Sodium Carbonate → 4-((3 S,4S)-3-amino-4-hydroxypyrrolidin-1-yl)-3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)benzamide

HRID 924122Notes

Reaction equation

[Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1F)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([Cl:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].Cl.Cl.[NH2:25][C@H:26]1[CH2:30][NH:29][CH2:28][C@@H:27]1[OH:31].C([O-])([O-])=O.[Na+].[Na+]>CS(C)=O>[NH2:25][C@@H:26]1[C@@H:27]([OH:31])[CH2:28][N:29]([C:21]2[CH:20]=[CH:19][C:4]([C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([Cl:18])([F:17])[F:16])=[CH:10][CH:9]=3)=[O:6])=[CH:3][C:2]=2[Br:1])[CH2:30]1

Participants

Conditions

Temperature: 100 °C

Procedure

3-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-fluorobenzamide (240 mg, 0.596 mmol) and TEA (0.332 mL, 2.384 mmol) were added to a vial containing DMSO (0.5 mL). (3S,4S)-4-aminopyrrolidin-3-ol dihydrochloride (Stage 245.2, 128 mg, 0.715 mmol) was added. The RM was stirred at 100° C. for 40 h. The RM was treated with sat. aq. Na2CO3 (50 mL) and was extracted with EtOAc. The combined extracts were washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered and the filtrate was evaporated off under reduced pressure to give a crude product that was purified by flash chromatography (from 100% EtOAc to EtOAc/EtOH/NH3 aq. 90:9:1) to afford the title product as a beige solid. HPLC (Condition 10) tR=6.08 min, UPLC-MS (Condition 3) tR=0.82 min, m/z=476.1/478.1 [M+H]+.

Workup

extractionwas extracted with EtOAc
washThe combined extracts were washed with water (30 mL) and brine (30 mL)
dry with materialdried over Na2SO4
filtrationfiltered
customthe filtrate was evaporated off under reduced pressure
customto give a crude product that
customwas purified by flash chromatography (from 100% EtOAc to EtOAc/EtOH/NH3 aq. 90:9:1)

Sources & evidence

ORD record: ord-19b1ca265ecd4fe8905976e715cfca59
Source dataset: uspto-grants-2016_03
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09278981B2

Reaction notes

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