Diisopropylethylamine → Ethyl 10-((((3R)-3-fluoro-1-pyrrolidinyl)(oxo)acetyl)(methyl)amino)-4-oxo-3-((phenylcarbonyl)oxy)-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylate

HRID 1093083Notes

Reaction equation

HRID 1093083 reaction equation
Cl.[CH3:2][NH:3][C:4]12[CH2:12][CH2:11][CH:8]([CH2:9][CH2:10]1)[CH2:7][N:6]1[C:13](=[O:31])[C:14]([O:22][C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:24])=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:16]=[C:5]21.[F:32][C@@H:33]1[CH2:37][CH2:36][N:35]([C:38](=[O:42])[C:39]([OH:41])=O)[CH2:34]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.CN(C)C1C=CN=CC=1>[F:32][C@@H:33]1[CH2:37][CH2:36][N:35]([C:38](=[O:42])[C:39]([N:3]([CH3:2])[C:4]23[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12]2)[CH2:7][N:6]2[C:13](=[O:31])[C:14]([O:22][C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:24])=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:16]=[C:5]32)=[O:41])[CH2:34]1

Participants

7

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)HCID 66588781Ethyl 10-(methylamino)-4-oxo-3-((phenylcarbonyl)oxy)-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylate hydrochlorideHCID 66588867(R)-2-(3-fluoropyrrolidin-1-yl)-2-oxoacetic acid

Product 1

HCID 66588806Ethyl 10-((((3R)-3-fluoro-1-pyrrolidinyl)(oxo)acetyl)(methyl)amino)-4-oxo-3-((phenylcarbonyl)oxy)-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylateYield 54%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6228DimethylformamideSolvent

Procedure

To a stirred solution of ethyl 10-(methylamino)-4-oxo-3-((phenylcarbonyl)oxy)-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylate hydrochloride (120 mg, 0.268 mmol) in DMF (4 mL) was added (R)-2-(3-fluoropyrrolidin-1-yl)-2-oxoacetic acid (130 mg, 0.804 mmol), diisopropylethylamine (0.281 mL, 1.607 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (306 mg, 0.804 mmol), 4-(dimethylamino)pyridine (DMAP) (9.82 mg, 0.080 mmol) and the resulting mixture stirred at room temperature for 16 h. The mixture was quenched with water and diluted with ethyl acetate, washed with 1N HCl, followed by sat.NaHCO3, dried (Na2SO4) filtered and concentrated. The crude product was purified on Biotage flash chromatography system using 30-100% ethyl acetate/hexane gradient to afford the title compound (80 mg, 0.144 mmol, 54% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ: 8.12-8.23 (2 H, m), 7.64 (1 H, t, J=7.48 Hz), 7.44-7.56 (2 H, m), 5.11-5.42 (1 H, m), 4.08-4.27 (2 H, m), 3.28-4.01 (9 H, m), 3.18 (3 H, d, J=3.05 Hz), 2.50 (1 H, brs), 1.72-2.37 (6 H, m), 0.99-1.11 (3 H, m). LCMS (M+H)=555.76.

Workup

  1. customThe mixture was quenched with water
  2. additiondiluted with ethyl acetate
  3. washwashed with 1N HCl
  4. dry with materialNaHCO3, dried (Na2SO4)
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe crude product was purified on Biotage flash chromatography system

Sources & evidence

ORD record
ord-a54a37533df14f9d9621c57c2b8712e9
Source dataset
uspto-grants-2012_03
Patent number
US08129398B2

Reaction notes

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