CN117800906A - Synthesis method of 5-cyano-2-methoxy nicotinic acid - Google Patents
Synthesis method of 5-cyano-2-methoxy nicotinic acid Download PDFInfo
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- CN117800906A CN117800906A CN202211171800.0A CN202211171800A CN117800906A CN 117800906 A CN117800906 A CN 117800906A CN 202211171800 A CN202211171800 A CN 202211171800A CN 117800906 A CN117800906 A CN 117800906A
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- compound
- cyano
- nicotinic acid
- methoxy nicotinic
- reaction
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- WOWUICFHYZZNAD-UHFFFAOYSA-N 5-cyano-2-methoxypyridine-3-carboxylic acid Chemical compound C(#N)C=1C=C(C(=NC=1)OC)C(=O)O WOWUICFHYZZNAD-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 238000001308 synthesis method Methods 0.000 title claims abstract description 11
- 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
- 150000001875 compounds Chemical class 0.000 claims description 31
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- 238000003756 stirring Methods 0.000 claims description 16
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 9
- 229910052794 bromium Inorganic materials 0.000 claims description 9
- 238000002156 mixing Methods 0.000 claims description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 230000002194 synthesizing effect Effects 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 abstract description 31
- 239000002994 raw material Substances 0.000 abstract description 11
- 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 54
- 239000007787 solid Substances 0.000 description 21
- 239000012065 filter cake Substances 0.000 description 13
- 238000001914 filtration Methods 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 239000005457 ice water Substances 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 239000000203 mixture Substances 0.000 description 8
- 239000012071 phase Substances 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 6
- 239000012452 mother liquor Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 238000001816 cooling Methods 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 238000002386 leaching Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000001376 precipitating effect Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- FTEZJSXSARPZHJ-UHFFFAOYSA-N 2-methoxypyridine-3-carboxylic acid Chemical compound COC1=NC=CC=C1C(O)=O FTEZJSXSARPZHJ-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000008346 aqueous phase 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
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000001228 spectrum Methods 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
- C07D213/84—Nitriles
- C07D213/85—Nitriles in position 3
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention belongs to the technical field of chemistry, and particularly relates to a synthesis method of 5-cyano-2-methoxy nicotinic acid. The invention provides a synthesis method of 5-cyano-2-methoxy nicotinic acid, which takes a compound A as a basic raw material and synthesizes a product through four-step reaction, so that the reaction condition is simple and easy to operate, the reaction process is easy to control, the reaction yield is high, and the industrial mass production can be realized.
Description
Technical Field
The invention belongs to the technical field of chemistry, and particularly relates to a synthesis method of 5-cyano-2-methoxy nicotinic acid.
Background
2-methoxy nicotinic acid is an important intermediate for synthesizing various compounds, and 5-cyano-2-methoxy nicotinic acid is an important derivative of 2-methoxy nicotinic acid, but no suitable synthesis method of 5-cyano-2-methoxy nicotinic acid exists in the market at present, and the previous chemical synthesis method is often low in yield and is not suitable for industrial large-scale production.
Disclosure of Invention
The invention aims to overcome the existing defects and provide a method for synthesizing 5-cyano-2-methoxy nicotinic acid with high synthesis efficiency and high purity.
The aim of the invention is realized by the following technical scheme:
a synthesis method of 5-cyano-2-methoxy nicotinic acid comprises the following steps:
(1) Mixing the compound A with water at low temperature, adding bromine, stirring at room temperature to react to obtain a compound B
；
(2) Mixing compound B with methanol, adding concentrated sulfuric acid, heating to 70-80deg.C, and stirring to obtain compound C
；
(3) Under the protection of nitrogen, the compound C, cuCN, cuI and N, N-dimethylformamide are mixed and reacted at 100-105 ℃ to obtain the compound D
；
(4) Mixing the compound D with tetrahydrofuran, adding lithium hydroxide, and reacting to obtain 5-cyano-2-methoxy nicotinic acid
。
Preferably, in the step (1), the mass ratio of the compound A to the bromine is 1:2-6.
Preferably, in the step (2), the mass ratio of the compound B to the concentrated sulfuric acid is 1:1-3.
Preferably, the mass ratio of the compound C, cuCN, cuI in the step (3) is 13-16:8:11-15.
Preferably, in the step (4), the mass ratio of the compound D to the lithium hydroxide is 1:2-4.
The invention has the beneficial effects that:
the invention provides a synthesis method of 5-cyano-2-methoxy nicotinic acid, 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 2.
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.
A synthesis method of 5-cyano-2-methoxy nicotinic acid comprises the following steps:
(1) Taking materials according to the mass ratio of the compound A to bromine of 1:2-6, mixing the compound A with water at low temperature, adding bromine, and stirring at room temperature to react to obtain a compound B;
(2) Taking materials according to the mass ratio of the compound B to the concentrated sulfuric acid of 1:1-3, adding methanol into the compound B to mix, adding the concentrated sulfuric acid, heating to 70-80 ℃, and stirring to react to obtain a compound C;
(3) Taking materials according to the mass ratio of the compound C, cuCN, cuI of 13-16:8:11-15, mixing the compound C, cuCN, cuI with N, N-dimethylformamide under the protection of nitrogen, and reacting at 100-105 ℃ to obtain a compound D;
(4) Taking materials according to the mass ratio of the compound D to the lithium hydroxide of 1:2-4, mixing the compound D with tetrahydrofuran, adding the lithium hydroxide, and reacting to obtain the 5-cyano-2-methoxy nicotinic acid.
Example 1
A synthesis method of 5-cyano-2-methoxy nicotinic acid comprises the following steps:
(1) Adding 20g of compound A and 1.5L of water into a reaction bottle, cooling at 0 ℃, dropwise adding 40g of bromine, stirring at room temperature for 16h after completion of the dropwise adding, detecting by HPLC, filtering the reaction solution after the raw materials react, leaching a filter cake with water (150 ml is 3), and drying the filter cake to obtain 29.5g of white solid, thereby obtaining compound B with the yield of 97.4% and the purity of 98.2%;
(2) Adding 20g of compound B and 250mL of methanol into a reaction bottle, dropwise adding 20g of concentrated sulfuric acid under ice-water bath, heating to 70 ℃ and stirring for 5h, detecting by TLC, concentrating an organic phase after the raw material reaction is finished, adding a concentrate into ice water (200 mL), precipitating a large amount of white solid, filtering, adding 300mL of ethyl acetate into a filter cake for dissolution, adding saturated sodium bicarbonate into the ethyl acetate phase for washing (pH to 7-8), separating liquid, concentrating the organic phase to obtain 16.2 g of white solid, adding 300mL of ethyl acetate, washing (100 mL) of saturated sodium bicarbonate, and concentrating the organic phase to obtain 20.3g of white solid, namely the compound C with the yield of 95.7% and the purity of 99.1%;
(3) 13g of compound C, 8g of CuCN, 11g of CuI and 150mL of LDMF are added into a reaction bottle, nitrogen is replaced for 3 times, the mixture is heated to 110 ℃ for reaction for 24 hours, TLC detection is carried out, a small amount of raw materials are left, the mixture is cooled to room temperature, the mixture is filtered, cuI and CuCN are removed, mother liquor is concentrated, the mother liquor is concentrated and dried, dichloromethane/ethyl acetate=8/1 (500 mL) is added, stirring is carried out for 15 minutes, filtration is carried out, filtrate is concentrated, silica gel is stirred, the mixture is filtered, a mobile phase is n-hexane/ethyl acetate=1/1, a target product is collected, and concentration is carried out, 10g of white solid is obtained, thus obtaining compound D, the yield is 98.5%, and the purity is 98.6%;
(4) 2g of compound D and 20mL of THF were added to a reaction flask, 4g of lithium hydroxide was stirred at room temperature under ice-water bath for 3 hours, TLC was performed, 30mL of water was added, ethyl acetate was used to extract impurities (30 mL), the pH of the aqueous phase was adjusted to 2-3 with 3M hydrochloric acid, a large amount of white solid was precipitated, filtered, the cake was washed with water (10 mL), and the cake was dried to obtain 1.8g of a white solid, 5-cyano-2-methoxynicotinic acid was obtained in a yield of 97.1% and a purity of 99.6%.
Example 2
(1) Adding 20g of compound A and 1.5L of water into a reaction bottle, cooling at 0 ℃, dropwise adding 58g of bromine, stirring at room temperature for 16h after finishing the dropwise adding, detecting by HPLC, filtering the reaction solution after the raw materials react, adding water into a filter cake for leaching (150 ml is 3), and drying the filter cake to obtain 29.6g of white solid, thereby obtaining compound B with the yield of 97.7% and the purity of 98.5%;
(2) Adding 20g of compound B and 250mL of methanol into a reaction bottle, dropwise adding 40g of concentrated sulfuric acid under an ice-water bath, heating to 70 ℃ and stirring for 5h, detecting by TLC, concentrating an organic phase after the raw material reaction is finished, adding a concentrate into ice water (200 mL), precipitating a large amount of white solid, filtering, adding 300mL of ethyl acetate into a filter cake for dissolution, adding saturated sodium bicarbonate into the ethyl acetate phase for washing (pH to 7-8), separating liquid, concentrating the organic phase to obtain 16.2 g of white solid, adding 300mL of ethyl acetate, washing (100 mL) of saturated sodium bicarbonate, and concentrating the organic phase to obtain 20.6g of white solid, namely the compound C with the yield of 97.1% and the purity of 99%;
(3) 15g of compound C, 8g of CuCN, 11g of CuI and 150mL of LDMF are added into a reaction bottle, nitrogen is replaced for 3 times, the mixture is heated to 110 ℃ for reaction for 24 hours, TLC detection is carried out, a small amount of raw materials are left, the mixture is cooled to room temperature, the mixture is filtered, cuI and CuCN are removed, mother liquor is concentrated, the mother liquor is concentrated and dried, dichloromethane/ethyl acetate=8/1 (500 mL) is added, stirring is carried out for 15 minutes, filtration is carried out, filtrate is concentrated, silica gel is stirred, the mixture is filtered, a mobile phase is n-hexane/ethyl acetate=1/1, a target product is collected, and concentration is carried out, 11.6g of white solid is obtained, namely compound D is obtained, the yield is 99%, and the purity is 98.4%;
(4) 2g of compound D and 20mL of THF are added into a reaction bottle, 6g of lithium hydroxide is stirred for 3h at room temperature under ice water bath, TLC detection is carried out, 30mL of water is added after the reaction of the raw materials, ethyl acetate is used for extracting impurities (30 mL), the pH of the water phase is adjusted to 2-3 by 3M hydrochloric acid, a large amount of white solid is separated out, filtration is carried out, a filter cake is washed by water (10 mL), and the filter cake is dried to obtain 1.84g of white solid, thus obtaining 5-cyano-2-methoxy nicotinic acid with the yield of 99.2% and the purity of 99.5%.
Example 3
(1) Adding 20g of compound A and 1.5L of water into a reaction bottle, cooling at 0 ℃, dropwise adding 120g of bromine, stirring at room temperature for 16h after finishing the dropwise adding, detecting by HPLC, filtering the reaction solution after finishing the reaction, adding water into a filter cake for leaching (150 ml is 3), and drying the filter cake to obtain 28.3g of white solid, thereby obtaining compound B with the yield of 93.4% and the purity of 97.9%;
(2) Adding 20g of compound B and 250mL of methanol into a reaction bottle, dropwise adding 60g of concentrated sulfuric acid under an ice-water bath, heating to 70 ℃ and stirring for 5h, detecting by TLC, concentrating an organic phase after the raw material reaction is finished, adding a concentrate into ice water (200 mL), precipitating a large amount of white solid, filtering, adding 300mL of ethyl acetate into a filter cake for dissolution, adding saturated sodium bicarbonate into the ethyl acetate phase for washing (pH to 7-8), separating liquid, concentrating the organic phase to obtain 16.2 g of white solid, adding 300mL of ethyl acetate, washing (100 mL) of saturated sodium bicarbonate, and concentrating the organic phase to obtain 20g of white solid, thereby obtaining compound C with the yield of 94.3% and the purity of 98.3%;
(3) Adding 16g of compound C, 8g of CuCN, 15g of CuI and 150mL of LDMF into a reaction bottle, replacing 3 times with nitrogen, heating to 110 ℃ for reaction for 24 hours, detecting TLC, cooling a small amount of raw materials to room temperature, filtering, removing the CuI and the CuCN, concentrating mother liquor, concentrating the mother liquor to dryness, adding dichloromethane/ethyl acetate=8/1 (500 mL), stirring for 15 minutes, filtering, concentrating filtrate, stirring a sample with silica gel, passing through a column, enabling a mobile phase to be n-hexane/ethyl acetate=1/1, collecting a target product, concentrating to obtain 12g of white solid, namely the compound D, wherein the yield is 96%, and the purity is 98.3%;
(4) 2g of compound D and 20mL of THF are added into a reaction bottle, 8g of lithium hydroxide is stirred for 3h at room temperature under ice water bath, TLC detection is carried out, 30mL of water is added after the reaction of the raw materials, ethyl acetate is used for extracting impurities (30 mL), the pH of the water phase is adjusted to 2-3 by 3M hydrochloric acid, a large amount of white solid is separated out, filtration is carried out, a filter cake is washed by water (10 mL), and the filter cake is dried to obtain 1.6g of white solid, thus obtaining 5-cyano-2-methoxy nicotinic acid with the yield of 86.3% and the purity of 98.4%.
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 (5)
1. The synthesis method of the 5-cyano-2-methoxy nicotinic acid is characterized by comprising the following steps:
(1) Mixing the compound A with water at low temperature, adding bromine, stirring at room temperature to react to obtain a compound B
；
(2) Mixing compound B with methanol, adding concentrated sulfuric acid, heating to 70-80deg.C, and stirring to obtain compound C
；
(3) Under the protection of nitrogen, the compound C, cuCN, cuI and N, N-dimethylformamide are mixed and reacted at 100-105 ℃ to obtain the compound D
；
(4) Mixing the compound D with tetrahydrofuran, adding lithium hydroxide, and reacting to obtain 5-cyano-2-methoxy nicotinic acid
。
2. The method for synthesizing 5-cyano-2-methoxy nicotinic acid according to claim 1, wherein the mass ratio of the compound A to bromine in the step (1) is 1:2-6.
3. The method for synthesizing 5-cyano-2-methoxy nicotinic acid according to claim 1, wherein the mass ratio of the compound B to the concentrated sulfuric acid in the step (2) is 1:1-3.
4. The method for synthesizing 5-cyano-2-methoxy nicotinic acid according to claim 1, wherein the mass ratio of the compound C, cuCN, cuI in the step (3) is 13-16:8:11-15.
5. The method for synthesizing 5-cyano-2-methoxy nicotinic acid according to claim 1, wherein the mass ratio of the compound D to the lithium hydroxide in the step (4) is 1:2-4.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202211171800.0A CN117800906A (en) | 2022-09-26 | 2022-09-26 | Synthesis method of 5-cyano-2-methoxy nicotinic acid |
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| CN202211171800.0A CN117800906A (en) | 2022-09-26 | 2022-09-26 | Synthesis method of 5-cyano-2-methoxy nicotinic acid |
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