CN110885290A - Synthetic method of 3-fluoro-2-methyl-4-trifluoromethylaniline hydrochloride - Google Patents
Synthetic method of 3-fluoro-2-methyl-4-trifluoromethylaniline hydrochloride Download PDFInfo
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- CN110885290A CN110885290A CN201911295142.4A CN201911295142A CN110885290A CN 110885290 A CN110885290 A CN 110885290A CN 201911295142 A CN201911295142 A CN 201911295142A CN 110885290 A CN110885290 A CN 110885290A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
Abstract
The invention discloses a method for synthesizing 3-fluoro-2-methyl-4-trifluoromethyl aniline hydrochloride, belonging to the field of pharmaceutical chemical synthesis. The method comprises the following steps: dissolving the compound B in an organic solvent, and reacting with tert-butyl carbamate, 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene, alkali and a catalyst under the protection of nitrogen to obtain a compound C; and dissolving the compound C in an organic solvent, and reacting with an organic solvent of hydrogen chloride to obtain a target product compound D. Wherein the compound B is prepared by self-made synthesis by taking 4-bromo-2-fluorobenzotrifluoride as a raw material. The method has the advantages of mild reaction conditions, simple synthesis operation and higher yield of the prepared product.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry synthesis, in particular to a synthesis method of 3-fluoro-2-methyl-4-trifluoromethylaniline hydrochloride.
Background
The fluorine-containing compound has special properties, so that the fluorine-containing compound has important application value in the fields of biochemistry, pesticides, functional materials and the like. Among these fluorine-containing compounds, trifluoromethylbenzenes occupy a large proportion. The trifluoromethyl benzene compound has high fat solubility, good metabolic stability, high electronegativity and bioavailability, so that the trifluoromethyl benzene compound has wide application in the fields of novel medicines and pesticides.
As early as 1928, some simple trifluoromethylbenzenes have found utility in bioactive molecules. Compounds such as trifluoromethyl benzene, m-nitrotrifluoromethyl benzene, m-trifluoromethylbenzoic acid and m-trifluoromethylaniline can affect the central nervous system of the frog; the m-nitrotrifluoromethylbenzene and the m-trifluoromethylbenzoic acid are obvious as the stimulant, and on the contrary, the anesthetic action of the m-trifluoromethylaniline is quick in response and long in duration, and can be used as the sedative. After that, the trifluoromethyl benzene compounds are rapidly developing and are more and more. Aluminum fermin (Flufenamate aluminum) marketed in 1967, ifenphenate (Ufenamate) marketed in 1982, Bicalutamide (Bicalutamide) marketed in 1995, Cinacalcet Hydrochloride marketed in 2004 (Cinacalcet Hydrochloride), lapitan Hydrochloride Hydrate (rolapitan Hydrochloride) marketed in 2015, Tafenoquine Succinate (Tafenoquine Succinate) marketed in 2018, sinimod (Siponimod) marketed in 2019, and trifluralin as herbicide, geum, flutolanilide as and flutolanilide as fungicide, etc., are trifluoromethylbenzenes.
In view of the potential value and market application prospect of the trifluoromethyl benzene compound, the invention provides a synthesis method of the trifluoromethyl benzene compound, and the method has no literature report at present.
Disclosure of Invention
The invention aims to provide a method for synthesizing 3-fluoro-2-methyl-4-trifluoromethyl aniline hydrochloride, which has the advantages of reasonable design, simple synthesis operation and easy realization. Mainly solves the technical problem that no literature reports a synthetic method at present.
In order to achieve the above purpose, the invention provides the following technical scheme:
a synthetic method of 3-fluoro-2-methyl-4-trifluoromethylaniline hydrochloride comprises the following steps:
the synthesis method is realized by the following steps:
(1) dissolving the compound B in an organic solvent, and reacting with tert-butyl carbamate, 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene, alkali and a catalyst under the protection of nitrogen to obtain a compound C;
(2) and dissolving the compound C in an organic solvent, and reacting with an organic solvent of hydrogen chloride to obtain a compound D.
Preferably, the organic solvent in the step (1) is dioxane, the reaction temperature is 60-100 ℃, and the reaction time is 0.5-8 hours.
Preferably, in step (1), the base is cesium carbonate, the catalyst is tris (dibenzylideneacetone) dipalladium, the molar ratio of compound B, tert-butyl carbamate, 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene, base and catalyst is 1: 1.1: 0.02-0.06: 1.5-3: 0.01 to 0.05.
Preferably, the molar amount of 4, 5-bis diphenylphosphino-9, 9-dimethylxanthene in step (1) is greater than the molar amount of the catalyst.
Preferably, the organic solvent in the step (2) is methanol, the reaction temperature is 20-60 ℃, and the reaction time is 1-30 hours.
Preferably, the organic solvent of hydrogen chloride in step (2) is a methanol solution of hydrogen chloride or an ethyl acetate solution of hydrogen chloride or a dioxane solution of hydrogen chloride.
Preferably, the concentration of the methanol solution of hydrogen chloride is 4mol/L, the ethyl acetate solution of hydrogen chloride is 2mol/L, and the dioxane solution of hydrogen chloride is 4 mol/L.
Preferably, the compound B in step (1) is prepared from 4-bromo-2-fluorobenzotrifluoride as a raw material, and the synthetic route thereof is as follows:
the synthesis steps are as follows: adding diisopropylamine and tetrahydrofuran into a reaction bottle, cooling to-78 ℃, and dropwise adding n-butyl lithium under the protection of nitrogen. After the completion of the dropwise addition, the mixture was stirred at 25 ℃ for 1 hour. Re-cooling to-78 deg.c and dropping 4-bromo-2-fluoro benzotrifluoride. After the end of the dropwise addition, the mixture was stirred at-78 ℃ for 2 hours. And adding methyl iodide dropwise, and heating to 25 ℃ for reacting for 16 hours.
Preferably, in the step of preparing the compound B from the compound A, the molar ratio of the compound A to the diisopropylamine to the n-butyllithium to the methyl iodide is 1: 1.2: 1.1: 1.1.
preferably, in the step of preparing the compound B from the compound A, the concentration of n-butyllithium is 2.5 mol/L.
The Chinese explanation of the invention: n-BuLi: n-butyl lithium; DIPA: diisopropylamine; CH (CH)3I: methyl iodide; BocNH2: tert-butyl carbamate, wherein Boc is tert-butoxycarbonyl; xantphos: 4, 5-bis diphenylphosphino-9, 9-dimethylxanthene.
The invention has the beneficial effects that:
a. the invention provides a method for synthesizing 3-fluoro-2-methyl-4-trifluoromethyl aniline hydrochloride for the first time, and provides a synthetic route for preparing 3-fluoro-2-methyl-4-trifluoromethyl aniline hydrochloride;
b. the invention has mild reaction conditions, simple synthesis operation and easy realization;
c. the product obtained by the method has high yield.
Detailed Description
The invention is further illustrated by the following examples, without restricting its scope to these examples. Numerous other changes and modifications can be made by those skilled in the art without departing from the spirit and scope of the invention. In particular, certain agents which are both chemically and structurally related may be substituted for the agents described herein to achieve the same or similar results, and reactions may be carried out under conditions outside the preferred ranges, albeit less than optimally. Accordingly, such obvious substitutions and modifications are intended to be included within the scope of the appended claims.
Example 1
(1) Synthesis of Compound B
4-bromo-2-fluorobenzotrifluoride (24.3g, 100mmol, 1eq.) was placed in the addition funnel for use. Diisopropylamine (12.1g, 120mmol, 1.2eq.) and 200ml tetrahydrofuran were added to a reaction flask, cooled to-78 ℃ and n-butyllithium (44ml, 110mmol, 1.1eq.) was added dropwise under nitrogen. After the completion of the dropwise addition, the mixture was stirred at 25 ℃ for 1 hour. Re-cooling to-78 deg.c and dropping 4-bromo-2-fluoro benzotrifluoride. After the end of the dropwise addition, the mixture was stirred at-78 ℃ for 2 hours. Methyl iodide (15.6g, 110mmol, 1.1eq.) was added dropwise and the reaction was gradually warmed to 25 ℃ for 16 hours.
After the reaction, the reaction mixture was cooled in an ice-water bath and quenched by dropping 120ml of a saturated ammonium chloride solution. Extraction with ethyl acetate and concentration of the organic phase gave 22.1g of 1-bromo-3-fluoro-2-methyl-4- (trifluoromethyl) benzene as a yellow oil in 86% yield. Used directly in the next step.
(2) Synthesis of Compound C
1-bromo-3-fluoro-2-methyl-4- (trifluoromethyl) benzene (22.1g, 86mmol, 1eq.) was dissolved in 330ml dioxane, and tert-butyl carbamate (11.1g, 94.6mmol, 1.1eq.) 4, 5-bis diphenylphosphine-9, 9-dimethylxanthene (2g, 3.4mmol, 0.04eq.) cesium carbonate (56g, 172mmol, 2eq.) and tris (dibenzylideneacetone) dipalladium (2.4g, 2.6mmol, 0.03eq.) were added. Under the protection of nitrogen, the temperature is raised to 85 ℃, and the reaction is carried out for 3 hours under the condition of heat preservation.
After the reaction, the reaction solution was cooled to room temperature and filtered, and the filter cake was washed with ethyl acetate. The filtrate was spin-dried and purified by column chromatography to give 23g of 3-fluoro-2-methyl-4-trifluoromethyl-N- (tert-butoxycarbonyl) aniline as a white solid in 91% yield.
(3) Synthesis of Compound D
3-fluoro-2-methyl-4-trifluoromethyl-N- (tert-butoxycarbonyl) aniline (23g, 78.3mmol, 1eq.) was dissolved in 150ml of methanol, and 150ml of a methanol solution of hydrogen chloride (concentration 4mol/L) was added dropwise in an ice-water bath. After completion of the dropwise addition, the reaction was carried out at 28 ℃ for 16 hours.
After the reaction, the reaction solution was spin-dried with methanol, washed with acetonitrile, filtered and dried to obtain 17.1g of 3-fluoro-2-methyl-4-trifluoromethylaniline hydrochloride as a white solid with a yield of 95%.
1H NMR(d6-DMSO):8.09(s,br,3H),7.22(t,J＝8.4Hz,1H),6.61(d,J＝8.4Hz,1H),2.02(d,J＝1.8Hz,3H)。
Example 2
(1) Synthesis of Compound B
4-bromo-2-fluorobenzotrifluoride (19.4g, 80mmol, 1eq.) was placed in the addition funnel for use. Diisopropylamine (9.7g, 96mmol, 1.2eq.) and 150ml tetrahydrofuran were added to a reaction flask, cooled to-78 ℃ and n-butyllithium (35.2ml, 88mmol, 1.1eq.) was added dropwise under nitrogen. After the completion of the dropwise addition, the mixture was stirred at 25 ℃ for 1 hour. Re-cooling to-78 deg.c and dropping 4-bromo-2-fluoro benzotrifluoride. After the end of the dropwise addition, the mixture was stirred at-78 ℃ for 2 hours. Methyl iodide (12.5g, 88mmol, 1.1eq.) was added dropwise and the reaction was gradually warmed to 25 ℃ for 16 hours.
After the reaction, the reaction mixture was cooled in an ice-water bath and quenched by dropping 100ml of a saturated ammonium chloride solution. Extraction with ethyl acetate and concentration of the organic phase gave 17.5g of 1-bromo-3-fluoro-2-methyl-4- (trifluoromethyl) benzene as a yellow oil in 85% yield. Used directly in the next step.
(2) Synthesis of Compound C
1-bromo-3-fluoro-2-methyl-4- (trifluoromethyl) benzene (17.5g, 68mmol, 1eq.) was dissolved in 260ml dioxane, and tert-butyl carbamate (8.8g, 74.8mmol, 1.1eq.) 4, 5-bis diphenylphosphine-9, 9-dimethylxanthene (2.4g, 4.1mmol, 0.06eq.) cesium carbonate (66.5g, 204mmol, 3eq.) and tris (dibenzylideneacetone) dipalladium (3.1g, 3.4mmol, 0.05eq.) were added. Under the protection of nitrogen, the temperature is raised to 60 ℃, and the reaction is carried out for 8 hours under the condition of heat preservation.
After the reaction, the reaction solution was cooled to room temperature and filtered, and the filter cake was washed with ethyl acetate. The filtrate was spin-dried and purified by column chromatography to give 16.8g of 3-fluoro-2-methyl-4-trifluoromethyl-N- (tert-butoxycarbonyl) aniline as a white solid in 84% yield.
(3) Synthesis of Compound D
3-fluoro-2-methyl-4-trifluoromethyl-N- (tert-butoxycarbonyl) aniline (16.8g, 57.1mmol, 1eq.) was dissolved in 110ml of ethyl acetate and 220ml of an ethyl acetate solution of hydrogen chloride (concentration 2mol/L) was added dropwise in an ice-water bath. After completion of the dropwise addition, the reaction was carried out at 60 ℃ for 1 hour.
After the reaction, the reaction solution was spin-dried with methanol, washed with acetonitrile, filtered and dried to obtain 11.9g of 3-fluoro-2-methyl-4-trifluoromethylaniline hydrochloride as a white solid with a yield of 91%.
1H NMR(d6-DMSO):8.09(s,br,3H),7.22(t,J＝8.4Hz,1H),6.61(d,J＝8.4Hz,1H),2.02(d,J＝1.8Hz,3H)。
Example 3
(1) Synthesis of Compound B
4-bromo-2-fluorobenzotrifluoride (29.2g, 120mmol, 1eq.) was placed in the addition funnel for use. Diisopropylamine (14.6g, 144mmol, 1.2eq.) and 220ml tetrahydrofuran were added to a reaction flask, cooled to-78 ℃ and n-butyllithium (52.8ml, 132mmol, 1.1eq.) was added dropwise under nitrogen. After the completion of the dropwise addition, the mixture was stirred at 25 ℃ for 1 hour. Re-cooling to-78 deg.c and dropping 4-bromo-2-fluoro benzotrifluoride. After the end of the dropwise addition, the mixture was stirred at-78 ℃ for 2 hours. Methyl iodide (18.7g, 132mmol, 1.1eq.) was added dropwise and the reaction was gradually warmed to 25 ℃ for 16 hours.
After the reaction, the reaction mixture was cooled in an ice-water bath and quenched by dropping 150ml of a saturated ammonium chloride solution. Extraction with ethyl acetate and concentration of the organic phase gave 26.8g of 1-bromo-3-fluoro-2-methyl-4- (trifluoromethyl) benzene as a yellow oil in 87% yield. Used directly in the next step.
(2) Synthesis of Compound C
1-bromo-3-fluoro-2-methyl-4- (trifluoromethyl) benzene (26.8g, 104.4mmol, 1eq.) was dissolved in 400ml dioxane, and tert-butyl carbamate (13.5g, 114.8mmol, 1.1eq.) 4, 5-bis diphenylphosphino-9, 9-dimethylxanthene (1.2g, 2.1mmol, 0.02eq.) cesium carbonate (51g, 156.6mmol, 1.5eq.) and tris (dibenzylideneacetone) dipalladium (1g, 1mmol, 0.01eq.) were added. Under the protection of nitrogen, the temperature is raised to 100 ℃, and the reaction is carried out for 0.5 hour under the heat preservation condition.
After the reaction, the reaction solution was cooled to room temperature and filtered, and the filter cake was washed with ethyl acetate. The filtrate was spin-dried and purified by column chromatography to give 22g of 3-fluoro-2-methyl-4-trifluoromethyl-N- (tert-butoxycarbonyl) aniline as a white solid in a yield of 72%.
(3) Synthesis of Compound D
3-fluoro-2-methyl-4-trifluoromethyl-N- (tert-butoxycarbonyl) aniline (22g, 75.2mmol, 1eq.) was dissolved in 150ml dioxane, and 150ml dioxane solution of hydrogen chloride (concentration 4mol/L) was added dropwise under an ice-water bath. After completion of the dropwise addition, the reaction was carried out at 20 ℃ for 30 hours.
After the reaction, the reaction solution was spin-dried with methanol, washed with acetonitrile, filtered and dried to obtain 16.1g of 3-fluoro-2-methyl-4-trifluoromethylaniline hydrochloride as a white solid with a yield of 93%.
1H NMR(d6-DMSO):8.09(s,br,3H),7.22(t,J＝8.4Hz,1H),6.61(d,J＝8.4Hz,1H),2.02(d,J＝1.8Hz,3H)。
Claims (10)
1. A synthetic method of 3-fluoro-2-methyl-4-trifluoromethylaniline hydrochloride is characterized by comprising the following steps:
the method comprises the following steps:
(1) dissolving the compound B in an organic solvent, and reacting with tert-butyl carbamate, 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene, alkali and a catalyst under the protection of nitrogen to obtain a compound C;
(2) and dissolving the compound C in an organic solvent, and reacting with an organic solvent of hydrogen chloride to obtain a compound D.
2. The method for synthesizing 3-fluoro-2-methyl-4-trifluoromethylaniline hydrochloride according to claim 1, wherein the organic solvent in the step (1) is dioxane, the reaction temperature is 60 to 100 ℃, and the reaction time is 0.5 to 8 hours.
3. The method for synthesizing 3-fluoro-2-methyl-4-trifluoromethylaniline hydrochloride according to claim 1, wherein in the step (1), the base is cesium carbonate, the catalyst is tris (dibenzylideneacetone) dipalladium, and the molar ratio of the compound B, the tert-butyl carbamate, the 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene, the base and the catalyst is 1: 1.1: 0.02-0.06: 1.5-3: 0.01 to 0.05.
4. The method for synthesizing 3-fluoro-2-methyl-4-trifluoromethylaniline hydrochloride according to claim 3, wherein the molar amount of the 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene in the step (1) is larger than that of the catalyst.
5. The method for synthesizing 3-fluoro-2-methyl-4-trifluoromethylaniline hydrochloride according to claim 1, wherein the organic solvent in the step (2) is methanol, the reaction temperature is 20 to 60 ℃, and the reaction time is 1 to 30 hours.
6. The method for synthesizing 3-fluoro-2-methyl-4-trifluoromethylaniline hydrochloride according to claim 1, wherein the organic solvent of hydrogen chloride in the step (2) is a methanol solution of hydrogen chloride or an ethyl acetate solution of hydrogen chloride or a dioxane solution of hydrogen chloride.
7. The method for synthesizing 3-fluoro-2-methyl-4-trifluoromethylaniline hydrochloride according to claim 6, wherein the concentration of the methanol solution of hydrogen chloride is 4mol/L, the concentration of the ethyl acetate solution of hydrogen chloride is 2mol/L, and the concentration of the dioxane solution of hydrogen chloride is 4 mol/L.
8. The method for synthesizing 3-fluoro-2-methyl-4-trifluoromethylaniline hydrochloride according to claim 1, wherein the compound B in step (1) is prepared from 4-bromo-2-fluorobenzotrifluoride as a raw material, and the synthetic route is as follows:
9. the method according to claim 8, wherein the compound a is used to prepare the compound B in a molar ratio of 1: 1.2: 1.1: 1.1.
10. the method for synthesizing 3-fluoro-2-methyl-4-trifluoromethylaniline hydrochloride according to claim 8, wherein the concentration of n-butyllithium in the step of preparing the compound B from the compound A is 2.5 mol/L.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112174832A (en) * | 2020-10-29 | 2021-01-05 | 阿里生物新材料（常州）有限公司 | Method for synthesizing 5-chloro-2-methyl-4- (trifluoromethyl) aniline in one step |
| CN115073299A (en) * | 2022-06-14 | 2022-09-20 | 爱斯特（成都）生物制药股份有限公司 | Method for preparing 2-fluoro-3-trifluoromethylaniline |
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| CN112174832A (en) * | 2020-10-29 | 2021-01-05 | 阿里生物新材料（常州）有限公司 | Method for synthesizing 5-chloro-2-methyl-4- (trifluoromethyl) aniline in one step |
| CN112174832B (en) * | 2020-10-29 | 2022-05-13 | 阿里生物新材料（常州）有限公司 | Method for synthesizing 5-chloro-2-methyl-4- (trifluoromethyl) aniline in one step |
| CN115073299A (en) * | 2022-06-14 | 2022-09-20 | 爱斯特（成都）生物制药股份有限公司 | Method for preparing 2-fluoro-3-trifluoromethylaniline |
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Application publication date: 20200317 |