CN112194558A - Synthetic method of 2-fluoro-3-methyl-4- (trifluoromethyl) benzylamine hydrochloride - Google Patents
Synthetic method of 2-fluoro-3-methyl-4- (trifluoromethyl) benzylamine hydrochloride Download PDFInfo
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Abstract
The invention belongs to the technical field of medical intermediates, and particularly relates to a synthetic method of 2-fluoro-3-methyl-4- (trifluoromethyl) benzylamine hydrochloride. The method comprises the steps of taking a compound A and a compound E as initial raw materials for the first time to form a compound B, reacting the compound B to form a compound C, and preparing 2-fluoro-3-methyl-4- (trifluoromethyl) benzylamine hydrochloride by using the compound C.
Description
Technical Field
The invention belongs to the technical field of medical intermediates, and particularly relates to a synthetic method of 2-fluoro-3-methyl-4- (trifluoromethyl) benzylamine hydrochloride.
Background
The compound 2-fluoro-3-methyl-4- (trifluoromethyl) benzylamine hydrochloride and related derivatives have wide application in pharmaceutical chemistry and organic synthesis. At present, the synthesis method of 2-fluoro-3-methyl-4- (trifluoromethyl) benzylamine hydrochloride is only reported in documents. Therefore, it is necessary to develop a synthesis method which has easily available raw materials, convenient operation, easy control of reaction, proper overall yield and suitability for industrial production.
Disclosure of Invention
The technical problems to be solved by the invention are as follows: aiming at the problems, the method for synthesizing the 2-fluoro-3-methyl-4- (trifluoromethyl) benzylamine hydrochloride is provided.
In order to solve the technical problems, the invention adopts the following technical scheme:
a synthetic method of 2-fluoro-3-methyl-4- (trifluoromethyl) benzylamine hydrochloride comprises the following steps:
(1) adding the compound A, the compound E and tetrahydrofuran into a reactor, uniformly stirring, cooling to-80-75 ℃ under the protection of nitrogen, adding n-butyl lithium, preserving heat, adding methyl iodide, heating and stirring to obtain a compound B
(2) Placing the compound B, tert-butyl carbamate, tris (dibenzylideneacetone) dipalladium, 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene, potassium carbonate and dioxane into a reactor, replacing for 3 times with nitrogen, protecting with nitrogen, heating, and reacting to obtain a compound C
(3) Dissolving the compound C in ethanol, adding hydrochloric acid ethanol solution at low temperature, and stirring to obtain compound D, i.e. 2-fluoro-3-methyl-4- (trifluoromethyl) benzylamine hydrochloride
Preferably, in the step (1), the mass ratio of the compound A to the compound E to methyl iodide is 20: 10-12: 15-18, the solid-liquid g/mL ratio of the compound A to n-butyllithium is 1:2, and the volume ratio of n-butyllithium to tetrahydrofuran is 1: 7.
Preferably, in the step (2), the mass ratio of the compound B, tert-butyl carbamate, dibenzylideneacetone dipalladium, 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene to potassium carbonate is 8-9: 3-5: 0.5-1: 6-10, and the solid-liquid g/mL ratio of the compound B to dioxane is 1: 15.
Preferably, the solid-to-liquid ratio of the compound C and the ethanol hydrochloride solution in the step (3) is 1:10, and the volume ratio of ethanol to the ethanol hydrochloride solution is 2: 3.
Compared with other methods, the method has the beneficial technical effects that:
(1) the method comprises the steps of taking a compound A and a compound E as initial raw materials for the first time to form a compound B, reacting the compound B to form a compound C, and preparing 2-fluoro-3-methyl-4- (trifluoromethyl) benzylamine hydrochloride by using the compound C;
(2) the synthetic method of the 2-fluoro-3-methyl-4- (trifluoromethyl) benzylamine hydrochloride provided by the invention is short in route, reasonable in design, simple to operate and easy to control;
(3) the product obtained by the method has high yield.
Detailed Description
A synthetic method of 2-fluoro-3-methyl-4- (trifluoromethyl) benzylamine hydrochloride comprises the following steps:
(1) according to the mass ratio of 20: 10-12: 15-18 of a compound A, a compound E and methyl iodide, the solid-liquid g/mL ratio of the compound A to n-butyl lithium is 1:2, the volume ratio of n-butyl lithium to tetrahydrofuran is 1:7, taking materials, adding the compound A, the compound E and tetrahydrofuran into a reactor, uniformly stirring, protecting with nitrogen, cooling to-80-75 ℃, adding n-butyl lithium, preserving heat for 1-2 hours, adding methyl iodide, heating to 30-35 ℃, and stirring for 15-20 hours to obtain a compound B;
(2) according to the mass ratio of the compound B, tert-butyl carbamate, palladium-tris-dibenzylideneacetone, 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene and potassium carbonate: 8-9: 3-5: 0.5-1: 6-10, wherein the solid-liquid g/mL ratio of the compound B to dioxane is 1:15, taking materials, putting the compound B, tert-butyl carbamate, tris (dibenzylidene) acetone dipalladium, 4, 5-bis (diphenylphosphino) -9, 9-dimethyl xanthene, potassium carbonate and dioxane into a reactor, replacing for 3 times with nitrogen, protecting with nitrogen, heating to 80-90 ℃, and reacting for 7-10 hours to obtain a compound C;
(3) according to the solid-liquid ratio of the compound C to 0.5mol/L ethanol hydrochloride solution of 1:10 and the volume ratio of ethanol to 0.5mol/L ethanol hydrochloride solution of 3:2, taking materials, dissolving the compound C in ethanol, adding 0.5mol/L ethanol hydrochloride solution at the low temperature of-1 ℃, stirring for 5-10 min, heating to 30-35 ℃, and stirring for 15-20 h to obtain the compound D, namely 2-fluoro-3-methyl-4- (trifluoromethyl) benzylamine hydrochloride.
Example 1
A synthetic method of 2-fluoro-3-methyl-4- (trifluoromethyl) benzylamine hydrochloride comprises the following steps:
(1) adding 20g of the compound A, 10g of the compound E and 280mL of tetrahydrofuran into a reactor, uniformly stirring, cooling to-80 ℃ under the protection of nitrogen, adding 40mL of n-butyl lithium, preserving heat for 1h, adding 15g of methyl iodide, heating to 30 ℃, stirring for 15h, performing HPLC (high performance liquid chromatography) detection, finishing the reaction of raw materials, dropwise adding saturated ammonium chloride (120 mL) in an ice water bath, extracting with ethyl acetate (250 mL of 2), concentrating an organic phase, and finishing concentration to obtain 16.9g of yellow oily matter to obtain a compound B, wherein the yield is 79.89%, and the purity is 96.3%;
(2) putting 8g of the compound B, 3g of tert-butyl carbamate, 0.5g of dibenzylideneacetone dipalladium, 0.4g of 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene, 6g of potassium carbonate and 120mL of dioxane into a reactor, replacing 3 times with nitrogen, heating to 80 ℃ under the protection of nitrogen, reacting for 7 hours, detecting by TLC (thin layer chromatography), cooling a reaction system to room temperature after the reaction of raw materials is finished, filtering a small amount of diatomite, leaching a filter cake (100 mL) with ethyl acetate, spin-drying the filtrate, mixing the filtrate with a sample, and passing the mixture through a column to obtain 7.8g of yellow oily matter, namely the compound C, wherein the yield is 85.45%, and the purity is 95.3%;
(3) dissolving 3g of the compound C in 20mL of ethanol, adding 30mL of 0.5mol/L hydrochloric acid ethanol solution at the low temperature of-1 ℃, stirring for 5min, heating to 30 ℃, stirring for 15h, detecting by HPLC, separating out a large amount of white solids after the reaction of the raw materials is finished, filtering the reaction solution, washing a filter cake with ethyl acetate (15 mL of 2), and drying the filter cake to obtain 2.1g of white solids, namely the compound D, namely the 2-fluoro-3-methyl-4- (trifluoromethyl) benzylamine hydrochloride, wherein the yield is 89.41%, and the purity is 97.8%.
Nuclear magnetic data for 2-fluoro-3-methyl-4- (trifluoromethyl) benzylamine hydrochloride: 1H NMR (d 6-DMSO) 7.70(brs, 3H), 7.14(d, J =8.7Hz, 1H), 6.66(d, J =8.7Hz, 1H), 2.22(s, 3H).
Example 2
A synthetic method of 2-fluoro-3-methyl-4- (trifluoromethyl) benzylamine hydrochloride comprises the following steps:
(1) adding 20g of the compound A, 11g of the compound E and 280mL of tetrahydrofuran into a reactor, uniformly stirring, cooling to-78 ℃ under the protection of nitrogen, adding 40mL of n-butyllithium, preserving heat for 1.5h, adding 17g of methyl iodide, heating to 33 ℃, stirring for 18h, detecting by HPLC (high performance liquid chromatography), after the reaction of the raw materials is finished, dropwise adding saturated ammonium chloride (120 mL) in an ice water bath, extracting with ethyl acetate (250 mL of 2), concentrating an organic phase, and after the concentration is finished, obtaining 17.5g of yellow oily matter to obtain a compound B, wherein the yield is 82.73%, and the purity is 95.8%;
(2) putting 8g of the compound B, 4g of tert-butyl carbamate, 0.8g of dibenzylideneacetone dipalladium, 0.7g of 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene, 8g of potassium carbonate and 120mL of dioxane into a reactor, replacing 3 times with nitrogen, heating under the protection of nitrogen, reacting for 8 hours, detecting by TLC (thin layer chromatography), cooling a reaction system to room temperature after the reaction of raw materials is finished, filtering a small amount of diatomite, leaching a filter cake (100 mL) with ethyl acetate, spin-drying the filtrate, mixing the filtrate with a sample, and passing the mixture through a column to obtain 8.1 yellow oily matter, namely the compound C, wherein the yield is 88.74%, and the purity is 96.1%;
(3) dissolving 3g of the compound C in 20mL of ethanol, adding 30mL of 0.5mol/L hydrochloric acid ethanol solution at the low temperature of 0 ℃, stirring for 8min, heating to 33 ℃, stirring for 8h, detecting by HPLC (high performance liquid chromatography), separating out a large amount of white solids after the reaction of the raw materials is finished, filtering the reaction solution, washing filter cakes with ethyl acetate (15 mL of 2), and drying the filter cakes to obtain 2.2g of white solids, namely the compound D, namely the 2-fluoro-3-methyl-4- (trifluoromethyl) benzylamine hydrochloride, wherein the yield is 93.66% and the purity is 97.4%.
Nuclear magnetic data for 2-fluoro-3-methyl-4- (trifluoromethyl) benzylamine hydrochloride: 1H NMR (d 6-DMSO) 7.70(brs, 3H), 7.14(d, J =8.7Hz, 1H), 6.66(d, J =8.7Hz, 1H), 2.22(s, 3H).
Example 3
A synthetic method of 2-fluoro-3-methyl-4- (trifluoromethyl) benzylamine hydrochloride comprises the following steps:
(1) adding 20g of the compound A, 12g of the compound E and 280mL of tetrahydrofuran into a reactor, uniformly stirring, cooling to-75 ℃ under the protection of nitrogen, adding 40mL of n-butyl lithium, preserving heat for 2h, adding 18g of methyl iodide, heating to 35 ℃, stirring for 20h, performing HPLC (high performance liquid chromatography) detection, finishing the reaction of raw materials, dropwise adding saturated ammonium chloride (120 mL) in an ice water bath, extracting with ethyl acetate (250 mL of 2), concentrating an organic phase, and finishing concentration to obtain 16.5g of yellow oily matter to obtain a compound B, wherein the yield is 78.0% and the purity is 95.5%;
(2) placing 2g of the compound B, 5g of tert-butyl carbamate, 1g of dibenzylidene acetone dipalladium, 1g of 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene, 10g of potassium carbonate and 120mL of dioxane into a reactor, replacing 3 times with nitrogen, heating to 90 ℃ under the protection of nitrogen, reacting for 10 hours, detecting by TLC (thin layer chromatography), cooling a reaction system to room temperature after the reaction of raw materials is finished, filtering a small amount of diatomite, leaching a filter cake (100 mL) with ethyl acetate, spin-drying the filtrate, stirring the filtrate with a sample, and passing through a column to obtain 7.5g of yellow oily matter, namely the compound C, wherein the yield is 82.16%, and the purity is 95.0%;
(3) dissolving 3g of the compound C in 20mL of ethanol, adding 30mL0.5mol/L hydrochloric acid ethanol solution at the low temperature of 1 ℃, stirring for 10min, heating to 35 ℃, stirring for 20h, detecting by HPLC, separating out a large amount of white solid after the reaction of the raw materials is finished, filtering the reaction solution, washing a filter cake with ethyl acetate (15 mL. times.2), and drying the filter cake to obtain 2g of white solid, namely the compound D, namely the 2-fluoro-3-methyl-4- (trifluoromethyl) benzylamine hydrochloride, wherein the yield is 85.15%, and the purity is 96.2%.
Nuclear magnetic data for 2-fluoro-3-methyl-4- (trifluoromethyl) benzylamine hydrochloride: 1H NMR (d 6-DMSO) 7.70(brs, 3H), 7.14(d, J =8.7Hz, 1H), 6.66(d, J =8.7Hz, 1H), 2.22(s, 3H).
Claims (4)
1. A synthetic method of 2-fluoro-3-methyl-4- (trifluoromethyl) benzylamine hydrochloride is characterized by comprising the following steps:
(1) adding the compound A, the compound E and tetrahydrofuran into a reactor, uniformly stirring, cooling to-80-75 ℃ under the protection of nitrogen, adding n-butyl lithium, preserving heat, adding methyl iodide, heating and stirring to obtain a compound B
(2) Placing the compound B, tert-butyl carbamate, tris (dibenzylideneacetone) dipalladium, 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene, potassium carbonate and dioxane into a reactor, replacing for 3 times with nitrogen, protecting with nitrogen, heating, and reacting to obtain a compound C
(3) Dissolving the compound C in ethanol, adding hydrochloric acid ethanol solution at low temperature, and stirring to obtain compound D, i.e. 2-fluoro-3-methyl-4- (trifluoromethyl) benzylamine hydrochloride
2. The synthesis method of 2-fluoro-3-methyl-4- (trifluoromethyl) benzylamine hydrochloride according to claim 1, wherein the mass ratio of the compound A to the compound E to methyl iodide in the step (1) is 20: 10-12: 15-18, the solid-liquid g/mL ratio of the compound A to n-butyllithium is 1:2, and the volume ratio of n-butyllithium to tetrahydrofuran is 1: 7.
3. The method for synthesizing 2-fluoro-3-methyl-4- (trifluoromethyl) benzylamine hydrochloride according to claim 1, wherein in the step (2), the mass ratio of the compound B, tert-butyl carbamate, dibenzylidene acetone dipalladium, 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene and potassium carbonate is 8-9: 3-5: 0.5-1: 6-10, and the solid-liquid g/mL ratio of the compound B and dioxane is 1: 15.
4. The method for synthesizing 2-fluoro-3-methyl-4- (trifluoromethyl) benzylamine hydrochloride according to claim 1, wherein the solid-to-liquid ratio of compound C to the ethanol hydrochloride solution in step (3) is 1:10, and the volume ratio of ethanol to the ethanol hydrochloride solution is 2: 3.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101012147A (en) * | 2007-02-09 | 2007-08-08 | 陈天度 | Method of preparing R-(+)-3-chlorophenylpropanol |
| CN105601495A (en) * | 2016-02-24 | 2016-05-25 | 合肥利夫生物科技有限公司 | Synthesis method of netupitant intermediates |
| CN105777610A (en) * | 2015-10-16 | 2016-07-20 | 浙江沙星医药化工有限公司 | Method for preparing 4-chlorine-2-(trifluoroacetyl) aniline hydrochloride hydrate |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101012147A (en) * | 2007-02-09 | 2007-08-08 | 陈天度 | Method of preparing R-(+)-3-chlorophenylpropanol |
| CN105777610A (en) * | 2015-10-16 | 2016-07-20 | 浙江沙星医药化工有限公司 | Method for preparing 4-chlorine-2-(trifluoroacetyl) aniline hydrochloride hydrate |
| CN105601495A (en) * | 2016-02-24 | 2016-05-25 | 合肥利夫生物科技有限公司 | Synthesis method of netupitant intermediates |
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