2-(Dicyclohexylphosphino)biphenyl → HCID 86727258, compound

HRID 2173072Notes

Reaction equation

HRID 2173072 reaction equation
[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:35]([C:37]1[S:41][C:40](B(O)O)=[CH:39][CH:38]=1)#[N:36].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>O1CCOCC1.CN(C=O)C.CCOC(C)=O.C([O-])(O)=O.[Na+].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:40]3[S:41][C:37]([C:35]#[N:36])=[CH:38][CH:39]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

9

Reactant 3

HCID 27342162-(Dicyclohexylphosphino)biphenylHCID 41987435-Cyanothiophene-2-boronic acidHCID 86654748tert-Butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate

Product 1

HCID 86727258HCID 86727258, compound

Reagents, catalysts & solvents 5

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolventHCID 516892Sodium BicarbonateSolvent

Procedure

A solution of tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (30 mg, 0.060 mmol), 5-cyanothiophen-2-ylboronic acid (27.5 mg, 0.180 mmol), tris(dibenzylideneacetone)dipalladium(0) (3.29 mg, 3.59 mol) and 2-(dicyclohexylphosphino)biphenyl (1.259 mg, 3.59 mol) in dioxane (2 mL) and DMF (0.500 mL) was heated to 160° C. via microwave irradiation for 60 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 combined organic layers were dried over Na2SO4 and the solvent was removed in vacuo to give the intermediate, tert-butyl 6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-4-(5-cyanothiophen-2-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate. The intermediate was dispersed in TFA and DCM (10 mL). The mixture was stirred at room temperature for 60 minutes and then concentrated. The resulting crude material was reconstituted in MeOH and DCM (10.0 mL) and was purified via preparative HPLC, eluting with a gradient of 20-25% ACN (0.035% TFA) and H2O (0.05% TFA). The collected fractions were combined and the solvent was stripped to dryness via rotary evaporation to yield a TFA salt of the title compound (3.3 mg, 15%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.78 (d, J=14.16 Hz, 1H), 2.04-2.21 (m, 1H), 3.57-3.67 (m, 1H), 3.73-3.88 (m, 2H), 4.01 (d, J=10.74 Hz, 2H), 4.36 (d, J=11.23 Hz, 1H), 4.48 (br s, 2H), 7.47 (br s, 1H), 7.91-8.02 (m, 3H), 8.73 (br s, 1H), 9.13 (br s, 1H). ESI-MS m/z [M+H]+ calc'd for C17H16FN5O2S, 374. found, 374.

Workup

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

Sources & evidence

ORD record
ord-66775da1cd82456d915ad9e2f6b0c3aa
Source dataset
uspto-grants-2015_06
Patent number
US09056873B2

Reaction notes

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