Synthesis method of 2-cyano-5-fluorobenzyl bromide

Abstract

The invention relates to the technical field of organic synthesis, and discloses a synthesis method of 2-cyano-5-fluorobenzyl bromide, which comprises the following steps: mixing a compound I with sulfuric acid, adding potassium bromate, reacting, adding water, layering, distilling and purifying to obtain a compound II; mixing the compound II, cuprous cyanide and DMF, carrying out reflux reaction under stirring, cooling, adding water, extracting and filtering with ethyl acetate, layering, washing with water, desolventizing, and recrystallizing and purifying with methanol to obtain a compound III; mixing the compound III, tetrahydrofuran, water and methanol, dropwise adding a mixed solution of potassium borohydride, water and methanol while stirring, adding water, layering, extracting, desolventizing, cooling to separate out a solid, and filtering to obtain a compound IV; and mixing the compound IV, DCM and DMF, dropwise adding boron tribromide in batches while stirring, adding water, layering, desolventizing, cooling to separate out a solid, and filtering to obtain the 2-cyano-5-fluorobenzyl bromide. The method is reasonable in design route, short in synthesis route, high in safety coefficient and suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing 2-cyano-5-fluorobenzyl bromide. Background Art

[0002] Trelagliptin is a DPP-4 inhibitor, an oral hypoglycemic drug that inhibits DPP-4 and controls blood sugar levels. Incretin is a hormone secreted by the intestine that stimulates insulin secretion, thereby lowering blood sugar levels. However, the hormone's effect in the body is short-lived and is broken down by the DPP-4 enzyme after a period of time. Trelagliptin can inhibit the activity of the DPP-4 enzyme, slowing the breakdown of incretins and thereby increasing the activity of incretins to achieve the purpose of controlling blood sugar. It can also inhibit the inactivation of incretins when blood sugar is high, but generally does not exert an inhibitory effect when blood sugar reaches normal or low levels.

[0003] 2-Cyano-5-fluorobenzyl bromide can be used as a pharmaceutical synthesis intermediate. In the field of pharmaceutical chemical synthesis, it is an important intermediate in the synthesis of the drug molecule trelagliptin. Currently, the synthesis route of 2-cyano-5-fluorobenzyl bromide reported in existing literature is as follows: 2-methyl-4-fluorobromobenzene and 4-methyl-2-fluorobromobenzene are prepared by bromination of m-fluorotoluene with bromine. The two isomers are separated by distillation to obtain 2-methyl-4-fluorobromobenzene; 2-methyl-4-fluorobromobenzene is then cyanided with DMF and cuprous cyanide to obtain 2-methyl-4-fluorobenzonitrile; 2-methyl-4-fluorobenzonitrile is then brominated with carbon tetrachloride, p-toluenesulfonic acid, and N-bromosuccinimide (NBS), and then purified with petroleum ether and ethyl acetate to obtain 2-cyano-5-fluorobenzyl bromide.

[0004] This synthetic route is long, and the boiling points of 2-methyl-4-fluorobromobenzene and 4-methyl-2-fluorobromobenzene prepared by bromination of m-fluorotoluene with bromine are similar, the distillation separation efficiency is low, and industrial scale-up production is difficult. Summary of the Invention

[0005] Purpose of the invention: To address the problems existing in the prior art, the present invention provides a method for synthesizing 2-cyano-5-fluorobenzyl bromide. The method has a reasonable design route, mild reaction conditions in each step, and a high safety factor.

[0006] Technical solution: The present invention provides a method for synthesizing 2-cyano-5-fluorobenzyl bromide. The synthetic route is as follows: .

[0007] Furthermore, the specific steps are as follows: S1. Compound Ⅰ was mixed with sulfuric acid, potassium bromate was added in batches under stirring, water was added after the reaction, the layers were separated, and the mixture was purified by distillation to obtain compound Ⅱ; S2. Compound II, cuprous cyanide, and N,N-dimethylformamide were mixed and refluxed under stirring. After the reaction, the temperature was lowered and water was added. The mixture was extracted with ethyl acetate, filtered, separated, washed with water, and desolventized. The mixture was then recrystallized from methanol to obtain compound III. S3. Compound III, tetrahydrofuran, water and methanol were mixed and a mixed solution of potassium borohydride, water and methanol was added dropwise under stirring. After the reaction, water was added, the layers were separated, extracted, desolvated, cooled and the precipitated solid was filtered to obtain compound IV. S4. Compound IV, dichloromethane, and N,N-dimethylformamide were mixed, and boron tribromide was added dropwise in batches under stirring. After the reaction, water was added. The mixture was separated, desolventized, and cooled to precipitate a solid, which was then filtered to obtain compound V, 2-cyano-5-fluorobenzyl bromide.

[0008] Furthermore, in S1, the molar ratio of compound I, sulfuric acid and potassium bromate is 1:15:1.05-2; In S1, the specific conditions of the reaction are: reaction temperature is 10-40°C, and reaction time is 3-4h.

[0009] Furthermore, in S1, the specific conditions of the distillation are: vacuum degree -0.098 MPa, temperature 110-120°C.

[0010] Furthermore, in S2, the molar ratio of compound II, N,N-dimethylformamide and cuprous cyanide is 1:5:1.2-2; In S2, the specific conditions of the reaction are: reaction temperature 130-135° C., reaction time 2-4 h.

[0011] Furthermore, in S2, the specific operation of cooling and adding water is: adding 3 times the volume of water after cooling to 20-30°C.

[0012] Furthermore, in S3, the molar ratio of compound III, tetrahydrofuran, water, methanol and potassium borohydride is 1:5:20:10:1.4-2; In S3, the specific conditions of the reaction are: reaction temperature is 20-30°C, and reaction time is 3-5h.

[0013] Preferably, in S3, the temperature is lowered to 5-10°C to precipitate solid.

[0014] Furthermore, in S4, the molar ratio of compound IV, dichloromethane, N,N-dimethylformamide and phosphorus tribromide is 1:6:0.05:1.1-2.

[0015] Preferably, in S3, the temperature is lowered to 5-10°C to precipitate solid.

[0016] Beneficial effects: Compared with the prior art, the present invention has the following specific beneficial effects: The present invention provides a rationally designed route for synthesizing 2-cyano-5-fluorobenzyl bromide with high purity. The synthetic route designed by the present invention is short, has a high conversion rate, generates no significant by-products, and offers low production costs while maintaining mild reaction conditions in each step. The synthetic route provided by the present invention has a high safety factor and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 This is the mass spectrum of 2-cyano-5-fluorobenzyl bromide obtained in the present invention; Figure 2 is the hydrogen nuclear magnetic resonance spectrum of 2-cyano-5-fluorobenzyl bromide obtained in the present invention; Figure 3 This is a purity detection chart of 2-cyano-5-fluorobenzyl bromide obtained in the present invention. DETAILED DESCRIPTION

[0017] The present invention is described in detail below with reference to the embodiments.

[0018] Implementation method 1: This embodiment provides a method for synthesizing 2-cyano-5-fluorobenzyl bromide, and the specific synthetic route is as follows: .

[0019] The specific process steps are as follows: S1. Synthesis: Add 1470 g (15 mol) of 80% sulfuric acid to a reaction flask with stirring. Add 154 g (1.0 mol) of methyl m-fluorobenzoate. Heat externally and add 175 g (1.05 mol) of potassium bromate in portions. Control the temperature between 10-20°C throughout the addition process. Add the mixture over approximately 3 hours. Continue stirring at this temperature for 30 minutes. Add 2 times the volume of water, allow the mixture to stand and separate into layers. Wash the organic layer with water to a neutral pH of 7. Isolate 230 g of the crude product (0.987 mol, 96% methyl 2-bromo-5-fluorobenzoate).

[0020] Refining: The crude product was distilled under vacuum degree -0.098MPa and temperature 110-120℃ to obtain 210g of product (content 98%, yield 90%).

[0021] S2. Synthesis: Place 365 g (6 mol) of N,N-dimethylformamide (DMF) into a reaction flask with stirring, add 233 g (1 mol) of methyl 2-fluoro-5-bromobenzoate, and then add 108 g (1.2 mol) of cuprous cyanide. Heat to 130-135°C and reflux to react for about 3 hours. After the reaction is complete, cool to 20°C and add 3 times the volume of water. Extract with ethyl acetate, filter, separate the layers, wash with pure water, and remove the ethyl acetate under reduced pressure to obtain 162 g of crude product (0.9 mol 96% methyl 2-cyano-5-bromo-5-benzoate).

[0022] Refining: Crude product: 80% methanol = 1:1 (mass ratio) recrystallization to obtain 140 g of the intermediate 2-cyano-5-bromo-5-benzoic acid methyl ester (content 98%, yield 77.7%).

[0023] S3. Synthesis: Add 360 g (5 mol) of tetrahydrofuran, 180 g (10 mol) of water, and 160 g (5 mol) of methanol to a reaction flask, start stirring, add 180 g (1.0 mol) of methyl 2-cyano-5-fluorobenzoate, control the temperature between 20-30°C, and begin to dropwise add a mixture of 76 g (1.4 mol) of potassium borohydride, 180 g (10 mol) of water, and 160 g (5 mol) of methanol. Control the temperature between 20-30°C throughout the process and add the mixture over about 3-4 hours. After the addition is complete, continue to stir while maintaining the temperature for 30 minutes. Add 2 times the volume of water, let stand to separate the layers, add 300 ml of ethyl acetate to the aqueous layer, extract the organic layers, combine the organic layers, remove 2 / 3 of the solvent, cool to 5-10°C, precipitate the solid, and filter to obtain 145 g of 2-cyano-5-fluorobenzyl alcohol (content 98%, yield 96%).

[0024] S4. Synthesis: Add 906 g (6 mol) of dichloromethane (DCM) to a reaction flask with stirring. Add 151 g (1.0 mol) of 2-cyano-5-fluorobenzyl alcohol and DMF (catalyst, 0.05 mol). Control the temperature between 20-30°C. Add 297 g (1.1 mol) of phosphorus tribromide dropwise. Control the temperature between 20-30°C throughout the process. Add the mixture over a period of about 3 hours. Continue stirring at this temperature for 30 minutes. Add 2 times the volume of water, allow the mixture to stand and separate into layers. Wash the organic layer twice with 2 times the volume of water until it is neutral. Remove 2 / 3 of the solvent from the organic layer, cool the temperature to 5-10°C, precipitate the solid, and filter to obtain 200 g of the finished product 2-cyano-5-fluorobenzyl bromide (content 98%, yield 93.4%).

[0025] Implementation 2: This embodiment is substantially the same as embodiment 1, except that the reaction temperature of the bromination reaction in embodiment S1 is increased from 10-20° C. to 30-40° C. The specific steps of embodiment S1 are as follows: S1. Synthesis: Add 1470 g (15 mol) of 80% sulfuric acid to a reaction flask with stirring. Add 154 g (1.0 mol) of methyl m-fluorobenzoate and heat to 30-40°C. Begin adding 175 g (1.05 mol) of potassium bromate in batches, maintaining the temperature between 30-40°C. Add the mixture over a period of approximately 3 hours. Continue stirring for 30 minutes, then add twice the volume of water. Allow the mixture to stand for stratification. Wash the organic layer with water until the pH is neutral (pH 7). Isolate the crude product (0.815 mol of 83% methyl 2-bromo-5-fluorobenzoate).

[0026] Refining: The crude product was distilled under vacuum degree -0.098MPa and temperature 110-120℃ to obtain 145g of product (content 98%, yield 62.2%), with a large amount of residue in the distillation kettle (by-products m-fluorobenzoic acid and 2-bromo-5-fluorobenzoic acid).

[0027] Compared with Implementation Example 1, the yield of the target product 2-bromo-5-fluorobenzoic acid methyl ester obtained by S1 in this implementation example is reduced. This is because the reaction temperature of S1 in this implementation example is increased, and the bromination reaction process is significantly accelerated. However, a side reaction also occurs at the same time. The side reaction is that a portion of the unbrominated methyl m-fluorobenzoate and a portion of the brominated methyl 2-bromo-5-fluorobenzoate are hydrolyzed to benzoic acid. This side reaction will significantly reduce the yield and purity of the target product.

[0028] In this embodiment, the final product 2-cyano-5-fluorobenzyl bromide was obtained in an amount of 92.6 g (content 98%, yield 61.3%). Apart from this, this embodiment is identical to Embodiment 1 and will not be described in detail here. Implementation 3:

[0029] This embodiment is substantially the same as embodiment 1, except that in embodiment S3, the amount of potassium borohydride added is increased to 2 mol. The specific steps of embodiment S3 are as follows: S3. Synthesis: Add 360g (5mol) of tetrahydrofuran, 180g (10mol) of water, and 160g (5mol) of methanol to a reaction flask. Start stirring and add 180g (1.0mol) of methyl 2-cyano-5-fluorobenzoate. Control the temperature between 20-30°C. Start adding a mixture of 108g (2.0mol) of potassium borohydride, 180g (10mol) of water, and 160g (5mol) of methanol dropwise. Control the temperature between 20-30°C throughout the process. The reaction mixture was added for about 1 hour. After the addition was completed, the mixture was stirred for 30 minutes at a temperature of 2 times the volume of water. The mixture was allowed to stand for stratification. 300 ml of ethyl acetate was added to the aqueous layer for extraction. The organic layers were combined and 2 / 3 of the solvent was removed. The mixture was cooled to 5-10 ° C to precipitate a solid which was filtered to obtain 103 g of 2-cyano-5-fluorobenzyl alcohol (content 98%, yield 68.2%). The aqueous layer was adjusted to pH = 3 with 31% hydrochloric acid to precipitate a solid which was filtered to obtain 45 g of a by-product (2-bromo-5-fluorobenzoic acid).

[0030] Compared with embodiment 1, the yield of the target product 2-cyano-5-fluorobenzyl alcohol obtained in S3 in this embodiment decreases. This is because the amount of potassium borohydride fed increases. As the amount of potassium borohydride increases, the pH value of the reaction system becomes more alkaline, and there are more side reactions, mainly methyl 2-bromo-5-fluorobenzoate is hydrolyzed to benzoic acid under alkaline conditions, thereby reducing the yield of the target product.

[0031] In this embodiment, the final product 2-cyano-5-fluorobenzyl bromide 103g (content 98%, yield 68.2%) was obtained. Apart from this, this embodiment is identical to Embodiment 1 and will not be described in detail here.

[0032] The above embodiments are intended only to illustrate the technical concepts and features of the present invention. Their purpose is to enable those skilled in the art to understand the contents of the present invention and implement them accordingly. They are not intended to limit the scope of protection of the present invention. Any equivalent changes or modifications made in accordance with the spirit of the present invention are intended to be covered by the scope of protection of the present invention.

Claims

1. A method for synthesizing 2-cyano-5-fluorobenzyl bromide, characterized in that: The synthetic route is as follows: 。 2. The method for synthesizing 2-cyano-5-fluorobenzyl bromide according to claim 1, wherein: The specific steps are as follows: S1. Compound Ⅰ was mixed with sulfuric acid, potassium bromate was added in batches under stirring, water was added after the reaction, the layers were separated, and the mixture was purified by distillation to obtain compound Ⅱ; S2. Compound II, cuprous cyanide, and N,N-dimethylformamide were mixed and refluxed under stirring. After the reaction, the temperature was lowered and water was added. The mixture was extracted with ethyl acetate, filtered, separated, washed with water, and desolventized. The mixture was then recrystallized from methanol to obtain compound III. S3. Compound III, tetrahydrofuran, water and methanol were mixed and a mixed solution of potassium borohydride, water and methanol was added dropwise under stirring. After the reaction, water was added, the layers were separated, extracted, desolvated, cooled and the precipitated solid was filtered to obtain compound IV. S4. Compound IV, dichloromethane, and N,N-dimethylformamide were mixed, and boron tribromide was added dropwise in batches under stirring. After the reaction, water was added. The mixture was separated, desolventized, and cooled to precipitate a solid, which was then filtered to obtain compound V, 2-cyano-5-fluorobenzyl bromide.

3. The method for synthesizing 2-cyano-5-fluorobenzyl bromide according to claim 2, characterized in that: In S1, the molar ratio of compound I, sulfuric acid and potassium bromate is 1:15:1.05-2; In S1, the specific conditions of the reaction are: reaction temperature is 10-40°C, and reaction time is 3-4h.

4. The method for synthesizing 2-cyano-5-fluorobenzyl bromide according to claim 2, wherein: In S1, the specific conditions of the distillation are: vacuum degree -0.098 MPa, temperature 110-120°C.

5. The method for synthesizing 2-cyano-5-fluorobenzyl bromide according to claim 2, wherein: In S2, the molar ratio of compound II, N,N-dimethylformamide and cuprous cyanide is 1:5:1.2-2; In S2, the specific conditions of the reaction are: reaction temperature 130-135° C., reaction time 2-4 h.

6. The method for synthesizing 2-cyano-5-fluorobenzyl bromide according to claim 2, characterized in that: In S2, the specific operation of cooling and adding water is: adding 3 times the volume of water after cooling to 20-30°C.

7. The method for synthesizing 2-cyano-5-fluorobenzyl bromide according to claim 2, characterized in that: In S3, the molar ratio of compound III, tetrahydrofuran, water, methanol and potassium borohydride is 1:5:20:10:1.4-2; In S3, the specific conditions of the reaction are: reaction temperature is 20-30°C, and reaction time is 3-5h.

8. The method for synthesizing 2-cyano-5-fluorobenzyl bromide according to claim 2, characterized in that: In S3, the temperature is lowered to 5-10°C to precipitate a solid.

9. The method for synthesizing 2-cyano-5-fluorobenzyl bromide according to claim 2, wherein: In S4, the molar ratio of compound IV, dichloromethane, N,N-dimethylformamide and phosphorus tribromide is 1:6:0.05:1.1-2.

10. The method for synthesizing 2-cyano-5-fluorobenzyl bromide according to claim 2, characterized in that: In S3, the temperature is lowered to 5-10°C to precipitate a solid.

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