Method for preparing 2-bromo-5-chlorobenzaldehyde

Abstract

The invention discloses a method for preparing 2-bromo-5-chlorobenzaldehyde. The method is characterized by comprising the following steps: a, controlling the system temperature to be less than or equal to 10 DEG C, and sequentially and slowly dropwise adding 3-chlorobenzaldehyde and an iodine-containing catalyst in an inorganic strong-acid solvent; b, controlling the system temperature to be lessthan or equal to 15 DEG C, and adding N-bromosuccinimide NBS for multiple times in batches; and c, insulating to react for 2-10 hours, heating to 25-55 DEG C to keep on reacting for 1-6 hours, and performing post-treatment to obtain a solid product. The method has the advantages of one-step reaction, 90% high yield, simple operation, low cost, easily available raw materials, environmental friendliness and little pollution, and is suitable for the requirement for large-scale industrial production since only acid liquid is contained in waste liquid and can be neutralized in alkali liquor.

Description

technical field

[0001] The invention relates to the field of drug synthesis, in particular to a preparation method of 2-bromo-5-chlorobenzaldehyde. Background technique

[0002] 2-bromo-5-chlorobenzaldehyde (compound B), has the following structure:

[0003]

[0004] 2-Bromo-5-chlorobenzaldehyde is an important pharmaceutical intermediate, which can be used in the synthesis of various drugs. For the synthetic method of this compound, many articles of literature have reported its synthetic method at present, and general preparation method comprises the following steps (Scheme1):

[0005]

[0006] Use raw material C (2-bromobenzimide) to carry out simple chlorination in NCS (N-chlorosuccinimide) and sulfuric acid (≧98%) system to obtain 2-bromo-5-chlorobenzylformic acid; then 2-bromobenzimide -5-chlorobenzyl formic acid obtains compound D (2-bromo-5-chlorobenzylmethanol) by sodium borohydride and sulfuric acid (≧98%) system reduction; Finally 2-bromo-5-chlorobenzylmeth...

Examples

Embodiment 1

[0035] Put concentrated sulfuric acid (mass fraction 98%, 150mL) into the reaction kettle and stir to lower the temperature, control the temperature of the system to ≤10°C, slowly add compound A liquid (3-chlorobenzaldehyde, 0.5mol) dropwise, after the addition is complete, add an appropriate amount of catalyst I 2 (0.236-2.36mmol, the present embodiment is 30mg), add 3-chlorobenzaldehyde and catalyst I 2 When there is a relatively obvious exothermic phenomenon, it is necessary to control the reaction temperature of the system to ≤10°C;

[0036] System temperature control ≤ 15°C, add NBS (N-bromosuccinimide, 0.5mol) in batches for 5-10 times;

[0037] Insulate and react for 2 hours, slowly rise to 25°C, and then stir and react for 1 hour. GC detects that the content of 3-chlorobenzaldehyde in the raw material is ≤1%, and the reaction solution is post-processed and purified to obtain 98 g of needle-like off-white solid Compound B with a purity of 98.0%. Yield 90.1%.

Embodiment 2

[0039] Put concentrated sulfuric acid (mass fraction 98%, 100mL) into the reaction kettle and stir to lower the temperature, control the temperature of the system to ≤10°C, slowly add compound A liquid (3-chlorobenzaldehyde, 0.5mol) dropwise, after the addition is complete, add an appropriate amount of catalyst I 2 (0.236-2.36mmol, the present embodiment is 31.8mg), add 3-chlorobenzaldehyde and catalyst I 2 When there is a relatively obvious exothermic phenomenon, it is necessary to control the reaction temperature of the system to ≤10°C;

[0040] System temperature control ≤ 15°C, add NBS (N-bromosuccinimide, 0.5mol) in batches for 5-10 times;

[0041] Insulate and react for 2 hours, slowly raise to 25°C, and then stir for 1 hour. GC detects that the content of 3-chlorobenzaldehyde in the raw material is ≤1%, and the reaction solution is post-processed and purified to obtain 97.9 g of needle-like off-white solid compound B with a purity of 97.5%. , yield 90.0%.

Embodiment 3

[0043] Put concentrated sulfuric acid (98% mass fraction, 80mL) into the reaction kettle and stir to lower the temperature, control the temperature of the system to ≤10°C, slowly add compound A liquid (3-chlorobenzaldehyde, 0.5mol) dropwise, after the addition is complete, add an appropriate amount of catalyst I 2 (0.236-2.36mmol, the present embodiment is 63.5mg), add 3-chlorobenzaldehyde and catalyst I 2 When there is a relatively obvious exothermic phenomenon, it is necessary to control the reaction temperature of the system to ≤10°C;

[0044] System temperature control ≤ 15°C, add NBS (N-bromosuccinimide, 0.55mol) in batches for 5-10 times;

[0045] Insulated for 3 hours, slowly raised to 28°C, and then stirred for 4 hours. GC detected that the content of 3-chlorobenzaldehyde in the raw material was ≤1%, and the reaction solution was purified by post-processing to obtain 98.5 g of needle-like off-white solid compound B with a purity of 98%. , yield 90.6%.

technical field

[0001] The invention relates to the field of drug synthesis, in particular to a preparation method of 2-bromo-5-chlorobenzaldehyde. Background technique

[0002] 2-bromo-5-chlorobenzaldehyde (compound B), has the following structure:

[0003]

[0004] 2-Bromo-5-chlorobenzaldehyde is an important pharmaceutical intermediate, which can be used in the synthesis of various drugs. For the synthetic method of this compound, many articles of literature have reported its synthetic method at present, and general preparation method comprises the following steps (Scheme1):

[0005]

[0006] Use raw material C (2-bromobenzimide) to carry out simple chlorination in NCS (N-chlorosuccinimide) and sulfuric acid (≧98%) system to obtain 2-bromo-5-chlorobenzylformic acid; then 2-bromobenzimide -5-chlorobenzyl formic acid obtains compound D (2-bromo-5-chlorobenzylmethanol) by sodium borohydride and sulfuric acid (≧98%) system reduction; Finally 2-bromo-5-chlorobenzylmeth...

Examples

Embodiment 1

[0035] Put concentrated sulfuric acid (mass fraction 98%, 150mL) into the reaction kettle and stir to lower the temperature, control the temperature of the system to ≤10°C, slowly add compound A liquid (3-chlorobenzaldehyde, 0.5mol) dropwise, after the addition is complete, add an appropriate amount of catalyst I 2 (0.236-2.36mmol, the present embodiment is 30mg), add 3-chlorobenzaldehyde and catalyst I 2 When there is a relatively obvious exothermic phenomenon, it is necessary to control the reaction temperature of the system to ≤10°C;

[0036] System temperature control ≤ 15°C, add NBS (N-bromosuccinimide, 0.5mol) in batches for 5-10 times;

[0037] Insulate and react for 2 hours, slowly rise to 25°C, and then stir and react for 1 hour. GC detects that the content of 3-chlorobenzaldehyde in the raw material is ≤1%, and the reaction solution is post-processed and purified to obtain 98 g of needle-like off-white solid Compound B with a purity of 98.0%. Yield 90.1%.

Embodiment 2

[0039] Put concentrated sulfuric acid (mass fraction 98%, 100mL) into the reaction kettle and stir to lower the temperature, control the temperature of the system to ≤10°C, slowly add compound A liquid (3-chlorobenzaldehyde, 0.5mol) dropwise, after the addition is complete, add an appropriate amount of catalyst I 2 (0.236-2.36mmol, the present embodiment is 31.8mg), add 3-chlorobenzaldehyde and catalyst I 2 When there is a relatively obvious exothermic phenomenon, it is necessary to control the reaction temperature of the system to ≤10°C;

[0040] System temperature control ≤ 15°C, add NBS (N-bromosuccinimide, 0.5mol) in batches for 5-10 times;

[0041] Insulate and react for 2 hours, slowly raise to 25°C, and then stir for 1 hour. GC detects that the content of 3-chlorobenzaldehyde in the raw material is ≤1%, and the reaction solution is post-processed and purified to obtain 97.9 g of needle-like off-white solid compound B with a purity of 97.5%. , yield 90.0%.

Embodiment 3

[0043] Put concentrated sulfuric acid (98% mass fraction, 80mL) into the reaction kettle and stir to lower the temperature, control the temperature of the system to ≤10°C, slowly add compound A liquid (3-chlorobenzaldehyde, 0.5mol) dropwise, after the addition is complete, add an appropriate amount of catalyst I 2 (0.236-2.36mmol, the present embodiment is 63.5mg), add 3-chlorobenzaldehyde and catalyst I 2 When there is a relatively obvious exothermic phenomenon, it is necessary to control the reaction temperature of the system to ≤10°C;

[0044] System temperature control ≤ 15°C, add NBS (N-bromosuccinimide, 0.55mol) in batches for 5-10 times;

[0045] Insulated for 3 hours, slowly raised to 28°C, and then stirred for 4 hours. GC detected that the content of 3-chlorobenzaldehyde in the raw material was ≤1%, and the reaction solution was purified by post-processing to obtain 98.5 g of needle-like off-white solid compound B with a purity of 98%. , yield 90.6%.

Images