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【结 构 式】

【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
      (±)-2-[4-[1-Hydroxy-4-[4-(hydroxydiphenylmethyl)piperidin-1-yl]butyl]phenyl]-2-methylpropionic 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
Extended Information