CN102382040A - Preparation of nifedipine and impurity separation method and application thereof - Google Patents
Preparation of nifedipine and impurity separation method and application thereof Download PDFInfo
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- CN102382040A CN102382040A CN2010102727737A CN201010272773A CN102382040A CN 102382040 A CN102382040 A CN 102382040A CN 2010102727737 A CN2010102727737 A CN 2010102727737A CN 201010272773 A CN201010272773 A CN 201010272773A CN 102382040 A CN102382040 A CN 102382040A
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Abstract
The invention provides a preparation method of nifedipine, comprising the steps of cyclizing and refining o-nitrobenzaldehyde, methyl acetoacetate and ammonium bicarbonate and the like. The invention further determines a chemical structure of an impurity in preparing nifedipine. The chemical name of the impurity is 6-methyl-2,4-bi(2-nitryl phenyl)-1,2,3,4-tetrahydropyridine-5-methyl formate. The invention provides a preparation method of the impurity. The impurity can be used as a reference substance for detecting corresponding impurities in nifedipine. The impurity is controlled in preparing the nifedipine, thereby effectively ensuring the purity of nifedipine with greater industrial application value.
Description
Technical field:
The present invention relates to the preparation method of medicine, be specifically related to a kind of preparation and impurity separation method and application of calcium ion antagonist nifedipine.
Background technology:
Nifedipine (nifedipine, Formula I), chemical name: 2,6-dimethyl--4-(2-nitrophenyl)-1,4-dihydro-3,5-dinicotinic acid dimethyl ester belongs to the calcium ion antagonist hypotensor.It can direct loose vascular smooth muscle, coronary artery dilator, coronary blood flow increasing; Improve the tolerance of cardiac muscle to ischemic, arteriole around expanding simultaneously reduces peripheral vascular resistance; Thereby blood pressure is reduced, and this medicine also is the anginal a kind of new drug of treatment, and good effect, spinoff are little.
The nifedipine original production process is following: in reaction kettle, drop into Ortho Nitro Benzaldehyde, methyl acetoacetate and methyl alcohol in 1: 2.9: 6.54 mole ratio; Be warming up to 60-70 ℃; Dropping ammonia (being equivalent to 4.14 normal ammonia) dropwised reflux 4 hours.Stirring is cooled to 10 ℃ of-20 ℃ of filtrations, and uses methanol rinse, gets yellow solid and is the nifedipine bullion.Obtain product after the exquisiteness, nifedipine HPLC purity is 99.586%.
According to ICH (human drugs registration technology standard international coordination meeting) requirement, the single impurity level in the bulk drug is as surpassing 0.05%, in requisition for report; Single impurity level just need be proved conclusively as surpassing 0.1%; Single impurity level then needs the data of safety support as surpassing 0.15%.The inventor in 2009 observes from aforesaid method carries out the production of nifedipine: in analyzing nifedipine related substance HPLC collection of illustrative plates; Position in relative retention time 0.80; A unknown impuritie (name and be X) appears; Wherein in the part producing batch, the content of impurity X has surpassed 0.05%, between 0.05%-0.1%.And this impurity X does not have the special argumentation and the limit of regulation in CP (Chinese Pharmacopoeia), BP (British Pharmacopoeia), USP (USP), JP standards of pharmacopoeia such as (Japan's pharmacopeia).
For improving the purity of nifedipine, need the preparation of nifedipine be improved, with control impurity X, and impurity X proved conclusively, improve the quality of product.
Summary of the invention:
Technical problem to be solved by this invention is to improve the preparation method of nifedipine, controls impurity X, and it is carried out structural identification.
The invention provides a kind of nifedipine preparation method, as shown in the formula expression:
The inventive method comprises the following steps:
(1) cyclization: in reaction kettle, drop into Ortho Nitro Benzaldehyde, methyl acetoacetate and methyl alcohol in 1: 2.9: 6.54 mole ratio; Be warming up to 60-70 ℃; Insulated and stirred 30-45 minute; The complete 4.14 normal bicarbonate of ammonia that in batches drop into of insulation have all been thrown the post-heating backflow and had been carried out ring-closure reaction in 4 hours.Reaction is finished, and stirs ℃-25 ℃ of filtrations of cooling reaction thing to 20, abandons filtrating, and solid is used methanol rinse, gets yellow solid and is the nifedipine bullion.
(2) refining: the nifedipine bullion is with ethanol and gac, bullion (wetting): 95% ethanol: gac=1: (5.2～5.8): 0.01 (weight ratio), preferred 1: 5.5: 0.01 (weight ratio); Reflux 30～60 minutes, filtered while hot, filtrating is cooled to 3-8 ℃; Preferred 4-6 ℃, suction filtration, filter cake is with a small amount of 95% washing with alcohol; Dry, obtain the nifedipine crystalline product.
The inventor improves aldehydo-ester condensation time and this two steps operation of cold filtration temperature of nifedipine cyclization in the technological process; Be to be that 30-45 minute, cooling temperature are 20 ℃-25 ℃ the aldehydo-ester condensation time; The nifedipine that makes according to aforesaid method; The content of its impurity X is no more than 0.02%, has reached the object of the invention.
In order to establish the limit of these two key influence factors, the inventor has done orthogonal experiment many times to this; The content of impurity X adopts the HPLC area normalization method to measure content in the nifedipine, and part Orthogonal experiment results data are seen table 1 for example:
Table 1 aldehydo-ester condensation time and cooling temperature are to the correspondence table as a result that influences of impurity X content
Can confirm that from last table the content of aldehydo-ester condensation time and cooling temperature and impurity X is certain proportionlity: the aldehydo-ester condensation time, content longer, the high more then impurity of cooling temperature X was low more.When the aldehydo-ester condensation time be 30-45 minute, when cooling temperature is 20 ℃-25 ℃, the content of impurity X is lower than 0.02% in the may command nifedipine.
The inventor has passed through repeatedly related experiment, has just established preparation method of the present invention.
Selecting the bicarbonate of ammonia solid is the source of amine in the nifedipine, advantage: be the transportation and the convenience that feeds intake on the one hand, be convenient to metering on the other hand, production control is comparatively precise and stable.Preparing method of the present invention can be stable produce and meet the nifedipine that 2010 editions pharmacopeia (impurity A, B all must not cross 0.1%, and other single impurity must not cross 0.2%, and total impurities must not cross 0.5%) require.
Another purpose of the present invention provides the preparation method of impurity X in the nifedipine preparation:
15.1g Ortho Nitro Benzaldehyde and 5.8g methyl acetoacetate are dissolved in the 70mL95% ethanol, drip the ammoniacal liquor of 7.8mL25% while stirring, dripped off stirring at room 24 hours.The most of solvent of pressure reducing and steaming, residuum is compounds X and alcoholic acid mixture, about altogether 8.5g leaches compounds X, and uses 95% ethyl alcohol recrystallization, gets the about 2.3g of light yellow solid, is impurity X.
Another object of the present invention has provided the structural identification of impurity X in the nifedipine preparation: the inventor to impurity X carry out (HRMS,
1H NMR,
13C NMR, HSQC, HMBC, COSY, DEPT) test, the result is following:
(1), to record its molecular weight be 399.1312 ([M+H] to high resolution mass spectrum
+), ultimate analysis records its elementary composition C of being
19H
18N
4O
6
(2), can know that by hydrogen spectrum and carbon spectrum compare with nifedipine, the main variation is:
1. high field region has lacked 1 methyl and methoxyl group, many 1-CH-; Explain and have only 1 methyl acetoacetate to participate in reaction in this compound structure;
2. 4 fragrant hydrogen protons and 1-NH-have been hanged down more than the place;
3. combine HRMS result, infer that should have 2 in the structure replaces aromatic ring, combine the document reaction mechanism again, infer the product that should be 2 molecule Ortho Nitro Benzaldehydes and 1 molecule methyl acetoacetate and the reaction of 2 molecules of ammonia.
(3), can be known: 3 protons of 5.57-3.32-4.97ppm have correlationship, and wherein 5.57, the proton of 4.93ppm is 2 methine protons, and 3.32ppm is 1-NH-, i.e. existence-CH-NH-CH-segment in these article by COSY spectrum.
(4), impurity X molecular formula is C
19H
18N
4O
6, degree of unsaturation is 13, wherein 2 oil of mirbane have 10 degrees of unsaturation, 2 two keys (C=O ,-C=C-) accounting for 2 degrees of unsaturation, 1 remaining degree of unsaturation Ying Youhuan causes, i.e. 1 ring texture of existence in these article.
(5), comprehensive The above results, infer that the possible structure of impurity X is following:
Impurity X
Chemistry is by name: 6-methyl-2,4-two (2-nitrophenyl)-1,2,3,4-tetrahydropyridine-5-methyl-formiate
Before not obtaining its monocrystalline data, the inventor confirms the reasonableness of above-mentioned impurity X structure through MS and 2D-NMR data:
1. have m/z 249 peaks among the .MS, this is contrary D-A reaction fragment:
2.. the proton of impurity X and C signal belong to as follows:
The hydrogen spectrum of table 2 impurity X
1H NMR measures the result
The carbon spectrum of table 3 impurity X
13C NMR measures the result
A further object of the invention provides the application of impurity X described in the nifedipine preparation.Impurity X can be used as reference substance, in order to corresponding impurity in the detection nifedipine, and in the nifedipine preparation, this impurity is controlled, and can guarantee the purity of nifedipine effectively.
Figure of description
Fig. 1 impurity X's
1H NMR tests collection of illustrative plates;
Fig. 2 impurity X's
13C NMR tests collection of illustrative plates;
The HSQC test collection of illustrative plates of Fig. 3 impurity X;
The HMBC test collection of illustrative plates of Fig. 4 impurity X;
The COSY test collection of illustrative plates of Fig. 5 impurity X;
The DEPT test collection of illustrative plates of Fig. 6 impurity X.
Embodiment
Below further specify the present invention through embodiment, but not as restriction of the present invention.
The preparation of embodiment 1. nifedipines
In the 500mL four-necked bottle, add 134g methyl acetoacetate and 120g methyl alcohol, stir down and drop into the 60g Ortho Nitro Benzaldehyde, be warming up to 60-70 ℃, insulated and stirred 30 minutes.Insulation is finished and to be dropped into 49.6g bicarbonate of ammonia in batches, stir half a hour after reheat refluxed 4 hours.Reactant stirs and is cooled to 20 ℃ of filtrations, and filter cake washs with small amount of methanol, gets the 105g yellow solid and is the nifedipine bullion.
In the 1000mL four-necked bottle, drop into above-mentioned 105g nifedipine bullion, 577.5g95% ethanol and 1.1g gac, reflux 30 minutes, filtered while hot; Filtrating is cooled to 5 ℃, suction filtration, and filter cake is with a small amount of 95% washing with alcohol; Dry; Obtain 86g nifedipine crystalline product, nifedipine HPLC purity is 99.745%, and impurity X content is 0.017%.
The preparation of embodiment 2. nifedipines
In the 500mL four-necked bottle, add 134g methyl acetoacetate and 120g methyl alcohol, stir down and drop into the 60g Ortho Nitro Benzaldehyde, be warming up to 60-70 ℃, insulated and stirred 30 minutes.Insulation is finished and to be dropped into 49.6g bicarbonate of ammonia in batches, stir half a hour after reheat refluxed 4 hours.Reactant stirs and is cooled to 12 ℃ of filtrations, and filter cake washs with small amount of methanol, gets the 110g yellow solid and is the nifedipine bullion.
In the 1000mL four-necked bottle, drop into above-mentioned 110g nifedipine bullion, 605g95% ethanol and 1.1g gac, reflux 30 minutes, filtered while hot; Filtrating is cooled to 5 ℃, suction filtration, and filter cake is with a small amount of 95% washing with alcohol; Dry; Obtain 89g nifedipine crystalline product, nifedipine HPLC purity is 99.599%, and impurity X content is 0.089%.
The preparation of embodiment 3. impurity X
15.1g Ortho Nitro Benzaldehyde and 5.8g methyl acetoacetate are dissolved in the 70mL95% ethanol, drip the ammoniacal liquor of 7.8mL25% while stirring, dripped off stirring at room 24 hours.The most of solvent of pressure reducing and steaming, residuum is compounds X and alcoholic acid mixture, 8.5g leaches compounds X altogether; And use 95% ethyl alcohol recrystallization, and get the about 2.3g of light yellow solid, be impurity X, i.e. 6-methyl-2; 4-two (2-nitrophenyl)-1,2,3,4-tetrahydropyridine-5-methyl-formiate.Fusing point 202-203 ℃, its HPLC purity is 98.582%.
Attach 1: the HPLC chromatographic condition of embodiment 1-3 nifedipine
Chromatographic column: C18,4.6 * 250mm, 5 μ m
Moving phase: methyl alcohol: water=6: 5
Detect wavelength: 235nm
Flow velocity: 1.0mL/min
Column temperature: 30 ℃
Sample size: 20 μ L
Attach 2: the hydrogen spectrum of embodiment 3 impurity X
1H NMR and carbon spectrum
13C NMR measures the result
The hydrogen spectrum of table 1 impurity X
1H NMR measures the result
The carbon spectrum of table 2 impurity X
13C NMR measures the result
Claims (6)
1. a nifedipine preparation method is characterized in that, this method comprises the following steps, as shown in the formula expression:
(1) cyclization: the ratio in 1: 2.9: 6.54 mol ratio drops into Ortho Nitro Benzaldehyde, methyl acetoacetate and methyl alcohol in reaction kettle, is warming up to 60-70 ℃, insulated and stirred 30-45 minute; The complete 4.14 normal bicarbonate of ammonia that in batches drop into of insulation have all been thrown the post-heating backflow and had been carried out ring-closure reaction in 4 hours, and reaction is finished; Stir ℃-25 ℃ of filtrations of cooling reaction thing to 20; Abandon filtrating, solid is used methanol rinse, gets yellow solid and is the nifedipine bullion;
(2) refining: the nifedipine bullion obtains the nifedipine crystalline product with 95% ethanol and absorbent charcoal fine purification.
2. according to the said a kind of nifedipine preparation method of claim 1, it is characterized in that said step (2) process for purification is with the nifedipine bullion: 95% ethanol: gac=1: 5.2～5.8: 0.01 weight ratios; Reflux 30～60 minutes; Filtered while hot, filtrating is cooled to 3-8 ℃, filters; With 95% ethanol rinsing, dry the nifedipine crystalline product.
3. according to the method for claim 2, it is characterized in that said step (2) is refining to be with the nifedipine bullion: 95% ethanol: gac=1: 5.5: 0.01 weight ratio; Reflux 30～60 minutes; Filtered while hot, filtrating is cooled to 4 ℃-6 ℃, filters; With 95% ethanol rinsing, dry the nifedipine crystalline product.
4. isolating impurity 6-methyl-2 during a nifedipine prepares, 4-two (2-nitrophenyl)-1,2,3,4-tetrahydropyridine-5-methyl-formiate, structure is following:
Said impurity
1H NMR measures the result:
Said impurity
13C NMR measures the result:
5. like the said impurity 6-of claim 4 methyl-2,4-two (2-nitrophenyl)-1,2,3, the preparation method of 4-tetrahydropyridine-5-methyl-formiate is characterized in that, this method is:
15.1g Ortho Nitro Benzaldehyde and 5.8g methyl acetoacetate are dissolved in the 70mL95% ethanol, drip the ammoniacal liquor of 7.8mL25% while stirring, dripped off stirring at room 24 hours; The most of solvent of pressure reducing and steaming, residuum is the mixture of compounds X and small amount of ethanol, leaches compounds X, and uses 95% ethyl alcohol recrystallization; Get the about 2.3g of light yellow solid, be impurity 6-methyl-2,4-two (2-nitrophenyl)-1; 2,3,4-tetrahydropyridine-5-methyl-formiate.
6. like the said impurity 6-of claim 4 methyl-2,4-two (2-nitrophenyl)-1,2,3,4-tetrahydropyridine-5-methyl-formiate be as reference substance, the application in detecting the corresponding impurity of nifedipine.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103497147A (en) * | 2013-09-11 | 2014-01-08 | 常州大学 | Synthesis method of 1,4-dihydropyridine compounds by using ytterbium trifluoromethanesulfonate as catalyst |
| CN105348174A (en) * | 2015-11-23 | 2016-02-24 | 浙江大学 | Method for synthesis of nifedipine in continuous flow micro-reactor |
| CN108752263A (en) * | 2018-06-08 | 2018-11-06 | 威海迪素制药有限公司 | A kind of preparation method of high-purity nifedipine crystallization |
| CN113582913A (en) * | 2021-08-18 | 2021-11-02 | 河北广祥制药有限公司 | Method for continuously refining nifedipine |
| CN115353485A (en) * | 2022-07-26 | 2022-11-18 | 山西双雁药业有限公司 | Method for recovering nifedipine from nifedipine mother liquor and application |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103497147A (en) * | 2013-09-11 | 2014-01-08 | 常州大学 | Synthesis method of 1,4-dihydropyridine compounds by using ytterbium trifluoromethanesulfonate as catalyst |
| CN105348174A (en) * | 2015-11-23 | 2016-02-24 | 浙江大学 | Method for synthesis of nifedipine in continuous flow micro-reactor |
| CN108752263A (en) * | 2018-06-08 | 2018-11-06 | 威海迪素制药有限公司 | A kind of preparation method of high-purity nifedipine crystallization |
| CN108752263B (en) * | 2018-06-08 | 2021-10-26 | 迪嘉药业集团有限公司 | Preparation method of high-purity nifedipine crystal |
| CN113582913A (en) * | 2021-08-18 | 2021-11-02 | 河北广祥制药有限公司 | Method for continuously refining nifedipine |
| CN115353485A (en) * | 2022-07-26 | 2022-11-18 | 山西双雁药业有限公司 | Method for recovering nifedipine from nifedipine mother liquor and application |
| CN115353485B (en) * | 2022-07-26 | 2024-04-19 | 山西双雁药业有限公司 | Method for recovering nifedipine from nifedipine mother solution and application thereof |
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Application publication date: 20120321 Assignee: Pharmaceutical Co., Ltd., Changzhou Pharmaceutical Factory No.4 Assignor: Changzhou City No.4 Pharmaceutical Factory Co., Ltd. Contract record no.: 2014320000280 Denomination of invention: Preparation method of nifedipine as well as impurity separating method and application of nifedipine Granted publication date: 20130925 License type: Exclusive License Record date: 20140331 |
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