CN117800907A - Method for synthesizing 6-amino-3-cyanopyridine-2-carboxylic acid methyl ester in one step - Google Patents
Method for synthesizing 6-amino-3-cyanopyridine-2-carboxylic acid methyl ester in one step Download PDFInfo
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- CN117800907A CN117800907A CN202211171998.2A CN202211171998A CN117800907A CN 117800907 A CN117800907 A CN 117800907A CN 202211171998 A CN202211171998 A CN 202211171998A CN 117800907 A CN117800907 A CN 117800907A
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- Prior art keywords
- cyanopyridine
- amino
- carboxylic acid
- methyl ester
- acid methyl
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- -1 6-amino-3-cyanopyridine-2-carboxylic acid methyl ester Chemical compound 0.000 title claims abstract description 24
- 238000000034 method Methods 0.000 title abstract description 6
- 230000002194 synthesizing effect Effects 0.000 title abstract description 5
- 229940126062 Compound A Drugs 0.000 claims abstract description 10
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims abstract description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 238000001308 synthesis method Methods 0.000 claims description 10
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 238000002156 mixing Methods 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 16
- 239000002994 raw material Substances 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 60
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 239000008346 aqueous phase Substances 0.000 description 5
- 239000012295 chemical reaction liquid Substances 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- GZPHSAQLYPIAIN-UHFFFAOYSA-N 3-pyridinecarbonitrile Chemical compound N#CC1=CC=CN=C1 GZPHSAQLYPIAIN-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000003674 animal food additive Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000000810 peripheral vasodilating agent Substances 0.000 description 1
- 229960002116 peripheral vasodilator Drugs 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Landscapes
- Pyridine Compounds (AREA)
Abstract
The invention belongs to the technical field of chemistry, and particularly relates to a method for synthesizing 6-amino-3-cyanopyridine-2-carboxylic acid methyl ester in one step. The method takes the compound A as the initial raw material, synthesizes the 6-amino-3-cyanopyridine-2-carboxylic acid methyl ester through one-step operation, has simple and easy operation reaction conditions, easily controlled reaction process and high reaction yield, and can realize industrialized mass production.
Description
Technical Field
The invention belongs to the technical field of chemistry, and particularly relates to a method for synthesizing 6-amino-3-cyanopyridine-2-carboxylic acid methyl ester in one step.
Background
The 3-cyanopyridine is mainly applied to intermediates of medicines, food additives, feed additives, pesticides and the like. The preparation method is mainly used for preparing peripheral vasodilators, namely nicotinol and the like in the pharmaceutical industry. Methyl 6-amino-3-cyanopyridine-2-carboxylate is an important derivative of 3-cyanopyridine, but no corresponding synthetic route exists in the market at present, and the yield is low.
Disclosure of Invention
The invention aims to overcome the existing defects and provide a method for synthesizing the 6-amino-3-cyanopyridine-2-carboxylic acid methyl ester by one step, which has high synthesis efficiency, high yield and simple operation.
The aim of the invention is realized by the following technical scheme:
a one-step synthesis method of 6-amino-3-cyanopyridine-2-carboxylic acid methyl ester is characterized by comprising the following steps: mixing the compound A, cuprous cyanide and N, N-dimethylformamide, and reacting at high temperature under nitrogen protection to obtain 6-amino-3-cyanopyridine-2-carboxylic acid methyl ester
。
Preferably, the mass ratio of the compound A to the cuprous cyanide is 12-16:5.
Preferably, the elevated temperature is 110-115 ℃.
The invention has the beneficial effects that:
the invention provides a synthesis method of 6-amino-3-cyanopyridine-2-carboxylic acid methyl ester, which has simple reaction conditions, easy operation, easy control of reaction process and high reaction yield, and can realize industrialized mass production.
Drawings
FIG. 1 is a spectrum of example 1.
Detailed Description
The preferred embodiments of the present invention will be described below with reference to the accompanying drawings, it being understood that the preferred embodiments described herein are for illustration and explanation of the present invention only, and are not intended to limit the present invention.
Example 1
The one-step synthesis method of the 6-amino-3-cyanopyridine-2-carboxylic acid methyl ester comprises the following steps:
12g of compound A,5g of cuprous cyanide, DMF and nitrogen are added into a reaction bottle to replace 2 times, the reaction is carried out for 3 hours at 113 ℃, the TLC detection is carried out, the raw materials are basically finished, the reaction liquid is poured into 500mL of ice water, 300mL of ethyl acetate is added, stirring is carried out for 5 minutes, diatomite is added for filtration, the filtrate is split, and the aqueous phase is extracted by ethyl acetate (200 mL x 10) until no product exists. The filter cake was rinsed with ethyl acetate/methanol=1/1 (100 ml x 5) until no product was present. The organic phases were combined, concentrated, loaded with silica gel, and passed through a column with n-hexane/ethyl acetate=45-55%. The organic phase was concentrated to give a pale green solid, acetonitrile (4 mL) was added, slurried, filtered, and dried to give 9.4g of a pale yellow solid, namely methyl 6-amino-3-cyanopyridine-2-carboxylate, in 94.3% yield and 99.3% purity.
Example 2
The one-step synthesis method of the 6-amino-3-cyanopyridine-2-carboxylic acid methyl ester comprises the following steps:
13g of compound A,5g of cuprous cyanide, DMF and nitrogen are added into a reaction bottle to replace 2 times, the reaction is carried out for 3 hours at 113 ℃, the TLC detection is carried out, the raw materials are basically finished, the reaction liquid is poured into 500mL of ice water, 300mL of ethyl acetate is added, stirring is carried out for 5 minutes, diatomite is added for filtration, the filtrate is split, and the aqueous phase is extracted by ethyl acetate (200 mL of 10) until no product exists. The filter cake was rinsed with ethyl acetate/methanol=1/1 (100 ml x 5) until no product was present. The organic phases were combined, concentrated, loaded with silica gel, and passed through a column with n-hexane/ethyl acetate=45-55%. The organic phase was concentrated to give a pale green solid, acetonitrile (4 mL) was added, slurried, filtered, and dried to give 8.6g of a pale yellow solid, namely methyl 6-amino-3-cyanopyridine-2-carboxylate, in 93.5% yield and 97.6% purity.
Example 3
The one-step synthesis method of the 6-amino-3-cyanopyridine-2-carboxylic acid methyl ester comprises the following steps:
16g of compound A,5g of cuprous cyanide, DMF and nitrogen are added into a reaction bottle to replace 2 times, the reaction is carried out for 3 hours at 115 ℃, the TLC detection is carried out, the raw materials are basically finished, the reaction liquid is poured into 500mL of ice water, 300mL of ethyl acetate is added, stirring is carried out for 5min, diatomite is added for filtration, the filtrate is split, and the aqueous phase is extracted by ethyl acetate (200 mL x 10) until no product exists. The filter cake was rinsed with ethyl acetate/methanol=1/1 (100 ml x 5) until no product was present. The organic phases were combined, concentrated, loaded with silica gel, and passed through a column with n-hexane/ethyl acetate=45-55%. The organic phase was concentrated to give a pale green solid, acetonitrile (4 mL) was added, slurried, filtered, and dried to give 9.9g of a pale yellow solid, namely methyl 6-amino-3-cyanopyridine-2-carboxylate, in 80.7% yield and 95.9% purity.
Example 4
The one-step synthesis method of the 6-amino-3-cyanopyridine-2-carboxylic acid methyl ester comprises the following steps:
13g of compound A,5g of cuprous cyanide, DMF and nitrogen are added into a reaction bottle to replace 2 times, reaction is carried out for 3 hours at 110 ℃, TLC detection is carried out, the raw materials are basically finished, the reaction liquid is poured into 500mL of ice water, 300mL of ethyl acetate is added, stirring is carried out for 5min, diatomite is added for filtration, the filtrate is split, and the aqueous phase is extracted with ethyl acetate (200 mL x 10) until no product exists. The filter cake was rinsed with ethyl acetate/methanol=1/1 (100 ml x 5) until no product was present. The organic phases were combined, concentrated, loaded with silica gel, and passed through a column with n-hexane/ethyl acetate=45-55%. The organic phase was concentrated to give a pale green solid, acetonitrile (4 mL) was added, slurried, filtered, and dried to give 9.1g of a pale yellow solid, namely methyl 6-amino-3-cyanopyridine-2-carboxylate, in a yield of 91.3% and a purity of 99.2%.
Example 5
The one-step synthesis method of the 6-amino-3-cyanopyridine-2-carboxylic acid methyl ester comprises the following steps:
13g of compound A,5g of cuprous cyanide, DMF and nitrogen are added into a reaction bottle to replace 2 times, the reaction is carried out for 3 hours at 115 ℃, the TLC detection is carried out, the raw materials are basically finished, the reaction liquid is poured into 500mL of ice water, 300mL of ethyl acetate is added, stirring is carried out for 5min, diatomite is added for filtration, the filtrate is split, and the aqueous phase is extracted by ethyl acetate (200 mL x 10) until no product exists. The filter cake was rinsed with ethyl acetate/methanol=1/1 (100 ml x 5) until no product was present. The organic phases were combined, concentrated, loaded with silica gel, and passed through a column with n-hexane/ethyl acetate=45-55%. The organic phase was concentrated to give a pale green solid, acetonitrile (4 mL) was added, slurried, filtered, and dried to give 9.3g of a pale yellow solid, namely methyl 6-amino-3-cyanopyridine-2-carboxylate, in 93.3% yield and 99% purity.
The foregoing description is only a preferred embodiment of the present invention, and the present invention is not limited thereto, but it is to be understood that modifications and equivalents of some of the technical features described in the foregoing embodiments may be made by those skilled in the art, although the present invention has been described in detail with reference to the foregoing embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (3)
1. A one-step synthesis method of 6-amino-3-cyanopyridine-2-carboxylic acid methyl ester is characterized by comprising the following steps: mixing the compound A, cuprous cyanide and N, N-dimethylformamide, and reacting at high temperature under nitrogen protection to obtain 6-amino-3-cyanopyridine-2-carboxylic acid methyl ester
。
2. The one-step synthesis method of 6-amino-3-cyanopyridine-2-carboxylic acid methyl ester according to claim 1, wherein the mass ratio of the compound A to the cuprous cyanide is 12-16:5.
3. The one-step synthesis method of 6-amino-3-cyanopyridine-2-carboxylic acid methyl ester according to claim 1, wherein the high temperature is 110-115 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211171998.2A CN117800907A (en) | 2022-09-26 | 2022-09-26 | Method for synthesizing 6-amino-3-cyanopyridine-2-carboxylic acid methyl ester in one step |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211171998.2A CN117800907A (en) | 2022-09-26 | 2022-09-26 | Method for synthesizing 6-amino-3-cyanopyridine-2-carboxylic acid methyl ester in one step |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117800907A true CN117800907A (en) | 2024-04-02 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211171998.2A Pending CN117800907A (en) | 2022-09-26 | 2022-09-26 | Method for synthesizing 6-amino-3-cyanopyridine-2-carboxylic acid methyl ester in one step |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117800907A (en) |
-
2022
- 2022-09-26 CN CN202211171998.2A patent/CN117800907A/en active Pending
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