CN101560199B - Preparation method of Escitalopram - Google Patents
Preparation method of Escitalopram Download PDFInfo
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- CN101560199B CN101560199B CN 200810104149 CN200810104149A CN101560199B CN 101560199 B CN101560199 B CN 101560199B CN 200810104149 CN200810104149 CN 200810104149 CN 200810104149 A CN200810104149 A CN 200810104149A CN 101560199 B CN101560199 B CN 101560199B
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- 0 C*(C)CCC[C@@]1(c(cc2)ccc2N)OCc2cc(*)ccc12 Chemical compound C*(C)CCC[C@@]1(c(cc2)ccc2N)OCc2cc(*)ccc12 0.000 description 1
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Abstract
The invention relates to a preparation method of Escitalopram for resisting depression, wherein a key intermediate shown in formula (2) is adopted. The preparation method has the advantages of moderate reaction conditions and high yield, and is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of preparation method of antidepressant drug escitalopram, comprise the step that makes the key intermediate closed loop, becomes ether.
Background technology
Selectivity 5-HT reuptake inhibitor (SSRIs) is the novel antidepressive in the whole world of having passed unimpeded since the nineties, this class medicine is used the more Sertraline that has at present, paroxetine, fluoxetine, fluvoxamine, citalopram (Citalopram, raceme for escitalopram) etc., its antidepressant effect is considered to by the re-uptake of the serotoninergic neuron in the inhibition central nervous system to serotonin, owing to re-uptake reduces, the activity of increase serotonin energy path thereby the outer serotonin neurotransmitter concentration of neurocyte raises.It is to cholinergic receptor, histamine and alpha-adrenergic receptor unrestraint effect.
Citalopram was ratified listing in 1989 first in Denmark, and on July 17th, 1998, the drugs approved by FDA citalopram went on the market in the U.S..Citalopram is the purest SSRIs, and it is the highest in similar drugs to the relative selectivity that 5-HT produces inhibition again; Seldom cause significant drug interaction, untoward reaction seldom; With Sertraline, paroxetine, fluoxetine, fluvoxamine is compared, and citalopram has significantly potent, low toxicity advantage, and it has also become antidepressant desirable choice drug very soon.
Escitalopram (Escitalopram) is the dextrorotatory form of citalopram, and its levo form is without substantial activity.Escitalopram is gone on the market in the U.S. in 2002 by Denmark Ling Bei pharmaceutical factory.Escitalopram will be the renewal product of other thymoleptic and even citalopram.
Escitalopram has following features as antidepressant drug:
The first, as the SSRIs antidepressant time, three advantages is arranged: 1. therapeutic index is high; 2. adverse reaction rate is low; 3. action spectrum is wide, and patient and the depressed associated disorders obsession (OCD) invalid to tricyclic antidepressants are all effective.
Second, escitalopram is compared with other SSRIs, it possesses following advantage: 1. simple SSRI, and it is the highest in similar drugs to the relative selectivity that 5-HT produces inhibition again, to cholinergic receptor, Histamine Receptors and alpha-adrenergic receptor unrestraint effect; 2. clinical effective rate approximately 70%, strong drug action; 3. untoward reaction seldom, incidence approximately 5%; Do not affect conducting system of heart and blood pressure.4. on average eliminating the transformation period is 33 hours, and once a day medication is the produce effects fruit, has made things convenient for patient's medication.
The 3rd, escitalopram is compared with its raceme, and the simplification of activeconstituents obviously will be saved the clinical treatment cost of half, the untoward reaction that dosage reduces by half and brings eliminating the non-activity levo form.
The 4th, there are many front patients of growing up of dysthymia disorders that suffer from the statistics demonstration, and uses the escitalopram oral liquid and helps to improve their doctor's advice compliance.
Estimate that according to the World Health Organization whole world approximately has 500,000,000 people just suffering from various mental disorderes, by modern process, the importance of dysthymia disorders also will continue to increase, estimation is after 25 years, about 10% of the total burden of disease will be accounted for, in a sense, dysthymia disorders is cross-centennial challenge, will become the 21 century mankind's main killer.And the curative effect of the recovery down of the drug selectivity serotonin aspect the treatment of dysthymia disorders (SSRI) certainly, and side reaction is few, is subject to doctor and patient's welcome.Therefore escitalopram will bring preferably economic benefit and social benefit, and its structure is shown below:
By inquiry all documents about escitalopram and citalopram, examined all about compound formula (II) closed loop, become ether to obtain the literature method of compound formula (I), have no the report relevant with similar with the inventive method.Therefore, involved in the present invention with compound formula (II) closed loop, become ether to obtain the special methods of compound formula (I), have very strong novelty.
The purpose of this invention is to provide the new preparation method of the high escitalopram of a kind of yield.
Summary of the invention
This patent invention provides the preparation method of compound shown in the formula (I).Detailed synthetic equation is as follows:
Being characterized as of the method: add a certain amount of certain or multi-solvents, substrate (formula II) and catalyzer in the reaction unit.Be heated to certain temperature, reaction regular hour, stopped reaction.Cooling, suction filtration, filtrate is used solution washing, drying, suction filtration screws out solvent, obtains oily matter, and the underpressure distillation of condition of high vacuum degree oil pump obtains colorless oil and is target product (formula I).
Difference according to the catalyst type that uses can be divided into method one, method two to the method that the present invention relates to, and better narrates the feature of the inventive method.Method one is the method that catalyzer prepares compound formula (I) for resin; Method two is that binary or multi-element, inorganic acid hydrogen salt are the method that catalyzer prepares compound formula (I).
Being characterized as of method one: in reaction unit, add by solvent claimed in claim 4, substrate (formula II) and resin catalyst claimed in claim 2.Be heated to temperature range claimed in claim 6 and time range internal reaction claimed in claim 8, reaction is finished.Stopped reaction, cooling, suction filtration, filtrate is used the saturated common salt water washing, drying, suction filtration screws out solvent, obtains oily matter, and the underpressure distillation of condition of high vacuum degree oil pump obtains colorless oil and is target product (formula I).
Being characterized as of method two: in reaction unit, add by solvent claimed in claim 5, substrate (formula II) and hydrogen salt catalyzer claimed in claim 3.Be heated to the reaction of temperature range claimed in claim 7 and time range claimed in claim 8, react complete.Stopped reaction, cooling, suction filtration, filtrate is used the saturated common salt water washing, drying, suction filtration screws out solvent, obtains oily matter, and the underpressure distillation of condition of high vacuum degree oil pump obtains colorless oil and is target product (formula I).
The inventive method is simple to operate, and yield is higher, is fit to suitability for industrialized production.
Of the present invention open in detail:
Disclosing in detail of method one:
Reaction solvent is methylene dichloride, chloroform, 1 more preferably, 2-ethylene dichloride, tetracol phenixin.The solid-to-liquid ratio scope of solvent and substrate, more preferably 5: 1.
Reaction is with catalyzer more preferably strongly acidic styrene type cation exchange resin (001 * 7) and strongly-acid phenolic type cation exchange resin (021 * 8).
Range of reaction temperature, more preferably: 20-85 ℃.
Reaction time range, more preferably: 2-36 hour.
Disclosing in detail of method two:
Reaction solvent is chlorobenzene, dichlorobenzene more preferably, the solid-to-liquid ratio scope of solvent and substrate, more preferably 5: 1.
Reaction is with catalyzer more preferably sodium pyrosulfate, sal enixum, SODIUM PHOSPHATE, MONOBASIC.
Range of reaction temperature, more preferably: 90-190 ℃.
Reaction time range, more preferably: 2-36 hour.
Embodiment
Following embodiment is to describe in detail the present invention, and unrestricted the present invention.
Embodiment 1
The 1L there-necked flask adds 60g substrate (formula II) and 300ml methylene dichloride, adds the strongly acidic styrene type cation exchange resin (001 * 7) of catalytic amount, back flow reaction 26 hours, stopped reaction.Cooling, suction filtration, drip washing obtains filtrate.Filtrate is used the saturated common salt water washing, drying, and suction filtration screws out solvent, obtains oily matter, and condition of high vacuum degree oil pump (0.2mm Hg) underpressure distillation obtains colorless oil 52g, yield 92%.
Embodiment 2
The 2L there-necked flask, add 120g substrate (formula II) and 600ml chloroform and 1,2-methylene dichloride mixed solvent (volume ratio is: 5: 3), add the strongly acidic styrene type cation exchange resin (001 * 7) of catalytic amount and the strongly-acid phenolic type cation exchange resin (021 * 8) of catalytic amount, backflow was answered 20 hours, stopped reaction.Cooling, suction filtration, drip washing obtains filtrate.Filtrate is used the saturated common salt water washing, drying, and suction filtration screws out solvent, obtains oily matter, and condition of high vacuum degree oil pump (0.2mm Hg) underpressure distillation obtains colorless oil 107.4g, yield 92%.
Embodiment 3
The 2L there-necked flask, add 120.0g substrate (formula II) and 600ml chloroform and tetracol phenixin mixed solvent (volume ratio is 1: 1), the strongly acidic styrene type cation exchange resin (001 * 7) that adds catalytic amount, 50-60 ℃ was reacted stopped reaction 16 hours.Cooling, suction filtration, drip washing obtains filtrate.Filtrate is used the saturated common salt water washing, drying, and suction filtration screws out solvent, obtains oily matter, and condition of high vacuum degree oil pump (0.2mm Hg) underpressure distillation obtains colorless oil 108.6g, yield 96%.
Embodiment 4
The 20L reactor adds 1200.0g substrate (formula II) and 6000ml chloroform and 1,2-ethylene dichloride (volume ratio is 1: 5), the strongly-acid phenolic type cation exchange resin (021 * 8) of catalytic amount, and 30-50 ℃ was reacted stopped reaction 3 hours.Cooling, suction filtration, drip washing obtains filtrate.Filtrate is used the saturated common salt water washing, drying, and suction filtration screws out solvent, obtains oily matter, and condition of high vacuum degree oil pump (0.2mm Hg) underpressure distillation obtains colorless oil 1090.1g, yield 96%.
Embodiment 5
The 1L there-necked flask adds 80g substrate (formula II) and 400ml dichlorobenzene, adds the sodium pyrosulfate of catalytic amount, and 175-185 ℃ was reacted fraction water device water-dividing in the reaction, stopped reaction 6 hours.Cooling, suction filtration, drip washing obtains filtrate.Filtrate is used the saturated common salt water washing, drying, and suction filtration screws out solvent, obtains oily matter, and condition of high vacuum degree oil pump (0.2mm Hg) underpressure distillation obtains colorless oil 69.4g, yield 92%.
Embodiment 6
The 2L there-necked flask adds 250g substrate (formula II) and 1250ml chlorobenzene, adds the sal enixum of catalytic amount and the sodium hydrogen phosphate of catalytic amount, and 70-85 ℃ was reacted stopped reaction 36 hours.Cooling, suction filtration, drip washing obtains filtrate.Filtrate is used the saturated common salt water washing, drying, and suction filtration screws out solvent, obtains oily matter, and condition of high vacuum degree oil pump (0.2mm Hg) underpressure distillation obtains colorless oil 170.3g, yield 72%.
Embodiment 7
The 2L there-necked flask, add 250g substrate (formula II) and 1250ml chlorobenzene and dichlorobenzene mixed solvent (volume ratio is 20: 1), add the sal enixum of catalytic amount and the Sodium phosphate dibasic of catalytic amount, 120-130 ℃ was reacted 2 hours, fraction water device water-dividing in the reaction, stopped reaction.Cooling, suction filtration, drip washing obtains filtrate.Filtrate is used the saturated common salt water washing, drying, and suction filtration screws out solvent, obtains oily matter, and condition of high vacuum degree oil pump (0.2mm Hg) underpressure distillation obtains colorless oil 225.8g, yield 96%.
Claims (9)
1. the preparation method of an escitalopram is characterized by in certain solvent, under certain temperature, uses catalyzer, and make its key intermediate formula (II) closed loop, become ether,
Formula (II)
Catalyzer is acidic resins.
2. method according to claim 1 is characterized in that catalyzer is preferably strongly acidic styrene type cation exchange resin, the strongly-acid acrylic acid type cation exchange resin, the strongly-acid phenolic type cation exchange resin, strongly-acid epoxy cation exchange resin, strongly-acid vinylpyridine cation exchange resin, strongly-acid urea aldehyde cation exchange resin, strongly-acid vinyl chloride Zeo-karb, the slightly acidic styrene type cation exchange resin, acidulous acrylic acid's cation exchange resin, the slightly acidic phenolic type cation exchange resin, slightly acidic epoxy cation exchange resin, slightly acidic vinylpyridine cation exchange resin, slightly acidic urea aldehyde cation exchange resin, slightly acidic vinyl chloride Zeo-karb.
3. according to claim 1 and 2, it is characterized in that catalyzer is preferably strongly acidic styrene type cation exchange resin 001 * 7 and strongly-acid phenolic type cation exchange resin 021 * 8.
4. method according to claim 1, it is characterized in that reaction solvent is one or more mixtures in a halohydrocarbon, dihalo hydrocarbon and the polyhalohydrocarbon of C1-C5, temperature of reaction is 30-250 ℃, and the reaction times is 0.5-100 hour, and the solid-to-liquid ratio of solvent and substrate is 1: 1-20: 1.
5. according to claim 4, reaction solvent is preferably methylene dichloride, chloroform, 1,2-ethylene dichloride, tetracol phenixin, and temperature of reaction is preferably 90-190 ℃, and the reaction times is preferably 2-36 hour, and the solid-to-liquid ratio of solvent and substrate is preferably 5: 1.
6. the preparation method of an escitalopram is characterized by in certain solvent, under certain temperature, uses catalyzer, and make its key intermediate formula (II) closed loop, become ether,
Formula (II)
Catalyzer is in binary and the multi-element, inorganic acid hydrogen salt, the mixture of one or more in hydrosulfate, hydrosulphite, pyrosulfuric acid hydrogen salt, dithionic acid hydrogen salt, hydrophosphate, the phosphorous acid hydrogen salt, the metal ion in the salt are basic metal, alkaline-earth metal, transition metal and third and fourth main group element metal ion.
7. method according to claim 6 is characterized in that catalyzer preferably sulfuric acid hydrogen sodium, sal enixum, SODIUM PHOSPHATE, MONOBASIC.
8. method according to claim 6, it is characterized in that reaction solvent is one or more the mixture in aromatic hydrocarbons, a halogenated aryl hydrocarbon, dihalo aromatic hydrocarbons and the many halogenated aryl hydrocarbons, temperature of reaction is-20-180 ℃, reaction times is 0.5-100 hour, and the solid-to-liquid ratio of solvent and substrate is 1: 1-20: 1.
9. according to claim 8, reaction solvent is preferably chlorobenzene, dichlorobenzene, and temperature of reaction is preferably 20-85 ℃, preferably 2-36 hour reaction times, the solid-to-liquid ratio of solvent and substrate preferably 5: 1.
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| CN 200810104149 CN101560199B (en) | 2008-04-16 | 2008-04-16 | Preparation method of Escitalopram |
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| CN 200810104149 CN101560199B (en) | 2008-04-16 | 2008-04-16 | Preparation method of Escitalopram |
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Citations (4)
| 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 |
| CN1520405A (en) * | 2001-06-25 | 2004-08-11 | H��¡�±�������˾ | Process for prepn. of racemic citalopram and/or S-or R-citalopram by separation of mixture of R-and S-citalopram |
| WO2005012278A2 (en) * | 2003-07-25 | 2005-02-10 | Meditab Specialities Pvt. Ltd | Process for purifying citalopram using polybasic acids |
| WO2007012954A1 (en) * | 2005-07-27 | 2007-02-01 | Aurobindo Pharma Limited | An improved process for the preparation of escitalopram |
-
2008
- 2008-04-16 CN CN 200810104149 patent/CN101560199B/en active Active
Patent Citations (4)
| 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 |
| CN1520405A (en) * | 2001-06-25 | 2004-08-11 | H��¡�±�������˾ | Process for prepn. of racemic citalopram and/or S-or R-citalopram by separation of mixture of R-and S-citalopram |
| WO2005012278A2 (en) * | 2003-07-25 | 2005-02-10 | Meditab Specialities Pvt. Ltd | Process for purifying citalopram using polybasic acids |
| WO2007012954A1 (en) * | 2005-07-27 | 2007-02-01 | Aurobindo Pharma Limited | An improved process for the preparation of escitalopram |
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Owner name: HUNAN DONGTING PHARMACEUTICAL CO., LTD. Free format text: FORMER OWNER: DEZHONG WANQUAN PHARMACEUTICALS TECH. DEV. CO., LTD., BEIJING Effective date: 20140620 |
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Free format text: CORRECT: ADDRESS; FROM: 100097 HAIDIAN, BEIJING TO: 415001 CHANGDE, HUNAN PROVINCE |
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Effective date of registration: 20140620 Address after: 375 No. 415001 Hunan province Changde City Deshan economic and Technological Development Zone Avenue Patentee after: Hunan Dongting Pharmaceutical Co., Ltd. Address before: 100097 Beijing city Haidian District Sijiqing Wanquan Zhuang 3 Building Patentee before: Dezhong Wanquan Pharmaceuticals Tech. Dev. Co., Ltd., Beijing |