CN113354579B - High-yield synthesis method of methyl 4-aminonicotinate - Google Patents
High-yield synthesis method of methyl 4-aminonicotinate Download PDFInfo
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- 238000001308 synthesis method Methods 0.000 title claims abstract description 17
- OCARFFAPQGYGBP-UHFFFAOYSA-N methyl 4-aminopyridine-3-carboxylate Chemical compound COC(=O)C1=CN=CC=C1N OCARFFAPQGYGBP-UHFFFAOYSA-N 0.000 title claims description 38
- 238000006243 chemical reaction Methods 0.000 claims abstract description 46
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 15
- MUYSADWCWFFZKR-UHFFFAOYSA-N cinchomeronic acid Chemical compound OC(=O)C1=CC=NC=C1C(O)=O MUYSADWCWFFZKR-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 230000018044 dehydration Effects 0.000 claims abstract description 5
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 5
- 229910021529 ammonia Inorganic materials 0.000 claims abstract description 4
- 238000006467 substitution reaction Methods 0.000 claims abstract description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 38
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 32
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 24
- 238000010992 reflux Methods 0.000 claims description 20
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- KFKMGUPDWTWQFM-UHFFFAOYSA-N furo[3,4-c]pyridine-1,3-dione Chemical compound N1=CC=C2C(=O)OC(=O)C2=C1 KFKMGUPDWTWQFM-UHFFFAOYSA-N 0.000 claims description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 14
- 239000007787 solid Substances 0.000 claims description 13
- 238000012544 monitoring process Methods 0.000 claims description 12
- 239000012153 distilled water Substances 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 9
- YNBADRVTZLEFNH-UHFFFAOYSA-N Methyl nicotinate Natural products COC(=O)C1=CC=CN=C1 YNBADRVTZLEFNH-UHFFFAOYSA-N 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 229960001238 methylnicotinate Drugs 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- PUXXPJODVNKSAT-UHFFFAOYSA-N 4-carbamoylpyridine-3-carboxylic acid Chemical compound NC(=O)C1=CC=NC=C1C(O)=O PUXXPJODVNKSAT-UHFFFAOYSA-N 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 238000001704 evaporation Methods 0.000 claims description 4
- 230000001376 precipitating effect Effects 0.000 claims description 4
- 239000007800 oxidant agent Substances 0.000 claims description 3
- 230000001590 oxidative effect Effects 0.000 claims description 3
- 230000003197 catalytic effect Effects 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 238000000967 suction filtration Methods 0.000 claims description 2
- 230000008707 rearrangement Effects 0.000 claims 1
- 238000007167 Hofmann rearrangement reaction Methods 0.000 abstract description 4
- 235000001968 nicotinic acid Nutrition 0.000 abstract 2
- 239000011664 nicotinic acid Substances 0.000 abstract 2
- 230000015572 biosynthetic process Effects 0.000 description 14
- 238000003786 synthesis reaction Methods 0.000 description 14
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- ITQTTZVARXURQS-UHFFFAOYSA-N 3-methylpyridine Chemical compound CC1=CC=CN=C1 ITQTTZVARXURQS-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000012286 potassium permanganate Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- XYYYTUCWSSREHK-UHFFFAOYSA-N N1=CC=CC=C1.[N]=O Chemical compound N1=CC=CC=C1.[N]=O XYYYTUCWSSREHK-UHFFFAOYSA-N 0.000 description 1
- SARBWQDFRCAJGR-UHFFFAOYSA-N [N]=O.CC=1C=NC=CC1[N+](=O)[O-] Chemical compound [N]=O.CC=1C=NC=CC1[N+](=O)[O-] SARBWQDFRCAJGR-UHFFFAOYSA-N 0.000 description 1
- USBHQTSMWCBZJE-UHFFFAOYSA-N [O-][N+]([Fe])=O Chemical compound [O-][N+]([Fe])=O USBHQTSMWCBZJE-UHFFFAOYSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- 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
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention discloses a high-yield synthesis method of 4-methyl amino nicotinate, which takes 3, 4-pyridine dicarboxylic acid as a raw material, and hydrolyzes the raw material after intramolecular dehydration substitution, ammonia ammoniation and improved NBS Hofmann rearrangement to obtain the 4-methyl amino nicotinate. The synthesis method provided by the invention is simpler to operate, mild in reaction conditions, higher in total yield and extremely high in application value.
Description
Technical Field
The invention belongs to the field of chemical pharmacy, and particularly relates to a high-yield synthesis method of methyl 4-aminonicotinate.
Background
The 4-aminonicotinic acid methyl ester is a commonly used medical intermediate, and the traditional synthesis method mainly comprises the following two methods:
3-methyl pyridine is used as a starting material, pyridine nitrogen oxide is generated by oxidation, amino is introduced by nitration and reduction, the amino is protected, potassium permanganate oxidizes methyl and the amino is deprotected, finally esterification reaction is carried out, and the synthesis of 4-amino methyl nicotinate is completed by seven steps of reaction, wherein the synthesis route is shown as follows. The key intermediate 3-methyl-4-nitropyridine nitrogen oxide of the method has explosiveness and unsafe operation; the oxidation of potassium permanganate of methyl and the reduction yield of nitroiron powder are not high, and the post-reaction treatment is complicated; the protection and deprotection operation of amino groups are unavoidable, resulting in long synthetic routes and being unsuitable for large-scale preparation.
3, 4-Pyridine dicarboxylic acid is taken as a raw material, and is dehydrated in molecules under the action of acetic anhydride to obtain 3, 4-pyridine dicarboxylic anhydride, and the target product is obtained through ammoniation of ammonia water, huffman degradation and esterification, wherein the synthetic route is shown as follows. The method has the advantages of complex operation, high production energy consumption and low yield, and the yield is about 70 percent according to the literature.
Disclosure of Invention
The invention provides a high-yield synthesis method of methyl 4-aminonicotinate aiming at the defects existing in the prior art. The invention takes 3, 4-pyridine dicarboxylic acid as raw material, firstly, the 3, 4-pyridine dicarboxylic acid anhydride is obtained through intramolecular dehydration under the action of acetic anhydride, then, the second step of solvent is changed into dichloromethane, ammonia water is changed into ammonia gas for ammoniation, so that the reaction in the step is more complete, the yield of the 3-carboxylic acid-4-amide pyridine intermediate is improved, then, the improved NBS Hofmann rearrangement reaction is carried out, and finally, the hydrolysis reaction is directly carried out, thus obtaining the 4-amino methyl nicotinate.
The high-yield synthesis method of the 4-aminonicotinic acid methyl ester comprises the following steps:
Step 1: adding 3, 4-pyridine dicarboxylic acid and acetic anhydride into a reaction bottle, controlling the temperature to 115 ℃ for reaction, monitoring by TLC, concentrating under reduced pressure after the reaction is completed for about 2-3 hours, evaporating acetic acid and acetic anhydride, and cooling the residual oily matter to room temperature to become solid to obtain 3, 4-pyridine dicarboxylic anhydride;
Step 2: dissolving 3, 4-pyridine dicarboxylic anhydride in a solvent, introducing ammonia gas at room temperature (20-30 ℃) for reaction, monitoring by TLC, adjusting the pH to about 4 by hydrochloric acid after the reaction is completed for about 2-3 hours, separating out solids, filtering, washing by distilled water, and carrying out suction filtration and drying to obtain 3-carboxylic acid-4-amide pyridine;
Step 3: adding 3-carboxylic acid-4-amide pyridine, alkali and methanol into a round bottom three-neck flask with a reflux device, heating to 65 ℃, refluxing for 15min, slowly adding an oxidant, continuing the reflux reaction, monitoring by TLC, directly carrying out the next reaction after the reaction is completed for about 1.5h, adding a certain catalytic amount of acid and two equivalents of distilled water (based on 3-carboxylic acid-4-amide pyridine), continuing heating and refluxing, observing by a spot plate, extracting by ethyl acetate, decompressing and shrinking, evaporating a solvent, and drying to obtain 4-amino methyl nicotinate.
In step2, the solvent is dichloromethane.
In step2, the concentration of hydrochloric acid was 20%.
In the step 3, the oxidant is NBS, and the alkali is sodium methoxide.
In step 3, the molar ratio of 4- (aminocarbonyl) -3-pyridinecarboxylic acid to sodium methoxide was 1:2, and the molar ratio of 4- (aminocarbonyl) -3-pyridinecarboxylic acid to NBS was 1:1.1.
In step 3, the acid is typically a strong acid, such as hydrochloric acid, sulfuric acid, and the like.
In the step3, the next hydrolysis reaction can be directly carried out after the previous reaction is finished, so that the operation of the steps is reduced, and the yield is improved.
The synthetic route of the invention is as follows:
According to the synthesis method, 3, 4-pyridine dicarboxylic acid is used as a raw material, and the 4-aminonicotinic acid methyl ester is obtained through intramolecular dehydration substitution, ammonia ammoniation and hydrolysis after improved NBS Hofmann rearrangement, so that the method is simpler in operation, mild in reaction condition, high in total yield and extremely high in application value.
Drawings
FIG. 1 shows the nuclear magnetic resonance hydrogen spectrum of 3, 4-pyridinedicarboxylic acid used as a raw material in the present invention.
FIG. 2 shows the nuclear magnetic resonance hydrogen spectrum of methyl 4-aminonicotinate as the product of the present invention.
Detailed Description
The technical solution of the present invention is further illustrated by the following specific examples, which are given for illustrative purposes only and are not intended to be limiting.
Example 1:
the high-yield synthesis method of the methyl 4-aminonicotinate in the embodiment comprises the following steps:
1. synthesis of 3, 4-pyridine dicarboxylic anhydride
3, 4-Pyridinedicarboxylic acid (70 g,0.42 mol) and acetic anhydride (180 ml,1.91 mol) were added to a reaction flask, heated to 115℃in an oil bath, stirred for reaction, monitored by TLC for about 2-3 hours, concentrated under reduced pressure, and the remaining oil was cooled to room temperature to become a solid, yielding 55g of 3, 4-Pyridinedicarboxylic anhydride in a yield of 87.8% and an HPLC purity of 98%.
2. Synthesis of 3-carboxylic acid-4-amide pyridine
Adding the 3, 4-pyridine dicarboxylic anhydride (50 g,0.34 mol) and 200ml of dichloromethane into a reaction bottle, introducing ammonia gas at room temperature (20-30 ℃) for reaction, monitoring by TLC, adjusting the pH to about 4 after about 2-3 hours, precipitating solid matters by hydrochloric acid, filtering, washing by distilled water, and drying to obtain 51.3g of 3-carboxylic acid-4-amide pyridine, wherein the yield is 90.8%, and the HPLC purity is 98.4%.
3. Synthesis of methyl 4-aminonicotinate
3-Carboxylic acid-4-amide pyridine (20 g,0.12 mol), sodium methoxide (13 g,0.24 mol) and 100ml of methanol are added into a round-bottom three-neck flask with a reflux device, the temperature is raised to 65 ℃, NBS (23.5 g,0.132 mol) is slowly added after reflux for 15min, reflux reaction is continued, TLC monitoring is carried out after about 1.5h, 15ml of hydrochloric acid and 5ml of distilled water are added after reaction is completed, heating reflux is continued, spot plate observation is carried out, about 0.5h of reaction is completed, extraction is carried out three times by ethyl acetate, the solvent is evaporated, the solid is dried to obtain 16.1g of 4-amino methyl nicotinate, the yield is 88.2%, and the HPLC purity is 99.3%.
1H NMR(400MHz,DMSO-d6)δ8.66(s,1H),8.06(d,J＝5.9Hz,1H),7.24(s,2H),6.68(d,J＝6.2Hz,1H),3.81(s,3H).
Example 2:
the high-yield synthesis method of the methyl 4-aminonicotinate in the embodiment comprises the following steps:
1. synthesis of 3, 4-pyridine dicarboxylic anhydride
3, 4-Pyridinedicarboxylic acid (70 g,0.42 mol) and acetic anhydride (180 ml,1.91 mol) were added to a reaction flask, heated to 115℃in an oil bath, stirred for reaction, monitored by TLC for about 2-3 hours, concentrated under reduced pressure, and the remaining oil was cooled to room temperature to become a solid, yielding 56.1g of 3, 4-Pyridinedicarboxylic anhydride in 89.6% yield and 96.8% HPLC purity.
2. Synthesis of 3-carboxylic acid-4-amide pyridine
Adding the 3, 4-pyridine dicarboxylic anhydride (50 g,0.34 mol) and 200ml of dichloromethane into a reaction bottle, introducing ammonia gas at room temperature (20-30 ℃) for reaction, monitoring by TLC, adjusting the pH to about 4 after about 2-3 hours, precipitating solid matters by hydrochloric acid, filtering, washing by distilled water, and drying to obtain 50.2g of 3-carboxylic acid-4-amide pyridine, wherein the yield is 89%, and the HPLC purity is 98.6%.
3. Synthesis of methyl 4-aminonicotinate
3-Carboxylic acid-4-amide pyridine (20 g,0.12 mol), sodium methoxide (13 g,0.24 mol) and 100ml of methanol are added into a round-bottom three-neck flask with a reflux device, the temperature is raised to 65 ℃, NBS (23.5 g,0.132 mol) is slowly added after reflux for 15min, reflux reaction is continued, TLC monitoring is carried out after about 1.5h, 15ml of hydrochloric acid and 5ml of distilled water are added after reaction is completed, heating reflux is continued, spot plate observation is carried out, about 0.5h of reaction is completed, extraction is carried out three times by ethyl acetate, the solvent is evaporated, the solid is dried to obtain 16.4g of 4-amino methyl nicotinate, the yield is 89.8%, and the HPLC purity is 98.1%.
1H NMR(400MHz,DMSO-d6)δ8.66(s,1H),8.06(d,J＝5.9Hz,1H),7.24(s,2H),6.68(d,J＝6.2Hz,1H),3.81(s,3H).
Example 3:
the high-yield synthesis method of the methyl 4-aminonicotinate in the embodiment comprises the following steps:
1. synthesis of 3, 4-pyridine dicarboxylic anhydride
3, 4-Pyridinedicarboxylic acid (70 g,0.42 mol) and acetic anhydride (180 ml,1.91 mol) were added to a reaction flask, heated to 115℃in an oil bath, stirred for reaction, monitored by TLC for about 2-3 hours, concentrated under reduced pressure, and the remaining oil was cooled to room temperature to become a solid, giving 55.4g of 3, 4-Pyridinedicarboxylic anhydride in 88.5% yield and 97.5% HPLC purity.
2. Synthesis of 3-carboxylic acid-4-amide pyridine
Adding the 3, 4-pyridine dicarboxylic anhydride (50 g,0.34 mol) and 200ml of dichloromethane into a reaction bottle, introducing ammonia gas at room temperature (20-30 ℃) for reaction, monitoring by TLC, adjusting the pH to about 4 after about 2-3 hours, precipitating solid matters by hydrochloric acid, filtering, washing by distilled water, and drying to obtain 49.7g of 3-carboxylic acid-4-amide pyridine, wherein the yield is 88.1%, and the HPLC purity is 99.1%.
3. Synthesis of methyl 4-aminonicotinate
3-Carboxylic acid-4-amide pyridine (20 g,0.12 mol), sodium methoxide (13 g,0.24 mol) and 100ml of methanol are added into a round-bottom three-neck flask with a reflux device, the temperature is raised to 65 ℃, NBS (23.5 g,0.132 mol) is slowly added after reflux for 15min, reflux reaction is continued, TLC monitoring is carried out after about 1.5h, 15ml of hydrochloric acid and 5ml of distilled water are added after reaction is completed, heating reflux is continued, spot plate observation is carried out, about 0.5h of reaction is completed, extraction is carried out three times by ethyl acetate, the solvent is evaporated, the solid is dried to obtain 16.2g of 4-amino methyl nicotinate, the yield is 88.7%, and the HPLC purity is 99%.
1H NMR(400MHz,DMSO-d6)δ8.66(s,1H),8.06(d,J＝5.9Hz,1H),7.24(s,2H),6.68(d,J＝6.2Hz,1H),3.81(s,3H).
The following conclusions can be drawn by the above three examples:
1. In the synthesis of 3, 4-pyridinedicarboxylic acid anhydride, an excessive amount of acetic anhydride should be added so that it can sufficiently react with 3, 4-pyridinedicarboxylic acid, thereby improving the yield of 3, 4-pyridinedicarboxylic acid anhydride.
2. In the synthesis of 3-carboxylic acid-4-amide pyridine, ammonia gas should be sufficiently contacted with the reaction solution to allow sufficient reaction of 3, 4-pyridine dicarboxylic anhydride, thereby improving the yield of 3-carboxylic acid-4-amide pyridine.
3. In the synthesis of methyl 4-aminonicotinate, an excess of NBS should be added to allow the 3-carboxylic acid-4-amide pyridine to react sufficiently, thereby increasing the yield of the final product methyl 4-aminonicotinate.
The experimental path provided by the invention is feasible, and the yield and purity of the obtained final product 4-aminonicotinic acid methyl ester are also greatly improved compared with those of the prior method.
The invention provides a high-yield synthesis method of 4-methyl aminonicotinate, which takes 3, 4-pyridine dicarboxylic acid as a raw material, and the 4-methyl aminonicotinate is obtained by hydrolysis after intramolecular dehydration substitution, ammonia ammoniation and improved NBS Hofmann rearrangement, the reaction condition is mild, the total yield is more than 85%, the total yield introduced by the literature is greatly improved by 70%, the operation is simpler, and the method has extremely high application.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications could be made by those skilled in the art without departing from the principles of the invention, which modifications would also be considered to be within the scope of the invention.
Claims (4)
1. A high-yield synthesis method of 4-aminonicotinic acid methyl ester is characterized by comprising the following steps of:
3, 4-pyridine dicarboxylic acid is taken as a raw material, and is subjected to intramolecular dehydration substitution, ammonia ammoniation and improved NBS Huffman rearrangement and then hydrolyzed to obtain a target product 4-aminonicotinic acid methyl ester; the synthetic route is as follows:
The method comprises the following steps:
Step 1: adding 3, 4-pyridine dicarboxylic acid and acetic anhydride into a reaction bottle, controlling the temperature to 115 ℃ for reaction, monitoring the reaction by TLC, concentrating under reduced pressure, evaporating acetic acid and acetic anhydride, and cooling the residual oily matter to room temperature to become solid to obtain 3, 4-pyridine dicarboxylic anhydride;
Step 2: dissolving 3, 4-pyridine dicarboxylic anhydride in a solvent dichloromethane, introducing ammonia gas at room temperature for reaction, monitoring the reaction by TLC, adjusting the pH to 4 by using hydrochloric acid, precipitating solids, filtering, washing by using distilled water, and performing suction filtration and drying to obtain 3-carboxylic acid-4-amide pyridine;
Step 3: adding 3-carboxylic acid-4-amide pyridine, sodium methoxide and methanol into a round bottom three-neck flask with a reflux device, heating to 65 ℃, refluxing for 15min, slowly adding an oxidant NBS, continuing the reflux reaction, monitoring the reaction completion by TLC, directly carrying out the next reaction, adding a certain catalytic amount of acid and two equivalents of distilled water under the equivalent weight of 3-carboxylic acid-4-amide pyridine as the reference, continuing heating and refluxing, extracting with ethyl acetate after the reaction is completed, concentrating under reduced pressure, evaporating the solvent, and drying to obtain 4-amino methyl nicotinate.
2. The synthesis method according to claim 1, wherein:
in step2, the concentration of hydrochloric acid was 20%.
3. The synthesis method according to claim 1, wherein:
in step 3, the molar ratio of 4- (aminocarbonyl) -3-pyridinecarboxylic acid to sodium methoxide was 1:2, and the molar ratio of 4- (aminocarbonyl) -3-pyridinecarboxylic acid to NBS was 1:1.1.
4. The synthesis method according to claim 1, wherein:
in step3, the acid is hydrochloric acid or sulfuric acid.
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| CN202110798884.XA CN113354579B (en) | 2021-07-15 | 2021-07-15 | High-yield synthesis method of methyl 4-aminonicotinate |
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| CN202110798884.XA CN113354579B (en) | 2021-07-15 | 2021-07-15 | High-yield synthesis method of methyl 4-aminonicotinate |
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| Title |
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| 4-氨基烟酸的合成研究;苏策等;《高校化学工程学报》;第24卷(第5期);第909页第2.3节 * |
| Direct Probing of Regioregularity for Polycarbodiimide Systems via 15N NMR Analysis;James F. Reuther等;《Macromolecules》;第45卷;第7721页方案2、右栏最后一段、第7722页左栏第2段 * |
| o-Aminoformylquinolines, new heterocyclic synthons;Godard, Alain等;《Journal of Heterocyclic Chemistry》;第17卷;第465-473页 * |
| 不同甲酯化方法分析羊肉膻味脂肪酸;李秋桐等;《中国调味品》;第44卷(第12期);第148-154页 * |
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