Preparation method of 2-bromine-4-fluorobenzaldehyde

A technology of fluorobenzaldehyde and bromination reagent, applied in the field of preparation of 2-bromo-4-fluorobenzaldehyde, can solve the problem that 2-bromo-4-fluorobenzonitrile is expensive, has no commercial value, and cannot be scaled up and other problems, to achieve the effect of optimizing purification steps, good industrialization potential, production and application prospects, and reducing unit quality price

Inactive Publication Date: 2019-05-28
JIANGSU UNIV OF TECH
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0005] 2) Another synthetic strategy is the selective controlled reduction of 2-bromo-4-fluorobenzonitrile [AngewandteChemie, International Edition, 2017, 56(9), 2473-2477] (such as the following chemical formula), but this method uses DIBAL reduces the nitrile functional group at low temperature, and then hydrolyzes to obtain aldehyde. Due to the high activity of the intermediate aldehyde, it is easy to form a by-product of excessive reduction into alcohol, so the yield is not high, and it cannot be scaled up. The raw material 2-bromo-4-fluoro The price of benzonitrile is also relatively expensive, so it does not have commercial value

Method used

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  • Preparation method of 2-bromine-4-fluorobenzaldehyde
  • Preparation method of 2-bromine-4-fluorobenzaldehyde
  • Preparation method of 2-bromine-4-fluorobenzaldehyde

Examples

Experimental program
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Effect test

Embodiment 1

[0028] Add 100 mL of TFA / HO to a 250 mL two-neck flask 2 SO 4 Mixed solvent (volume ratio 5 / 1), down to 0 ° C, then add 12.4 grams (500 mmol) of 4-fluorobenzaldehyde, then rise to 50 ° C under stirring, add 14.3 grams (50 mmol) from the feeding port Dibromohydantoin solid, seal the feeding port after adding, keep the reaction system at 50°C and stir for 8 hours; open the feeding product, add 14.3 grams (50 mmol) of dibromohydantoin solid, keep stirring at 50°C for 48 hours . The reaction of the raw materials was complete, lowered to room temperature, the reaction solution was poured into 1L of ice water, the aqueous phase was extracted with n-hexane (100mL×3), the organic phase was combined, the organic phase was washed once with 20mL of saturated sodium bicarbonate solution, and 20mL of saturated chlorinated The sodium solution was washed once, and the n-hexane was removed by concentration under reduced pressure to obtain the crude product of 2-bromo-4-fluorobenzaldehyde. T...

Embodiment 2

[0035] Add 500 mL of TFA / HO to a 1 L three-necked flask 2 SO 4 Mix solvent (volume ratio 10 / 1), be down to 0 ℃, then add 62 grams (500 millimoles) 4-fluorobenzaldehyde, rise to 50 ℃ under stirring then, add 250 millimoles N-bromo For substituted succinimide solid, seal the feeding port after adding, keep the reaction system at 50°C and stir for 8 hours; open the feeding port, add 50 mmol N-bromosuccinimide solid, keep at 50°C Stir for 48 hours. After the reaction of the raw materials is complete, cool down to room temperature, slowly pour the reaction solution into 5 liters of ice water, extract the aqueous phase (500mL×3) with toluene, combine the organic phases, wash the organic phases with 100mL saturated sodium bicarbonate solution once, and wash with 100mL saturated sodium bicarbonate solution. The sodium chloride solution was washed once, the organic phase was concentrated under reduced pressure to remove toluene to obtain the crude product of 2-bromo-4-fluorobenzaldeh...

Embodiment 3

[0037] Into a 100 L reactor equipped with an electric stirrer unit was charged 50 L of TFA / H 2 SO 4Mixed solvent (volume ratio 5 / 1), down to 0 ° C, then add 6.24 kg (25 moles) of 4-fluorobenzaldehyde, then rise to 50 ° C under stirring, add 7.15 kg (25 moles) from the feeding port Dibromohydantoin solid, seal the feeding port after adding, keep the reaction system at 50°C and stir for 8 hours; open the feeding port, add 7.15 kg (50 mmol) of dibromohydantoin solid, keep stirring at 50°C for 48 hours . After the reaction of the raw materials is complete, cool down to room temperature, slowly pour the reaction solution into 500 liters of ice water, extract the aqueous phase (50L×3) with n-hexane, combine the organic phases, and wash the organic phases once with 10L saturated sodium bicarbonate solution, 10L The saturated sodium chloride solution was washed once, and the organic phase was concentrated under reduced pressure to remove n-hexane to obtain the crude product of 2-bro...

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Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of 2-bromine-4-fluorobenzaldehyde. The method comprises the following steps that (1)4-fluorobenzaldehyde is dissolved in an acid solution to be prepared into 0.1 to 100mol/L of 4-fluorobenzaldehyde acid solution; (2) the temperature of the solution is raised to 30 to 100 DEG C; bromination reagents are added while stirring is performed; stirring reaction is performed for 1 to 24h; (3) the bromination reagents are added again; stirring reaction is performed for 24 to 72h; (4) after the reaction is finished, reaction liquid is poured into ice water; (5) water phases are extracted by alkane solvents; organic phases are merged and are washed; pressure reduction concentration isperformed to remove organic solvents; 2-bromine-4-fluorobenzaldehyde crude products are obtained; the crude products are refined; the target product of 2-bromine-4-fluorobenzaldehyde is obtained. Theraw materials are cheap and can be easily obtained; the used bromination reagents are environment-friendly water treatment agents; the purification method of the target product is simple; the industrial production is facilitated.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a preparation method of 2-bromo-4-fluorobenzaldehyde. Background technique [0002] 2-Bromo-4-fluorobenzaldehyde is an important intermediate used in the synthesis of fluorine-containing drugs, and can be used as an important synthetic raw material for drugs such as prostaglandin D2 inhibitors [US 2004 / 0162323 Al, WO 02 / 22621 A2] ; or the synthetic raw material of benzylamine derivatives [ZL 97194737.6] for the treatment of depression. Therefore, its synthesis has very important practical value and industrial application prospect. [0003] For the synthesis of 2-bromo-4-fluorobenzaldehyde, there are two main synthetic strategies: 1) Oxidation of 2-bromo-4-fluorobenzyl alcohol [Document: Synthesis, 2013, 45(24), 3387-3391; Tetrahedron, 2015, 71(38), 6744-6748]. As reported patents [WO 02 / 22621 A2; US 2004 / 0162323 Al; US 2005 / 0065200 Al, ZL97194737.6] are m...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C47/55C07C45/63C07C45/80
Inventor 罗世鹏张金龙王欣杨廷海刘维桥
Owner JIANGSU UNIV OF TECH
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