CN111187206A - Method for synthesizing 2-amino-5-bromopyridine under catalysis of microwave and ionic liquid - Google Patents
Method for synthesizing 2-amino-5-bromopyridine under catalysis of microwave and ionic liquid Download PDFInfo
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- CN111187206A CN111187206A CN202010109436.XA CN202010109436A CN111187206A CN 111187206 A CN111187206 A CN 111187206A CN 202010109436 A CN202010109436 A CN 202010109436A CN 111187206 A CN111187206 A CN 111187206A
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- ionic liquid
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- bromopyridine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
- B01J2231/4277—C-X Cross-coupling, e.g. nucleophilic aromatic amination, alkoxylation or analogues
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0277—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature
- B01J31/0278—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature containing nitrogen as cationic centre
- B01J31/0281—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature containing nitrogen as cationic centre the nitrogen being a ring member
- B01J31/0284—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature containing nitrogen as cationic centre the nitrogen being a ring member of an aromatic ring, e.g. pyridinium
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention belongs to the technical field of synthesis of 2-amino-5-bromopyridine, and particularly relates to a method for synthesizing 2-amino-5-bromopyridine under catalysis of microwave and ionic liquid, which comprises the steps of taking 2-aminopyridine as a raw material, adding the raw material into an organic solvent, adding bromine under the action of an ionic liquid catalyst and under microwave radiation, and carrying out halogenation; and removing the solvent from the obtained reaction solution by reduced pressure distillation and further recrystallizing to obtain the high-purity 2-amino-5-bromopyridine. Compared with the prior art, the method has the advantages of simplified production process, mild reaction conditions, higher product purity, capability of recycling the Lewis acidic ionic liquid and low production cost.
Description
Technical Field
The invention belongs to the technical field of synthesis of 2-amino-5-bromopyridine, and particularly relates to a method for synthesizing 2-amino-5-bromopyridine under catalysis of microwave and ionic liquid.
Background
2-amino-5-bromopyridine is an important chemical intermediate and is widely applied to the fields of medicines, pesticides and dyes. The 2-amino-5 bromopyridine can be used for synthesizing a plurality of substances, such as zopiclone serving as a sedative hypnotic drug, PI3 kinase inhibitor and the like. At present, the market demand at home and abroad is large, but the domestic synthesis report on the compound is few.
The synthesis method of the compound mainly takes 2-aminopyridine as a raw material and comprises the following synthesis routes:
(1) n-bromosuccinimide (NBS) is taken as a bromization reagent, 2-aminopyridine is taken as a raw material to synthesize 2-amino-5-bromopyridine, such as patents CN107540604A and WO2013126608A1, the method has good selectivity and high yield which can reach over 90 percent, but NBS with high price is used, and the method is not beneficial to industrial production.
(2) Liquid bromine is a bromization reagent, 2-aminopyridine is used as a raw material, and the raw material is subjected to acetic anhydride amino protection, bromine halogenation and strong base solution hydrolysis to prepare the 2-amino-5-bromopyridine, wherein amino protection and deprotection operations are added in the method, so that the reaction yield is only 65%, the operation is complex, and a large amount of wastewater is generated.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: overcomes the defects of the prior art, provides a method for synthesizing 2-amino-5-bromopyridine under the catalysis of microwave and ionic liquid, and aims to solve the problems of high cost, harsh reaction conditions and the like in the prior art.
The method for synthesizing 2-amino-5-bromopyridine under the catalysis of microwave and ionic liquid comprises the steps of taking 2-aminopyridine as a raw material, adding the raw material into an organic solvent, adding bromine under the action of an ionic liquid catalyst and under the action of microwave radiation, and carrying out halogenation reaction; and removing the solvent from the obtained reaction solution by reduced pressure distillation and further recrystallizing to obtain the high-purity 2-amino-5-bromopyridine.
Preferably, the organic solvent is one or more of acetone, dichloromethane, acetonitrile, chloroform and ethyl acetate, and more preferably, acetone and/or acetonitrile.
Preferably, the ionic liquid catalyst is Lewis acidic ionic liquid, and the Lewis acidic ionic liquid comprises one or more of zinc chloride, ferric trichloride or aluminum trichloride. The dosage of the ionic liquid catalyst is 5-20% of the dosage of the 2-aminopyridine by weight.
Preferably, the microwave power is 50-160W, and more preferably 50-60W; the microwave radiation reaction time is 30-120 min, and more preferably 30-50 min.
Preferably, the amount of the bromine is 0.7-1.5 times of the amount of the 2-aminopyridine by weight.
Preferably, the solvent used for recrystallization is one or more of methanol, ethanol, dichloromethane, chloroform, ethyl acetate or petroleum ether. More preferably, the solvent used for recrystallization is one or more of methanol, ethanol or ethyl acetate.
The reaction mechanism of the present invention is as follows:
compared with the prior art, the invention has the following beneficial effects:
(1) the microwave-assisted organic synthesis technology is a novel green chemical synthesis method, is used for organic synthesis, and can greatly shorten the reaction time. The ionic liquid has extremely high polarizability, can well absorb microwave energy, so that the temperature of a reaction system is quickly increased, and the microwave-assisted ionic liquid method has the advantages of both the microwave method and the ionic liquid catalysis.
(2) Compared with the prior art that bromine or NBS is directly used as a bromination reagent, the method provided by the invention adopts Lewis acidic ionic liquid as a catalyst, so that bromine in a solvent can be polarized more quickly, and the bromination reaction time is reduced. Different from the conventional heating mode, the microwave-assisted method belongs to internal heating, and the system is heated more uniformly, so that the conversion rate of raw materials is improved.
(3) The invention has the advantages of simplified production process, mild reaction conditions, higher product purity, recyclable Lewis acidic ionic liquid and low production cost.
Detailed Description
The present invention will be further described with reference to the following examples.
All the starting materials used in the examples are commercially available, except where otherwise indicated.
Example 1
Under the radiation of 50W microwave, 20g (0.21mol) of 2-aminopyridine and 200mL of acetone are sequentially added into a 500mL three-neck round-bottom flask, stirred and dissolved, then 3.4g N-butylpyridinium chloride-aluminum trichloride ionic liquid is added, then 20g (0.12mol) of bromine is added for halogenation reaction for 45min, the obtained reaction liquid is subjected to reduced pressure distillation to remove the solvent, and further is recrystallized by methanol, and after drying, 33.1g of 2-amino-5-bromopyridine white crystals are obtained, the GC purity is 99.6%, and the molar yield is 90.0%.
Example 2
Under the radiation of 60W microwave, 20g (0.21mol) of 2-aminopyridine and 200mL of acetonitrile are sequentially added into a 500mL three-neck round-bottom flask, stirred and dissolved, then 1.8g N-ethylpyridine chloride-aluminum trichloride ionic liquid is added, 30g (0.19mol) of bromine is added for halogenation reaction for 50min, the obtained reaction liquid is subjected to reduced pressure distillation to remove the solvent, and then is recrystallized by methanol and dried to obtain 33.3g of 2-amino-5-bromopyridine white crystals, the GC purity is 99.4%, and the molar yield is 90.5%.
Example 3
Under the irradiation of a 160W blue light LED lamp, 20g (0.21mol) of 2-aminopyridine and 200mL of dichloromethane are sequentially added into a 500mL three-neck round-bottom flask, stirred and dissolved, then 1.8g of N-ethylpyridinium chloride-zinc chloride ionic liquid is added, after the solution fades, 20g (0.12mol) of bromine is added for halogenation reaction for 30min, the obtained reaction solution is subjected to reduced pressure distillation to remove the solvent, and further ethanol recrystallization and drying are carried out to obtain 33.8g of 2-amino-5-clopidogrel white crystals, wherein the GC purity is 99.6%, and the molar yield is 92.0%.
Of course, the foregoing is only a preferred embodiment of the invention and should not be taken as limiting the scope of the embodiments of the invention. The present invention is not limited to the above examples, and equivalent changes and modifications made by those skilled in the art within the spirit and scope of the present invention should be construed as being included in the scope of the present invention.
Claims (8)
1. A method for synthesizing 2-amino-5-bromopyridine under the catalysis of microwave and ionic liquid is characterized by comprising the following steps: adding 2-aminopyridine serving as a raw material into an organic solvent, and adding bromine under the action of an ionic liquid catalyst and microwave radiation to perform halogenation reaction; and removing the solvent from the obtained reaction solution by reduced pressure distillation and further recrystallizing to obtain the high-purity 2-amino-5-bromopyridine.
2. The method for synthesizing 2-amino-5-bromopyridine by microwave synergistic ionic liquid catalysis according to claim 1, wherein the method comprises the following steps: the organic solvent is one or more of acetone, dichloromethane, acetonitrile, chloroform or ethyl acetate.
3. The method for synthesizing 2-amino-5-bromopyridine by microwave synergistic ionic liquid catalysis according to claim 1, wherein the method comprises the following steps: the ionic liquid catalyst is Lewis acidic ionic liquid.
4. The method for synthesizing 2-amino-5-bromopyridine by microwave synergistic ionic liquid catalysis according to claim 3, wherein the method comprises the following steps: the Lewis acidic ionic liquid comprises one or more of zinc chloride, ferric trichloride or aluminum trichloride.
5. The method for synthesizing 2-amino-5-bromopyridine by microwave synergistic ionic liquid catalysis according to claim 1, wherein the method comprises the following steps: the microwave power is 50-160W, and the microwave radiation reaction time is 30-120 min.
6. The method for synthesizing 2-amino-5-bromopyridine by microwave synergistic ionic liquid catalysis according to claim 1, wherein the method comprises the following steps: the dosage of the ionic liquid catalyst is 5-20% of the dosage of the 2-aminopyridine by weight.
7. The method for synthesizing 2-amino-5-bromopyridine by microwave synergistic ionic liquid catalysis according to claim 1, wherein the method comprises the following steps: the bromine consumption is 0.7-1.5 times of the 2-aminopyridine consumption by weight.
8. The method for synthesizing 2-amino-5-bromopyridine by microwave synergistic ionic liquid catalysis according to claim 1, wherein the method comprises the following steps: the solvent used for recrystallization is one or more than one of methanol, ethanol, dichloromethane, chloroform, ethyl acetate or petroleum ether.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202010109436.XA CN111187206A (en) | 2020-02-22 | 2020-02-22 | Method for synthesizing 2-amino-5-bromopyridine under catalysis of microwave and ionic liquid |
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| CN202010109436.XA CN111187206A (en) | 2020-02-22 | 2020-02-22 | Method for synthesizing 2-amino-5-bromopyridine under catalysis of microwave and ionic liquid |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112745290A (en) * | 2020-12-30 | 2021-05-04 | 山东金城柯瑞化学有限公司 | Method for synthesizing 4-bromomethyl-5-methyl-1, 3-dioxole-2-one under catalysis of microwave and ionic liquid |
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2020
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112745290A (en) * | 2020-12-30 | 2021-05-04 | 山东金城柯瑞化学有限公司 | Method for synthesizing 4-bromomethyl-5-methyl-1, 3-dioxole-2-one under catalysis of microwave and ionic liquid |
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Application publication date: 20200522 |