CN101367759B - Synthesis of high-purity amlodipine besylate - Google Patents
Synthesis of high-purity amlodipine besylate Download PDFInfo
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- CN101367759B CN101367759B CN2008102236583A CN200810223658A CN101367759B CN 101367759 B CN101367759 B CN 101367759B CN 2008102236583 A CN2008102236583 A CN 2008102236583A CN 200810223658 A CN200810223658 A CN 200810223658A CN 101367759 B CN101367759 B CN 101367759B
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- amlodipine
- methyl
- amlodipine besylate
- glacial acetic
- acetic acid
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Abstract
The present invention relates to a synthesis method of high-purity amlodipine besylate. In particular, o-chlorobenzaldehyde, 4-(2-phthalyl imino radical ethoxy) acetoacetic ester and 3-amino methyl cro-tonate are used as raw materials for ring closure in an alcohol solvent, and when the amount of the 3-amino methyl cro-tonate is three times, the intermediate for ring closure can be prepared; the intermediate is refined by toluene/glacial acetic acid, dissolved in methylamine to form a salt in the aqueous solution, and the high-purity amlodipine besylate can be acquired after recrystallizationwith ethyl alcohol.
Description
Technical field:
The present invention relates to a kind of preparation method of antihypertensive drug amlodipine besylate, this method can obtain highly purified amlodipine besylate.
Background technology:
Amlodipine besylate is developed by Pfizer, and domestic goods name Norvasc is to be used for the treatment of a hypertensive line medication, and this product has following structure:
Document US 4572909 has been reported a kind of preparation method of amlodipine besylate, is the method for raw material synthetic intermediate phthalyl amlodipine in organic solvent with o-chlorobenzaldehyde, 4-(2-phthaloyl imino oxyethyl group) methyl aceto acetate, 3-aminobutene acid methyl esters.The amlodipine besylate product purity that makes by this method can't reach requirement.
The present invention transforms on the basis of above synthetic method, we have carried out the HPLC-MS analysis to impurity, two transesterify by products of major impurity (F3, E3) in the phthalyl amlodipine liquid matter analysed preparation of discovery cyclization gained, methylamine is separated, obtain behind the salify amlodipine besylate liquid matter and impurity analysis, two by products are converted into impurity F, impurity E.
At these two master control impurity, we examine or check from several aspects such as charging capacity, solvent, temperature of reaction, phase-transfer catalyst and ester exchange inhibitor cyclization process and optimize.Found that, adopt alcohol to do reaction solvent, with 4-(2-phthaloyl imino oxyethyl group) methyl aceto acetates: during 3-aminobutene acid methyl esters=1:3 (greater than 3) feed ratio, by-product impurities E3, impurity F 3 content minimums in the intermediate, methylamine is separated again after toluene/glacial acetic acid is refining, aqueous solution salify obtains the amlodipine besylate crude product, obtains high-purity amlodipine besylate through the dehydrated alcohol recrystallizing and refining.
Summary of the invention:
The invention provides a kind of synthetic method of high-purity amlodipine besylate.
Method of the present invention, adopt following reaction scheme:
Above route is a prior art, sees the US4572909 literary composition.
The condition that the present invention selectes is:
1, requires with o-chlorobenzaldehyde, 4-(2-phthaloyl imino oxyethyl group) methyl aceto acetates, 3-aminobutene acid methyl esters is raw material synthetic intermediate phthalyl amlodipine in alcoholic solvent, methyl esters and 4-(2-phthaloyl imino oxyethyl group) methyl aceto acetate molar ratio is more than or equal to 3:1 for the acid of 3-aminobutene, and above condition can be controlled impurity E 3, F3 less than 0.10%.
2, intermediate phthalyl amlodipine adopts toluene/glacial acetic acid system recrystallization.
3, the purity of intermediate phthalyl amlodipine is greater than 97%,
4, the purity of finished product is 99.7%.
5, the detection limit of impurity E, impurity F requires less than 0.10%.
Wherein toluene/glacial acetic acid system is: volume ratio is the toluene of 1:1 and the mixing solutions of glacial acetic acid.
The assay of relevant product uses existing routine techniques, as the HPLC method.
In the detection method of amlodipine besylate, use HPLC to carry out assay, its chromatographic condition is:
Moving phase 2.3g/L Spirit of Mindererus-methyl alcohol (30:70) detects wavelength 237nm.
The present invention can obtain highly purified amlodipine besylate by controlling above reaction conditions.
Embodiment:
Further specify the present invention by the following examples, but not as limitation of the present invention.
Embodiment 1: impurity E synthetic
(4RS)-4-(2-chloro-phenyl-)-2-[(2-amino ethoxy) methyl]-6-methyl-1,4-dihydropyridine-3,5-ethyl dicarboxylate
Synthetic method
1, the preparation of 3-aminobutene acetoacetic ester
In the 500ml three-necked bottle, add methyl aceto acetate 300ml, ethanol 150ml, cooling is below 10 ℃, and logical ammonia 5 hours is separated out crystallization, filters, and gets the 100g product.
2, (4RS)-4-(2-chloro-phenyl-)-2-[[2-(1,3-dioxy-1,3-dihydro-2H-isoindole-2-yl) oxyethyl group] methyl]-6-methyl-1,4-dihydropyridine-3,5-ethyl dicarboxylate's (impurity E 3) preparation
In the 250ml reaction flask, add 3-aminobutene acetoacetic ester 15g, add 4-(2-phthaloyl imino oxyethyl group) methyl aceto acetate 18g, add the 7g o-chlorobenzaldehyde, methyl alcohol 100ml, stirring and refluxing 20 hours finishes, decompression and solvent recovery, add Glacial acetic acid 30ml, be stirred to crystallization and separate out, filter, get the 5.5g light yellow solid, the toluene recrystallization gets pure product.
3, the preparation of impurity E
3g product of last step finishes with 15940% aqueous methylamine solution stirred overnight at room temperature, some plate reaction, and filtration is washed to the neutral impurity E 1g of getting.
Nuclear magnetic data
1H-NMR(500M)：solvent(CDCl
3)
| Proton | δvalues(ppm) | Coupling?constant | number | Mult | |
| NH | 7.804 | 1 | s | NH | |
| H1～H4 | 7.022～7.393 | 4 | m | Ar-H | |
| H5 | 5.408 | 1 | s? | CH | |
| H7 | 4.688～4.8 | J AB＝19Hz | 2 | q | CH2O，AB?system |
| H12、H10 | 4.031～4.101 | 4 | m | COO CH2CH3 |
| H9 | 3.570～3.610 | 2 | m | OCH2 CH2NH | |
| H8 | 2.971 | 2 | m | O CH2CH2NH | |
| H6 | 2.355 | 3 | s | CH3 | |
| NH 2 | 1.49 | 2 | s | NH 2 | |
| H11、H13 | 1.190 | 6 | m | COOCH2 CH3 |
Embodiment 2: the preparation of impurity F
(4RS)-4-(2-chloro-phenyl-)-2-[(2-amino ethoxy) methyl]-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid methyl esters
Synthetic method
1,4-ethyl bromoacetoacetate (B) is synthetic
In the 500ml chloroformic solution that contains the 58g methyl acetoacetate,, drip off room temperature reaction 15 hours in 2 hours in-5 ℃～0 ℃ dropping liquid bromine 80g, add entry 500ml * 2 extractions, tell organic layer, the decompression of dry back is steamed and is got chloroform (recyclable applying mechanically), get product 100g, productive rate 82%.
2, the preparation of 4-[2-(phthaloyl imino) oxyethyl group] methyl aceto acetates (C)
There-necked flask adds tetrahydrofuran (THF) 350ml, NaH43g, add phthaloyl imino ethanol 97g in batches, be chilled to-10 ℃ of dropping 4-acetobrom methyl acetate 100g ,-5 ℃～0 ℃ was reacted 1 hour, rose to room temperature reaction 24 hours, add the dilution of 200ml water, extract with ethyl acetate 200ml * 3, the combined ethyl acetate layer is used anhydrous sodium sulfate drying, reclaim solvent, column chromatography purification gets the 21g product.
3, (4RS)-4-(2-chloro-phenyl-)-2-[[2-(1,3-dioxy-1,3-dihydro-2H-isoindole-2-yl) oxyethyl group] methyl]-6-methyl-1,4-dihydropyridine-3,5-ethyl dicarboxylate's (impurity F 3) preparation
In the 250ml reaction flask, add 3-aminobutene acetoacetic ester 16g, add 4-(2-phthaloyl imino oxyethyl group) methyl acetoacetate 21g, add the 9.67g o-chlorobenzaldehyde, methyl alcohol 100ml, stirring and refluxing 20 hours, there is solid to generate in the reaction solution, filter, methanol wash gets the 4.5g white solid
4, the preparation of impurity F
Last step product finishes with 30940% aqueous methylamine solution stirred overnight at room temperature, some plate reaction, and filtration is washed to the neutral impurity E 1.3g of getting.
Nuclear magnetic data
1H-NMR(500M)：solvent(CDCl
3)
| Proton | δvalues(ppm) | Coupling?constant | number | Mult |
| NH | 7.888 | 1 | s | NH | |
| H1～H4 | 7.003～7.382 | 4 | m | Ar-H | |
| H5 | 5.414 | 1 | s | CH | |
| H7 | 4.694～4.808 | J AB＝15Hz | 2 | q | CH2O，AB?system |
| H11、H10 | 3.609、3.601 | 6 | s、s | COO CH3 | |
| H9 | 3.567 | 2 | t | OCH2 CH2NH | |
| H8 | 2.986 | 2 | t | O CH2CH2NH | |
| H6 | 2.370 | 3 | s | CH3 | |
| NH 2 | 1.858 | 2 | s | NH 2 |
Embodiment 3: the preparation of high-purity amlodipine besylate
1, the preparation of phthalyl amlodipine
In the cyclization still, suck 4-(2-phthaloyl imino oxyethyl group) methyl aceto acetate 50Kg (content 90%), suck anhydrous methanol 200kg, o-chlorobenzaldehyde 22Kg adds 3-aminobutene acid methyl esters 54Kgkg, and the insulation back flow reaction is after 20 hours, reclaim under reduced pressure methyl alcohol, recovery finishes.Add glacial acetic acid 100kg, stirred about 12 hours at 12-18 ℃, the gradation blowing gets rid of filter in whizzer, gets the slightly wet about 50kg of product of phthalyl amlodipine.(molar ratio 4-(2-phthaloyl imino oxyethyl group) methyl aceto acetate: 3-aminobutene acid methyl esters=1:1.12:3.35)
Use toluene: the glacial acetic acid=above-mentioned crude product of 1:1 system mixed solvent 70kg heating for dissolving, naturally cool to 20-30 ℃ of insulations 1 hour then, get rid of filter, use cold toluene drip washing, get the refining wet about 24kg of product of phthalyl amlodipine, advance square Vacuumdrier, 50 ℃ of vacuum-drying 12 hours, the refining dry product 22kg of phthalyl amlodipine.
2, the quality standard of intermediate phthalyl amlodipine, detection method and result
2.1 quality standard
Chromatographic purity: E3≤0.10%, F3≤0.10%, phthalyl amlodipine 〉=97%;
2.2 detection method
Instrument: high performance liquid chromatograph; UV-detector
Moving phase: triethylamine solution (7 → 1000): acetonitrile=(40:60), the phosphoric acid adjust pH is 7.0
Flow velocity: 1.0mL/min
Detect wavelength: 237nm
2.3 check result
The phthalyl amlodipine: 98.6%, E3:0.02; F3:0.03
3, the preparation of amlodipine base
Suck the 100kg40% aqueous methylamine solution toward the aminolysis still, add phthalyl amlodipine 22kg, room temperature reaction 20～24 hours.Add purified water 50kg, be cooled to 0～5 ℃, be incubated after 1 hour, get rid of filter, the gained solid promptly gets the wet about 15kg of product of amlodipine base with the gradation washing in batches of 100kg purified water, is directly used in the next step.
4, the preparation of amlodipine besylate
In the preparation bucket, add about 7kg Phenylsulfonic acid and 10.5kg purified water, it is standby to be stirred to complete molten back suction Phenylsulfonic acid solution tank with sticking plaster; Become the salt oven vacuum valve to add the 90kg purified water, the wet product of step product amlodipine base on the input.Finish, open 40% aqueous solution that begins to drip the 7kg Phenylsulfonic acid when chilled brine cools to 5-8 ℃,,, drip and finish, be incubated 1 hour, get rid of and leach material, promptly get the wet product of amlodipine besylate crude product and be about 30kg.
Behind the product drying,, filter the dry amlodipine besylate 13kg that gets with 100kg dehydrated alcohol recrystallization.
5, the related substance of amlodipine besylate detects
5.1 related substance standard
Impurity E≤0.10%,, impurity F≤0.10%, other unknown impurities≤0.10%, deduction Phenylsulfonic acid chromatographic peak, total impurities≤0.30%,
5.2 detection method
Instrument: high performance liquid chromatograph; UV-detector
Moving phase: 2.3g/L Spirit of Mindererus-methyl alcohol (30:70)
Flow velocity: 1.0mL/min
Detect wavelength: 237nm
5.3 detected result
Impurity E: do not detect impurity F: 0.02, total impurities 0.08.
Claims (2)
1. the synthetic method of an amlodipine besylate, through following steps:
It is characterized in that reaction conditions is as follows:
(1) with o-chlorobenzaldehyde, 4-(2-phthaloyl imino oxyethyl group) methyl aceto acetate, 3-aminobutene acid methyl esters is raw material synthetic intermediate phthalyl amlodipine in alcoholic solvent; Wherein, 3-aminobutene acid methyl esters and 4-(2-phthaloyl imino oxyethyl group) methyl aceto acetate molar ratio were more than or equal to 3: 1;
(2) intermediate phthalyl amlodipine is purified through toluene/glacial acetic acid recrystallizing and refining; The purity of intermediate phthalyl amlodipine is greater than 97%; Toluene/glacial acetic acid system recrystallization, glacial acetic acid content 0～50%.
2. the method for claim 1 is characterized in that, the detection method of amlodipine besylate is the HPLC method, and chromatographic condition is: moving phase 2.3g/L Spirit of Mindererus-methyl alcohol=30: 70, detect wavelength 237nm.
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| CN101367759B true CN101367759B (en) | 2011-03-16 |
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Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2014511867A (en) * | 2011-04-18 | 2014-05-19 | 合肥貝霓医薬科技有限公司 | Purification of dihydropyridine calcium channel blocker and method for preparing nanoparticles thereof |
| CN102659672B (en) * | 2012-05-07 | 2014-04-09 | 山东新华制药股份有限公司 | Preparation method of high-purity levamlodipine besylate |
| CN104592099A (en) * | 2014-12-30 | 2015-05-06 | 山东鲁抗医药股份有限公司 | Refining method for improving optical purity of levoamlodipine besylate |
| CN105399660A (en) * | 2015-07-31 | 2016-03-16 | 浙江师范大学 | 4-substituted-1,4-dihydropyridine compound preparation method |
| CN105301164B (en) * | 2015-11-30 | 2017-06-27 | 宜昌东阳光长江药业股份有限公司 | A kind of detection method of Levamlodipine beaylate tablets about material |
| CN107445889A (en) * | 2017-08-01 | 2017-12-08 | 东瑞（南通）医药科技有限公司 | A kind of one kettle way prepares Amlodipine Besylate Tablet |
| CN107573279B (en) * | 2017-09-01 | 2020-06-09 | 扬子江药业集团江苏海慈生物药业有限公司 | Synthesis method of amlodipine besylate degradation impurities |
| CN113087656A (en) * | 2020-01-09 | 2021-07-09 | 鲁南制药集团股份有限公司 | Amorphous levamlodipine besylate |
| CN111948306B (en) * | 2020-07-27 | 2021-03-23 | 北京百奥药业有限责任公司 | Method for determining genotoxic impurities in amlodipine besylate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4572909A (en) * | 1982-03-11 | 1986-02-25 | Pfizer Inc. | 2-(Secondary aminoalkoxymethyl) dihydropyridine derivatives as anti-ischaemic and antihypertensive agents |
| WO2006003672A1 (en) * | 2004-07-02 | 2006-01-12 | Matrix Laboratories Ltd | Process for the preparation of pure amlodipine |
-
2008
- 2008-10-06 CN CN2008102236583A patent/CN101367759B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4572909A (en) * | 1982-03-11 | 1986-02-25 | Pfizer Inc. | 2-(Secondary aminoalkoxymethyl) dihydropyridine derivatives as anti-ischaemic and antihypertensive agents |
| WO2006003672A1 (en) * | 2004-07-02 | 2006-01-12 | Matrix Laboratories Ltd | Process for the preparation of pure amlodipine |
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Owner name: HUARUN SAIKE PHARMACEUTICAL CO., LTD. Free format text: FORMER NAME: SAIKE PHARMACEUTICAL CO., LTD., BEIJING |
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Address after: 100021 Beijing city Chaoyang District Jinsong three District No. 302 Huateng building room 1101 Patentee after: China Resources Saike Pharmaceutical Co., Ltd. Address before: 100021 Beijing city Chaoyang District Jinsong three District No. 302 Huateng building room 1101 Patentee before: Saike Pharmaceutical Co., Ltd., Beijing |