Synthesizing method of 3,5-dibromo-2-aminobenzaldehyde

Abstract

The invention discloses a synthesizing method of 3,5-dibromo-2-aminobenzaldehyde which comprises the following steps of adding methyl 2-aminobenzoate and tribromide-N-methyl-N-butylimidazole in a reactor, agitating and heating the mixture until the mixture is dissolved, and then adding an intermediate 1, keeping the temperature at 60+ / -2 DEG C, agitating the mixture for 2.5-3.5 hours, and then extracting, drying and condensing the mixture, obtaining an intermediate 2; adding absolute ethyl alcohol in the intermediate 2, cooling the mixture to 0 DEG C, and then adding NaBH3, controlling the temperature of the mixture no more than 5 DEG C, after finishing adding, cooling the mixture to 0 DEG C and performing an insulation reaction for 8-10 hours; after detecting the reaction is ended, slowly adding water in the reactant, agitating the reactant for 0.5-1 hour, filtering the reactant, condensing the filtrate to a dry state, heating and dissolving the filtrate with ethyl acetate, decoloring, filtering and cooling the mixture to separate out crystal, obtaining 3,5-dibromo-2-aminobenzaldehyde. The synthesizing method of the 3,5-dibromo-2-aminobenzaldehyde provided by the invention has the advantages of simple process and high yield, conditions are easy to control and industrialization production is easy to realize.

Description

technical field

[0001] The invention relates to the field of synthesis of pharmaceutical intermediates, in particular to a synthesis method of 3,5-dibromo-2-aminobenzaldehyde. Background technique

[0002] 3,5-Dibromo-2-aminobenzaldehyde is a widely used pharmaceutical intermediate with a large market usage and broad prospects. However, in the prior art, the synthesis of 3,5-dibromo-2-aminobenzaldehyde has the disadvantages of complex process, many steps, low yield, generally about 40%, and not easy to realize industrialized production. Contents of the invention

[0003] The present invention is just to overcome the above-mentioned deficiencies, and the technical problem to be solved is to provide a kind of synthetic method of 3,5-dibromo-2-aminobenzaldehyde which has simple process, high yield and can realize industrialized production.

[0004] In order to solve the problems of the technologies described above, the technical scheme adopted in the present invention is as ...

Examples

Embodiment 1

[0015] Add 15g of methyl 2-aminobenzoate (SM1) into a 500mL three-necked flask, then add 50mL of tribromo-N-methyl-N-n-butylimidazole, heat to 60°C while stirring to dissolve, then add 19g of intermediate Compound 1 (tribromo-N-methyl-N-n-butylimidazole), keep stirring at 60°C for 3h, TLC detects that the reaction is complete; then add 150mL*3 of diethyl ether, stir and extract, combine the diethyl ether layer, and use anhydrous Na 2 SO 4 Dry, filter out Na 2 SO 4 , the ether layer was concentrated to dryness under reduced pressure to obtain 25 g of intermediate 2 (5,6-dibromo-2-amino-benzoic acid methyl ester), with a yield of 81.6%.

[0016] Add 25g of intermediate 2 (5,6-dibromo-2-amino-benzoic acid methyl ester) and 250mL of anhydrous methanol into a 500mL three-necked flask, cool to 0°C, and then slowly add NaBH 3 9g, control the temperature not to exceed 5°C; after the addition is complete, keep the reaction at 0°C for 8 hours, and TLC detects that the reaction is co...

Embodiment 2

[0018] Add 24g of methyl 2-aminobenzoate (SM1) into a 500mL three-necked flask, then add 64mL of tribromo-N-methyl-N-n-butylimidazole, heat to 60°C while stirring to dissolve, then add 25g of intermediate Compound 1 (tribromo-N-methyl-N-n-butylimidazole), keep stirring at 60°C for 3h, TLC detects that the reaction is complete; then add 150mL*3 of diethyl ether, stir and extract, combine the diethyl ether layer, and use anhydrous Na 2 SO 4 Dry, filter out Na 2 SO 4 , the ether layer was concentrated to dryness under reduced pressure to obtain 38 g of intermediate 2 (5,6-dibromo-2-amino-benzoic acid methyl ester), with a yield of 77%.

[0019] Add 33g of intermediate 2 (5,6-dibromo-2-amino-benzoic acid methyl ester) and 250mL of anhydrous methanol to a 500mL three-necked flask, cool to 0°C, then slowly add NaBH316.6g, control the temperature not to exceed 5°C; after the addition, keep warm at 0°C for 8 hours, and TLC detects that the reaction is complete; then slowly add 10mL...

Embodiment 3

[0021] Add 42g of methyl 2-aminobenzoate (SM1) into a 500mL three-necked flask, then add 144mL of tribromo-N-methyl-N-n-butylimidazole, heat to 60°C while stirring to dissolve, then add 60g of intermediate Compound 1 (tribromo-N-methyl-N-n-butylimidazole), keep stirring at 60°C for 3h, TLC detects that the reaction is complete; then add 150mL*3 of diethyl ether, stir and extract, combine the diethyl ether layer, and use anhydrous Na 2 SO 4 Dry, filter out Na 2 SO 4 , the ether layer was concentrated to dryness under reduced pressure to obtain 69 g of intermediate 2 (5,6-dibromo-2-amino-benzoic acid methyl ester), with a yield of 75%.

[0022] Add 69g of intermediate 2 (5,6-dibromo-2-amino-benzoic acid methyl ester) and 250mL of anhydrous methanol into a 500mL three-necked flask, cool to 0°C, and then slowly add NaBH 3 41.4g, control the temperature not to exceed 5°C; after the addition, keep the temperature at 0°C for 8 hours, and TLC detects that the reaction is complete;...

technical field

[0001] The invention relates to the field of synthesis of pharmaceutical intermediates, in particular to a synthesis method of 3,5-dibromo-2-aminobenzaldehyde. Background technique

[0002] 3,5-Dibromo-2-aminobenzaldehyde is a widely used pharmaceutical intermediate with a large market usage and broad prospects. However, in the prior art, the synthesis of 3,5-dibromo-2-aminobenzaldehyde has the disadvantages of complex process, many steps, low yield, generally about 40%, and not easy to realize industrialized production. Contents of the invention

[0003] The present invention is just to overcome the above-mentioned deficiencies, and the technical problem to be solved is to provide a kind of synthetic method of 3,5-dibromo-2-aminobenzaldehyde which has simple process, high yield and can realize industrialized production.

[0004] In order to solve the problems of the technologies described above, the technical scheme adopted in the present invention is as ...

Examples

Embodiment 1

[0015] Add 15g of methyl 2-aminobenzoate (SM1) into a 500mL three-necked flask, then add 50mL of tribromo-N-methyl-N-n-butylimidazole, heat to 60°C while stirring to dissolve, then add 19g of intermediate Compound 1 (tribromo-N-methyl-N-n-butylimidazole), keep stirring at 60°C for 3h, TLC detects that the reaction is complete; then add 150mL*3 of diethyl ether, stir and extract, combine the diethyl ether layer, and use anhydrous Na 2 SO 4 Dry, filter out Na 2 SO 4 , the ether layer was concentrated to dryness under reduced pressure to obtain 25 g of intermediate 2 (5,6-dibromo-2-amino-benzoic acid methyl ester), with a yield of 81.6%.

[0016] Add 25g of intermediate 2 (5,6-dibromo-2-amino-benzoic acid methyl ester) and 250mL of anhydrous methanol into a 500mL three-necked flask, cool to 0°C, and then slowly add NaBH 3 9g, control the temperature not to exceed 5°C; after the addition is complete, keep the reaction at 0°C for 8 hours, and TLC detects that the reaction is co...

Embodiment 2

[0018] Add 24g of methyl 2-aminobenzoate (SM1) into a 500mL three-necked flask, then add 64mL of tribromo-N-methyl-N-n-butylimidazole, heat to 60°C while stirring to dissolve, then add 25g of intermediate Compound 1 (tribromo-N-methyl-N-n-butylimidazole), keep stirring at 60°C for 3h, TLC detects that the reaction is complete; then add 150mL*3 of diethyl ether, stir and extract, combine the diethyl ether layer, and use anhydrous Na 2 SO 4 Dry, filter out Na 2 SO 4 , the ether layer was concentrated to dryness under reduced pressure to obtain 38 g of intermediate 2 (5,6-dibromo-2-amino-benzoic acid methyl ester), with a yield of 77%.

[0019] Add 33g of intermediate 2 (5,6-dibromo-2-amino-benzoic acid methyl ester) and 250mL of anhydrous methanol to a 500mL three-necked flask, cool to 0°C, then slowly add NaBH316.6g, control the temperature not to exceed 5°C; after the addition, keep warm at 0°C for 8 hours, and TLC detects that the reaction is complete; then slowly add 10mL...

Embodiment 3

[0021] Add 42g of methyl 2-aminobenzoate (SM1) into a 500mL three-necked flask, then add 144mL of tribromo-N-methyl-N-n-butylimidazole, heat to 60°C while stirring to dissolve, then add 60g of intermediate Compound 1 (tribromo-N-methyl-N-n-butylimidazole), keep stirring at 60°C for 3h, TLC detects that the reaction is complete; then add 150mL*3 of diethyl ether, stir and extract, combine the diethyl ether layer, and use anhydrous Na 2 SO 4 Dry, filter out Na 2 SO 4 , the ether layer was concentrated to dryness under reduced pressure to obtain 69 g of intermediate 2 (5,6-dibromo-2-amino-benzoic acid methyl ester), with a yield of 75%.

[0022] Add 69g of intermediate 2 (5,6-dibromo-2-amino-benzoic acid methyl ester) and 250mL of anhydrous methanol into a 500mL three-necked flask, cool to 0°C, and then slowly add NaBH 3 41.4g, control the temperature not to exceed 5°C; after the addition, keep the temperature at 0°C for 8 hours, and TLC detects that the reaction is complete;...