CN115650905A - Preparation method of 6-amino nicotinic acid - Google Patents
Preparation method of 6-amino nicotinic acid Download PDFInfo
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- ZCIFWRHIEBXBOY-UHFFFAOYSA-N 6-aminonicotinic acid Chemical compound NC1=CC=C(C(O)=O)C=N1 ZCIFWRHIEBXBOY-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 64
- 239000007800 oxidant agent Substances 0.000 claims abstract description 28
- UAWMVMPAYRWUFX-UHFFFAOYSA-N 6-Chloronicotinic acid Chemical compound OC(=O)C1=CC=C(Cl)N=C1 UAWMVMPAYRWUFX-UHFFFAOYSA-N 0.000 claims abstract description 26
- 230000001590 oxidative effect Effects 0.000 claims abstract description 25
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims abstract description 19
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 17
- SKCNYHLTRZIINA-UHFFFAOYSA-N 2-chloro-5-(chloromethyl)pyridine Chemical compound ClCC1=CC=C(Cl)N=C1 SKCNYHLTRZIINA-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 13
- 239000007787 solid Substances 0.000 claims description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 39
- 239000002904 solvent Substances 0.000 claims description 29
- 238000001914 filtration Methods 0.000 claims description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 24
- 239000012065 filter cake Substances 0.000 claims description 21
- 238000003756 stirring Methods 0.000 claims description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 239000002244 precipitate Substances 0.000 claims description 18
- 238000005406 washing Methods 0.000 claims description 17
- 239000012286 potassium permanganate Substances 0.000 claims description 14
- 239000000243 solution Substances 0.000 claims description 14
- 238000001035 drying Methods 0.000 claims description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- 238000002386 leaching Methods 0.000 claims description 11
- 239000007788 liquid Substances 0.000 claims description 11
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 10
- 229910052751 metal Inorganic materials 0.000 claims description 10
- 239000002184 metal Substances 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 9
- 239000000706 filtrate Substances 0.000 claims description 9
- 238000002156 mixing Methods 0.000 claims description 9
- NYNRZJAGUQREMC-UHFFFAOYSA-N (6-chloropyridin-3-yl)methylhydrazine Chemical compound NNCC1=CC=C(Cl)N=C1 NYNRZJAGUQREMC-UHFFFAOYSA-N 0.000 claims description 8
- JHWIEAWILPSRMU-UHFFFAOYSA-N 2-methyl-3-pyrimidin-4-ylpropanoic acid Chemical compound OC(=O)C(C)CC1=CC=NC=N1 JHWIEAWILPSRMU-UHFFFAOYSA-N 0.000 claims description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
- 239000012295 chemical reaction liquid Substances 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 6
- KMUONIBRACKNSN-UHFFFAOYSA-N potassium dichromate Chemical compound [K+].[K+].[O-][Cr](=O)(=O)O[Cr]([O-])(=O)=O KMUONIBRACKNSN-UHFFFAOYSA-N 0.000 claims description 6
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 5
- 239000003570 air Substances 0.000 claims description 5
- 239000005457 ice water Substances 0.000 claims description 5
- 239000011259 mixed solution Substances 0.000 claims description 5
- 229910017604 nitric acid Inorganic materials 0.000 claims description 5
- 229910001316 Ag alloy Inorganic materials 0.000 claims description 4
- 229910001020 Au alloy Inorganic materials 0.000 claims description 4
- 229910000990 Ni alloy Inorganic materials 0.000 claims description 4
- 229910001252 Pd alloy Inorganic materials 0.000 claims description 4
- 229910001260 Pt alloy Inorganic materials 0.000 claims description 4
- 229910000629 Rh alloy Inorganic materials 0.000 claims description 4
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical group [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 3
- 229910052802 copper Inorganic materials 0.000 claims description 3
- 239000010949 copper Substances 0.000 claims description 3
- 238000001704 evaporation Methods 0.000 claims description 3
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 claims description 3
- 239000010931 gold Substances 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 239000010948 rhodium Substances 0.000 claims description 3
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 3
- 239000004332 silver Substances 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- 229910000881 Cu alloy Inorganic materials 0.000 claims description 2
- 239000003353 gold alloy Substances 0.000 claims description 2
- 230000008901 benefit Effects 0.000 abstract description 5
- 230000008569 process Effects 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000008399 tap water Substances 0.000 description 6
- 235000020679 tap water Nutrition 0.000 description 6
- 238000001514 detection method Methods 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 239000007868 Raney catalyst Substances 0.000 description 4
- 229910000564 Raney nickel Inorganic materials 0.000 description 4
- 210000003298 dental enamel Anatomy 0.000 description 3
- 238000011031 large-scale manufacturing process Methods 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000000575 pesticide Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- YUBHMOQVHOODEI-UHFFFAOYSA-N 5-chloro-2-nitropyridine Chemical compound [O-][N+](=O)C1=CC=C(Cl)C=N1 YUBHMOQVHOODEI-UHFFFAOYSA-N 0.000 description 1
- CMBSSVKZOPZBKW-UHFFFAOYSA-N 5-methylpyridin-2-amine Chemical compound CC1=CC=C(N)N=C1 CMBSSVKZOPZBKW-UHFFFAOYSA-N 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 229910045601 alloy Inorganic materials 0.000 description 1
- 239000000956 alloy Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 239000000498 cooling water Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a preparation method of 6-amino nicotinic acid, which is characterized by comprising the following steps: (1) Reacting 2-chloro-5-chloromethylpyridine with an oxidant to obtain 6-chloronicotinic acid; (2) Reacting 6-chloronicotinic acid with hydrazine hydrate to obtain 6-chlorohydrazine; (3) The 6-amino nicotinic acid is obtained by reacting 6-chloroniazid with a reducing agent, and has the advantages of simple process line, mild and safe reaction conditions, lower production cost and high total yield.
Description
Technical Field
The invention relates to the field of synthesis of medicine and pesticide intermediates, in particular to a preparation method of 6-amino nicotinic acid.
Background
6-amino nicotinic acid is an important intermediate of medicines and pesticides, 2-nitro-5-chloropyridine is traditionally subjected to nitro reduction, and then carbon dioxide replaces chlorine under the catalysis of metal to obtain 6-amino nicotinic acid (Tetrahedron Letters,2003, vol.44, #21, p.4133-4135); the disadvantages of the route include high raw material price, complex operation of the reaction process, special reaction equipment and unsuitability for large-scale production; or 2-amino-5-methylpyridine is subjected to amino protection, methyl oxidation and amino deprotection to obtain 6-amino nicotinic acid (Supramolecular Chemistry,2010, vol.22, #9, p.483-490), the method has the defects of high cost of starting materials, low total yield of only 18.6 percent, difficult bearing of industrial cost, and is not suitable for large-scale production. The synthetic route is shown below,
the processes all have the problems of high industrial cost and unsuitability for large-scale production due to the high price of the starting raw materials, complex operation of the process and the like.
Disclosure of Invention
The invention aims to solve the technical problem of providing a preparation method of 6-amino nicotinic acid, which has the advantages of simple process line, mild and safe reaction conditions, lower production cost and high total yield.
The technical scheme adopted by the invention for solving the technical problems is as follows: the preparation method comprises the following steps:
(1) Reacting 2-chloro-5-chloromethylpyridine with an oxidant to obtain 6-chloronicotinic acid;
(2) Reacting 6-chloronicotinic acid with hydrazine hydrate to obtain 6-chlorohydrazine;
(3) 6-chloronicotinyl hydrazine reacts with a reducing agent to obtain 6-amino nicotinic acid.
Wherein, the step (1) is specifically as follows: stirring 2-chloro-5-chloromethylpyridine and an oxidant in a solvent at the reaction temperature of 50-100 ℃ until the reaction is completed, cooling the reaction liquid to below 25 ℃, filtering, leaching the solid with water, mixing the filtrate and the leaching solution to obtain a reaction mixed liquid, adjusting the pH of the reaction mixed liquid to 3 with concentrated hydrochloric acid to form a precipitate, filtering the precipitate, washing with water, centrifuging, and drying to obtain the 6-chloronicotinic acid. Wherein the oxidant is oxygen, air, chlorine, sodium dichromate, potassium permanganate or nitric acid.
Wherein, the oxidant is oxygen, air, chlorine, sodium dichromate, potassium permanganate or nitric acid; the solvent selects different solvents according to different oxidants: the oxidant is potassium permanganate, and water is selected as a solvent of the oxidant; the oxidant is oxygen, and methanol, ethanol or isopropanol is selected as a solvent; the oxidant is sodium dichromate or potassium dichromate, and sulfuric acid is selected as a solvent.
Wherein, the mass ratio of the 2-chloro-5-chloromethylpyridine to the oxidant is 1: (1-3).
Wherein the step (2) specifically comprises the following steps: stirring 6-chloronicotinic acid and hydrazine hydrate at the temperature of 50-150 ℃ in the presence of a solvent until the reaction is completed, evaporating the solvent under reduced pressure, pouring the residue into cold water, adjusting the pH value to 5.5 by using concentrated HCl to form a precipitate, filtering and collecting a solid, washing a filter cake by using water, and drying to obtain the 6-chloronicotinyl hydrazine.
Wherein the mass ratio of the 6-chloronicotinic acid to the hydrazine hydrate is 1: (1-3).
Wherein the solvent is methanol, ethanol, isopropanol or n-butanol.
Wherein, the step (3) is specifically as follows: stirring 6-chloroniazid and a reducing agent under the action of a metal catalyst at the temperature of 0-150 ℃ until the mixture completely reacts, cooling the reaction solution to room temperature, and filtering; and washing a filter cake with water, removing solids, adding the obtained reaction mixed solution into ice water, adjusting the pH to 5.5 by using concentrated HCl to form a precipitate, filtering and collecting the solids, washing the filter cake with water, and drying to obtain the 6-aminonicotinic acid.
Wherein the mass ratio of the 6-chloroniazid, the metal catalyst and the reducing agent is 1: (0.05-0.2) (1-3).
Wherein, the metal catalyst is copper, nickel, palladium, silver, gold, platinum, rhodium or copper alloy, nickel alloy, palladium alloy, silver alloy, gold alloy, platinum alloy, rhodium alloy. The reducing agent is sodium borohydride, potassium borohydride, hydrazine hydrate or hydrogen.
Compared with the prior art, the invention has the advantages that: the preparation method of 6-amino nicotinic acid of the invention firstly uses 2-chloro-5-chloromethyl pyridine with wide raw material sources and low price as a starting raw material to obtain the 6-amino nicotinic acid through three steps of oxidation, hydrazinoization and reduction. The method has the advantages of simple selected process line, mild and safe reaction conditions, high total yield up to 65.5 percent, low raw material price, suitability for industrial mass production, and great implementation value and social and economic benefits.
Drawings
FIG. 1 is the NMR spectrum of 6-amino nicotinic acid prepared by the invention.
Detailed Description
The invention is described in further detail below with reference to the accompanying examples.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
A preparation method of 6-amino nicotinic acid comprises the following steps:
1. reacting 2-chloro-5-chloromethylpyridine with an oxidant to obtain 6-chloronicotinic acid (compound 1);
2. reacting 6-chloronicotinic acid with hydrazine hydrate to obtain 6-chloroniazid (compound 2);
3. reacting 6-chloroniazid with a reducing agent to obtain 6-amino nicotinic acid (compound 3),
the synthetic route is as follows:
the step 1 is specifically as follows: stirring 2-chloro-5-chloromethylpyridine and an oxidant in a solvent at the reaction temperature of 50-100 ℃ until the reaction is completed, cooling the reaction liquid to below 25 ℃, filtering, leaching the solid with water, mixing the filtrate and the leaching solution to obtain a reaction mixed liquid, adjusting the pH of the reaction mixed liquid to 3 with concentrated hydrochloric acid to form a precipitate, filtering the precipitate, washing with water, centrifuging, and drying to obtain the 6-chloronicotinic acid. Wherein the oxidant is oxygen, air, chlorine, sodium dichromate, potassium permanganate or nitric acid. The mass ratio of the 2-chloro-5-chloromethylpyridine to the oxidant is 1: (1-3). The solvent is selected according to different oxidants, such as potassium permanganate as oxidant, and water as solvent; the oxidant is oxygen, and methanol, ethanol or isopropanol is generally selected as a solvent; the oxidant is sodium dichromate or potassium dichromate, and sulfuric acid is generally selected as a solvent.
The step 2 is specifically as follows: stirring 6-chloronicotinic acid and hydrazine hydrate at the temperature of 50-150 ℃ in the presence of a solvent until the reaction is completed, evaporating the solvent under reduced pressure, pouring the residue into cold water, adjusting the pH value to 5.5 by using concentrated HCl to form a precipitate, filtering and collecting a solid, washing a filter cake by using water, and drying to obtain the 6-chloronicotinyl hydrazine. Wherein the mass ratio of the 6-chloronicotinic acid to the hydrazine hydrate is 1: (1-3). The solvent is methanol, ethanol, isopropanol, n-butanol, etc.
The step 3 is specifically: stirring 6-chloroniazid and a reducing agent under the action of a metal catalyst at the temperature of 0-150 ℃ until the mixture completely reacts, cooling the reaction solution to room temperature, and filtering; and washing a filter cake with water, removing solids, adding the obtained reaction mixed solution into ice water, adjusting the pH to 5.5 by using concentrated HCl to form a precipitate, filtering and collecting the solids, washing the filter cake with water, and drying to obtain the 6-aminonicotinic acid. Wherein the metal catalyst is at least one of copper, nickel (or alloys thereof such as Raney nickel), palladium, silver, gold, platinum and rhodium. The reducing agent is sodium borohydride, potassium borohydride, hydrazine hydrate or hydrogen. The mass ratio of the 6-chloroniazid, the metal catalyst and the reducing agent is 1: (0.05-0.3): (1-3).
Example 1
A preparation method of 6-amino nicotinic acid comprises the following steps:
1. synthesis of 6-chloronicotinic acid
1600kg of tap water is added into a 2000L enamel reaction kettle, 200kg of 2-chloro-5-chloromethyl pyridine is added into the enamel reaction kettle under the condition of room temperature stirring, and the reaction kettle is heated to 80-90 ℃; adding 450kg of potassium permanganate into a reaction kettle in batches (about 200-300 g of each batch), and controlling the reaction temperature to be not more than 100 ℃; after the potassium permanganate is added, the reaction temperature is controlled to be 90-100 ℃, and the mixture is stirred for 30 minutes. After TLC detection reaction is completed, cooling the reaction liquid to below 25 ℃ by using circulating cooling water, then filtering to remove solid manganese dioxide, leaching a filter cake by using water of about 100kg, mixing filtrate and leacheate to obtain a reaction mixed liquid, pumping the reaction mixed liquid into a 3000L enamel reaction kettle, adjusting the pH to 3 by using concentrated hydrochloric acid to separate out white solid, filtering, washing, centrifuging and drying the white solid to obtain 179kg of white solid 6-chloronicotinic acid, wherein the yield is as follows: 92 percent.
2. Synthesis of 6-chloronicotinyl hydrazine
Adding 2L of ethanol into a 5L three-necked bottle, adding 500g of 6-chloronicotinic acid while stirring, and adding 300g of hydrazine hydrate with the mass concentration of 80%; the mixture was stirred at 100 ℃ until complete reaction, then the solvent was evaporated under reduced pressure, the residue was poured into 5L of cold water and the pH was adjusted to 5.5 with concentrated HCl to form a precipitate, the solid was collected by filtration, the filter cake was washed with water and dried to give 432g of 6-chloroniazid as a yellow solid in yield: 89 percent.
3. Synthesis of 6-aminonicotinic acid
Adding 35kg of tap water into a 50L glass reaction kettle, stirring at room temperature, adding 2.3kg of solid potassium carbonate, 5kg of 6-chloroniazid and 500g of Raney nickel, and heating the reaction kettle to 80-90 ℃; 1.3kg of hydrazine hydrate with the mass concentration of 80 percent is slowly dripped into the reaction liquid for about 1 hour, and then the reaction temperature is controlled at 95 to 100 ℃ for 4 hours. Cooling the reaction liquid to room temperature, and filtering; washing a filter cake with water to remove solids, adding 5L of cold water and 5kg of crushed ice into reaction mixed liquid obtained by mixing filtrate and leacheate, adjusting the pH to 5.5 by using concentrated HCl to form a precipitate, filtering and collecting solids, washing the filter cake with water, and drying to obtain 3.6kg of off-white solid 6-aminonicotinic acid, wherein the yield is as follows: 80%, and its NMR spectrum is shown in FIG. 1.
Example 2
1. Synthesis of 6-chloronicotinic acid
1.6L of tap water was added to a 3L three-necked flask, and 200g of 2-chloro-5-chloromethylpyridine was added thereto under stirring at room temperature, and the internal temperature of the reaction solution was raised to 80 to 90 ℃. 200g of potassium permanganate is added into a reaction kettle in batches, and the reaction temperature is controlled to be not more than 100 ℃. After the potassium permanganate is added, the reaction temperature is controlled to be 90-100 ℃, and the mixture is stirred for 30 minutes. After TLC detection reaction is completed, cooling the reaction solution to below 25 ℃ by using an ice water bath, then filtering to remove solid manganese dioxide, leaching a filter cake by using about 150g of water, adjusting the pH of a reaction mixed solution obtained by mixing the filtrate and the leaching solution to 3 by using concentrated hydrochloric acid to precipitate a white solid, filtering, washing and drying the white solid to obtain 87g of white solid 6-chloronicotinic acid, wherein the yield is as follows: 45 percent.
2. Synthesis of 6-chloronicotinyl hydrazine
Adding 2L of ethanol into a 5L three-necked bottle, adding 500g of 6-chloronicotinic acid while stirring, and adding 300g of hydrazine hydrate with the mass concentration of 80%; the mixture was stirred at 50 ℃ until complete reaction, then the solvent was evaporated under reduced pressure, the residue was poured into 5L of cold water and the pH was adjusted to 5.5 with concentrated HCl to form a precipitate, the solid was collected by filtration, the filter cake was washed with water and dried to give 247g of 6-chloroniazid as a yellow solid in yield: 51 percent.
3. Synthesis of 6-aminonicotinic acid
3.5kg of tap water is added into a 5L three-necked bottle, 230g of solid potassium carbonate, 500g of 6-chloroniazid and 50g of Raney nickel are added into the three-necked bottle under stirring at room temperature, 130g of hydrazine hydrate with the mass concentration of 80% is slowly dropped into the reaction solution at room temperature for about 1 hour, and then the mixture is stirred and reacted at room temperature. After TLC detection reaction is completed, the reaction liquid is filtered, a filter cake is washed by water to remove solids, a reaction mixed liquid obtained by mixing a filtrate and a leacheate is added into 500mL of cold water and 500g of crushed ice, the pH is adjusted to 5.5 by using concentrated HCl to form a precipitate, the solid is collected by filtration, the filter cake is washed by water and dried to obtain 158g of off-white solid 6-aminonicotinic acid, and the yield is as follows: 35 percent.
Example 3
1. Synthesis of 6-chloronicotinic acid
1.6L of tap water was added to a 3L three-necked flask, and 200g of 2-chloro-5-chloromethylpyridine was added thereto under stirring at room temperature, and the internal temperature of the reaction solution was raised to 80 to 90 ℃.390g of potassium permanganate are added into the reaction kettle in batches, and the reaction temperature is controlled to be not more than 100 ℃. After the potassium permanganate is added, the reaction temperature is controlled to be 90-100 ℃, and the mixture is stirred for 30 minutes. After TLC detection reaction is completed, cooling the reaction solution to below 25 ℃ by using an ice water bath, then filtering to remove solid manganese dioxide, leaching a filter cake by using about 150g of water, adjusting the pH of a reaction mixed solution obtained by mixing the filtrate and the leaching solution to 3 by using concentrated hydrochloric acid, separating out a white solid, filtering, washing and drying the white solid to obtain 161g of white solid 6-chloronicotinic acid, and obtaining the yield: 83 percent.
2. Synthesis of 6-chloronicotinyl hydrazine
Adding 2L of ethanol into a 5L three-necked bottle, adding 500g of 6-chloronicotinic acid while stirring, and adding 300g of hydrazine hydrate with the mass concentration of 80%; the mixture was stirred at 75 ℃ until complete reaction, then the solvent was evaporated under reduced pressure, the residue was poured into 5L of cold water and the pH was adjusted to 5.5 with concentrated HCl to form a precipitate, the solid was collected by filtration, the filter cake was washed with water and dried to give 6-chloroniazid 339g as a yellow solid in yield: 70 percent.
3. Synthesis of 6-aminonicotinic acid
Adding 3.5kg of tap water into a 5L three-necked bottle, adding 230g of solid potassium carbonate, 500g of 6-chloroniazid and 50g of Raney nickel under stirring at room temperature, slowly dropping 130g of hydrazine hydrate with the mass concentration of 80% into the reaction solution at room temperature for about 1 hour, and then heating to 50 ℃ for stirring reaction. After TLC detection reaction is completed, the reaction liquid is filtered, a filter cake is washed by water to remove solids, reaction mixed liquid obtained by mixing filtrate and leacheate is added into 500mL of cold water and 500g of crushed ice, the pH is adjusted to 5.5 by using concentrated HCl to form a precipitate, the solid is collected by filtration, the filter cake is washed by water and dried to obtain 257g of off-white solid 6-aminonicotinic acid, and the yield is: 57 percent.
The above description is not intended to limit the present invention, and the present invention is not limited to the above examples. Those skilled in the art should also realize that changes, modifications, additions and substitutions can be made without departing from the true spirit and scope of the invention.
Claims (10)
1. A preparation method of 6-amino nicotinic acid is characterized by comprising the following steps:
(1) Reacting 2-chloro-5-chloromethylpyridine with an oxidant to obtain 6-chloronicotinic acid;
(2) Reacting 6-chloronicotinic acid with hydrazine hydrate to obtain 6-chlorohydrazine;
(3) Reacting 6-chloroniazid with a reducing agent to obtain 6-amino nicotinic acid.
2. The method for preparing 6-amino nicotinic acid according to claim 1, wherein the step (1) is specifically as follows: stirring 2-chloro-5-chloromethylpyridine and an oxidant in a solvent at the reaction temperature of 50-100 ℃ until the reaction is completed, cooling the reaction liquid to below 25 ℃, filtering, leaching the solid with water, mixing the filtrate and the leaching solution to obtain a reaction mixed liquid, adjusting the pH of the reaction mixed liquid to 3 with concentrated hydrochloric acid to form a precipitate, filtering the precipitate, washing with water, centrifuging, and drying to obtain the 6-chloronicotinic acid. Wherein the oxidant is oxygen, air, chlorine, sodium dichromate, potassium permanganate or nitric acid.
3. The method of claim 2, wherein the preparation method comprises the following steps: the oxidant is oxygen, air, chlorine, sodium dichromate, potassium permanganate or nitric acid; the solvent selects different solvents according to different oxidants: the oxidant is potassium permanganate, and water is selected as a solvent; the oxidant is oxygen, and methanol, ethanol or isopropanol is selected as a solvent; the oxidant is sodium dichromate or potassium dichromate, and sulfuric acid is selected as a solvent.
4. The method for preparing 6-amino nicotinic acid according to claim 2, which is characterized in that: the mass ratio of the 2-chloro-5-chloromethylpyridine to the oxidant is 1: (1-3).
5. The method for preparing 6-amino nicotinic acid according to claim 1, wherein the step (2) is specifically as follows: stirring 6-chloronicotinic acid and hydrazine hydrate at the temperature of 50-150 ℃ in the presence of a solvent until the reaction is completed, evaporating the solvent under reduced pressure, pouring the residue into cold water, adjusting the pH value to 5.5 by using concentrated HCl to form a precipitate, filtering and collecting a solid, washing a filter cake by using water, and drying to obtain the 6-chloronicotinyl hydrazine.
6. The method for preparing 6-amino nicotinic acid according to claim 1, which is characterized in that: the mass ratio of the 6-chloronicotinic acid to the hydrazine hydrate is 1: (1-3).
7. The method for preparing 6-amino nicotinic acid according to claim 1, which is characterized in that: the solvent is methanol, ethanol, isopropanol or n-butanol.
8. The method for preparing 6-amino nicotinic acid according to claim 1, wherein the step (3) is specifically as follows: stirring 6-chloroniazid and a reducing agent under the action of a metal catalyst at the temperature of 0-150 ℃ until the mixture completely reacts, cooling the reaction solution to room temperature, and filtering; and washing a filter cake with water, removing solids, adding the obtained reaction mixed solution into ice water, adjusting the pH to 5.5 by using concentrated HCl to form a precipitate, filtering and collecting the solids, washing the filter cake with water, and drying to obtain the 6-aminonicotinic acid.
9. The method for preparing 6-amino nicotinic acid according to claim 1, which is characterized in that: the quantitative ratio of the 6-chloronicotinyl hydrazine, the metal catalyst and the reducing agent is 1: (0.05-0.2) (1-3).
10. The method for preparing 6-amino nicotinic acid according to claim 5, wherein the method comprises the following steps: the metal catalyst is copper, nickel, palladium, silver, gold, platinum, rhodium or copper alloy, nickel alloy, palladium alloy, silver alloy, gold alloy, platinum alloy or rhodium alloy. The reducing agent is sodium borohydride, potassium borohydride, hydrazine hydrate or hydrogen.
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| CN101103008A (en) * | 2005-01-13 | 2008-01-09 | 诺瓦提斯公司 | Macrocyclic compounds useful as bace inhibitors |
| CN101351455A (en) * | 2005-12-30 | 2009-01-21 | 诺瓦提斯公司 | Macrocyclic compounds useful as BACE inhibitors |
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| CN101103008A (en) * | 2005-01-13 | 2008-01-09 | 诺瓦提斯公司 | Macrocyclic compounds useful as bace inhibitors |
| CN101351455A (en) * | 2005-12-30 | 2009-01-21 | 诺瓦提斯公司 | Macrocyclic compounds useful as BACE inhibitors |
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| RAMESH RAJU, R.等: "Electroorganic synthesis of 6-aminonicotinic acid from 2-amino-5-chloropyridine", TETRAHEDRON LETTERS, vol. 44, no. 21, 31 December 2003 (2003-12-31), pages 4133 - 4135, XP004423050, DOI: 10.1016/S0040-4039(03)00816-5 * |
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