Diisopropylethylamine → HCID 53380663, compound

HRID 1805297Notes

Reaction equation

HRID 1805297 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[C:23]([CH3:33])=[CH:24][C:25]([O:31][CH3:32])=[C:26]([CH:30]=1)[C:27]([OH:29])=O.CCN(C(C)C)C(C)C.[N:43]1[C:52]2[C:47](=[CH:48][N:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45][C:44]=1[C:53]1([NH2:56])[CH2:55][CH2:54]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:43]1[C:52]2[C:47](=[CH:48][N:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45][C:44]=1[C:53]1([NH:56][C:27]([C:26]2[C:25]([O:31][CH3:32])=[CH:24][C:23]([CH3:33])=[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:30]=2)=[O:29])[CH2:54][CH2:55]1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)2×HCID 592754645-(4-Fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl) 2-methoxy-4-methylbenzoic acidHCID 66604711HCID 66604711, compound

Product 1

HCID 53380663HCID 53380663, compoundYield 50%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a 50 mL RBF was added 5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (57.0 mg, 0.1263 mmol) in DMF (4 mL) along with Hunig's Base (110 μl, 0.632 mmol), 1-(1,6-naphthyridin-2-yl)cyclopropanamine (37.4 mg, 0.202 mmol) and HATU, O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (192 mg, 0.505 mmol). The vessel was sealed, placed under nitrogen, and 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 39.1 mgs (40% yield) of 5-(5-(1-(1,6-naphthyridin-2-yl)cyclopropylcarbamoyl)-4-methoxy-2-methylphenyl)-4-fluoro-2-(4-fluorophenyl)-N-methyl Benzofuran-3-carboxamide 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 1.51 (m, 2 H), 1.96 (m, 2 H), 2.27 (s, 3 H), 2.87 (d, J=4.77 Hz, 3 H), 4.07 (s, 3 H), 7.14 (s, 1 H), 7.21 (m, 3 H), 7.44 (d, J=8.53 Hz, 1 H), 7.70 (d, J=4.52 Hz, 1H), 7.91 (m, 3 H), 8.08 (m, 2 H), 8.40 (d, J=8.53 Hz, 1 H), 8.70 (m, 2 H). LCMS rt=2.525 min., m/z 619.4 (M+H), 96.4% purity. HPLC rt=7.201 min. (Sunfire C18), 93.4% purity and 11.724 min. (Gemini C18), 96.3% purity.

Workup

  1. customThe vessel was sealed
  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-9cc70c178a164026938d93cf6da22878
Source dataset
uspto-grants-2013_01
Patent number
US08354410B2

Reaction notes

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