Diisopropylethylamine → Indoline

HATU (266 mg, 0.700 mmol) was added to a solution of 2-(1H-tetrazol-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxylic acid [I-67] (148 mg, 0.637 mmol) in DMF (1 mL). The mixture was stirred at RT for 5 minutes then a solution of 6-fluoro-2-methyl-3-[(3S,9aS)-octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile [I-40A] (411 mg, 0.817 mmol), and Hunig's Base (0.70 mL, 4.0 mmol) in dichloromethane (1 mL) was added. The flask was rinsed twice with dichloromethane (0.3 mL). The reaction mixture was stirred at RT for 2 hours then diluted with EtOAc and washed with saturated NaHCO3 solution, water and brine, dried (MgSO4), filtered and the solvent evaporated to afford crude title compound as a mixture of two diastereomers. This crude material was purified by preparative TLC on silica (2000 μm, eluted twice) using CH2Cl2:MeOH 95:5 (B) to afford the title compound 2 GH as a mixture of diastereomers: LC/MS 512 (M+Na), 490 (M+H). The diastereomers were separated by chiral preparative SFC HPLC (ChiralCel IC, 21×250 mm, 60% MeOH:MeCN/CO2, 50 mL/min, 100 bar, 114 mg/mL in MeCN/MeOH, 35° C., 220 nm) to afford the separated aza-indane diastereomers Isomer 2G (faster eluting) and Isomer 2H (slower eluting). Each isomer was dissolved separately in 1 mL dichloromethane and 1 equivalent of 1 M HCl in ether was added. The solvent was evaporated to yield the HCL salt of each diastereomer. Isomer 2G HCL salt: NMR 600 MHz (CD3OD)(mixture amide rotamers) 10.012 (s, 0.5H); 10.007 (s, 0.5H); 8.72 (s, 0.5H); 8.68 (s, 0.5H); 8.00 (br app t, 1H); 7.31 (dt, 1H); 5.11 (t, 1H); 4.60-4.72 (m, 2H); 4.41 (d, 0.5H); 4.09-4.31 (m, 3H); 3.91 (t, 0.5H); 3.88 (dd, 1.5H); 3.31-3.62 (m, 4H); 3.20-3.28 (m, 2.5H); 2.72-2.86 (m, 1H); 2.61 (s, 3H); 2.30-2.37 (m, 0.5H); 2.21-2.27 (m, 0.5H); LC/MS 531 (M+H+CH3CN). Isomer 2H HCl salt: NMR 600 MHz (CD3OD) (mixture amide rotamers) 10.02 (s, 1H); 8.72 (s, 0.6H); 8.69 (s, 0.4H); 8.02 (app t, 0.4H); 7.98 (aap t, 0.6H); 7.28-7.33 (m, 1H); 5.09 (d, 1H); 4.72-4.77 (m, 1H); 4.64 (d, 0.5H); 4.57 (d, 3H); 4.34 (d, 0.5H); 4.28 (d, 0.5H); 4.05-4.20 (m, 2.5H); 3.86 (t, 1H); 3.75 (q, 1H); 3.48-3.63 (m, 2H); 3.26 (t, 1H); 3.23 (t, 1H); 2.74-2.81 (m, 1H); 2.61 (s, 3H); 2.30-2.36 (m, 0.5H); 2.20-2.27 (m, 0.5H); LC/MS 531 (M+H+CH3 CN).

1. washThe flask was rinsed twice with dichloromethane (0.3 mL)
2. stirringThe reaction mixture was stirred at RT for 2 hours
3. additionthen diluted with EtOAc
4. washwashed with saturated NaHCO3 solution, water and brine
5. dry with materialdried (MgSO4)
6. filtrationfiltered
7. customthe solvent evaporated
8. customto afford crude title compound
9. additionas a mixture of two diastereomers
10. customThis crude material was purified by preparative TLC on silica (2000 μm
11. washeluted twice)
12. customto afford the title compound 2 GH
13. additionas a mixture of diastereomers
14. customThe diastereomers were separated by chiral preparative SFC HPLC (ChiralCel IC, 21×250 mm, 60% MeOH:MeCN/CO2, 50 mL/min, 100 bar, 114 mg/mL in MeCN/MeOH, 35° C., 220 nm)

ORD record

ord-ea8121c3e32245fa98fcbad01abbf153

Source dataset

uspto-grants-2015_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09062070B2