tert-Butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate → HCID 86727261, compound

HRID 2173080Notes

Reaction equation

HRID 2173080 reaction equation
[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](Cl)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[C:44]2[CH:43]=[C:42](B(O)O)[S:41][C:40]=2[CH:39]=[CH:38][CH:37]=1>O1CCOCC1.C([O-])(O)=O.[Na+].CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:42]2[S:41][C:40]3[CH:39]=[CH:38][CH:37]=[C:36]([F:35])[C:44]=3[CH:43]=2)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

7

Reactant 2

HCID 86654740tert-Butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylateHCID 86727239HCID 86727239, compound

Product 1

HCID 86727261HCID 86727261, compound

Reagents, catalysts & solvents 4

HCID 178418397HCID 178418397, compoundCatalystHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolventHCID 516892Sodium BicarbonateSolvent2×

Procedure

A solution of tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (152 mg, 0.305 mmol), 4-fluorobenzo[b]thiophen-2-ylboronic acid (149 mg, 0.762 mmol) and tetrakis(triphenylphosphine)palladium(0) (352 mg, 0.305 mmol) in dioxane and saturated aqueous NaHCO3 (1:1, 5 mL) was heated to 120° C. via microwave irradiation for 30 minutes. The reaction mixture was diluted with EtOAc (50 mL) and saturated aqueous NaHCO3 (100 mL). The organic layer was separated and the aqueous layer was washed with EtOAc (50 mL). The organic layers were combined, dried over Na2SO4, and the solvent was removed in vacuo to give the intermediate, tert-butyl 6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-7-fluoro-4-(4-fluorobenzo[b]thiophen-2-yl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate. The intermediate was dispersed in TFA and DCM (1:1, 10 mL) and stirred at room temperature for 60 minutes. The mixture was concentrated and the resulting crude material was reconstituted in MeOH/DCM (10.0 mL) and was purified via preparative HPLC eluting with a gradient of 30-50% ACN (0.035% TFA) and H2O (0.05% TFA). The combined fractions were neutralized with saturated aqueous NaHCO3, washed with EtOAc (2×200 mL), dried over Na2SO4, and filtered. The organic phase was stripped to dryness via rotary evaporation to give the title compound (83 mg, 66%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.31-1.48 (m, 2H), 1.55-1.85 (m, 6H), 3.17 (s, 2H), 4.10 (dd, J=6.35, 2.93 Hz, 2H), 4.45 (s, 2H), 6.79 (d, J=6.35 Hz, 1H), 7.19 (dd, J=10.25, 7.81 Hz, 1H), 7.40 (td, J=8.05, 5.37 Hz, 1H), 7.82 (d, J=8.30 Hz, 1H), 8.56 (s, 1H), 9.56 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C21H20F2N4OS, 415. found, 415.

Workup

  1. customThe organic layer was separated
  2. washthe aqueous layer was washed with EtOAc (50 mL)
  3. dry with materialdried over Na2SO4
  4. customthe solvent was removed in vacuo

Sources & evidence

ORD record
ord-5b41b20429ef4d7284db4cf73b034917
Source dataset
uspto-grants-2015_06
Patent number
US09056873B2

Reaction notes

Loading…