Dimethylformamide → HCID 53380355, compound

HRID 1805292Notes

Reaction equation

HRID 1805292 reaction equation
[F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:25](O)=[O:26].C([N:34]([CH:38]([CH3:40])[CH3:39])C(C)C)C.CN(C(O[N:49]1N=N[C:51]2[CH:52]=[CH:53][CH:54]=[N:55][C:50]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:65](O)([C:67](F)(F)F)=O.[CH3:72]N(C=O)C>>[N:49]1[C:50]2[C:51](=[CH:52][CH:53]=[CH:54][N:55]=2)[CH:67]=[CH:65][C:72]=1[C:38]1([NH:34][C:25]([C:24]2[CH:28]=[CH:29][C:30]([CH3:31])=[C:22]([C:3]3[CH:4]=[CH:5][C:6]4[O:10][C:9]([C:11]5[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=5)=[C:8]([C:18]([NH:19][CH3:20])=[O:21])[C:7]=4[C:2]=3[F:1])[CH:23]=2)=[O:26])[CH2:39][CH2:40]1

Participants

6

Reactant 5

HCID 6228DimethylformamideHCID 6422Trifluoroacetic acidHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)2×HCID 592756803-(4-Fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid

Product 1

HCID 53380355HCID 53380355, compoundYield 96%

Procedure

To a 25 mL RBF was added 3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (20.5 mg, 0.049 mmol) in DMF (1 mL) along with N-ethyl-N-isopropylpropan-2-amine (0.042 mL, 0.243 mmol), 1-(1,8-naphthyridin-2-yl)cyclopropanamine, HCl (20.17 mg, 0.073 mmol) and finally 5 eq. of HATU, 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (74.0 mg, 0.195 mmol). The flask was sealed with a septa, placed under nitrogen and the mixture stirred overnight at room temperature. The crude product was purified using a Shimadzu preparative HPLC employing methanol/water/trifluoroacetic acid where solvent A was 10% methanol/90% water/0.1% trifluoroacetic acid and solvent B was 10% water/90% methanol/0.1% trifluoroacetic acid with a Phenomenex Luna 10 μm C18 30×100 mm column at a gradient of 40-100% B and a flow rate of 40 mL/min. over 12 minutes with a 13 minute hold. The solvent was removed giving 33.3 mgs (96% yield) of 5-(5-(1-(1,8-naphthyridin-2-yl)cyclopropylcarbamoyl)-2-methylphenyl)-4-fluoro-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide, TFA as a yellow powder. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex Luna 3 μm C18, 2×50 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. HPLC purity was determined using a Shimadzu analytical LC at 254 nm and 256 nm with a Waters Sunfire C18 3.5 μm 4.6×150 mm column employing water/acetonitrile/0.1% trifluoroacetic acid with a gradient of 10-100% B (B=95% HPLC grade acetonitrile/0.1% trifluoroacetic acid/5% HPLC grade water), (A=95% HPLC grade water/0.1% trifluoroacetic acid/5% HPLC grade acetonitrile), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute. The HPLC purity was then confirmed with an orthogonal solvent system and column using a Shimadzu analytical LC with a Xbridge Phenyl C18 3.0 μm 4.6×150 mm column employing water/methanol/10 mM ammonium bicarbonate with a gradient of 10-100% B (B=95% HPLC grade methanol/10 mM ammonium bicarbonate/5% HPLC grade water), (A=95% HPLC grade water/10 mM ammonium bicarbonate/5% HPLC grade methanol), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute. 1H NMR (400 MHz, THF-d8) δ ppm 1.40-1.49 (m, 2H), 1.95 (m, 2 H), 2.25 (s, 3 H), 2.88 (m, 3 H), 7.17-7.29 (m, 3 H), 7.37-7.47 (m, 2 H), 7.50 (dd, J=8.03, 4.52 Hz, 1 H), 7.74 (d, J=8.53 Hz, 2 H), 7.85-7.97 (m, 2 H), 8.03-8.09 (m, 2 H), 8.18 (d, J=8.53 Hz, 1 H), 8.33-8.39 (m, 1 H), 8.74 (s, 1 H), 9.05 (dd, J=4.27, 1.76 Hz, 1 H). LCMS rt=2.475 min, m/z 589.3 (M+H), 95.7% purity. HPLC rt=6.728 min. (Sunfire C18), 100% purity and 11.261 min. (XBridge C18), 99.0% purity.

Workup

  1. customThe flask was sealed with a septa
  2. customThe crude product was purified
  3. waita flow rate of 40 mL/min. over 12 minutes with a 13 minute hold
  4. customThe solvent was removed

Sources & evidence

ORD record
ord-0ccd1c3eb9514dcd97f06a496a300ea9
Source dataset
uspto-grants-2013_01
Patent number
US08354410B2

Reaction notes

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