CN103396408A - Preparation method of impurity B in candesartan cilexetil - Google Patents
Preparation method of impurity B in candesartan cilexetil Download PDFInfo
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- CN103396408A CN103396408A CN201310348807XA CN201310348807A CN103396408A CN 103396408 A CN103396408 A CN 103396408A CN 201310348807X A CN201310348807X A CN 201310348807XA CN 201310348807 A CN201310348807 A CN 201310348807A CN 103396408 A CN103396408 A CN 103396408A
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Abstract
The invention relates to a preparation method of an impurity B in candesartan cilexetil. According to the method, (+/-)-2-oxo-3-[[2'-(1H-tetrazole-5-yl)-4-biphenyl]methyl]-1H-benzimidazole-4-formic acid-1-[[(cyclohexyloxy)carbonyl]oxy]ethyl ester is prepared by taking triphenylmethyl candesartan cilexetil (C10) or candesartan cilexetil (C11) as raw materials in the presence of inorganic acid and organic solvent. 8 impurities exist in the candesartan cilexetil quality standards in USP35 and European pharmacopoeia (7th Version in 2012), wherein the impurity B is the main impurity. The preparation method is reasonable in process and simple and easy to implement; the prepared impurity B has high yield and favorable purity, thus providing a qualified reference substance for quality control on candesartan cilexetil; and meanwhile, the synthesis condition for impurity B preparation conversely provides a reference foundation for inhibiting generation of the impurity B in candesartan cilexetil synthesis, thereby ensuring that the quality of candesartan cilexetil reaches or exceeds the pharmacopoeia standards.
Description
Technical field
The present invention relates to the preparation method of impurity B in candesartan Cilexetil.
Background technology
Candesartan cilexetil comes former times to replace ester (candesartan cielxetli is called for short candesartan Cilexetil), chemistry (±)-2-oxyethyl group-1-[[2 '-(1 by name
H-tetrazolium-5-yl)-4-xenyl] methyl]-1
H-benzoglyoxaline-7-formic acid-1-[[(cyclohexyloxy) carbonyl] the oxygen base] ethyl ester (formula 1), at first by Japan military field pharmaceutical industries company, developed, Aktiebolaget Astra adds and develops jointly afterwards, and in December, 1997 first in Sweden's listing, commodity are called Atacand.It is the prodrug of Candesartan, can be in gi tract complete hydrolysis and change into the Candesartan with antihypertensive active.Candesartan Cilexetil is used for the treatment of all kinds of light moderate hypertensions clinically, this medicine usually can't be with untoward reactions such as tachycardias when reducing arteriotony, and after drug withdrawal, without the hypertension rebound phenomenon, easily by the hyperpietic, particularly the gerontal patient accepts.
Formula 1
American Pharmacopeia USP35 and European Pharmacopoeia had 8 impurity in 7 editions candesartan Cilexetil quality standards in 2012, and major impurity B wherein, have no sale on market, also do not have open source literature to report the synthetic method of impurity B.Candesartan Cilexetil is carried out to quality control need to have qualified candesartan Cilexetil impurity B (formula 2) compound product in contrast with analysis, and the generation of synthesizing middle inhibition of impurities B for candesartan Cilexetil simultaneously provides reference frame.
The candesartan Cilexetil impurity B, chemistry (±)-2-oxygen-3-[[2 '-(1 by name
H-tetrazolium-5-yl)-4-xenyl] methyl]-1
H-benzoglyoxaline-4-formic acid-1-[[(cyclohexyloxy) carbonyl] the oxygen base] ethyl ester (formula 2), the impurity that forms for sloughing ethyl on benzoglyoxaline ring in the Candesartan ester molecule.
Formula 2
Summary of the invention.
The preparation method who the purpose of this invention is to provide impurity B in a kind of candesartan Cilexetil, for the quality control of candesartan Cilexetil provides qualified reference substance.
Technical scheme of the present invention is to use two kinds of methods:
First method: take trityl group candesartan Cilexetil (C10) as raw material, under mineral acid and organic solvent existence condition, prepare (±)-2-oxygen-3-[[2 '-(1
H-tetrazolium-5-yl)-4-xenyl] methyl]-1
H-benzoglyoxaline-4-formic acid-1-[[(cyclohexyloxy) carbonyl] the oxygen base] ethyl ester (impurity B) (formula 3).
Formula 3
Second method: take candesartan Cilexetil (C11) as raw material, under mineral acid and organic solvent existence condition, prepare (±)-2-oxygen-3-[[2 '-(1
H-tetrazolium-5-yl)-4-xenyl] methyl]-1
H-benzoglyoxaline-4-formic acid-1-[[(cyclohexyloxy) carbonyl] the oxygen base] ethyl ester (impurity B) (formula 4).
Formula 4
Mineral acid used is hydrochloric acid or sulfuric acid or phosphoric acid, or the hydrogen chloride solution of methyl alcohol or ethanol.
The present invention preferably uses the hydrogen chloride solution of hydrochloric acid or methyl alcohol.
The usage quantity of the hydrogen chloride solution of the present invention's hydrochloric acid used or methyl alcohol is that raw materials used trityl group candesartan Cilexetil (C10) or candesartan Cilexetil (C11) 1 ~ 5 mole is doubly measured, and preferably uses 2 ~ 4 moles of trityl group candesartan Cilexetil (C10) or candesartan Cilexetil (C11) doubly to measure.
The organic solvent halogenated hydrocarbons of reacting used is methylene dichloride or trichloromethane or tetracol phenixin or the mixture of any two kinds wherein; Arene is benzene or toluene or both mixtures; Ketone is acetone or butanone or both mixtures; Alcohols is the mixture of methyl alcohol or ethanol or propyl alcohol or Virahol or any two kinds.
The present invention preferably uses hydrogen chloride solution reactive system or the acetone/hydrochloric acid reaction system of methylene chloride/methanol.
Reaction of the present invention is carried out to the reflux temperature of solvent for use or mixed solvent in room temperature.
Positively effect of the present invention is: the preparation method of impurity B in a kind of candesartan Cilexetil is provided, and this preparation method's technique is reasonable, simple and easy to do, and the impurity B yield for preparing is high, purity good, and qualified reference substance can be provided for the quality control of candesartan Cilexetil; The synthesis condition for preparing simultaneously impurity B, also for the generation of inhibition of impurities B in candesartan Cilexetil synthetic, provide reference frame conversely, help to optimize synthesis technique, improve the productive rate of candesartan Cilexetil, and then guarantee that the quality of candesartan Cilexetil meets or exceeds standards of pharmacopoeia.
Embodiment
Below the present invention is further described with specific embodiment, but the present invention is not imposed any restrictions.
In reaction of the present invention, high performance liquid chromatograph is used in control, wears UV-detector (LC-10A) method and detects: comprising:
Chromatographic condition:
Chromatographic column Kromasil C18 4.6 * 250mm
Moving phase: acetonitrile: water (80:20), with phosphoric acid, regulate pH=3.0
Detect wavelength: 220nm
Column temperature: 30 ℃
Flow velocity: 1.0mL/min
Sample size: 10 μ l
Under above-mentioned condition, record color atlas, the retention time of candesartan Cilexetil (C11) is about 8 minutes, the relative retention time of triphenyl candesartan Cilexetil (C10) is about 1.2 minutes, the relative retention time of impurity B is about 0.6 minute, the relative retention time of trityl alcohol is about 0.8 minute, and the relative retention time of trityl ether is about 1.7 minutes.Analytical procedure is that area normalization method calculates.
The mixture stirring at room of embodiment 1:50g (82mmol) candesartan Cilexetil (C11), 400mL methylene dichloride and 55mL (150.9mmol) 10% hydrochloric acid methanol 7 ~ 8 hours, sampling analysis, add 120mL water, with weak ammonia conditioned reaction liquid pH=4 ~ 5, separate dichloromethane layer, decompression desolventizes, residue adds 200mL ethanol, stirring at room was dissolved 1 ~ 3 hour, filter and collect product dry, obtain 44g white solid impurity B, yield 92%, purity 98.6%, fusing point: 236.3 ~ 236.5 ℃.MS(ESI):?
m/z?[M+Na]
+?605,?
m/z?[M+K]
+?621;?HRMS(ESI):?calcd?for?C
31H
30N
6O
6?582.2227,?found?582.2。
1H-NMR(400MHz,?DMSO-d
6,?TMS)：?
δ1.36(m,?9H,?3×CH
2;?CH
3),?1.62(s,?2H,?CH
2),?1.82(s,?2H,?CH
2),?4.57(s,?1H,?CH-OCOO),5.31(dd,?2H,?
2 J HCH=16.0Hz,?CH
2),?6.74(s,?1H,?CH),?6.96(d,?2H,?
3 J HCCH=6.8Hz,?2×Ar-H),?7.01(s,?2H,?2×Ar-H),?7.10(t,?1H,?
3 J HCCH=7.2Hz,?Ar-H),?7.29(t,?2H,?
3 J HCCH=8.8Hz,?2×Ar-H),?7.47(d,?1H,?
3 J HCCH=7.2Hz,?Ar-H),?7.55(d,?1H,?
3 J HCCH=6.8Hz,?Ar-H),?7.64(s,?2H,?2×Ar-H),?11.59(s,?1H,?NH)?ppm。
13C-NMR(100MHz,?DMSO-d
6?,TMS)?19.5,?23.4(2C),?25.0,?31.2(2C),?45.0,?77.3,?92.4,?113.5,?113.7,?121.2,?122.8,?122.9,?127.0(2×Ar-C),?128.2,?128.8,?129.5(2×Ar-C),?130.5,?131.0,?131.1,?131.5,?136.8,?138.6,?141.4,?152.4(C=O),?155.4(C=O),?163.9(C=O)?ppm。
The mixture reflux of embodiment 2:50g (82mmol) candesartan Cilexetil (C11), 400mL methylene dichloride and 58mL (159mmol) 10% hydrochloric acid methanol 2 ~ 3 hours, sampling analysis, add 120mL water, with weak ammonia conditioned reaction liquid pH=4 ~ 5, separate dichloromethane layer, decompression desolventizes, residue adds 200mL ethanol, stirring at room was dissolved 1 ~ 3 hour, filter and collect product dry, obtain 43g white solid impurity B, yield 90%, purity 98.5%, fusing point: 236.3 ~ 236.5 ℃.
embodiment 3:50g (58.6mmol) triphenyl candesartan Cilexetil (C10), the mixture stirring at room of 350mL methylene dichloride and 75mL (205.7mmol) 10% hydrochloric acid methanol 10 ~ 12 hours, sampling analysis, add 120mL water, with weak ammonia conditioned reaction liquid pH=4 ~ 5, separate dichloromethane layer, decompression desolventizes, residue added 30 ℃ of stirring and dissolving of 200mL ether 30 minutes, be cooled to 10 ~ 15 ℃, filter, filter cake adds 200mL ethanol, stirring at room was dissolved 1 ~ 3 hour, filter and collect product dry, obtain 30g white solid impurity B, yield 88%, purity 98.2%, fusing point: 236.1 ~ 236.7 ℃.
embodiment 4:50g (58.6mmol) triphenyl candesartan Cilexetil (C10), the mixture reflux of 350mL methylene dichloride and 80mL (219.4mmol) 10% hydrochloric acid methanol 5 ~ 6 hours, sampling analysis, add 120mL water, with weak ammonia conditioned reaction liquid pH=4 ~ 5, separate dichloromethane layer, decompression desolventizes, residue added 30 ℃ of stirring and dissolving of 200mL ether 30 minutes, be cooled to 10 ~ 15 ℃, filter, filter cake adds 200mL ethanol, stirring at room was dissolved 1 ~ 3 hour, filter and collect product dry, obtain 28g white solid impurity B, yield 83%, purity 98.1%, fusing point: 236 ~ 236.8 ℃.
The mixture reflux of embodiment 5:50g (82mmol) candesartan Cilexetil (C11), 350mL acetone and 17.5mL (205mmol) hydrochloric acid 6 ~ 7 hours, sampling analysis, decompression desolventizes, residue adds 200mL water, with weak ammonia conditioned reaction liquid pH=4 ~ 5, filter, filter cake adds 200mL ethanol, stirring at room was dissolved 1 ~ 3 hour, filter and collect product dry, obtain 38g white solid impurity B, yield 79%, purity 98.2%, fusing point: 236.1 ~ 236.7 ℃.
The mixture reflux of embodiment 6:50g (58.6mmol) triphenyl candesartan Cilexetil (C10), 350mL acetone and 20mL (235mmol) hydrochloric acid 9 ~ 10 hours, sampling analysis, decompression desolventizes, add 120mL water, with weak ammonia conditioned reaction liquid pH=4 ~ 5, filter, filter cake added 30 ℃ of stirring and dissolving of 200mL ether 30 minutes, was cooled to 10 ~ 15 ℃, filter, filter cake adds 200mL ethanol, and stirring at room was dissolved 1 ~ 3 hour, filters and collects product dry, obtain 27g white solid impurity B, yield 79%, purity 98.1%, fusing point: 236 ~ 236.8 ℃.
Claims (9)
1. the preparation method of impurity B in candesartan Cilexetil comprises two kinds of methods:
First method: take trityl group candesartan Cilexetil (C10) as raw material, under mineral acid and organic solvent existence condition, prepare (±)-2-oxygen-3-[[2 '-(1
H-tetrazolium-5-yl)-4-xenyl] methyl]-1
H-benzoglyoxaline-4-formic acid-1-[[(cyclohexyloxy) carbonyl] the oxygen base] ethyl ester is impurity B.
2. second method: take candesartan Cilexetil (C11) as raw material, under mineral acid and organic solvent existence condition, prepare (±)-2-oxygen-3-[[2 '-(1
H-tetrazolium-5-yl)-4-xenyl] methyl]-1
H-benzoglyoxaline-4-formic acid-1-[[(cyclohexyloxy) carbonyl] the oxygen base] ethyl ester is impurity B.
3. the preparation method of impurity B in candesartan Cilexetil according to claim 1, it is characterized in that: mineral acid used is hydrochloric acid or sulfuric acid or phosphoric acid, or the hydrogen chloride solution of methyl alcohol or ethanol.
4. the preparation method of impurity B in candesartan Cilexetil according to claim 2, is characterized in that: the hydrogen chloride solution that uses hydrochloric acid or methyl alcohol.
5. the preparation method of impurity B in candesartan Cilexetil according to claim 3 is characterized in that: the usage quantity of the hydrogen chloride solution of hydrochloric acid used or methyl alcohol is raw materials used trityl group candesartan Cilexetil (C10) or candesartan Cilexetil (C11) 1 ~ 5 mole doubly amount.
6. the preparation method of impurity B in candesartan Cilexetil according to claim 4 is characterized in that: the usage quantity of the hydrogen chloride solution of hydrochloric acid used or methyl alcohol is raw materials used trityl group candesartan Cilexetil (C10) or candesartan Cilexetil (C11) 2 ~ 4 moles doubly amounts.
7. the preparation method of impurity B in candesartan Cilexetil according to claim 1 is characterized in that: the organic solvent halogenated hydrocarbons of reacting used is methylene dichloride or trichloromethane or tetracol phenixin or the mixture of any two kinds wherein; Arene is benzene or toluene or both mixtures; Ketone is acetone or butanone or both mixtures; Alcohols is the mixture of methyl alcohol or ethanol or propyl alcohol or Virahol or any two kinds.
8. the preparation method of impurity B according to claim 3 with 6 described candesartan Cilexetil, is characterized in that: hydrogen chloride solution reactive system or the acetone/hydrochloric acid reaction system of reaction use methylene chloride/methanol.
9. the preparation method of impurity B in candesartan Cilexetil according to claim 1, is characterized in that: react and carry out to the reflux temperature of solvent for use or mixed solvent in room temperature.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108484581A (en) * | 2018-05-29 | 2018-09-04 | 宣城美诺华药业有限公司 | A kind of new Candesartan dimer impurity and its synthetic method |
| CN109507350A (en) * | 2018-11-08 | 2019-03-22 | 南京明捷生物医药检测有限公司 | A kind of 2- cyano -4 '-bromomethylbiphenyl content method in measurement ethyl ester of candesartan |
| CN115403567A (en) * | 2022-08-15 | 2022-11-29 | 珠海润都制药股份有限公司 | Recovery method of candesartan cilexetil mother liquor |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5578733A (en) * | 1994-01-28 | 1996-11-26 | Takeda Chemical Industries, Ltd. | Process for the production of tetrazolyl compounds |
-
2013
- 2013-08-13 CN CN201310348807XA patent/CN103396408A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5578733A (en) * | 1994-01-28 | 1996-11-26 | Takeda Chemical Industries, Ltd. | Process for the production of tetrazolyl compounds |
Non-Patent Citations (1)
| Title |
|---|
| JAROSLAV HAVLíČEK ET AL.: "Identification, Synthesis and Structural Determination of Some Impurities of Candesartan Cilexetil", 《COLLECT. CZECH. CHEM. COMMUN.》, vol. 74, no. 2, 18 February 2009 (2009-02-18), pages 347 - 362 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108484581A (en) * | 2018-05-29 | 2018-09-04 | 宣城美诺华药业有限公司 | A kind of new Candesartan dimer impurity and its synthetic method |
| CN109507350A (en) * | 2018-11-08 | 2019-03-22 | 南京明捷生物医药检测有限公司 | A kind of 2- cyano -4 '-bromomethylbiphenyl content method in measurement ethyl ester of candesartan |
| CN115403567A (en) * | 2022-08-15 | 2022-11-29 | 珠海润都制药股份有限公司 | Recovery method of candesartan cilexetil mother liquor |
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Application publication date: 20131120 |