I15-Hydroxy-4-oxo-IO-pentadecynoic acid lactone (2i): oil; 'H NMR (CDCI,, 300 MHz, ppm) 1.38 (6 H, m), 1.50-1.77 (4 H, m, C6-H2 and C14-H2), 2.12 (4 H, m, C9-H2 and C12-H2), 2.43 (2 H, t, J = 6.0 Hz, C5-H,), 2.50 (2 H, t, J = 5.8 Hz, C2-H2 or C3-H,), 2.68 (2 H, t, J = 5.8 Hz, C3-H2 or C2cm-l; EIMS, m / e (relative intensity) 93 (44), 79 (94). 67 (39), 55 (base, C4H7+); ClMS (isobutane), m / e 251 (M' + H); EIHRMS, m / e 250.1567 (C,5H2203 requires 250.1569). (Z)-15-Hydroxy-4-oxo-8-pentadecenoic acid lactone (2j): oil; IH NMR (CDCI,, 300 MHz, ppm) 1.36 (6 H, m). 1.56-1.77 (4 H, m), 2.02 (4 H, m, C7-H2 and CIO-HI), 2.46 (2 H, t. J = 6.0 Hz, C5-H,), 2.59 (2 H, t, J = 5.9 Hz, C2-H2 or C3-H2), 2.75 (2 H, t, J = 5.9 Hz, C3-H2 or C2-H2), 4.15 (2 H, t, J = 5.3 Hz, C15-H2), 5.40 (2 H, m, CH=CH); IR (neat) Y

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The β-amino alcohol 4β-morpholinocaran-3α-ol is prepared by addition of morpholine to α-3,4-epoxycarane utilizing anhydrous magnesium bromide as Lewis acid promoter. The enantiopure amino alcohol is uniquely effective as a chiral moderator for the addition of lithium cyclopropylacetylide to an unprotected N-acylketimine. This reaction provides an efficient route to the second generation NNRTI drug candidate DPC 963.

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This work describes the optimization and scale-up of a Buchwald−Hartwig amination reaction for the preparation of a pharmaceutical intermediate. This C− N bond formation is challenged by the use of a chiral primary amine, which both adds cost and favors formation of biaryl byproducts. In order to develop a scalable process, a number of factors had to be investigated including catalyst selection and stoichiometry of the chiral amine. These all needed to be optimized while maintaining low palladium levels in the isolated product. The reaction was found to be most effective using Pd(dba) 2 with BINAP and Cs 2 CO 3 in THF. When executed on 2.5 kg scale, these conditions provided 2.06 kg of the desired product in 80% yield with only 73 ppm residual palladium. To date, this process has been successfully executed to produce more than 12 kg of compound (S)-3.

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