CN111018775A - High-yield synthesis method of 3-amino methyl isonicotinate - Google Patents
High-yield synthesis method of 3-amino methyl isonicotinate Download PDFInfo
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- 238000001308 synthesis method Methods 0.000 title claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 15
- BZFGKBQHQJVAHS-UHFFFAOYSA-N 2-(trifluoromethyl)pyridine-4-carboxylic acid Chemical compound OC(=O)C1=CC=NC(C(F)(F)F)=C1 BZFGKBQHQJVAHS-UHFFFAOYSA-N 0.000 claims abstract description 12
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Natural products OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 claims abstract description 12
- AVXWWBFBRTXBRM-UHFFFAOYSA-N 3-bromopyridine-4-carboxylic acid Chemical compound OC(=O)C1=CC=NC=C1Br AVXWWBFBRTXBRM-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000002994 raw material Substances 0.000 claims abstract description 9
- 230000032050 esterification Effects 0.000 claims abstract description 5
- 238000005886 esterification reaction Methods 0.000 claims abstract description 5
- 230000031709 bromination Effects 0.000 claims abstract description 4
- 238000005893 bromination reaction Methods 0.000 claims abstract description 4
- 239000000706 filtrate Substances 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 49
- XLQIGLBALJNHKR-UHFFFAOYSA-N methyl 3-aminopyridine-4-carboxylate Chemical compound COC(=O)C1=CC=NC=C1N XLQIGLBALJNHKR-UHFFFAOYSA-N 0.000 claims description 24
- 238000001816 cooling Methods 0.000 claims description 20
- 230000015572 biosynthetic process Effects 0.000 claims description 19
- 238000003786 synthesis reaction Methods 0.000 claims description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- FYEQKMAVRYRMBL-UHFFFAOYSA-N 3-aminopyridine-4-carboxylic acid Chemical compound NC1=CN=CC=C1C(O)=O FYEQKMAVRYRMBL-UHFFFAOYSA-N 0.000 claims description 17
- 238000001914 filtration Methods 0.000 claims description 17
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 16
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 16
- 238000001035 drying Methods 0.000 claims description 15
- 238000010438 heat treatment Methods 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 15
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 14
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 7
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- PTMBWNZJOQBTBK-UHFFFAOYSA-N pyridine-4-methanol Natural products OCC1=CC=NC=C1 PTMBWNZJOQBTBK-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 239000000126 substance Substances 0.000 abstract description 3
- 239000002699 waste material Substances 0.000 abstract description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- PYTGOQORCFQPSZ-UHFFFAOYSA-N tert-butyl 2-propylpiperazine-1-carboxylate Chemical compound CCCC1CNCCN1C(=O)OC(C)(C)C PYTGOQORCFQPSZ-UHFFFAOYSA-N 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 3
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- GGHLRJMDFJQGDT-UHFFFAOYSA-N 5h-imidazo[1,5-a]pyridine-1,3-dione Chemical compound C1=CCN2C(=O)NC(=O)C2=C1 GGHLRJMDFJQGDT-UHFFFAOYSA-N 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000013064 chemical raw material Substances 0.000 description 1
- MUYSADWCWFFZKR-UHFFFAOYSA-N cinchomeronic acid Chemical compound OC(=O)C1=CC=NC=C1C(O)=O MUYSADWCWFFZKR-UHFFFAOYSA-N 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
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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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention belongs to the field of chemical pharmacy, and particularly discloses a high-yield synthesis method of 3-amino methyl isonicotinate, which is characterized in that 4-pyridine carboxylic acid is used as a raw material, and the 3-amino methyl isonicotinate is obtained through bromination, ammoniation and esterification. The high-yield synthesis method of 3-amino methyl isonicotinate has the advantages of mild reaction conditions and high total yield, and 3-bromo-4-pyridinecarboxylic acid reaction waste filtrate can be repeatedly used, so that the utilization rate of raw materials is improved, the resource waste is reduced, the production cost of the whole process is reduced to the maximum extent, and the method has extremely high application.
Description
Technical Field
The invention belongs to the field of chemical pharmacy, and particularly relates to a high-yield synthesis method of 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.
Disclosure of Invention
The purpose of the invention is as follows: aiming at the defects in the prior art, the invention provides a high-yield synthesis method of 3-amino methyl isonicotinate, which uses 4-pyridine carboxylic acid as a raw material and obtains the 3-amino methyl isonicotinate through bromination, ammoniation and esterification.
Further, the high-yield synthesis method of the methyl 3-aminoisonicotinate comprises the following steps:
step 1): adding 4-pyridine carboxylic acid and methanol into a reaction bottle, controlling the temperature to be 5-30 ℃, dropwise adding bromine while stirring, after the addition, heating to 40-45 ℃, preserving the temperature for 5 hours, cooling to room temperature, filtering, and drying to obtain 3-bromine-4-pyridine carboxylic acid;
step 2): adding 3-bromo-4-pyridinecarboxylic acid into ammonia water in batches, adding cuprous iodide, heating to 105 ℃ in a closed high-pressure kettle in a closed manner, stirring for reacting for 6-8 hours, cooling to room temperature, adjusting the pH value to 5.5-6 with hydrochloric acid, filtering, and drying to obtain 3-amino-4-pyridinecarboxylic acid;
step 3): adding 3-amino-4-pyridine carboxylic acid and methanol into a reaction bottle, dropwise adding sulfuric acid at the temperature of 0-30 ℃, heating and refluxing for 12 hours after adding, concentrating the methanol under negative pressure until no liquid is discharged, cooling to room temperature, adding 18% ammonia water to adjust the pH to 7-8, adding water, stirring and cooling to 0-5 ℃, filtering, and drying to obtain the 3-amino methyl isonicotinate.
Further, in the high-yield synthesis method of methyl 3-aminoisonicotinate, the molar ratio of 4-pyridinecarboxylic acid to bromine in the step 1) is 1: 1-2.
Further, in the high-yield synthesis method of methyl 3-aminoisonicotinate, the molar ratio of the 3-bromo-4-pyridinecarboxylic acid to the ammonia water and the cuprous iodide in the step 2) is 1: 3-5: 0.01-0.03.
Further, in the high-yield synthesis method of the methyl 3-aminoisonicotinate, the ammonia water is 18% ammonia water.
Further, in the high-yield synthesis method of methyl 3-aminoisonicotinate, the molar ratio of the 3-amino-4-pyridinecarboxylic acid to the methanol in the step 3) is 1: 15-30.
Further, in the high-yield synthesis method of methyl 3-aminoisonicotinate, the mass ratio of the 3-amino-4-pyridinecarboxylic acid to the sulfuric acid in the step 3) is 5: 1.
Further, in the method for synthesizing methyl 3-aminoisonicotinate in high yield, the hydrochloric acid in the step 2) is 26% hydrochloric acid.
Further, in the above method for synthesizing methyl 3-aminoisonicotinate in high yield, the filtrate obtained by filtering in step 1) is reused.
The high-yield synthesis method of 3-amino methyl isonicotinate provided by the invention uses 4-pyridine carboxylic acid as a raw material, and the 3-amino methyl isonicotinate is obtained through bromination, ammoniation and esterification, so that the reaction condition is mild, the total yield is high, and the production cost is greatly reduced.
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 high-yield synthesis method of methyl 3-aminoisonicotinate is shown in figure 2 and comprises the following steps:
1. synthesis of 3-bromo-4-pyridinecarboxylic acid
Adding 50g (0.41 mol) of 4-pyridinecarboxylic acid and 150ml of methanol into a reaction bottle, dropwise adding 71.5g (0.45 mol) of bromine while stirring at the controlled temperature of 20 ℃, heating to 40-45 ℃ after the addition, preserving the temperature for 5 hours, cooling to room temperature, filtering, and drying to obtain 76.3g of 3-bromine-4-pyridinecarboxylic acid, wherein the yield is 93.5 percent, and the HPLC purity is 97.8 percent.
2. Synthesis of 3-amino-4-pyridinecarboxylic acids
Adding 50g (0.25 mol) of 3-bromo-4-pyridinecarboxylic acid into 100ml of 18% ammonia water in batches, adding 1g (0.0053 mol) of cuprous iodide, heating to 100 ℃ in a closed autoclave, stirring for reaction at 105 ℃ for 6 hours, cooling to room temperature, adjusting the pH to 5.5-6 with 26% hydrochloric acid, filtering, and drying to obtain 32.1g of 3-amino-4-pyridinecarboxylic acid, wherein the yield is 93%, and the HPLC purity is 99.5%.
3. Synthesis of methyl 3-aminoisonicotinate
Adding 50g (0.36 mol) of 3-amino-4-pyridine carboxylic acid and 300ml of methanol into a reaction bottle, dropwise adding 10g of sulfuric acid at the temperature of 20 ℃, heating and refluxing for 12 hours after the addition is finished, concentrating the methanol under negative pressure until no liquid is discharged, cooling to room temperature, adding 18% ammonia water to adjust the pH to 7-8, adding water, stirring and cooling to 0-5 ℃, filtering, and drying to obtain 48.9g of 3-amino isonicotinic acid methyl ester, wherein the yield is 89.3%, and the HPLC purity is 99.3%.
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 high-yield synthesis method of methyl 3-aminoisonicotinate is shown in figure 2 and comprises the following steps:
1. synthesis of 3-bromo-4-pyridinecarboxylic acid
Adding 50g (0.41 mol) of 4-pyridinecarboxylic acid and 150ml of methanol into a reaction bottle, dropwise adding 64.9g (0.41 mol) of bromine while stirring at the controlled temperature of 5 ℃, heating to 40-45 ℃ after the addition, preserving the temperature for 5 hours, cooling to room temperature, filtering, and drying to obtain 74.1g of 3-bromine-4-pyridinecarboxylic acid, wherein the yield is 90.8 percent, and the HPLC purity is 96.6 percent.
2. Synthesis of 3-amino-4-pyridinecarboxylic acids
Adding 50g (0.25 mol) of 3-bromo-4-pyridinecarboxylic acid into 75ml of 18% ammonia water in batches, adding 0.48 g (0.0025 mol) of cuprous iodide, heating to 100 ℃ in a closed high-pressure kettle, stirring for reaction for 7 hours, cooling to room temperature, adjusting the pH value to 5.5-6 with hydrochloric acid, filtering, and drying to obtain 30.7g of 3-amino-4-pyridinecarboxylic acid, wherein the yield is 89%, and the HPLC purity is 99.3%.
3. Synthesis of methyl 3-aminoisonicotinate
Adding 50g (0.36 mmol) of 3-amino-4-pyridinecarboxylic acid and 220ml of methanol into a reaction bottle, dropwise adding 10g of sulfuric acid at the temperature of 0 ℃, heating and refluxing for 12 hours after the addition is finished, concentrating the methanol under negative pressure until no liquid is discharged, cooling to room temperature, adding 18% ammonia water to adjust the pH to 7-8, adding water, stirring and cooling to 0-5 ℃, filtering, and drying to obtain 47.1g of 3-amino isonicotinic acid methyl ester, wherein the yield is 86.1%, 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)。
Example 3
A high-yield synthesis method of methyl 3-aminoisonicotinate is shown in figure 2 and comprises the following steps:
1. synthesis of 3-bromo-4-pyridinecarboxylic acid
Adding 50g (0.41 mol) of 4-pyridinecarboxylic acid and 150ml of methanol into a reaction bottle, dropwise adding 129.8g (0.82 mol) of bromine while stirring at the temperature of 30 ℃, heating to 40-45 ℃ after the addition, preserving the temperature for 5 hours, cooling to room temperature, filtering, and drying to obtain 78.6g of 3-bromine-4-pyridinecarboxylic acid, wherein the yield is 96.3 percent, and the HPLC purity is 97.6 percent.
2. Synthesis of 3-amino-4-pyridinecarboxylic acids
Adding 50g (0.25 mol) of 3-bromo-4-pyridinecarboxylic acid into 125ml of 18% ammonia water in batches, adding 1.44 g (0.0075 mol) of cuprous iodide, heating to 100 ℃ in a closed autoclave in a closed manner, stirring for reaction at 105 ℃ for 8 hours, cooling to room temperature, adjusting the pH to 5.5-6 with 26% hydrochloric acid, filtering, and drying to obtain 32.9g of 3-amino-4-pyridinecarboxylic acid, wherein the yield is 95.2%, and the HPLC purity is 99.7%.
3. Synthesis of methyl 3-aminoisonicotinate
Adding 50g (0.36 mol) of 3-amino-4-pyridine carboxylic acid and 440ml of methanol into a reaction bottle, dropwise adding 10g of sulfuric acid at the temperature of 30 ℃, heating and refluxing for 12 hours after the addition is finished, concentrating the methanol under negative pressure until no liquid is discharged, cooling to room temperature, adding 18% ammonia water to adjust the pH to 7-8, adding water, stirring and cooling to 0-5 ℃, filtering, and drying to obtain 48.4g of 3-amino isonicotinic acid methyl ester, wherein the yield is 88.5%, 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)。
The invention provides a high-yield synthesis method of 3-amino isonicotinic acid methyl ester, which takes 4-pyridine carboxylic acid as a raw material, brominating, ammoniating and esterifying to obtain the 3-amino isonicotinic acid methyl ester, has mild reaction conditions, has the total yield of more than 85 percent, greatly improves the yield (68 percent) compared with the yield of WO2006090167, simultaneously can repeatedly apply filtrate in the first step, improves the utilization rate of the raw material, reduces the resource waste and furthest reduces the production cost of the whole process.
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 high-yield synthesis method of 3-amino methyl isonicotinate is characterized in that: 4-pyridine carboxylic acid is used as a raw material, and the 3-amino methyl isonicotinate is obtained through bromination, ammoniation and esterification.
2. The process for the synthesis of methyl 3-aminoisonicotinate in high yield according to claim 1, characterized in that: the method comprises the following steps:
step 1): adding 4-pyridine carboxylic acid and methanol into a reaction bottle, controlling the temperature to be 5-30 ℃, dropwise adding bromine while stirring, after the addition, heating to 40-45 ℃, preserving the temperature for 5 hours, cooling to room temperature, filtering, and drying to obtain 3-bromine-4-pyridine carboxylic acid;
step 2): adding 3-bromo-4-pyridinecarboxylic acid into ammonia water in batches, adding cuprous iodide, heating to 105 ℃ in a closed high-pressure kettle in a closed manner, stirring for reacting for 6-8 hours, cooling to room temperature, adjusting the pH value to 5.5-6 with hydrochloric acid, filtering, and drying to obtain 3-amino-4-pyridinecarboxylic acid;
step 3): adding 3-amino-4-pyridine carboxylic acid and methanol into a reaction bottle, dropwise adding sulfuric acid at the temperature of 0-30 ℃, heating and refluxing for 12 hours after adding, concentrating the methanol under negative pressure until no liquid is discharged, cooling to room temperature, adding 18% ammonia water to adjust the pH to 7-8, adding water, stirring and cooling to 0-5 ℃, filtering, and drying to obtain the 3-amino methyl isonicotinate.
3. The process for the synthesis of methyl 3-aminoisonicotinate in high yield according to claim 2, characterized in that: the molar ratio of the 4-pyridinecarboxylic acid to the bromine in the step 1) is 1: 1-2.
4. The process for the synthesis of methyl 3-aminoisonicotinate in high yield according to claim 2, characterized in that: the molar ratio of the 3-bromo-4-pyridinecarboxylic acid in the step 2) to the ammonia water and the cuprous iodide is 1: 3-5: 0.01-0.03.
5. The process for the synthesis of methyl 3-aminoisonicotinate in high yield according to claim 4, characterized in that: the ammonia water is 18% ammonia water.
6. The process for the synthesis of methyl 3-aminoisonicotinate in high yield according to claim 2, characterized in that: the molar ratio of the 3-amino-4-pyridine carboxylic acid to the methanol in the step 3) is 1: 15-30.
7. The process for the synthesis of methyl 3-aminoisonicotinate in high yield according to claim 6, characterized in that: the mass ratio of the 3-amino-4-pyridine carboxylic acid to the sulfuric acid in the step 3) is 5: 1.
8. The process for the synthesis of methyl 3-aminoisonicotinate in high yield according to claim 4, characterized in that: the hydrochloric acid in the step 2) is 26% hydrochloric acid.
9. The process for the synthesis of methyl 3-aminoisonicotinate in high yield according to claim 3, characterized in that: the filtrate obtained by filtering in the step 1) is repeatedly reused.
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Cited By (2)
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| CN113387881A (en) * | 2021-07-15 | 2021-09-14 | 安徽大学 | Synthetic method of 3-amino methyl isonicotinate |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112441968A (en) * | 2020-12-23 | 2021-03-05 | 阿里生物新材料（常州）有限公司 | Synthetic method of 2-amino-3-bromoisonicotinic acid methyl ester |
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| CN113387881A (en) * | 2021-07-15 | 2021-09-14 | 安徽大学 | Synthetic method of 3-amino methyl isonicotinate |
| CN113387881B (en) * | 2021-07-15 | 2024-05-14 | 安徽大学 | Synthesis method of 3-aminoisonicotinic acid methyl ester |
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