Process for Preparation of Cyclic Prodrugs of PMEA and PMPA
a technology of cyclic prodrugs and cyclic esters, which is applied in the field of process, can solve the problems of poor oral bioavailability, poor cell penetration, limited tissue distribution, etc., and achieve the effects of reducing trans levels, reducing the solubility of free base dichloridate, and increasing lipophilicity
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example 1
Preparation of 3-(3-Chlorophenyl)-3-oxo-propanoic acid (1)
[0101] A 12 L, 3-neck round bottom flask was equipped with a mechanical stirrer and addition funnel (2 L). The flask was flushed with nitrogen and charged with diisopropylamine (636 mL) and THF (1.80 L). The stirred contents were cooled to −20° C. n-Butyllithium (1.81 L of a 2.5 M solution in hexanes) was added slowly with stirring, and the temperature was maintained between −20 and −28° C. After the addition was complete (30 min), the addition funnel was rinsed with hexanes (30 mL) and the stirred solution was then cooled to −62° C. Trimethylsilyl acetate (300 g) was added slowly with stirring, maintaining the temperature at 4, 70 g), filtered and concentrated under reduced pressure to give 827 g of a yellow solid. The crude solid was slurried in hexanes (2.2 L) and transferred to a round bottom flask equipped with a mechanical stirrer. The mixture was stirred at 1H-NMR analysis for this example and all following examples w...
example 2
Preparation of (S)-3-(3-Chlorophenyl)-3-hydroxypropanoic acid (2)
[0105]
[0106] A 12 L, 3-neck round bottom flask was equipped with a mechanical stirrer and addition funnel (1 L). The flask was flushed with nitrogen and charged with 3-(3-chlorophenyl)-3-oxo-propanoic acid (275.5 g) 1 and dichloromethane (2.2 L). A thermocouple probe was immersed in the reaction slurry and the stirred contents were cooled to −20° C. Triethylamine (211 mL) was added over 5 minutes to the stirred slurry and all solids dissolved. A dichloromethane solution of (−)-B-chlorodiisopinocampheylborane (1.60 M, 1.04 L) was charged to the addition funnel, and then added slowly with stirring while maintaining the temperature between −20 and −25° C. After the addition was complete (approximately 35 min), the solution was warmed to ice bath temperature (2-3° C.) and stirred. After approximately 4 hours of stirring an in-process NMR analysis indicated the starting material 1 was <4%.
[0107] The residual starting mate...
example 3
Preparation of (S)-(−)-1-(3-Chlorophenyl)-1,3-propanediol (3)
[0112] A 12 L, 3-neck round bottom flask was equipped with a mechanical stirrer, addition funnel (2 L) and thermometer. The flask was flushed with nitrogen and charged with (S)-3-(3-chlorophenyl)-3-hydroxypropanoic acid 2 (206.7 g) and THF (850 mL), and the stirred solution was cooled to 5° C. (ice bath). A 1 M borane in THF solution (2.14 L) was charged to the addition funnel, and then added slowly with stirring maintaining the temperature at 4, 322 g), filtered and concentrated under reduced pressure to provide 189.0 g of a pale yellow oil (101%). Preliminary analysis of the oil was by 1H-NMR (CDCl3).
[0113] The oil was purified by vacuum distillation and the fraction at 125-155° C. / 0.15 mmHg was collected.
[0114] Recovery=180.9 g
[0115] Colorless oil 3 (94.0%).
[0116]1H-NMR (CDCl3): δ=2.9-3.1 (m, 2H), 2.5 (bs, 2H), 3.9 (t, J=5 Hz, 2H), 4.9(dd, J=7.4, 4.8 Hz, 1H), 7.2-7.4 (m, 4H).
Procedure for ee Determination
[0117] ...
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