CN100548974C - The extraction separating method of citalopram intermediate - Google Patents
The extraction separating method of citalopram intermediate Download PDFInfo
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- CN100548974C CN100548974C CNB2007101560744A CN200710156074A CN100548974C CN 100548974 C CN100548974 C CN 100548974C CN B2007101560744 A CNB2007101560744 A CN B2007101560744A CN 200710156074 A CN200710156074 A CN 200710156074A CN 100548974 C CN100548974 C CN 100548974C
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- hydroxybutyl
- fluorophenyl
- hydroxymethyl
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Abstract
The invention discloses a kind of extraction separating method of citalopram intermediate.Comprise the steps: 1) with acid anhydrides to racemization or optically pure 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile carries out derivatize; 2) alkaline aqueous solution with normal hexane or toluene and pH＞9 is an extraction agent, to 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile acetic ester carries out multi-stage solvent extraction with its derivative mixture to be separated, on mutually directly underpressure distillation obtain racemization or optically pure 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile acetic ester; Following to basic hydrolysis, toluene extraction, dehydration back underpressure distillation obtains racemization or optically pure 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile, the present invention can effectively separate racemization or optically pure 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile and its acetate mixture, the rate of recovery and product purity are all very high, technology is simple, running cost is low, and extraction agent is cheap and easy to get.
Description
Technical field
The present invention relates to a kind of extraction separating method of citalopram intermediate.
Background technology
4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile is the important intermediate of preparation citalopram (citalopram), has following structure:
Citalopram is an anti-depression drug of selling known structure for many years on the market, and it can selectivity suppress the re-uptake of 5-oxyamine (5-HT), so has antidepressant activity.Studies show that the S-enantiomer of citalopram has more significant curative effect than R-enantiomer.
The approach that obtains the S-enantiomer of citalopram mainly is asymmetric synthetic and mesotomy, and early stage research mainly concentrates on chemosynthesis and fractionation.Biological in recent years preparation method comes into one's own gradually, and particularly the enzymatic application of organic phase makes 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile enzyme process is synthetic to have more practicality with fractionation.Organic phase enzymatic process commonly used comprises that lipase-catalyzed selective esterification splits and lipase-catalyzed asymmetric alcoholysis splits, no matter adopt which kind of method, obtain highly purified 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile, just must carry out 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-separation of 3-(hydroxymethyl) benzonitrile and acetic ester thereof, and the two character is more close, directly carry out the routine separation and be difficult to reach the ideal effect, therefore, need be to 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile carries out separating behind the derivatize.Number of patent application is that the patent of CN1918112 has related to and utilizes the precipitation liberation method to carry out isolating method.
Summary of the invention
The extraction separating method that the purpose of this invention is to provide a kind of efficient, practical, citalopram intermediate that cost is low.
The extraction separating method of citalopram intermediate is characterized in that comprising the steps:
(1) with acid anhydrides and mol ratio be 9: 1 to 1: 9 racemization or optically pure 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile and racemization or optically pure 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-acetic ester of 3-(hydroxymethyl) benzonitrile carries out derivative reaction in solvent, underpressure distillation removes solvent, obtain racemization or optically pure 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile derivative and racemization or optically pure 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile acetate mixture, temperature of reaction is 0～70 ℃, and the reaction times is 0.5～10 hour;
(2) with above-mentioned racemization or optically pure 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile acetic ester and racemization or optically pure 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-mixture of 3-(hydroxymethyl) benzonitrile derivative directly adds in the extraction agent, fully vibration, mix, standing demix, after treating that two-phase is clarified fully up and down, separate two-phase up and down, on mutually for being dissolved with racemization or optically pure 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-normal hexane or the toluene of 3-(hydroxymethyl) benzonitrile acetic ester, down mutually for being dissolved with racemization or optically pure 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-water of 3-(hydroxymethyl) benzonitrile derivative, carry out multi-stage solvent extraction, extraction agent is the alkaline aqueous solution of normal hexane or toluene and pH＞9, wherein, the volume ratio of the alkaline aqueous solution of normal hexane or toluene and pH＞9 is 9: 1 to 1: 9, and extraction temperature is 0～60 ℃;
(3) will be added to the alkali lye hydrolysis down, and make extraction agent with toluene, and carry out back extraction, and anhydrate with anhydrous sodium sulphate, underpressure distillation obtains racemization or optically pure 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile;
(4) will go up mutually directly underpressure distillation and obtain racemization or optically pure 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile acetic ester.
Described racemization or optically pure 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-mol ratio of 3-(hydroxymethyl) benzonitrile and its acetate mixture is preferably 8: 2 to 2: 8.Temperature of reaction is preferably 10～60 ℃.Reaction times is preferably 1～9 hour.The volume ratio of the alkaline aqueous solution of normal hexane or toluene and pH＞9 is preferably 8: 2 to 2: 8.Extraction temperature is preferably 10～50 ℃.
The structural formula of described acid anhydrides is general formula 1 or general formula 2:
Wherein, X is-(CHR
3)
n-, n is 0-2.R
1, R
2, R
3Independently be selected from hydrogen, C
1-6-alkyl.
Acid anhydrides is Succinic anhydried, 2-ethyl succinic acid acid anhydride, MALEIC ANHYDRIDE, 2-methyl, 4-hexyl Pyroglutaric acid, adipic anhydride, Tetra hydro Phthalic anhydride, 2-ethyl Tetra hydro Phthalic anhydride or 4-sec.-propyl Tetra hydro Phthalic anhydride.Solvent is dioxane, tetrahydrofuran (THF), toluene, methylene dichloride, isopropyl ether or acetonitrile.The alkaline aqueous solution of pH＞9 is sodium hydroxide, yellow soda ash, ammoniacal liquor, sodium-acetate or Sodium phosphate dibasic.
The present invention can effectively separate racemization or optically pure 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile and its acetate mixture, the rate of recovery and product purity are all very high, technology is simple, and running cost is low, and extraction agent is cheap and easy to get.
Description of drawings
Accompanying drawing is racemization or optically pure 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile derivative and three grades of extraction process flow figure of acetate mixture (three grades of extractions are example) thereof.
Embodiment
Embodiment 1
Be racemization 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl of 9: 1 with mol ratio]-3-(hydroxymethyl) benzonitrile and acetic ester 72.6g thereof add in the dioxane.Add Succinic anhydried 11.0g, 60 ℃ are reacted 1h down.Underpressure distillation obtains racemization 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl after removing solvent]-3-(hydroxymethyl) benzonitrile Succinic anhydried derivative and racemization 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile acetic ester.
Extraction agent is each 1L of sodium acetate soln of normal hexane and pH=9.2, under 10 ℃ with racemization 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile Succinic anhydried derivative and racemization 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile acetic ester adds in the extraction agent, fully vibration, leave standstill 30min, separate two-phase up and down, and carry out secondary under the same conditions respectively, after three grades of extractions, to go up and use anhydrous sodium sulfate dehydration mutually, 40 ℃ of following underpressure distillation, obtain racemization 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile acetic ester, the rate of recovery is 91.2%, and purity is 90.8%.Under be added to the alkali lye hydrolysis, strip with toluene, compare (organic phase/water)=1: 1, to the anti-stripping agent anhydrous sodium sulfate dehydration, 40 ℃ of following underpressure distillation, obtain racemization 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile, its rate of recovery is 89.2%, purity is 96.8%.
Embodiment 2
With equimolar racemization 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile and acetic ester 31.8g thereof add in the tetrahydrofuran (THF).Add Tetra hydro Phthalic anhydride 8.6g, 70 ℃ are reacted 10h down.Underpressure distillation obtains racemization 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl after removing solvent]-3-(hydroxymethyl) benzonitrile Tetra hydro Phthalic anhydride derivative and racemization 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile acetic ester.
Extraction agent is the ammonia soln of toluene and pH=11, and the extraction agent cumulative volume is 1L, and each component volume ratio is the ammonia soln=9: 1 of toluene: pH=11.Add racemization 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile Tetra hydro Phthalic anhydride derivative and racemization 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile acetic ester.After three grades of 10 ℃ of continuous extractions, to go up and use anhydrous sodium sulfate dehydration mutually,, obtain racemization 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl 40 ℃ of following underpressure distillation]-3-(hydroxymethyl) benzonitrile acetic ester, the rate of recovery is 85.2%, and purity is 95.8%.Under be added to the alkali lye hydrolysis, strip with toluene, compare (organic phase/water)=1: 1, to the anti-stripping agent anhydrous sodium sulfate dehydration, 40 ℃ of following underpressure distillation, obtain racemization 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile, its rate of recovery is 92.3%, purity is 92.8%.
Embodiment 3
Be S-4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl of 1: 9 with mol ratio]-3-(hydroxymethyl) benzonitrile and R-4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile acetic ester 145.3g adds in the acetonitrile.Add 2-ethyl succinic acid acid anhydride 20.6g, 0 ℃ is reacted 0.5h down.Underpressure distillation obtains S-4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl after removing solvent]-the 2-ethyl succinic acid acid anhydride derivative and R-4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl of 3-(hydroxymethyl) benzonitrile]-3-(hydroxymethyl) benzonitrile acetic ester.
Extraction agent is the sodium carbonate solution of normal hexane and pH=9.5, and the extraction agent cumulative volume is 1.5L, and each ratio of component is the sodium carbonate solution=1: 9 of normal hexane: pH=9.5.After three grades of 0 ℃ of following continuous extractions, handle by the method for embodiment 1.R-4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) the benzonitrile rate of recovery is 90.9%, purity is 98.6%; S-4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) the benzonitrile acetic ester rate of recovery is 92.1%, purity is 94.0%.
Embodiment 4
Be R-4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl of 8: 2 with mol ratio]-3-(hydroxymethyl) benzonitrile and S-4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile acetic ester 36.3g adds in the toluene.Add Pyroglutaric acid 6.6g, 50 ℃ are reacted 9h down.Underpressure distillation obtains R-4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl after removing solvent]-3-(hydroxymethyl) benzonitrile Pyroglutaric acid derivative and S-4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile acetic ester.
Extraction agent is the sodium acetate soln of toluene and pH=9.5, cumulative volume is 0.5L, the sodium acetate soln of toluene: pH=9.5=8: 2, under 40 ℃, carry out the secondary extraction continuously, to go up and use anhydrous sodium sulfate dehydration mutually,, obtain S-4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl 40 ℃ of following underpressure distillation]-3-(hydroxymethyl) benzonitrile acetic ester, the rate of recovery is 93.1%, and purity is 92.1%.Under be added to the alkali lye hydrolysis, strip with toluene, compare (organic phase/water)=1: 1, to the anti-stripping agent anhydrous sodium sulfate dehydration, 40 ℃ of following underpressure distillation, obtain R-4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile, its rate of recovery is 89.9%, purity is 99.0%.
Embodiment 5
Be racemization 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl of 2: 8 with mol ratio]-3-(hydroxymethyl) benzonitrile and R-4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile acetic ester 290.4g adds in the methylene dichloride.Add the 2-methyl, 4-hexyl Pyroglutaric acid 44.0g, 50 ℃ are reacted 6h down.Underpressure distillation obtains racemization 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl after removing solvent]-the 2-methyl of 3-(hydroxymethyl) benzonitrile, 4-hexyl Pyroglutaric acid derivative and R-4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile acetic ester.
Get the disodium phosphate soln that agent is normal hexane and pH=10, the extraction agent cumulative volume is 2L, be in a ratio of normal hexane: the disodium phosphate soln of pH=10=2: 8, under 60 ℃, carry out the secondary extraction, to go up and use anhydrous sodium sulfate dehydration mutually,, obtain R-4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl 40 ℃ of following underpressure distillation]-3-(hydroxymethyl) benzonitrile acetic ester, the rate of recovery is 94.1%, and purity is 96.0%.Under be added to the alkali lye hydrolysis, strip with toluene, compare (organic phase/water)=1: 1, to the anti-stripping agent anhydrous sodium sulfate dehydration, 40 ℃ of following underpressure distillation, obtain racemization 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile, its rate of recovery is 87.9%, purity is 95.6%.
Embodiment 6
Be S-4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl of 6: 4 with mol ratio]-3-(hydroxymethyl) benzonitrile and racemization 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile acetic ester 14.5g adds in the isopropyl ether.Add adipic anhydride 3.4g, 30 ℃ are reacted 7h down.Underpressure distillation remove obtain behind the solvent S-4-[4-(dimethylamino-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile adipic anhydride derivative and racemization 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile acetic ester.
Extraction agent is the sodium hydroxide solution of toluene and pH=9.5, cumulative volume is 0.2L, the sodium hydroxide solution of toluene: pH=9.5=7: 3, under 50 ℃, carry out the secondary extraction continuously, to go up and use anhydrous sodium sulfate dehydration mutually,, obtain racemization 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl 40 ℃ of following underpressure distillation]-3-(hydroxymethyl) benzonitrile acetic ester, the rate of recovery is 91.9%, and purity is 94.9%.Under be added to the alkali lye hydrolysis, strip with toluene, compare (organic phase/water)=1: 1, to the anti-stripping agent anhydrous sodium sulfate dehydration, 40 ℃ of following underpressure distillation, obtain S-4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile, its rate of recovery is 90.3%, purity is 99.1%.
Embodiment 7
Be R-4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl of 6: 4 with mol ratio]-3-(hydroxymethyl) benzonitrile and S-4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile acetic ester 24.5g adds in the isopropyl ether.Add 2-ethyl Tetra hydro Phthalic anhydride 6.4g, 30 ℃ are reacted 8h down.Underpressure distillation obtains R-4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl after removing solvent]-3-(hydroxymethyl) benzonitrile 2-ethyl Tetra hydro Phthalic anhydride derivative and S-4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile acetic ester.
Extraction agent is the sodium hydroxide solution of toluene and pH=10, cumulative volume is 0.4L, the sodium hydroxide solution of toluene: pH=10=7: 3, under 0 ℃, carry out the secondary extraction continuously, to go up and use anhydrous sodium sulfate dehydration mutually,, obtain S-4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl 40 ℃ of following underpressure distillation]-3-(hydroxymethyl) benzonitrile acetic ester, the rate of recovery is 90.9%, and purity is 94.3%.Under be added to the alkali lye hydrolysis, strip with toluene, compare (organic phase/water)=1: 1, to the anti-stripping agent anhydrous sodium sulfate dehydration, 40 ℃ of following underpressure distillation, obtain R-4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile, its rate of recovery is 91.9%, purity is 99.0%.
Embodiment 8
Be S-4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl of 7: 3 with mol ratio]-3-(hydroxymethyl) benzonitrile and racemization 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile acetic ester 26.5g adds in the acetonitrile.Add 4-sec.-propyl Tetra hydro Phthalic anhydride 8.4g, 20 ℃ are reacted 5h down.Underpressure distillation obtains S-4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl after removing solvent]-3-(hydroxymethyl) benzonitrile adipic anhydride derivative and racemization 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile acetic ester.
Extraction agent is the sodium hydroxide solution of toluene and pH=11, cumulative volume is 0.2L, the sodium hydroxide solution of toluene: pH=11=3: 7, under 10 ℃, carry out the secondary extraction continuously, to go up and use anhydrous sodium sulfate dehydration mutually,, obtain racemization 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl 40 ℃ of following underpressure distillation]-3-(hydroxymethyl) benzonitrile acetic ester, the rate of recovery is 92.9%, and purity is 93.9%.Under be added to the alkali lye hydrolysis, strip with toluene, compare (organic phase/water)=1: 1, to the anti-stripping agent anhydrous sodium sulfate dehydration, 40 ℃ of following underpressure distillation, obtain S-4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile, its rate of recovery is 96.3%, purity is 98.1%.
Claims (8)
1. the extraction separating method of a citalopram intermediate is characterized in that comprising the steps:
(1) with acid anhydrides and mol ratio be 9: 1 to 1: 9 racemization or optically pure 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile and racemization or optically pure 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-acetic ester of 3-(hydroxymethyl) benzonitrile carries out derivative reaction in solvent, underpressure distillation removes solvent, obtain racemization or optically pure 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile derivative and racemization or optically pure 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile acetate mixture, temperature of reaction is 0～70 ℃, and the reaction times is 0.5～10 hour;
(2) with above-mentioned racemization or optically pure 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile acetic ester and racemization or optically pure 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-mixture of 3-(hydroxymethyl) benzonitrile derivative directly adds in the extraction agent, fully vibration, mix, standing demix, after treating that two-phase is clarified fully up and down, separate two-phase up and down, on mutually for being dissolved with racemization or optically pure 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-normal hexane or the toluene of 3-(hydroxymethyl) benzonitrile acetic ester, down mutually for being dissolved with racemization or optically pure 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-water of 3-(hydroxymethyl) benzonitrile derivative, carry out multi-stage solvent extraction, extraction agent is the alkaline aqueous solution of normal hexane or toluene and pH＞9, wherein, the volume ratio of the alkaline aqueous solution of normal hexane or toluene and pH＞9 is 9: 1 to 1: 9, and extraction temperature is 0～60 ℃;
(3) will be added to the alkali lye hydrolysis down, and make extraction agent with toluene, and carry out back extraction, and anhydrate with anhydrous sodium sulphate, underpressure distillation obtains racemization or optically pure 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile;
(4) will go up mutually directly underpressure distillation and obtain racemization or optically pure 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile acetic ester;
Described acid anhydrides is Succinic anhydried, 2-ethyl succinic acid acid anhydride, MALEIC ANHYDRIDE, 2-methyl, 4-hexyl Pyroglutaric acid, adipic anhydride, Tetra hydro Phthalic anhydride, 2-ethyl Tetra hydro Phthalic anhydride or 4-sec.-propyl Tetra hydro Phthalic anhydride.
2. the extraction separating method of a kind of citalopram intermediate according to claim 1 is characterized in that described racemization or optically pure 4-[4-(dimethylamino)-1-(4 '-fluorophenyl)-1-hydroxybutyl]-mol ratio of 3-(hydroxymethyl) benzonitrile and its acetate mixture is 8: 2 to 2: 8.
3. the extraction separating method of a kind of citalopram intermediate according to claim 1 is characterized in that described solvent is dioxane, tetrahydrofuran (THF), toluene, methylene dichloride, isopropyl ether or acetonitrile.
4. the extraction separating method of a kind of citalopram intermediate according to claim 1 is characterized in that described temperature of reaction is 10～60 ℃.
5. the extraction separating method of a kind of citalopram intermediate according to claim 1 is characterized in that the described reaction times is 1～9 hour.
6. the extraction separating method of a kind of citalopram intermediate according to claim 1, the alkaline aqueous solution that it is characterized in that described pH＞9 is sodium hydroxide, yellow soda ash, ammoniacal liquor, sodium-acetate or Sodium phosphate dibasic.
7. the extraction separating method of a kind of citalopram intermediate according to claim 1, the volume ratio that it is characterized in that the alkaline aqueous solution of described normal hexane or toluene and pH＞9 is 8: 2 to 2: 8.
8. the extraction separating method of a kind of citalopram intermediate according to claim 1 is characterized in that described extraction temperature is 10～50 ℃.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4650884A (en) * | 1984-08-06 | 1987-03-17 | H. Lundbeck A/S | Novel intermediate and method for its preparation |
| EP1412341B1 (en) * | 2001-06-25 | 2004-12-08 | H. Lundbeck A/S | Process for the preparation of racemic citalopram and/or s- or r-citalopram by separation of a mixture of r- and s-citalopram |
| CN1675144A (en) * | 2002-08-12 | 2005-09-28 | H·隆德贝克有限公司 | Method for the separation of intermediates which may be used for the preparation of escitalopram |
| CN1769265A (en) * | 2005-09-29 | 2006-05-10 | 浙江大学 | Alpha-cyano benzalcohol and alpha-cyano benzalcohol acetate mixture extraction and separation method |
| CN1918112A (en) * | 2004-02-12 | 2007-02-21 | H·隆德贝克有限公司 | Method for the separation of intermediates which may be used for the preparation of escitalopram |
-
2007
- 2007-10-11 CN CNB2007101560744A patent/CN100548974C/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4650884A (en) * | 1984-08-06 | 1987-03-17 | H. Lundbeck A/S | Novel intermediate and method for its preparation |
| EP1412341B1 (en) * | 2001-06-25 | 2004-12-08 | H. Lundbeck A/S | Process for the preparation of racemic citalopram and/or s- or r-citalopram by separation of a mixture of r- and s-citalopram |
| CN1675144A (en) * | 2002-08-12 | 2005-09-28 | H·隆德贝克有限公司 | Method for the separation of intermediates which may be used for the preparation of escitalopram |
| CN1918112A (en) * | 2004-02-12 | 2007-02-21 | H·隆德贝克有限公司 | Method for the separation of intermediates which may be used for the preparation of escitalopram |
| CN1769265A (en) * | 2005-09-29 | 2006-05-10 | 浙江大学 | Alpha-cyano benzalcohol and alpha-cyano benzalcohol acetate mixture extraction and separation method |
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