Trifluoroacetic acid → Trifluoroacetic acid

HRID 77210Notes

Reaction equation

[OH:1][CH:2]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:29]=[C:28]([C:30]3[O:34][N:33]=[C:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:31]=3[C:41]([F:44])([F:43])[F:42])[O:27][N:26]=2)=[CH:21][CH:20]=1)[C:3]([NH:5][CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][N:8]1C(OC(C)(C)C)=O)=[O:4].[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46]>>[OH:1][CH:2]([C:19]1[CH:20]=[CH:21][C:22]([C:25]2[N:29]=[C:28]([C:30]3[O:34][N:33]=[C:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:31]=3[C:41]([F:42])([F:43])[F:44])[O:27][N:26]=2)=[CH:23][CH:24]=1)[C:3]([NH:5][CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)=[O:4].[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46]

Participants

Reactant 2

HCID 6422Trifluoroacetic acid

HCID 131731878(R/S)-tert-butyl 2-((2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)methyl)pyrrolidine-1-carboxylate

Product 2

HCID 6422Trifluoroacetic acidYield 80.4%

HCID 53496344(R/S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)-N-(pyrrolidin-2-ylmethyl)acetamide

Procedure

(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 30 mg, 0.070 mmol), 2-(aminomethyl)-1N-Boc-pyrrolidine (20.9 mg, 0.104 mmol), 4-methylmorpholine (28.1 mg, 0.278 mmol), and HATU (34.4 mg, 0.090 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX® Luna 5u 21×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 25 mL/min, 220 nM, product retention=32.9 min) to provide (R/S)-tert-butyl 2-((2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)methyl)pyrrolidine-1-carboxylate (28 mg, 0.046 mmol, 65.6% yield): LCMS=614.3 [M+H]+. The (R/S)-tert-butyl 2-((2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)methyl)pyrrolidine-1-carboxylate (28 mg, 0.046 mmol) was added to TFA (1 mL, 12.98 mmol) and stirred for 30 min. The reaction mixture was concentrated to provide (R/S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)-N-(pyrrolidin-2-ylmethyl)acetamide, TFA (24 mg, 0.037 mmol, 80% yield): LCMS=514.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.18 (2 H, d, J=7.92 Hz), 7.54-7.79 (7 H, m), 5.21 (1 H, s), 3.66-3.81 (1 H, m), 3.48-3.62 (2 H, m), 3.16-3.30 (2 H, m), 1.91-2.18 (3 H, m), 1.70-1.82 (1 H, m); HPLC peak RT=8.3 min (Condition A).

Workup

concentrationThe reaction mixture was concentrated

Sources & evidence

ORD record: ord-00d15985189c4c47b04522dc6b15de83
Source dataset: uspto-grants-2014_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08835470B2

Reaction notes

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