HCID 10753885, compound → HCID 10800527, compound

Temperature

110 °C

A mixture of piperidone 3 (349 mg, 1.34 mmol) Lawesson's reagent (594 mg, 1.47 mmol) and toluene (1.5 mL) was heated to 110° C. for 2 h. The mixture was cooled to 25° C., aged for 15 min, and filtered through a cotton plug, washing with toluene (3.5 mL). The filtrate was evaporated, and the residue containing thiolactam 4 was dissolved in THF (2 mL) and EtOH (2 mL). A 50% aqueous slurry of Raney nickel (1 mL) was added. After a 5 min age another portion of the Raney nickel (1 mL) was added followed by NaBH4 (25 mg). After 15 min the mixture was filtered through a pad of solkafloc, washing the pad with THF (5 mL) and EtOH (5 mL). The filtrates were evaporated to 4 mL and diluted with MTBE (20 mL). The mixture was extracted with 0.5M aqueous HCl (2×3 mL), and the aqueous extract was basified with 5M aqueous NaOH (0.7 mL). The aqueous mixture was extracted with CH2Cl2 (2×3 mL). The organic extracts were dried over Na2SO4 and evaporated to give piperidine 5 (100 mg, 30%) as a colorless oil: 13C NMR (62.9 MHz, CDCl3) δ 175.1, 136.5, 129.6, 127.8, 126.4, 60.2, 53.1, 47.8, 46.1, 44.3, 32.8, 24.3, 13.9. HPLC analysis of the Marfey's derivative of 5 indicated >99.5 % ee. Sample preparation for Marfey's derivatization: 0.5 mg tartrate salt, 0.5 mg Marfey's reagent {N-(2,4-Dinitro-5-fluorophenyl)-L-alaninamide}, 50 μL of 6M NaHCO3 and 0.5 mL acetone were combined. The mixture was heated at 55° C. (4-5 min.) until it turned red in color from light yellow and made up to 1 mL with 1:1 MeCN and H2O. HPLC conditions: B-03-5 YMC Basic (S-5 micron) 250×4.6 mm column, isocratic elution over 10 min (42/58) MeCN/0.025% H3PO4, then gradient elution over 5 min (42/58→62/38) MeCN/0.025% H3PO4, then isocratic elution over 15 min (62/38) MeCN/0.025% H3PO4, 1.0 mL/min flow at 25° C. with detection at 220 nm.

1. temperatureThe mixture was cooled to 25° C.
2. filtrationfiltered through a cotton plug
3. washwashing with toluene (3.5 mL)
4. customThe filtrate was evaporated
5. additionthe residue containing thiolactam 4
6. dissolutionwas dissolved in THF (2 mL)
7. additionA 50% aqueous slurry of Raney nickel (1 mL) was added
8. additionAfter a 5 min age another portion of the Raney nickel (1 mL) was added
9. filtrationAfter 15 min the mixture was filtered through a pad of solkafloc
10. washwashing the pad with THF (5 mL) and EtOH (5 mL)
11. customThe filtrates were evaporated to 4 mL
12. additiondiluted with MTBE (20 mL)
13. extractionThe mixture was extracted with 0.5M aqueous HCl (2×3 mL)
14. extractionthe aqueous extract
15. extractionThe aqueous mixture was extracted with CH2Cl2 (2×3 mL)
16. dry with materialThe organic extracts were dried over Na2SO4
17. customevaporated

ORD record

ord-36a1aed466aa466995881c4ef6919f01

Source dataset

uspto-grants-1999_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05929243