Trifluoroacetic acid methylene chloride → Trifluoroacetic acid

HRID 2170384Notes

Reaction equation

[Br:1][C:2]1[C:3]([C@@H:16]([NH:26]C(=O)OC(C)(C)C)[CH2:17][C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=2)=[N:4][C:5]([Br:15])=[C:6]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:7]=1.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35].C(Cl)Cl>C(Cl)Cl>[NH2:26][C@H:16]([C:3]1[N:4]=[C:5]([Br:15])[C:6]([NH:8][C:9](=[O:14])[C:10]([F:11])([F:13])[F:12])=[CH:7][C:2]=1[Br:1])[CH2:17][C:18]1[CH:19]=[C:20]([F:25])[CH:21]=[C:22]([F:24])[CH:23]=1.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]

Participants

Conditions

Temperature: 0 °C

Procedure

A mixture of (S)-tert-butyl (1-(3,6-dibromo-5-(2,2,2-trifluoroacetamido)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (46C, 563 mg, 0.94 mmol) in 5 mL of methylene chloride was cooled down to 0° C. and to it was added 10 mL of 20% TFA/methylene chloride. The reaction was allowed to stir at room temperature for 1 hour and then concentrated to dryness to afford (S)—N-(6-(1-amino-2-(3,5-difluorophenyl)ethyl)-2,5-dibromopyridin-3-yl)-2,2,2-trifluoroacetamide as a TFA salt. 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid (265 mg, 0.94 mmol), the amine (TFA salt from last step) and HATU (429 mg, 1.1 mmol) were dissolved in 10 mL DMF, cooled to 0° C., then N,N-diisopropylethylamine (0.84 mL, 4.7 mmol) was added dropwise. The reaction mixture was allowed to stir at 0° C. for 5 min, and then partitioned between EtOAc and 5% LiCl aqueous solution. The organic layer was separated, washed with NaHCO3 (sat'd aq.) and brine. After dried over MgSO4, it was filtered and concentrated to yield the title product. MS (m/z): 767.84 [M+H]+.

Workup

concentrationconcentrated to dryness

Sources & evidence

ORD record: ord-74e5b3bf363e4e15ba57e19c2bd662a9
Source dataset: uspto-grants-2015_06
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09050344B2

Reaction notes

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