The compound (+)-2-(7-chloro-1,8-naphthyridin-2-yl)-3S-(5methyl-2-oxohexyl)-1-isoindolinone (pagoclone) shows anxiolytic activity due to partial agonism of the benzodiazepine site of the GABA A receptor. We describe the development of an economical and practical process for a 100+ kg pilot plant production used to supply development needs. For the key reaction, a β-keto phosphonium salt was prepared by selectively reacting a primary r-bromo ketone with triphenylphosphine in the presence of a secondary r-bromo ketone. A novel Wittig reaction with a 1-isoindolinone was used to produce racemic pagoclone. The enantiomerically pure drug substance was prepared by hydrolyzing a γ-lactam and resolving the resulting enantiomeric carboxylic acids with (+)-ephedrine hemihydrate. An alternate resolution, involving chiral multicolumn chromatography (MCC) was also developed. The synthesis was completed by a racemization-free lactam formation to afford pagoclone.
The reduction of (5S)-2-amino-5-dibenzylamino-4-oxo-1,6-diphenylhex-2-ene was optimized for diastereoselectivity and
overall conversion to (2S,3S,5S)-5-amino-2-dibenzylamino-3-hydroxy-1,6-diphenylhexane (2a). A two-step reduction sequence is described wherein the enamine is reduced with a
borane-sulfonate derivative followed by reduction of the resulting ketone with sodium borohydride. The desired 2a was
obtained with 84% diastereoselectivity and an acyclic 1,4
stereoinduction ratio of 14:1. This methodology has been used
to produce multikilogram quantities of the diamino alcohol core
of Ritonavir and should be general to the synthesis of related
diamino hydroxyethylene isosteres.
2957Brief illustrative experimental procedures serve to demonstrate the utility of these methods. First, treatment of 35 mmol of 5 with 50 mmol of LDA in 50 mL of THF for 2 h at 0 OC and hydrolytic workup gave a 96% yield of a 45:55 mixture of the cis and trans isomers of diphenyl-l-propenylamine (I 1). Although stoichiometric amounts of LDA are employed in this case, such isomerizations can be effected by catalytic amounts of LDA as well. Second, treatment of 20 mmol of 5 with 22 mmol of n-BuLi in 100 mL of THF at 0 OC for 1 h gave a deep red solution; then, 20 mmol of PhCHzCl were added and al-(6) A number of allylic diphenylamines, such as CH&H= CHCHPNPhl and PhC€h=CHCH2NPh2, have been prepared in thie manner. Eiech, J. J.; Chiu, C. S.; Shah, J. H. Unpublished studies.lowed to react for 6 h at 25 OC; hydrolytic workup and column chromatography of the dried and evaporated organic layer on silica gel (hexane:CHzClz = 8 2 as eluent) gave, separately, 4-phenylbutanal (75%) and recovered diphenylamine (95%). Third, treatment of 20 mmol of 5 with 22 mmol of n-BuLi in 100 mL of THF at 0 "C for 3 h and the subsequent addition of 20 mmol of benzophenone gave upon the usual hydrolytic workup a crude product that was recrystallized from ethanol to yield 65% of 2-(diphenylamino)-5,5-diphenyltetrahydrofuran, mp 124-125 OC. Treating this with dilute, aqueous HC1 eliminates diphenylamine and forms 2,2-diphenyl-2,3-dihydrofuran.Summary: Oxidation of synthetic manganese(II1) porphyrins attached to steroidal substrates at C(17) (cf. 2 and 3) gives rise to hydrogen atom abstraction at C(9) and/or C(12), thereby leading to hydroxyl incorporation at these sites. The use of more robust metalloporphyrins (cf. 9) results in substantial increases in the yields of hydroxylated 5cu-androstanes.
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