CN113461538A - Preparation method of 2-chloro-3-bromoaniline - Google Patents
Preparation method of 2-chloro-3-bromoaniline Download PDFInfo
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- CN113461538A CN113461538A CN202110786415.6A CN202110786415A CN113461538A CN 113461538 A CN113461538 A CN 113461538A CN 202110786415 A CN202110786415 A CN 202110786415A CN 113461538 A CN113461538 A CN 113461538A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/30—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds
- C07C209/32—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of nitro groups
- C07C209/36—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of nitro groups by reduction of nitro groups bound to carbon atoms of six-membered aromatic rings in presence of hydrogen-containing gases and a catalyst
- C07C209/365—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of nitro groups by reduction of nitro groups bound to carbon atoms of six-membered aromatic rings in presence of hydrogen-containing gases and a catalyst by reduction with preservation of halogen-atoms in compounds containing nitro groups and halogen atoms bound to the same carbon skeleton
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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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/02—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof
- C07C303/22—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof from sulfonic acids, by reactions not involving the formation of sulfo or halosulfonyl groups; from sulfonic halides by reactions not involving the formation of halosulfonyl groups
Abstract
The invention discloses a preparation method of 2-chloro-3-bromoaniline, which comprises the following specific steps: (1) performing electrophilic substitution reaction on the compound II and bromosuccinimide to generate a compound III; (2) removing sulfonic group of the compound III to generate a compound IV; (3) and reducing the compound IV into a compound I, namely the 2-chloro-3-bromoaniline, by using sodium hydrosulfite. The invention avoids a large amount of reagents with high toxicity and pollution in the process of the total synthesis route which takes 4-chloro-3-nitrobenzenesulfonic acid as the starting material, and simultaneously, the raw material has low price and higher yield.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemicals, in particular to a preparation method of 2-chloro-3-bromoaniline.
Background
2-chloro-3-bromoaniline is a key intermediate, and WO2017/15562 discloses the following route for synthesizing 2-chloro-3-bromoaniline compound I:
in the above synthesis method, the starting material is very expensive in the process of synthesizing the 2-chloro-3-bromobenzamide compound I, and the preparation of the starting material is prepared by nitration; the nitration yield is low, a large amount of waste water is generated, the method is not environment-friendly, and the method is not beneficial to industrial scale-up production.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a preparation method of 2-chloro-3-bromoaniline. The method has higher yield and lower product price.
The technical scheme of the invention is as follows:
the preparation method of 2-chloro-3-bromoaniline comprises the following synthetic routes:
the method comprises the following specific steps:
(1) performing electrophilic substitution reaction on the compound II and bromosuccinimide to generate a compound III;
(2) removing sulfonic group of the compound III to generate a compound IV;
(3) and reducing the compound IV into a compound I, namely the 2-chloro-3-bromoaniline, by using sodium hydrosulfite.
In the step (1), the electrophilic substitution reaction comprises the following specific processes:
and mixing the compound II with bromosuccinimide and concentrated sulfuric acid, reacting for 2-16 h at 40-80 ℃, performing HPLC tracking reaction until 4-chloro-3-nitrobenzenesulfonic acid completely reacts, extracting, and concentrating an organic phase to obtain a compound III. The molar ratio of the compound II to bromosuccinimide is 1: 1-1.2; water and n-butanol with the volume ratio of 1:1 are selected for extraction. The mass concentration of the concentrated sulfuric acid is 70-90%; the mass ratio of the compound II to concentrated sulfuric acid is 1: 1-10.
In the step (2), the temperature of the removing reaction is 100-150 ℃, and the reaction time is 1-3 h.
In the step (3), the molar ratio of the compound IV to the sodium hydrosulfite is 1: 3.0 to 5.0. The solvent adopted in the reduction reaction is one or more of methanol, ethanol and water. The reaction conditions of the reduction reaction are as follows: the temperature is 50-70 ℃, and the reaction time is 1-10 h.
The beneficial technical effects of the invention are as follows:
the invention avoids a large amount of reagents with high toxicity and pollution in the whole synthesis route process taking 4-chloro-3-nitrobenzenesulfonic acid as the starting material, and simultaneously, the price of the raw material is low, so that the whole synthesis process has small pollution and is easy to process, the lowest yield in each step also reaches 83.0 percent, and the total yield also reaches about 73.4 percent.
Drawings
FIG. 1 shows the preparation of 2-chloro-3-bromoaniline obtained in example 11An H-NMR spectrum;
FIG. 2 is a GC spectrum of 2-chloro-3-bromoaniline 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-chloro-3-bromoaniline comprises the following steps:
(1) synthesis of Compound III
Adding 237g (1mol) of 4-chloro-3-nitrobenzenesulfonic acid and 1000ml of concentrated sulfuric acid into a reaction bottle, adding 213.6g (1.2mol) of bromosuccinimide at 40 ℃, keeping the temperature for reacting for 16 hours, and carrying out HPLC tracking reaction until the 4-chloro-3-nitrobenzenesulfonic acid is completely reacted; adding 1000ml of water and 1000ml of n-butanol for layering, and concentrating an organic phase to obtain 252g of a compound III, wherein the molar yield is as follows: 80 percent.
(2) Synthesis of Compound IV
Adding 157.5g (0.5mol) of compound III and 1575g of 70% sulfuric acid into a reaction bottle, reacting for 3 hours at 100 ℃, and tracking the reaction by HPLC until the compound III is completely reacted; cooling, quenching to 3000ml water, filtering to obtain 99.9g of compound IV, molar yield: 85 percent.
(3) Synthesis of Compound I
Adding 23.5g (100mmol) of compound IV, 100ml of methanol and 200ml of water into a reaction bottle, adding 52.2g (300mmol) of sodium hydrosulfite, heating to 70 ℃, reacting for 10h, and carrying out HPLC tracking reaction until the compound IV is completely reacted; concentrating methanol, extracting with 200ml ethyl acetate, concentrating the organic phase, pulping with toluene, filtering the solid, and drying to obtain 19.1g of compound I, with the molar yield: 93.1 percent.
FIG. 1 is a hydrogen spectrum of a 2-chloro-3-bromoaniline compound I,1H-NMR(400MHz,CDCl3)δ:6.99～6.97(dd,1H，Ph-H),6.90～6.86(t,1H，Ph-H)，6.67～6.64(dd,1H，Ph-H)，4.14(s,2H，NH2)。
FIG. 2 is a gas chromatogram of 2-chloro-3-bromoaniline compound I, which shows that the purity of 2-chloro-3-bromoaniline compound I is more than 99%.
Example 2
A preparation method of 2-chloro-3-bromoaniline comprises the following steps:
(1) synthesis of Compound III
Adding 237g (1mol) of 4-chloro-3-nitrobenzenesulfonic acid and 1000ml of concentrated sulfuric acid into a reaction bottle, adding 195.8g (1.1mol) of bromosuccinimide at 60 ℃, keeping the temperature for reacting for 8 hours, and carrying out HPLC tracking reaction until the 4-chloro-3-nitrobenzenesulfonic acid is completely reacted; 1000ml of water and 1000ml of n-butanol are added for layer separation, and the organic phase is concentrated to obtain 261.5g of compound III with molar yield: 83 percent.
(2) Synthesis of Compound IV
Adding 157.5g (0.5mol) of compound III and 787.5g of 80% sulfuric acid into a reaction flask, reacting at 120 ℃ for 3 hours, and tracking the reaction by HPLC until the compound III is completely reacted; cooling, quenching to 3000ml water, filtering to obtain 103.4g of compound IV, molar yield: 88 percent.
(3) Synthesis of Compound I
Adding 23.5g (100mmol) of compound IV, 100ml of ethanol and 200ml of water into a reaction bottle, adding 69.6g (400mmol) of sodium hydrosulfite, heating to 60 ℃, reacting for 5h, and carrying out HPLC tracking reaction until the compound IV is completely reacted; concentrating methanol, extracting with 200ml ethyl acetate, concentrating the organic phase, pulping with toluene, filtering the solid, and drying to obtain 19.27g of compound I, with the molar yield: 94 percent.
Example 3
A preparation method of 2-chloro-3-bromoaniline comprises the following steps:
(1) synthesis of Compound III
Adding 237g (1mol) of 4-chloro-3-nitrobenzenesulfonic acid and 1000ml of concentrated sulfuric acid into a reaction bottle, adding 178g (1.0mol) of bromosuccinimide at 80 ℃, keeping the temperature for reacting for 2 hours, and carrying out HPLC tracking reaction until the 4-chloro-3-nitrobenzenesulfonic acid is completely reacted; adding 1000ml of water and 1000ml of n-butanol for layering, and concentrating an organic phase to obtain 258.3g of a compound III, wherein the molar yield is as follows: 82 percent.
(2) Synthesis of Compound IV
Adding 157.5g (0.5mol) of compound III and 157.5g of 90% sulfuric acid into a reaction bottle, reacting for 1h at 150 ℃, and tracking the reaction by HPLC until the compound III is completely reacted; cooling, quenching to 3000ml water, filtering to obtain 108.1g of compound IV, molar yield: 92 percent.
(3) Synthesis of Compound I
Adding 23.5g (100mmol) of compound IV, 100ml of methanol and 200ml of water into a reaction bottle, adding 87g (500mmol) of sodium hydrosulfite, heating to 50 ℃ for reaction for 1h, and carrying out HPLC tracking reaction until the compound IV is completely reacted; concentrating methanol, extracting with 200ml ethyl acetate, concentrating the organic phase, pulping with toluene, filtering the solid, and drying to obtain 19.7g of compound I, with the molar yield: 96.1 percent.
Claims (8)
1. The preparation method of 2-chloro-3-bromoaniline is characterized by comprising the following synthetic routes:
the method comprises the following specific steps:
(1) performing electrophilic substitution reaction on the compound II and bromosuccinimide to generate a compound III;
(2) removing sulfonic group of the compound III to generate a compound IV;
(3) and reducing the compound IV into a compound I, namely the 2-chloro-3-bromoaniline, by using sodium hydrosulfite.
2. The method according to claim 1, wherein in step (1), the electrophilic substitution reaction is performed by the following steps:
and mixing the compound II with bromosuccinimide and concentrated sulfuric acid, reacting for 2-16 h at 40-80 ℃, performing HPLC tracking reaction until 4-chloro-3-nitrobenzenesulfonic acid completely reacts, extracting, and concentrating an organic phase to obtain a compound III.
3. The preparation method according to claim 2, wherein the molar ratio of the compound II to bromosuccinimide is 1: 1-1.2; water and n-butanol with the volume ratio of 1:1 are selected for extraction.
4. The preparation method according to claim 2, wherein the mass concentration of the concentrated sulfuric acid is 70-90%; the mass ratio of the compound II to concentrated sulfuric acid is 1: 1-10.
5. The preparation method according to claim 1, wherein in the step (2), the temperature of the desorption reaction is 100 to 150 ℃ and the reaction time is 1 to 3 hours.
6. 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: 3.0 to 5.0.
7. The method according to claim 1, wherein in the step (3), the solvent used in the reduction reaction is one or more of methanol, ethanol, and water.
8. The production method according to claim 1, wherein in the step (3), the reaction conditions are: the temperature is 50-70 ℃, and the reaction time is 1-10 h.
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Citations (5)
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| US20090062258A1 (en) * | 2005-02-03 | 2009-03-05 | Takeda Pharmaceutical Company Limited | Fused pyrimidine derivative and use thereof |
| CN102491906A (en) * | 2011-12-21 | 2012-06-13 | 齐鲁动物保健品有限公司 | Synthetic method for 2-methyl-3-trifluoromethyl phenylamine |
| CN109311848A (en) * | 2016-06-07 | 2019-02-05 | 北京加科思新药研发有限公司 | It can be used as the new type heterocycle derivative of SHP2 inhibitor |
| CN110003204A (en) * | 2019-04-30 | 2019-07-12 | 上海勋和医药科技有限公司 | A kind of BET protein inhibitor, preparation method and the usage |
| CN110790758A (en) * | 2018-08-01 | 2020-02-14 | 上海轶诺药业有限公司 | Preparation and application of N-containing heterocyclic compound with immunoregulation function |
-
2021
- 2021-07-12 CN CN202110786415.6A patent/CN113461538A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090062258A1 (en) * | 2005-02-03 | 2009-03-05 | Takeda Pharmaceutical Company Limited | Fused pyrimidine derivative and use thereof |
| CN102491906A (en) * | 2011-12-21 | 2012-06-13 | 齐鲁动物保健品有限公司 | Synthetic method for 2-methyl-3-trifluoromethyl phenylamine |
| CN109311848A (en) * | 2016-06-07 | 2019-02-05 | 北京加科思新药研发有限公司 | It can be used as the new type heterocycle derivative of SHP2 inhibitor |
| CN110790758A (en) * | 2018-08-01 | 2020-02-14 | 上海轶诺药业有限公司 | Preparation and application of N-containing heterocyclic compound with immunoregulation function |
| CN110003204A (en) * | 2019-04-30 | 2019-07-12 | 上海勋和医药科技有限公司 | A kind of BET protein inhibitor, preparation method and the usage |
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| 郝素娥: "《精细有机合成单元反应与合成设计》", 哈尔滨工业大学出版社 * |
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