CN112390744A - Synthesis method of 6-methoxypyridine-3-methyl formate - Google Patents
Synthesis method of 6-methoxypyridine-3-methyl formate Download PDFInfo
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- CN112390744A CN112390744A CN202011392449.9A CN202011392449A CN112390744A CN 112390744 A CN112390744 A CN 112390744A CN 202011392449 A CN202011392449 A CN 202011392449A CN 112390744 A CN112390744 A CN 112390744A
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- methoxypyridine
- methyl
- mass ratio
- methanol
- reduced pressure
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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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
-
- 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
Abstract
The invention discloses a synthesis method of 6-methoxypyridine-3-methyl formate, which comprises the steps of taking 2-chloronicotinic acid as a main raw material, taking methanol as a solvent, a methylating agent and concentrated sulfuric acid as a catalyst, and preparing an intermediate through an esterification reaction; the intermediate takes methanol as a solvent and sodium methoxide as alkali to replace halogen, so as to obtain 6-methoxypyridine-3-methyl formate; the whole process has the advantages of simple and easily obtained raw materials, simple and easy operation and good economic benefit.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a synthesis method of 6-methoxypyridine-3-methyl formate.
Background
Pyridine medicine is a widely used medicine, such as antiphlogistic, anticancer, hypotensive, diabetes and other medicines. Also can be applied to biology, pesticide and the like, such as herbicide, cotton bollworm drug and the like. 6-methoxypyridine-3-methyl formate is an important chemical intermediate, is used as one of pyridine medicine intermediates, and is widely applied to biology and medicines. Regarding the synthesis of 6-methoxypyridine-3-methyl formate, the first report shows that 2-chloronicotinic acid is used as a main raw material, methanol is used as a solvent, a methylating agent and concentrated sulfuric acid are used as catalysts, and an intermediate is prepared through an esterification reaction; the intermediate takes methanol as a solvent and sodium methoxide as alkali to replace halogen to prepare a target product, and the whole process has the advantages of simple and easily obtained raw materials, simple and easy operation and good economic benefit.
Disclosure of Invention
In order to solve the problems, the invention discloses a synthesis method of 6-methoxypyridine-3-methyl formate, which has the advantages of simple and easily obtained raw materials, easily controlled reaction, no high-pressure dangerous operation, no dangerous solvent and simple post-treatment.
In order to achieve the purpose, the invention provides the following technical scheme:
a synthetic method of 6-methoxypyridine-3-methyl formate comprises the following steps:
(1) sequentially adding methanol, 6-chloronicotinic acid and concentrated sulfuric acid, heating to reflux, carrying out reflux reaction for 6 hours, then carrying out reduced pressure concentration, slowly adding the concentrated solution into ice water, and adding an aqueous sodium hydroxide solution to adjust the pH value; extracting with dichloromethane for three times, combining organic phases, concentrating under reduced pressure, and pulping the concentrated crude product with petroleum ether to obtain an intermediate;
(2) sequentially adding methanol, sodium methoxide and the intermediate prepared in the step (1), heating to reflux, carrying out reflux reaction for 10 hours, then carrying out reduced pressure concentration, slowly adding the concentrated solution into ice water, extracting with dichloromethane for three times, combining organic phases, carrying out reduced pressure concentration, and pulping the concentrated crude product with petroleum ether to obtain 6-methoxypyridine-3-methyl formate;
further, the mass ratio of the methanol to the concentrated sulfuric acid to the 6-chloronicotinic acid in the step (1) is 3.5-4.5: 0.05-0.15: 1.
Furthermore, the mass ratio of the dichloromethane and the 6-chloronicotinic acid added in each step in the step (1) is 4.5-5.5: 1.
Further, the pH value in the step (1) is 7-10; the concentration of the sodium hydroxide aqueous solution was 20%.
Further, the mass ratio of the petroleum ether to the 6-chloronicotinic acid in the step (1) is 1.5-2.4: 1.
Further, the mass ratio of the methanol and the sodium methoxide in the step (2) to the intermediate obtained in the step (1) is 3.5-4.5: 0.3-0.4: 1.
Further, the mass ratio of the ice water to the concentrated solution in the step (2) is 4-5: 1.
Further, the mass ratio of the dichloromethane added in each step in the step (2) to the intermediate obtained in the step (1) is 3-5: 1.
Further, the mass ratio of the petroleum ether in the step (2) to the intermediate obtained in the step (1) is 1-2: 1
Compared with the prior art, the invention has the following advantages and beneficial effects:
the synthesis method provided by the invention has the advantages of simple and easily obtained raw materials, easily controlled reaction, no high-pressure dangerous operation, no dangerous solvent, simple post-treatment, simple and easy operation and good economic benefit.
Detailed Description
The technical solutions provided by the present invention will be described in detail below with reference to specific examples, and it should be understood that the following specific embodiments are only illustrative of the present invention and are not intended to limit the scope of the present invention.
Example 1
(1) 1.2kg of methanol, 315g of 6-chloronicotinic acid and 31.5g of concentrated sulfuric acid are sequentially added into a 5L reaction bottle, heated to reflux and reacted for 6 hours under heat preservation. The reaction solution was concentrated under reduced pressure to a small volume and slowly added to 1.5kg of ice water. And adjusting the pH value of the system to 8-9 by using a 20% sodium hydroxide aqueous solution. It is extracted three times with 2kg of dichloromethane each time. And combining organic phases, and concentrating under reduced pressure at 40-50 ℃ to obtain a crude product. The crude product is pulped by 600g of petroleum ether to obtain 286g of intermediate in the first step, the yield is 83.3 percent, and the purity is 98 percent.
(2) 1.2kg of methanol, 130g of sodium methoxide and 343.2g of first-step intermediate are sequentially added into a 5L reaction bottle, heated to reflux and kept for reaction for 10 hours. The reaction solution was concentrated under reduced pressure to a small volume and slowly added to 1.5kg of ice water. It is extracted three times with 2kg of dichloromethane each time. Mixing organic phases, and concentrating at 40-50 deg.C under reduced pressure to obtain crude product. The crude product is pulped by 500g of petroleum ether to obtain 273g of product, the yield is 81.6 percent, and the purity is 98 percent.
Example 2
The process was scaled up according to the reaction conditions of example 1, with the specific steps:
(1) 48kg of methanol, 12.6kg of 6-chloronicotinic acid and 1.26kg of concentrated sulfuric acid are sequentially added into a 100L reaction kettle, heated to reflux and reacted for 8 hours under heat preservation. The reaction solution was concentrated under reduced pressure to a small volume and slowly added to 60kg of ice water. And adjusting the pH value of the system to 8-9 by using a 20% sodium hydroxide aqueous solution. It was extracted three times with 60kg of dichloromethane each time. And combining organic phases, and concentrating under reduced pressure at 40-50 ℃ to obtain a crude product. The crude product is pulped by 24kg of petroleum ether to obtain 11.62kg of the intermediate in the first step, the yield is 84.6 percent, and the purity is 98 percent.
(2) 48kg of methanol, 5.2kg of sodium methoxide and 13.73kg of first-step intermediate are sequentially added into a 100L reaction kettle, heated to reflux and kept for reaction for 16 hours. The reaction solution was concentrated under reduced pressure to a small volume and slowly added to 60kg of ice water. It was extracted three times with 60kg of dichloromethane each time. And combining organic phases, and concentrating under reduced pressure at 40-50 ℃ to obtain a crude product. The crude product is pulped by 22kg of petroleum ether to obtain 11.12kg of product, the yield is 83.1 percent, and the purity is 98 percent.
As can be seen from example 2, the synthesis process of the invention is stable, has repeatability and is suitable for industrial production.
The technical means disclosed in the invention scheme are not limited to the technical means disclosed in the above embodiments, but also include the technical scheme formed by any combination of the above technical features. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principle of the present invention, and such improvements and modifications are also considered to be within the scope of the present invention.
Claims (9)
1. A synthetic method of 6-methoxypyridine-3-methyl formate is characterized by comprising the following steps:
(1) sequentially adding methanol, 6-chloronicotinic acid and concentrated sulfuric acid, heating to reflux, carrying out reflux reaction for 6 hours, then carrying out reduced pressure concentration, slowly adding the concentrated solution into ice water, and adding an aqueous sodium hydroxide solution to adjust the pH value; extracting with dichloromethane for three times, combining organic phases, concentrating under reduced pressure, and pulping the concentrated crude product with petroleum ether to obtain an intermediate;
(2) sequentially adding methanol, sodium methoxide and the intermediate prepared in the step (1), heating to reflux, carrying out reflux reaction for 10 hours, then carrying out reduced pressure concentration, slowly adding the concentrated solution into ice water, extracting with dichloromethane for three times, combining organic phases, carrying out reduced pressure concentration, and pulping the concentrated crude product with petroleum ether to obtain 6-methoxypyridine-3-methyl formate;
2. the method for synthesizing methyl 6-methoxypyridine-3-carboxylate according to claim 1, wherein the mass ratio of methanol to concentrated sulfuric acid to 6-chloronicotinic acid in the step (1) is 3.5-4.5: 0.05-0.15: 1.
3. The method for synthesizing methyl 6-methoxypyridine-3-carboxylate according to claim 1, wherein the mass ratio of dichloromethane to 6-chloronicotinic acid added in each step (1) is 4.5-5.5: 1.
4. The synthesis method of methyl 6-methoxypyridine-3-carboxylate according to claim 1, wherein the pH in step (1) is 7 to 10; the concentration of the sodium hydroxide aqueous solution was 20%.
5. The method for synthesizing methyl 6-methoxypyridine-3-carboxylate according to claim 1, wherein the mass ratio of the petroleum ether to the 6-chloronicotinic acid in the step (1) is 1.5 to 2.4: 1.
6. The method for synthesizing 6-methoxypyridine-3-carboxylic acid methyl ester according to claim 1, wherein the mass ratio of methanol to sodium methoxide to the intermediate obtained in step (1) in step (2) is 3.5 to 4.5:0.3 to 0.4: 1.
7. The synthesis method of methyl 6-methoxypyridine-3-carboxylate according to claim 1, wherein the mass ratio of ice water to the concentrated solution in the step (2) is 4-5: 1.
8. The method for synthesizing methyl 6-methoxypyridine-3-carboxylate according to claim 1, wherein the mass ratio of dichloromethane added in each step (2) to the intermediate obtained in step (1) is 3-5: 1.
9. The synthesis method of methyl 6-methoxypyridine-3-carboxylate according to claim 1, wherein the mass ratio of the petroleum ether in the step (2) to the intermediate obtained in the step (1) is 1-2: 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN202011392449.9A CN112390744A (en) | 2020-12-02 | 2020-12-02 | Synthesis method of 6-methoxypyridine-3-methyl formate |
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| CN202011392449.9A CN112390744A (en) | 2020-12-02 | 2020-12-02 | Synthesis method of 6-methoxypyridine-3-methyl formate |
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2020
- 2020-12-02 CN CN202011392449.9A patent/CN112390744A/en active Pending
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