CN113372200B - Preparation method of 2-bromo-6-fluoroanisole - Google Patents
Preparation method of 2-bromo-6-fluoroanisole Download PDFInfo
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- CN113372200B CN113372200B CN202110786401.4A CN202110786401A CN113372200B CN 113372200 B CN113372200 B CN 113372200B CN 202110786401 A CN202110786401 A CN 202110786401A CN 113372200 B CN113372200 B CN 113372200B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
Abstract
The invention discloses a preparation method of 2-bromo-6-fluoroanisole, which comprises the following specific steps: (1) performing electrophilic substitution reaction on the 3, 4-difluoronitrobenzene and bromosuccinimide to generate a compound III; (2) reacting the compound III with sodium methoxide to generate a compound IV; (3) reducing the compound IV by sodium hydrosulfite to generate a compound V; (4) diazotizing and deaminating the compound V to generate a compound I; namely the 2-bromo-6-fluoroanisole. The preparation method has higher yield.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemicals, in particular to a preparation method of 2-bromo-6-fluoroanisole.
Background
2-bromo-6-fluoroanisole is a key intermediate, and WO2013/28474, WO2014/126944 and EP2744499 disclose the following routes for synthesizing 2-bromo-6-fluoroanisole compound I:
in the synthesis method, in the first step of the synthesis process of the 2-bromo-6-fluoroanisole compound I, an easy-explosion reagent nitric acid is used for nitration, and a large amount of wastewater is generated; the methyl on the highly toxic reagent methyl iodide is used in the second step of the reaction, which is not beneficial to the industrialized amplification production.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a preparation method of 2-bromo-6-fluoroanisole. The preparation method has higher yield.
The technical scheme of the invention is as follows:
a preparation method of 2-bromo-6-fluoroanisole is carried out according to the following synthetic route:
the method comprises the following specific steps:
(1) performing electrophilic substitution reaction on the 3, 4-difluoronitrobenzene and bromosuccinimide to generate a compound III;
(2) reacting the compound III with sodium methoxide to generate a compound IV;
(3) reducing the compound IV by sodium hydrosulfite to generate a compound V;
(4) diazotizing and deaminating the compound V to generate a compound I; namely the 2-bromo-6-fluoroanisole.
In the step (1), the process of electrophilic substitution reaction is as follows: and reacting the 3, 4-difluoronitrobenzene with bromosuccinimide under the condition of concentrated sulfuric acid to generate a compound III.
In the step (1), the mass concentration of the concentrated sulfuric acid is 98%. The molar ratio of the 3, 4-difluoronitrobenzene to the bromosuccinimide is 1: 1.1-1.5; the temperature of the electrophilic substitution reaction is 20-60 ℃, and the reaction time is 2-12 h.
In the step (2), the molar ratio of the compound III to sodium methoxide is 1: 1.1-1.5; the reaction conditions are as follows: the temperature is 40-60 ℃, and the reaction time is 2-6 h. In the step (2), the reaction solvent is methanol.
In the step (3), the molar ratio of the compound IV to the sodium hydrosulfite is 1: 2.0-5.0; the reaction conditions are as follows: the temperature is 40-80 ℃, and the reaction time is 2-6 h. In the step (3), the reaction solvent is one or more of methanol, ethanol and water.
In the step (4), the diazotization deamination reaction comprises the following steps: diazotizing the compound V and isoamyl nitrite, and further reacting to generate a compound I.
The molar ratio of the compound V to the isoamyl nitrite is 1: 1.1-1.3; the reaction solvent is N, N-dimethylformamide; the reaction conditions are as follows: the temperature is 50-70 ℃, and the reaction time is 2-6 h.
The beneficial technical effects of the invention are as follows:
in the process of the total synthesis route taking 3, 4-difluoronitrobenzene as the starting material, the invention avoids a large amount of reagents which are easy to produce poison and explode, and simultaneously, the price of the raw material is low, so that the whole synthesis process has little pollution and is easy to process, the lowest yield in each step also reaches 79 percent, and the total yield also reaches about 44 percent.
Drawings
FIG. 1 shows the preparation of 2-bromo-6-fluoroanisole obtained in example 11An H-NMR spectrum;
FIG. 2 is a GC spectrum of 2-bromo-6-fluoroanisole obtained in example 1.
Detailed Description
The present invention will be described in detail with reference to the accompanying drawings and examples.
Example 1
A preparation method of 2-bromo-6-fluoroanisole comprises the following steps:
(1) synthesis of Compound III
159g (1mol) of 3, 4-difluoronitrobenzene and 500g of concentrated sulfuric acid (the mass concentration is 98%) are added into a reaction bottle, 195.8g (1.1mol) of bromosuccinimide are added in batches at 40 ℃, the mixture is stirred for 12 hours under the condition of heat preservation, and the HPLC tracking reaction is carried out until the 3, 4-difluoronitrobenzene is completely reacted; quenched into 2000ml of ice water, filtered, and the filter cake recrystallized from an aqueous acetone system to give 194.3g of compound III in molar yield: 82 percent.
(2) Synthesis of Compound IV
Adding 118.5g (0.5mol) of compound III, 700ml of methanol and 29.7g (0.55mol) of sodium methoxide into a reaction bottle, stirring for 6 hours at 60 ℃, and tracking the reaction by HPLC until the compound III is completely reacted; quenched into 2000ml of ice water, filtered and dried to obtain 103.3g of compound IV, molar yield: 83 percent.
(3) Synthesis of Compound V
Adding 74.7g (0.3mol) of compound IV, 300ml of methanol, 600ml of water and 104.4g (0.6mol) of sodium hydrosulfite into a reaction bottle, stirring for 6 hours at the temperature of 60 ℃, and carrying out HPLC tracking reaction until the compound III is completely reacted; adding 1000ml of ethyl acetate for extraction, washing with saturated sodium chloride, concentrating an organic layer, and recrystallizing with toluene to obtain 57.1g of a compound V, wherein the molar yield is as follows: 87 percent.
(4) Synthesis of Compound I
Adding 21.9g (0.1mol) of compound V and 100ml of N, N-dimethylformamide into a reaction bottle, dropwise adding 12.87g (0.11mol) of isoamyl nitrite at 70 ℃, keeping the temperature and stirring for 4 hours, and carrying out HPLC tracking reaction until the compound V is completely reacted; quenching to 500ml of ice water, adding 400ml of ethyl acetate for extraction, concentrating the organic phase, and recrystallizing in n-hexane to obtain 15.3g of compound I, with molar yield: 75 percent.
FIG. 1 shows a hydrogen spectrum of 2-bromo-6-fluoroanisole compound I, 1H-NMR (400MHz, DMSO). delta.7.47-7.43 (m,1H, Ph-H), 7.36-7.29 (m,1H, Ph-H), 7.12-7.05 (m,1H, Ph-H), 3.86(s,1H, OCH)3)。
FIG. 2 is a gas chromatogram of 2-bromo-6-fluorobenzyl ether compound I, which shows that the purity of 2-bromo-6-fluorobenzyl ether compound I is 100%.
Example 2
A preparation method of 2-bromo-6-fluoroanisole comprises the following steps:
(1) synthesis of Compound III
159g (1mol) of 3, 4-difluoronitrobenzene and 500g of concentrated sulfuric acid (the mass concentration is 98%) are added into a reaction bottle, 231.4g (1.3mol) of bromosuccinimide are added in batches at 60 ℃, the mixture is stirred for 6 hours under the condition of heat preservation, and the HPLC tracking reaction is carried out until the 3, 4-difluoronitrobenzene is completely reacted; quenching into 2000ml of ice water, filtering, and recrystallizing the filter cake with an acetone water system to obtain 199.1g of compound III with molar yield: 84 percent.
(2) Synthesis of Compound IV
Adding 118.5g (0.5mol) of compound III, 700ml of methanol and 35.1g (0.65mol) of sodium methoxide into a reaction bottle, stirring for 4 hours at 50 ℃, and tracking the reaction by HPLC until the compound III is completely reacted; quenched into 2000ml of ice water, filtered and dried to give 109.5g of compound IV, molar yield: 88 percent.
(3) Synthesis of Compound V
Adding 74.7g (0.3mol) of compound IV, 300ml of ethanol, 600ml of water and 156.6g (0.9mol) of sodium hydrosulfite into a reaction bottle, stirring for 2 hours at 80 ℃, and carrying out HPLC tracking reaction until the compound III is completely reacted; adding 1000ml of ethyl acetate for extraction, washing with saturated sodium chloride, concentrating an organic layer, and recrystallizing with toluene to obtain 59.1g of a compound V, wherein the molar yield is as follows: 90 percent.
(4) Synthesis of Compound I
Adding 21.9g (0.1mol) of compound V and 100ml of N, N-dimethylformamide into a reaction bottle, dropwise adding 14.04g (0.12mol) of isoamyl nitrite at 60 ℃, keeping the temperature and stirring for 2 hours, and carrying out HPLC tracking reaction until the compound V is completely reacted; quenching to 500ml of ice water, adding 400ml of ethyl acetate for extraction, concentrating the organic phase, and recrystallizing in n-hexane to obtain 15.9g of compound I, with molar yield: 78 percent.
Example 3
A preparation method of 2-bromo-6-fluoroanisole comprises the following steps:
(1) synthesis of Compound III
159g (1mol) of 3, 4-difluoronitrobenzene and 500g of concentrated sulfuric acid (the mass concentration is 98%) are added into a reaction bottle, 267g (1.5mol) of bromosuccinimide are added in batches at 20 ℃, the mixture is stirred for 12 hours under the condition of heat preservation, and the HPLC tracking reaction is carried out until the 3, 4-difluoronitrobenzene is completely reacted; quenched into 2000ml of ice water, filtered, and the filter cake recrystallized from an aqueous acetone system to yield 189.6g of compound III, molar yield: 80 percent.
(2) Synthesis of Compound IV
Adding 118.5g (0.5mol) of compound III, 700ml of methanol and 40.5g (0.75mol) of sodium methoxide into a reaction bottle, stirring for 2 hours at 40 ℃, and tracking the reaction by HPLC until the compound III is completely reacted; quenched into 2000ml of ice water, filtered and dried to obtain 99.6g of compound IV, molar yield: 80 percent.
(3) Synthesis of Compound V
Adding 74.7g (0.3mol) of compound IV, 300ml of methanol, 600ml of water and 261g (1.5mol) of sodium hydrosulfite into a reaction bottle, stirring for 4 hours at 40 ℃, and tracking the reaction by HPLC until the compound III is completely reacted; adding 1000ml of ethyl acetate for extraction, washing with saturated sodium chloride, concentrating an organic layer, and recrystallizing with toluene to obtain 57.8g of a compound V, wherein the molar yield is as follows: 88 percent.
(4) Synthesis of Compound I
Adding 21.9g (0.1mol) of compound V and 100ml of N, N-dimethylformamide into a reaction bottle, dropwise adding 15.21g (0.13mol) of isoamyl nitrite at 50 ℃, keeping the temperature and stirring for 6 hours, and performing HPLC tracking reaction until the compound V is completely reacted; quenching to 500ml of ice water, adding 400ml of ethyl acetate for extraction, concentrating the organic phase, and recrystallizing in n-hexane to obtain 16.1g of compound I, with molar yield: 79 percent.
Claims (10)
1. The preparation method of 2-bromo-6-fluoroanisole is characterized by being carried out according to the following synthetic route:
the method comprises the following specific steps:
(1) performing electrophilic substitution reaction on the 3, 4-difluoronitrobenzene and bromosuccinimide to generate a compound III;
(2) reacting the compound III with sodium methoxide to generate a compound IV;
(3) reducing the compound IV by sodium hydrosulfite to generate a compound V;
(4) diazotizing and deaminating the compound V to generate a compound I; namely the 2-bromo-6-fluoroanisole.
2. The process according to claim 1, wherein in step (1), the electrophilic substitution reaction is carried out by: and reacting the compound II with bromosuccinimide under the condition of concentrated sulfuric acid to generate a compound III.
3. The production method according to claim 2, wherein the mass concentration of the concentrated sulfuric acid in the step (1) is 98%.
4. The preparation method of claim 2, wherein the molar ratio of 3, 4-difluoronitrobenzene to bromosuccinimide is 1: 1.1-1.5; the temperature of the electrophilic substitution reaction is 20-60 ℃, and the reaction time is 2-12 h.
5. The preparation method according to claim 1, wherein in the step (2), the molar ratio of the compound III to the sodium methoxide is 1: 1.1-1.5; the reaction conditions are as follows: the temperature is 40-60 ℃, and the reaction time is 2-6 h.
6. The process according to claim 1, wherein in the step (2), the reaction solvent is methanol.
7. The preparation method according to claim 1, wherein in the step (3), the molar ratio of the compound IV to the sodium hydrosulfite is 1: 2.0-5.0; the reaction conditions are as follows: the temperature is 40-80 ℃, and the reaction time is 2-6 h.
8. The method according to claim 1, wherein in the step (3), the reaction solvent is one or more of methanol, ethanol, and water.
9. The method of claim 1, wherein in step (4), the diazotization deamination reaction is: diazotizing the compound V and isoamyl nitrite, and further reacting to generate a compound I.
10. The method according to claim 9, wherein the molar ratio of the compound V to the isoamyl nitrite is 1:1.1 to 1.3; the reaction solvent is N, N-dimethylformamide; the reaction conditions are as follows: the temperature is 50-70 ℃, and the reaction time is 2-6 h.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1827569A (en) * | 2005-02-28 | 2006-09-06 | 北京金源化学集团有限公司 | Process for preparing 1,2-di alkoxy-3-fluorobenzene from intermediate 2-fluoro-6-halogeno phenol |
| WO2010020363A1 (en) * | 2008-08-21 | 2010-02-25 | Bayer Schering Pharma Aktiengesellschaft | Substituted 5-aminopyrazoles and use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1827569A (en) * | 2005-02-28 | 2006-09-06 | 北京金源化学集团有限公司 | Process for preparing 1,2-di alkoxy-3-fluorobenzene from intermediate 2-fluoro-6-halogeno phenol |
| WO2010020363A1 (en) * | 2008-08-21 | 2010-02-25 | Bayer Schering Pharma Aktiengesellschaft | Substituted 5-aminopyrazoles and use thereof |
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