Dimethylformamide → HCID 53380354, compound

HRID 1805291Notes

Reaction equation

[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:24]([OH:26])=O)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.C([N:33]([CH:37]([CH3:39])[CH3:38])C(C)C)C.CN(C(O[N:48]1N=N[C:50]2[CH:51]=[CH:52][CH:53]=[N:54][C:49]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:64](O)([C:66](F)(F)F)=O.[CH3:71]N(C=O)C>>[N:48]1[C:49]2[C:50](=[CH:51][CH:52]=[CH:53][N:54]=2)[CH:66]=[CH:64][C:71]=1[C:37]1([NH:33][C:24]([C:23]2[CH:27]=[CH:28][C:29]([CH3:30])=[C:21]([C:18]3[CH:19]=[CH:20][C:10]4[O:9][C:8]([C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=5)=[C:12]([C:13]([NH:14][CH3:15])=[O:16])[C:11]=4[CH:17]=3)[CH:22]=2)=[O:26])[CH2:38][CH2:39]1

Participants

Reactant 5

HCID 6228Dimethylformamide

HCID 6422Trifluoroacetic acid

HCID 81531Diisopropylethylamine

HCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)2×

HCID 592756533-(2-(4-Fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid

Product 1

HCID 53380354HCID 53380354, compoundYield 87%

Procedure

To a 1 dram vial was added 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (30.3 mg, 0.075 mmol) in DMF (1 mL) along with N-ethyl-N-isopropylpropan-2-amine (0.065 mL, 0.375 mmol), 1-(1,8-naphthyridin-2-yl)cyclopropanamine, HCl (31.1 mg, 0.113 mmol) and finally HATU (2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethyl isouronium hexafluorophosphate(V), (114 mg, 0.300 mmol). The vial was sealed and the tan mixture shaken overnight at room temperature. The crude product was purified using a Shimadzu preparative HPLC employing acetonitrile/water/trifluoroacetic acid where solvent A was 10% acetonitrile/90% water/0.1% trifluoroacetic acid and solvent B was 10% water/90% acetonitrile/0.1% trifluoroacetic acid with a Waters Sunfire 5 μm C18 19×150 mm column at a gradient of 20-100% B and a flow rate of 25 mL/min. over 22 minutes with a 8 minute hold. The solvent was removed giving 45.0 mgs (87% yield) of 5-(5-(1-(1,8-naphthyridin-2-yl)cyclopropylcarbamoyl)-2-methylphenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide, TFA as a tan solid. 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 1.44 (q, J=4.18 Hz, 2 H), 1.90-1.98 (m, 2 H), 2.30 (s, 3 H), 2.89 (d, J=4.77 Hz, 3 H), 7.18-7.26 (m, 2 H), 7.29 (dd, J=8.28, 1.76 Hz, 1 H), 7.34-7.39 (m, 1 H), 7.50 (dd, J=8.03, 4.52 Hz, 2 H), 7.57 (d, J=8.53 Hz, 1H), 7.69 (d, J=1.25 Hz, 1H), 7.74 (d, J=8.53 Hz, 1 H), 7.85-7.91 (m, 2H), 8.07-8.14 (m, 2 H), 8.18 (d, J=8.53 Hz, 1 H), 8.34 (dd, J=8.03, 1.76 Hz, 1 H), 8.73 (s, 1 H), 9.04 (dd, 1 H). LCMS rt=1.430 min., m/z 571.3 (M+H), 98.3% purity. HPLC (Sunfire C18) rt=6.931 min, 99.4% purity and (XBridge Phenyl C18) rt=11.521 min., 100% purity.

Workup

customThe vial was sealed
customThe crude product was purified
waita flow rate of 25 mL/min. over 22 minutes with a 8 minute hold
customThe solvent was removed

Sources & evidence

ORD record: ord-02ff91a902fe486fbbaa572c9d121a6c
Source dataset: uspto-grants-2013_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08354410B2

Reaction notes

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