合成路线1

The reduction of the chiral propionic acid (VII) with NaBH4 in THF gives the primary alcohol (XXIX), which by reaction with SOCl2 and pyridine in CHCl3 yields the chloride (XXX). Condensation of (XXX) with the butyrolactone intermediate (XXVII) by means of Mg and dibromoethane affords the ketonic adduct (XXXI). Reduction of the exocyclic carbonyl group of (XXXI) with NaBH4 in THF/ methanol provides a 3:1 diastereomeric mixture of the desired chiral alcohol (XXXII) and its OH-epimer (XXXIII) that are separated by flash chromatography. Reaction of (XXXII) with MsCl and TEA, followed by treatment with NaN3, affords the azido derivative (XXXIV), which is condensed with 4-amino-3,3-dimethylbutyramide (XIX) by means of 2-hydroxypyridine and TEA to provide the adduct (XXXV). Finally, the azido group of (XXXV) is reduced with H2 over Pd/ in MeOH to yield the target amino alcohol. An extensive study on the stereoselective reduction of the ketonic adduct (XXXI) has been performed. No better diastereoselectivity than 3:1 has been obtained for the synthesis of the chiral alcohol (XXXII). However, excellent diastereoselectivity (97:3) has been obtained for the synthesis of its OH-epimer, alcohol (XXXIII), with K-selectride in THF, which could potentially provide access to the target amino alcohol via a double inversion protocol.

合成路线2

Alternatively, the chiral phenylpropyl chloride (XXX) can also be prepared as follows: Reduction of the cinnamic acid (XXXVI) with H2 over Pd/C in ethyl acetate gives the phenylpropionic acid (XXXVII), which is treated with oxalyl chloride to yield the acyl chloride (XXXVIII). Condensation of (XXXVIII) with (+)-pseudoephedrine (XXXIX) by means of NaOH in toluene/water affords the chiral amide (XL), which is enantioselectively alkylated with 2-iodopropane (XLI) by means of LDA in THF to provide the adduct (XLII). Reduction of the amide group of (XLII) with BH3/NH3 in THF gives the already reported primary alcohol (XXIX), which is finally treated with POCl3 in hot toluene to afford the phenylpropyl chloride intermediate (XXX).

合成路线3

The chiral azido intermediate (XXXIV) can also be obtained as follows: Reaction of (+)-pseudoephedrine isovaleramide (XLIII) with allyl bromide (XXI) by means of LDA in THF gives the pentenoyl amide (XLIV), which is treated with NBS in DME/water to yield the spiro compound (XLV). Hydrolysis of the bromomethyl group of (XLV) with tetrabutylammonium acetate and K2CO3 affords the carbinol (XLVI), which is oxidized to aldehyde (XLVII) with SO3/pyridine and TEA in DMSO/dichloromethane. Condensation of (XLVII) with the propyl chloride intermediate (XXX) by means of Mg, dibromoethane and CeCl3 in refluxing THF provides the already reported chiral hydroxylactone (XXXII), which is treated first with 4-bromobenzenesulfonyl chloride and then with NaN3 to give the desired azido derivative (XXXIV).

合成路线4

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).

合成路线5

Alternatively, the spiro aldehyde (XLVII) is treated with N-benzylhydroxylamine in dichloromethane to give nitrone (LII), which is submitted to a Grignard reaction with the magnesium derivative of intermediate (XXX) in THF to afford the adduct (LIII) as a mixture of epimers at the amino group. Simultaneous N-dehydroxylation and cleavage of the spiro function of (LIII) by means of Zn, Cu(OAc)2 in AcOH/water gives lactone (LIV), which is condensed with 3-amino-2,2-dimethylpropionamide (XIX) by means of TEA and 2-hydroxypyridine giving the adduct (LV). Finally, the benzylamino group of (LV) is removed with H2 over Pd/C in methanol to yield a mixture of two epimers at the amino group, from which aliskiren is separated.

合成路线6

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7

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.

合成路线8

合成路线9

合成路线10