The reaction of tert-butoxycarbonyl-L-phenylalanine (I) with isobutyl chloroformate in THF gives the expected mixed anhydride which is treated with diazomethane and HCl yielding the corresponding chloromethyl ketone (II). The reduction of (II) with NaBH4 in THF affords the (S)-chlorohydrin (IV), which is treated with KOH in ethanol to obtain the chiral epoxide (V)(1,2). Ring opening of (V) with (?(cis)-N-tert-butyl-4-(4-pyridylmethoxy)piperidine-2-carboxamide (VI) by a treatment with LiCl in refluxing ethanol gives a mixture of diastereomers that is separated by chromatography giving the pure isomer (VII). The reaction of (VII) with tert-butoxycarbonyl-L-valine (VIII) by treatment first with trifluoroacetic acid (TFA), and condesation by means of BOP ((benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate) and NMM (N-methylmorpholine) affords the expected condensation product (IX). Finally, this compound is condensed with quinoline-2-carboxylic acid (X) by means of BOP and NMM as before. 2) The piperidine (VI) has been obtained by condensation of (?(cis)-N-(tert-butoxycarbonyl)-4-hydroxypiperidine-2-carboxamide (XI) with 4-(chloromethyl)pyridine (XII) by means of NaH in DMS, followed by hydrolysis with HCl.
Palinavir can also be obtained as follows: The controlled oxidation of 2(S)-(dibenzylamino)-3-phenyl-1-propanol (XIII) with pyridine-SO3 complex in DMSO gives the corresponding aldehyde (XIV), which is condensed with bromochloromethane (XV) by means of Li in THF followed by hydrolysis with HCl yielding regioselectively the 1-chloro-2-butanol (XVI). The debenzylation of (XVI) by hydrogenation over Pd/C affords the free amine (XVII), which is treated with tert-butoxycarbonyl anhydride/triethylamine and dehydrochlorinated with KOH in methanol to give the desired chiral epoxide (V).
The chiral piperidine (2S,4R)(VI) has been obtained as follows: The cyclization of 3-buten-1-ol (XXII) with (S)-1-phenylethylamine (XXIII) and glyoxylic acid (XXIV) by means of tosyl chloride in THF gives a mixture of the (2S,4R) and (2R,4S) lactones (XXV), which is resolved by fractional crystallyzation of their salts with the chiral camphorsulfonic acid (XXVI), followed by elimination of the acid with ammonia to afford (2S,4R)(XXVII). The reaction of lactone (XXVII) with isopropylmagnesium chloride and tert-butylamine in THF gives (2S,4R)-N-tert-butyl-4-hydroxy-1-(1(S)-phenylethyl)piperidine-2-carboxamide (XXVIII), which is debenzylated by hydrogenation and protected with tert-butoxycarbonyl anhydride yielding (2S,4R)-N-(tert-butoxycarbonyl)-4-hydroxypiperidine-2-carboxamide (2S,4R)(XI), which is finally condensed with 4-(chloromethyl)pyridine (XII) as before to obtain the chiral piperidine (2S,4R)(VI), already reported.
The condendsation of epoxide (V) with (2S,4R)(VI) by means of basic alumina in THF, followed by elimination of the protecting group with HCl and NaOH yields directly the condensation product (XVIII) as a pure diastereomer and with a free amino group. Finally, this compound is condensed with N-(2-quinolylcarbonyl)-L-valine (XIX) through its activation compound with isobutyl chloroformate (the 4(S)-isopropyl-2-(2-quinolyl)oxazol-5(4H)-one (XX)). The N-acyl-L-valine (XIX) has been obtained by acylation of L-valine (XXI) with quinoline-2-carboxylic acid (X) through its acyl chloride obtained with SOCl2.