Hydrochloric Acid → HCID 71506753, compound

To a solution of {(1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(6-{[(1R,2S)-5-chloro-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)oxy]cyclopentyl}methanol (16) (11.5 g, 0.0221 mol) in N,N-dimethylacetamide (160 mL, 1.7 mol) was added chlorosulfonamide (6.64 g, 0.0575 mol), and the reaction stirred at room temperature for 1 hour. The reaction mixture was then cooled to 0° C., at which point 12 M hydrochloric acid (90 mL, 1.1 mol) was added dropwise via an addition funnel over 25 min, keeping the internal reaction temp below 50° C. Once the addition was complete, the cooling bath was removed and the reaction was allowed to warm to room temperature with stirring for 2 hours. The reaction was next quenched carefully via slow addition of a suspension of sodium carbonate (70.30 g, 0.6633 mol) in water (200.0 mL, 11.10 mol). The resulting suspension was filtered and the solids were rinsed with EtOAc (3 rinses, total—800 mL). The solids were set aside, and the filtrate was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted 3×EtOAc (total EtOAc—2000 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified via column chromatography (applied with CH2Cl2, 400 g column, eluent 0-10% MeOH:CH2Cl2 over 80 min then 10% MeOH: CH2Cl2 for 20 min) to afford {(1S,2S,4R)-4-[(6-{[(1R,2S)-5-chloro-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)oxy]-2-hydroxycyclopentyl}methyl sulfamate (10.3 g, 96%). LCMS: (FA) ES+ 485; 1H NMR (400 MHz, MeOD) δ 8.16 (s, 1H), 7.25 (s, 1H), 7.22-7.13 (m, 2H), 5.98 (s, 1H), 5.52 (d, J=32.8, 1H), 5.34 (s, 1H), 4.43-4.35 (m, 1H), 4.32 (dd, J=7.5, 9.8, 1H), 4.22 (td, J=2.5, 5.0, 1H), 4.16 (dd, J=7.3, 9.8, 1H), 3.34 (s, 4H), 3.10 (dd, J=2.1, 16.6, 1H), 3.02 (dd, J=4.8, 16.6, 1H), 2.58-2.46 (m, 1H), 2.28 (ddd, J=2.2, 6.9, 14.8, 1H), 2.12-1.90 (m, 4H).

1. additionwas added dropwise via an addition funnel over 25 min
2. customthe internal reaction temp below 50° C
3. additionOnce the addition
4. customthe cooling bath was removed
5. temperatureto warm to room temperature
6. stirringwith stirring for 2 hours
7. filtrationThe resulting suspension was filtered
8. washthe solids were rinsed with EtOAc (3 rinses, total—800 mL)
9. customthe filtrate was transferred to a separatory funnel
10. customthe layers were separated
11. extractionThe aqueous layer was extracted 3×EtOAc (total EtOAc—2000 mL)
12. dry with materialthe combined organic layers were dried over Na2SO4
13. filtrationfiltered
14. concentrationconcentrated in vacuo
15. customThe crude residue was purified via column chromatography (
16. waitCH2Cl2 over 80 min

ORD record

ord-aa656093639b4696a2f36686bd8380e3

Source dataset

uspto-grants-2014_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08809356B2