CN103360353A - Preparation methods for impurities of escitalopram oxalate - Google Patents
Preparation methods for impurities of escitalopram oxalate Download PDFInfo
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- CN103360353A CN103360353A CN2013103399362A CN201310339936A CN103360353A CN 103360353 A CN103360353 A CN 103360353A CN 2013103399362 A CN2013103399362 A CN 2013103399362A CN 201310339936 A CN201310339936 A CN 201310339936A CN 103360353 A CN103360353 A CN 103360353A
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- TXMJPSIYRIVCED-UHFFFAOYSA-N CC#Cc1ccc(C(CCCN(C)C)(c(cc2)ccc2F)OC2=O)c2c1 Chemical compound CC#Cc1ccc(C(CCCN(C)C)(c(cc2)ccc2F)OC2=O)c2c1 TXMJPSIYRIVCED-UHFFFAOYSA-N 0.000 description 1
- LYYWQJNKWCANAC-UHFFFAOYSA-N CN(C)CCCC1(c(cc2)ccc2F)OCc2cc(C(N)=O)ccc12 Chemical compound CN(C)CCCC1(c(cc2)ccc2F)OCc2cc(C(N)=O)ccc12 LYYWQJNKWCANAC-UHFFFAOYSA-N 0.000 description 1
- UTXZEQNGGLSWCI-UHFFFAOYSA-N C[N](C)(CCCC1(c(cc2)ccc2F)OCc2cc(C#N)ccc12)[O-] Chemical compound C[N](C)(CCCC1(c(cc2)ccc2F)OCc2cc(C#N)ccc12)[O-] UTXZEQNGGLSWCI-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention relates to novel synthetic methods for three impurities of escitalopram oxalate. The methods have great significance for synthesis of the escitalopram oxalate with high purity. The invention mainly study syntheses of a citalopram amide impurity 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-isobenzofuran-5-formamide (II), a citalopram lactone impurity 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-3-oxo-1,3-dihydro-isobenzofuran-5-carbonitrile (III) and a citalopram-N-oxide impurity 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-isobenzofuran-5-cyano-N-oxide (IV). Specific synthetic routes of the impurities are showed as follows.
Description
Technical field
The present invention relates to the preparation method of escitalopram oxalate impurity.
Background technology
Escitalopram oxalate (Escitalopram Oxalate), chemical name: S-(+)-1-[3-(dimethylamino) propyl group]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-nitrile oxalate, being a kind of serotonin reuptake inhibitor (SSRI), is the S type isomer (trade(brand)name Lexapro) of citalopram (I) (structural formula is as follows).Studies show that escitalopram oxalate has unique serotonin isomery site binding mechanism, has high selectivity to 5-hydroxytryptamine receptor.Developed jointly by American Forest laboratory (Forest Laboratories) company and Denmark Ling Bei (Lundbeck) company, escitalopram oxalate went on the market in American-European countries such as Switzerland first in March, 2002, obtain the FDA approval August, be used for the treatment of Serious depression and the depressed treatment of keeping.
The synthetic principal reaction route of escitalopram oxalate and citalopram (I) is as follows:
(1) by 5-Cyano-phthalide and the reaction of p-Fluoro bromo benzene Grignard reagent, again with N, N-dimethyl-3-chlorine propylamine Grignard reagent reaction becomes hydrobromate free again, generates 4-(4-dimethylamino-1-is to fluorophenyl-1-hydroxyl butyl)-3-methylol-1-cyanophenyl; Split behind the purifying, make (S)-4-(4-dimethylamino-1-is to fluorophenyl-1-hydroxyl butyl)-3-methylol-1-cyanophenyl; With triethylamine, the Tosyl chloride ring-closure reaction makes (S)-citalopram; Make escitalopram oxalate with the oxalic acid reaction again.This route is relatively short, and cost is suitable, is beneficial to suitability for industrialized production (WO2010004575; US2011092719; US2011065938; U.S.Pat.NO.4650884; U.S.Pat.NO.4943590), synthetic route is shown below.
(2) by 5-Cyano-phthalide and the reaction of p-Fluoro bromo benzene Grignard reagent, again with N, N-dimethyl-3-chlorine propylamine Grignard reagent reaction, after the quencher, become hydrobromate, free again, generate 4-(4-dimethylamino-1-is to fluorophenyl-1-hydroxyl butyl)-3-methylol-1-cyanophenyl; Last and triethylamine, the Tosyl chloride ring-closure reaction makes citalopram (I) (US2010/0087664A1).This technique comparative maturity, cost compare is cheap, uses more extensive.
(3) by 5-Cyano-phthalide and the reaction of p-Fluoro bromo benzene Grignard reagent, generate 4-(4-fluoro benzoyl)-3-methylol-1-cyanophenyl, the Lithium Aluminium Hydride reduction, generate 4-[1-(4-fluorophenyl) methylol)]-3-methylol-1-cyanophenyl, cyclization generates 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-nitrile, with N, N-dimethyl-3-chloropropane generation alkylated reaction obtains citalopram (I) (WO2005/077927A1 in the presence of sodium hydride; WO2004080988).This route adopts the inflammable hazardous agents such as Lithium Aluminium Hydride and sodium hydride, is unfavorable for suitability for industrialized production.
(4) take 5-Cyano-phthalide as raw material, through reacting with the p-Fluoro bromo benzene Grignard reagent, be hydrolyzed, sodium borohydride reduction, closed loop, again with N, N-dimethyl-3-chlorine propylamine Grignard reagent reaction also can make citalopram (I) (W098/19511)
Make the control that highly purified escitalopram oxalate key is impurity, therefore significant to the study on the synthesis of escitalopram oxalate impurity.Point out among the American Pharmacopeia USP35-NF30 that escitalopram oxalate always mix must not above 0.5%, six impurity that wherein need to study comprise: the citalopram amide impurities, chemical name: 1-[3-(dimethylamino) propyl group]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-methane amide; Citalopram lactone impurity, chemical name: 1-[3-(dimethylamino) propyl group]-1-(4-fluorophenyl)-3-oxygen-1, the different phenylpropyl alcohol furans of 3-dihydro-5-nitrile; Citalopram N-oxidation impurities, chemical name: 1-[3-(dimethylamino) propyl group]-1-(4-fluorophenyl)-1, the different phenylpropyl alcohol furans of 3-dihydro-5-nitrile N-oxide compound; Citalopram demethyl impurity, chemical name: 1-[3-(methylamino-) propyl group]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-nitrile; Citalopram acetal impurity, chemical name: 1-[3-(dimethylamino) propyl group]-1-(4-fluorophenyl)-3-oxygen-3H-2-cumarone-5-nitrile; Citalopram grignard reaction impurity, chemical name: 4-(dimethylamino)-1-[1-[3-(dimethylamino) propyl group]-1-(4-fluorophenyl)-3H-2-cumarone-5-yl]-the 1-butanone.Few for the synthetic report document of citalopram impurity both at home and abroad, especially synthesizing of citalopram amide impurities (II), citalopram lactone impurity (III) and three impurity of citalopram N-oxidation impurities (IV) (structural formula is as follows) had no bibliographical information at present.
Summary of the invention
The present invention relates to three impurity of escitalopram oxalate: the synthetic method of citalopram amide impurities (II), citalopram lactone impurity (III) and citalopram-N-oxidation impurities (IV), synthetic route of the present invention is as follows:
The preparation of these three impurity is all take citalopram (I) as raw material.The preparation of its citalopram (I) can be adopted prior art, its synthesis step is: by 5-Cyano-phthalide and the reaction of p-Fluoro bromo benzene Grignard reagent, again with N, N-dimethyl-3-chlorine propylamine Grignard reagent reaction, after the quencher, become hydrobromate, get 4-(4-dimethylamino-1-is to fluorophenyl-1-hydroxyl butyl)-3-methylol-1-cyanophenyl after dissociating; Make citalopram (I) (US2010/0087664A1) finally by ring-closure reaction.
The preparation method of these three impurity still has no bibliographical information so far, belongs to brand-new synthetic method.
Synthesis step of the present invention:
(1) 1-[3-(dimethylamino) propyl group]-1-(4-fluorophenyl)-1, the preparation of 3-dihydroisobenzofuran-5-methane amide (II)
1. citalopram amide impurities (II) adds hydrogen peroxide under the alkaline condition and makes take citalopram (I) as raw material, and temperature of reaction is-10~10 ℃.
2. among the preparation method of citalopram amide impurities (II), solvent for use is selected from methyl alcohol, ethanol, Virahol, propyl carbinol, acetone, tetrahydrofuran (THF), methylene dichloride, chloroform, acetonitrile, ethyl acetate, Pyrrolidine, pyridine, piperidines, N-Methyl pyrrolidone.
Among the preparation method of citalopram amide impurities (II), citalopram (I) is 1: 0.3~0.6 with the weightmeasurement ratio of 30% hydrogen peroxide; Citalopram (I) is 1: 35~45 with the weightmeasurement ratio of solvent.
3. add the citalopram amide impurities (II) that hydrogen peroxide makes under the alkaline condition, wherein, the kind of described alkali and consumption all can be conventional solvent and the consumption of this type of reaction of this area, the consumption of the preferred following alkali of the present invention and alkali: wherein, what described alkali was better is sodium hydride, lithium hydride, hydrolith, sodium hydroxide, potassium hydroxide, calcium hydroxide, hydrated barta, lithium hydroxide, potassium tert.-butoxide, trimethyl carbinol lithium; What the consumption of described alkali was better is regulator solution pH to 9~11.
4. add the citalopram amide impurities (II) that hydrogen peroxide makes under the alkaline condition, extract with the larger mixed solvent of polarity, solvent for use is selected from propyl carbinol, Virahol, ethanol, methyl alcohol, ethyl acetate, toluene, acetone, methylene dichloride, chloroform, acetonitrile, tetrahydrofuran (THF), the preferred propyl carbinol of the present invention/ethyl acetate series solvent.
5. among the preparation method of citalopram amide impurities (II), citalopram amide impurities (II) is made with extra care and is adopted silica gel column chromatography method, and eluent adopts ethanol/methylene system, particular methanol: methylene dichloride=1: 2~4.
(2) 1-[3-(dimethylamino) propyl group]-1-(4-fluorophenyl)-3-oxygen-1, the preparation of 3-dihydroisobenzofuran-5-nitrile (III)
1. the preparation method of citalopram lactone impurity (III), citalopram (I) and Jones reagent reaction, reaction is carried out in non-protonic solvent, and solvent for use is selected from acetone, acetonitrile, DMF, ethyl acetate, DMSO, tetrahydrofuran (THF), ether, isopropyl ether, methylene dichloride, chloroform, tetracol phenixin, toluene, benzene or dimethylbenzene.
2. the preparation method of citalopram lactone impurity (III), in citalopram (I) and the Jones reagent reaction response, citalopram (I) is 1: 5~15 with the weightmeasurement ratio of solvent; Temperature of reaction is-10~10 ℃.
3. the preparation method of citalopram lactone impurity (III), in citalopram (1) and the Jones reagent reaction, citalopram (I) is 1: 2~5 with the weightmeasurement ratio of Jones reagent.
4. make citalopram lactone impurity (III) with the larger solvent extraction of polarity, used solvent is selected from Virahol, ethanol, methyl alcohol, propyl carbinol, ethyl acetate, acetone, tetrahydrofuran (THF), methylene dichloride, chloroform, acetonitrile, the preferred Virahol of the present invention, ethyl acetate, acetone.
5. make citalopram lactone impurity (III) and become oxalate, with the larger solvent recrystallization of polarity, refining used solvent is selected from ethanol, methyl alcohol, Virahol, propyl carbinol, ethyl acetate, acetone, tetrahydrofuran (THF), methylene dichloride, chloroform, acetonitrile, preferred alcohols series of the present invention.
(3) 1-[3-(dimethylamino) propyl group]-1-(4-fluorophenyl)-1, the preparation of the different phenylpropyl alcohol furans of 3-dihydro-5-nitrile-N-oxide compound (IV)
1. the preparation method of citalopram-N-oxidation impurities (IV), citalopram (I) carries out in aprotic solvent with the metachloroperbenzoic acid reaction, and solvent for use is selected from methylene dichloride, acetone, acetonitrile, DMF, ethyl acetate, DMSO, tetrahydrofuran (THF), ether, isopropyl ether, chloroform, tetracol phenixin, toluene, benzene or dimethylbenzene.
2. the preparation method of citalopram-N-oxidation impurities (IV), citalopram (I) and metachloroperbenzoic acid reaction citalopram (I) are 1: 18~25 with the weightmeasurement ratio of solvent; Temperature of reaction is-10~10 ℃.
3. the preparation method of citalopram-N-oxidation impurities (IV), citalopram (I) and metachloroperbenzoic acid reaction citalopram (I) and the mol ratio 1: 1.0~2.5 of asking chloroperoxybenzoic acid.
4. the preparation method of citalopram-N-oxidation impurities (IV), making citalopram-N-oxidation impurities (IV) extracts with mixed solvent, used solvent is selected from propyl carbinol, Virahol, ethanol, methyl alcohol, ethyl acetate, acetone, tetrahydrofuran (THF), methylene dichloride, chloroform, acetonitrile, the mixing solutions of the preferred propyl carbinol of the present invention and ethyl acetate.
5. make N-oxidation impurities (IV), adopt the method for silica gel column chromatography refining, eluent is selected propyl carbinol/ethyl acetate system.The preferred propyl carbinol of eluent ratio of silica gel column chromatography: ethyl acetate=1: 2~4.
Embodiment
Following example further specifies the present invention, but the present invention is not limited.
Embodiment:
Embodiment 11-[3-(dimethylamino) propyl group]-1-(4-fluorophenyl)-1, the preparation of 3-dihydroisobenzofuran-5-methane amide (II)
In the 100ml three-necked bottle, add 2.0g citalopram (I), under 0~5 ℃, add 80ml methyl alcohol stirring and dissolving, transfer to pH to 10 with diluted sodium hydroxide solution, drip 30% hydrogen peroxidase 10 .6ml, then add 30% hydrogen peroxidase 10 .2ml every 30min, react completely until TCL follows the tracks of.Add an amount of saturated sodium sulfite solution and stir, to the starch potassium iodide paper nondiscoloration, then regulate pH to alkalescence with dilute sodium hydroxide aqueous solution, propyl carbinol/ethyl acetate extraction (15ml * 3), merge organic layer, anhydrous sodium sulfate drying, concentrating under reduced pressure get crude product (II).Silica gel column chromatography (ethanol/methylene=1/3) gets sterling white solid (II) 0.9g, yield 42.6%.
Its Structural Identification data are as follows:
1H-NMR(DMSO-d
6)δ:7.90(s,1H),7.80(d,1H),7.75(s,1H),7.57(m,3H),7.30(s,1H),7.13(t,2H),5.15(m,2H),2.13(m,4H),2.02(d,6H),1.30(s,1H),1.22(s,1H)。
MS(m/z):343(M
+)。
Embodiment 21-[3-(dimethylamino) propyl group]-1-(4-fluorophenyl)-3-oxygen-1, the preparation of 3-dihydroisobenzofuran-5-nitrile (III)
In the 250ml three-necked bottle, add citalopram 8.0g and 80ml acetone, 0~5 ℃ of lower stirring and dissolving, stir 30min after the dropping 30ml Jones reagent, move to normal-temperature reaction and spend the night.Add an amount of Virahol, stir 30min, the diatomite suction filtration, filtrate is regulated pH to 13 in ice-water bath, and ethyl acetate extraction (20ml * 3) merges organic layer, saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure.The Virahol dissolving adds the oxalic acid salify, Virahol recrystallization, the faint yellow oily thing of sterling (III) 6.0g that dissociates to get, yield 75.8%.
Its Structural Identification data are as follows:
1H-NMR(DMSO-d
6)δ:8.45(s,1H),8.28(d,1H),8.08(d,1H),7.62(m,2H),7.26(t,2H),2.93(t,2H),2.64(t,1H),2.50(d,6H),2.40(m,1H),1.48(s,1H),1.35(s,1H)。
MS(m/z):339(M
+)。
Embodiment 31-[3-(dimethylamino) propyl group]-1-(4-fluorophenyl)-1, the preparation of the different phenylpropyl alcohol furans of 3-dihydro-5-nitrile-N-oxide compound (IV)
In the 250ml three-necked bottle, add 2.34g citalopram alkali (I), methylene dichloride 50ml, stirring and dissolving under the cryosel bath condition drips the dichloromethane solution 50ml that contains metachloroperbenzoic acid 1.72g, dropwises to continue to stir 2h.Reaction solution sodium sulfite solution quencher, concentrating under reduced pressure, residue adds suitable quantity of water, add diluted sodium hydroxide solution and regulate pH to alkalescence, propyl carbinol/ethyl acetate extraction (20ml * 3), anhydrous sodium sulfate drying, concentrating under reduced pressure gets crude product (IV), silica gel column chromatography (propyl carbinol/ethyl acetate=1/3) gets the faint yellow oily thing of sterling (IV) 0.13g, yield 5.6%.
Its Structural Identification data are as follows:
1H-NMR(DMSO-d
6)δ:7.82(m,3H),7.62(m,2H),7.20(t,2H),5.25(m,2H),3.60(t,2H),3.35(s,6H),2.26(t,2H),1.67(m,2H)。
MS(m/z):341(M
+)。
Claims (10)
1. the preparation method of escitalopram oxalate impurity, it is characterized in that 1-[3-(dimethylamino) propyl group]-1-(4-fluorophenyl)-1, the different phenylpropyl alcohol furans of 3-dihydro-5-nitrile (I) (abbreviation citalopram) is by being hydrolyzed to get 1-[3-(dimethylamino) propyl group]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-methane amide (II) (being called for short the citalopram amide impurities); Citalopram (I) reacts to get 1-[3-(dimethylamino) propyl group with Jones reagent]-1-(4-fluorophenyl)-3-oxygen-1, the different phenylpropyl alcohol furans of 3-dihydro-5-nitrile (III) (being called for short citalopram lactone impurity); Citalopram (I) reacts to get 1-[3-(dimethylamino) propyl group with metachloroperbenzoic acid]-1-(4-fluorophenyl)-1, the different phenylpropyl alcohol furans of 3-dihydro-5-nitrile-N-oxide compound (IV) (being called for short citalopram-N-oxidation impurities).
2. the preparation method of citalopram amide impurities according to claim 1 (II), (II) preparation is as raw material take citalopram (I), adding hydrogen peroxide under the alkaline condition makes, temperature of reaction is-10~10 ℃, and the reaction solvent for use is selected from methyl alcohol, ethanol, Virahol, propyl carbinol, acetone, tetrahydrofuran (THF), methylene dichloride, chloroform, acetonitrile, ethyl acetate, Pyrrolidine, pyridine, piperidines, N-Methyl pyrrolidone.
3. described according to claim 2, add the citalopram amide impurities (II) that hydrogen peroxide makes under the alkaline condition, alkaline condition needs highly basic control pH value of solution: scope 9~11; Citalopram (I) is 1: 0.3~0.6 with the weightmeasurement ratio of 30% hydrogen peroxide; Citalopram (I) is 1: 35~45 with the weightmeasurement ratio of solvent.
4. according to claim 2,3 is described, among the preparation method of citalopram amide impurities (II), the citalopram amide impurities (II) that makes is extracted with the larger mixed solvent of polarity, and solvent for use is selected from propyl carbinol, Virahol, ethanol, methyl alcohol, ethyl acetate, toluene, acetone, methylene dichloride, chloroform, acetonitrile, tetrahydrofuran (THF); Refining silica gel column chromatography method (the eluent employing methyl alcohol: methylene dichloride=1: 2~4) that adopts of citalopram amide impurities (II).
5. the preparation method of citalopram lactone impurity according to claim 1 (III), citalopram (I) and Jones reagent reaction, reaction is carried out in non-protonic solvent, and solvent for use is selected from acetone, acetonitrile, DMF, ethyl acetate, DMSO, tetrahydrofuran (THF), ether, isopropyl ether, methylene dichloride, chloroform, tetracol phenixin, toluene, benzene or dimethylbenzene; Reaction citalopram (I) is 1: 5~15 with the weightmeasurement ratio of solvent; Temperature of reaction is-10~10 ℃.
6. the preparation method of citalopram lactone impurity according to claim 1 (III), during citalopram (I) reacts with Jones reagent, citalopram (I) is 1: 2~5 with the weightmeasurement ratio of Jones reagent, make citalopram lactone impurity (III) with the larger solvent extraction of polarity, used solvent is selected from Virahol, ethanol, methyl alcohol, propyl carbinol, ethyl acetate, acetone, tetrahydrofuran (THF), methylene dichloride, chloroform, acetonitrile.
7. according to claim 1, the 6 described citalopram lactone impurity (III) that make become oxalate, with the larger solvent recrystallization of polarity, refining used solvent is selected from ethanol, methyl alcohol, Virahol, propyl carbinol, ethyl acetate, acetone, tetrahydrofuran (THF), methylene dichloride, chloroform, acetonitrile, preferred alcohols series of the present invention.
8. the preparation method of citalopram according to claim 1-N-oxidation impurities (IV), citalopram (I) carries out in non-protonic solvent with the metachloroperbenzoic acid reaction, and solvent for use is selected from methylene dichloride, acetone, acetonitrile, DMF, ethyl acetate, DMSO, tetrahydrofuran (THF), ether, isopropyl ether, chloroform, tetracol phenixin, toluene, benzene or dimethylbenzene; Reaction citalopram (I) is 1: 18~25 with the weightmeasurement ratio of solvent; Temperature of reaction is-10~10 ℃.
9. the preparation method of citalopram according to claim 1-N-oxidation impurities (IV), citalopram (I) and the mol ratio 1: 1.0~2.5 of metachloroperbenzoic acid reaction citalopram (I) with metachloroperbenzoic acid, making citalopram-N-oxidation impurities (IV) extracts with mixed solvent, used solvent is selected from propyl carbinol, Virahol, ethanol, methyl alcohol, ethyl acetate, acetone, tetrahydrofuran (THF), methylene dichloride, chloroform, acetonitrile, the mixing solutions of preferred propyl carbinol and ethyl acetate.
10. according to claim 1, the 9 described citalopram-N-oxidation impurities (IV) that make, adopt refining (the preferred propyl carbinol of eluent: ethyl acetate=1: 2~4) of method of silica gel column chromatography.
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Cited By (6)
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CN103936702A (en) * | 2014-05-07 | 2014-07-23 | 成都诺维尔生物医药有限公司 | Synthetic method of escitalopram impurity J |
CN106018618A (en) * | 2016-07-05 | 2016-10-12 | 湖南洞庭药业股份有限公司 | Escitalopram oxalate tablet composition and quality control method |
CN106928094A (en) * | 2017-02-10 | 2017-07-07 | 万全万特制药(厦门)有限公司 | The preparation method of escitalopram process contaminants |
CN110873761A (en) * | 2018-09-03 | 2020-03-10 | 万全万特制药江苏有限公司 | Gas chromatography detection method for escitalopram oxalate intermediate related substances |
CN112574147A (en) * | 2020-07-31 | 2021-03-30 | 国药集团工业有限公司 | Preparation method of citalopram impurity |
WO2022151968A1 (en) * | 2021-01-14 | 2022-07-21 | 浙江华海药业股份有限公司 | Method for purifying key intermediates of citalopram |
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Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
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CN103936702A (en) * | 2014-05-07 | 2014-07-23 | 成都诺维尔生物医药有限公司 | Synthetic method of escitalopram impurity J |
CN106018618A (en) * | 2016-07-05 | 2016-10-12 | 湖南洞庭药业股份有限公司 | Escitalopram oxalate tablet composition and quality control method |
CN106018618B (en) * | 2016-07-05 | 2018-06-22 | 湖南洞庭药业股份有限公司 | Escitalopram oxalate tablet composition and quality control method |
CN106928094A (en) * | 2017-02-10 | 2017-07-07 | 万全万特制药(厦门)有限公司 | The preparation method of escitalopram process contaminants |
CN110873761A (en) * | 2018-09-03 | 2020-03-10 | 万全万特制药江苏有限公司 | Gas chromatography detection method for escitalopram oxalate intermediate related substances |
CN112574147A (en) * | 2020-07-31 | 2021-03-30 | 国药集团工业有限公司 | Preparation method of citalopram impurity |
WO2022151968A1 (en) * | 2021-01-14 | 2022-07-21 | 浙江华海药业股份有限公司 | Method for purifying key intermediates of citalopram |
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