o-chloromethylbenzoate used in this invention is cheaper than methyl o-bromomethylbenzoate used in the prior art, has a lower preparation cost and less pollution, and is more environmentally friendly.

[0131] (2) The benzylation reaction of the present invention has a higher conversion rate and fewer dibenzyl impurities compared with the prior art, which facilitates the post-processing purification of the product, resulting in higher yield and better product quality. Detailed Implementation

[0132] To enable those skilled in the art to better understand the technical solutions of this invention, the technical solutions in the embodiments of this invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of this invention, and not all embodiments. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort should fall within the scope of protection of this invention.

[0133] Example 1: Preparation of N-(4-chloro-2-fluoro-5-((2,2,2-trifluoroethyl)thio)phenyl)acetamide

[0134]

[0135] N,N'-(dithionylbis(4-chloro-6-fluoro-3,1-phenylene))diacetamide (43.7 g, 0.1 mol) was added to DMF (300 mL), followed by potassium carbonate (27.6 g, 0.2 mol), sodium formaldehyde sulfoxylate (23.6 g, 0.2 mol), and trifluoroethyl p-toluenesulfonate (55.88 g, 0.22 mol). The reaction mixture was heated to 100 °C and stirred for 4 hours. After cooling, the reaction mixture was added to ice water, and the mixture was filtered under reduced pressure to obtain 45.6 g of a grayish-white solid with an HPLC purity of 96.2%.

[0136] 1H NMR (400MHz, CDCl3): δ8.65 (d, J = 8.1Hz, 1H), 7.34 (s, 1H), 7.21 (d, J = 10.4Hz, 1H), 3.47 (q, J = 9.5Hz, 2H), 2.23 (s, 3H).

[0137] MS(m / z,ESI):302.20(m+H).

[0138] Example 2 Preparation of 4-chloro-2-fluoro-5-((2,2,2-trifluoroethyl)thio)aniline

[0139]

[0140] N-(4-chloro-2-fluoro-5-((2,2,2-trifluoroethyl)thio)phenyl)acetamide (30.15 g, 0.1 mol) was added to 150 mL of concentrated hydrochloric acid. The reaction flask was heated to reflux and reacted for 3 hours. The reaction solution was then cooled to room temperature and filtered under reduced pressure to obtain a light brown solid. After drying, 26.7 g of crude product hydrochloride was obtained. The above hydrochloride was added to 300 mL of 5% sodium hydroxide aqueous solution, stirred at room temperature for 30 minutes, and then filtered under reduced pressure. The filter cake was dried under reduced pressure to obtain 22.3 g of light brownish-red solid with an HPLC purity of 99.6%.

[0141] 1 H NMR (400MHz, CDCl3) δ7.10 (d, J = 10.5Hz, 1H), 7.06 (t, J = 7.1Hz, 1H), 4.02–3.45 (m, 2H), 3.40 (q, J = 9.7Hz, 2H).

[0142] Example 3 Preparation of methyl 2-(((4-chloro-2-fluoro-5-((2,2,2-trifluoroethyl)thio)phenyl)amino)methyl)benzoate

[0143]

[0144] 25.95 g (0.1 mol) of 4-chloro-2-fluoro-5-((2,2,2-trifluoroethyl)thio)aniline was added to a single-necked flask, followed by 100 mL of DMF, 18.45 g (0.1 mol) of 2-chloromethylbenzoate, and 10.6 g (0.1 mol) of sodium carbonate. The reaction mixture was stirred at room temperature for 36 hours. HPLC analysis showed a product yield of 84.2% and a dibenzylamine impurity of 4.6%. 300 mL of water was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The mixture was then filtered under reduced pressure. The filter cake was washed three times with water and dried under reduced pressure to obtain a crude, off-white solid. 70 mL of methanol was added to the crude product, and the mixture was stirred at room temperature for 30 minutes. The mixture was then filtered under reduced pressure. The filter cake was dried again to obtain 30.11 g of a purified white solid with an HPLC purity of 98.8% and a dibenzylamine impurity of 0.6%. Melting point: 84.3–85.4 °C. Yield: 73.0%.

[0145] 1 H-NMR (500MHz, CDCl3): δ = 8.00 (dd, J1 = 1.5Hz, J2 = 9.5Hz, 1H), 7.43-7.50 (m, 2H), 7.33-7.38 (m, 1 H),7.05(d,J=14Hz,1H),6.91(d,J=6.0Hz,1H),4.69(s,2H),3.92(s,3H),3.32(q,J=14.0Hz,2H).

[0146] MS(m / z,ESI):408.38(m+H).

[0147] Example 4 Preparation of methyl 2-(((2-fluoro-4-methyl-5-((2,2,2-trifluoroethyl)thio)phenyl)amino)methyl)benzoate

[0148]

[0149] N-(2-fluoro-4-methyl-5-((2,2,2-trifluoroethyl)thio)phenyl)acetamide (28.10 g, 0.1 mol) was added to 150 mL of concentrated hydrochloric acid. The reaction flask was heated to reflux and reacted for 3 hours. The reaction solution was then cooled to room temperature and filtered under reduced pressure. The filter cake was washed three times with water to obtain an off-white solid. After drying, 26.6 g of white solid was obtained, with a yield of 96.72% and an HPLC purity of 100%.

[0150] Example 5 Preparation of 2-fluoro-4-methyl-5-((2,2,2-trifluoroethyl)thio)aniline hydrochloride

[0151]

[0152] 2-Fluoro-4-methyl-5-((2,2,2-trifluoroethyl)thio)aniline (23.90 g, 0.1 mol) was added to a single-necked flask, followed by DMF (100 mL), methyl 2-(((methanesulfonyl)oxy)methyl)benzoate (26.84 g, 0.11 mol), and sodium carbonate (11.66 g, 0.11 mol). The reaction mixture was heated to 80 °C and stirred for 12 hours, then cooled to room temperature. 300 mL of water was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The mixture was then filtered under reduced pressure. The filter cake was washed three times with water and dried under reduced pressure to obtain a crude, off-white solid. 70 mL of methanol was added to the crude product, and the mixture was stirred at room temperature for 30 minutes. The mixture was then filtered under reduced pressure, and the filter cake was dried again to obtain 28.30 g of purified white solid with an HPLC purity of 98.5% and a yield of 71.95%.

[0153] Preparation of Comparative Example 2-(((4-chloro-2-fluoro-5-((2,2,2-trifluoroethyl)thio)phenyl)amino)methyl)benzoate

[0154]

[0155] 25.95 g (0.1 mol) of 4-chloro-2-fluoro-5-((2,2,2-trifluoroethyl)thio)aniline was added to a single-necked flask, followed by 100 mL of DMF, 22.90 g (0.1 mol) of methyl 2-bromomethylbenzoate, and 10.6 g (0.1 mol) of sodium carbonate. The reaction mixture was stirred at room temperature for 36 hours. HPLC analysis showed a product yield of 70.2% and a dibenzylamine impurity of 11.7%. 300 mL of water was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The mixture was then filtered under reduced pressure. The filter cake was washed three times with water and dried under reduced pressure to obtain a crude, off-white solid. 70 mL of methanol was added to the crude product, and the mixture was stirred at room temperature for 30 minutes. The mixture was then filtered under reduced pressure, and the filter cake was dried again to obtain 21.95 g of a purified off-white solid with an HPLC purity of 94.6%, a dibenzylamine impurity of 3.6%, and a yield of 50.91%.

[0156] Although the present invention has been described in detail by way of preferred embodiments, the present invention is not limited thereto. Various equivalent modifications or substitutions can be made to the embodiments of the present invention by those skilled in the art without departing from the spirit and essence of the invention, and such modifications or substitutions should all be within the scope of the present invention. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should also be covered within the protection scope of the present invention.

Claims

1. A method for preparing a benzylamine compound, characterized in that, The reaction formula is as follows: ； Where n is 0, 1 or 2; X and Y are each independently a halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or C1-C3 haloalkoxy; L2 is chlorine or methanesulfonyloxy; R1 is a C1-C6 haloalkyl, C2-C6 alkynyl, C2-C6 alkenyl, C1-C6 alkyl, C3-C6 cycloalkyl, or C3-C6 epoxyalkyl; R3 is C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkyl groups, C1-C 10 Alkoxy C1-C 10 Alkyl, C1-C 10 Halogenated alkyl C1-C 10 Alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl, C1-C5 alkyl, C3-C7 cycloalkyloxy, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C6 cycloalkyl; R4, R5, R6, and R7 are each independently hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxymethyl, carboxyl, hydroxyl, mercapto, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkoxy groups, C1-C 10 alkoxycarbonyl, C1-C 10 Haloalkoxycarbonyl; The preparation method involves adding sodium carbonate to compound (VI) and compound (VII) in a solvent and at a certain temperature to carry out a substitution reaction, thereby preparing compound (I).

2. The preparation method according to claim 1, characterized in that, n is 0 or 1; X and Y can be independently halogen, cyano, methyl, or trifluoromethyl. R1 is 1,1,1-trifluoroethyl, 1,1-difluoroethyl, or n-propyl; R3 is a C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 halooxyalkyl, C1-C3 alkoxyC1-C3 alkyl, C1-C3 halooxyalkylC1-C3 alkyl, C3-C6 cycloalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, or C2-C4 alkynyl. R4, R6, and R7 are each independently hydrogen; R5 can be hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, amino, trifluoromethyl, or trifluoromethoxy.

3. The preparation method according to claim 1, characterized in that, n is 0 or 1; X represents methyl or chlorine; Y represents fluorine, chlorine, methyl, or trifluoromethyl. L2 is chlorine; R1 is 1,1,1-trifluoroethyl; R3 can be methyl, ethyl, propyl, isopropyl, or trifluoromethyl. R4, R5, R6, and R7 are each hydrogen atoms.

4. The preparation method according to any one of claims 1-3, characterized in that, The solvent is selected from organic solvents and / or water; The temperature is selected from -10°C to the solvent boiling point.

5. The preparation method according to any one of claims 1-3, characterized in that, The solvent is at least one of methanol, ethanol, isopropanol, propanol, butanol, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, ethyl acetate, toluene, xylene, acetonitrile, tetrahydrofuran, acetone, N,N-dimethylformamide, N-methylpyrrolidone, dioxane, or water.

6. The preparation method according to any one of claims 1-3, characterized in that, The solvent is at least one of methanol, ethanol, dichloromethane, dichloroethane, toluene, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, or water.

7. The preparation method according to claim 1, characterized in that, The preparation method of the compound of formula (VI) is as follows: The reaction formula is as follows: ； Where n is 0, 1 or 2; X and Y are each independently a halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or C1-C3 haloalkoxy; R1 is a C1-C6 haloalkyl, C2-C6 alkynyl, C2-C6 alkenyl, C1-C6 alkyl, C3-C6 cycloalkyl, or C3-C6 epoxyalkyl; R2 is C1-C 10 Alkyl, C2-C 10 Halogenated alkyl, chloromethyl, trichloromethyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkyl groups, C1-C 10 Alkoxy C1-C 10 Alkyl, C1-C 10 Halogenated alkyl C1-C 10 Alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkylC1-C5 alkyl, C3-C7 cycloalkyloxy, C1-C6 alkyl-substituted phenyl, halogen-substituted phenyl, haloalkyl-substituted phenyl, C1-C6 alkyl-substituted aromatic heterocycle, halogen-substituted aromatic heterocycle, haloalkyl-substituted aromatic heterocycle; Compound of formula (V) is prepared by adding hydrochloric acid to a solvent and at a certain temperature to obtain compound of general formula (VI) or its salt.

8. The preparation method according to claim 7, characterized in that, n is 0 or 1; X and Y can be independently halogen, cyano, methyl, or trifluoromethyl. R1 is trifluoroethyl, difluoroethyl, or n-propyl; R2 is a C1-C6 alkyl, C2-C4 haloalkyl, chloromethyl, trichloromethyl, C1-C4 alkoxy, C1-C4 halooxyalkyl, C1-C4 alkoxy-C1-C4 alkyl, C1-C4 halooxyalkyl-C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C4 alkyl, C3-C6 cycloalkyloxy, C1-C3 alkyl-substituted phenyl, halogen-substituted phenyl, trifluoromethyl-substituted phenyl, C1-C3 alkyl-substituted aromatic heterocycle, halogen-substituted aromatic heterocycle, or trifluoromethyl-substituted aromatic heterocycle.

9. The preparation method according to claim 7, characterized in that, n is 0; X represents methyl or chlorine; Y represents fluorine, chlorine, methyl, or trifluoromethyl. R1 is trifluoroethyl; R2 is methyl, ethyl, propyl, chloromethyl, trichloromethyl, methoxymethyl, ethoxymethyl, phenyl, p-tolyl, p-chlorophenyl, 2-furanyl, 3-furanyl, 2-thienyl, or 3-thienyl.

10. The preparation method according to claim 7, characterized in that, The preparation method of the compound of formula (V) is as follows: The reaction formula is as follows: ； Wherein, X and Y are each independently a halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or C1-C3 haloalkoxy; L1 is p-toluenesulfonyloxy; R1 is a C1-C6 haloalkyl, C2-C6 alkynyl, C2-C6 alkenyl, C1-C6 alkyl, C3-C6 cycloalkyl, or C3-C6 epoxyalkyl; R2 is C1-C 10 Alkyl, C2-C 10 Halogenated alkyl, chloromethyl, trichloromethyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkyl groups, C1-C 10 Alkoxy, C1-C 10 Halogenated alkyl C1-C 10 Alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkylC1-C5 alkyl, C3-C7 cycloalkyloxy, C1-C6 alkyl-substituted phenyl, halogen-substituted phenyl, haloalkyl-substituted phenyl, C1-C6 alkyl-substituted aromatic heterocycle, halogen-substituted aromatic heterocycle, haloalkyl-substituted aromatic heterocycle; The preparation method involves reacting compound (II) and compound (III) in a solvent and at a certain temperature with the addition of a base and a reducing agent to obtain compound (V).

11. The preparation method according to claim 10, characterized in that, X and Y can be independently halogen, cyano, methyl, or trifluoromethyl. R1 is trifluoroethyl, difluoroethyl, or n-propyl; R2 is a C1-C6 alkyl, C2-C4 haloalkyl, chloromethyl, trichloromethyl, C1-C4 alkoxy, C1-C4 halooxyalkyl, C1-C4 alkoxy-C1-C4 alkyl, C1-C4 halooxyalkyl-C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C4 alkyl, C3-C6 cycloalkyloxy, C1-C3 alkyl-substituted phenyl, halogen-substituted phenyl, trifluoromethyl-substituted phenyl, C1-C3 alkyl-substituted aromatic heterocycle, halogen-substituted aromatic heterocycle, or trifluoromethyl-substituted aromatic heterocycle.

12. The preparation method according to claim 10, characterized in that, X represents methyl or chlorine; Y represents fluorine, chlorine, methyl, or trifluoromethyl. R1 is trifluoroethyl; R2 is methyl, ethyl, propyl, chloromethyl, trichloromethyl, methoxymethyl, ethoxymethyl, phenyl, p-tolyl, p-chlorophenyl, 2-furanyl, 3-furanyl, 2-thienyl, or 3-thienyl.

13. The preparation method according to claim 7, characterized in that, The preparation method of the compound of formula (V) is as follows: The reaction formula is as follows: ； Wherein, X and Y are each independently a halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or C1-C3 haloalkoxy; L1 is a leaving group; R1 is a C1-C6 haloalkyl, C2-C6 alkynyl, C2-C6 alkenyl, C1-C6 alkyl, C3-C6 cycloalkyl, or C3-C6 epoxyalkyl; R2 is C1-C 10 Alkyl, C2-C 10 Halogenated alkyl, chloromethyl, trichloromethyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkyl groups, C1-C 10 Alkoxy, C1-C 10 Halogenated alkyl C1-C 10 Alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkylC1-C5 alkyl, C3-C7 cycloalkyloxy, C1-C6 alkyl-substituted phenyl, halogen-substituted phenyl, haloalkyl-substituted phenyl, C1-C6 alkyl-substituted aromatic heterocycle, halogen-substituted aromatic heterocycle, haloalkyl-substituted aromatic heterocycle; The preparation method involves reacting compound (VII) and compound (III) in a solvent and at a certain temperature with the addition of a base to obtain compound (V).

14. The preparation method according to claim 13, characterized in that, X and Y can be independently halogen, cyano, methyl, or trifluoromethyl. L1 represents chlorine, bromine, iodine, methanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, and p-toluenesulfonyloxy. R1 is trifluoroethyl, difluoroethyl, or n-propyl; R2 is a C1-C6 alkyl, C2-C4 haloalkyl, chloromethyl, trichloromethyl, C1-C4 alkoxy, C1-C4 halooxyalkyl, C1-C4 alkoxy-C1-C4 alkyl, C1-C4 halooxyalkyl-C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C4 alkyl, C3-C6 cycloalkyloxy, C1-C3 alkyl-substituted phenyl, halogen-substituted phenyl, trifluoromethyl-substituted phenyl, C1-C3 alkyl-substituted aromatic heterocycle, halogen-substituted aromatic heterocycle, or trifluoromethyl-substituted aromatic heterocycle.

15. The preparation method according to claim 13, characterized in that, X represents methyl or chlorine; Y represents fluorine, chlorine, methyl, or trifluoromethyl. L1 represents bromine, iodine, methanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, and p-toluenesulfonyloxy. R1 is trifluoroethyl; R2 is methyl, ethyl, propyl, chloromethyl, trichloromethyl, methoxymethyl, ethoxymethyl, phenyl, p-tolyl, p-chlorophenyl, 2-furanyl, 3-furanyl, 2-thienyl, or 3-thienyl.

16. The preparation method according to any one of claims 11-15, characterized in that, The solvent is selected from organic solvents and / or water; The temperature is selected from -10°C to the solvent boiling point; The alkali is selected from inorganic alkalis or organic alkalis.

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