CN102977003A - Preparation method of flecainide acetate - Google Patents
Preparation method of flecainide acetate Download PDFInfo
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- CN102977003A CN102977003A CN2012104918850A CN201210491885A CN102977003A CN 102977003 A CN102977003 A CN 102977003A CN 2012104918850 A CN2012104918850 A CN 2012104918850A CN 201210491885 A CN201210491885 A CN 201210491885A CN 102977003 A CN102977003 A CN 102977003A
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Abstract
The invention discloses a preparation method of flecainide acetate. The method takes 2,5-di(2,2,2-trifluoroethoxy)benzoic acid, chloroacetonitrile, triethylamine and ethyl acetate as raw materials, and comprises the following steps of: under the protection of nitrogen, performing a reflux reaction to generate cyanomethyl-2,5-di(2,2,2-trifluoroethoxy)benzoate; adding 2-aminomethylpiperidine and solvent ethyl acetate, and reacting under the protection of nitrogen to generate flecainide; adding acetic acid and ethyl acetate into the flecainide, and reacting under the protection of nitrogen to generate a crude product of flecainide acetate; and finally refining the crude product to obtain a product flecainide acetate. The preparation method of flecainide acetate disclosed by the invention is simple to operate and low in cost and realizes high yield; and the purity of the obtained product is relatively high. According to the invention, nitrogen is used as a protective gas, and the price of nitrogen is low; and compared with the prior art taking argon as a protective gas, the production cost is obviously lowered.
Description
Technical field
The present invention relates to a kind of preparation method of medicine, belong to technical field of pharmaceuticals; The preparation method who particularly relates to a kind of flecainide acetate.
Background technology
Flecainide acetate is developed by U.S. Riker company, goes on the market in Germany first in nineteen eighty-two.This product mainly is applicable to supraventricular tachycardia, atrioventricular node or the chamber tachycardia of turning back, atrial fibrillation, children's intractable junctional tachycardia and with the irritability syndrome person.
At present, all take foreign literature as main, the preparation method of the disclosed flecainide acetate of foreign literature mainly contains following several about the related data of flecainide acetate:
(1), take 5-bromo-2-chloro-phenylformic acid as starting raw material, first form two (2,2, the 2-trifluoro ethoxy) phenylformic acid of 2,5-with the 2,2,2 tfifluoroethyl alcohol reaction, then prepare cyanogen methyl-2 with chloromethyl cyanide, 5-pair of (2,2,2-trifluoro ethoxy) benzoic ethers; Cyanogen methyl-2, two (2,2, the 2-trifluoro ethoxy) benzoic ethers of 5-and the reaction of 2-aminomethyl-pyridine form Tamboar through reduction again, then prepare flecainide acetate with the acetic acid salify.
(2), take the 2-chloro-benzoic acid as starting raw material, prepare 2-(2,2,2-trifluoro ethoxy with the reaction of 2,2,2 tfifluoroethyl alcohol and cupric bromide) phenylformic acid, prepare 5-bromo-2-(2,2,2-trifluoro ethoxy with bromine reaction again) phenylformic acid; Through preparing two (2,2, the 2-trifluoro ethoxy) phenylformic acid of 2,5-with the 2,2,2 tfifluoroethyl alcohol reaction; Two (2,2, the 2-trifluoro ethoxy) phenylformic acid of 2,5-are at SOCl
2Have the lower methyl 2 that forms with methyl alcohol, two (2,2, the 2-trifluoro ethoxy) benzoic ethers of 5-form Tamboar with the reaction of 2-aminomethyl piperidines again, then prepare flecainide acetate with the acetic acid salify.
(3), be starting raw material with 2,5-dibromomethylbenzene, form two (2,2, the 2-trifluoro ethoxy) toluene of 2,5-with the 2,2,2 tfifluoroethyl alcohol reaction; In the presence of potassium permanganate, form 2, two (2,2, the 2-trifluoro ethoxy) phenylformic acid of 5-; Two (2,2, the 2-trifluoro ethoxy) phenylformic acid of 2,5-are reacted into ester with Vinyl chloroformate first, form 2,5-two (2,2 with the reaction of 2-aminomethyl-pyridine again, the 2-trifluoro ethoxy)-(2-picoline) benzamide forms Tamboar after reduction, forms flecainide acetate with acetic acidreaction again.
(4), take DHB as starting raw material, prior to trifluoromethanesulfonic acid-2,2,5-two (2 is prepared in the reaction of 2,2-trifluoro ethyl ester, 2,2-trifluoro ethoxy) phenylformic acid-2 ＇, 2 ＇, 2 ＇-trifluoro ethyl ester prepare N-(α-picolyl)-2 with the reaction of 2-aminomethyl-pyridine again, and 5-two (2,2, the 2-trifluoro ethoxy) benzamide forms Tamboar after reduction, become the salt formation flecainide acetate with acetic acid again.
More than four kinds of preparation method's operating processes complicated, and production cost is higher, reaction yield is lower, products obtained therefrom purity is lower.Use the objectionable impurities bromine in the method (two), used the objectionable impuritiess such as dioxan and pyridine in the method (three).
Summary of the invention
The technical problem to be solved in the present invention provides a kind of preparation method of flecainide acetate.Adopt technical solution of the present invention to prepare flecainide acetate, its preparation method is simple to operate, cost is low, yield high (yield reaches more than 40%); Products obtained therefrom purity is higher, and the purity of products obtained therefrom flecainide acetate is greater than 99.9%.
In order to address the above problem, the technical solution used in the present invention is:
The reaction equation that the present invention prepares flecainide acetate is:
The invention provides a kind of preparation method of flecainide acetate, described preparation method may further comprise the steps:
A, cyanogen methyl-2, the preparation of two (2,2, the 2-trifluoro ethoxy) benzoic ethers of 5-:
At first with raw material 2,5-two (2,2, the 2-trifluoro ethoxy) phenylformic acid and chloromethyl cyanide add in the reactor, and add triethylamine and ethyl acetate, pass into simultaneously nitrogen as shielding gas, be heated to 70～78 ℃ of back flow reaction 3h, reaction is cooled to below 10 ℃ after finishing, and then filters, remove insoluble substance, and steam and to desolventize, solvent obtains cyanogen methyl-2 after steaming and removing, and 5-two (2,2,2-trifluoro ethoxy) benzoic ether;
Described 2, two (2,2, the 2-trifluoro ethoxy) phenylformic acid of 5-and the chloromethyl cyanide mol ratio between the two is 1:1.5～2.0; Described 2, two (2,2, the 2-trifluoro ethoxy) phenylformic acid of 5-and the triethylamine mol ratio between the two is 1:1.5～2.0; Described 2, two (2,2, the 2-trifluoro ethoxy) phenylformic acid of 5-and ethyl acetate between the two the ratio of add-on be 1g:4～5ml;
The preparation of b, Tamboar:
With the cyanogen methyl-2 that step a prepares, 5-two (2,2, the 2-trifluoro ethoxy) benzoic ether adds in the reaction vessel, pass into nitrogen as shielding gas, and add raw material 2-aminomethyl piperidines and solvent ethyl acetate, under 25～30 ℃ of conditions, stir and react 14～16h; Reaction is washed the gained reaction solution 2～3 times after finishing, and water intaking is washed rear gained organic phase and carried out drying, filtration with anhydrous sodium sulphate, then steams to desolventize, and obtains Tamboar;
Described cyanogen methyl-2, two (2,2, the 2-trifluoro ethoxy) benzoic ethers of 5-and the 2-aminomethyl piperidines mol ratio between the two is 1:2; Described cyanogen methyl-2, two (2,2, the 2-trifluoro ethoxy) benzoic ethers of 5-and the ethyl acetate ratio between the two is 1g:5.5ml;
The preparation of c, flecainide acetate crude product:
Step b gained Tamboar is added in the reaction vessel, and add acetic acid and solvent ethyl acetate, pass into simultaneously nitrogen as shielding gas, stirring reaction 30～40min at ambient temperature, there is solid product to separate out, then is cooled to 0 ℃ and be incubated 4～4.5h, its solid product is fully separated out; Then filter, the gained filter cake washs 2～3 times with 0 ℃ ethyl acetate, obtains the flecainide acetate crude product after the washing;
Described Tamboar and acetic acid between the two the mol ratio of add-on be 1:1; Described Tamboar and ethyl acetate between the two the ratio of add-on be 1g:3ml;
Making with extra care of d, flecainide acetate crude product:
The flecainide acetate crude product that step c is obtained adds in the reaction vessel, and adding solvent ethyl acetate, described flecainide acetate crude product and ethyl acetate between the two the ratio of add-on be 1g:10ml, after being heated to fully dissolving, filter gained filtrate naturally cooling crystallization, filtration, the gained filter cake adopts ethyl acetate to wash, obtain flecainide acetate after the washing, the flecainide acetate after the washing is carried out vacuum-drying, obtain the product flecainide acetate after the drying.
According to the preparation method of above-mentioned flecainide acetate, described in the step a 2, two (2,2, the 2-trifluoro ethoxy) phenylformic acid of 5-and the chloromethyl cyanide mol ratio between the two is 1:1.5; Described 2, two (2,2, the 2-trifluoro ethoxy) phenylformic acid of 5-and the triethylamine mol ratio between the two is 1:1.5; Described 2, two (2,2, the 2-trifluoro ethoxy) phenylformic acid of 5-and ethyl acetate between the two the ratio of add-on be 1g:4ml.
According to the preparation method of above-mentioned flecainide acetate, its vacuum tightness of vacuum-drying described in the steps d is 0.09mPa, and drying temperature is 50 ℃, and be 12h time of drying.
Positive beneficial effect of the present invention:
1, adopt technical solution of the present invention to prepare flecainide acetate, its preparation method is simple to operate, cost is low, yield is high (with 2,5-two (2,2, the 2-trifluoro ethoxy) phenylformic acid meter, its yield reaches 40～45%), products obtained therefrom purity is higher, the purity of products obtained therefrom flecainide acetate sees accompanying drawing for details greater than the 99.9%(product purity).
2, as shielding gas, its nitrogen is cheap with nitrogen in the present invention, adopts argon gas to compare as shielding gas with prior art, and its production cost obviously reduces.
3, adopt technical solution of the present invention to prepare flecainide acetate, its stable yield; And products obtained therefrom can meet the demands fully (product of the present invention relevant detection data see table 1 for details).
The detection data of table 1 product of the present invention
Four, description of drawings:
The stratographic analysis figure of Fig. 1 embodiment of the invention 1 products obtained therefrom flecainide acetate;
The stratographic analysis figure of Fig. 2 embodiment of the invention 2 products obtained therefrom flecainide acetates;
The stratographic analysis figure of Fig. 3 embodiment of the invention 3 products obtained therefrom flecainide acetates.
Five, embodiment:
Further set forth the present invention below in conjunction with embodiment, but do not limit content of the present invention.
Embodiment 1:
The preparation method of flecainide acetate of the present invention, its detailed step is as follows:
A, cyanogen methyl-2, the preparation of two (2,2, the 2-trifluoro ethoxy) benzoic ethers of 5-:
At first with raw material 2,5-two (2,2, the 2-trifluoro ethoxy) phenylformic acid and chloromethyl cyanide add in the reactor, and add triethylamine and ethyl acetate, pass into simultaneously nitrogen as shielding gas, be heated to 78 ℃ of back flow reaction 3h, reaction is cooled to below 10 ℃ after finishing, and then filters, remove insoluble substance, and steam and to desolventize, solvent obtains cyanogen methyl-2 after steaming and removing, and 5-two (2,2,2-trifluoro ethoxy) benzoic ether;
Described 2, two (2,2, the 2-trifluoro ethoxy) phenylformic acid of 5-and the chloromethyl cyanide mol ratio between the two is 1:1.5; Described 2, two (2,2, the 2-trifluoro ethoxy) phenylformic acid of 5-and the triethylamine mol ratio between the two is 1:1.5; Described 2, two (2,2, the 2-trifluoro ethoxy) phenylformic acid of 5-and ethyl acetate between the two the ratio of add-on be 1g:4ml;
The preparation of b, Tamboar:
With the cyanogen methyl-2 that step a prepares, 5-two (2,2, the 2-trifluoro ethoxy) benzoic ether adds in the reaction vessel, pass into nitrogen as shielding gas, and add raw material 2-aminomethyl piperidines and solvent ethyl acetate, under 25 ℃ of conditions, stir and react 16h; Reaction is washed the gained reaction solution 3 times after finishing, and water intaking is washed rear gained organic phase and carried out drying, filtration with anhydrous sodium sulphate, then steams to desolventize, and obtains Tamboar;
Described cyanogen methyl-2, two (2,2, the 2-trifluoro ethoxy) benzoic ethers of 5-and the 2-aminomethyl piperidines mol ratio between the two is 1:2; Described cyanogen methyl-2, two (2,2, the 2-trifluoro ethoxy) benzoic ethers of 5-and the ethyl acetate ratio between the two is 1g:5.5ml;
The preparation of c, flecainide acetate crude product:
Step b gained Tamboar is added in the reaction vessel, and add acetic acid and solvent ethyl acetate, pass into simultaneously nitrogen as shielding gas, stirring reaction 30min at ambient temperature, there is solid product to separate out, then is cooled to 0 ℃ and be incubated 4h, its solid product is fully separated out; Then filter, the gained filter cake washs 2～3 times with 0 ℃ ethyl acetate, obtains the flecainide acetate crude product after the washing;
Described Tamboar and acetic acid between the two the mol ratio of add-on be 1:1; Described Tamboar and ethyl acetate between the two the ratio of add-on be 1g:3ml;
Making with extra care of d, flecainide acetate crude product:
The flecainide acetate crude product that step c is obtained adds in the reaction vessel, and adding solvent ethyl acetate, described flecainide acetate crude product and ethyl acetate between the two the ratio of add-on be 1g:10ml, after being heated to fully dissolving, filter, gained filtrate naturally cooling crystallization, filtration, the gained filter cake adopts ethyl acetate to wash, obtain flecainide acetate after the washing, flecainide acetate after the washing is carried out vacuum-drying, and (vacuum tightness is 0.09mPa, drying temperature is 50 ℃, and be 12h time of drying), obtain the product flecainide acetate after the drying.
Embodiment 2:
The preparation method of flecainide acetate of the present invention, its detailed step is as follows:
A, cyanogen methyl-2, the preparation of two (2,2, the 2-trifluoro ethoxy) benzoic ethers of 5-:
At first with raw material 2,5-two (2,2, the 2-trifluoro ethoxy) phenylformic acid and chloromethyl cyanide add in the reactor, and add triethylamine and ethyl acetate, pass into simultaneously nitrogen as shielding gas, be heated to 75 ℃ of back flow reaction 3h, reaction is cooled to below 10 ℃ after finishing, and then filters, remove insoluble substance, and steam and to desolventize, solvent obtains cyanogen methyl-2 after steaming and removing, and 5-two (2,2,2-trifluoro ethoxy) benzoic ether;
Described 2, two (2,2, the 2-trifluoro ethoxy) phenylformic acid of 5-and the chloromethyl cyanide mol ratio between the two is 1:1.7; Described 2, two (2,2, the 2-trifluoro ethoxy) phenylformic acid of 5-and the triethylamine mol ratio between the two is 1:1.8; Described 2, two (2,2, the 2-trifluoro ethoxy) phenylformic acid of 5-and ethyl acetate between the two the ratio of add-on be 1g:4.5ml;
The preparation of b, Tamboar:
With the cyanogen methyl-2 that step a prepares, 5-two (2,2, the 2-trifluoro ethoxy) benzoic ether adds in the reaction vessel, pass into nitrogen as shielding gas, and add raw material 2-aminomethyl piperidines and solvent ethyl acetate, under 28 ℃ of conditions, stir and react 15h; Reaction is washed the gained reaction solution 3 times after finishing, and water intaking is washed rear gained organic phase and carried out drying, filtration with anhydrous sodium sulphate, then steams to desolventize, and obtains Tamboar;
Described cyanogen methyl-2, two (2,2, the 2-trifluoro ethoxy) benzoic ethers of 5-and the 2-aminomethyl piperidines mol ratio between the two is 1:2; Described cyanogen methyl-2, two (2,2, the 2-trifluoro ethoxy) benzoic ethers of 5-and the ethyl acetate ratio between the two is 1g:5.5ml;
The preparation of c, flecainide acetate crude product:
Step b gained Tamboar is added in the reaction vessel, and add acetic acid and solvent ethyl acetate, pass into simultaneously nitrogen as shielding gas, stirring reaction 30min at ambient temperature, there is solid product to separate out, then is cooled to 0 ℃ and be incubated 4h, its solid product is fully separated out; Then filter, the gained filter cake washs 2～3 times with 0 ℃ ethyl acetate, obtains the flecainide acetate crude product after the washing;
Described Tamboar and acetic acid between the two the mol ratio of add-on be 1:1; Described Tamboar and ethyl acetate between the two the ratio of add-on be 1g:3ml;
Making with extra care of d, flecainide acetate crude product:
The flecainide acetate crude product that step c is obtained adds in the reaction vessel, and adding solvent ethyl acetate, described flecainide acetate crude product and ethyl acetate between the two the ratio of add-on be 1g:10ml, after being heated to fully dissolving, filter, gained filtrate naturally cooling crystallization, filtration, the gained filter cake adopts ethyl acetate to wash, obtain flecainide acetate after the washing, flecainide acetate after the washing is carried out vacuum-drying, and (vacuum tightness is 0.09mPa, drying temperature is 50 ℃, and be 12h time of drying), obtain the product flecainide acetate after the drying.
Embodiment 3:
The preparation method of flecainide acetate of the present invention, its detailed step is as follows:
A, cyanogen methyl-2, the preparation of two (2,2, the 2-trifluoro ethoxy) benzoic ethers of 5-:
At first with raw material 2,5-two (2,2, the 2-trifluoro ethoxy) phenylformic acid and chloromethyl cyanide add in the reactor, and add triethylamine and ethyl acetate, pass into simultaneously nitrogen as shielding gas, be heated to 78 ℃ of back flow reaction 3h, reaction is cooled to below 10 ℃ after finishing, and then filters, remove insoluble substance, and steam and to desolventize, solvent obtains cyanogen methyl-2 after steaming and removing, and 5-two (2,2,2-trifluoro ethoxy) benzoic ether;
Described 2, two (2,2, the 2-trifluoro ethoxy) phenylformic acid of 5-and the chloromethyl cyanide mol ratio between the two is 1:2.0; Described 2, two (2,2, the 2-trifluoro ethoxy) phenylformic acid of 5-and the triethylamine mol ratio between the two is 1:2.0; Described 2, two (2,2, the 2-trifluoro ethoxy) phenylformic acid of 5-and ethyl acetate between the two the ratio of add-on be 1g:5ml;
The preparation of b, Tamboar:
With the cyanogen methyl-2 that step a prepares, 5-two (2,2, the 2-trifluoro ethoxy) benzoic ether adds in the reaction vessel, pass into nitrogen as shielding gas, and add raw material 2-aminomethyl piperidines and solvent ethyl acetate, under 30 ℃ of conditions, stir and react 14h; Reaction is washed the gained reaction solution 3 times after finishing, and water intaking is washed rear gained organic phase and carried out drying, filtration with anhydrous sodium sulphate, then steams to desolventize, and obtains Tamboar;
Described cyanogen methyl-2, two (2,2, the 2-trifluoro ethoxy) benzoic ethers of 5-and the 2-aminomethyl piperidines mol ratio between the two is 1:2; Described cyanogen methyl-2, two (2,2, the 2-trifluoro ethoxy) benzoic ethers of 5-and the ethyl acetate ratio between the two is 1g:5.5ml;
The preparation of c, flecainide acetate crude product:
Step b gained Tamboar is added in the reaction vessel, and add acetic acid and solvent ethyl acetate, pass into simultaneously nitrogen as shielding gas, stirring reaction 30min at ambient temperature, there is solid product to separate out, then is cooled to 0 ℃ and be incubated 4h, its solid product is fully separated out; Then filter, the gained filter cake washs 2～3 times with 0 ℃ ethyl acetate, obtains the flecainide acetate crude product after the washing;
Described Tamboar and acetic acid between the two the mol ratio of add-on be 1:1; Described Tamboar and ethyl acetate between the two the ratio of add-on be 1g:3ml;
Making with extra care of d, flecainide acetate crude product:
The flecainide acetate crude product that step c is obtained adds in the reaction vessel, and adding solvent ethyl acetate, described flecainide acetate crude product and ethyl acetate between the two the ratio of add-on be 1g:10ml, after being heated to fully dissolving, filter, gained filtrate naturally cooling crystallization, filtration, the gained filter cake adopts ethyl acetate to wash, obtain flecainide acetate after the washing, flecainide acetate after the washing is carried out vacuum-drying, and (vacuum tightness is 0.09mPa, drying temperature is 50 ℃, and be 12h time of drying), obtain the product flecainide acetate after the drying.
Claims (3)
1. the preparation method of a flecainide acetate is characterized in that, described preparation method may further comprise the steps:
A, cyanogen methyl-2, the preparation of two (2,2, the 2-trifluoro ethoxy) benzoic ethers of 5-:
At first with raw material 2,5-two (2,2, the 2-trifluoro ethoxy) phenylformic acid and chloromethyl cyanide add in the reactor, and add triethylamine and ethyl acetate, pass into simultaneously nitrogen as shielding gas, be heated to 70～78 ℃ of back flow reaction 3h, reaction is cooled to below 10 ℃ after finishing, and then filters, remove insoluble substance, and steam and to desolventize, solvent obtains cyanogen methyl-2 after steaming and removing, and 5-two (2,2,2-trifluoro ethoxy) benzoic ether;
Described 2, two (2,2, the 2-trifluoro ethoxy) phenylformic acid of 5-and the chloromethyl cyanide mol ratio between the two is 1:1.5～2.0; Described 2, two (2,2, the 2-trifluoro ethoxy) phenylformic acid of 5-and the triethylamine mol ratio between the two is 1:1.5～2.0; Described 2, two (2,2, the 2-trifluoro ethoxy) phenylformic acid of 5-and ethyl acetate between the two the ratio of add-on be 1g:4～5ml;
The preparation of b, Tamboar:
With the cyanogen methyl-2 that step a prepares, 5-two (2,2, the 2-trifluoro ethoxy) benzoic ether adds in the reaction vessel, pass into nitrogen as shielding gas, and add raw material 2-aminomethyl piperidines and solvent ethyl acetate, under 25～30 ℃ of conditions, stir and react 14～16h; Reaction is washed the gained reaction solution 2～3 times after finishing, and water intaking is washed rear gained organic phase and carried out drying, filtration with anhydrous sodium sulphate, then steams to desolventize, and obtains Tamboar;
Described cyanogen methyl-2, two (2,2, the 2-trifluoro ethoxy) benzoic ethers of 5-and the 2-aminomethyl piperidines mol ratio between the two is 1:2; Described cyanogen methyl-2, two (2,2, the 2-trifluoro ethoxy) benzoic ethers of 5-and the ethyl acetate ratio between the two is 1g:5.5ml;
The preparation of c, flecainide acetate crude product:
Step b gained Tamboar is added in the reaction vessel, and add acetic acid and solvent ethyl acetate, pass into simultaneously nitrogen as shielding gas, stirring reaction 30～40min at ambient temperature, there is solid product to separate out, then is cooled to 0 ℃ and be incubated 4～4.5h, its solid product is fully separated out; Then filter, the gained filter cake washs 2～3 times with 0 ℃ ethyl acetate, obtains the flecainide acetate crude product after the washing;
Described Tamboar and acetic acid between the two the mol ratio of add-on be 1:1; Described Tamboar and ethyl acetate between the two the ratio of add-on be 1g:3ml;
Making with extra care of d, flecainide acetate crude product:
The flecainide acetate crude product that step c is obtained adds in the reaction vessel, and adding solvent ethyl acetate, described flecainide acetate crude product and ethyl acetate between the two the ratio of add-on be 1g:10ml, after being heated to fully dissolving, filter gained filtrate naturally cooling crystallization, filtration, the gained filter cake adopts ethyl acetate to wash, obtain flecainide acetate after the washing, the flecainide acetate after the washing is carried out vacuum-drying, obtain the product flecainide acetate after the drying.
2. the preparation method of flecainide acetate according to claim 1 is characterized in that: described in the step a 2, two (2,2, the 2-trifluoro ethoxy) phenylformic acid of 5-and the chloromethyl cyanide mol ratio between the two is 1:1.5; Described 2, two (2,2, the 2-trifluoro ethoxy) phenylformic acid of 5-and the triethylamine mol ratio between the two is 1:1.5; Described 2, two (2,2, the 2-trifluoro ethoxy) phenylformic acid of 5-and ethyl acetate between the two the ratio of add-on be 1g:4ml.
3. the preparation method of flecainide acetate according to claim 1, it is characterized in that: its vacuum tightness of vacuum-drying described in the steps d is 0.09mPa, and drying temperature is 50 ℃, and be 12h time of drying.
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| CN103720670A (en) * | 2013-12-20 | 2014-04-16 | 郑州大明药物科技有限公司 | Flecainide acetate oral solid preparation and preparation method thereof |
| CN111018694A (en) * | 2019-12-12 | 2020-04-17 | 贵州省欣紫鸿药用辅料有限公司 | Production method of flecainide |
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| CN103720670A (en) * | 2013-12-20 | 2014-04-16 | 郑州大明药物科技有限公司 | Flecainide acetate oral solid preparation and preparation method thereof |
| CN111018694A (en) * | 2019-12-12 | 2020-04-17 | 贵州省欣紫鸿药用辅料有限公司 | Production method of flecainide |
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