Tert-Butylamine → 5-(2-(2-amino-2-oxoethoxy)-4-methoxy-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl) phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

HRID 1877681Notes

Reaction equation

HRID 1877681 reaction equation
[NH2:1][C:2](=[O:36])[CH2:3][O:4][C:5]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]3[O:21][C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)=[C:19]([C:29](=[O:32])[NH:30][CH3:31])[C:18]=3[CH:33]=2)=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([O:34][CH3:35])[CH:6]=1.[CH3:37][C:38]([NH2:41])([CH3:40])[CH3:39].CN(C(O[N:50]1N=N[C:52]2[CH:53]=[CH:54]C=N[C:51]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2](=[O:36])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([O:34][CH3:35])[C:8]([C:9](=[O:11])[NH:41][C:38]2([C:40]3[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=3)[CH2:39][CH2:37]2)=[CH:12][C:13]=1[C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[C:19]([C:29]([NH:30][CH3:31])=[O:32])[C:18]=2[CH:33]=1

Participants

5

Reactant 3

HCID 6385Tert-ButylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 666060174-(2-Amino-2-oxoethoxy)-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxybenzoic acid

Product 1

HCID 592754695-(2-(2-amino-2-oxoethoxy)-4-methoxy-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl) phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamideYield 52%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a 25 mL flask was added 4-(2-amino-2-oxoethoxy)-5-(2-(4-fluorophenyl)-3-(methyl carbamoyl)benzofuran-5-yl)-2-methoxybenzoic acid (49.2 mg, 0.1 mmol), DMF (2 mL), N-ethyl-N-diisopropylpropan-2-amine (0.069 mL, 0.396 mmol), 2-methylpropan-2-amine (18 mg, 26 μL, 0.246 mmol) and finally HATU (2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethyl isouronium hexafluorophosphate(V), 151 mg, 0.396 mmol). The flask was sealed with a septum, placed under N2 and stirred at room temperature overnight. 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 28.3 mgs (52% yield) of 5-(2-(2-amino-2-oxoethoxy)-4-methoxy-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide 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 Phenomenex Gemini 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 1.43 (s, 9H), 2.91 (d, J=4.77 Hz, 3H), 4.03 (s, 3H), 4.51 (s, 2H), 6.43 (br. s., 1H), 6.71-6.77 (m, 1H), 6.78 (s, 1H), 7.21 (t, J=8.78 Hz, 2H), 7.46-7.52 (m, 1H), 7.52-7.54 (m, 1H), 7.54-7.59 (m, 1H), 7.67 (s, 1H), 7.92 (s, 1H), 8.10-8.16 (m, 2H), 8.19 (s, 1 H). LCMS rt=2.976 min., m/z 548.2 (M+H), 98.3% purity. HPLC rt=9.088 min. (Sunfire C18), 99.0% purity and 11.588 min. (Gemini C18), 99.4% purity.

Workup

  1. customThe flask was sealed with a septum
  2. customThe crude product was purified
  3. waita flow rate of 25 mL/min. over 22 minutes with a 8 minute hold
  4. customThe solvent was removed

Sources & evidence

ORD record
ord-a41513fd1b324716bf687328933d1f83
Source dataset
uspto-grants-2012_11
Patent number
US08309558B2

Reaction notes

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