CN101538257B - Method for preparing citalopram and S-citalopram - Google Patents
Method for preparing citalopram and S-citalopram Download PDFInfo
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- CN101538257B CN101538257B CN200810034958A CN200810034958A CN101538257B CN 101538257 B CN101538257 B CN 101538257B CN 200810034958 A CN200810034958 A CN 200810034958A CN 200810034958 A CN200810034958 A CN 200810034958A CN 101538257 B CN101538257 B CN 101538257B
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Abstract
The invention provides a method for preparing citalopram and S-citalopram. In the method, 1-[2-(hydroxymethyl)-5-substituting group-]phenyl-4-(dimethylamino)-1-(4-fluorophenyl)-1- butyl alcohol undergoes a cyclization reaction with halogenated acylate in water and an organic solvent immiscible with water under the alkali condition to form a citalopram product. The method has high yield and high purity and is suitable for industrialized production.
Description
Technical field:
The present invention relates to pharmaceutical chemistry, be specifically related to a kind of method for preparing citalopram and S-citalopram.
Background technology
Citalopram, chemistry 1-[3-(dimethylin) propyl group] by name-1-(4-fluorophenyl)-1,3-dihydro-5-cyanic acid isobenzofuran is a kind of novel medicine that is used to treat dysthymia disorders, it belongs to selective serotonin reuptake inhibitor.Concrete like structural formula I, its S-configuration structural formula II is a main active ingredient.
Citalopram is developed by Denmark LUNDBECK company; Be disclosed in patent DE2657013 first; Corresponding to patent US4136193, the synthetic of S-citalopram is disclosed in patent USRE34712 first, has a lot of patent reports that the synthetic of citalopram studied afterwards.
Patent US4136193, US4650884, WO9819512 and WO9819513 etc. have reported the method for preparing citalopram, and like reaction formula-1, wherein Z can be a cyanic acid; Perhaps any group that can change into cyanic acid through chemical reaction, as: halogen, carboxamido-group; Carboxyl, aldehyde radical etc.See reaction formula one:
In above-mentioned patented process; 5-replaces glycol such as the structural formula II I (abbreviation of 1-[2-(methylol)-5-substituting group-] phenyl-4-(dimethylin)-1-(4-fluorophenyl)-1-butanols; Chemical combination under the catalysis of excessive strong acid down together) has a large amount of impurity (like structure V) to generate, and has caused reaction yield on the low side like this; And because the consumption of acid is big, three-waste pollution is quite serious.In addition, in reaction process, the chiral carbon of structural formula I can be accompanied by the chirality racemization, changes the chirality of the finished product.
Adopt the S-enantiomorph of 5-cyanic acid glycol to form a kind of unstable ester with methylsulfonyl, p-toluenesulfonyl, 10-camphor sulfonyl, trifluoro acyl group or trifyl reaction among the patent USRE34712, this unstable ester closed loop under the organic bases action condition obtains the S-citalopram.Though this method condition is gentle, reaction is easier to, and the chirality after the closed loop can keep or have a spot of racemization, and this method severe reaction conditions needs anhydrous low temperature to carry out, and used a large amount of organic basess are difficult to recycle, and three-waste pollution is very serious.
Adopt compound III or its S enantiomorph among the patent WO2006037714, closed loop under DEAD, phosphorus hydrogen type compound and highly basic (like the alkali alkyl thing) condition, preparation citalopram or S-citalopram.There is the big problem of suitability for industrialized production environmental protection pressure in this method equally owing to used materials such as a large amount of DEAD and triphenyl phosphorus.
Summary of the invention
The technical problem that the present invention will solve is to overcome above-mentioned weak point, and research and design is suitable for the method for preparing citalopram and S-citalopram of suitability for industrialized production.
The invention provides a kind of preparation citalopram, 1-[3-(dimethylin) propyl group]-1-(4-fluorophenyl)-1, the method for 3-dihydro-5-cyanic acid isobenzofuran (structural formula I) or S-citalopram (structural formula II).
The present invention adopts the 5-of racemization or single configuration to replace glycol III or its salt, forms unsettled ester derivative, and closed loop under alkaline condition obtains citalopram or S-citalopram through conversion reaction again.The present invention makes the inert organic solvents that water and other a kind of and water can not be miscible, adopts K
2CO
3Replace organic bases Deng mineral alkali.Following reaction formula two.
Compound III or its salt (S-, R-or raceme) react under the base catalysis condition with RX, and RX is 0.5～5 with the molar ratio of compound III, are preferably 1.0～1.5 and form unstable ester derivative VII, and cyclization obtains compound IV again.This is reflected at the alkaline aqueous solution existence and directly carries out down; Reaction finishes after aftertreatment; Directly prepare citalopram or S-citalopram (when the Z of compound III is cyanic acid); Or further preparing citalopram or its enantiomorph (when the Z of compound III is other group except that cyanic acid) by the routine techniques conversion reaction, chirality does not take place or rare conversion in the reaction process.
Reacting used solvent is and the not miscible inert solvent of water, and promptly in reaction process, not dissolving each other fully with water forms the solvent of homogeneous reaction system.These solvents can be aromatic hydrocarbons, fat hydrocarbon, halogenated hydrocarbon, ethers, ester class, specifically include but are not limited to benzene,toluene,xylene, hexanaphthene, heptane, sherwood oil, methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, THF, methyltetrahydrofuran, ETHYLE ACETATE, butylacetate etc.
The RX that uses in the reaction formula-2 is the halo acylate, shown in structural formula VI, forms the ester group that the ability of leaving away is stronger behind RX and the hydroxyl reaction.RX can be preferably 1～1.5 times at 1～5 times with respect to the mole dosage of glycol.R in structure VI
1Can be alkane, alkane substitute, aromatic nucleus or substituted aroma ring; X is halogens such as chlorine, bromine or iodine, is preferably chlorine.Corresponding acylating reagent is but is not limited only to methylsulfonyl chloride, third SULPHURYL CHLORIDE, benzene sulfonyl chloride, Tosyl chloride, p-nitrophenyl SULPHURYL CHLORIDE, 10-sulphur acyl chloride of camphor or the like.
The alkali that uses in the reaction can be organic bases and mineral alkali, and it partly or entirely is dissolved in the water uses; Be preferably mineral alkali; Optimization is selected the carbonate of basic metal and earth alkali metal for use.The consumption of alkali can be preferably 2～6 times at 1～20 times effective alkali equivalent with respect to the mole dosage of intermediate III.These alkali can be but be not limited only in Lithium Hydroxide MonoHydrate, sodium hydroxide, Pottasium Hydroxide, hydrated barta, calcium hydroxide, Quilonum Retard, yellow soda ash, salt of wormwood, lithium bicarbonate, sodium hydrogencarbonate, saleratus, Calcium hydrogen carbonate, barium bicarbonate, triethylamine, pyridine, the quinoline etc. one or more.
Through preparing with 4-fluorophenyl magnesium bromide and the addition of 3-dimethylamine propyl magnesium chloride, the III referenced patent USRE34712 of single configuration splits with (+) or (-) two pairs of toluyl tartrate and obtains the III referenced patent US4650884 that the present invention uses by the 5-substituted phthalide.When compound III is that the 5-of racemic modification replaces glycol, it is racemic modification that respective reaction obtains compound IV, and finally obtains racemization citalopram or S-citalopram through transforming.Replace glycol when compound III is the S enantiomeric ratio greater than 50% 5-, respective reaction obtain compound VI be the S ratio greater than 50% enantiomorph, and final the conversion obtains S-citalopram or racemization citalopram.Replace glycol when compound III is the R enantiomeric ratio greater than 50% 5-, respective reaction obtain compound IV be the R ratio greater than 50% enantiomorph, and final the conversion obtains S-citalopram or racemization citalopram.
Certainly, compound III 5-among the present invention replaces glycol and also can use with acid and combine salifiable form to use as raw material, and these acid of can salify using include but are not limited to hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid or oxalic acid etc.
The inventive method product yield is high, and purity is high, and it is few that material loss produces the three wastes, is suitable for suitability for industrialized production.
Embodiment:
Raw material that adopts among the embodiment and quality situation:
(1) .4-[4-(dimethylin)-1-(4-fluorophenyl)-1-hydroxyl butyl]-3-(methylol)-benzene nitrile, the quality situation is: HPLC:99.9%;
(2). (S)-(-)-4-[4-(dimethylin)-1-(4-fluorophenyl)-1-hydroxyl butyl]-3-(methylol)-benzene nitrile, the quality situation is: HPLC:99.9%, R isomer: 0.3%;
(3) .4-[4-(dimethylin)-1-(4-fluorophenyl)-1-hydroxyl butyl]-3-(methylol)-bromobenzene, the quality situation is: HPLC:99.9%;
Embodiment 1 (S)-(+)-1-[3-(dimethylin) propyl group]-1-(4-fluorophenyl)-1, the preparation of 3-dihydro-5-cyanic acid isobenzofuran (formula II) oxalate
In the 1000mL there-necked flask that is equipped with powerful stirring and constant pressure funnel, add 19.1g (S)-(-)-4-[4-(dimethylin)-1-(4-fluorophenyl)-1-hydroxyl butyl]-3-(methylol)-benzene nitrile, 17.4gK
2CO
3, adding 200mL toluene, 80mL water is opened and is stirred, and bathes cooling system to 0 ℃ with cryosel; The solution of 8.4g methylsulfonyl chloride and 70mL toluene is added dropwise to reaction solution through constant pressure funnel, and 0 ℃ of temperature in the control reaction flask dropwised and controlled through TLC (thin-layer chromatography) and reacts completely in 2 hours.Reaction finishes after-filtration, the filtrating layering, and water layer is used the 100mL methylbenzene extraction once again, and the combining methylbenzene layer is with twice of 100mL water washing.To doing, adding 100mL absolute ethyl alcohol, 10g oxalic acid stir and dissolve clear postcooling crystallization, filter with the toluene underpressure distillation, and oven dry gets (S)-(+)-1-[3-(dimethylin) propyl group]-1-(4-fluorophenyl)-1,3-dihydro-5-cyanic acid isobenzofuran oxalate 10g.Yield: 45.2%, HPLC: purity: 99.19%, R isomer: 1.72%.
Embodiment 2 (S)-(+)-1-[3-(dimethylin) propyl group]-1-(4-fluorophenyl)-1, the preparation of 3-dihydro-5-cyanic acid isobenzofuran (formula II) oxalate
In the 1000mL there-necked flask that is equipped with powerful stirring and constant pressure funnel, add 28.8g (S)-(-)-4-[4-(dimethylin)-1-(4-fluorophenyl)-1-hydroxyl butyl]-3-(methylol)-benzene nitrile, 20.8gNa
2CO
3, adding 200mL toluene, 80mL water is opened and is stirred, and bathes cooling system to 0 ℃ with cryosel; The solution of 17g Tosyl chloride and 150mL toluene is added dropwise to reaction solution through constant pressure funnel, and 0 ℃ of temperature in the control reaction flask dropwised and controlled through TLC (thin-layer chromatography) and reacts completely in 2 hours.Filter, the filtrating layering, water layer is used the 100mL methylbenzene extraction once again, and the combining methylbenzene layer is with twice of 100mL water washing.To doing, adding 110mL absolute ethyl alcohol, 16g oxalic acid stir and dissolve clear postcooling crystallization, filter with the toluene underpressure distillation, and oven dry gets S)-(+)-1-[3-(dimethylin) propyl group]-1-(4-fluorophenyl)-1,3-dihydro-5-cyanic acid isobenzofuran oxalate 22.5g.Yield: 73.9%, HPLC: purity: 99.62%, R isomer: 0.31%.
Embodiment 3 (S)-(+)-1-[3-(dimethylin) propyl group]-1-(4-fluorophenyl)-1, the preparation of 3-dihydro-5-cyanic acid isobenzofuran (formula II) oxalate
In the 500mL there-necked flask that is equipped with powerful stirring and constant pressure funnel, add 19.5g (S)-(-)-4-[4-(dimethylin)-1-(4-fluorophenyl)-1-hydroxyl butyl]-3-(methylol)-benzene nitrile; 3.36gNaOH, add 80mL toluene, 20mL water; Open to stir, bathe cooling system to 0 ℃ with cryosel; The solution of 8.5g Tosyl chloride and 65mL toluene is added dropwise to reaction solution through constant pressure funnel, and 0 ℃ of temperature in the control reaction flask dropwised and controlled through TLC (thin-layer chromatography) and reacts completely in 2 hours.Reaction finishes after-filtration, the filtrating layering, and water layer is used the 50mL methylbenzene extraction once again, and the combining methylbenzene layer is with twice of 100mL water washing.To doing, adding 60mL absolute ethyl alcohol, 6.9g oxalic acid stir and dissolve clear postcooling crystallization, filter with the toluene underpressure distillation, and oven dry gets (S)-(+)-1-[3-(dimethylin) propyl group]-1-(4-fluorophenyl)-1,3-dihydro-5-cyanic acid isobenzofuran oxalate 19.4g.Yield: 82.0%, HPLC: purity: 99.90%, R isomer: 0.58%.
Embodiment 4 (S)-(+)-1-[3-(dimethylin) propyl group]-1-(4-fluorophenyl)-1, the preparation of 3-dihydro-5-cyanic acid isobenzofuran (formula II) oxalate
In the 1000mL there-necked flask that is equipped with powerful stirring and constant pressure funnel, add 19.1g (S)-(-)-4-[4-(dimethylin)-1-(4-fluorophenyl)-1-hydroxyl butyl]-3-(methylol)-benzene nitrile; 11g KOH adds 200mL toluene, 80mL water; Open to stir, bathe cooling system to 0 ℃ with cryosel; The solution of 15g Tosyl chloride and 100mL toluene is added dropwise to reaction solution through constant pressure funnel, and 0 ℃ of temperature in the control reaction flask dropwised and controlled through TLC (thin-layer chromatography) and reacts completely in 2 hours.Reaction finishes after-filtration, the filtrating layering, and water layer is used the 100mL methylbenzene extraction once again, and the combining methylbenzene layer is with twice of 100mL water washing.To doing, adding 100mL absolute ethyl alcohol, 10g oxalic acid stir and dissolve clear postcooling crystallization, filter with the toluene underpressure distillation, and oven dry gets (S)-(+)-1-[3-(dimethylin) propyl group]-1-(4-fluorophenyl)-1,3-dihydro-5-cyanic acid isobenzofuran oxalate 19.8g.Yield: 83.0%, HPLC: purity: 99.97%, R isomer: 0.48%.
Embodiment 5 (S)-(+)-1-[3-(dimethylin) propyl group]-1-(4-fluorophenyl)-1, the preparation of 3-dihydro-5-cyanic acid isobenzofuran (formula II) oxalate
In the 1000mL there-necked flask that is equipped with powerful stirring and constant pressure funnel, add 19.1g (S)-(-)-4-[4-(dimethylin)-1-(4-fluorophenyl)-1-hydroxyl butyl]-3-(methylol)-benzene nitrile, 17.4gK
2CO
3, adding 200mL toluene, 80mL water is opened and is stirred, and bathes cooling system to 0 ℃ with cryosel; The solution of 18.6g p-nitrophenyl SULPHURYL CHLORIDE and 190mL toluene is added dropwise to reaction solution through constant pressure funnel, and 0 ℃ of temperature in the control reaction flask dropwised and controlled through TLC (thin-layer chromatography) and reacts completely in 2 hours.Reaction finishes after-filtration, the filtrating layering, and water layer is used the 100mL methylbenzene extraction once again, and the combining methylbenzene layer is with twice of 100mL water washing.The toluene underpressure distillation to doing, is added 100mL absolute ethyl alcohol, 10g oxalic acid, stir and dissolve clear postcooling crystallization, after crystal is separated out, put the crystallization that spends the night to the refrigerator.Next day, to filter, oven dry gets (S)-(+)-1-[3-(dimethylin) propyl group]-1-(4-fluorophenyl)-1,3-dihydro-5-cyanic acid isobenzofuran. oxalate 18.6g.Yield: 80.3%, HPLC: purity: 99.46%, R isomer: 0.42%.
Embodiment 6 (S)-(+)-1-[3-(dimethylin) propyl group]-1-(4-fluorophenyl)-1, the preparation of 3-dihydro-5-cyanic acid isobenzofuran (formula II) oxalate
In the 1000mL there-necked flask that is equipped with powerful stirring and constant pressure funnel, add 19.1g (S)-(-)-4-[4-(dimethylin)-1-(4-fluorophenyl)-1-hydroxyl butyl]-3-(methylol)-benzene nitrile, 27gK
2CO
3, adding 200mL toluene, 100mL water is opened and is stirred, and bathes cooling system to 0 ℃ with cryosel; The solution of 15g Tosyl chloride and 150mL toluene is added dropwise to reaction solution through constant pressure funnel, and 0 ℃ of temperature in the control reaction flask dropwised and controlled through TLC (thin-layer chromatography) and reacts completely in 2 hours.Reaction finishes after-filtration, the filtrating layering, and water layer is used the 100mL methylbenzene extraction once again, and the combining methylbenzene layer is with twice of 100mL water washing.To doing, adding 100mL absolute ethyl alcohol, 10g oxalic acid stir and dissolve clear postcooling crystallization, filter with the toluene underpressure distillation, and oven dry gets (S)-(+)-1-[3-(dimethylin) propyl group]-1-(4-fluorophenyl)-1,3-dihydro-5-cyanic acid isobenzofuran oxalate 20.6g.Yield: 85.8%, HPLC: purity: 99.48%, R isomer: 0.33%.
Embodiment 7 (S)-(+)-1-[3-(dimethylin) propyl group]-1-(4-fluorophenyl)-1, the preparation of 3-dihydro-5-cyanic acid isobenzofuran (formula II) oxalate
In the 1000mL there-necked flask that is equipped with powerful stirring and constant pressure funnel, add 18.5g (S)-(-)-4-[4-(dimethylin)-1-(4-fluorophenyl)-1-hydroxyl butyl]-3-(methylol)-benzene nitrile, 26.2gK
2CO
3, adding 250mL ETHYLE ACETATE, 80mL water is opened and is stirred, cooling system to 0 ℃; The solution of 14.5g methylsulfonyl chloride and 150mL ETHYLE ACETATE is added dropwise to reaction solution through constant pressure funnel, and 0 ℃ of temperature in the control reaction flask dropwised and controlled through TLC (thin-layer chromatography) and reacts completely in 2 hours.Reaction finishes after-filtration, the filtrating layering, and water layer is used the 100mL ethyl acetate extraction once again, merges organic layer, with twice of 100mL water washing.The ETHYLE ACETATE underpressure distillation to doing, is added 100mL absolute ethyl alcohol, 10g oxalic acid, stir and dissolve clear postcooling crystallization; Filter; Oven dry gets (S)-(+)-1-[3-(dimethylin) propyl group]-1-(4-fluorophenyl)-1,3-dihydro-5-cyanic acid isobenzofuran oxalate 18.9g.Yield: 81.4%, HPLC: purity: 99.74%, R isomer: 0.54%.
Embodiment 8 1-[3-(dimethylin) propyl group]-1-(4-fluorophenyl)-1, the preparation of 3-dihydro-5-cyanic acid isobenzofuran (structure I) hydrobromate:
In the 1000mL there-necked flask that is equipped with powerful stirring and constant pressure funnel, add 22.5g4-[4-(dimethylin)-1-(4-fluorophenyl)-1-hydroxyl butyl]-3-(methylol)-benzene nitrile, 33.4gK
2CO
3, adding 200mL toluene, 90mL water is opened and is stirred, and bathes cooling system to 0 ℃ with cryosel; The solution of 18g Tosyl chloride and 180mL toluene is added dropwise to reaction solution through constant pressure funnel, and 0 ℃ of temperature in the control reaction flask dropwised and controlled through TLC (thin-layer chromatography) and reacts completely in 2 hours.Reaction finishes after-filtration, the filtrating layering, and water layer is used the 100mL methylbenzene extraction once again, and the combining methylbenzene layer is with twice of 100mL water washing.The toluene underpressure distillation to dried, added 150mL ETHYLE ACETATE, drips the about 10mL of Hydrogen bromide, and stirring and crystallizing is filtered, and oven dry gets 1-[3-(dimethylin) propyl group]-1-(4-fluorophenyl)-1,3-dihydro-5-cyanic acid isobenzofuran hydrobromate 18.8g.Yield: 71.0%, HPLC: purity: 99.48%
Embodiment 9 1-[3-(dimethylin) propyl group]-1-(4-fluorophenyl)-1, the 3-dihydro-phosphatic preparation of 5-bromine isobenzofuran
In the 1000mL there-necked flask that is equipped with powerful stirring and constant pressure funnel, add 20g 4-[4-(dimethylin)-1-(4-fluorophenyl)-1-hydroxyl butyl]-3-(methylol)-bromobenzene, 25gK
2CO
3, adding 200mL toluene, 80mL water is opened and is stirred, and bathes cooling system to 0 ℃ with cryosel; The solution of 14g Tosyl chloride and 140mL toluene is added dropwise to reaction solution through constant pressure funnel, and 0 ℃ of temperature in the control reaction flask dropwised and controlled through TLC (thin-layer chromatography) and reacts completely in 2 hours.Reaction finishes after-filtration, the filtrating layering, and water layer is used the 100mL methylbenzene extraction once again, and the combining methylbenzene layer is with twice of 100mL water washing.The toluene underpressure distillation to dried, is added 80mL acetone, drip the about 10mL of SPA, stirring and crystallizing is filtered, and oven dry gets 1-[3-(dimethylin) propyl group]-1-(4-fluorophenyl)-1,3-dihydro-5-cyanic acid isobenzofuran. phosphoric acid salt 19g.Yield: 76.2%, HPLC: purity: 98.9%.
Claims (8)
1. a method for preparing citalopram or S-citalopram is characterized in that this method comprises the following steps:
(1) compound III or its salt water and with the immiscible inert solvent of water in, under the mineral alkali condition, obtain compound IV with RX reaction cyclization, RX is 0.5-5 with the molar ratio of compound III;
Z is cyanic acid, halogen, carboxamido-group, carboxyl or aldehyde radical in the formula;
RX is halo acylate VI:
Described halo acylate VI is methylsulfonyl chloride, third SULPHURYL CHLORIDE, benzene sulfonyl chloride, Tosyl chloride, p-nitrophenyl SULPHURYL CHLORIDE or 10-sulphur acyl chloride of camphor;
(2) preparation citalopram I or S-citalopram II;
, the Z of compound IV directly prepares citalopram or S-citalopram when being cyanic acid through the aftertreatment purifying; Or when the Z of compound IV is other group except that cyanic acid, need further press routine techniques conversion preparation citalopram or S-citalopram,
2. a kind of method for preparing citalopram or S-citalopram according to claim 1 is characterized in that said and the immiscible inert solvent of water is aromatic hydrocarbons, fat hydrocarbon, halogenated hydrocarbon, ethers or ester class.
3. method according to claim 2 is characterized in that said and the immiscible inert solvent of water is benzene,toluene,xylene, hexanaphthene, heptane, sherwood oil, methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, THF, methyltetrahydrofuran, ETHYLE ACETATE or ethyl ester butyl ester.
4. a kind of method for preparing citalopram or S-citalopram according to claim 1, the consumption that it is characterized in that said alkali is the effective alkali equivalent with respect to 1～20 times of the mole dosage of intermediate III.
5. method according to claim 4 is characterized in that the consumption of said alkali is the mole dosage 2-6 effective alkali equivalent doubly with respect to intermediate III.
6. according to the said method of claim 4, it is characterized in that said alkali is the carbonate of basic metal or earth alkali metal.
7. according to the said method of claim 4, it is characterized in that said alkali is one or more in Lithium Hydroxide MonoHydrate, sodium hydroxide, Pottasium Hydroxide, hydrated barta, calcium hydroxide, Quilonum Retard, yellow soda ash, salt of wormwood, lithium bicarbonate, sodium hydrogencarbonate, saleratus, Calcium hydrogen carbonate or the barium bicarbonate.
8. according to the said method of claim 1, it is characterized in that RX is 1.0-1.5 with the molar ratio of compound III.
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| CN107848958B (en) | 2015-06-09 | 2020-10-23 | 浙江华海药业股份有限公司 | Preparation method of citalopram diol intermediate |
| CN114763329A (en) * | 2021-01-14 | 2022-07-19 | 浙江华海药业股份有限公司 | Method for purifying citalopram key intermediate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4943590A (en) * | 1988-06-14 | 1990-07-24 | H. Lundbeck A/S | Pharmaceutically useful (+)-1-(3-dimethylaminopropyl)-1-(4'-fluorophenyl)-1,3-dihydrosobenzofuran-5-carbonitrile and non-toxic acid addition salts thereof |
| CN1331685A (en) * | 1999-10-25 | 2002-01-16 | H·隆德贝克有限公司 | Method for preph. of citalopram |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4943590A (en) * | 1988-06-14 | 1990-07-24 | H. Lundbeck A/S | Pharmaceutically useful (+)-1-(3-dimethylaminopropyl)-1-(4'-fluorophenyl)-1,3-dihydrosobenzofuran-5-carbonitrile and non-toxic acid addition salts thereof |
| CN1331685A (en) * | 1999-10-25 | 2002-01-16 | H·隆德贝克有限公司 | Method for preph. of citalopram |
Non-Patent Citations (2)
| Title |
|---|
| 余红霞等.西酞普兰合成路线图解.《中国医药工业杂志》.2003,第34卷(第10期),535-536. * |
| 吴秋业 等.氢溴酸西酞普兰的合成.《中国医药工业杂志》.2005,第36卷(第1期),6-8. * |
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