CN114539073A - Synthesis method of 3-bromo-2-chloro-4, 6-difluoroaniline - Google Patents
Synthesis method of 3-bromo-2-chloro-4, 6-difluoroaniline Download PDFInfo
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- CN114539073A CN114539073A CN202210150166.6A CN202210150166A CN114539073A CN 114539073 A CN114539073 A CN 114539073A CN 202210150166 A CN202210150166 A CN 202210150166A CN 114539073 A CN114539073 A CN 114539073A
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- difluoroaniline
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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
- C07C201/08—Preparation of nitro compounds by substitution of hydrogen atoms by nitro groups
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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
- C07C209/325—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 reduction by other means than indicated in C07C209/34 or C07C209/36
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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
- C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
- C07C209/74—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton by halogenation, hydrohalogenation, dehalogenation, or dehydrohalogenation
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a method for synthesizing 3-bromo-2-chloro-4, 6-difluoroaniline, and relates to the technical field of organic synthesis. The synthesis method of the 3-bromo-2-chloro-4, 6-difluoroaniline and the synthesis method of the 3-bromo-2-chloro-4, 6-difluoroaniline have the advantages of low cost of raw materials adopted for synthesis, short synthesis route, simple and convenient synthesis operation and can be used for large-scale production.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing 3-bromo-2-chloro-4, 6-difluoroaniline.
Background
The 3-bromo-2-chloro-4, 6-difluoroaniline is an important intermediate of some medical products, and the synthesis method which is simple and convenient and has low cost is of great significance.
Disclosure of Invention
Technical problem to be solved
The invention aims to provide a method for synthesizing 3-bromo-2-chloro-4, 6-difluoroaniline, which has low cost and a short route.
In order to achieve the purpose, the invention is realized by the following technical scheme: a synthetic method of 3-bromo-2-chloro-4, 6-difluoroaniline comprises the following synthetic route:
which comprises the following steps:
s1, preparing a compound II: adding a compound I into sulfuric acid, slowly dripping nitric acid at 0-10 ℃ under uniform stirring, and uniformly stirring until the reaction is finished, wherein the molar ratio of the compound I to the sulfuric acid to the nitric acid is 1: 3.0-10: (3.0-10);
s2, preparing a compound III: dissolving a compound II in an organic solvent a, dropwise adding a solvent mixture of ammonium chloride and a reducing agent, and well stirring until the reaction is finished, wherein the reaction temperature is 20-60 ℃;
s3, preparing a compound IV: dissolving the compound III in an organic solvent b, adding NCS in batches, uniformly stirring until the reaction is finished, wherein the reaction temperature is 20-100 ℃.
Preferably, the reducing agent in step S2 is iron powder, and the molar ratio of the compound ii, ammonium chloride and iron powder is 1: (3.0-10.0): (3.0-10.0).
Preferably, the reducing agent in step S2 is one or more of zinc powder, stannous chloride, palladium on carbon, sodium borohydride, and lithium aluminum hydride.
Preferably, the organic solvent a in step S2 is one or more of methanol, ethanol, tetrahydrofuran, dioxane, and N, N-dimethylformamide.
Preferably, the organic solvent b in step S3 is one or more selected from acetonitrile, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, dioxane and N, N-dimethylformamide.
Advantageous effects
The invention provides a synthesis method of 3-bromo-2-chloro-4, 6-difluoroaniline, which has the following beneficial effects: the synthesis method of the 3-bromo-2-chloro-4, 6-difluoroaniline has the advantages of low cost of raw materials adopted for synthesis, short synthetic route and contribution to large-scale production.
Drawings
FIG. 1 is a graph of the H-NMR spectrum of 3-bromo-2-chloro-4, 6-difluoroaniline synthesized in the present invention;
FIG. 2 is a schematic diagram of the synthetic route of the present invention.
Detailed Description
For the sake of understanding, the present invention will be described in detail below by way of specific examples. It is specifically intended that the examples be given solely for the purpose of illustration and that all modifications that would be apparent to one skilled in the art from this disclosure are within the scope of the invention.
The synthetic route of the 3-bromo-2-chloro-4, 6-difluoroaniline provided by the invention is shown in figure 2.
EXAMPLE 1 Synthesis of Compound II
Adding 2L of concentrated sulfuric acid into a 5L three-necked bottle, adding 1kg of compound I, cooling to 0 ℃, dropwise adding 390ml of 65% nitric acid, controlling the temperature between 0 and 10 ℃ in the dropwise adding process, and reacting for 3 hours after the dropwise adding is finished.
And (3) post-treatment: the reaction solution was poured into 5kg of ice water, extracted with dichloromethane, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain 1.7kg of a crude product of compound ii.
1H NMR (400 MHz,CDCl3) δ: 8.41-8.37 (t, 1H),7.12-7.17 (q, 1H)。
EXAMPLE 2 Synthesis of Compound III
Adding 8.5L of ethanol and 1.7L of water into a 20L three-necked bottle, adding 1097g of ammonium chloride, adding 1999g of iron powder while stirring, slowly dropwise adding 1.7kg of compound I, controlling the temperature to be 20-60 ℃ while dropwise adding, and stirring for reacting for 4 hours after dropwise adding.
And (3) treatment: and (3) carrying out suction filtration under reduced pressure, washing a filter cake by using dichloromethane, combining filtrates, and evaporating to dryness under reduced pressure to obtain 1.35kg of a crude product of the compound III.
1H NMR (400 MHz,CDCl3) δ: 6.85-6.89 (q, 1H),6.75-6.80 (q, 1H),3.6（s，2H）。
EXAMPLE 3 Synthesis of Compound IV
1kg of compound III and 3L of acetonitrile are added into a 5L three-neck round-bottom flask, stirred and heated to 60 ℃, NCS is slowly added in batches (heat is released, the temperature is controlled to be less than 70 ℃), and after the addition is finished, the mixture is stirred and reacted for 1h at 60 ℃.
And (3) treatment: cooling the reaction solution, adding water for quenching, evaporating acetonitrile, standing, separating lower layer silica gel for sample mixing, washing PE, extracting upper layer water phase PE, concentrating and filtering the PE phase, leaching the PE to obtain 700g of solid (85: 15), distilling and purifying (130 ℃) to obtain 93% yield.
1H NMR (400 MHz,CDCl3) δ:7.38-7.42 (m, 1H),5.50（s，2H）.[M+]=244。
Claims (5)
1. A synthetic method of 3-bromo-2-chloro-4, 6-difluoroaniline is disclosed, and the synthetic route is as follows:
which comprises the following steps:
s1, preparing a compound II: adding a compound I into sulfuric acid, slowly dripping nitric acid at 0-10 ℃ under uniform stirring, and uniformly stirring until the reaction is finished, wherein the molar ratio of the compound I to the sulfuric acid to the nitric acid is 1: 3.0-10: (3.0-10);
s2, preparing a compound III: dissolving a compound II in an organic solvent a, dropwise adding a solvent mixture of ammonium chloride and a reducing agent, and well stirring until the reaction is finished, wherein the reaction temperature is 20-60 ℃;
s3, preparing a compound IV: dissolving the compound III in an organic solvent b, adding NCS in batches, uniformly stirring until the reaction is finished, wherein the reaction temperature is 20-100 ℃.
2. The method of synthesis according to claim 1, characterized in that: in the step S2, the reducing agent is iron powder, and the molar ratio of the compound II to the ammonium chloride to the iron powder is 1: 3.0-10.0: (3.0-10.0).
3. The method of synthesis according to claim 1, characterized in that: the reducing agent in step S2 is one or more of zinc powder, stannous chloride, palladium on carbon, sodium borohydride, and lithium aluminum hydride.
4. The method of synthesis according to claim 1, characterized in that: the organic solvent a in the step S2 is one or more of methanol, ethanol, tetrahydrofuran, dioxane, and N, N-dimethylformamide.
5. The method of synthesis according to claim 1, characterized in that: the organic solvent b in the step S3 is one or more of acetonitrile, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, dioxane and N, N-dimethylformamide.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007114902A2 (en) * | 2006-04-04 | 2007-10-11 | H.Lundbeck A/S | Alkylthiobenzylpiperidine compounds |
| CN103080101A (en) * | 2010-05-17 | 2013-05-01 | 阵列生物制药公司 | Piperidinyl-substituted lactams as GPR119 modulators |
| CN109195965A (en) * | 2016-03-01 | 2019-01-11 | 普罗佩纶治疗公司 | The inhibitor that WDR5 protein-protein combines |
| CN110627655A (en) * | 2018-06-22 | 2019-12-31 | 苏州旺山旺水生物医药有限公司 | Synthetic method and intermediate of 2-bromo-5-fluoro-4-nitroaniline |
| CN112074520A (en) * | 2018-05-08 | 2020-12-11 | 阿斯利康(瑞典)有限公司 | Tetracycloheteroaryl compounds |
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2022
- 2022-02-18 CN CN202210150166.6A patent/CN114539073A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007114902A2 (en) * | 2006-04-04 | 2007-10-11 | H.Lundbeck A/S | Alkylthiobenzylpiperidine compounds |
| CN103080101A (en) * | 2010-05-17 | 2013-05-01 | 阵列生物制药公司 | Piperidinyl-substituted lactams as GPR119 modulators |
| CN109195965A (en) * | 2016-03-01 | 2019-01-11 | 普罗佩纶治疗公司 | The inhibitor that WDR5 protein-protein combines |
| CN112074520A (en) * | 2018-05-08 | 2020-12-11 | 阿斯利康(瑞典)有限公司 | Tetracycloheteroaryl compounds |
| CN110627655A (en) * | 2018-06-22 | 2019-12-31 | 苏州旺山旺水生物医药有限公司 | Synthetic method and intermediate of 2-bromo-5-fluoro-4-nitroaniline |
Non-Patent Citations (2)
| Title |
|---|
| COLUMBUS, OHIO, US REGISTRY[ONLINE]: "STN检索报告", 《STN REGISTRY》, pages 1 * |
| YU JIANG ET AL.: "Synthesis and SAR Investigations for Novel Melanin-Concentrating Hormone 1 Receptor (MCH1) Antagonists Part 1. The Discovery of Arylacetamides as Viable Replacements for the Dihydropyrimidinone Moiety of an HTS Hit", 《J. MED. CHEM.》, vol. 50, pages 3876 - 3877 * |
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