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【结 构 式】 
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【药物名称】Fexofenadine hydrochloride, Terfenadine carboxylate hydrochloride, MDL-16455A, Allegra Flash, Altiva, Telfast, Allegra 【化学名称】(±)-4-[1-Hydroxy-4-[4-(hydroxydiphenylmethyl)piperidin-1-yl]butyl]-alpha,alpha-dimethylbenzeneacetic acid hydrochloride 【CA登记号】153439-40-8, 138452-21-8 (free base), 83799-24-0 (undefined isomer; free base) 【 分 子 式 】C32H40ClNO4 【 分 子 量 】538.1329 |
【开发单位】Aventis Pharma (Originator), Sepracor (Originator), Lepetit (Not Determined), ViroPharma (Marketer) 【药理作用】Allergic Skin Disorders, Treatment for, Asthma Therapy, Atopic Dermatitis, Agents for, DERMATOLOGIC DRUGS, Drugs for Allergic Rhinitis, RESPIRATORY DRUGS, Treatment of Upper Respiratory Tract Disorders, Urticaria, Treatment for, Histamine H1 Antagonists |
合成路线1
1) The reduction of 2-methyl-2-phenylpropionic acid with LiAlH4 in THF gives 2-methyl-2-phenyl-1-propanol (II), which is acetylated with acetic anhydride in pyridine yielding the acetate (III). The Friedel-Crafts condensation of (III) with 4-chlorobutyryl chloride (IV) by means of AlCl3 in dichloromethane affords the butyrophenone (V), which is condensed with alpha,alpha-diphenylipiperidine-4-methanol (VI) by means of KHCO3 and KI in refluxing toluene/water to give the butyrophenone (VII). The deacetylation of (VII) with NaOH in refluxing methanol yields the primary alcohol (VIII), which is oxidized with oxalyl chloride and DMSO in methylene chloride to the corresponding aldehyde (IX). The oxidation of (IX) with KMnO4 in acetone affords the ketoacid (X), which is finally reduced with NaBH4 in water. 2) The acetate (III) can also be obtained by Friedel-Crafts condensation of 2-methyl-2-propenyl acetate (XI) with refluxing benzene (XII) by means of AlCl3. 3) The ketoacid (X) can also be obtained by direct oxidation of the primary alcohol (VIII) with H5IO6 in chloroform/acetonitrile, or K2S2O8 in acetone/acetonitrile, both catalyzed by RuCl3.5H2O.
| 【1】 Graul, A.; Castañer, J.; Fexofenadine Hydrochloride. Drugs Fut 1996, 21, 10, 1017. |
| 【2】 King, C.-H.; Kaminski, M.A. (Merrell Pharmaceuticals, Inc.); 4-Diphenylmethyl piperidine derivs. and process for their preparation. JP 1996502022; WO 9321156 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 17173 | 2-Methyl-2-phenylpropionic acid; 2-Methyl-2-phenyl-propionic acid | 826-55-1 | C10H12O2 | 详情 | 详情 |
| (II) | 17174 | 2-methyl-2-phenyl-1-propanol | C10H14O | 详情 | 详情 | |
| (III) | 17175 | 2-methyl-2-phenylpropyl acetate | 2901-13-5 | C12H16O2 | 详情 | 详情 |
| (IV) | 11265 | 4-Chlorobutanoyl chloride; 4-Chlorobutyric acid chloride | 4635-59-0 | C4H6Cl2O | 详情 | 详情 |
| (V) | 17177 | 2-[4-(4-chlorobutanoyl)phenyl]-2-methylpropyl acetate | C16H21ClO3 | 详情 | 详情 | |
| (VI) | 17178 | diphenyl(4-piperidinyl)methanol; alpha,alpha-Diphenyl-4-piperidinomethanol; Azacyclonol | 115-46-8 | C18H21NO | 详情 | 详情 |
| (VII) | 17179 | 2-[4-(4-[4-[hydroxy(diphenyl)methyl]-1-piperidinyl]butanoyl)phenyl]-2-methylpropyl acetate | 76811-96-6 | C34H41NO4 | 详情 | 详情 |
| (VIII) | 17180 | 1-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-4-[4-[hydroxy(diphenyl)methyl]-1-piperidinyl]-1-butanone | C32H39NO3 | 详情 | 详情 | |
| (IX) | 17181 | 2-[4-(4-[4-[hydroxy(diphenyl)methyl]-1-piperidinyl]butanoyl)phenyl]-2-methylpropanal | C32H37NO3 | 详情 | 详情 | |
| (X) | 17182 | 2-[4-(4-[4-[hydroxy(diphenyl)methyl]-1-piperidinyl]butanoyl)phenyl]-2-methylpropionic acid | 76811-98-8 | C32H37NO4 | 详情 | 详情 |
| (XI) | 17183 | 2-methyl-2-propenyl acetate；methallyl acetate | 820-71-3 | C6H10O2 | 详情 | 详情 |
| (XII) | 13364 | Benzene | 71-43-2 | C6H6 | 详情 | 详情 |
| (XIV) | 17609 | ethyl 2-methyl-2-phenylpropanoate | C12H16O2 | 详情 | 详情 | |
| (XV) | 17610 | ethyl 2-[4-(cyclopropylcarbonyl)phenyl]-2-methylpropanoate | C16H20O3 | 详情 | 详情 | |
| (XVI) | 17611 | ethyl 2-[4-(4-chlorobutanoyl)phenyl]-2-methylpropanoate | C16H21ClO3 | 详情 | 详情 | |
| (XVII) | 17612 | ethyl 2-[4-(4-[4-[hydroxy(diphenyl)methyl]-1-piperidinyl]butanoyl)phenyl]-2-methylpropanoate | C34H41NO4 | 详情 | 详情 | |
| (XVIII) | 17613 | ethyl 2-[4-(1-hydroxy-4-[4-[hydroxy(diphenyl)methyl]-1-piperidinyl]butyl)phenyl]-2-methylpropanoate | C34H43NO4 | 详情 | 详情 |
合成路线2
4) The Friedel-Crafts condensation of cyclopropylcarbonyl chloride (XIII) with 2-methyl-2-phenylpropionic acid ethyl ester (XIV) gives 2-[4-(cyclopropylcarbonyl)phenyl]-2-methylpropionic acid ethyl ester (XV), which by reaction with dry HCl in hot acetonitrile yields the 4-chlorobutyryl derivative (XVI). The condensation of (XVI) with the piperidine (VI) by means of KHCO3 affords the omega-piperidylbutyrophenone (XVII), which is reduced with NaBH4 in methanol to give the dihydroxy ester (XVIII). Finally, this compound is saponified with NaOH in refluxing methanol. 5) The chlorobutyryl derivative (XVI) can also be obtained by direct Friedel-Crafts condensation of propionic ester (XIV) with 4-chlorobutyryl chloride (IV) by means of AlCl3 as before.
| 【1】 Graul, A.; Castañer, J.; Fexofenadine Hydrochloride. Drugs Fut 1996, 21, 10, 1017. |
| 【2】 Krauss, R.C.; Strom, R.M.; Scortichini, C.L.; Kruper, W.J.; Wolf, R.A.; Carr, A.A.; Rudisill, D.E.; Panzone, G.; Hay, D.A.; Wu, W.W. (Merrell Pharmaceuticals, Inc.); Novel intermediates for the preparation of antihistaminic 4-diphenylmethyl/diphenylmethoxy piperidine derivs. WO 9500480 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 11265 | 4-Chlorobutanoyl chloride; 4-Chlorobutyric acid chloride | 4635-59-0 | C4H6Cl2O | 详情 | 详情 |
| (VI) | 17178 | diphenyl(4-piperidinyl)methanol; alpha,alpha-Diphenyl-4-piperidinomethanol; Azacyclonol | 115-46-8 | C18H21NO | 详情 | 详情 |
| (XIII) | 14061 | Cyclopropanecarbonyl chloride; Cyclopropanecarboxylic acid chloride | 4023-34-1 | C4H5ClO | 详情 | 详情 |
| (XIV) | 17609 | ethyl 2-methyl-2-phenylpropanoate | C12H16O2 | 详情 | 详情 | |
| (XV) | 17610 | ethyl 2-[4-(cyclopropylcarbonyl)phenyl]-2-methylpropanoate | C16H20O3 | 详情 | 详情 | |
| (XVI) | 17611 | ethyl 2-[4-(4-chlorobutanoyl)phenyl]-2-methylpropanoate | C16H21ClO3 | 详情 | 详情 | |
| (XVII) | 17612 | ethyl 2-[4-(4-[4-[hydroxy(diphenyl)methyl]-1-piperidinyl]butanoyl)phenyl]-2-methylpropanoate | C34H41NO4 | 详情 | 详情 | |
| (XVIII) | 17613 | ethyl 2-[4-(1-hydroxy-4-[4-[hydroxy(diphenyl)methyl]-1-piperidinyl]butyl)phenyl]-2-methylpropanoate | C34H43NO4 | 详情 | 详情 |
合成路线3
Fexofenadine has been obtained by two new related ways: 1) The Grignard condensation of ethyl 2-(4-formylphenyl)-2-methylpropionate (I) with 2-(1,3-dioxolan-2-yl)ethylmagnesium bromide (II) gives the corresponding carbinol (III), which by a treatment with Amberlyst-15 yields the lactol (IV). The reductocondensation of (IV) with the piperidine derivative (V) by means of NaBH4 in methanol affords the ethyl ester (VI), which is finally hydrolyzed with NaOH. 2) The Grignard condensation of ethyl 2-[4-(chloroformyl)phenyl]-2-methylpropionate (VII) with 2-(1,3-dioxolan-2-yl)ethylmagnesium bromide (II) gives the corresponding ketone (VIII), which is reduced to carbinol (III) in the usual way. 3) The (S)-enantiomer of fexofenadine can be synthesized through the asymmetric reduction of the prochiral ketone (VIII) with chiral catalysts to afford the (S)-enantiomer of carbinol (III).
| 【1】 Fang, Q.K.; Senanayake, C.H.; Wilkinson, H.S.; Wald, S.A.; Li, H.; An efficient and facile synthesis of racemic and optically active fexofenadine. Tetrahedron Lett 1998, 39, 18, 2701. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 28700 | ethyl 2-(4-formylphenyl)-2-methylpropanoate | C13H16O3 | 详情 | 详情 | |
| (II) | 28701 | bromo[2-(1,3-dioxolan-2-yl)ethyl]magnesium | C5H9BrMgO2 | 详情 | 详情 | |
| (III) | 28702 | ethyl 2-[4-[3-(1,3-dioxolan-2-yl)-1-hydroxypropyl]phenyl]-2-methylpropanoate | C18H26O5 | 详情 | 详情 | |
| (IV) | 28703 | ethyl 2-[4-(5-hydroxytetrahydro-2-furanyl)phenyl]-2-methylpropanoate | C16H22O4 | 详情 | 详情 | |
| (V) | 17178 | diphenyl(4-piperidinyl)methanol; alpha,alpha-Diphenyl-4-piperidinomethanol; Azacyclonol | 115-46-8 | C18H21NO | 详情 | 详情 |
| (VI) | 17613 | ethyl 2-[4-(1-hydroxy-4-[4-[hydroxy(diphenyl)methyl]-1-piperidinyl]butyl)phenyl]-2-methylpropanoate | C34H43NO4 | 详情 | 详情 | |
| (VII) | 28704 | ethyl 2-[4-(chlorocarbonyl)phenyl]-2-methylpropanoate | C13H15ClO3 | 详情 | 详情 | |
| (VIII) | 28705 | ethyl 2-[4-[3-(1,3-dioxolan-2-yl)propanoyl]phenyl]-2-methylpropanoate | C18H24O5 | 详情 | 详情 |
合成路线4
The Friedel Craft's condensation of 2-methyl-2-phenylpropionic acid methyl ester (I) with succinic anhydride (II) by means of AlCl3 in CS2 or dichloromethane/nitrobenzene gives 2-[4-(hydroxysuccinyl)phenyl]-2-methylpropionic acid methyl ester (III) (purified through its phenethylamine salt), which is condensed with 4-(1-hydroxy-1,1-diphenylmethyl)piperidine (IV) by means of ethyl chloroformate and TEA in THF or with DCC and p-nitrophenol in ethyl acetate to yield the adduct (V). The reduction of the oxo groups of (V) by means of BH3/Me2S in THF affords the ester precursor (VI), which is finally hydrolyzed with NaOH in refluxing methanol to provide the target compound.
| 【1】 Schroeder, C.; Huddleston, R.; Charles, R. (Aventis Pharma Deutschland GmbH); Process for the production of the piperidine deriv. fexofenadine. WO 02102776 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 58227 | methyl 2-methyl-2-phenylpropanoate; Methyl alpha,alpha-dimethylbenzeneacetate | C11H14O2 | 详情 | 详情 | |
| (II) | 11291 | Dihydro-2,5-furandione; Succinic anhydride | 108-30-5 | C4H4O3 | 详情 | 详情 |
| (III) | 58228 | 4-[4-(2-methoxy-1,1-dimethyl-2-oxoethyl)phenyl]-4-oxobutanoic acid | C15H18O5 | 详情 | 详情 | |
| (IV) | 17178 | diphenyl(4-piperidinyl)methanol; alpha,alpha-Diphenyl-4-piperidinomethanol; Azacyclonol | 115-46-8 | C18H21NO | 详情 | 详情 |
| (V) | 58229 | methyl 2-[4-(4-{4-[hydroxy(diphenyl)methyl]-1-piperidinyl}-4-oxobutanoyl)phenyl]-2-methylpropanoate | C33H37NO5 | 详情 | 详情 | |
| (VI) | 58230 | methyl 2-[4-(1-hydroxy-4-{4-[hydroxy(diphenyl)methyl]-1-piperidinyl}butyl)phenyl]-2-methylpropanoate | C33H41NO4 | 详情 | 详情 |