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Preparation method of 3-methoxy-4-fluorobenzaldehyde

A technology of fluorobenzaldehyde and methoxy group, which is applied in the field of preparation of 3-methoxy-4-fluorobenzaldehyde, can solve the problems of unfriendly environment, high cost, danger and the like, and achieves low price, low pollution, manageable effect

Active Publication Date: 2021-02-02
无锡双启科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] In the above-mentioned synthetic method, in the process of synthesizing 3-methoxyl-4-fluorobenzaldehyde compound I, first step reaction generates 4-fluoro-3-methoxybenzyl alcohol with borane dimethyl sulfide reduction carboxyl, It is easy to punch materials during enlargement, which is dangerous, and borane dimethyl sulfide is highly toxic and unfriendly to the environment; in the final step of oxidation of hydroxyl to aldehyde groups, manganese dioxide and pyridinium chlorochromate are used as oxidants, not only the yield Low, pollution, high cost, and a large amount of heavy metal compounds are produced, which is not conducive to industrial scale-up

Method used

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  • Preparation method of 3-methoxy-4-fluorobenzaldehyde
  • Preparation method of 3-methoxy-4-fluorobenzaldehyde
  • Preparation method of 3-methoxy-4-fluorobenzaldehyde

Examples

Experimental program
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Embodiment 1

[0024] A preparation method of 3-methoxy-4-fluorobenzaldehyde, said preparation method comprising the steps of:

[0025] (1) Synthesis of compound III

[0026] Add 193g (1mol) 3,4-difluorobromobenzene, 1000ml methanol, 54g (1mol) sodium methoxide to the reaction flask, heat up to 65°C and stir for 2 hours, and follow the reaction by HPLC until 3,4-difluorobromobenzene The reaction was complete; the reaction liquid was concentrated, 1000ml of ethyl acetate was added, and 500ml of water was used to extract and separate layers, the organic phase was dried and concentrated, and high vacuum distillation was carried out at 63°C (12Torr) to obtain 160g of compound III with a molar yield of 78%.

[0027] (2) Synthesis of compound I

[0028] Add 1000ml of tetrahydrofuran and 21g (878mmol) magnesium to the reaction flask, heat up to 65°C, slowly add 150g (731.7mmol) of compound III dropwise, and reflux for 2 hours until the magnesium dust basically disappears, and follow the reaction b...

Embodiment 2

[0032] A preparation method of 3-methoxy-4-fluorobenzaldehyde, said preparation method comprising the steps of:

[0033] (1) Synthesis of compound III

[0034] Add 193g (1mol) 3,4-difluorobromobenzene, 1000ml methanol, 67.5g (1.25mol) sodium methoxide to the reaction flask, raise the temperature to 50°C and stir for 6 hours, and follow the reaction by HPLC until 3,4-difluoro The reaction of bromobenzene was complete; the reaction solution was concentrated, 1000ml of ethyl acetate was added, and 500ml of water was extracted to separate the layers, the organic phase was dried and concentrated, and high vacuum distillation was carried out at 63°C (12Torr) to obtain 168g of compound III with a molar yield of 81.9%.

[0035] (2) Synthesis of compound I

[0036] Add 1000ml of methyl tetrahydrofuran and 17.5g (731.7mmol) of magnesium to the reaction flask, raise the temperature to 40°C, slowly add 150g (731.7mmol) of compound III dropwise, and stir for 6 hours until the magnesium du...

Embodiment 3

[0038] A preparation method of 3-methoxy-4-fluorobenzaldehyde, said preparation method comprising the steps of:

[0039] (1) Synthesis of compound III

[0040] Add 193g (1mol) 3,4-difluorobromobenzene, 1000ml methanol, 81g (1.5mol) sodium methoxide to the reaction flask, heat up to 57°C and stir for 4 hours, and follow the reaction by HPLC until 3,4-difluorobromobenzene The benzene reaction was complete; the reaction solution was concentrated, 1000ml of ethyl acetate was added, and 500ml of water was added to extract and separate layers, the organic phase was dried and concentrated, and high vacuum distillation was carried out at 63°C (12Torr) to obtain 169.6g of compound III with a molar yield of 82.7%.

[0041] (2) Synthesis of compound I

[0042] Add 1000ml tetrahydrofuran and 19.25g (804.9mmol) magnesium to the reaction flask, raise the temperature to 55°C, slowly add 150g (731.7mmol) compound III dropwise, and stir for 4 hours until the magnesium dust basically disappear...

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Abstract

The invention discloses a preparation method of 3-methoxy-4-fluorobenzaldehyde. The method comprises the following steps: (1) reacting 3,4-difluorobromobenzene serving as a starting raw material withsodium methoxide to generate a compound III; and (2) reacting the compound III with magnesium to generate a Grignard reagent, and reacting under the condition of N,N-dimethylformamide to generate a compound I, wherein the obtained product is the 3-methoxy-4-fluorobenzaldehyde. The preparation method provided by the invention is higher in yield.

Description

technical field [0001] The invention relates to the technical field of medicine and chemical industry, in particular to a preparation method of 3-methoxy-4-fluorobenzaldehyde. Background technique [0002] 3-methoxy-4-fluorobenzaldehyde is a key intermediate for the preparation of dopamine agonists for the treatment of pain. WO2008087512, Bioorganic & Medicinal Chemistry, 9(3), 677-694; 2001 discloses the following synthesis of 3-methoxy -Route of 4-fluorobenzaldehyde compound I: [0003] [0004] In the above-mentioned synthetic method, in the process of synthesizing 3-methoxyl-4-fluorobenzaldehyde compound I, first step reaction generates 4-fluoro-3-methoxybenzyl alcohol with borane dimethyl sulfide reduction carboxyl, It is easy to punch materials during enlargement, which is dangerous, and borane dimethyl sulfide is highly toxic and unfriendly to the environment; in the final step of oxidation of hydroxyl to aldehyde groups, manganese dioxide and pyridinium chlorochr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C45/00C07C47/575
CPCC07C41/01C07C45/00C07C43/225C07C47/575
Inventor 张国强
Owner 无锡双启科技有限公司
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