Aliskiren fumarate, CGP-60536(free base), SPP-100B, SPP-100(free base), CGP-60536B

合成路线:Alternatively,the chiral azido intermediate (XXXIV) can also be synthesized as follows: Alkylation of oxazolidinone (V) with 1-chloro-3-iodopropene (XLVIII) by means of LiHMDS in THF gives compound (XLIX),which is condensed with the magnesium derivative of the phenylpropyl chloride (XXX) to yield,after working up,amide (L).Bromination of (L) with NBS and phosphoric acid affords the bromolactone (LI),which by treatment with NaN3 in tripropylene glycol/water provides the azido derivative (XXXIV).

参考文献标题:2-Alkyl-5-halogen-pent-4-ene carboxylic acids and their production
文献作者:Stutz,S.; Herold,P.(Speedel Pharma Inc.)
参考来源:WO 0109079; WO 0109083


合成路线:The condensation of benzaldehyde (I) with ethyl isovalerate (II) by means of hexyl lithium and DIA in THF gives the hydroxyester (III),which is acylated with Ac2O and DMAP in THF to yield the acetoxy derivate (IV).The elimination reaction in (IV) by means of t-BuOK in THF affords the unsaturated ester (V),which is hydrolyzed with KOH in ethanol to provide the unsaturated free acid (VI).Finally,this compound is enantioselectively reduced with H2 over several chiral Rh catalysts {[Rh(NBD)2BF4,[Rh(NBD)(OCOCF3)2],[Rh(NBD)Cl2],etc} to give the target intermediate 2(R)-isopropyl-3-[4-methoxy-3-(3-methoxypropoxy)phenyl]propionic acid (VII).(see scheme 26758001a,intermediate (VII)).

参考文献标题:Preparation of (R)-2-alkyl-3-phenylpropionic acids
文献作者:Herold,P.; Stutz,S.(Speedel Pharma Inc.)
参考来源:WO 0202500


合成路线:The condensation of benzaldehyde (I) with ethyl isovalerate (II) by means of hexyl lithium and DIA in THF gives the hydroxyester (III),which is acylated with Ac2O and DMAP in THF to yield the acetoxy derivative (IV).The elimination reaction in (IV) by means of t-BuOK in THF affords the unsaturated ester (V),which is reduced with diisobutylaluminum hydride in toluene to provide the unsaturated alcohol (VI).Finally,this compound is enantioselectively reduced with H2 over a chiral biphenylyl diphenylphosphine catalyst and a [Rh(norbornadiene)Cl]2 catalyst in toluene to give the target intermediate 2(R)-isopropyl-3-[4-methoxy-3-(3-methoxypropoxy)phenyl]-1-propanol (VII).(see scheme 26758001d,intermediate (XXIX)).

参考文献标题:Process for the preparation of (R)-2-alkyl-3-phenyl-1-propanols
文献作者:Herold,P.; Stutz,S.; Spindler,F.(Speedel Pharma Inc.)
参考来源:WO 0202487


合成路线:The condensation of ethyl isovalerate (I) with 1,3-dichloropropene (II) by means of BuLi and DIA in THF gives 5-chloro-2-isopropyl-4-pentenoic acid ethyl ester (III),which is hydrolyzed with NaOH in ethanol to yield the corresponding racemic acid (IV).The optical resolution of (IV) is carried out by means of cinchonidine and TEA in THF to afford 5-chloro-2(S)-isopropyl-4-pentenoic acid (V),which can also be obtained by asymmetric synthesis as follows: Condensation of 4(S)-benzyl-3-(3-methylbutyryl)oxazolidin-2-one (VI) with 3-iodo-1-propenyl chloride (VII) by means of LiHMDS in THF gives 4(S)-benzyl-3-(2(S)-isopropyl-3-methylbutyryl)oxazolidin-2-one (VIII),which is hydrolyzed with LiOH in THF/water to afford the chiral pentanoic acid (V).The reaction of (V) with oxalyl chloride in toluene gives the corresponding acyl chloride (IX),which is treated with dimethylamine and pyridine in dichloromethane to yield the dimethylamide (X).The condensation of (X) with the chiral chloro derivative (XI) (obtained by reaction of the corresponding alcohol (XII) with CCl4 and trioctylphosphine) by means of Mg and 1,2-dibromoethane in THF affords the octenamide (XIII).The cyclization of (XIII) by means of phosphoric acid and simultaneous bromination with NBS in THF provides the chiral bromolactone (XIV),which is opened by means of dimethylamine and Et2AlCl in dichloromethane to give the chiral 5-bromo-4-hydroxy-2,7-diisopropyloctanamide (XV).The reaction of (XV) with acetic anhydride and pyridine in dichloromethane yields the acetoxy derivative (XVI),which is treated with LiN3 to afford the 5(S)-azido derivative (XVII).

合成路线:The cyclization of (XVII) by means of TsOH in refluxing methanol gives the chiral lactone (XVIII),which is condensed with 3-amino-2,2-dimethylpropionamide (XIX) by means of TEA and 2-hydroxypyridine at 90 C to yield the corresponding amide (XX).Finally,the azido group of (XX) is reduced with H2 over Pd/C in tert-butyl methyl ether to afford the target Aliskiren.

参考文献标题:Process for the preparation of substd.octanoyl amides
文献作者:Herold,P.; Stutz,S.(Speedel Pharma Inc.)
参考来源:WO 0208172


合成路线:The condensation of the chiral chloro derivative (I) with 5-chloro-[2(S)-isopropyl]-4-pentanoic acid methyl ester (II) by means of Mg and dibromoethane in THF gives the chiral octenoic ester (III) which is converted to the corresponding acid (IV) by means of LiOH in THF/methanol/water.The reaction of (IV) with NBS in dichloromethane yields the bromolactone (V),which is treated with LiOH in isopropanol to yield the epoxide (VI).This compound,without isolation,is treated with HCl in the same solvent to afford the chiral hydroxylactone (VII).The reaction of the OH group of (VII) with MsCl and pyridine in toluene provides the mesylate (VIII),which is treated with NaN3 in hot 1,3-dimethylperhydropyrimidin-2-one to give the azido derivative (IX).The condensation of (IX) with 3-amino-2,2-dimethylpropionamide (X) by means of 2-hydroxypyridine in hot TEA yields the carboxamide (XI).Finally,the azido group of (XI) is reduced with H2 over Pd/C in tert-butyl methyl ether to provide the target Aliskiren.

参考文献标题:Process for the preparation of substd.octanoyl amides
文献作者:Herold,P.; Stutz,S.; Spindler,F.(Speedel Pharma Inc.)
参考来源:WO 0202508


合成路线:Alkylation of 3-hydroxy-4-methoxybenzyl alcohol (I) with 1-bromo-3-methoxypropane (II) gives ether (III).Subsequent conversion of benzyl alcohol (III) into bromide (IV) is carried out using bromotrimetylsilane.The chiral isovaleryloxazolidinone (V) is alkylated with bromide (IV) by means of LiHMDS to afford (VI),which is hydrolyzed to the (S)-2-aryl-2-isopropylpropionic acid (VII) by means of lithium peroxide.The reduction of acid (VII) to the corresponding alcohol with NaBH4/I2 reagent,followed by treatment with PPh3 and NBS,provides bromide (VIII).Alkylation of the chiral dimethoxydihydropyrazin (IX) with bromide (VIII) produces (X).Further hydrolysis of the pyrazine ring of (X) with HCl,followed by Boc protection of the resulting (S,S)-amino ester,yields compound (XI).Reduction of the ester group of (XI) with DIBAL gives aldehyde (XII).This compound is condensed with the Grignard reagent (XIII) to afford the diastereomeric mixture of amino alcohols (XIV).Treatment of mixture (XIV) with 2,2-dimethoxypropane (XV) and TsOH produces a mixture of oxazolidines,from which the required (S,S,S)-isomer (XVI) is isolated by flash chromatography.Hydrogenolitic deprotection of the benzyl ether of (XVI) gives alcohol (XVII).

合成路线:This alcohol is oxidized to aldehyde with NMMO and tetrapropylammonium perruthenate (TPAP),and further oxidized to carboxylic acid (XVIII) with KMnO4 and tetrabutylammonium bromide (TBAB).Coupling of (XVIII) with aminoamide (XIX) by means of diethyl cyanophosphonate and TEA gives (XX).Finally,acid hydrolysis of the oxazolidine ring and Boc protecting groups of (XX) furnishes the corresponding amino alcohol,which is finally converted to the hemifumarate salt.

参考文献标题:Structural modification of the P2' position of 2,7-dialkyl substituted 5(S)-amino-4(S)-hydroxy-8-phenyl-octane-carboxamides: Discovery of a potent non-peptide renin inhibitor active after once daily dosing in marmosets
文献作者:Rigollier,P.; Stutz,S.; Goeschke,R.; Yamaguchi,Y.; Maibaum,J.; Wood,J.
参考来源:15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998,Edinburgh) 1998,Abst P.230