CN111100068A - Method for quickly and efficiently synthesizing 3-amino methyl isonicotinate - Google Patents
Method for quickly and efficiently synthesizing 3-amino methyl isonicotinate Download PDFInfo
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- CN111100068A CN111100068A CN201911386631.0A CN201911386631A CN111100068A CN 111100068 A CN111100068 A CN 111100068A CN 201911386631 A CN201911386631 A CN 201911386631A CN 111100068 A CN111100068 A CN 111100068A
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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
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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
- C07D213/803—Processes of preparation
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Abstract
The invention belongs to the field of chemical pharmacy, and particularly discloses a method for quickly and efficiently synthesizing 3-amino isonicotinic acid methyl ester, which is obtained by nitration, reduction and esterification. The method for quickly and efficiently synthesizing the 3-amino methyl isonicotinate has the advantages of mild reaction conditions, high overall reaction rate, high overall yield, repeated utilization of the main component palladium-carbon in the catalyst, improvement of the utilization rate of raw materials, reduction of resource waste, reduction of the production cost of the whole process to the maximum extent and extremely high application.
Description
Technical Field
The invention belongs to the field of chemical pharmacy, and particularly relates to a method for quickly and efficiently synthesizing 3-amino methyl isonicotinate.
Background
The 3-amino methyl isonicotinate is a common chemical raw material, and the traditional synthesis method uses 3, 4-pyridinedicarboxylic acid as a raw material, firstly amidates the raw material with acetamide at high temperature under the catalysis of acetic anhydride to obtain pyridinedicarboximide, and then obtains a target compound through Hofmann degradation and esterification. The chemical equation is shown in figure 1, the method needs high-temperature reaction, the production energy consumption is high, the Hofmann degradation yield is low, the yield reported in patent WO2006090167 is 68%, and the production cost is high. Meanwhile, the traditional method of using palladium-carbon to catalyze hydrogenation reduction reaction has incomplete reaction, low utilization rate of raw materials, low yield of products and easy poisoning of palladium-carbon in the reaction, so that the reaction is difficult to carry out.
Disclosure of Invention
The purpose of the invention is as follows: aiming at the defects in the prior art, the method for quickly and efficiently synthesizing the 3-amino methyl isonicotinate takes 4-pyridine carboxylic acid as a raw material and obtains the 3-amino methyl isonicotinate through nitration, reduction and esterification.
Further, the method for quickly and efficiently synthesizing the 3-amino methyl isonicotinate comprises the following steps:
A. synthesis of 3-nitro-4-pyridinecarboxylic acid
Adding 4-pyridine carboxylic acid, sulfuric acid and sodium nitrate into a reactor, controlling the temperature to be 10-30 ℃, dropwise adding nitric acid while stirring, heating to 60-65 ℃, keeping the temperature for 5 hours after adding, cooling to room temperature, adding the reaction liquid into ice water, filtering, and drying to obtain 3-nitro-4-pyridine carboxylic acid;
B. synthesis of methyl 3-amino-4-pyridinecarboxylate
Adding 3-nitro-4-pyridine carboxylic acid, a catalyst and methanol into a hydrogenation reaction kettle, performing nitrogen displacement for 3 times, introducing hydrogen to 0.5-1.5MPa, reacting for 1-5 hours, performing nitrogen displacement for 3 times after pressure relief, filtering for 2 times, transferring mother liquor into a reactor, controlling the temperature to be 0-30 ℃, dropwise adding sulfuric acid, heating and refluxing for 12 hours after the addition is finished, concentrating the methanol under negative pressure until no liquid is discharged, adding 18% ammonia water to adjust the pH value to 7-8, adding water, stirring and cooling to 0-5 ℃, filtering, and drying to obtain the 3-amino methyl isonicotinate.
Further, in the method for rapidly and efficiently synthesizing the methyl 3-aminoisonicotinate, the catalyst in the step B is a palladium-carbon sodium metaaluminate solution or Raney nickel.
In a preferable mode of the present invention, in the above method for rapidly and efficiently synthesizing methyl 3-aminoisonicotinate, the catalyst in the step B is a palladium-carbon sodium metaaluminate solution
Further, in the method for quickly and efficiently synthesizing the methyl 3-aminoisonicotinate, 1g of palladium-carbon sodium metaaluminate solution is soaked in 10m of 10% sodium metaaluminate solution.
Further, in the above method for rapidly and efficiently synthesizing methyl 3-aminoisonicotinate, in the step a, the ratio of 4-pyridinecarboxylic acid: nitric acid: sodium nitrate =1:1-1.5:0.2-0.5 (molar ratio).
Further, in the above method for rapidly and efficiently synthesizing methyl 3-aminoisonicotinate, in the step a, the ratio of 4-pyridinecarboxylic acid: sulfuric acid =1:1 (weight ratio).
Further, in the above method for rapidly and efficiently synthesizing methyl 3-aminoisonicotinate, in step B, the ratio of 3-nitro-4-pyridinecarboxylic acid to sulfuric acid =1: 0.2 (by weight).
Further, in the above method for rapidly and efficiently synthesizing methyl 3-aminoisonicotinate, TLC is used in step B to analyze whether the reaction is complete.
Further, in the method for quickly and efficiently synthesizing the methyl 3-aminoisonicotinate, the catalyst in the step B is recycled.
The method for quickly and efficiently synthesizing the 3-amino methyl isonicotinate takes 4-pyridine carboxylic acid as a raw material, and the 3-amino methyl isonicotinate is obtained by nitration, catalytic reduction and esterification. The sodium nitrate is used in the nitration reaction, so that the reaction efficiency can be improved, the sodium nitrate absorbs water generated by the reaction, the reaction can be promoted to be carried out in the positive direction, and meanwhile, the participation of nitrate ions increases the probability of nitro on a pyridine ring, so that the reaction efficiency is improved. The palladium-carbon sodium metaaluminate solution is used as a catalyst in the catalytic reduction reaction, the reduction of the nitro group can be quickly and efficiently realized, the alkaline environment of the sodium metaaluminate solution can effectively prevent palladium-carbon poisoning, carboxylic acid on a pyridine ring can be protected, the generation of impurities is effectively reduced, meanwhile, the existence of aluminum ions can improve the catalytic activity of the palladium-carbon, the reaction speed is accelerated, the reaction rate is improved, and the reaction is thorough.
The technical scheme shows that the invention has the following beneficial effects:
1. the invention provides a brand new synthetic route, adopts palladium carbon sodium metaaluminate solution as a catalyst, accelerates the reaction speed, improves the reaction rate and ensures thorough reaction.
2. The method adopts a mode of adding sodium nitrate in the nitration reaction, and can improve the rate of the nitration reaction.
3. The catalytic palladium-added carbon or Raney nickel used in the invention can be recycled, so that the resource waste and the environmental pollution are reduced, and the production cost of the whole process is reduced to the maximum extent.
Drawings
FIG. 1 is a schematic representation of the synthesis of methyl 3-aminoisonicotinate of the prior art;
FIG. 2 is a scheme showing the synthesis of methyl 3-aminoisonicotinate according to the present invention.
Detailed Description
The invention will be further illustrated by the following specific examples, which are given for the purpose of illustration only and are not intended to be limiting.
Example 1
A method for rapidly and efficiently synthesizing 3-amino methyl isonicotinate is shown in figure 2 and comprises the following steps:
1. synthesis of 3-bromo-4-pyridinecarboxylic acid
Adding 50g (406.5 mmol) of 4-pyridinecarboxylic acid, 50g of sulfuric acid and 10.4g (122.0 mmol) of sodium nitrate into a reaction bottle, dropwise adding 30.7g (487.8 mmol) of nitric acid under stirring at the temperature of 20 ℃, heating to 60 +/-65 ℃, preserving the temperature for 5 hours after the addition is finished, cooling to room temperature, dropwise adding the reaction liquid into 200ml of ice water, and filtering to obtain 58.8g of 3-nitro-4-pyridinecarboxylic acid with the yield of 86% and the HPLC purity of 97.8%.
2. Synthesis of methyl 3-aminoisonicotinate
Adding 50g (297.6 mmol) of 3-nitro-4-pyridinecarboxylic acid, 10ml of palladium-carbon sodium metaaluminate solution and 300ml of methanol into a hydrogenation reaction kettle, replacing 3 times with nitrogen, introducing hydrogen to 0.5MPa, keeping the pressure for reaction for 1 hour, completely performing TLC detection reaction, replacing 3 times with nitrogen after pressure relief, filtering, transferring mother liquor into a reaction bottle, controlling the temperature to be 20 ℃, dropwise adding 10g of sulfuric acid, after the addition is finished, heating and refluxing for 12 hours, concentrating the methanol under negative pressure until no liquid is discharged, adding 18% ammonia water to adjust the PH to 7-8, adding 200ml of water, stirring and cooling to 0-5 ℃, and filtering to obtain 40.26g of white crystalline solid, wherein the yield is 89%, and the HPLC purity is 99.6%.
1H NMR (DMSO，300MHz) δ：3.95（3H，s），5.82（2H，s），7.45,（1H，d）, 7.73,（1H，d）,8.21（1H，s）。FAB-MS(m/z)：153(M+H)。
Example 2
A method for rapidly and efficiently synthesizing 3-amino methyl isonicotinate is shown in figure 2 and comprises the following steps:
1. synthesis of 3-bromo-4-pyridinecarboxylic acid
Adding 50g (406.5 mmol) of 4-pyridinecarboxylic acid, 50g (406.5 mmol) of sulfuric acid and 17.3g (203.3 mmol) of sodium nitrate into a reaction bottle, controlling the temperature to be 30 ℃, dropwise adding 25.6g (406.5 mmol) of nitric acid under stirring, raising the temperature to 60 +/-2 ℃, preserving the temperature for 5 hours, cooling to room temperature, dropwise adding the reaction liquid into 200ml of ice water, and filtering to obtain 55.3g of 3-nitro-4-pyridinecarboxylic acid, wherein the yield is 81 percent and the HPLC purity is 98.6 percent.
2. Synthesis of methyl 3-aminoisonicotinate
Adding 50g (297.6 mmol) of 3-nitro-4-pyridinecarboxylic acid, 5g of raney nickel and 300ml of methanol into a hydrogenation reaction kettle, replacing 3 times with nitrogen, introducing hydrogen to 1.5MPa, keeping the pressure for reaction for 5 hours, completely detecting by TLC, replacing 3 times with nitrogen after pressure relief, filtering, transferring mother liquor into a reaction bottle, dropwise adding 10g of sulfuric acid at the temperature of 30 ℃, heating and refluxing for 12 hours after adding, concentrating the methanol under negative pressure until no liquid is discharged, adding 18% ammonia water to adjust the PH to 7-8, adding 150ml of water, stirring and cooling to 0-5 ℃, filtering to obtain 39.3g of white crystalline solid, wherein the yield is 86.5%, and the HPLC purity is 99.1%.
1H NMR (DMSO，300MHz) δ：3.95（3H，s），5.82（2H，s），7.45,（1H，d）, 7.73,（1H，d）,8.21（1H，s）。FAB-MS(m/z)：153(M+H)。
Example 3
A method for rapidly and efficiently synthesizing 3-amino methyl isonicotinate is shown in figure 2 and comprises the following steps:
1. synthesis of 3-bromo-4-pyridinecarboxylic acid
Adding 50g (406.5 mmol) of 4-pyridinecarboxylic acid, 50g of sulfuric acid and 6.9g (81.3 mmol) of sodium nitrate into a reaction bottle, dropwise adding 38.4g (609.8 mmol) of nitric acid under stirring at the temperature of 20 ℃, heating to 60 +/-65 ℃, preserving the temperature for 5 hours after the addition is finished, cooling to room temperature, dropwise adding the reaction liquid into 150ml of ice water, and filtering to obtain 56.3g of 3-nitro-4-pyridinecarboxylic acid, wherein the yield is 83.2 percent and the HPLC purity is 98.3 percent.
2. Synthesis of methyl 3-aminoisonicotinate
Adding 50g (297.6 mmol) of 3-nitro-4-pyridinecarboxylic acid, 20ml of palladium-carbon sodium metaaluminate solution and 300ml of methanol into a hydrogenation reaction kettle, replacing 3 times by nitrogen, introducing hydrogen to 1MPa, keeping the pressure for reaction for 3 hours, completely performing TLC detection reaction, replacing 3 times by nitrogen after pressure relief, filtering, transferring mother liquor into a reaction bottle, dropwise adding 10g of sulfuric acid at the temperature of 20 ℃, heating and refluxing for 12 hours after addition, concentrating the methanol under negative pressure until no liquid is discharged, adding 18% ammonia water to adjust the PH to 7-8, adding 150ml of water, stirring and cooling to 0-5 ℃, filtering to obtain 41.5g of white crystalline solid, wherein the yield is 91.7%, and the HPLC purity is 99.5%.
1H NMR (DMSO，300MHz) δ：3.95（3H，s），5.82（2H，s），7.45,（1H，d）, 7.73,（1H，d）,8.21（1H，s）。FAB-MS(m/z)：153(M+H)。
The invention provides a method for quickly and efficiently synthesizing 3-amino methyl isonicotinate, which takes 4-pyridine carboxylic acid as a raw material, obtains the 3-amino methyl isonicotinate through nitration, catalytic reduction and esterification, has mild reaction conditions, quick and efficient reaction, total yield of more than 85 percent, and yield (68 percent) of more than patent WO2006090167, and is greatly improved.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that modifications can be made by those skilled in the art without departing from the principle of the present invention, and these modifications should also be construed as the protection scope of the present invention.
Claims (9)
1. A method for quickly and efficiently synthesizing 3-amino methyl isonicotinate is characterized by comprising the following steps: 4-pyridine carboxylic acid is used as a raw material, and the 3-amino methyl isonicotinate is obtained through nitration, reduction and esterification.
2. The method for rapidly and efficiently synthesizing 3-aminoisonicotinic acid methyl ester according to claim 1, characterized in that: the method comprises the following steps:
A. synthesis of 3-nitro-4-pyridinecarboxylic acid
Adding 4-pyridine carboxylic acid, sulfuric acid and sodium nitrate into a reactor, controlling the temperature to be 10-30 ℃, dropwise adding nitric acid while stirring, heating to 60-65 ℃, keeping the temperature for 5 hours after adding, cooling to room temperature, adding the reaction liquid into ice water, filtering, and drying to obtain 3-nitro-4-pyridine carboxylic acid;
B. synthesis of methyl 3-amino-4-pyridinecarboxylate
Adding 3-nitro-4-pyridine carboxylic acid, a catalyst and methanol into a hydrogenation reaction kettle, performing nitrogen displacement for 3 times, introducing hydrogen to 0.5-1.5MPa, reacting for 1-5 hours, performing nitrogen displacement for 3 times after pressure relief, filtering for 2 times, transferring mother liquor into a reactor, controlling the temperature to be 0-30 ℃, dropwise adding sulfuric acid, heating and refluxing for 12 hours after the addition is finished, concentrating the methanol under negative pressure until no liquid is discharged, adding 18% ammonia water to adjust the pH value to 7-8, adding water, stirring and cooling to 0-5 ℃, filtering, and drying to obtain the 3-amino methyl isonicotinate.
3. The method for rapidly and efficiently synthesizing 3-aminoisonicotinic acid methyl ester according to claim 2, characterized in that: and the catalyst in the step B is a palladium-carbon sodium metaaluminate solution or Raney nickel.
4. The method for rapidly and efficiently synthesizing 3-aminoisonicotinic acid methyl ester according to claim 3, characterized in that: the palladium carbon sodium metaaluminate solution is obtained by soaking 1g of palladium carbon in 10m of 10% sodium metaaluminate solution.
5. The method for rapidly and efficiently synthesizing 3-aminoisonicotinic acid methyl ester according to claim 2, characterized in that: the ratio of 4-pyridinecarboxylic acid in step A: nitric acid: sodium nitrate =1:1-1.5:0.2-0.5 (molar ratio).
6. The method for rapidly and efficiently synthesizing 3-aminoisonicotinic acid methyl ester according to claim 5, characterized in that: the ratio of 4-pyridinecarboxylic acid in step A: sulfuric acid =1:1 (weight ratio).
7. The method for rapidly and efficiently synthesizing 3-aminoisonicotinic acid methyl ester according to claim 3, characterized in that: the 3-nitro-4-pyridinecarboxylic acid: sulfuric acid =1: 0.2 (weight ratio) in step B.
8. The method for rapidly and efficiently synthesizing 3-aminoisonicotinic acid methyl ester according to claim 7, characterized in that: and in the step B, TLC is adopted to analyze whether the reaction is complete.
9. The method for rapidly and efficiently synthesizing 3-aminoisonicotinic acid methyl ester according to claim 2, characterized in that: and the catalyst in the step B is repeatedly utilized.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1743313A (en) * | 2005-07-06 | 2006-03-08 | 湛江师范学院 | One-step reaction method for preparing 4-nitropyridine-nitrogen oxide and halogenated-4-nitropyridine-nitrogen oxide |
| US20100004292A1 (en) * | 2005-09-08 | 2010-01-07 | Bayer Healthcare Ag | Iminooxazolidine Derivatives and Their Use |
| CN105175691A (en) * | 2015-09-17 | 2015-12-23 | 南京邮电大学 | Conjugated polymer semiconductor materials based on thienoarylindole unit and preparation method thereof, and application of conjugated polymer semiconductor materials in high-efficiency polymer solar cells. |
| WO2019057053A1 (en) * | 2017-09-20 | 2019-03-28 | 北京加科思益新药研发有限公司 | Fused ring derivative used as fgfr4 inhibitor |
-
2019
- 2019-12-29 CN CN201911386631.0A patent/CN111100068A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1743313A (en) * | 2005-07-06 | 2006-03-08 | 湛江师范学院 | One-step reaction method for preparing 4-nitropyridine-nitrogen oxide and halogenated-4-nitropyridine-nitrogen oxide |
| US20100004292A1 (en) * | 2005-09-08 | 2010-01-07 | Bayer Healthcare Ag | Iminooxazolidine Derivatives and Their Use |
| CN105175691A (en) * | 2015-09-17 | 2015-12-23 | 南京邮电大学 | Conjugated polymer semiconductor materials based on thienoarylindole unit and preparation method thereof, and application of conjugated polymer semiconductor materials in high-efficiency polymer solar cells. |
| WO2019057053A1 (en) * | 2017-09-20 | 2019-03-28 | 北京加科思益新药研发有限公司 | Fused ring derivative used as fgfr4 inhibitor |
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| JAN M. BAKKE等: "The synthesis of β-nitropyridine compounds", 《ACTA CHEMICA SCANDINAVICA》 * |
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| 张枫等: "《医学化学基础》", 30 June 2010, 中国协和医科大学出版社 * |
| 张玮: "吡啶的亲电取代反应及其亲核性", 《石家庄职业技术学院学报》 * |
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