CN111732534A - Method for synthesizing 2-amino-5-chloropyridine under catalysis of microwave and Lewis acidic ionic liquid - Google Patents
Method for synthesizing 2-amino-5-chloropyridine under catalysis of microwave and Lewis acidic ionic liquid Download PDFInfo
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- CN111732534A CN111732534A CN201911392754.5A CN201911392754A CN111732534A CN 111732534 A CN111732534 A CN 111732534A CN 201911392754 A CN201911392754 A CN 201911392754A CN 111732534 A CN111732534 A CN 111732534A
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- 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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Abstract
The invention relates to a method for synthesizing 2-amino-5-chloropyridine under the catalysis of microwave and Lewis acidic ionic liquid, which comprises the following steps: taking 2-aminopyridine as a raw material, adding the 2-aminopyridine into an organic solvent, and introducing chlorine gas under the action of Lewis acidic ionic liquid serving as a catalyst and microwave radiation to perform chlorination reaction; and distilling the obtained reaction solution under reduced pressure to remove the solvent, and further recrystallizing to obtain the high-purity 2-amino-5-chloropyridine. Compared with the prior art, the method has the advantages of simplified production process, mild reaction conditions, higher product purity, recyclable Lewis acidic ionic liquid and low production cost.
Description
Technical Field
The invention belongs to the technical field of synthesis of 2-amino-5-chloropyridine, and particularly relates to a method for synthesizing 2-amino-5-chloropyridine under catalysis of microwave and Lewis acidic ionic liquid.
Background
2-amino-5-chloropyridine is an important chemical intermediate and is widely applied to the fields of medicines, pesticides and dyes. 2-amino-5-chloropyridine can be used for synthesizing various substances, such as zopiclone serving as a sedative-hypnotic drug, edoxaban serving as a novel anticoagulant and the like, and meanwhile, 2-amino-5-chloropyridine is an antiparasitic drug with a good effect. 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) U.S. Thomas et al, in its patent US3985759, propose to dissolve 2-aminopyridine in a strong acid solvent, and directly prepare 2-amino-5-chloropyridine by introducing chlorine gas at low temperature, with a reaction yield up to 80%. Although the method has high yield, the reaction conditions are severe and the requirements on equipment are high, and the method needs to be carried out at the temperature of minus 20 ℃ and under the condition of a strong acid medium.
(2) The 2-aminopyridine is subjected to nitration, acylation, reduction, chlorination and hydrolysis reaction to prepare the target product 2-amino-5-chloropyridine, and although the reaction conditions of the process are mild, the operation steps are complex and are not suitable for industrial production.
(3) N-chlorosuccinimide (NCS) is a chlorinating agent to synthesize the product 2-amino-5-chloropyridine, the yield of the method can reach 90 percent, but the expensive chlorinating agent NCS is used, dichloro products are inevitably generated in the reaction, and the separation and purification of the product are difficult.
(4) Hydrochloric acid and an oxidant are used for chlorination instead of chlorine gas, for example, a hydrochloric acid and sodium hypochlorite method is adopted in patent CN106432069, and a hydrochloric acid and hydrogen peroxide method is adopted in patent CN 106632014. The method has better selectivity, but can not avoid the generation of dichlorinated products, and the addition of the oxidant can cause partial oxidation of the raw material 2-aminopyridine and the product 2-amino-5-chloropyridine, thereby causing the loss of materials and products and larger wastewater yield.
Disclosure of Invention
The invention aims to overcome the defects of the prior art, provides a method for synthesizing 2-amino-5-chloropyridine under the catalysis of microwave and ionic liquid, and aims to solve the problems of high cost, harsh reaction conditions, difficult separation of products and the like in the prior art.
The invention relates to a method for synthesizing 2-amino-5-chloropyridine under the catalysis of microwave and ionic liquid, which comprises the following steps:
taking 2-aminopyridine as a raw material, adding the 2-aminopyridine into an organic solvent, and introducing chlorine gas under the action of Lewis acidic ionic liquid serving as a catalyst and microwave radiation to perform chlorination reaction; and distilling the obtained reaction solution under reduced pressure to remove the solvent, and further recrystallizing to obtain the high-purity 2-amino-5-chloropyridine.
Preferably, the organic solvent comprises more than one of acetone, dichloromethane, acetonitrile, chloroform or ethyl acetate; more preferably, acetone and/or acetonitrile are included.
Preferably, the power of the microwave radiation is 50-160W, and more preferably, 50-60W; the radiation reaction time is 30min to 120min, and more preferably 30min to 50 min.
Preferably, the Lewis acidic ionic liquid comprises more than one of zinc chloride, ferric trichloride and aluminum trichloride, and the dosage of the Lewis acidic ionic liquid is 5-20% of that of 2-aminopyridine by weight.
Preferably, the amount of the chlorine is 0.7 to 1.5 times of the amount of the 2-aminopyridine in weight.
Preferably, the solvent used for recrystallization comprises more than one of methanol, ethanol, dichloromethane, chloroform, ethyl acetate or petroleum ether; more preferably, it comprises 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 chlorine or hydrochloric acid and an oxidant are directly used as a chlorination reagent, Lewis acidic ionic liquid is used as a catalyst, so that chlorine in a solvent can be polarized more quickly, and the chlorination reaction time is shortened. Different from the conventional heating mode, the microwave-assisted method belongs to internal heating, and the system is heated more uniformly, so that the generation of polychlorinated products by the cascade reaction of 2-amino-5-chloropyridine due to the overhigh temperature of a certain site of the system is avoided, and the chlorination selectivity is better and the high-content 2-amino-5-chloropyridine is obtained at the same time.
(3) Through the improvement, compared with the prior art, the method has the advantages of simplified production process, mild reaction conditions, higher product purity, recyclable Lewis acidic ionic liquid and low production cost.
Detailed Description
In order to better explain the present invention and to facilitate the understanding of the technical solutions of the present invention, the present invention is further described in detail below. However, the following examples are only illustrative of the present invention and do not represent or limit the scope of the present invention, which is defined by the claims.
Example 1
Under 50W microwave radiation, 20g (0.21 mol) 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 16g (4.3L) of chlorine is introduced, reaction is carried out for 45min, recrystallization is carried out by methanol, and drying is carried out, thus obtaining 24.6g of white crystals of 2-amino-5-clopidogrel, the GC purity is 99.6%, and the molar yield is 90.0%.
Example 2
Under 60W microwave radiation, 20g (0.21 mol) 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-ethylpyridinium chloride-aluminum trichloride ionic liquid is added, 30g (9.46L) of chlorine is introduced, reaction is carried out for 50min, recrystallization is carried out by methanol, and drying is carried out, thus obtaining 25.7g of 2-amino-5-clopidogrel white crystals with the GC purity of 99.4 percent and the molar yield of 99.4 percent.
Example 3
Under the irradiation of a 160W blue light LED lamp, 20g (0.21 mol) 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 (6.3L) of chlorine is introduced, the reaction is carried out for 30min, and the white crystals of 2-amino-5-clopidogrel are obtained after recrystallization and drying by ethanol, wherein the GC purity is 99.6 percent, and the molar yield is 95.6 percent.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (10)
1. A method for synthesizing 2-amino-5-chloropyridine 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 introducing chlorine gas under the radiation of Lewis acidic ionic liquid serving as a catalyst and microwave to perform chlorination reaction; and distilling the obtained reaction solution under reduced pressure to remove the solvent, and further recrystallizing to obtain the high-purity 2-amino-5-chloropyridine.
2. The method for synthesizing 2-amino-5-chloropyridine under catalysis of microwave and ionic liquid according to claim 1, wherein the method comprises the following steps: the organic solvent comprises more than one of acetone, dichloromethane, acetonitrile, trichloromethane or ethyl acetate.
3. The method for synthesizing 2-amino-5-chloropyridine under catalysis of microwave and ionic liquid according to claim 1, wherein the method comprises the following steps: the microwave power is 50-160W; the radiation reaction time is 30 min-120 min.
4. The method for synthesizing 2-amino-5-chloropyridine under catalysis of microwave and ionic liquid according to claim 1, wherein the method comprises the following steps: the microwave power is 50-60W; the radiation reaction time is 30 min-50 min.
5. The method for synthesizing 2-amino-5-chloropyridine under catalysis of microwave and ionic liquid according to claim 1, wherein the method comprises the following steps: the microwave power is 60W; the radiation reaction time is 50 min.
6. The method for synthesizing 2-amino-5-chloropyridine by microwave synergistic ionic liquid catalysis according to any one of claims 1 to 4, wherein the method comprises the following steps: the dosage of the Lewis acidic ionic liquid is 5-20% of that of the 2-aminopyridine by weight.
7. The method for synthesizing 2-amino-5-chloropyridine under catalysis of microwave and ionic liquid according to claim 5, wherein the method comprises the following steps: the Lewis acidic ionic liquid comprises more than one of zinc chloride, ferric trichloride and aluminum trichloride.
8. The method for synthesizing 2-amino-5-chloropyridine by microwave synergistic ionic liquid catalysis according to any one of claims 1 to 4, wherein the method comprises the following steps: the amount of chlorine is 0.7-1.5 times of the amount of 2-aminopyridine by weight.
9. The method for synthesizing 2-amino-5-chloropyridine by microwave synergistic ionic liquid catalysis according to any one of claims 1 to 4, wherein the method comprises the following steps: the solvent for recrystallization comprises more than one of methanol, ethanol, dichloromethane, chloroform, ethyl acetate or petroleum ether.
10. The method for synthesizing 2-amino-5-chloropyridine by microwave synergistic ionic liquid catalysis according to any one of claim 9, wherein the method comprises the following steps: the solvent used for recrystallization is methanol or ethanol.
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| 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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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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: 20201002 |