Acetic Acid → tert-butyl[2-(4-{[3-carbamoyl-8-(methylsulfanyl)-1H-pyrazolo[4,3-h]quinazolin-1-yl]methyl}piperidin-1-yl)ethyl]carbamate

HRID 45802

Reaction equation

HRID 45802 reaction equation
[CH3:1][S:2][C:3]1[N:12]=[CH:11][C:10]2[CH:9]=[CH:8][C:7]3[C:13]([C:23]([NH2:25])=[O:24])=[N:14][N:15]([CH2:16][CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:6]=3[C:5]=2[N:4]=1.C(O)(=O)C.O=[CH:31][CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37].[BH3-]C#N.[Na+]>CO.CN(C=O)C>[C:36]([O:35][C:34](=[O:40])[NH:33][CH2:32][CH2:31][N:20]1[CH2:21][CH2:22][CH:17]([CH2:16][N:15]2[C:6]3[C:5]4[N:4]=[C:3]([S:2][CH3:1])[N:12]=[CH:11][C:10]=4[CH:9]=[CH:8][C:7]=3[C:13]([C:23](=[O:24])[NH2:25])=[N:14]2)[CH2:18][CH2:19]1)([CH3:39])([CH3:38])[CH3:37]

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 4247255tert-butyl N-(2-oxoethyl)carbamateHCID 5003444Sodium cyanoborohydrideHCID 573895548-(methylsulfanyl)-1-(piperidin-4-ylmethyl)-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide

Product 1

HCID 68171502tert-butyl[2-(4-{[3-carbamoyl-8-(methylsulfanyl)-1H-pyrazolo[4,3-h]quinazolin-1-yl]methyl}piperidin-1-yl)ethyl]carbamateYield 75%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6228DimethylformamideSolvent

Procedure

To a solution of 8-(methylsulfanyl)-1-(piperidin-4-ylmethyl)-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide 26 mg (0.073 mmol) in methanol (1.5 ml) and DMF (1 ml), acetic acid 13 μl (0.219 mmol), tert-butyl (2-oxoethyl)carbamate 69.6 mg (0.438 mmol) and NaCNBH3 28 mg (0.438 mmol) were added. The mixture was stirred at r.t. for 18 hours, consequently the volatiles were removed in vacuo. The residue was dissolved with ethyl acetate and portioned with water; the organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude was purified by flash chromatography (DCM/MeOH 95/5) to give tert-butyl[2-(4-{[3-carbamoyl-8-(methylsulfanyl)-1H-pyrazolo[4,3-h]quinazolin-1-yl]methyl}piperidin-1-yl)ethyl]carbamate 27 mg as a white solid (75%). LC/MS (254) HPLC method 2 Rt 3.86 min. 1H NMR (401 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.28 (d, J=8.67 Hz, 1H), 7.81 (s, 1H), 7.74 (d, J=8.79 Hz, 1H), 7.54 (br. s., 1H), 6.56 (br. s., 1H), 5.08 (d, J=7.32 Hz, 2H), 2.93-3.05 (m, 2H), 2.76-2.84 (m, J=10.25 Hz, 2H), 2.71 (s, 3H), 2.27 (br. s., 1H), 2.14 (br. s., 1H), 1.75-1.94 (m, 2H), 1.12-1.49 (m, 17H). HRMS (ESI) calcd for C24H33N7O3S [M+H]+ 500.2439 found 500.2436.

Workup

  1. customconsequently the volatiles were removed in vacuo
  2. dissolutionThe residue was dissolved with ethyl acetate
  3. washthe organic layer was washed with brine
  4. dry with materialdried over Na2SO4
  5. concentrationconcentrated
  6. customThe crude was purified by flash chromatography (DCM/MeOH 95/5)

Sources & evidence

ORD record
ord-40ed8d2a2420424f8d044ea37cc2b8b8
Source dataset
uspto-grants-2013_09
Patent number
US08541576B2

Linked notes

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