Dimethyl Sulfoxide → Methyl 2-[(1-{bis[(tert-butoxy)carbonyl]amino}isoquinolin-6-yl)amino]-15,15-difluoro-4,17,20-trimethyl-3,12-dioxo-13-oxa-4,11-diazatricyclo[14.2.2.16,10]henicosa-1(18),6,8,10 (21),16,19-hexaene-7-carboxylate

HRID 708822Notes

Reaction equation

HRID 708822 reaction equation
Br[C:2]1[CH:19]=[CH:18][C:17]2=[CH:20][C:3]=1[CH2:4][N:5]([CH3:55])[C:6](=[O:54])[CH:7]([NH:28][C:29]1[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=1)[C:35]([N:39]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[N:34][CH:33]=[CH:32]3)[C:8]1[CH:25]=[C:24]([CH3:26])[C:11]([C:12]([F:23])([F:22])[CH2:13][O:14][C:15](=[O:21])[NH:16]2)=[C:10]([CH3:27])[CH:9]=1.CS(C)=O.C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C]=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CO>[C:50]([O:49][C:47]([N:39]([C:40]([O:41][C:42]([CH3:45])([CH3:43])[CH3:44])=[O:46])[C:35]1[C:36]2[C:31](=[CH:30][C:29]([NH:28][CH:7]3[C:6](=[O:54])[N:5]([CH3:55])[CH2:4][C:3]4[CH:20]=[C:17]([CH:18]=[CH:19][C:2]=4[C:15]([O:14][CH3:13])=[O:21])[NH:16][C:15](=[O:21])[O:14][CH2:13][C:12]([F:22])([F:23])[C:11]4[C:10]([CH3:27])=[CH:9][C:8]3=[CH:25][C:24]=4[CH3:26])=[CH:38][CH:37]=2)[CH:32]=[CH:33][N:34]=1)=[O:48])([CH3:51])([CH3:53])[CH3:52]

Participants

7

Reactant 4

HCID 679Dimethyl SulfoxideHCID 812191,3-Bis(diphenylphosphino)propaneHCID 118098689tert-Butyl N-[6-({7-bromo-15,15-difluoro-4,17,20-trimethyl-3,12-dioxo-13-oxa-4,11-diazatricyclo[14.2.2.16,10]henicosa-1(18),6,8,10 (21),16,19-hexaen-2-yl}amino)isoquinolin-1-yl]-N-[(tert-butoxy)carbonyl]carbamateHCID 178418416HCID 178418416, compound

Product 1

HCID 118093104Methyl 2-[(1-{bis[(tert-butoxy)carbonyl]amino}isoquinolin-6-yl)amino]-15,15-difluoro-4,17,20-trimethyl-3,12-dioxo-13-oxa-4,11-diazatricyclo[14.2.2.16,10]henicosa-1(18),6,8,10 (21),16,19-hexaene-7-carboxylateYield 150.7%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 887MethanolSolvent

Conditions

Temperature
80 °C

Procedure

To a pressured-bottle charged with 4B (177 mg, 0.215 mmol), palladium(II) acetate (24.09 mg, 0.107 mmol), TEA (0.089 mL, 0.644 mmol) and DMSO (5 mL)/MeOH (2.500 mL) was added dppp (44.3 mg, 0.107 mmol). The resulting mixture was charged with carbon monoxide at 25 psi and stirred at 80° C. under an atmosphere of CO overnight. The reaction mixture was cooled to rt, filtered though CELITE® and concentrated to about ½ original volume. Water (50 mL) was added to the mixture and then extracted using 50% EtOAc/hexanes (3×). The combined organics were washed with water, dried with NaSO4 then filtered and concentrated. The residue was purified on Isco (40 g) eluting with 0 to 30% EtOAc/dichloromethane to give 4C (130 mg, 0.162 mmol, 75% yield) as a white solid. MS and 1H NMR are consistent with the desired product.

Workup

  1. temperatureThe reaction mixture was cooled to rt
  2. filtrationfiltered though CELITE®
  3. concentrationconcentrated to about ½ original volume
  4. additionWater (50 mL) was added to the mixture
  5. extractionextracted
  6. washThe combined organics were washed with water
  7. dry with materialdried with NaSO4
  8. filtrationthen filtered
  9. concentrationconcentrated
  10. customThe residue was purified on Isco (40 g)
  11. washeluting with 0 to 30% EtOAc/dichloromethane

Sources & evidence

ORD record
ord-e4c5b10d09f1492d9e100ff5f07513e8
Source dataset
uspto-grants-2015_11
Patent number
US09174974B2

Reaction notes

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