CN114920691B - Preparation method of N- (2-hydroxyethyl) nicotinamide and preparation method of nicorandil - Google Patents
Preparation method of N- (2-hydroxyethyl) nicotinamide and preparation method of nicorandil Download PDFInfo
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- LBHIOVVIQHSOQN-UHFFFAOYSA-N nicorandil Chemical compound [O-][N+](=O)OCCNC(=O)C1=CC=CN=C1 LBHIOVVIQHSOQN-UHFFFAOYSA-N 0.000 title claims abstract description 78
- SJZLOWYUGKIWAK-UHFFFAOYSA-N n-(2-hydroxyethyl)pyridine-3-carboxamide Chemical compound OCCNC(=O)C1=CC=CN=C1 SJZLOWYUGKIWAK-UHFFFAOYSA-N 0.000 title claims abstract description 66
- 229960002497 nicorandil Drugs 0.000 title claims abstract description 65
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 238000006243 chemical reaction Methods 0.000 claims abstract description 100
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 51
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims abstract description 44
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims abstract description 27
- 235000005152 nicotinamide Nutrition 0.000 claims abstract description 22
- 239000011570 nicotinamide Substances 0.000 claims abstract description 22
- 229960003966 nicotinamide Drugs 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 19
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 19
- 238000004519 manufacturing process Methods 0.000 claims abstract description 13
- 238000003756 stirring Methods 0.000 claims description 75
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 54
- 239000000047 product Substances 0.000 claims description 40
- 238000001816 cooling Methods 0.000 claims description 38
- 238000001914 filtration Methods 0.000 claims description 28
- 230000001276 controlling effect Effects 0.000 claims description 26
- 239000000706 filtrate Substances 0.000 claims description 25
- 229910017604 nitric acid Inorganic materials 0.000 claims description 24
- 238000010438 heat treatment Methods 0.000 claims description 23
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 239000003054 catalyst Substances 0.000 claims description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 18
- 238000004090 dissolution Methods 0.000 claims description 17
- 238000004821 distillation Methods 0.000 claims description 17
- 238000002425 crystallisation Methods 0.000 claims description 15
- 230000008025 crystallization Effects 0.000 claims description 15
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 14
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 14
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 14
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 13
- 239000004327 boric acid Substances 0.000 claims description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 239000007788 liquid Substances 0.000 claims description 12
- 239000008213 purified water Substances 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 229960000583 acetic acid Drugs 0.000 claims description 11
- 239000012362 glacial acetic acid Substances 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- DFPAKSUCGFBDDF-ZQBYOMGUSA-N [14c]-nicotinamide Chemical compound N[14C](=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-ZQBYOMGUSA-N 0.000 claims description 9
- 239000007810 chemical reaction solvent Substances 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 9
- 238000001953 recrystallisation Methods 0.000 claims description 9
- 239000012141 concentrate Substances 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 230000001105 regulatory effect Effects 0.000 claims description 5
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 3
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 3
- 238000004042 decolorization Methods 0.000 claims description 3
- 125000005619 boric acid group Chemical group 0.000 claims 2
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 8
- 239000000203 mixture Substances 0.000 abstract description 7
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 238000003912 environmental pollution Methods 0.000 abstract description 3
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- 238000007056 transamidation reaction Methods 0.000 abstract description 2
- 239000000376 reactant Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 30
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 11
- 238000006396 nitration reaction Methods 0.000 description 6
- 239000002699 waste material Substances 0.000 description 6
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- XBLVHTDFJBKJLG-UHFFFAOYSA-N Ethyl nicotinate Chemical compound CCOC(=O)C1=CC=CN=C1 XBLVHTDFJBKJLG-UHFFFAOYSA-N 0.000 description 4
- 241000208125 Nicotiana Species 0.000 description 4
- -1 ethoxynicotinamide nitrate Chemical compound 0.000 description 4
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 3
- 229910002651 NO3 Inorganic materials 0.000 description 3
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 210000004351 coronary vessel Anatomy 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 230000000916 dilatatory effect Effects 0.000 description 2
- 229940064982 ethylnicotinate Drugs 0.000 description 2
- YNBADRVTZLEFNH-UHFFFAOYSA-N methyl nicotinate Chemical compound COC(=O)C1=CC=CN=C1 YNBADRVTZLEFNH-UHFFFAOYSA-N 0.000 description 2
- 235000001968 nicotinic acid Nutrition 0.000 description 2
- 239000011664 nicotinic acid Substances 0.000 description 2
- 229960003512 nicotinic acid Drugs 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 206010002388 Angina unstable Diseases 0.000 description 1
- 244000061176 Nicotiana tabacum Species 0.000 description 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000007814 Unstable Angina Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000010923 batch production Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 201000004332 intermediate coronary syndrome Diseases 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 229960001238 methylnicotinate Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000002464 muscle smooth vascular Anatomy 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 230000000802 nitrating effect Effects 0.000 description 1
- 230000001546 nitrifying effect Effects 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000036316 preload Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- ATBIAJXSKNPHEI-UHFFFAOYSA-N pyridine-3-carbonyl chloride Chemical compound ClC(=O)C1=CC=CN=C1 ATBIAJXSKNPHEI-UHFFFAOYSA-N 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 239000002351 wastewater 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
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
Abstract
The invention discloses a preparation method of nicorandil, which takes nicotinamide as a starting material, directly synthesizes N- (2-hydroxyethyl) nicotinamide by a transamidation method, and then uses a mixture of non-fuming nitric acid, acetic anhydride and concentrated sulfuric acid to nitrify to prepare the nicorandil. The method simplifies the existing synthesis process, is simple and convenient to operate, and is more suitable for large-scale production; meanwhile, the yield of the product obtained in each step of reaction is improved, the types and the dosage of the reactant are greatly reduced, and the production cost is lower. Solves the technical problems of more reaction steps, high reagent consumption, low production efficiency, high environmental pollution, poor quality of the prepared product and low yield of the existing preparation process.
Description
The present application claims priority from the chinese patent office filed at 22 of 2021, 06, under application number CN202110691715.6, chinese patent application entitled "a method for preparing nicorandil", the entire contents of which are incorporated herein by reference.
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of N- (2-hydroxyethyl) nicotinamide and a preparation method of nicorandil.
Background
Nicotil, named Nicotiana nitrate, ethoxynicotinamide nitrate and Nicotiana tabacum, named N- (2-hydroxyethyl) nicotinamide nitrate, is a nitrate anti-angina drug, and has the effects of dilating large coronary artery, dilating volume blood vessel and reducing preload. Meanwhile, nicorandil is used as a high-selectivity potassium ATP channel opener, and can relax vascular smooth muscle, dilate tiny coronary arteries, increase coronary blood flow, simulate ischemia pre-adaptation and protect cardiac muscle.
Nicotiana was originally developed by Chinese and foreign pharmaceutical Co., ltd, japanese China and foreign pharmaceutical Co., 1976 applied for patent DT2714713, and simultaneously applied for U.S. Pat. No. 5, 4200640, which discloses for the first time the preparation method, pharmacological toxicology and clinical use of Nicotiana. Trial production was successful in 1978 and was used in clinical studies in 1981. Nicotiana Kogyo Co., ltd., japan was first developed, approved in 9/21 of 1983, and used clinically. The company develops an injection capable of rapidly taking effect and adjusting dosage according to clinical needs, two specifications of 2mg and 12mg of nicorandil for injection are approved in 7 th month and 2 nd 1993, and 48mg of the specifications are approved in 12 th month and 5 th 1996, so that the injection is used for treating unstable angina.
Currently, nicorandil is generally prepared by nitration using N- (2-hydroxyethyl) nicotinamide.
The above-mentioned nitration reaction generally uses fuming nitric acid or concentrated sulfuric acid/nitric acid mixed acid, this method has limitations, on one hand the course of reaction can produce a large amount of heat, if the temperature is raised rapidly, even raise the risk of explosion, especially in the industrial mass production, the risk will be more difficult to control; on the other hand, in order to ensure that the reaction proceeds normally, an excessive amount of nitric acid is required, which causes oxidation of nicorandil or its intermediate or the reaction is diverted to form other nitro derivatives, so that the reaction yield is generally not high and the impurity content is high. In addition, in order to separate nicorandil from the reaction liquid, it is necessary to neutralize excess nitric acid or concentrated sulfuric acid with a large amount of aqueous ammonia, thereby producing a large amount of highly contaminated wastewater.
Chinese patent CN103370301a discloses a process for the synthesis of nicorandil from N- (2-hydroxyethyl) nicotinamide by nitration with nitric acid in the presence of acetic anhydride, solving the safety problems involved with fuming nitric acid or nitric acid/concentrated sulfuric acid as nitrating agent and allowing the isolated product to have excellent yields and quality. Because 1 equivalent of nitric acid is required to be consumed to generate the nitrate of N- (2-hydroxyethyl) nicotinamide or nicorandil, the use amount of the nitric acid is larger, and the molar ratio of the nitric acid to the nitrifying substrate is 2.0-2.4; and the amount of acetic anhydride is also required to be increased according to the corresponding proportion. In addition, the synthesis method slowly pours the reaction content into 24% ammonia water, which is not suitable for large-scale production; the ammonia water is used in a large amount in order to neutralize glacial acetic acid, acetic anhydride and the residual nitric acid added in the nitration process, so that a large amount of high-pollution waste liquid is generated.
The key intermediate N- (2-hydroxyethyl) nicotinamide for the synthesis reaction is usually prepared by reacting ethyl nicotinate or methyl ester with ethanolamine. In order to obtain ethyl nicotinate or methyl nicotinate, nicotinic acid is generally used as a raw material to carry out esterification reaction with alcohol under the catalysis of concentrated sulfuric acid, or nicotinyl chloride is reacted with alcohol to obtain the product. The synthesis method needs two steps of reactions, so that the overall yield is low, the production cost is high, the reagent dosage is large, and a large amount of highly-polluted and highly-corrosive waste liquid is generated.
There is a domestic literature (Xiaoglum. Heilongjiang medicine, 1993, (3) to 8-9) which discloses a process for preparing N- (2-hydroxyethyl) nicotinamide by direct acylation of nicotinic acid with ethanolamine. However, the reaction temperature is as high as 180 ℃, and the reaction yield is only 69.6%.
In order to solve the technical problems of more reaction steps, high reagent consumption, low production efficiency and high environmental pollution in the existing preparation process, the prepared product has poor quality and low yield, and a nicorandil synthesis process route needs to be re-designed.
Disclosure of Invention
The invention provides a preparation method of nicorandil, which takes nicotinamide as a starting material, directly synthesizes N- (2-hydroxyethyl) nicotinamide through a transamidation method, optimizes the nitration reaction step, replaces glacial acetic acid with concentrated sulfuric acid, and greatly reduces the consumption of reaction reagents and waste liquid by adding an organic solvent for crystallization compared with the prior art, thereby greatly reducing the waste liquid and improving the production efficiency, and simultaneously, the prepared product has high quality and high yield.
In view of this, the present invention provides a method for preparing N- (2-hydroxyethyl) nicotinamide, comprising the steps of:
adding nicotinamide, ethanolamine and a catalyst into a reaction kettle, heating to 120-180 ℃, and stirring for reacting for 4-10 h to obtain N- (2-hydroxyethyl) nicotinamide.
The invention also provides a preparation method of the nicorandil, which comprises the following steps:
step (1): adding nicotinamide, ethanolamine and a catalyst into a reaction kettle, heating to 120-180 ℃, and stirring for reaction for 4-10 hours, wherein the specific reaction equation is as follows:
after the reaction is finished, carrying out reduced pressure distillation at 120-180 ℃, controlling the vacuum degree to be less than or equal to minus 0.08Mpa until no obvious liquid is distilled, and ending the distillation; cooling the concentrate to 60-80 ℃, adding glacial acetic acid for dissolution under stirring, cooling to room temperature to obtain N- (2-hydroxyethyl) nicotinamide solution, and taking out for standby.
Step (2): adding the reaction solvent into a reaction kettle, introducing nitrogen for protection, cooling to 15-20 ℃, sequentially adding acetic anhydride, nitric acid and concentrated sulfuric acid under stirring, controlling the temperature in the reaction kettle not to exceed 30 ℃, and continuing stirring for 0.5-2 h after the addition is finished. Dripping the N- (2-hydroxyethyl) nicotinamide solution prepared in the step (1) into a reaction kettle, controlling the reaction temperature to be 10-30 ℃, wherein a specific reaction equation is as follows:
after the reaction is finished, cooling to 10-15 ℃, adding a crystallization solvent under stirring, cooling to 15-20 ℃ after the addition, stirring and crystallizing for 1-2 hours, filtering to obtain nicorandil salt, and taking out for later use. The reaction solvent and crystallization solvent include ethyl acetate, methyl acetate, acetone or methyl tert-butyl ether.
Step (3): adding purified water into a reaction kettle, adding the nicorandil salt prepared in the step (2), heating to 25-30 ℃ for dissolution, adding active carbon, stirring for decolorization, filtering, cooling filtrate to 10-15 ℃, dropwise adding ammonia water, controlling the temperature of the filtrate to be within 25 ℃, and regulating the pH value of the filtrate to 5.0-7.0; cooling to 5-20 deg.c, stirring and crystallizing for 0.5-3 hr, filtering to obtain coarse nicorandil product, and taking out for use.
Step (4): adding the recrystallization solvent into a reaction kettle, adding the crude nicorandil product prepared in the step (3), heating to 30-35 ℃ for dissolution under stirring, adding activated carbon for stirring and decoloring, filtering, cooling the filtrate to 10-15 ℃ under stirring, adding purified water for stirring and crystallizing for 1-2 h, filtering to obtain a wet nicorandil product, and drying the wet nicorandil product in an oven at 30-40 ℃ under reduced pressure for 10-16 h to obtain the final nicorandil product.
Optionally, in step (1), the catalyst comprises boric acid, a borate or a borate ester.
Optionally, in step (1), the molar ratio of catalyst to nicotinamide is from 0.01 to 0.3:1.
Optionally, in step (1), the molar ratio of ethanolamine to nicotinamide is 1.0-2.0:1.
Optionally, in step (1), the molar ratio of ethanolamine to nicotinamide is 1.4-1.6:1.
Optionally, in the step (1), the reaction temperature is 150-160 ℃.
Optionally, in the step (2), the molar ratio of the N- (2-hydroxyethyl) nicotinamide to the nitric acid in the N- (2-hydroxyethyl) nicotinamide solution is 1:1.0-1.8.
Optionally, in the step (2), the molar ratio of the N- (2-hydroxyethyl) nicotinamide to the concentrated sulfuric acid in the N- (2-hydroxyethyl) nicotinamide solution is 1:0.1-1.0.
Optionally, in step (2), the molar ratio of N- (2-hydroxyethyl) nicotinamide to acetic anhydride in the N- (2-hydroxyethyl) nicotinamide solution is 1:7.
Optionally, in step (4), the recrystallization solvent comprises methanol, ethanol, isopropanol, or acetone.
From the above technical solutions, the embodiment of the present invention has the following advantages:
1. the invention provides a preparation method of nicorandil, which takes nicotinamide as an initial raw material, and directly reacts with ethanolamine to synthesize an intermediate N- (2-hydroxyethyl) nicotinamide of nicorandil, and ammonia generated by the reaction is continuously discharged from a reaction kettle, so that the reaction is fast and thoroughly carried out; the invention simplifies the prior synthesis process steps, has simpler and more convenient operation, low raw materials and low cost, and is beneficial to industrial production.
2. In the process of synthesizing the N- (2-hydroxyethyl) nicotinamide, a small amount of catalyst is added, other chemical reagents are not used any more, excessive ethanolamine can be recycled, and the concentrate obtained by the reaction is directly used for the next reaction, so that three wastes are not generated basically.
3. In the invention, concentrated sulfuric acid is used for replacing glacial acetic acid in the prior art in the nitration reaction, so that the consumption of nitric acid and acetic anhydride in the reaction is greatly reduced; meanwhile, crystallization is carried out by adding an organic solvent, so that neutralization reaction with reduced ammonia water consumption is realized, and nicorandil is obtained.
4. Compared with the prior art, the method has the advantages that the yield of the product obtained in each step of reaction is high, the dosage and the variety of the reaction reagent are greatly reduced, the raw materials of the reaction are utilized to the maximum extent, the industrial production cost is saved, and the finally prepared nicorandil has high purity and good product quality.
5. The method has the advantages of simple post-treatment of the reaction, less discharge of three wastes, environmental friendliness and higher market application value.
The invention provides a preparation method of nicorandil, which is used for solving the technical problems of more reaction steps, high reagent consumption, low production efficiency, high environmental pollution, poor quality of the prepared product and low yield of the existing preparation technology.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required for the description of the embodiments will be briefly described below, and it is apparent that the drawings in the following description are only some embodiments described in the present invention, and other drawings may be obtained according to these drawings for those of ordinary skill in the art.
FIG. 1 is a schematic diagram of the structure of nicorandil prepared in the embodiment of the invention;
FIG. 2 is a schematic diagram of the reaction equation in step (3) according to the embodiment of the present invention.
Detailed Description
In order to better understand the solution of the present invention, the following description of the solution of the embodiment of the present invention will be clear and complete, and it is obvious that the described embodiment is only a part of the embodiments of the present invention, not all the embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention. Unless otherwise specifically indicated, the various raw materials, reagents, instruments, equipment and the like used in the present invention are commercially available or may be prepared by existing methods.
For ease of understanding, please refer to fig. 1-2.
The invention provides a preparation method of N- (2-hydroxyethyl) nicotinamide, which comprises the following steps:
adding nicotinamide, ethanolamine and a catalyst into a reaction kettle, heating to 120-180 ℃, preferably heating to 150-160 ℃, and stirring for reacting for 4-10 h; the mol ratio of the ethanolamine to the nicotinamide is 1.0-2.0:1, and the mol ratio of the ethanolamine to the nicotinamide is 1.4-1.6:1 is preferred; the catalyst comprises boric acid, borate or borate ester, preferably boric acid, so that the reaction is milder; the molar ratio of the catalyst to the nicotinamide is 0.01-0.3:1. The specific reaction equation is as follows:
after the reaction is finished, the obtained product system is subjected to reduced pressure distillation at 120-180 ℃, the vacuum degree is controlled to be less than or equal to-0.08 Mpa until no obvious liquid is distilled, and the distillation is finished; cooling the concentrate to 60-80 ℃, adding glacial acetic acid for dissolution under stirring, cooling to room temperature to obtain N- (2-hydroxyethyl) nicotinamide solution, and taking out for standby.
The invention also provides a preparation method of the nicorandil, which comprises the following steps:
step (1): adding nicotinamide, ethanolamine and a catalyst into a reaction kettle, heating to 120-180 ℃, preferably heating to 150-160 ℃, stirring and reacting for 4-10 h, wherein the mol ratio of ethanolamine to nicotinamide is 1.0-2.0:1, and the mol ratio of ethanolamine to nicotinamide is 1.4-1.6:1. The catalyst comprises boric acid, borate or borate ester, preferably boric acid, so that the reaction is milder. The molar ratio of the catalyst to the nicotinamide is 0.01-0.3:1. The specific reaction equation is as follows:
after the reaction is finished, carrying out reduced pressure distillation at 120-180 ℃, controlling the vacuum degree to be less than or equal to minus 0.08Mpa until no obvious liquid is distilled, and ending the distillation; cooling the concentrate to 60-80 ℃, adding glacial acetic acid for dissolution under stirring, cooling to room temperature to obtain N- (2-hydroxyethyl) nicotinamide solution, and taking out for standby.
Step (2): adding the reaction solvent into a reaction kettle, introducing nitrogen for protection, cooling to 15-20 ℃, sequentially adding acetic anhydride, nitric acid and concentrated sulfuric acid under stirring, controlling the temperature in the reaction kettle not to exceed 30 ℃, and continuing stirring for 0.5-2 h after the addition is finished. And (3) dropwise adding the N- (2-hydroxyethyl) nicotinamide solution prepared in the step (1) into a reaction kettle, and controlling the reaction temperature to be 10-30 ℃. Wherein the molar ratio of the N- (2-hydroxyethyl) nicotinamide to nitric acid in the N- (2-hydroxyethyl) nicotinamide solution is 1:1.0-1.8, and the mass fraction of nitric acid is preferably 67% or 68%; the molar ratio of the N- (2-hydroxyethyl) nicotinamide to the concentrated sulfuric acid in the N- (2-hydroxyethyl) nicotinamide solution is 1:0.1-1.0, and the molar ratio of the N- (2-hydroxyethyl) nicotinamide to the acetic anhydride in the N- (2-hydroxyethyl) nicotinamide solution is 1:7. The dripping time of the N- (2-hydroxyethyl) nicotinamide solution dropwise added into the reaction kettle is preferably 80min or 110min, and a specific reaction equation is as follows:
after the reaction is finished, cooling to 10-15 ℃, adding a crystallization solvent under stirring, cooling to 15-20 ℃ after the addition, stirring and crystallizing for 1-2 hours, filtering to obtain nicorandil salt, and taking out for later use.
The reaction solvent and crystallization solvent include ethyl acetate, methyl acetate, acetone or methyl tert-butyl ether, preferably methyl tert-butyl ether;
step (3): adding purified water into a reaction kettle, adding the nicorandil salt prepared in the step (2), heating to 25-30 ℃ for dissolution, adding active carbon for stirring and decoloring, filtering, cooling the filtrate to 10-15 ℃, dropwise adding ammonia water, controlling the temperature of the filtrate within 25 ℃, adjusting the pH value of the filtrate to 5.0-7.0, and preferably enabling the dropwise adding time of the ammonia water to be 100min, 130min or 150min; cooling to 5-20 deg.c, stirring and crystallizing for 0.5-3 hr, filtering to obtain coarse nicorandil product, and taking out for use. Specific reaction equations can be seen in FIG. 2.
Step (4): adding a recrystallization solvent into a reaction kettle, wherein the recrystallization solvent comprises methanol, ethanol, isopropanol or acetone, preferably methanol, and has low cost and good purification effect; adding the crude nicorandil product prepared in the step (3), heating to 30-35 ℃ for dissolution under stirring, adding active carbon, stirring for decolorization, filtering, cooling the filtrate to 10-15 ℃ under stirring, adding purified water, stirring for crystallization for 1-2 h, and filtering to obtain a nicorandil wet product; and (3) placing the nicorandil wet product in an oven, and drying the nicorandil wet product for 10-16 hours at 30-40 ℃ under reduced pressure to obtain a nicorandil finished product.
Example 1
The invention provides an embodiment of a preparation method of nicorandil, which comprises the following steps:
step (1): 122g of nicotinamide, boric acid serving as a catalyst and ethanolamine are taken and respectively added into a reaction kettle, the molar ratio of boric acid to nicotinamide is 0.1:1, the molar ratio of ethanolamine to nicotinamide is 1.6:1, the heating temperature is 140 ℃, and the reaction is stirred for 10 hours. And (3) after the reaction is finished, performing reduced pressure distillation to remove excessive ethanolamine, opening vacuum at 140 ℃, controlling the vacuum degree to be less than or equal to-0.08 Mpa, and stopping distillation when almost no liquid flows out. The product of the reduced pressure distillation was cooled to 60℃and 122g of glacial acetic acid was added with stirring to dissolve, and cooled to room temperature to give an N- (2-hydroxyethyl) nicotinamide solution. The N- (2-hydroxyethyl) nicotinamide solution was tested by HPLC for N- (2-hydroxyethyl) nicotinamide content in 88.9% yield.
Step (2): 200g of ethyl acetate serving as a reaction solvent is placed in a reaction kettle, nitrogen is introduced for protection, the temperature is reduced to 15 ℃, acetic anhydride, 67% nitric acid and concentrated sulfuric acid are added under stirring, the temperature in the reaction kettle is controlled to be not more than 30 ℃, and stirring is continued for 30min after the addition is completed; adding the N- (2-hydroxyethyl) nicotinamide solution prepared in the step (1) under stirring, controlling the dripping time to be 80min, controlling the reaction temperature to be 15-22 ℃, and continuing to react for 1h after the N- (2-hydroxyethyl) nicotinamide solution is added. Wherein, the mol ratio of the N- (2-hydroxyethyl) nicotinamide to the nitric acid is 1:1.4, the mol ratio of the N- (2-hydroxyethyl) nicotinamide to the concentrated sulfuric acid is 1:0.5, and the mol ratio of the N- (2-hydroxyethyl) nicotinamide to the acetic anhydride is 1:7.
After the reaction is finished, the reaction product is cooled to 10-15 ℃, 600g of crystallization solvent ethyl acetate is dripped under stirring, the dripping temperature is controlled to be not more than 20 ℃, the temperature is cooled to 15-20 ℃ after the ethyl acetate is added, the mixture is stirred and crystallized for 1h, the mixture is filtered, and the ethyl acetate is leached for 2 times, so that the nicorandil salt is obtained, and the yield is 91.4%.
Step (3): adding 580g of purified water into a reaction kettle, adding the nicorandil salt prepared in the step (2), heating to 25 ℃ for dissolution under stirring, adding 11.6g of active carbon, stirring for decoloration for 10min, filtering, cooling the filtrate to 10 ℃, dropwise adding ammonia water, controlling the dropwise adding time to be 100min, controlling the temperature of the filtrate to be within 20 ℃, and regulating the pH value of the filtrate to 6.5 by using the ammonia water; cooling to 5-20 deg.c, stirring and crystallizing for 1 hr, and filtering to obtain coarse nicorandil product. The yield was 82.4% and the purity was 99.65%.
Step (4): adding 227g of recrystallization solvent methanol into a reaction kettle, adding the crude nicorandil product obtained in the step (3) under stirring, heating to 32 ℃ for dissolution, adding 5.6g of active carbon, stirring for decoloration for 10min, filtering, cooling the filtrate to 10 ℃, adding 567g of purified water, stirring for crystallization for 1h, filtering to obtain a wet nicorandil product, drying under reduced pressure at 40 ℃ in an oven for 16h, turning over the material once every 4h, and obtaining the nicorandil product after the drying is finished. The yield was 82.0% and the purity was 99.95%.
Example 2
The embodiment provides a preparation method of nicorandil, which comprises the following steps:
step (1): 122g of nicotinamide, boric acid serving as a catalyst and ethanolamine are taken and respectively added into a reaction kettle, the molar ratio of boric acid to nicotinamide is 0.1:1, the molar ratio of ethanolamine to nicotinamide is 1.6:1, the heating temperature is 155 ℃, and the reaction is stirred for 8 hours. After the reaction is finished, the excess ethanolamine is distilled off under reduced pressure, the temperature is 155 ℃, the vacuum is started, the vacuum degree is controlled to be less than or equal to-0.08 Mpa, and the distillation is stopped when almost no liquid flows out again. The concentrate distilled under reduced pressure was cooled to 65℃and 122g of glacial acetic acid was added thereto with stirring to dissolve, and the solution was cooled to room temperature to give an N- (2-hydroxyethyl) nicotinamide solution. The N- (2-hydroxyethyl) nicotinamide solution was tested by HPLC for its N- (2-hydroxyethyl) nicotinamide content in 89.6% yield.
Step (2): 200g of methyl tertiary butyl ether serving as a reaction solvent is placed in a reaction kettle, nitrogen is introduced for protection, the temperature is reduced to 15 ℃, acetic anhydride, 67% nitric acid and concentrated sulfuric acid are added under stirring, the temperature in the reaction kettle is controlled to be not more than 30 ℃, and stirring is continued for 30min after the addition is completed; adding the N- (2-hydroxyethyl) nicotinamide solution prepared in the step (1) under stirring, controlling the dripping time to be 80min, controlling the reaction temperature to be 15-22 ℃, and continuing to react for 1h after the N- (2-hydroxyethyl) nicotinamide solution is added. Wherein, the mol ratio of the N- (2-hydroxyethyl) nicotinamide to the nitric acid is 1:1.4, the mol ratio of the N- (2-hydroxyethyl) nicotinamide to the concentrated sulfuric acid is 1:0.5, and the mol ratio of the N- (2-hydroxyethyl) nicotinamide to the acetic anhydride is 1:7.
After the reaction is finished, the reaction product is cooled to 12 ℃, 600g of crystallization solvent methyl tertiary butyl ether is dripped under stirring, the dripping temperature is controlled to be not more than 20 ℃, the mixture is stirred and crystallized for 1.5 hours after the addition is finished, and the nicorandil salt is obtained after filtration, and the yield is 93.1%.
Step (3): adding 600g of purified water into a reaction kettle, adding the nicorandil salt prepared in the step (2), heating to 26 ℃ for dissolution under stirring, adding 12g of active carbon, stirring for decoloration for 10min, filtering, cooling the filtrate to 12 ℃, dropwise adding ammonia water, controlling the dropwise adding time to be 130min, controlling the temperature of the filtrate to be within 20 ℃, and regulating the pH value of the filtrate to 6.8 by using the ammonia water; cooling to 15 ℃, continuously stirring and crystallizing for 2 hours, and filtering to obtain a crude nicorandil product. The yield thereof was found to be 83.0% and the purity thereof was found to be 99.71%.
Step (4): adding 230g of recrystallization solvent methanol into a reaction kettle, adding the crude nicorandil product obtained in the step (3) under stirring, heating to 33 ℃ for dissolution, adding 4.6g of active carbon, stirring for decoloration for 10min, filtering, cooling the filtrate to 12 ℃ under stirring, adding 460g of purified water, stirring for crystallization for 1.5h, filtering to obtain wet nicorandil product, drying under reduced pressure for 10h in an oven at 40 ℃, turning over once every 2h, and obtaining the nicorandil product after the drying is finished. The yield was 82.7% and the purity was 99.98%.
Example 3
The embodiment provides a preparation method of nicorandil, which comprises the following steps:
step (1): taking 12.2kg of nicotinamide, boric acid serving as a catalyst and ethanolamine, respectively adding the catalyst into a reaction kettle, wherein the molar ratio of boric acid to nicotinamide is 0.1:1, the molar ratio of ethanolamine to nicotinamide is 1.6:1, heating the mixture to 160 ℃, and stirring the mixture for reaction for 8 hours. And (3) after the reaction is finished, performing reduced pressure distillation to remove excessive ethanolamine, opening vacuum at 160 ℃, controlling the vacuum degree to be less than or equal to-0.08 Mpa, and stopping distillation when almost no liquid flows out. The product of the reduced pressure distillation was cooled to 70℃and 12.2kg of glacial acetic acid was added with stirring to dissolve, and cooled to room temperature to give an N- (2-hydroxyethyl) nicotinamide solution. The N- (2-hydroxyethyl) nicotinamide solution was tested by HPLC for the N- (2-hydroxyethyl) nicotinamide content in a yield of 90.0%.
Step (2): placing 22.8kg of methyl tertiary butyl ether serving as a reaction solvent into a reaction kettle, introducing nitrogen for protection, cooling to 18 ℃, adding acetic anhydride, 68% nitric acid and concentrated sulfuric acid under stirring, and controlling the temperature in the reaction kettle to be not more than 30 ℃; the dropping time of the nitric acid is controlled to be 160min, and stirring is continued for 30min after the completion of the dropping.
And (3) taking the step (1), dropwise adding the N- (2-hydroxyethyl) nicotinamide solution obtained in the step (1) into a reaction kettle, wherein the dropwise adding time is controlled to be 110min, and the reaction temperature is controlled to be 15-22 ℃. The molar ratio of the N- (2-hydroxyethyl) nicotinamide to the nitric acid is 1:1.4, the molar ratio of the N- (2-hydroxyethyl) nicotinamide to the concentrated sulfuric acid is 1:0.5, the molar ratio of the N- (2-hydroxyethyl) nicotinamide to the acetic anhydride is 1:7, and the reaction is continued for 1h after the addition is completed. After the reaction is finished, the reaction product is cooled to 13 ℃, 67.8kg of crystallization solvent methyl tertiary butyl ether is added under stirring, the temperature of the dripping temperature is controlled to be no more than 20 ℃, the mixture is cooled to 15-20 ℃ after the methyl tertiary butyl ether is added, stirred and crystallized for 1.5h, filtered, and the methyl tertiary butyl ether is leached for 2 times, so that the nicorandil salt is obtained, and the yield is 92.5%.
Step (3): adding 60kg of purified water into a reaction kettle, adding the nicorandil salt prepared in the step (2), heating to 28 ℃ for dissolution under stirring, adding 120g of active carbon, stirring for decoloration for 10min, filtering, cooling the filtrate to 12 ℃, dropwise adding ammonia water, controlling the dropwise adding time to 150min, controlling the temperature of the filtrate to be within 20 ℃, and regulating the pH value of the filtrate to 7.0 by using the ammonia water; cooling the filtrate to 10 ℃ after the pH value is qualified, continuously stirring and crystallizing for 0.5h, and filtering to obtain a crude nicorandil product. The yield was 83.4% and the purity was 99.78%.
Step (4): adding 22kg of recrystallization solvent methanol into a reaction kettle, adding the crude nicorandil product obtained in the step (3) under stirring, heating to 33 ℃ for dissolution, adding 44g of active carbon, stirring for decoloration for 10min, filtering, cooling the filtrate to 13 ℃, adding 44kg of purified water, stirring for crystallization for 1.5h, filtering to obtain a wet nicorandil product, placing the wet nicorandil product into an oven for drying under reduced pressure for 12h at 40 ℃, turning over once every 4h, and obtaining a finished nicorandil product after drying is finished. The yield was 83.1% and the purity was 99.99%.
The embodiment is an implementation mode of the preparation method of the nicorandil in industrial scale-up production, and the yield and the purity of the nicorandil obtained in small-batch production in the embodiment are almost the same as those of the embodiment 1-2, so that the preparation method of the nicorandil provided by the invention can be better applied to industrial production and has higher production application value.
The above embodiments are only for illustrating the technical solution of the present invention, and not for limiting the same; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit and scope of the technical solutions of the embodiments of the present invention.
Claims (7)
1. A method for preparing N- (2-hydroxyethyl) nicotinamide, which is characterized by comprising the following steps:
adding nicotinamide, ethanolamine and a catalyst into a reaction kettle, heating to 120-180 ℃, and stirring for reaction for 4-10 h; the catalyst is boric acid; the molar ratio of the catalyst to the nicotinamide is 0.01-0.3:1, and the molar ratio of the ethanolamine to the nicotinamide is 1.0-2.0:1;
after the reaction is finished, carrying out reduced pressure distillation at 120-180 ℃, controlling the vacuum degree to be less than or equal to minus 0.08MPa until no obvious liquid is distilled, and ending the distillation; cooling the concentrate to 60-80 ℃, adding glacial acetic acid for dissolution under stirring, and cooling to room temperature to obtain an N- (2-hydroxyethyl) nicotinamide solution.
2. The preparation method of the nicorandil is characterized by comprising the following steps:
step (1): adding nicotinamide, ethanolamine and a catalyst into a reaction kettle, heating to 120-180 ℃, and stirring for reacting for 4-10 h, wherein the catalyst is boric acid; the molar ratio of the catalyst to the nicotinamide is 0.01-0.3:1, and the molar ratio of the ethanolamine to the nicotinamide is 1.0-2.0:1; the specific reaction equation is as follows:
after the reaction is finished, carrying out reduced pressure distillation at 120-180 ℃, controlling the vacuum degree to be less than or equal to minus 0.08MPa until no obvious liquid is distilled, and ending the distillation; cooling the concentrate to 60-80 ℃, adding glacial acetic acid for dissolution under stirring, cooling to room temperature to obtain an N- (2-hydroxyethyl) nicotinamide solution, and taking out for later use;
step (2): adding a reaction solvent into a reaction kettle, introducing nitrogen for protection, cooling to 15-20 ℃, sequentially adding acetic anhydride, nitric acid and concentrated sulfuric acid under stirring, controlling the temperature in the reaction kettle not to exceed 30 ℃, and continuing stirring for 0.5-2 h after the addition is finished;
dripping the N- (2-hydroxyethyl) nicotinamide solution prepared in the step (1) into a reaction kettle, controlling the reaction temperature to be 10-30 ℃, wherein a specific reaction equation is as follows:
cooling to 10-15 ℃ after the reaction is finished, adding a crystallization solvent under stirring, cooling to 15-20 ℃ after the addition, stirring and crystallizing for 1-2 hours, filtering to obtain nicorandil salt, and taking out for later use;
the reaction solvent and the crystallization solvent are ethyl acetate, methyl acetate, acetone or methyl tertiary butyl ether;
step (3): adding purified water into a reaction kettle, adding the nicorandil salt prepared in the step (2), heating to 25-30 ℃ for dissolution, adding active carbon, stirring for decolorization, filtering, cooling filtrate to 10-15 ℃, dropwise adding ammonia water, controlling the temperature of the filtrate to be within 25 ℃, and regulating the pH value of the filtrate to 5.0-7.0; cooling to 5-20 ℃, continuously stirring and crystallizing for 0.5-3 h, filtering to obtain a crude nicorandil product, and taking out for later use;
step (4): adding a recrystallization solvent into a reaction kettle, adding the crude nicorandil product prepared in the step (3), heating to 30-35 ℃ for dissolution under stirring, adding activated carbon for stirring and decoloring, filtering, cooling the filtrate to 10-15 ℃ under stirring, adding purified water for stirring and crystallizing for 1-2 h, and filtering to obtain a wet nicorandil product; and (3) placing the nicorandil wet product in an oven, and drying the nicorandil wet product for 10-16 hours at 30-40 ℃ under reduced pressure to obtain a nicorandil finished product.
3. The process for preparing nicorandil as claimed in claim 2, wherein in the step (1), the reaction temperature is 150 to 160 ℃.
4. The method for preparing nicorandil according to claim 2, wherein in the step (2), the molar ratio of the N- (2-hydroxyethyl) nicotinamide to nitric acid in the N- (2-hydroxyethyl) nicotinamide solution is 1:1.0-1.8.
5. The method for preparing nicorandil according to claim 2, wherein in the step (2), the molar ratio of the N- (2-hydroxyethyl) nicotinamide to the concentrated sulfuric acid in the N- (2-hydroxyethyl) nicotinamide solution is 1:0.1-1.0.
6. The process for preparing nicorandil as claimed in claim 2, wherein in the step (2), the molar ratio of N- (2-hydroxyethyl) nicotinamide to acetic anhydride in the N- (2-hydroxyethyl) nicotinamide solution is 1:7.
7. The method for preparing nicorandil as claimed in claim 2, wherein in the step (4), the recrystallization solvent is methanol, ethanol, isopropanol or acetone.
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| CN103370301A (en) * | 2010-12-28 | 2013-10-23 | 普罗克斯股份公司 | Process for the manufacture of nicorandil |
| KR20140013232A (en) * | 2012-07-22 | 2014-02-05 | 미래파인켐 주식회사 | Process for the preparation of n-(2-hydroxyethyl)nicotinamide and nicorandil |
| CN110845403A (en) * | 2019-10-30 | 2020-02-28 | 北京沃邦医药科技有限公司 | Preparation method of nicorandil |
| CN111269175A (en) * | 2020-02-13 | 2020-06-12 | 张家港九力新材料科技有限公司 | Nicorandil preparation method |
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| CN103370301A (en) * | 2010-12-28 | 2013-10-23 | 普罗克斯股份公司 | Process for the manufacture of nicorandil |
| KR20140013232A (en) * | 2012-07-22 | 2014-02-05 | 미래파인켐 주식회사 | Process for the preparation of n-(2-hydroxyethyl)nicotinamide and nicorandil |
| CN110845403A (en) * | 2019-10-30 | 2020-02-28 | 北京沃邦医药科技有限公司 | Preparation method of nicorandil |
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