CN102659667B - Synthetic method of fexofenadine intermediate - Google Patents
Synthetic method of fexofenadine intermediate Download PDFInfo
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Abstract
The invention discloses a synthetic method of a fexofenadine intermediate 2-[4-[4-[4-(Hydroxy diphenylmethyl)-1-piperidyl]-1-oxobutyl]phenyl]-2,2-dimethyl acetate, which comprises the following steps: carrying out condensation reaction on 4-(4-chlorobu-tyrylcyclohexanone)-alpha, alpha-dimethyl phenylacetate and 4-cyanoacrylate piperidine to obtain 2-[4-[4-(4-cyanoacrylate-1-piperidyl)]butyryl]phenyl]-2-methyl-propionate shown in a formula V and carrying out coupling reaction with benzophenone to obtain the 2-[4-[4-(Hydroxy diphenylmethyl)-1-piperidyl]-1-oxobutyl]phenyl]-2,2-dimethyl acetate shown in a formula VI. The synthetic method has the advantages of simple process, convenience in operation and higher yield and is a route suitable for industrial production, thereby having wide application prospect.
Description
Technical field
The present invention relates to the organic chemical synthesis field, be specifically related to a kind of fexofenadine key intermediate-2-[4-[4-[4-(hydroxy benzophenone base)-piperidino]-1-oxo butyl] phenyl]-2, the synthetic method of 2-dimethyl acetic acid ester.
Background technology
2-[4-[4-[4-(hydroxy benzophenone base)-piperidino]-1-oxo butyl] phenyl]-2,2-dimethyl acetic acid ester, its structural formula is as follows:
2-[4-[4-[4-(hydroxy benzophenone base)-piperidino]-1-oxo butyl] phenyl]-2,2-dimethyl acetic acid ester is a kind of important medicine intermediate, can obtain the antihistamine drug fexofenadine by hydrolysis and reduction two-step reaction, specifically can be referring to disclosed with 2-[4-[4-[4-(hydroxy benzophenone base)-piperidino in the US Patent No. 4254129]-1-oxo butyl] phenyl]-2,2-dimethyl acetic acid ester is that raw material is through hydrolysis, at NaBH
4And ethanol (EtOH) exists reduction down to make the method for fexofenadine.
Fexofenadine (fexofenadine), chemistry α by name, alpha-alpha-dimethyl-4-[1-hydroxyl-4-[4-(hydroxy benzophenone base)-piperidino] butyl] toluylic acid, commodity are called Allegra, researched and developed successfully by German Hoechest Marion Roussel company, went on the market in the U.S. first in 1996, it is s-generation H1 receptor antagonist, it is the carboxylated metabolite of Triludan, it optionally blocks the H1 acceptor, have good antihistamine effect, be applicable to clinically to alleviate the symptom that seasonal allergic rhinitis and chronic idiopathic urticaria cause.
2-[4-[4-[4-(hydroxy benzophenone base)-piperidino]-1-oxo butyl] phenyl]-2, synthetic German patent DE 3007498 and the US Patent No. 4254129 of seeing the earliest of 2-dimethyl acetic acid methyl esters, with α, alpha-alpha-dimethyl phenyl acetic acid (shown in the formula I) is starting raw material, at the vitriol oil (H
2SO
4) generate α with methyl alcohol (MeOH) esterification under the catalyst system; alpha-alpha-dimethyl phenyl acetic acid methyl esters (shown in the formula II); under methylene dichloride (DCM), aluminum trichloride (anhydrous) condition, obtain 4-(4-chlorobutyryl)-α with 4-chlorobutanoylchloride generation Friedel-Crafts reaction then; alpha-alpha-dimethyl phenyl acetic acid methyl esters (shown in the formula III); last and α; α-phenylbenzene-4-piperidine carbinols (AZA) condensation obtains 2-[4-[4-[4-(hydroxy benzophenone base)-piperidino]-1-oxo butyl] phenyl]-2; 2-dimethyl acetic acid methyl esters, synthetic route is as follows:
The drawback of this method is to obtain 4-(4-chlorobutyryl)-α by Friedel-Crafts reaction, in the time of the alpha-alpha-dimethyl phenyl acetic acid methyl esters, can produce a certain proportion of meta-isomer-3-(4-chlorobutyryl)-α, the alpha-alpha-dimethyl phenyl acetic acid methyl esters, the molar ratio of contraposition and a position is about 1: 1, the physico-chemical property of meta-isomer is extremely similar to the registration target thing, is difficult to its removal; Need reflux in toluene 72 hours with the condensation reaction of AZA, the reaction times is extremely long, and yield very low (or not having yield data).In addition, because China does not still have AZA large-scale production producer, the synthetic long-term dependence on import of fexofenadine and intermediate thereof, cost is higher.
Disclosed fexofenadine intermediate 2-[4-[4-[4-(hydroxy benzophenone base)-piperidino among the Chinese patent application CN201110262895.2]-1-oxo butyl] phenyl]-2; method in the preparation method of 2-dimethyl acetic acid ester and German patent DE 3007498 and the US Patent No. 4254129 is basic identical; it mainly is to have increased by hydrolysis, refining and purification step reduction 4-(4-chloro-1-butyryl radicals)-α, alpha-alpha-dimethyl phenyl acetic acid ester interposition content of isomer.
A kind of 4-(4-chlorobutyryl)-α is disclosed among the Chinese patent application CN201110027330.6; alpha-alpha-dimethyl phenyl acetic acid ester new synthetic method; almost there is not meta-isomer in the product that obtains with this method, for the synthetic of follow-up intermediate and even fexofenadine had laid a good foundation.
Summary of the invention
The invention provides fexofenadine key intermediate-2-[4-[4-[4-that a kind of technology is simple, easy to operate and yield is higher (hydroxy benzophenone base)-piperidino]-1-oxo butyl] phenyl]-2, the synthetic method of 2-dimethyl acetic acid ester.
A kind of fexofenadine key intermediate 2-[4-[4-[4-(hydroxy benzophenone base)-piperidino]-1-oxo butyl] phenyl]-2, the synthetic method of 2-dimethyl acetic acid ester comprises step:
(1) 4-shown in the formula IV (4-chlorobutyryl)-α, alpha-alpha-dimethyl phenyl acetic acid ester and 4-cyano group piperidines obtain 2-[4-[4-shown in the formula V (4-cyano group-piperidino) through condensation reaction] butyryl radicals] phenyl]-2-methyl-propionic ester;
(2) 2-[4-[4-shown in the formula V (4-cyano group-piperidino)] butyryl radicals] phenyl]-2-methyl-propionic ester and benzophenone obtain 2-[4-[4-[4-shown in the formula VI (hydroxy benzophenone base)-piperidino through linked reaction]-1-oxo butyl] phenyl]-2,2-dimethyl acetic acid ester;
Formula IV, formula V have identical implication with R among the formula VI, and R is alkyl, and the further straight chained alkyl of preferred 1 to 6 carbon atom or the branched-chain alkyl of 1 to 6 carbon atom are as methyl.
Further preferred in order to realize the present invention better, described synthetic method comprises step:
(1) with 4-shown in the formula IV (4-chlorobutyryl)-α, the alpha-alpha-dimethyl phenyl acetic acid ester is starting raw material, in the presence of acid binding agent salt of wormwood and catalyzer in first organic solvent with 2-[4-[4-(4-cyano group-piperidino) shown in the 4-cyano group piperidines generation condensation reaction production V] butyryl radicals] phenyl]-2-methyl-propionic ester;
(2) in second organic solvent under the sodium Metal 99.5 effect; 2-[4-[4-shown in the formula V (4-cyano group-piperidino)] butyryl radicals] phenyl]-2-methyl-propionic ester and benzophenone reaction production VI shown in 2-[4-[4-[4-(hydroxy benzophenone base)-piperidino]-1-oxo butyl] phenyl]-2,2-dimethyl acetic acid ester.
In the step (1); 4-shown in the described formula IV (4-chlorobutyryl)-α; the alpha-alpha-dimethyl phenyl acetic acid ester can adopt the commercially available prod; also can be synthetic according to existing preparation method; as can be with reference to disclosed 4-among the Chinese patent application CN201110027330.6 (4-chlorobutyryl)-α; the synthetic method of alpha-alpha-dimethyl phenyl acetic acid ester is not almost had 4-(4-the chlorobutyryl)-α of meta-isomer, alpha-alpha-dimethyl phenyl acetic acid ester.
Described catalyzer is selected one or both in sodium iodide, the potassiumiodide for use, and preferred potassiumiodide can further improve reaction yield.Described catalyst consumption can be according to 4-shown in the reaction substrate formula IV (4-chlorobutyryl)-α; the consumption of alpha-alpha-dimethyl phenyl acetic acid ester is adjusted; there is not strict especially restriction; take into account catalyzed reaction effect and raw materials cost; 4-shown in catalyzer and the formula IV (4-chlorobutyryl)-α; the weight ratio of alpha-alpha-dimethyl phenyl acetic acid ester is 0.003～0.01: 1, preferred 0.007: 1.
4-shown in the described formula IV (4-chlorobutyryl)-α, the mol ratio of alpha-alpha-dimethyl phenyl acetic acid ester and salt of wormwood is 1: 2～3, preferred 1: 2.5.Find that through test when the salt of wormwood mole number was less than 2 equivalents, reaction not exclusively suitably excessively was conducive to reaction and carries out, when surpassing 2.5 equivalents, reaction conversion ratio no longer increases, so the consumption optimal selection of salt of wormwood is 2.5 equivalents.
Described first organic solvent is selected 4-methyl-2 pentanone (MIBK), toluene, N for use, a kind of in dinethylformamide (DMF), the tetrahydrofuran (THF) etc., and preferred 4-methyl 2 pentanone can further improve reaction yield.
The temperature of described condensation reaction is 80 ℃～110 ℃, preferred 90 ℃.Experiment shows that temperature of reaction is lower than 80 ℃, reacts slower, has part material and is difficult for reacting completely, and when temperature of reaction raise, impurity also can rise to some extent, therefore selects 80 ℃～110 ℃, takes all factors into consideration, and reaction is best under 90 ℃ of conditions.
In the step (2), described second organic solvent is selected a kind of in toluene, dimethylbenzene (xylene), DMF, the ethylene glycol etc. for use, and preferred dimethylbenzene can further improve reaction yield.
2-[4-[4-shown in the described formula V (4-cyano group-piperidino)] butyryl radicals] phenyl]-mol ratio of 2-methyl-propionic ester and sodium Metal 99.5 is 1: 2～3, preferred 1: 2.44.The theoretical consumption of sodium Metal 99.5 is 2 equivalents, suitably more excessively is conducive to improve reaction conversion ratio, when more, can produce adverse influence when excessive to aftertreatment, our experiments show that 1: 2.44 the best of mol ratio.
Described benzophenone preferably drops to reaction system with the form of second organic solvent solution of benzophenone, and the temperature that drips the process reaction system is 50 ℃～80 ℃, preferred 70 ℃.The benefit that drips with the solution form is that exothermic heat of reaction comparatively relaxes, and is easier to control.Show that by a large amount of orthogonal experiments selecting temperature is that to drip yield under 50 ℃～80 ℃ conditions better, be chosen under 70 ℃ of conditions and drip that yield is the highest.
2-[4-[4-shown in the described formula V (4-cyano group-piperidino)] butyryl radicals] phenyl]-2-methyl-propionic ester is preferably with 2-[4-[4-(4-cyano group-piperidino)] butyryl radicals] phenyl]-form of second organic solvent solution of 2-methyl-propionic ester drops to reaction system; the temperature that drips the process reaction system is 120 ℃～150 ℃, preferred 135 ℃.Select the solution form to drip herein, react comparatively mild, the unlikely material that fills.Experiment showed, that selecting temperature is that the dropping yield is better under 120 ℃～150 ℃ conditions, under 135 ℃ of conditions, drip that yield is the highest.
In the step (2), described linked reaction is preferably under nitrogen or the protection of inert gas carries out, and the generation that can significantly reduce big impurity improves yield.Described rare gas element can be selected the rare gas element of this area for use, and a kind of as in helium, the argon gas etc. is from saving the cost consideration preferred nitrogen.
To the not strict restriction of the consumption of each raw material, generally get final product than being that mol ratio 1: 1 or part material are excessive by the chemical reaction equation metering in each step reaction of the present invention.Consider reaction yield, in the step (1), 4-shown in the described formula IV (4-chlorobutyryl)-α, the mol ratio of alpha-alpha-dimethyl phenyl acetic acid ester and 4-cyano group piperidines is 1: 0.9～1.1, preferred 1: 1; In the step (2), 2-[4-[4-shown in the described formula V (4-cyano group-piperidino)] butyryl radicals] phenyl]-mole of 2-methyl-propionic ester and benzophenone is 1: 1～1.12, preferred 1: 1.05～1.12.
The reaction times of the linked reaction described in the condensation reaction described in the step (1) and the step (2) does not all have strict restriction, pass through timing sampling, carry out trace analysis with existing method for judging reaction end such as tlc (TLC), liquid chromatography or gas-chromatography etc., all react when wherein a certain raw material or plurality of raw materials and to finish, the terminal point that is considered as reacting gets final product.Through overtesting, to carry out fully in order to make reaction, the reaction times of the condensation reaction described in the step (1) was generally 4 to 10 hours; The reaction times of the linked reaction described in the step (2) was generally 5 to 6 hours.
With 4-(4-chlorobutyryl)-α; the alpha-alpha-dimethyl phenyl acetic acid methyl esters is starting raw material, and 4-methyl-2 pentanone is the reaction solvent of step (1), and potassiumiodide is the catalyzer of step (1); dimethylbenzene is that the reaction solvent of step (2) is example, and the concrete synthetic route of the inventive method is as follows:
The method of calculation of yield are among the present invention: Theoretical Mass * 100% of the actual mass ÷ product of yield=product, total recovery=respectively the go on foot product of reaction yield.
Content detecting method among the present invention: chromatographic column: internal diameter 4.6nm, long 15cm fills the stainless steel analytical column of 5 μ m phenylating silica gel.Column temperature: 35 ℃, wavelength 220nm, moving phase: phosphate dihydrate one sodium 7.51g and sodium perchlorate 0.84g are dissolved in the 1000ml water, add phosphoric acid and regulate pH to 2.0, accurately measure 510ml configuration solution, in this 510ml obtain solution, add acetonitrile 490ml, triethylamine 3ml, the mixed moving phase that gets.
Compared with prior art, the present invention has following advantage:
The present invention utilizes 4-(4-chlorobutyryl)-α; the alpha-alpha-dimethyl phenyl acetic acid ester is raw material; with the condensation of 4-cyano group piperidines, obtained 2-[4-[4-[4-(hydroxy benzophenone base)-piperidino with the benzophenone linked reaction again]-1-oxo butyl] phenyl]-2,2-dimethyl acetic acid ester.This method reaction scheme novelty is not seen bibliographical information so far, and technology is simple, easy to operate, and yield is higher, and the two-step reaction total recovery can reach 79%, is a route that is suitable for suitability for industrialized production.Because China does not still have AZA large-scale production producer; the synthetic long-term dependence on import of fexofenadine and intermediate thereof; synthetic route of the present invention has not only successfully got around the use of AZA; and avoided 4-(4-chlorobutyryl)-α; therefore alpha-alpha-dimethyl phenyl acetic acid ester and the drawback that the AZA condensation reaction time is long and yield is low excessively have great application prospect.
Embodiment
Embodiment 1
(1) with 4-(4-chlorobutyryl)-α; alpha-alpha-dimethyl phenyl acetic acid methyl esters 28.3g (0.10mol) is dissolved in 100ml4-methyl-2 pentanone; stir, add 4-cyano group piperidinyl-1 1.0g (0.10mol), salt of wormwood 34.5g (0.25mol); catalyzer potassiumiodide 0.2g; be warming up to 90 ℃, reflux after 4 hours, filter; filtration catalizer and inorganic salt salt of wormwood; filtrate decompression is concentrated into dried, adds toluene 100ml, water 100ml; layering; water layer is used toluene (50ml*2) extraction again, merges organic layer, drying; be concentrated into 1/3 volume; cooling adularescent solid is separated out, and filters, and solid is 70 ℃ of dryings; obtain 32.1g 2-(4-(4-(4-cyano group-piperidino) butyryl radicals) phenyl)-2-methyl-methyl propionate, yield 90.1%.
(2) sodium Metal 99.5 5.0g (0.22mol) is slowly dropped in the 100ml dimethylbenzene in batches, feed nitrogen protection, be warming up to 70 ℃, open and stir, (17.3g, 0.10mol) clear liquor dripped off in 2 hours to drip dimethylbenzene 100ml and benzophenone continuously.Be warming up to 135 ℃, drip dimethylbenzene 200ml and 2-(4-(4-(4-cyano group-piperidino) butyryl radicals) phenyl)-2-methyl-methyl propionate 32.1g (0.09mol) clear liquor continuously, dripped in about 2 hours, drip off back insulation 6 hours.After reaction finishes, be cooled to 40 ℃, add water 200ml, stir half an hour, filter, filter cake is extremely neutral with the clear water washing, the solid crude product re-crystallizing in ethyl acetate obtains 2-[4-[4-[4-(hydroxy benzophenone base)-piperidino]-1-oxo butyl] phenyl]-2,2-dimethyl acetic acid methyl esters 40.5g, content 98%, yield 87.7%.
1H-MNR (500MHz, CDCl
3): δ=7.92 (d, J=8.53Hz, 2H, Har), 7.15-7.48 (m, 12H, Har), 3.63 (s, 3H, OCH
3), 2.88-2.96 (m, 4H, CH
2NCH
2'), 2.38-2.44 (m, 1H, CH), 2.37 (t, 2H, COCH
2), 1.89-1.97 (m, 4H, NCH
2CH
2), 1.60 (s, 6H, CH
3), 1.24-1.47 (m, 4H, (CH
2)
2CH), nucleus magnetic hydrogen spectrum data and 2-[4-[4-[4-(hydroxy benzophenone base)-piperidino]-1-oxo butyl] phenyl]-2,2-dimethyl acetic acid methyl esters reference substance basically identical, structure obtains confirming.
Embodiment 2
(1) with 4-(4-chlorobutyryl)-α, α-Jia Jibenyisuanjiazhi 28.3g (0.1mol) is dissolved in the 100ml toluene, stirs; add 4-cyano group piperidinyl-1 1.0g (0.1mol), salt of wormwood 34.5g (0.25mol), catalyzer potassiumiodide 0.2g; be warming up to 90 ℃; reflux after 10 hours, filter filtration catalizer and inorganic salt salt of wormwood; filtrate adds water 100ml; toluene (50ml*2) extraction is used in layering, water layer again, merges organic layer; dry; be concentrated into 1/3 volume, cooling, the adularescent solid is separated out; filter; solid obtains 30.8g 2-(4-(4-(4-cyano group-piperidino) butyryl radicals) phenyl)-2-methyl-methyl propionate, yield 86.5% 70 ℃ of dryings.
(2) sodium Metal 99.5 5.0g (0.22mol) is slowly dropped in the 100ml dimethylbenzene in batches, feed nitrogen protection, be warming up to 70 ℃, open and stir, drip dimethylbenzene 100ml and benzophenone 16.5g (0.09mol) clear liquor continuously, dripped off in 2 hours.Be warming up to 135 ℃, drip dimethylbenzene 200ml and 2-(4-(4-(4-cyano group-piperidino) butyryl radicals) phenyl)-2-methyl-methyl propionate 30.8g (0.09mol) clear liquor continuously, dripped in about 2 hours, drip off back insulation 5 hours.After reaction finishes, be cooled to 40 ℃, add water 200ml, stir half an hour, filter, filter cake is extremely neutral with the clear water washing, the solid crude product re-crystallizing in ethyl acetate obtains 2-[4-[4-[4-(hydroxy benzophenone base)-piperidino]-1-oxo butyl] phenyl]-2,2-dimethyl acetic acid methyl esters 38.3g, content 98%, yield 82.9%.
1H-MNR (500MHz, CDCl
3): δ=7.92 (d, J=8.53Hz, 2H, Har), 7.15-7.48 (m, 12H, Har), 3.63 (s, 3H, OCH
3), 2.88-2.96 (m, 4H, CH
2NCH
2'), 2.38-2.44 (m, 1H, CH), 2.37 (t, 2H, COCH
2), 1.89-1.97 (m, 4H, NCH
2CH
2), 1.60 (s, 6H, CH
3), 1.24-1.47 (m, 4H, (CH
2)
2CH), nucleus magnetic hydrogen spectrum data and 2-[4-[4-[4-(hydroxy benzophenone base)-piperidino]-1-oxo butyl] phenyl]-2,2-dimethyl acetic acid methyl esters reference substance basically identical, structure obtains confirming.
Embodiment 3
(1) except substituting the 0.2g potassiumiodide with the 0.2g sodium iodide, other steps obtain 31.0g 2-(4-(4-(4-cyano group-piperidino) butyryl radicals) phenyl)-2-methyl-methyl propionate, yield 87.0% with embodiment 1.
(2) except substituting the 0.22mol sodium Metal 99.5 with the 0.18mol sodium Metal 99.5, other steps obtain 2-[4-[4-[4-(hydroxy benzophenone base)-piperidino with embodiment 1]-1-oxo butyl] phenyl]-2,2-dimethyl acetic acid methyl esters 39.2g, content 98%, yield 84.9%.The nucleus magnetic hydrogen spectrum data of product and 2-[4-[4-[4-(hydroxy benzophenone base)-piperidino]-1-oxo butyl] phenyl]-2,2-dimethyl acetic acid methyl esters reference substance basically identical, structure obtains confirming.
Embodiment 4
(1) except substituting 0.10mol 4-cyano group piperidines with 0.09mol 4-cyano group piperidines; substitute 0.25mol salt of wormwood with 0.20mol salt of wormwood; other steps are with embodiment 1; obtain 31.2g 2-(4-(4-(4-cyano group-piperidino) butyryl radicals) phenyl)-2-methyl-methyl propionate, yield 87.6%.
(2) except substituting the 0.10mol benzophenone with the 0.0945mol benzophenone, substitute the 0.22mol sodium Metal 99.5 with the 0.27mol sodium Metal 99.5, other steps are with embodiment 1, obtain 2-[4-[4-[4-(hydroxy benzophenone base)-piperidino]-1-oxo butyl] phenyl]-2,2-dimethyl acetic acid methyl esters 39.5g, content 98%, yield 85.5%.The nucleus magnetic hydrogen spectrum data of product and 2-[4-[4-[4-(hydroxy benzophenone base)-piperidino]-1-oxo butyl] phenyl]-2,2-dimethyl acetic acid methyl esters reference substance basically identical, structure obtains confirming.
Embodiment 5
(1) except substituting 0.10mol 4-cyano group piperidines with 0.11mol 4-cyano group piperidines; substitute 0.25mol salt of wormwood with 0.30mol salt of wormwood; other steps are with embodiment 1; obtain 31.5g 2-(4-(4-(4-cyano group-piperidino) butyryl radicals) phenyl)-2-methyl-methyl propionate, yield 88.5%.
(2) except using the helium place of nitrogen, other steps obtain 2-[4-[4-[4-(hydroxy benzophenone base)-piperidino with embodiment 1]-1-oxo butyl] phenyl]-2,2-dimethyl acetic acid methyl esters 40.5g, content 98%, yield 87.7%.The nucleus magnetic hydrogen spectrum data of product and 2-[4-[4-[4-(hydroxy benzophenone base)-piperidino]-1-oxo butyl] phenyl]-2,2-dimethyl acetic acid methyl esters reference substance basically identical, structure obtains confirming.
Embodiment 6
(1) except substituting the 0.2g potassiumiodide with the 0.0849g potassiumiodide, other steps obtain 32.0g 2-(4-(4-(4-cyano group-piperidino) butyryl radicals) phenyl)-2-methyl-methyl propionate, yield 89.9% with embodiment 1.
(2) except substituting dimethylbenzene with toluene, other steps obtain 2-[4-[4-[4-(hydroxy benzophenone base)-piperidino with embodiment 1]-1-oxo butyl] phenyl]-2,2-dimethyl acetic acid methyl esters 37.5g, content 98%, yield 81.2%.The nucleus magnetic hydrogen spectrum data of product and 2-[4-[4-[4-(hydroxy benzophenone base)-piperidino]-1-oxo butyl] phenyl]-2,2-dimethyl acetic acid methyl esters reference substance basically identical, structure obtains confirming.Embodiment 7
(1) except substituting the 0.2g potassiumiodide with the 0.283g potassiumiodide, other steps obtain 32.1g 2-(4-(4-(4-cyano group-piperidino) butyryl radicals) phenyl)-2-methyl-methyl propionate, yield 90.1% with embodiment 1.
(2) except substituting dimethylbenzene with DMF, other steps obtain 2-[4-[4-[4-(hydroxy benzophenone base)-piperidino with embodiment 1]-1-oxo butyl] phenyl]-2,2-dimethyl acetic acid methyl esters 37.1g, content 98%, yield 80.3%.The nucleus magnetic hydrogen spectrum data of product and 2-[4-[4-[4-(hydroxy benzophenone base)-piperidino]-1-oxo butyl] phenyl]-2,2-dimethyl acetic acid methyl esters reference substance basically identical, structure obtains confirming.
Embodiment 8
(1) except substituting 4-methyl-2 pentanone with DMF, other steps obtain 30.6g2-(4-(4-(4-cyano group-piperidino) butyryl radicals) phenyl)-2-methyl-methyl propionate, yield 86.0% with embodiment 1.
(2) substitute dimethylbenzene except spent glycol, other steps obtain 2-[4-[4-[4-(hydroxy benzophenone base)-piperidino with embodiment 1]-1-oxo butyl] phenyl]-2,2-dimethyl acetic acid methyl esters 37.0g, content 98%, yield 80.1%.The nucleus magnetic hydrogen spectrum data of product and 2-[4-[4-[4-(hydroxy benzophenone base)-piperidino]-1-oxo butyl] phenyl]-2,2-dimethyl acetic acid methyl esters reference substance basically identical, structure obtains confirming.
Embodiment 9
(1) except substituting 4-methyl-2 pentanone with tetrahydrofuran (THF), other steps obtain 30.8g 2-(4-(4-(4-cyano group-piperidino) butyryl radicals) phenyl)-2-methyl-methyl propionate, yield 86.5% with embodiment 1.
(2) with embodiment 1, obtain 2-[4-[4-[4-(hydroxy benzophenone base)-piperidino]-1-oxo butyl] phenyl]-2,2-dimethyl acetic acid methyl esters 40.5g, content 98%, yield 87.7%.The nucleus magnetic hydrogen spectrum data of product and 2-[4-[4-[4-(hydroxy benzophenone base)-piperidino]-1-oxo butyl] phenyl]-2,2-dimethyl acetic acid methyl esters reference substance basically identical, structure obtains confirming.
Embodiment 10
(1) except substituting " be warming up to 90 ℃, refluxed 4 hours " with " being warming up to 80 ℃; refluxed 10 hours ", other steps are with embodiment 1; obtain 30.2g 2-(4-(4-(4-cyano group-piperidino) butyryl radicals) phenyl)-2-methyl-methyl propionate, yield 84.8%.
(2) except with " be warming up to 50 ℃, open stir, (17.3g, 0.10mol) clear liquor dripped off in 2 hours to drip dimethylbenzene 100ml and benzophenone continuously.Be warming up to 120 ℃; drip dimethylbenzene 200ml and 2-(4-(4-(4-cyano group-piperidino) butyryl radicals) phenyl)-2-methyl-methyl propionate 32.1g (0.09mol) clear liquor continuously; dripped in about 2 hours; dripped off back insulation 6 hours " substitute and " be warming up to 70 ℃; open and stir; (17.3g, 0.10mol) clear liquor dripped off in 2 hours to drip dimethylbenzene 100ml and benzophenone continuously.Be warming up to 135 ℃; drip dimethylbenzene 200ml and 2-(4-(4-(4-cyano group-piperidino) butyryl radicals) phenyl)-2-methyl-methyl propionate 32.1g (0.09mol) clear liquor continuously; dripped in about 2 hours; drip off back insulation 6 hours "; other steps obtain 2-[4-[4-[4-(hydroxy benzophenone base)-piperidino with embodiment 1]-1-oxo butyl] phenyl]-2,2-dimethyl acetic acid methyl esters 37.3g; content 98%, yield 80.7%.The nucleus magnetic hydrogen spectrum data of product and 2-[4-[4-[4-(hydroxy benzophenone base)-piperidino]-1-oxo butyl] phenyl]-2,2-dimethyl acetic acid methyl esters reference substance basically identical, structure obtains confirming.
Embodiment 11
(1) except substituting " be warming up to 90 ℃, refluxed 4 hours " with " being warming up to 110 ℃; refluxed 8 hours ", other steps are with embodiment 1; obtain 30.6g 2-(4-(4-(4-cyano group-piperidino) butyryl radicals) phenyl)-2-methyl-methyl propionate, yield 86.0%.
(2) except with " be warming up to 80 ℃, open stir, (17.3g, 0.10mol) clear liquor dripped off in 2 hours to drip dimethylbenzene 100ml and benzophenone continuously.Be warming up to 150 ℃; drip dimethylbenzene 200ml and 2-(4-(4-(4-cyano group-piperidino) butyryl radicals) phenyl)-2-methyl-methyl propionate 32.1g (0.09mol) clear liquor continuously; dripped in about 2 hours; dripped off back insulation 6 hours " substitute and " be warming up to 70 ℃; open and stir; (17.3g, 0.10mol) clear liquor dripped off in 2 hours to drip dimethylbenzene 100ml and benzophenone continuously.Be warming up to 135 ℃; drip dimethylbenzene 200ml and 2-(4-(4-(4-cyano group-piperidino) butyryl radicals) phenyl)-2-methyl-methyl propionate 32.1g (0.09mol) clear liquor continuously; dripped in about 2 hours; drip off back insulation 6 hours "; other steps obtain 2-[4-[4-[4-(hydroxy benzophenone base)-piperidino with embodiment 1]-1-oxo butyl] phenyl]-2,2-dimethyl acetic acid methyl esters 37.7g; content 98%, yield 81.6%.The nucleus magnetic hydrogen spectrum data of product and 2-[4-[4-[4-(hydroxy benzophenone base)-piperidino]-1-oxo butyl] phenyl]-2,2-dimethyl acetic acid methyl esters reference substance basically identical, structure obtains confirming.
Embodiment 12
(1) except using 0.1mol (35.3g) 4-(4-chlorobutyryl)-α; the own ester of alpha-alpha-dimethyl phenyl acetic acid substitutes 0.10mol (28.3g) 4-(4-chlorobutyryl)-α; the alpha-alpha-dimethyl phenyl acetic acid methyl esters; other steps are with embodiment 1; obtain 37.9g 2-(4-(4-(4-cyano group-piperidino) butyryl radicals) phenyl)-2-methyl-n-hexyl propionate, yield 88.9%.
(2) except substituting 0.09mol 2-(4-(4-(4-cyano group-piperidino) butyryl radicals) phenyl)-2-methyl-methyl propionate with 0.09mol 2-(4-(4-(4-cyano group-piperidino) butyryl radicals) phenyl)-2-methyl-n-hexyl propionate; other steps are with embodiment 1; obtain 2-[4-[4-[4-(hydroxy benzophenone base)-piperidino]-1-oxo butyl] phenyl]-2; the own ester 45.8g of 2-dimethyl acetic acid; content 98%, yield 87.3%.The nucleus magnetic hydrogen spectrum data of product and 2-[4-[4-[4-(hydroxy benzophenone base)-piperidino]-1-oxo butyl] phenyl]-2, the own ester reference substance of 2-dimethyl acetic acid basically identical, structure obtains confirming.
Claims (8)
1. a fexofenadine key intermediate 2-[4-[4-[4-(hydroxy benzophenone base)-piperidino]-1-oxo butyl] phenyl]-2, the synthetic method of 2-dimethyl acetic acid ester is characterized in that, comprises step:
(1) with 4-shown in the formula IV (4-chlorobutyryl)-α, the alpha-alpha-dimethyl phenyl acetic acid ester is starting raw material, in the presence of acid binding agent salt of wormwood and catalyzer in first organic solvent with 2-[4-[4-(4-cyano group-piperidino) shown in the 4-cyano group piperidines generation condensation reaction production V] butyryl radicals] phenyl]-2-methyl-propionic ester; Described catalyzer is selected one or both in sodium iodide, the potassiumiodide for use;
(2) in second organic solvent under the sodium Metal 99.5 effect, 2-[4-[4-shown in the formula V (4-cyano group-piperidino)] butyryl radicals] phenyl]-2-methyl-propionic ester and benzophenone be through 2-[4-[4-[4-shown in the linked reaction production VI (hydroxy benzophenone base)-piperidino]-1-oxo butyl] phenyl]-2,2-dimethyl acetic acid ester;
R in formula IV, formula V and the formula VI has identical implication, and R is alkyl.
2. synthetic method according to claim 1 is characterized in that, R is the straight chained alkyl of 1 to 6 carbon atom or the branched-chain alkyl of 1 to 6 carbon atom.
3. synthetic method according to claim 1 and 2 is characterized in that, in the step (1), and 4-shown in described catalyzer and the formula IV (4-chlorobutyryl)-α, the weight ratio of alpha-alpha-dimethyl phenyl acetic acid ester is 0.003～0.01:1.
4. synthetic method according to claim 1 is characterized in that, in the step (1), and 4-shown in the described formula IV (4-chlorobutyryl)-α, the mol ratio of alpha-alpha-dimethyl phenyl acetic acid ester and salt of wormwood is 1:2～3;
In the step (2), 2-[4-[4-shown in the described formula V (4-cyano group-piperidino)] butyryl radicals] phenyl]-mol ratio of 2-methyl-propionic ester and sodium Metal 99.5 is 1:2～3.
5. synthetic method according to claim 1 is characterized in that, in the step (1), described first organic solvent is 4-methyl-2 pentanone, toluene, N, a kind of in dinethylformamide, the tetrahydrofuran (THF);
In the step (2), described second organic solvent is toluene, dimethylbenzene, N, a kind of in dinethylformamide, the ethylene glycol.
6. synthetic method according to claim 1 is characterized in that in the step (1), and the temperature of described condensation reaction is 80 ℃～110 ℃.
7. synthetic method according to claim 1 is characterized in that, in the step (2), described benzophenone drops to reaction system with the form of second organic solvent solution of benzophenone, and the temperature that drips the process reaction system is 50 ℃～80 ℃;
2-[4-[4-shown in the described formula V (4-cyano group-piperidino)] butyryl radicals] phenyl]-2-methyl-propionic ester is with 2-[4-[4-(4-cyano group-piperidino)] butyryl radicals] phenyl]-form of second organic solvent solution of 2-methyl-propionic ester drops to reaction system, and the temperature that drips the process reaction system is 120 ℃～150 ℃.
8. synthetic method according to claim 1 is characterized in that, in the step (2), described linked reaction is carried out under protection of inert gas.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4254129A (en) * | 1979-04-10 | 1981-03-03 | Richardson-Merrell Inc. | Piperidine derivatives |
| US4254130A (en) * | 1979-04-10 | 1981-03-03 | Richardson-Merrell Inc. | Piperidine derivatives |
| WO2003000658A1 (en) * | 2001-06-25 | 2003-01-03 | Aurobindo Pharma Limited | PROCESS FOR THE PREPARATION OF A HIGHLY PURE PHARMACEUTICAL INTERMEDIATE, 4-(CYCLOPROPYLCARBONYL)-α,α-DIMETHYLPHENYLACETIC ACID |
| CN102079708A (en) * | 2011-02-11 | 2011-06-01 | 浙江启明药业有限公司 | Synthetic method of 4-(4-halobutyryl)-alpha, alpha-dimethyl phenylacetate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20020007068A1 (en) * | 1999-07-16 | 2002-01-17 | D'ambra Thomas E. | Piperidine derivatives and process for their production |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4254129A (en) * | 1979-04-10 | 1981-03-03 | Richardson-Merrell Inc. | Piperidine derivatives |
| US4254130A (en) * | 1979-04-10 | 1981-03-03 | Richardson-Merrell Inc. | Piperidine derivatives |
| WO2003000658A1 (en) * | 2001-06-25 | 2003-01-03 | Aurobindo Pharma Limited | PROCESS FOR THE PREPARATION OF A HIGHLY PURE PHARMACEUTICAL INTERMEDIATE, 4-(CYCLOPROPYLCARBONYL)-α,α-DIMETHYLPHENYLACETIC ACID |
| CN102079708A (en) * | 2011-02-11 | 2011-06-01 | 浙江启明药业有限公司 | Synthetic method of 4-(4-halobutyryl)-alpha, alpha-dimethyl phenylacetate |
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