CN108892660B - Preparation method of azelnidipine impurity B - Google Patents
Preparation method of azelnidipine impurity B Download PDFInfo
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- CN108892660B CN108892660B CN201810600091.0A CN201810600091A CN108892660B CN 108892660 B CN108892660 B CN 108892660B CN 201810600091 A CN201810600091 A CN 201810600091A CN 108892660 B CN108892660 B CN 108892660B
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- azelnidipine
- impurity
- dichloromethane
- chloroperoxybenzoic acid
- silica gel
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- ZKFQEACEUNWPMT-UHFFFAOYSA-N Azelnidipine Chemical compound CC(C)OC(=O)C1=C(C)NC(N)=C(C(=O)OC2CN(C2)C(C=2C=CC=CC=2)C=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZKFQEACEUNWPMT-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 229950004646 azelnidipine Drugs 0.000 title claims abstract description 35
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 16
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 4
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 3
- 238000010898 silica gel chromatography Methods 0.000 claims abstract description 3
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 60
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 239000000243 solution Substances 0.000 claims description 11
- 239000000741 silica gel Substances 0.000 claims description 10
- 229910002027 silica gel Inorganic materials 0.000 claims description 10
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 8
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 5
- LULAYUGMBFYYEX-UHFFFAOYSA-N 3-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 claims description 4
- 239000003480 eluent Substances 0.000 claims description 4
- 239000012074 organic phase Substances 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 3
- 238000004587 chromatography analysis Methods 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- BUQNPHOBMVKITJ-UHFFFAOYSA-N 3-chlorobenzenecarboperoxoic acid;dichloromethane Chemical compound ClCCl.OOC(=O)C1=CC=CC(Cl)=C1 BUQNPHOBMVKITJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 claims 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims 1
- 235000017557 sodium bicarbonate Nutrition 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 239000012535 impurity Substances 0.000 description 5
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000013558 reference substance Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 230000036772 blood pressure Effects 0.000 description 2
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000011345 viscous material Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 1
- 206010005746 Blood pressure fluctuation Diseases 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 208000007530 Essential hypertension Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229960000528 amlodipine Drugs 0.000 description 1
- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 125000004925 dihydropyridyl group Chemical class N1(CC=CC=C1)* 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000001559 infrared map Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000001603 reducing effect Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical compound [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention relates to a preparation method of azelnidipine impurity B, belonging to the technical field of preparation of raw material medicines. The technical scheme of the invention is as follows: firstly, azelnidipine and m-chloroperoxybenzoic acid are subjected to oxidation reaction to generate an intermediate state shown in a formula 1, and then the intermediate state shown in the formula I is subjected to silica gel column chromatography to generate an impurity B under the catalysis of silica. The invention provides a preparation method of high-purity azelnidipine impurity B.
Description
Technical Field
The invention relates to a preparation method of azelnidipine impurity B, belonging to the technical field of preparation of raw material medicines.
Background
Azelnidipine is a calcium channel blocker belonging to the Dihydropyridine (DHP) class. Azelnidipine can significantly reduce the blood pressure of old patients with primary hypertension, has small blood pressure fluctuation, and has better blood pressure reducing effect than amlodipine [ Huangrongjie ]; chinese New drug and clinical journal [ J ];2014, 33 (7): 542-.
Azelnidipine (azelnidipine) has a remarkable advantage in treating mild to moderate hypertension, but is not loaded in pharmacopoeia internationally. At present, only the Japanese pharmacopoeia is loaded. According to the latest edition of the japanese pharmacopoeia (JP 17)), there are four impurities, the relative retention times being about 0.1, 0.3, 0.5 and 1.42, respectively. However, the structure and name of each impurity are not listed in the Japanese pharmacopoeia. By study, we have identified an impurity wherein the relative retention time is 0.3, referred to as impurity B, of the formula:
the document [ Journal of Pharmaceutical and Biomedical Analysis;2012,61: 277-. And it is produced by dissolving azelnidipine and Azobisisobutyronitrile (AIBN) in acetonitrile: in a solvent with the concentration of 1.7-2.0 mmol/L and the concentration of water =1:1, reacting at 40 ℃, sampling and detecting, wherein the content can reach 15.02% after 7 days of reaction. The reaction conditions disclosed in this document are easy to implement and can only be used as a method for studying the degradation thereof, and the process for preparing an impurity reference is very unsuitable for three reasons: firstly, the reaction solvent is dilute, the solvent ratio is too large, and the one-time reaction enrichment amount is very small; secondly, the reaction time is long, and the efficiency is very low; thirdly, the conversion rate and the content are very low, so that the separation and the purification are difficult, and the preparation needs to be carried out through a liquid phase preparation column.
The impurity B is an impurity that must be controlled for drug consistency evaluation, and must be used for each product test. The standard reference substance has high purity requirement, and although the required amount is not too large, 1-10 g of azelnidipine impurity B is necessary to be prepared each time, so that an efficient preparation method of azelnidipine impurity B is necessary.
Disclosure of Invention
Aiming at the characteristic that the existing preparation method of the impurity B is not mature enough, the preparation method of the azelnidipine impurity B with high efficiency is provided.
The technical scheme of the invention is as follows:
a preparation method of azelnidipine impurity B comprises the following steps:
in the first step, azelnidipine and m-chloroperoxybenzoic acid are subjected to oxidation reaction to generate an intermediate state shown in a formula 1.
The solvent is selected from dichloromethane.
Respectively dissolving azelnidipine and m-chloroperoxybenzoic acid in dichloromethane. The concentration of the azelnidipine dichloromethane solution is 0.06-0.1 g/ml; the concentration of the obtained m-chloroperoxybenzoic acid dichloromethane solution is 0.06g/ml
Slowly dripping the m-chloroperoxybenzoic acid solution into the azelnidipine solution, controlling the dripping time within 0.5 hour, keeping the system stable at the temperature of between 15 ℃ below zero and 10 ℃ below zero for reaction, and monitoring the complete reaction of the raw materials by TLC. Adding sodium bisulfite water solution to remove unreacted m-chloroperoxybenzoic acid, washing off m-chlorobenzoic acid generated in the reaction by sodium bicarbonate water solution, and concentrating the organic phase under reduced pressure to obtain an oily intermediate state I. Preferably, the aqueous sodium bisulfite solution is selected from a saturated aqueous solution of sodium bisulfite.
The feeding molar ratio of the m-chloroperoxybenzoic acid to the azelnidipine is 1.0-1.05, the oxidation is incomplete below 1.0, the consumption of the m-chloroperoxybenzoic acid cannot be improved by increasing the consumption of the m-chloroperoxybenzoic acid above 1.05, and more reducing agent is consumed in the post-treatment.
And secondly, carrying out silica gel column chromatography on the intermediate state shown in the formula I to generate an impurity B under the catalysis of silica.
And loading the intermediate state I prepared in the first step into a chromatographic silica gel column. The chromatographic silica gel used herein is 200-300 mesh chromatographic silica gel. The amount of the silica gel is 20-30 times of the amount of the azelnidipine in the first step. The eluent is a mixed solvent of dichloromethane and methanol, and the mass ratio of dichloromethane to methanol is as follows: methanol =20:1, the chromatographic silica gel used in the invention has catalytic effect and separation and purification effect, and the impurity B solid is obtained by concentration, crystallization, filtration and drying.
The preparation reaction equation is as follows:
has the advantages that: the invention provides a preparation method of azelnidipine impurity B, and the prepared impurity B meets the quality requirement of a reference substance and can be used as the reference substance.
Drawings
FIG. 1 of impurity B1H-NMR spectrum.
FIG. 2 of impurity B13C-NMR spectrum.
FIG. 3 Infrared spectrum of impurity B.
FIG. 4 UV spectrum of impurity B.
FIG. 5 liquid mass spectrum of impurity B.
Example 1
2.0 g (3.4 mmol) of azelnidipine and 30ml of dichloromethane are added into a 100ml three-neck flask, and then the mixture is dissolved and cooled to-15 ℃. 0.6g (3.5 mmol) of m-chloroperoxybenzoic acid (dissolved in 10ml of dichloromethane) is added into a reaction system dropwise, the dropwise adding process is kept at minus 10 ℃, the addition is finished for about 20min, the reaction is finished at minus 15 ℃ for 10min, TLC monitors the complete reaction, the reaction system is moved to the room temperature, 30ml of saturated aqueous solution of sodium bisulfite is added and stirred for 20min, the dichloromethane phase is taken by layers, 20 ml of saturated sodium bicarbonate is added and washed for 2 times, the organic phase is kept, and the dichloromethane solvent is distilled off under reduced pressure at 30-35 ℃ to obtain oily viscous substance.
The viscous oil was loaded onto a column containing 60g of chromatography silica gel and purified with dichloromethane: methanol =20:1 as eluent, and the ultraviolet absorbed part is collected, concentrated, crystallized, filtered, dried at 50 ℃ to obtain white solid with HPLC purity: 99.86% and yield 88.21%.
The structure identification shows that the compound conforms to the structure of the impurity B. Its attribution and resolution are as follows:
the liquid mass showed that its M + H molecular weight was 600.23, indicating a molecular weight of 599.23, consistent with the theoretical molecular weight.
1, map analysis:
13C-NMR spectrum analysis:
infrared map analysis
The sigma values are 3379, 3279, 2978, 1754, 1703, 1661, 1528 which are N-H, O-H, -CH313-ester group, 21-ester group, amide, benzene ring, etc.
The ultraviolet image shows that the absorption is E2 of benzene ring near 200-210 nm, and the absorption is K band of nitrobenzene near 270 nm. The above data analysis shows that the description completely agrees with the structure.
Example 2
Adding 10.0 g (17.2 mmol) of azelnidipine and 100ml of dichloromethane into a 500ml three-neck flask, dissolving, and cooling to-10 ℃. Dropwise adding 3.0g (17.4 mmol) of m-chloroperoxybenzoic acid (dissolved in 50ml of dichloromethane) into a reaction system, keeping the temperature below-10 ℃ in the dropwise adding process, finishing the addition for about 30min, reacting for 10min at the temperature below-10 ℃, monitoring the reaction by TLC, moving to room temperature, adding 200ml of saturated aqueous solution of sodium bisulfite, stirring for 20min, taking dichloromethane phases by layers, adding 200ml of saturated sodium bicarbonate, washing for 2 times, keeping an organic phase, and evaporating the dichloromethane solvent under reduced pressure at the temperature of 30-35 ℃ to obtain an oily viscous substance.
The viscous oil was loaded onto a column containing 200g of chromatography silica gel, purified with dichloromethane: methanol =20:1 as eluent, and the fraction with ultraviolet absorption is collected, concentrated, crystallized, filtered, and dried at 50 ℃ to obtain white solid with HPLC purity: 99.81% and a yield of 89.6%. The infrared spectrum comparison of the obtained product is completely consistent with that of example 1.
Claims (5)
1. A preparation method of azelnidipine impurity B is characterized by comprising the following steps:
firstly, respectively dissolving azelnidipine and m-chloroperoxybenzoic acid by dichloromethane, wherein the concentration of an obtained azelnidipine dichloromethane solution is 0.06-0.1g/ml, the concentration of an obtained m-chloroperoxybenzoic acid dichloromethane solution is 0.06g/ml, the feeding molar ratio of the m-chloroperoxybenzoic acid to the azelnidipine is 1.0-1.05, slowly dropwise adding the m-chloroperoxybenzoic acid solution into the azelnidipine solution, controlling the dropwise adding time within 0.5 hour, keeping the system stable at-15 to-10 ℃ for reaction, and carrying out oxidation reaction on the azelnidipine and the m-chloroperoxybenzoic acid in a dichloromethane solvent to generate an intermediate state I;
secondly, performing silica gel column chromatography on the intermediate state I, and generating an impurity B under the catalysis of silica, wherein an eluent is a mixed solvent of dichloromethane and methanol in a mass ratio of dichloromethane: methanol =20: 1;
2. the process for preparing azelnidipine as impurity B in claim 1, wherein after the first reaction step, an aqueous solution of sodium bisulfite is added to remove unreacted m-chloroperoxybenzoic acid.
3. The process for preparing azelnidipine as impurity B in claim 1, wherein m-chlorobenzoic acid produced in the reaction is washed away with an aqueous solution of sodium bicarbonate in the first step, and the organic phase is concentrated under reduced pressure to obtain intermediate I as an oily substance.
4. The method for preparing azelnidipine impurity B as set forth in claim 2, wherein the aqueous solution of sodium bisulfite in the first step is selected from a saturated aqueous solution of sodium bisulfite.
5. The method for preparing azelnidipine impurity B according to claim 1, wherein the silica gel used in the second step is 200-300 mesh chromatography silica gel, and the amount of the silica gel is 20-30 times of the amount of the azelnidipine used in the first step.
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| CN201810600091.0A CN108892660B (en) | 2018-06-12 | 2018-06-12 | Preparation method of azelnidipine impurity B |
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| CN108892660B true CN108892660B (en) | 2020-09-22 |
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- 2018-06-12 CN CN201810600091.0A patent/CN108892660B/en active Active
Non-Patent Citations (1)
| Title |
|---|
| Mechanistic study on degradation of azelnidipine solution under radical initiator-based oxidative conditions;Eiji Ueyama et al.;《Journal of Pharmaceutical and Biomedical Analysis》;20111217;第61卷;第277-283页 * |
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