Toluene → HCID 86727260, compound

HRID 2173078Notes

Reaction equation

HRID 2173078 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[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:40]1[S:48][C:47]2[CH:46]=[CH:45][N:44]=[CH:43][C:42]=2[CH:41]=1)CCC.[C:57]1(C)C=CC=CC=1>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[CH2:10][CH2:57][CH2:12][CH2:13][C@H:14]1[NH:15][C:16]1[N:21]=[C:20]([C:40]2[S:48][C:47]3[CH:46]=[CH:45][N:44]=[CH:43][C:42]=3[CH:41]=2)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:2])([CH3:3])[CH3:4]

Participants

5

Reactant 3

HCID 1140TolueneHCID 71143878HCID 71143878, compoundHCID 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 86727260HCID 86727260, compound

Reagents, catalysts & solvents 1

HCID 178418397HCID 178418397, compoundCatalyst

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 (200 mg, 0.399 mmol), 2-(tributylstannyl)thieno[3,2-c]pyridine (339 mg, 0.798 mmol) and tetrakis(triphenylphosphine)palladium(0) (461 mg, 0.399 mmol) in toluene (3 mL) was heated to 120° C. via microwave irradiation for 30 minutes. After the solvent was removed, the crude product was purified by silica gel column chromatography, eluting with a gradient of 10-50% EtOAc and hexane over a period of 60 minutes. The fractions were collected to give the intermediate, tert-butyl 6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-7-fluoro-3-oxo-4-(thieno[3,2-c]pyridin-2-yl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate. The intermediate was first dissolved in DCM (3 mL) and then TFA/DCM (1:1, 10 mL) at 60° C. for 1 hour. After removal of solvent, the resulting crude material was reconstituted in MeOH/DMF/DCM (30.0 mL) and purified via preparative mass triggered LCMS, eluting with a gradient of 30-40% ACN (0.035% TFA) and H2O (0.05% TFA). The collected fractions were combined and the ACN was removed via rotary evaporation. The mixture was neutralized with saturated aqueous NaHCO3, washed with EtOAc (2×300 mL), dried over Na2SO4, and filtered. The organic phase was stripped to dryness via rotary evaporation to give the title compound (30 mg, 19%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44-2.10 (m, 8H), 3.82 (br s, 1H), 4.33 (d, J=3.54 Hz, 1H), 4.47 (s, 2H), 7.30 (d, J=6.06 Hz, 1H), 7.89 (br s, 2H), 8.39 (d, J=5.05 Hz, 1H), 8.57 (s, 1H), 8.77 (s, 1H), 9.44 (s, 1H), 9.71 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C20H20FN5OS, 398. found, 398.

Workup

  1. customAfter the solvent was removed
  2. customthe crude product was purified by silica gel column chromatography
  3. washeluting with a gradient of 10-50% EtOAc and hexane over a period of 60 minutes
  4. customThe fractions were collected

Sources & evidence

ORD record
ord-024eb925a6f945d0a584555d37475986
Source dataset
uspto-grants-2015_06
Patent number
US09056873B2

Reaction notes

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