CN102190641A - Preparation method for citalopram and key intermediate of escitalopram - Google Patents
Preparation method for citalopram and key intermediate of escitalopram Download PDFInfo
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- CN102190641A CN102190641A CN2011100710878A CN201110071087A CN102190641A CN 102190641 A CN102190641 A CN 102190641A CN 2011100710878 A CN2011100710878 A CN 2011100710878A CN 201110071087 A CN201110071087 A CN 201110071087A CN 102190641 A CN102190641 A CN 102190641A
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Abstract
The invention discloses a novel preparation method for citalopram and a key intermediate of escitalopram. The method comprises the following steps: taking phthalic anhydride as the initial raw material, and successively carrying out a Friedel-Crafts reaction, a reaction that catalyzes an acid into an ester, a reduction reaction, and a cyclization reaction so as to obtain the intermediate, that is, 5-substituted-1-(4-fluorophenyl)-1.3-isobenzofu rancarbonitrile derivative. The initial raw material of the method provided is cheap and easily available and the operation is simple; therefore, the method is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of method for preparing citalopram and S-escitalopram key intermediate, belong to the pharmaceutical industry field.
Background technology
Citalopram is a kind of thymoleptic that gone on the market for many years, belongs to the selective serotonin reuptake inhibitor.Be that a kind of racemization two ring phthalandione derivatives have following chemical structural formula (I):
The English name Citalopram of citalopram, its chemistry is by name: 1-[3-(dimethylin) propyl group]-1-(4 fluorophenyl)-5-cyano group-1, the 3-dihydroisobenzofuran, 1-[3-(dimethylamino) propyl]-1-(4-fluorophenyl)-1.3-dihydro-5-isobenzofu rancarbonitrile.Now known that its chemical structure of dextrorotatory form S-escitalopram (II) of citalopram possesses following clear superiority: dosage is little, and patient tolerability is good; Untoward reaction is little, does not influence conducting system of heart and blood pressure.
The synthetic bibliographical information of citalopram and S-escitalopram is a lot, is WO2004/16602 with document that key intermediate 5-replacement-1-(4-fluorophenyl)-1.3-dihydroisobenzofuran derivative (chemical structure III) is relevant in it, (2004); WO2004/20425, (2004); WO2005/66185 (2005); Bigler, A.J.et al., European Journal of Medicinal Chemistry; Vol.12; (1977); P.289-295Jin, Chunyang; Boldt, Karl G.Rehder, Kenneth S.; Brine, George A.; Synthetic Communications; Vol.37; Nb.6; (2007); P.901-908.
The present synthetic route of 5-replacement-1-(4-the fluorophenyl)-1.3-dihydroisobenzofuran derivative of bibliographical information, all routes have all used grignard reaction, and this type of reaction response condition harshness, aftertreatment complexity, yield is on the low side.Therefore develop one under mild conditions, efficiently synthetic this key intermediate is very important and urgent.
Summary of the invention
The object of the invention be to provide a kind of easy, prepare the method for citalopram and S-escitalopram key intermediate (being 5-replacement-1-(4-fluorophenyl)-1.3-dihydroisobenzofuran derivative) efficiently.
Preparation method of the present invention comprises the steps: that to replace Tetra hydro Phthalic anhydride be starting raw material, becomes ester, reduction, the 4 step reaction of pass ring to make this intermediate (as IV) via Friedel-Crafts reaction, acid catalysis.
The preferred halophthalic acid acid anhydride of described replacement Tetra hydro Phthalic anhydride.Halogen element can be chlorine, bromine, iodine etc.
Above-mentioned four-step reaction can carry out as follows:
(a) Friedel-Crafts reaction: with the halophthalic acid acid anhydride is starting raw material, under Louis acid catalysis such as aluminum chloride, zinc chloride and fluorobenzene 40-80 degree centigrade down reaction generate 5-halo-2-(4-fluoro benzoyl) phenylformic acid.Wherein the mole proportioning of halophthalic acid acid anhydride and fluorobenzene is between 1: 10～1: 30.Preferred 60 degrees centigrade of temperature.
(b) acid catalysis becomes ester: 5-halo-2-(4-fluoro benzoyl) phenylformic acid under mineral acid catalysis such as sulfuric acid, hydrochloric acid and alcohol such as methyl alcohol, ethanol esterifications take place generates 5-halo-2-(4-fluoro benzoyl) benzoic ethers.
(c) reduction reaction: 5-halo-2-(4-fluoro benzoyl) benzoic ether with sodium borohydride reduction generate 2-methylol-4-bromo-4 '-the fluorine benzhydrol, the mole proportioning of 5-halo-2-(4-fluoro benzoyl) benzoic ether and sodium borohydride is between 1: 1～1: 3.Solvent for use can be the mixed solvent of alcohol compounds such as methyl alcohol, ethanol or tetrahydrofuran (THF), 1.4-dioxane and water three arbitrary proportion.
(d) ring closure reaction: 2-methylol-4-bromo-4 '-fluorine benzhydrol dehydration condensation obtains target compound 5-replacement-1-(4-fluorophenyl)-1.3-dihydroisobenzofuran.Adopting mineral acid or organic acid is catalyzer, mineral acid such as phosphoric acid, sulfuric acid, hydrochloric acid etc., and organic acid such as Phenylsulfonic acid, tosic acid, methylsulfonic acid etc., toluene is as solvent.
The technology of the present invention incidence of criminal offenses preferred method is:
(a) synthetic 5-bromo-2-(4-fluoro benzoyl) phenylformic acid
The 4-phthalate bromine acid anhydride that in reaction flask, adds 1mol, 10～30mol fluorobenzene.Under mechanical stirring, add 2～3mol aluminum trichloride (anhydrous), stir then and heat up 40～80 degrees centigrade, under this temperature, reacted 2.5～3.5 hours, after reaction finishes, be cooled to room temperature, add 0.8～1.2 premium on currency and stirred 30 minutes, tell organic layer.In organic phase, add 100ml 36% concentrated hydrochloric acid; distillation is reclaimed does not have the fluorobenzene that reacted; resistates is cooled to 10 degrees centigrade, has yellow solid to separate out, filtration, washing, dry yellow solid 5-bromo-2-(4-fluoro benzoyl) phenylformic acid that gets under 65-70 degree centigrade.
(b) synthetic 5-bromo-2-(4-fluoro benzoyl) ethyl benzoate
In reaction flask, add 0.5mol5-bromo-2-(4-fluoro benzoyl) phenylformic acid, 8～12 liters of ethanol.Under mechanical stirring, add the 0.05～0.1mol mineral acid such as the vitriol oil or concentrated hydrochloric acid, stir then and heat up 40～80 degrees centigrade, under this temperature, reacted 5～8 hours.After finishing, reaction is cooled to room temperature; decompression recycling ethanol is to thickness oily matter; oily matter is dissolved in 0.8～1.2L ethyl acetate; add ammoniacal liquor conditioned reaction liquid pH value and be neutral; wash at twice with the 1.0L saturated aqueous common salt again; the reclaim under reduced pressure ethyl acetate is to thickness oily matter, this oily matter of sampling analysis 5-bromo-2-(4-fluoro benzoyl) ethyl benzoate, and this oily matter is directly used in next step reaction.
(c) Synthetic 2-methylol-4-bromo-4 '-the fluorine benzhydrol
In reaction flask; add 0.5mol and go up step reaction gained oily matter 5-bromo-2-(4-fluoro benzoyl) ethyl benzoate (0.5mol is a theoretical yield), mixture (the volume ratio v/v=1 of water and tetrahydrofuran (THF): 1) of 0.8～1.2 liter of ethanol or water and tetrahydrofuran (THF).Under mechanical stirring, be cooled to below 0 ℃, add 0.65～0.85mol sodium borohydride in batches, added in about 1 hour, slowly be warming up to room temperature then, kept room temperature reaction 3～5 hours.After reaction finishes, reaction solution is joined in 0.8～1.2L mixture of ice and water, add 6mol/L hydrochloric acid conditioned reaction liquid pH value and be acid, decompression recycling ethanol, water layer extracts at twice with 0.8～1.2L ethyl acetate, wash at twice with 0.8～1.2L saturated aqueous common salt again, the reclaim under reduced pressure ethyl acetate is to thickness oily matter, this oily matter of sampling analysis 2-methylol-4-bromo-4 '-the fluorine benzhydrol, this oily matter is directly used in next step reaction.
(d) synthetic 5-bromo-1-(4-fluorophenyl)-1.3-dihydroisobenzofuran
In reaction flask, the last step reaction of adding 0.5mol gained oily matter 2-methylol-4-bromo-4 '-fluorine benzhydrol (0.5mol is a theoretical yield), 0.8～1.2L toluene.Under mechanical stirring, add 0.1mol organic acid such as tosic acid or phosphoric acid, stir then and be warming up to backflow, adopt fraction water device water-dividing, when no longer including moisture in the water trap and go out, thin-layer chromatography is followed the tracks of reaction end, after reaction finishes, be cooled to room temperature, add ammoniacal liquor conditioned reaction liquid pH value and be neutral, wash at twice with 0.8～1.2L saturated aqueous common salt again, separatory reclaim under reduced pressure toluene is to thickness oily matter, cut is collected in rectifying, and gained oily matter room temperature is placed and solidified.Get white solid 5-bromo-1-(4-fluorophenyl)-1.3-dihydroisobenzofuran.
The method of the invention compared with prior art has the following advantages: 1. the used starting raw material of this route cheaply is easy to get.2. this route comprises that Friedel-Crafts reaction, acid catalysis become the totally 4 steps reaction of ester, reduction, pass ring, easy and simple to handle, mild condition, yield is higher, cost is lower.3. this route avoids having used grignard reaction, and grignard reaction condition harshness, solvent difficulty are recycled, cost is higher, has limited the feasibility that its industry is amplified.4. industrialized possibility is considered in the per step reaction of this route, has the basis that industry is amplified.
Following embodiment is used to explain the present invention, but the invention is not restricted to following embodiment.
Embodiment
Embodiment 1:
1.1 synthetic 5-bromo-2-(4-fluoro benzoyl) phenylformic acid
In 3000 milliliters of three mouthfuls of reaction flasks of thermometer, airway and mechanical stirring device are housed, add 227 gram (1mol) 4-phthalate bromine acid anhydrides, 1.8 liters of (19.2mol) fluorobenzene.Under mechanical stirring, add 293.7 gram (2.2mol) aluminum trichloride (anhydrous)s, stir then and heat up 60 degrees centigrade, keep 60 degrees centigrade of reactions 3 hours.Thin-layer chromatography is followed the tracks of reaction end, is cooled to room temperature after reaction finishes, and adds 1 premium on currency and stirs 30 minutes, tells organic layer.In organic phase, add 100ml 36% concentrated hydrochloric acid; distillation is reclaimed does not have the fluorobenzene that reacted; resistates is cooled to 10 degrees centigrade; there is yellow solid to separate out; filter, wash, restrain at 65-70 degree centigrade of dry down yellow solid 5-bromo-2-(4-fluoro benzoyl) phenylformic acid 268 that gets; yield 83%, mp=152.5 ℃.
1.2 synthetic 5-bromo-2-(4-fluoro benzoyl) ethyl benzoate
In 2000 milliliters of three mouthfuls of reaction flasks of thermometer, return line and mechanical stirring device are housed, add 161.5 gram (0.5mol) 5-bromo-2-(4-fluoro benzoyl) phenylformic acid, 1.0 liters of ethanol.Under mechanical stirring, add 4.9 gram (0.05mol) vitriol oils, stir then and heat up 80 degrees centigrade, keep 80 degrees centigrade of reactions 5 hours.Thin-layer chromatography is followed the tracks of reaction end; after finishing, reaction is cooled to room temperature; decompression recycling ethanol is to thickness oily matter; oily matter is dissolved in the 1.0L ethyl acetate, adds ammoniacal liquor conditioned reaction liquid pH value and is neutral, washs at twice with the 1.0L saturated aqueous common salt again; the reclaim under reduced pressure ethyl acetate is to thickness oily matter; this oily matter of sampling analysis 5-bromo-2-(4-fluoro benzoyl) ethyl benzoate, purity is 94.8%, this oily matter is directly used in next step reaction.
1.3 Synthetic 2-methylol-4-bromo-4 '-the fluorine benzhydrol
In 2000 milliliters of three mouthfuls of reaction flasks of thermometer, airway pipe and mechanical stirring device are housed, add oily matter 5-bromo-2-(4-fluoro benzoyl) ethyl benzoate, 1.0 liters of ethanol.Under mechanical stirring, be cooled to below 0 ℃, add 27.8 gram (0.75mol) sodium borohydrides in batches, added in about 1 hour, slowly be warming up to room temperature then, kept room temperature reaction 5 hours.Thin-layer chromatography is followed the tracks of reaction end, after reaction finishes, reaction solution is joined in the 1.0L mixture of ice and water, add 6mol/L hydrochloric acid conditioned reaction liquid pH value and be acid, decompression recycling ethanol, water layer extracts at twice with the 1.0L ethyl acetate, washs at twice with the 1.0L saturated aqueous common salt again, the reclaim under reduced pressure ethyl acetate is to thickness oily matter, this oily matter of sampling analysis 2-methylol-4-bromo-4 '-the fluorine benzhydrol, purity is 89.8%, this oily matter is directly used in next step reaction.
1.4 synthetic 5-bromo-1-(4-fluorophenyl)-1.3-dihydroisobenzofuran
In 2000 milliliters of three mouthfuls of reaction flasks of thermometer, return line, Dean-Stark water trap and mechanical stirring device are housed, adding oily matter 2-methylol-4-bromo-4 '-the fluorine benzhydrol, 1.0L toluene.Under mechanical stirring, add 17 gram (0.1mol) tosic acid, stir then and be warming up to backflow, adopt fraction water device water-dividing, when no longer including moisture in the water trap and go out, thin-layer chromatography is followed the tracks of reaction end, after reaction finishes, be cooled to room temperature, add ammoniacal liquor conditioned reaction liquid pH value and be neutral, wash at twice with the 1.0L saturated aqueous common salt again, separatory reclaim under reduced pressure toluene is to thickness oily matter, cut is collected in rectifying, and gained oily matter room temperature is placed and solidified.Get white solid 5-bromo-1-(4-fluorophenyl)-1.3-dihydroisobenzofuran 95.5 grams, three-step reaction total recovery 65.5%.
Embodiment 2:
2.1 synthetic 5-chloro-2-(4-fluoro benzoyl) phenylformic acid
In 3000 milliliters of three mouthfuls of reaction flasks of thermometer, airway and mechanical stirring device are housed, add 182 gram (1mol) 4-chloro-phthalic anhydrides, 1.8 liters of (19.2mol) fluorobenzene.Under mechanical stirring, add 293.7 gram (2.2mol) aluminum trichloride (anhydrous)s, stir then and heat up 60 degrees centigrade, keep 60 degrees centigrade of reactions 3 hours.Thin-layer chromatography is followed the tracks of reaction end, is cooled to room temperature after reaction finishes, and adds 1 premium on currency and stirs 30 minutes, tells organic layer.In organic phase, add 100ml 36% concentrated hydrochloric acid, distillation is reclaimed does not have the fluorobenzene that reacted, resistates is cooled to 10 degrees centigrade, there is yellow solid to separate out, filter, wash, restrain at the 65-70 degree centigrade of dry down yellow solid 5-chloro-1-(4-fluorophenyl) of getting-1.3-dihydroisobenzofuran 224.8, yield 80.6%, mp=139.5 ℃.
2.2 synthetic 5-chloro-2-(4-fluoro benzoyl) methyl benzoate
In 2000 milliliters of three mouthfuls of reaction flasks of thermometer, return line and mechanical stirring device are housed, add 139 gram (0.5mol) 5-chloro-2-(4-fluoro benzoyl) phenylformic acid, 1.0 liters of methyl alcohol.Under mechanical stirring, add 3.7 gram (0.1mol) concentrated hydrochloric acids, stir then and heat up 60 degrees centigrade, keep 60 degrees centigrade of reactions 8 hours.Thin-layer chromatography is followed the tracks of reaction end; after finishing, reaction is cooled to room temperature; decompression recycling ethanol is to thickness oily matter; oily matter is dissolved in the 1.0L ethyl acetate,, add ammoniacal liquor conditioned reaction liquid pH value and be neutral; wash at twice with the 1.0L saturated aqueous common salt again; the reclaim under reduced pressure ethyl acetate is to thickness oily matter, and this oily matter of sampling analysis 5-chloro-2-(4-fluoro benzoyl) methyl benzoate purity is 90.8%, and this oily matter is directly used in next step reaction.
2.3 Synthetic 2-methylol-4-chloro-4 '-the fluorine benzhydrol
In 2000 milliliters of three mouthfuls of reaction flasks of thermometer, airway pipe and mechanical stirring device are housed, add oily matter 5-chloro-2-(4-fluoro benzoyl) methyl benzoate, the mixture of 1.0 premium on currency and tetrahydrofuran (THF) (v/v=1: 1).Under mechanical stirring, be cooled to below 0 ℃, add 27.8 gram (0.75mol) sodium borohydrides in batches, added in about 1 hour, slowly be warming up to room temperature then, kept room temperature reaction 3 hours.Thin-layer chromatography is followed the tracks of reaction end, after reaction finishes, reaction solution is joined in the 1.0L mixture of ice and water, add 6mol/L hydrochloric acid conditioned reaction liquid pH value and be acid, the reclaim under reduced pressure tetrahydrofuran (THF), water layer extracts at twice with the 1.0L ethyl acetate, wash at twice with the 1.0L saturated aqueous common salt again, the reclaim under reduced pressure ethyl acetate to thickness oily matter 2-methylol-4-chloro-4 '-the fluorine benzhydrol, this oily matter purity of sampling analysis is 92.8%, and this oily matter is directly used in next step reaction.
2.4 synthetic 5-chloro-1-(4-fluorophenyl)-1.3-dihydroisobenzofuran
In 2000 milliliters of three mouthfuls of reaction flasks of thermometer, return line, Dean-Stark water trap and mechanical stirring device are housed, adding oily matter 2-methylol-4-chloro-4 '-the fluorine benzhydrol, 1.0L toluene.Under mechanical stirring, add 10 gram (0.1mol) phosphoric acid, stir then and be warming up to backflow, adopt fraction water device water-dividing, when no longer including moisture in the water trap and go out, thin-layer chromatography is followed the tracks of reaction end, after reaction finishes, be cooled to room temperature, add ammoniacal liquor conditioned reaction liquid pH value and be neutral, wash at twice with the 1.0L saturated aqueous common salt again, separatory reclaim under reduced pressure toluene is to thickness oily matter 5-chloro-1-(4-fluorophenyl)-1.3-dihydroisobenzofuran, cut is collected in rectifying, and gained oily matter room temperature is placed and solidified.Get white solid 75.5 grams, three step total recoverys 60.1%.
Claims (8)
1. a method for preparing citalopram and S-escitalopram key intermediate is characterized in that this method comprises the steps: that to replace Tetra hydro Phthalic anhydride be starting raw material, becomes ester, reduction, the 4 step reaction of pass ring to make via Friedel-Crafts reaction, acid catalysis.
2. the method for claim 1 is characterized in that this method comprises the steps:
(a) be starting raw material with the halophthalic acid acid anhydride, react generation 5-halo-2-(4-fluoro benzoyl) phenylformic acid with fluorobenzene down at 40-80 degree centigrade under Louis acid catalysis, wherein the mole proportioning of halophthalic acid acid anhydride and fluorobenzene is between 1: 10～1: 30;
(b) 5-halo-2-(4-fluoro benzoyl) phenylformic acid under mineral acid catalysis and alcohol esterification takes place generates 5-halo-2-(4-fluoro benzoyl) benzoic ether;
(c) 5-halo-2-(4-fluoro benzoyl) benzoic ether with sodium borohydride reduction generate 2-methylol-4-bromo-4 '-the fluorine benzhydrol, the mole proportioning of 5-halo-2-(4-fluoro benzoyl) benzoic ether and sodium borohydride is between 1: 1～1: 3;
(d) 2-methylol-4-bromo-4 '-fluorine benzhydrol dehydration condensation obtains target compound 5-replacement-1-(4-fluorophenyl)-1.3-dihydroisobenzofuran.
3. method as claimed in claim 2 is characterized in that Lewis acid is aluminum chloride or zinc chloride in the step (a).
4. method as claimed in claim 2 is characterized in that temperature of reaction is 60 degrees centigrade in the step (a).
5. method as claimed in claim 2 is characterized in that mineral acid is sulfuric acid or hydrochloric acid in the step (b), and alcohol is methyl alcohol or ethanol.
6. method as claimed in claim 2 is characterized in that solvent for use is an alcohol compound in the step (c), or the mixed solvent of tetrahydrofuran (THF), 1.4-dioxane and water three arbitrary proportion.
7. method as claimed in claim 2 is characterized in that adopting mineral acid or organic acid in the step (d) is catalyzer, and toluene is as solvent.
8. method as claimed in claim 7 is characterized in that mineral acid is phosphoric acid, sulfuric acid, hydrochloric acid, and organic acid is Phenylsulfonic acid, tosic acid, methylsulfonic acid.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114516817A (en) * | 2022-02-14 | 2022-05-20 | 九江善水科技股份有限公司 | Chemical intermediate and preparation method thereof |
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| US20020095051A1 (en) * | 2000-02-17 | 2002-07-18 | Sumika Fine Chemicals Co., Ltd. | Production method of citalopram, intermediate therefor and production method of the intermediate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114516817A (en) * | 2022-02-14 | 2022-05-20 | 九江善水科技股份有限公司 | Chemical intermediate and preparation method thereof |
| CN114516817B (en) * | 2022-02-14 | 2022-11-11 | 九江善水科技股份有限公司 | Chemical intermediate and preparation method thereof |
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