tert-Butyldimethylsilyl chloride → HCID 11166097, compound

HRID 397214Notes

Reaction equation

HRID 397214 reaction equation
[OH:1][C:2]1[C:3]2[C:19]3[C:10](=[C:11]4[C:16](=[CH:17][CH:18]=3)[NH:15][C:14]([CH3:21])([CH3:20])[CH:13]=[C:12]4[CH3:22])[C:9](=[O:23])[O:8][C:4]=2[CH:5]=[CH:6][CH:7]=1.CC([O-])(C)C.[K+].[CH3:30][C:31]([Si:34](Cl)([CH3:36])[CH3:35])([CH3:33])[CH3:32].CCOC(C)=O.CCCCCCC>C1COCC1.CC#N.O>[Si:34]([O:1][C:2]1[C:3]2[C:19]3[C:10](=[C:11]4[C:16](=[CH:17][CH:18]=3)[NH:15][C:14]([CH3:20])([CH3:21])[CH:13]=[C:12]4[CH3:22])[C:9](=[O:23])[O:8][C:4]=2[CH:5]=[CH:6][CH:7]=1)([C:31]([CH3:33])([CH3:32])[CH3:30])([CH3:36])[CH3:35]

Participants

8

Reactant 4

HCID 28928tert-Butyldimethylsilyl chlorideHCID 11066762HCID 11066762, compoundHCID 21899848Ethylacetate heptaneHCID 23665647Potassium tert-butoxide

Product 1

HCID 11166097HCID 11166097, compound

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6342AcetonitrileSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

10-hydroxy-2,2,4-trimethyl-1,2-dihydro-5H-chromeno[3,4-f]quinolin-5-one (HCl salt) (131.6 g), prepared as described in WO99/41256, in THF (2.6L) in a 5L 4-necked flask fitted with N2 inlet, temperature probe and overhead stirrer was treated with t-BuOK in approximately 20 g portions over 15 minutes (103.4 g total) at 0° C. under a N2 atmosphere. The cooled reaction mixture was stirred for 30 minutes. The mixture was treated with TBSCl in approximately 20 g portions over 15 minutes. The reaction was monitored by TLC, EtOAc:heptane (2:3), and/or HPLC, Zorbax Rx-C8 4.6 mm×25 cm column; mobile phase 90% H2O (0.1% H3PO4): 10% CH3CN (0.1% H3PO4) to 30:70 over 15 minutes, then to 10:90 over 20 minutes before ramping back to 10:90 over 2 minutes; 45 minute run; flow rate of 1 mL/minute; UV detection at 225 nm. Retention times: starting material—17.6 minutes; product—29.9 minutes, until starting material was consumed, about 30 minutes. The reaction mixture was quenched with 50% NH4Cl solution (1L) and extracted with EtOAc (1L). The organic layer was washed with brine (500 mL) before concentrating to a crude solid (180.8 g). The crude solid was slurried in CH3CN (900 mL) with heating until an even suspension was obtained. The suspension was then cooled to approximately 0° C., filtered and washed with cold CH3CN. The wet cake was dried at 40° C. in a vacuum oven to yield 82.2 g of the title compound as a yellow solid. The mother liquors were concentrated to a solid (69 g) and re-slurried in CH3CN (250 mL). A second crop was collected and dried to yield an additional 11.8 g (81% combined yield). A small sample was crystallized from CH3CN. Anal. calcd for C25H31NO3Si: C, 71.22; H, 7.41; N, 3.32. Found: C, 68.38; H, 7.45; N, 3.16; 1H NMR (CDCl3) δ0.32 (6H, s), 1.05 (9H, s), 1.33 (6H, s), 2.12 (3H, s), 4.26 (1H, br), 6.75 (1H, d), 6.94˜6.97 (2H, m), 7.17 (1H, t), 8.75 (1H, d); 13C NMR (CDCl3)δ−3.9, 18.4, 21.2, 25.9, 28.3, 50.4, 77.2, 110.1, 111.3, 115.4, 118.2, 120.0, 124.2, 126.9, 126.9, 127.3, 131.7, 132.0, 144.9, 151.9, 153.2, 160.1 with 3 peaks overlapping; HRMS-FAB: calcd m/z 422.2151, found 422.2137.

Workup

  1. customfitted with N2 inlet
  2. customThe cooled reaction mixture
  3. waitto 10:90 over 20 minutes before ramping back to 10:90 over 2 minutes
  4. custom45 minute
  5. custommaterial—17.6 minutes
  6. customproduct—29.9 minutes
  7. customwas consumed, about 30 minutes
  8. customThe reaction mixture was quenched with 50% NH4Cl solution (1L)
  9. extractionextracted with EtOAc (1L)
  10. washThe organic layer was washed with brine (500 mL)
  11. concentrationbefore concentrating to a crude solid (180.8 g)
  12. temperaturewith heating until an even suspension
  13. customwas obtained
  14. filtrationfiltered
  15. washwashed with cold CH3CN
  16. customThe wet cake was dried at 40° C. in a vacuum oven

Sources & evidence

ORD record
ord-978cd3b57ffd4bd0b6065cc92faf100f
Source dataset
uspto-grants-2003_08
Patent number
US06608216B2

Reaction notes

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