(5-Fluoro-1-benzothiophen-2-yl)boronic acid → HCID 86727259, compound

HRID 2173077Notes

Reaction equation

HRID 2173077 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[CH:47]=[CH:46][C:39]2[S:40][C:41](B(O)O)=[CH:42][C:38]=2[CH:37]=1>O1CCOCC1.C([O-])(O)=O.[Na+].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:41]2[S:40][C:39]3[CH:46]=[CH:47][C:36]([F:35])=[CH:37][C:38]=3[CH:42]=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

6

Reactant 2

HCID 53234193(5-Fluoro-1-benzothiophen-2-yl)boronic acidHCID 86654740tert-Butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate

Product 1

HCID 86727259HCID 86727259, compound

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 312751,4-DioxaneSolventHCID 516892Sodium BicarbonateSolvent

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 (300 mg, 0.601 mmol), 5-fluorobenzo[b]thiophen-2-ylboronic acid (236 mg, 1.202 mmol) and tetrakis(triphenylphosphine)palladium(0) (695 mg, 0.601 mmol) in dioxane and saturated aqueous NaHCO3 (1:1, 5 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-4-(5-fluorobenzo[b]thiophen-2-yl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate. The intermediate was first dissolved in DCM (3 mL) then TFA/DCM (1:1, 10 mL) and the mixture was stirred at 60° C. for 1 hour. After solvent was removed, the resulting crude material was reconstituted in MeOH/DMF/DCM (30.0 mL) and purified via preparative mass trigger LCMS, eluting with gradient of 30-40 ACN (0.035% TFA) and H2O (0.05% TFA). The collected fractions were combined and 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 (77 mg, 31%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.36-2.09 (m, 8H), 3.82 (br s, 1H), 4.31 (d, J=1.95 Hz, 1H), 4.42-4.53 (m, 2H), 7.13 (d, J=5.86 Hz, 1H), 7.27 (td, J=8.91, 2.69 Hz, 1H), 7.56-7.82 (m, 3H), 7.94-8.04 (m, 1H), 8.64 (s, 1H), 9.41 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C21H20F2N4OS, 415. found, 415.

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-9f21e328e7274fcb8bce38c5b4d364f5
Source dataset
uspto-grants-2015_06
Patent number
US09056873B2

Reaction notes

Loading…