CN113372223B - Preparation method of 2-fluoro-3-bromo-benzylamine - Google Patents
Preparation method of 2-fluoro-3-bromo-benzylamine Download PDFInfo
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- CN113372223B CN113372223B CN202110549446.XA CN202110549446A CN113372223B CN 113372223 B CN113372223 B CN 113372223B CN 202110549446 A CN202110549446 A CN 202110549446A CN 113372223 B CN113372223 B CN 113372223B
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/44—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers
- C07C209/48—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers by reduction of nitriles
Abstract
The invention provides a synthesis method of 2-fluoro-3-bromo-benzylamine, which comprises the following steps: dissolving 2-fluoro-3-bromoxynil in an organic solvent to form a 2-fluoro-3-bromoxynil solution, and dropwise adding BH into the 2-fluoro-3-bromoxynil solution 3 .Me 2 Reacting with an S (borane dimethyl sulfide) solution, and then dropwise adding methanol to quench the reaction until no hydrogen is released; and (3) concentrating the reactant, adding methanol to dissolve the reactant, refluxing and stirring for 2-5 h, removing the solvent, passing the concentrate through a chromatographic column, and eluting to obtain the 2-fluoro-3-bromo-benzylamine. The synthesis method has the advantages of low production cost, high product yield and purity, and simple operation, and is suitable for industrial mass production.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of 2-fluoro-3-bromo-benzylamine.
Background
The 2-fluoro-3-bromo-benzylamine is an important chemical intermediate and has wide application prospects in the fields of drug synthesis and the like.
The currently disclosed methods for synthesizing 2-fluoro-3-bromo-benzylamine mainly include the following methods:
(1) US patent US 8067408B 2 uses 3-bromo-2-fluorobenzene as a raw material, and prepares benzoyl chloride through multi-step reaction, and then reacts with ammonia water to prepare 3-bromo-2-fluorobenzamide, and finally adopts borane dimethylsulfide as a reducing agent to obtain 2-fluoro-3-bromo-benzylamine in a yield of 46% by reduction reaction.
(2) PCT patent WO2018/15879 uses 3-bromo-2-fluorobenzaldehyde to prepare 3-bromo-2-fluorobenzaldehyde-oxo-methyl oxime, then uses 10 equivalents of borane dimethylsulfide to reduce, and then reacts with 20% hydrochloric acid to prepare 2-fluoro-3-bromo-benzylamine hydrochloride with 87% yield.
(3) PCT patent WO2012/93101 discloses a hydrochloride salt of the target compound prepared by using 3-bromo-2-fluorobenzonitrile as a substrate, performing hydrogen reduction under catalysis of raney nickel in a 4% ammonia-ethanol solution, reacting at room temperature for 6.5 hours, and reacting with 1M hydrochloric acid.
The above method has the following problems: or the raw material cost is high; or the reaction steps are complicated, resulting in low reaction yield; or hazardous reagents involved, which are not conducive to safe operation in a batch process.
Disclosure of Invention
The invention provides a novel synthesis method of 2-fluoro-3-bromo-benzylamine aiming at the problems existing in the synthesis of 2-fluoro-3-bromo-benzylamine in the prior art, and the synthesis method is low in production cost, high in product yield and suitable for industrial production.
The above purpose of the invention is realized by the following technical scheme:
a method of synthesizing 2-fluoro-3-bromo-benzylamine, said method comprising the steps of:
dissolving 2-fluoro-3-bromoxynil in an organic solvent to form a 2-fluoro-3-bromoxynil solution, and dropwise adding BH into the 2-fluoro-3-bromoxynil solution 3 .Me 2 Reacting with an S (borane dimethyl sulfide) solution, and then dropwise adding methanol to quench the reaction until no hydrogen is released; and (3) concentrating the reactant, adding methanol for dissolving, carrying out reflux stirring, preferably carrying out reflux stirring for 2-5 hours, removing the solvent, passing the concentrate through a chromatographic column, and eluting to obtain the 2-fluoro-3-bromo-benzylamine.
Preferably, the concentration of 2-fluoro-3-bromoxynil in the 2-fluoro-3-bromoxynil solution is 0.05 to 0.5g/mL.
More preferably, the concentration of 2-fluoro-3-bromoxynil in the 2-fluoro-3-bromoxynil solution is 0.1 to 0.3g/mL.
Preferably, BH is added dropwise 3 .Me 2 Before the S solution, the temperature of the 2-fluoro-3-bromoxynil solution is reduced to-5 ℃, and inert gas is filled for protection. The inert gas is preferably nitrogen or argon.
More preferably, the temperature of the 2-fluoro-3-bromoxynil solution is lowered to-2 to 2 ℃.
Preferably, BH 3 .Me 2 S solution is BH 3 .Me 2 S is formed by dissolving in an organic solvent, BH 3 .Me 2 The concentration of S is 1-5 mol/L.
Preferably, the organic solvent in which 2-fluoro-3-bromoxynil is dissolved and BH 3 .Me 2 The organic solvent for dissolving S is one or two of dichloromethane and tetrahydrofuran.
More preferably, an organic solvent in which 2-fluoro-3-bromoxynil is dissolved and BH 3 .Me 2 The organic solvent in which S is dissolved is the same.
Preferably, 2-fluoro-3-bromoxynil and BH 3 .Me 2 The molar ratio of S is 1: (1.2-2.2).
Further preferably, 2-fluoro-3-bromoxynil and BH 3 .Me 2 The molar ratio of S is 1: (1.5-2.0).
Preferably, BH is added dropwise to the 2-fluoro-3-bromoxynil solution 3 .Me 2 Keeping the temperature of the S solution, stirring for 20-60 min, and then reacting for 8-15 h at room temperature.
The room temperature in the present invention is defined as 18 to 37 ℃.
More preferably, the reaction is carried out at room temperature for 9 to 12 hours.
Preferably, the chromatography column is an alumina column and the eluent is ethyl acetate.
Preferably, the yield of 2-fluoro-3-bromo-benzylamine is not less than 93% and the purity is not less than 99%.
Compared with the prior art, the invention has the following beneficial effects:
1. the invention takes the low-cost 2-fluoro-3-bromoxynil as the raw material, and realizes the low-cost preparation of the 2-fluoro-3-bromo-benzylamine;
2. the invention selects BH 3 .Me 2 S is taken as a reducing agent, and the yield of the 2-fluoro-3-bromo-benzylamine can be effectively improved compared with other reducing agents;
3. the reaction system of the invention reacts for 8-15 h at room temperature, and has higher yield of 2-fluoro-3-bromo-benzylamine compared with high-temperature reaction;
4. the synthesis method of the 2-fluoro-3-bromo-benzylamine avoids the use of gas reactants, an azidation reagent and a metal catalyst, has low production cost, high product yield and purity and simple operation, and is suitable for industrial mass production.
Detailed Description
Hereinafter, the technical scheme of the present invention will be further described with respect to the method for synthesizing 2-fluoro-3-bromo-benzylamine of the present invention, but the present invention is not limited thereto.
In some embodiments of the invention, the synthetic route for 2-fluoro-3-bromo-benzylamine is as follows:
the synthesis method of the 2-fluoro-3-bromo-benzylamine specifically comprises the following steps:
dissolving 2-fluoro-3-bromoxynil in an organic solvent to form a 2-fluoro-3-bromoxynil solution, and adding 5-50g of 2-fluoro-3-bromoxynil into every 100ml of the organic solvent, wherein the organic solvent is one or two of dichloromethane and tetrahydrofuran; reducing the temperature of the 2-fluoro-3-bromoxynil solution to-5 ℃, filling inert gas for protection, and then slowly dripping BH 3 .Me 2 S solution of 2-fluoro-3-bromoxynil with BH 3 .Me 2 The molar ratio of S is 1: (1.2-2.2), after the dripping is finished, keeping the temperature of minus 5-5 ℃, stirring for 20-60 min, and then reacting for 8-15 h at room temperature, wherein BH 3 .Me 2 S solution is BH 3 .Me 2 S is formed by dissolving in organic solvent, wherein the organic solvent is one or two of dichloromethane and tetrahydrofuran, BH 3 .Me 2 BH in S solution 3 .Me 2 The concentration of S is 1-5 mol/L; then methanol is dripped to quench the reaction until no hydrogen is released; and (3) evaporating the solvent under reduced pressure, adding methanol into the concentrate to dissolve the concentrate, refluxing and stirring for 2-5 h, removing the solvent under reduced pressure again, and eluting the concentrate through an aluminum peroxide chromatographic column and ethyl acetate to obtain the 2-fluoro-3-bromo-benzylamine.
According to the synthetic method of the 2-fluoro-3-bromo-benzylamine, cheap 2-fluoro-3-bromoxynil is used as a raw material, borane dimethyl sulfide is used as a reducing agent, the reaction is carried out for 8-15 hours at room temperature, then methanol is used as a quenching agent, and column chromatography is carried out to obtain the 2-fluoro-3-bromo-benzylamine. The synthesis method of the 2-fluoro-3-bromo-benzylamine avoids the use of gas reactants, an azide reagent and a metal catalyst, has low production cost, high product yield and purity and simple operation, and is suitable for industrial production.
The technical solutions of the present invention are further described and illustrated below by specific examples, it should be understood that the specific examples described herein are only for assisting understanding of the present invention, and are not intended to limit the present invention specifically. The raw materials used in the examples of the present invention are those commonly used in the art, and the methods used in the examples are those conventional in the art, unless otherwise specified.
Example 1
The 2-fluoro-3-bromo-benzylamine of this example was synthesized by the following steps:
dissolving 2.37g of 2-fluoro-3-bromoxynil in 20ml of tetrahydrofuran to form a 2-fluoro-3-bromoxynil solution, reducing the temperature of the 2-fluoro-3-bromoxynil solution to 0 ℃, filling nitrogen for protection, and then slowly dropwise adding 8.9ml of 2mol/L BH 3 .Me 2 S, after the dripping is finished, keeping the temperature of 0 ℃, stirring for 30min, and then continuously reacting for 12h at room temperature; then slowly dripping methanol into the reaction system to quench the reaction until no hydrogen is released; the solvent was evaporated under reduced pressure, the concentrate was dissolved in 20ml of methanol, refluxed and stirred for 3 hours, the boride was completely quenched, the solvent was removed again under reduced pressure, and the concentrate was eluted with an aluminum peroxide column and ethyl acetate to give 2.32g of 2-fluoro-3-bromo-benzylamine as a colorless oil with a yield of 95.7%.
1 H NMR(300MHz,D 2 O) δ 4.10 (s, 2H), 7.01 (t, J =7.8hz, 1h), 7.27 (t, J =7.2hz, 1h), 7.55 (t, J =7.5hz, 1h); purity (99.7%, HPLC).
Yield = (mass of colorless oily substance actually obtained ×. 2-fluoro-3-bromo-benzylamine purity)/mass of 2-fluoro-3-bromo-benzylamine theoretically obtained
Example 2
Dissolving 4g of 2-fluoro-3-bromoxynil in 20ml of dichloromethane to form a 2-fluoro-3-bromoxynil solution, reducing the temperature of the 2-fluoro-3-bromoxynil solution to-2 ℃, introducing nitrogen for protection, and then slowly dropwise adding 18ml of 2mol/L BH 3 .Me 2 S methylene dichloride solutionAfter the dropwise addition, keeping the temperature of-2 ℃, stirring for 40min, and then continuously reacting for 11h at room temperature; then slowly dripping methanol into the reaction system to quench the reaction until no hydrogen is discharged; the solvent was evaporated under reduced pressure, the concentrate was dissolved in 40ml of methanol, refluxed and stirred for 4h, the boride was quenched completely, the solvent was removed again under reduced pressure, and the concentrate was eluted through an alumina column chromatography with ethyl acetate to give 3.87g of colorless oily 2-fluoro-3-bromo-benzylamine in 94.5% yield and purity (99.6%, HPLC).
Example 3
6g of 2-fluoro-3-bromoxynil is dissolved in 20ml of tetrahydrofuran to form a 2-fluoro-3-bromoxynil solution, the temperature of the 2-fluoro-3-bromoxynil solution is reduced to 2 ℃, argon gas is filled for protection, and then 12ml of 5mol/L BH is slowly dripped 3 .Me 2 S tetrahydrofuran solution, after the dripping is finished, keeping the temperature of 2 ℃, stirring for 60min, and then continuously reacting for 10h at room temperature; then slowly dripping methanol into the reaction system to quench the reaction until no hydrogen is released; the solvent was evaporated under reduced pressure, the concentrate was dissolved in 60ml of methanol, refluxed and stirred for 5h, the boride was completely quenched, the solvent was removed again under reduced pressure, and the concentrate was eluted through an alumina column chromatography and ethyl acetate to give 5.92g of colorless oily 2-fluoro-3-bromo-benzylamine in 96.2% yield and purity (99.4%, HPLC).
Example 4
Dissolving 2g 2-fluoro-3-bromoxynil in 20ml tetrahydrofuran to form 2-fluoro-3-bromoxynil solution, reducing the temperature of the 2-fluoro-3-bromoxynil solution to 1 ℃, filling argon for protection, and then slowly dropwise adding 13ml 1mol/L BH 3 .Me 2 S tetrahydrofuran solution, after the dripping is finished, keeping the temperature at 1 ℃, stirring for 50min, and then continuously reacting for 11h at room temperature; then slowly dripping methanol into the reaction system to quench the reaction until no hydrogen is discharged; the solvent was evaporated under reduced pressure, the concentrate was dissolved in 30ml of methanol, refluxed and stirred for 5h, the boride was completely quenched, the solvent was removed again under reduced pressure, and the concentrate was eluted with an aluminum peroxide column and ethyl acetate to give 1.91g of 2-fluoro-3-bromo-benzylamine as a colorless oil in 93.2% yield and purity (99.5%, HPLC).
Comparative example 1
Comparative example 1 differs from example 1 in that the reducing agent BH is used 3 THF tetrahydrofuran solution in place of BH 3 .Me 2 S tetrahydrofuran solution, the rest is the same as example 1. The yield of the obtained 2-fluoro-3-bromo-benzylamine was 90.9% with purity (99.3%, HPLC).
Comparative example 2
Comparative example 2 differs from example 1 in that BH is added dropwise 3 .Me 2 And (3) keeping the temperature of the tetrahydrofuran solution at 0 ℃, stirring the tetrahydrofuran solution for 30min, then heating the tetrahydrofuran solution to 65 ℃, and continuing to react for 1h, wherein the rest is the same as that of the example 1. The yield of the obtained 2-fluoro-3-bromo-benzylamine was 92.8% with purity (99.2%, HPLC).
Comparative example 3
Comparative example 3 differs from example 1 in that BH is added dropwise 3 .Me 2 And (3) keeping the temperature of the tetrahydrofuran solution at 0 ℃, stirring the solution for 30min, then heating the solution to 65 ℃, and continuing to react for 2h, wherein the rest is the same as the example 1. The yield of 2-fluoro-3-bromo-benzylamine obtained was 92.2% purity (99.4%, HPLC).
The present invention employs BH 3 .Me 2 S as reducing agent, with respect to the reducing agent BH 3 THF has better yield. Comparative example 2 and comparative example 3, which employ a high temperature reaction, although the reaction time can be shortened, the yield of 2-fluoro-3-bromo-benzylamine is significantly reduced with respect to 95.7% of example 1.
The specific embodiments described herein are merely illustrative of the spirit of the invention and do not limit the scope of the invention. Various modifications or additions may be made to the described embodiments or alternatives may be employed by those skilled in the art without departing from the spirit or ambit of the invention as defined in the appended claims.
Claims (7)
1. A method of synthesizing 2-fluoro-3-bromo-benzylamine, comprising the steps of:
dissolving 2-fluoro-3-bromoxynil in an organic solvent to form a 2-fluoro-3-bromoxynil solution, and dropwise adding BH into the 2-fluoro-3-bromoxynil solution 3 .Me 2 Reacting the S solution, and then dropwise adding methanol to quench the reaction until no hydrogen is released; concentrating the reactant, adding methanol for dissolving, refluxing and stirring, removingRemoving solvent, passing the concentrate through chromatographic column, and eluting to obtain 2-fluoro-3-bromo-benzylamine;
dropwise addition of BH 3 .Me 2 Before the solution S, reducing the temperature of the 2-fluoro-3-bromoxynil solution to-5 to 5 ℃, and filling inert gas for protection;
adding BH dropwise into 2-fluoro-3-bromoxynil solution 3 .Me 2 And (S) keeping the temperature of the solution, stirring for 20 to 60min, and then reacting for 8 to 15h at room temperature.
2. The method for synthesizing 2-fluoro-3-bromo-benzylamine according to claim 1, wherein the concentration of 2-fluoro-3-bromoxynil in the 2-fluoro-3-bromoxynil solution is 0.05 to 0.5g/mL.
3. The method of claim 1, wherein BH is incorporated into the synthesis of 2-fluoro-3-bromo-benzylamine 3 .Me 2 S solution is BH 3 .Me 2 S is formed by dissolving S in an organic solvent, BH 3 .Me 2 The concentration of S is 1 to 5mol/L.
4. A process for the synthesis of 2-fluoro-3-bromo-benzylamine according to claim 1 or 3, characterized in that the organic solvent is one or both of dichloromethane and tetrahydrofuran.
5. The method for synthesizing 2-fluoro-3-bromo-benzylamine according to claim 1 or 3, characterized in that 2-fluoro-3-bromoxynil is reacted with BH 3 .Me 2 The molar ratio of S is 1: (1.2 to 2.2).
6. The method of synthesizing 2-fluoro-3-bromo-benzylamine according to claim 1, wherein the chromatography column is an alumina column and the eluent is ethyl acetate.
7. The process for the synthesis of 2-fluoro-3-bromo-benzylamine according to claim 1, characterized in that the yield of 2-fluoro-3-bromo-benzylamine is 93% or more and the purity is 99% or more.
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