Tirofiban hydrochloride, MK-383, L-700462, Aggrastat

合成路线:4-Pyridineacetic acid (I) was hydrogenated to the corresponding piperidine (II) in the presence of PtO2.After protection of (II) as the N-Boc derivative (III),reduction of its carboxylate group with borane in THF provided alcohol (IV).Subsequent Swern oxidation of alcohol (IV) furnished aldehyde (V).This was then subjected to a Wittig condensation with carbomethoxytriphenylphosphorane to yield the unsaturated ester (VI),which was further hydrogenated to (VII) in the presence of Pd/C.After saponification of the methyl ester function of (VII),the resultant carboxylic acid was reduced to alcohol (VIII) by means of borane in THF.Conversion of alcohol (VIII) into the alkyl bromide (IX) was accomplished by treatment with carbon tetrabromide and triphenylphosphine.Then,alkylation of the phenolic hydroxyl of N-Cbz-L-tyrosine (X) with bromide (IX) in the presence of NaH in DMF afforded adduct (XI).

合成路线:Acid (XI) was converted to the methyl ester (XII) by alkylation with iodomethane in the presence of Cs2CO3.After removal of the N-Cbz group of (XII) by catalytic hydrogenolysis,the resultant amine (XIII) was acylated by butanesulfonyl chloride (XIV) producing sulfonamide (XV).Saponification of the ester group of (XV) with LiOH gave acid (XVI).The N-Boc group of (XVI) was finally cleaved by treatment with HCl in EtOAc.

参考文献标题:Novel sulfonamide fibrinogen receptor antagonists
文献作者:Egbertson,M.S.; Hartman,G.D.; Halczenko,W.; Laswell,W.L.; Duggan,M.E.(Merck & Co.,Inc.)
参考来源:WO 9319046


合成路线:In a different strategy,the lithium derivative of 4-picoline (XVII) was alkylated with 2-(3-bromopropoxy)tetrahydropyran (XVIII) to afford (XIX).Acidic hydrolysis of the tetrahydropyranyl protecting group furnished 4-(4-pyridinyl)butanol (XX).Alternatively,lithiation of 4-picoline (XVII),followed by alkylation with 1-bromo-3-chloropropane (XXI) gave rise to 4-(4-pyridinyl)butyl chloride (XXII).

合成路线:Tyrosine methyl ester (XXIII) was acylated with butanesulfonyl chloride (XIV) in the presence of pyridine to produce sulfonamide (XXIV).Mitsunobu coupling of pyridinyl butanol (XX) with the phenolic compound (XXIV) furnished ether (XXV).Subsequent hydrolysis of the methyl ester group of (XXV) employing LiOH afforded acid (XXVI).The title piperidine compound was then obtained by catalytic hydrogenation of the pyridine ring of (XXVI) in the presence of Pd/C.

参考文献标题:Process for preparing fibrinogen receptor antagonists
文献作者:Chung,J.Y.L.; Zhao,D.; Hughes,D.L.(Merck & Co.,Inc.)
参考来源:US 5312923; WO 9316994


合成路线:In a different strategy,the lithium derivative of 4-picoline (XVII) was alkylated with 2-(3-bromopropoxy)tetrahydropyran (XVIII) to afford (XIX).Acidic hydrolysis of the tetrahydropyranyl protecting group furnished 4-(4-pyridinyl)butanol (XX).Alternatively,lithiation of 4-picoline (XVII),followed by alkylation with 1-bromo-3-chloropropane (XXI) gave rise to 4-(4-pyridinyl)butyl chloride (XXII).

合成路线:In a variation of this process,L-tyrosine (XXVII) was initially protected as the bis-O-silylated derivative (XXVIII) employing N,O-bis(trimethylsilyl) trifluoroacetamide.Acylation of (XXVIII) with butanesulfonyl chloride (XIV),followed by hydrolysis of the silyl groups,gave rise to N-butanesulfonyl tyrosine (XXIX).The phenolic hydroxyl of (XXIX) was then alkylated by 4-(4-pyridinyl)butyl chloride (XXII) to produce ether (XXVI).Finally,hydrogenation of the pyridine ring furnished the target piperidine derivative,which was isolated as the corresponding hydrochloride salt.

参考文献标题:Process for preparing fibrinogen receptor antagonists
文献作者:Chung,J.Y.L.; Zhao,D.; Hughes,D.L.(Merck & Co.,Inc.)
参考来源:WO 9316995


合成路线:In a different strategy,the lithium derivative of 4-picoline (XVII) was alkylated with 2-(3-bromopropoxy)tetrahydropyran (XVIII) to afford (XIX).Acidic hydrolysis of the tetrahydropyranyl protecting group furnished 4-(4-pyridinyl)butanol (XX).Alternatively,lithiation of 4-picoline (XVII),followed by alkylation with 1-bromo-3-chloropropane (XXI) gave rise to 4-(4-pyridinyl)butyl chloride (XXII).

合成路线:In a variation of this process,L-tyrosine (XXVII) was initially protected as the bis-O-silylated derivative (XXVIII) employing N,O-bis(trimethylsilyl) trifluoroacetamide.Acylation of (XXVIII) with butanesulfonyl chloride (XIV),followed by hydrolysis of the silyl groups,gave rise to N-butanesulfonyl tyrosine (XXIX).The phenolic hydroxyl of (XXIX) was then alkylated by 4-(4-pyridinyl)butyl chloride (XXII) to produce ether (XXVI).Finally,hydrogenation of the pyridine ring furnished the target piperidine derivative,which was isolated as the corresponding hydrochloride salt.

参考文献标题:A practical synthesis of fibrinogen receptor antagonist MK-383 - Selective functionalization of (S)-tyrosine
文献作者:Chung,J.Y.L.; Zhao,D.; Hughes,D.L.; Grabowski,E.E.
参考来源:Tetrahedron 1993,49(26),5767


合成路线:4-Pyridineacetic acid (I) was hydrogenated to the corresponding piperidine (II) in the presence of PtO2.After protection of (II) as the N-Boc derivative (III),reduction of its carboxylate group with borane in THF provided alcohol (IV).Subsequent Swern oxidation of alcohol (IV) furnished aldehyde (V).This was then subjected to a Wittig condensation with carbomethoxytriphenylphosphorane to yield the unsaturated ester (VI),which was further hydrogenated to (VII) in the presence of Pd/C.After saponification of the methyl ester function of (VII),the resultant carboxylic acid was reduced to alcohol (VIII) by means of borane in THF.Conversion of alcohol (VIII) into the alkyl bromide (IX) was accomplished by treatment with carbon tetrabromide and triphenylphosphine.Then,alkylation of the phenolic hydroxyl of N-Cbz-L-tyrosine (X) with bromide (IX) in the presence of NaH in DMF afforded adduct (XI).

合成路线:Acid (XI) was converted to the methyl ester (XII) by alkylation with iodomethane in the presence of Cs2CO3.After removal of the N-Cbz group of (XII) by catalytic hydrogenolysis,the resultant amine (XIII) was acylated by butanesulfonyl chloride (XIV) producing sulfonamide (XV).Saponification of the ester group of (XV) with LiOH gave acid (XVI).The N-Boc group of (XVI) was finally cleaved by treatment with HCl in EtOAc.

合成路线:Intermediate (XI) was converted to the title compound by an alternative method,reported to provide a higher enantiomeric excess.Hydrogenolysis of the N-Cbz group of (XI) in the presence of Pd/C gave the aminoacid (XV).Subsequent acylation of (XV) with butanesulfonyl chloride (XIV) under Schotten-Baumann conditions furnished sulfonamide (XVI),which was then treated with HCl in EtOAc to remove the N-Boc protecting group.
参考文献标题:Non-peptide fibrinogen receptor antagonists.2.Optimization of a tyrosine template as a mimic for Arg-Gly-Asp
文献作者:Duggan,M.E.; Chang,C.T.C.; Egbertson,M.S.; Gould,R.J.; Halczenko,W.; Hartman,G.D.; Laswell,W.L.; Lynch,J.J .Jr.; Lynch,R.J.; Manno,P.D.; et al.
参考来源:J Med Chem 1994,37(16),2537