CN101182306A - Method for synthesizing intermediate of fexofenadine - Google Patents
Method for synthesizing intermediate of fexofenadine Download PDFInfo
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Abstract
The present invention provides a synthesis method of the intermediates of fexofenadine. The intermediates are 4-[4-[4-(hydroxyl diphenyl methyl)-1-piperidyl]-1-butyryl]-alpha and alpha-dimethyl phenyl acetic acid (v). The method considers methyl allyl alcohol acetic ester and benzene as raw materials to be synthesized as the intermediate (i) by the Friedel-Crafts alkylation reaction, the ortho-para-orientation effect of phenylethyl alcohol and two methyl are used to increase steric hindrance; the intermediate (ii) with the comparatively pure intermediate is obtained by the Friedel-Crafts alkylation reaction; the intermediate (iii) is obtained by alkaline hydrolysis; then the intermediate (iv) is obtained by potassium permanganate oxidation; the intermediate (v) is generated by the condensation under the alkaline condition by the phase transfer catalysis; the v is deoxidized by sodium borohydride as slat to obtain the fexofenadine. The method has smooth technology, short route, high yield, low cost and friendly environment and is a feasible route for the industrialization.
Description
Technical field
The present invention relates to a kind of intermediate 4-[4-[4-(hydroxyl diphenyl methyl)-piperidino of non-sofinadine]-the 1-butyryl radicals]-α, the synthetic method of alpha-alpha-dimethyl phenyl acetic acid.
Background technology
(±)-4-[1-hydroxyl-4-[4-(hydroxy benzophenone base)-piperidino]-butyl]-α, the alpha-alpha-dimethyl phenyl acetic acid hydrochloride, medication name non-sofinadine (Fexofenadine) is specially controlled seasonal allergic rhinitis, chronic sudden rubella.This medicine is the active metabolite of terfenadine (Terfenadine), and its major advantage is a cardiac toxic of having removed its parent drug terfenadine.Fexofenadine is the antihistaminic agent with the effect of selectivity antagonism peripheral H1-receptor, and its enantiomer all demonstrates the antihistamine effect of about equalization.It is by key intermediate 4-[4-[4-(hydroxyl diphenyl methyl)-piperidino]-the 1-butyryl radicals]-α, alpha-alpha-dimethyl phenyl acetic acid reduction and hydrochloric acid salify and get.
At present, intermediate 4-[4-[4-(the hydroxyl diphenyl methyl)-piperidino of relevant fexofenadine]-the 1-butyryl radicals]-α, the synthetic method of alpha-alpha-dimethyl phenyl acetic acid mainly contains:
The route of U.S. Pat 4254129 is as follows:
This route is initial patent route, advantage is that route is short, shortcoming is with α, alpha-alpha-dimethyl phenyl acetic acid ethyl ester and 4-chlorobutanoylchloride generate 2-(4-(4-chloro-1-oxo-butyl)) phenyl-2 Methylpropionic acid ethyl ester through Friedel-Crafts reaction, adjacency pair position product is difficult to separation and purification (adjacency pair position ratio is 85%: 15%), causes relatively difficulty of cost up, industrialization.
U.S. Pat 6348597 routes are as follows:
Though this method improvement the method for US4254129, make adjacency pair position ratio increase (90: 10), make that still separation costs is higher.
The method of world patent WO9321156 is as follows:
This technology is with α, and the alpha-alpha-dimethyl phenyl acetic acid ethyl ester is through LiAlH
4Reduction, esterification generate intermediate 2-phenyl-2-methylpropanol acetic ester, make product through friedel-crafts reaction, condensation, hydrolysis, oxidation, reduction, its advantage is to have solved adjacency pair position product problem, deficiency is route long (reaction of 8 steps), the reduction lithium aluminium hydride, the cost height, and can only small serial production, the industrialization difficulty.
World patent WO02/102776 reported method is:
This route is by using Succinic anhydried and α, the alpha-alpha-dimethyl phenyl acetic acid ethyl ester carries out friedel-crafts reaction, though fail to solve the control problem of the adjacency pair position product of route US4254129 and US6348597, but adjacency pair position product is made with extra care purifying by salify, make intermediate purity be improved, solved quality problems, but lost yield, and route is long, and total recovery is low-cost high.
U.S. Pat 6242606 routes are as follows:
This route is a route that industrialization is feasible, after utilizing industrialization and benzene feedstock and methacrylic alcohol acetic ester synthetic mesophase 2-phenyl-2-methylpropanol acetic ester with low cost, utilize the adjacency pair position orientation effect of phenylethyl alcohol, two methyl increases are sterically hindered with introducing, make the contraposition product increase, the ortho position proportion of products is less, has solved the product purity problem; Through hydrolysis, phenyl-2 Methylpropionic acid (iv) for oxygenant synthetic intermediate 2-(4-(4-chloro-1-oxo-butyl)), esterification Synthetic 2 under the catalysis under acid catalysis-(4-(4-chloro-1-oxo-butyl)) phenyl-2 Methylpropionic acid ethyl ester, condensation gets intermediate 4-[4-[4-(hydroxyl diphenyl methyl)-piperidino under alkaline condition then]-the 1-butyryl radicals]-α, the alpha-alpha-dimethyl phenyl acetic acid ethyl ester; Sodium borohydride reduction generates intermediate (±)-4-[1-hydroxyl-4-[4-(hydroxy benzophenone base)-piperidino]-butyl]-α, a-dimethyl phenyl acetic acid ethyl ester is hydrolyzed into hydrochloride and promptly gets salt calculation fexofenadine.The problem of this route maximum be the reaction obtain key intermediate 2-(4-(4-chloro-1-oxo-butyl)) phenyl-2 Methylpropionic acid (iv) after, also will be through over-churning, condensation, reduction, hydrolysis, four unit processes of salify, because the reversible yield of esterification generally all 70～85%, makes whole route total recovery have only about 28%.
Summary of the invention
Purpose of the present invention is exactly for synthetic fexofenadine in the technology that solves above-mentioned US6242606, (±)-4-[1-hydroxyl-4-[4-(hydroxy benzophenone base)-piperidino]-butyl]-α, in the alpha-alpha-dimethyl phenyl acetic acid hydrochloride process, 2-(4-(4-chloro-1-oxo-butyl)) phenyl-2 Methylpropionic acid (iv) just can must be carried out condensation reaction after the esterification, then also to be hydrolyzed, what increase two-step reaction makes general line elongated, the problem that yield reduces cost and raises.
For reaching goal of the invention the technical solution used in the present invention be:
A kind of structure suc as formula (4-[4-[4-v) (hydroxyl diphenyl methyl)-piperidino]-the 1-butyryl radicals]-α, the synthetic method of alpha-alpha-dimethyl phenyl acetic acid, described method is as follows:
(1) use benzene feedstock and methacrylic alcohol acetic ester through AlCl
3Gram alkylated reaction synthetic mesophase 2-phenyl-2-methylpropanol acetic ester (i) is paid in catalysis;
(2) utilize the adjacency pair position orientation effect of phenylethyl alcohol (i), two methyl increases are sterically hindered with introducing, make the contraposition product increase, the less synthetic intermediate 2-of ortho position proportion of products (4-(4-chloro-1-oxo-butyl)) phenyl-2-methylpropanol acetic ester has (ii) solved the product purity problem;
(3) 2-(4-(4-chloro-1-oxo-butyl)) phenyl-2-methylpropanol acetic ester (ii) gets intermediate 2-(4-(4-chloro-1-oxo-butyl)) through hydrolysis phenyl-the 2-methylpropanol (iii);
(4) 2-(4-(4-chloro-1-oxo-butyl)) phenyl-2-methylpropanol (iii) gets intermediate 2-(4-(4-chloro-1-oxo-butyl)) through potassium permanganate oxidation phenyl-2 Methylpropionic acid (iv);
(5) intermediate 2-(4-(4-chloro-1-oxo-butyl)) phenyl-2 Methylpropionic acid (iv) under phase-transfer catalysis, alkaline condition condensation generate intermediate 4-[4-[4-(hydroxyl diphenyl methyl)-piperidino]-the 1-butyryl radicals]-α, alpha-alpha-dimethyl phenyl acetic acid is (v);
(6) 4-[4-[4-(hydroxyl diphenyl methyl)-piperidino]-the 1-butyryl radicals]-α, alpha-alpha-dimethyl phenyl acetic acid (v) promptly gets salt through sodium borohydride reduction acidifying salify and calculates fexofenadine.
The present invention has found one-step synthesis key intermediate 4-[4-[4-(hydroxyl diphenyl methyl)-piperidino]-the 1-butyryl radicals]-α, (method v) reduces two-step reaction to alpha-alpha-dimethyl phenyl acetic acid, makes synthetic total recovery bring up to 40% by 28%.
Principle of the present invention is: intermediate 2-(4-(4-chloro-1-oxo-butyl)) phenyl-2 Methylpropionic acid is (iv) in phase-transfer catalysis; condensation generates intermediate 4-[4-[4-(hydroxyl diphenyl methyl)-piperidino under the alkaline condition]-the 1-butyryl radicals]-α, alpha-alpha-dimethyl phenyl acetic acid is (v).
Described 4-[4-[4-(hydroxyl diphenyl methyl)-piperidino]-the 1-butyryl radicals]-α; 2-in the building-up reactions of alpha-alpha-dimethyl phenyl acetic acid (4-(4-chloro-1-oxo-butyl)) phenyl-2 Methylpropionic acid, α, the ratio of the amount of α-phenylbenzene-4-piperidine carbinols, phase-transfer catalyst, alkaloid substance is 1: 0.8～1.5: 0.1～1.0: 1.5～2.5.
Described 2-(4-(4-chloro-1-oxo-butyl)) phenyl-2 Methylpropionic acid, α, the ratio of the amount of α-phenylbenzene-4-piperidine carbinols, phase-transfer catalyst, alkaloid substance is preferably 1: 1: 0.66: 2.1.
Described 4-[4-[4-(hydroxyl diphenyl methyl)-piperidino]-the 1-butyryl radicals]-α, the synthetic phase-transfer catalyst of alpha-alpha-dimethyl phenyl acetic acid is preferably benzyltriethylammoinium chloride (TEBA).
Described 4-[4-[4-(hydroxyl diphenyl methyl)-piperidino]-the 1-butyryl radicals]-α, alpha-alpha-dimethyl phenyl acetic acid alkali is preferably NaOH.
Described 4-[4-[4-(hydroxyl diphenyl methyl)-piperidino]-the 1-butyryl radicals]-α, the temperature of the building-up reactions of alpha-alpha-dimethyl phenyl acetic acid is 5～8 hours at 35～40 ℃, reaction times.
Described 4-[4-[4-(hydroxyl diphenyl methyl)-piperidino]-the 1-butyryl radicals]-α, the building-up reactions of alpha-alpha-dimethyl phenyl acetic acid is carried out in the aqueous solution.
Described 4-[4-[4-(hydroxyl diphenyl methyl)-piperidino]-the 1-butyryl radicals]-α, the synthesis reaction solution pH scope of alpha-alpha-dimethyl phenyl acetic acid is controlled at 7.5-8.5.
Embodiment:
Synthesizing of embodiment one intermediate 2-phenyl-2-methylpropanol acetic ester (i)
(228g 2.0mol) and behind the benzene 1200ml, is cooled to 5 ℃ to add the methacrylic alcohol acetic ester in there-necked flask.And maintain the temperature at and add aluminum trichloride (anhydrous) (399g below 5 ℃, 3.0mol), pour in the mixture of ice and water after 1 hour in insulation reaction under this temperature, and add hydrochloric acid 100ml, separate organic phase, wash organic phase with water to neutral, dried over sodium sulfate is behind the recovery benzene, underpressure distillation obtains intermediate 2-phenyl-metallyl alcohol acetic ester, GC detection level.
(ii) synthetic of embodiment two 2-(4-(4-chloro-1-oxo-butyl)) phenyl-2-methylpropanol acetic ester
(150g 0.78mol) is dissolved in the 500ml methylene dichloride, is cooled to add aluminum trichloride (anhydrous) below 5 ℃ (208g 1.56mol), and drips the 4-chlorobutanoylchloride under this temperature, at 0-5 ℃ of reaction 15h with intermediate i.Reaction solution is slowly poured in the mixture of ice and water, added hydrochloric acid 150ml, separate organic phase, use sodium bicarbonate aqueous solution, water washing organic phase respectively, drying, solvent evaporated, obtaining intermediate ii is oily matter (221.1g, 95.6%).Not purifiedly be directly used in next step reaction.
1H?NMR(300MHz，CDCl
3)δ1.34(6H，s)，1.95(3H，s)，2.18(2H，quent.)，3.13(2H，t)，3.65(2H，t)，4.12(2H，s)，7.43，7.90(2H?each，d).
(iii) synthetic of embodiment three 2-(4-(4-chloro-1-oxo-butyl)) phenyl-2-methylpropanol
With 2-(4-(4-chloro-1-oxo-butyl)) phenyl-metallyl alcohol acetic ester, 25% hydrochloric acid 600ml, ethanol 1500ml add in the reaction flask, back flow reaction 3 hours.Behind the evaporate to dryness ethanol, methylene dichloride is added in the residual solution, use sodium bicarbonate aqueous solution, water washing organic phase respectively, drying, solvent evaporated, obtaining intermediate iii is oily matter (211g, 95%).Not purifiedly be directly used in next step reaction.
1H?NMR(300MHz，CDCl
3)δ1.35(6H，s)，2.21(2H，quent.)3.15，(2H，t)，3.64(2H，s)，3.66 (2H，5)，7.48，7.93(2Heach，d).
(iv) synthetic of embodiment four 2-(4-(4-chloro-1-oxo-butyl)) phenyl-2 Methylpropionic acid
With 2-(4-(4-chloro-1-oxo-butyl)) phenyl-2-methylpropanol (24.5g, 0.1mol) water 34ml and acetate 150ml add in the there-necked flask, be cooled to below 10 ℃, gradation adds potassium permanganate powder under the vigorous stirring, 1.5 hour add, and stirring 5 hours below 10 ℃, filter, add frozen water 300ml, sodium bisulfite 45g, dichloromethane extraction 150ml * 3 time merge organic layer, after 100ml water washing once, with 15%NaOH aqueous solution 150ml * 2 washing dichloromethane layers, combining water layer behind the dichloromethane extraction water, transfers to 3 with hydrochloric acid with water layer pH.Use dichloromethane extraction, washing and drying obtains crystalline solid 21.25g (mp78.5-80.3) after the solvent evaporated.
1H?NMR(300MHz，CDCl
3)δ1.63(6H，s)，2.22(2H，quent.)，3.17(2H，t)，3.67(2H，t)，7.50，7.92(2H?each，d)，12.3(1H，s，br).
Embodiment five 4-[4-[4-(hydroxyl diphenyl methyl)-piperidino]-the 1-butyryl radicals]-α, alpha-alpha-dimethyl phenyl acetic acid (synthesizing v)
With TEBA 50g, α, α-phenylbenzene-4-piperidine carbinols (101.8g, 0.335mol), 2-(4-(4-chloro-1-oxo-butyl)) phenyl-2 Methylpropionic acid, 0.355mol and 800ml water adds in the reaction flask, controlled temperature is not higher than 40 degree, and the sodium hydroxide solution of dropping 40% is adjusted to pH8.0, and keeps temperature to be no more than 40 ℃, finish to reaction by dripping NaOH aqueous solution control pH8.0, TLC controls reaction end.Question response back fully uses hydrochloric acid neutralization reaction liquid to pH5.0, uses dichloromethane extraction 300ml*2, and anhydrous sodium sulfate drying, evaporated under reduced pressure solvent obtain this step product 200g.IR(KBr)3422，3057，2965，1677，1604，1570，1470，1448，1406，1363，1249，1189，1099，750，705cm
-1。
1H?NMR(CDCl
3)：7.75(d，2H)，7.4(m，6H)，7.2(m，4H)，7.2(m，2H)，3.9(br.s，2H)，3.2(m，2H)，2.9(m，2H)，2.6(m，2H)，2.4(m，2H)，1.9(m，3H)，1.8(m，2H)，1.44(s，6H)，1.4(m，2H)。
Embodiment six～eight
Other conditions are with embodiment five, and with the α of reaction, the amount of α-phenylbenzene-4-piperidine carbinols changes 81.44g, 112g, 152.7g into, are respectively 151g, 198g, 192g with the amount of method treating product
Embodiment nine～ten
Other conditions are with embodiment five, and transfer catalyst changes Tetrabutyl amonium bromide 50g, benzyl triethyl ammonium ammonium hydroxide 50g into, and product must be measured and be respectively 199.3g, 198.5g.
Embodiment 11～13
Other conditions are with embodiment five, and the reaction times is respectively 3,12,18 hours, and the amount of product is respectively 175g, 198.2g, 199.4g.
Embodiment 14～15
Other conditions are with embodiment five, and the temperature of reaction is at 10,60 ℃, and the amount of product is respectively 122g, 118.2g
Embodiment 16～18
Other conditions are with embodiment five, and the amount that pH is controlled at 7.0,10.0,12.0 products is respectively 130.4g, 189.3g, 145.7g
Synthesizing of embodiment 19 fexofenadine hydrochlorides
With 4-[4-[4-(hydroxyl diphenyl methyl)-piperidino]-the 1-butyryl radicals]-α, (0.7g 1.31mmol) is dissolved in the 30ml ethanol alpha-alpha-dimethyl phenyl acetic acid, and (0.06g 1.5mmol) with water 5ml, is cooled to 5 ℃, and gradation adds NaBH to add sodium hydroxide
4(0.105g 2.77mmol), rises to room temperature reaction 3 hours then gradually, transfers pH5 with hydrochloric acid, the evaporated under reduced pressure solvent adds the entry methylene dichloride, extraction, and organic layer washes with water, dried over mgso after the solvent evaporated, adds dissolve with ethanol, transfers pH2.5-3 with acidic alcohol then, the adularescent xln is separated out, and filters, filter cake adds anhydrous propanone again and refluxed 1 hour, and cooling is filtered, filter cake is in 45～50 ℃ of drying under reduced pressure 8h, target product (0.68g), mp:197～199 ℃.
IR(KBr)3403，3058，2971，?1718，1634，1492，1471，1448，1393，1227，1150，1099，1069，839，750，706cm
-1；
1H?NMR?(CDCl
3)δ7.50(d，4H，J＝8.2Hz)，7.3(m，8H)，7.2(m，2H)，4.66(t，1H，J＝5.6Hz)，3.5(m，2H)，3.0(m，4H)，2.8(m，2H)，1.7(m，8H)，1.53(s，6H)；
13C?NMR(CDCl
3)δ181.1，147.4，146.1，144.4，129.5，128.0，127.4，127.2，79.9，73.9，57.0，54.1，42.7，36.8，27.1?，25.7，21.7；
MS(CI，CH
4)m/z(rel，intensity)502(MH
+，50)，485(33)，484(100)，458(25)，454(33)，424(17).
Claims (1)
1. the synthetic method of the intermediate of non-sofinadine, the structural formula of this intermediate is
4-[4-[4-(hydroxyl diphenyl methyl)-piperidino]-the 1-butyryl radicals]-α, alpha-alpha-dimethyl phenyl acetic acid
(v), it is characterized in that described method is as follows:
Phenyl-2 Methylpropionic acid (iv) with 2-(4-(4-chloro-1-oxo-butyl)), and α, α-phenylbenzene-4-piperidine carbinols, through phase-transfer catalysis, condensation reaction generates 4-[4-[4-(hydroxyl diphenyl methyl)-piperidino under the environment of alkalescence]-the 1-butyryl radicals]-α, (compound v) for alpha-alpha-dimethyl phenyl acetic acid, 2-(4-(4-chloro-1-oxo-butyl)) phenyl-2 Methylpropionic acid, the α of reaction, the ratio of the amount of α-phenylbenzene-4-piperidine carbinols, phase-transfer catalyst, NaOH matter is 1: 0.8～1.5: 0.1～1.0: 1.5～2.5; The temperature of reaction is at 10～60 ℃, and the reaction times is 3～18 hours.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101585804B (en) * | 2009-06-06 | 2011-03-16 | 浙江大学宁波理工学院 | Synthetic method of a fexofenadine hydrochloride |
| CN102070570A (en) * | 2009-11-21 | 2011-05-25 | 浙江华海药业股份有限公司 | 2-methyl-2(4-(2-oxo-tetrahydrofuran-3-carbonyl)phenyl)propionitrile of fexofenadine intermediate and preparation method for salt thereof |
| CN102070490A (en) * | 2009-11-21 | 2011-05-25 | 浙江华海药业股份有限公司 | Method for preparing fexofenadine intermediate 2-(4-(4-maloyl) phenyl)-2-methylpropionitrile |
| CN102070512A (en) * | 2009-11-21 | 2011-05-25 | 浙江华海药业股份有限公司 | Synthesizing route and preparation method of high-purity fexofenadine and intermediate thereof |
-
2007
- 2007-12-14 CN CN2007100931338A patent/CN101182306B/en not_active Expired - Fee Related
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101585804B (en) * | 2009-06-06 | 2011-03-16 | 浙江大学宁波理工学院 | Synthetic method of a fexofenadine hydrochloride |
| CN102070570A (en) * | 2009-11-21 | 2011-05-25 | 浙江华海药业股份有限公司 | 2-methyl-2(4-(2-oxo-tetrahydrofuran-3-carbonyl)phenyl)propionitrile of fexofenadine intermediate and preparation method for salt thereof |
| CN102070490A (en) * | 2009-11-21 | 2011-05-25 | 浙江华海药业股份有限公司 | Method for preparing fexofenadine intermediate 2-(4-(4-maloyl) phenyl)-2-methylpropionitrile |
| CN102070512A (en) * | 2009-11-21 | 2011-05-25 | 浙江华海药业股份有限公司 | Synthesizing route and preparation method of high-purity fexofenadine and intermediate thereof |
| CN102070490B (en) * | 2009-11-21 | 2014-07-30 | 浙江华海药业股份有限公司 | Method for preparing fexofenadine intermediate 2-(4-(4-maloyl) phenyl)-2-methylpropionitrile |
| CN102070512B (en) * | 2009-11-21 | 2014-11-19 | 浙江华海药业股份有限公司 | Synthesizing route and preparation method of high-purity fexofenadine and intermediate thereof |
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