Sodium hydride → HCID 11467415, compound

HRID 2099742Notes

Reaction equation

HRID 2099742 reaction equation
[OH:1][NH:2][C:3](=[NH:11])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[H-].[Na+].CO[C:16](=O)[CH:17]([CH2:38][C:39]1[CH:40]=[C:41]2[C:45](=[C:46]([CH3:48])[CH:47]=1)[NH:44][N:43]=[CH:42]2)[CH2:18][C:19](=[O:37])[N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[NH:28][C:27]2=[O:36])[CH2:22][CH2:21]1>O1CCCC1>[CH2:4]([C:3]1[N:11]=[C:16]([CH:17]([CH2:38][C:39]2[CH:40]=[C:41]3[C:45](=[C:46]([CH3:48])[CH:47]=2)[NH:44][N:43]=[CH:42]3)[CH2:18][C:19]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[NH:28][C:27]3=[O:36])[CH2:22][CH2:21]2)=[O:37])[O:1][N:2]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 24863326HCID 24863326, compoundHCID 178510798HCID 178510798, compound

Product 1

HCID 11467415HCID 11467415, compoundYield 27%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
65 °C

Procedure

To a solution of N-hydroxy-2-phenyl-acetamidine (0.27 mmol, 3 equiv, this and the other amidine intermediates of the present invention were prepared as described in J. Med. Chem. 1993, 1529-1538) in anhydrous tetrahydrofuran (4 mL) was added sodium hydride (0.27 mmol, 3 equiv) under nitrogen. The mixture was heated at 65° C. for 30 min before addition of a solution of (±)-2-(7-methyl-1H-indazol-5-ylmethyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butyric acid methyl ester (0.09 mmol, 1 equiv) in tetrahydrofuran (3 mL). The reaction mixture was heated at 65° C. overnight. Tetrahydrofuran was removed in vacuo and the reaction mixture was taken up in methylene chloride, washed with water (3×4 mL), dried over sodium sulfate and concentrated. Flash chromatography on silica gel using methanol/methylene chloride from 0 to 10% gave an impure product. The final product was obtained by preparative HPLC in 27% yield. LC/MS: tR=1.60 min, 590 (MH)+. 1H-NMR (400 MHz, CD3OD) δ 7.92 (1H, s), 6.90-7.25 (10H, m), 6.74 (1H, d, J=8.00 Hz), 4.32-4.57 (2H, m), 4.24-4.29 (2H, m), 3.79-4.06 (5H, m), 2.79-3.31 (5H, m), 2.57 (1H, m), 2.44 (3H, s), 1.50-1.82 (4H, m).

Workup

  1. customTetrahydrofuran was removed in vacuo
  2. washwashed with water (3×4 mL)
  3. dry with materialdried over sodium sulfate
  4. concentrationconcentrated
  5. customgave an impure product

Sources & evidence

ORD record
ord-c5787764dfce43cbae4a64448af78d6f
Source dataset
uspto-grants-2009_08
Patent number
US07569578B2

Reaction notes

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