Dimethylformamide → 5-(4-chloro-3-(1-(pyridin-2-yl)cyclopropyl carbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

HRID 555148Notes

Reaction equation

HRID 555148 reaction equation
[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)=[C:16]([C:26](=[O:29])[NH:27][CH3:28])[C:15]=3[CH:30]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]1([NH2:40])[CH2:39][CH2:38]1.CN(C=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([C:19]4[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=4)=[C:16]([C:26]([NH:27][CH3:28])=[O:29])[C:15]=3[CH:30]=2)=[CH:7][C:3]=1[C:4](=[O:5])[NH:40][C:37]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=2)[CH2:39][CH2:38]1

Participants

6

Reactant 4

HCID 6228DimethylformamideHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 111054091-(Pyridin-2-yl)cyclopropanamineHCID 592751302-Chloro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid

Product 1

HCID 592756625-(4-chloro-3-(1-(pyridin-2-yl)cyclopropyl carbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamideYield 68.6%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

To a 250 mL round-bottomed flask was added 2-chloro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid (0.299 g, 0.705 mmol), 1-(pyridin-2-yl)cyclopropanamine (0.142 g, 1.058 mmol), DMF (8.50 mL), N-ethyl-N,N-diisopropylpropan-2-amine (0.493 mL, 2.82 mmol), and HATU (2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V), 1.073 g, 2.82 mmol). The flask was sealed, placed under N2 and stirred overnight at room temperature. The reaction mixture was diluted with 50 mL of ethyl acetate, washed with 5 mL of 1M HCl, extracted, dried over magnesium sulfate, filtered and evaporated to a red oil. The crude reaction mixture was then evacuated to near dryness, taken up in 8 mL of 1:1 methanol and DMF and 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 50-100% B and a flow rate of 40 mL/min. over 8 minutes with a 7 minute hold. Solvent was evaporated giving 261.3 mgs (66.4% yield) of 5-(4-chloro-3-(1-(pyridin-2-yl)cyclopropyl carbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide as a light yellow 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: Waters Sunfire 5 μm C18, 4.6×50 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 3 minutes with a 1 minute hold at a rate of 4 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 20-100% 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 PHENOMENEX® Gemini C18 3.0 μm 4.6×150 mm column employing water/methanol/10 mM ammonium bicarbonate with a gradient of 20-100% 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, DMSO-d6) δ ppm 1.33-1.40 (m, 2H), 1.56-1.64 (m, 2H), 2.83-2.91 (m, 3H), 7.27 (dd, J=6.78, 5.27 Hz, 1H), 7.35-7.45 (m, 2H), 7.63 (d, J=8.28 Hz, 1H), 7.69-7.96 (m, 7H), 7.97-8.06 (m, 2H), 8.50 (d, J=4.52 Hz, 2H), 9.34 (s, 1H). LCMS m/z 540.39 (M+H), Rt=1.643 min., 94.2% purity. HPLC (Sunfire C18) Rt=6.388 min, 94% purity and (Gemini C18) Rt=11.238 min., 99.6% purity.

Workup

  1. customThe flask was sealed
  2. washwashed with 5 mL of 1M HCl
  3. extractionextracted
  4. dry with materialdried over magnesium sulfate
  5. filtrationfiltered
  6. customevaporated to a red oil
  7. customThe crude reaction mixture
  8. customwas then evacuated
  9. customDMF and purified
  10. waita flow rate of 40 mL/min. over 8 minutes with a 7 minute hold
  11. customSolvent was evaporated

Sources & evidence

ORD record
ord-113f89547c9b4290bdef943a203fb51a
Source dataset
uspto-grants-2011_11
Patent number
US08048887B2

Reaction notes

Loading…