4-Chlorobenzoyl chloride → (+/-)-(3-{(4-Methylbenzoyl)-[1-(4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4] triazin-2-yl)-propyl]amino}propyl)carbamic acid tert-butyl ester

HRID 1795935Notes

Reaction equation

HRID 1795935 reaction equation
[C:1]([O:5][C:6](=[O:41])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:21]([C:24]1[N:29](CC2C=CC=CC=2)[C:28](=[O:37])[C:27]2=[CH:38][CH:39]=[CH:40][N:26]2[N:25]=1)[CH2:22][CH3:23])[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].ClC1C=CC(C(Cl)=O)=CC=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6](=[O:41])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([C:12](=[O:20])[C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1)[CH:21]([C:24]1[NH:29][C:28](=[O:37])[C:27]2=[CH:38][CH:39]=[CH:40][N:26]2[N:25]=1)[CH2:22][CH3:23])([CH3:3])([CH3:2])[CH3:4]

Participants

6

Reactant 3

HCID 85014-Chlorobenzoyl chlorideHCID 69591887HCID 69591887, compoundHCID 178418361HCID 178418361, compound

Product 1

HCID 136411691(+/-)-(3-{(4-Methylbenzoyl)-[1-(4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4] triazin-2-yl)-propyl]amino}propyl)carbamic acid tert-butyl esterYield 65%

Reagents, catalysts & solvents 2

HCID 9942167Palladium hydroxideCatalystHCID 702EthanolSolvent

Procedure

A mixture of {3-[[1-(3-benzyl-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)-propyl]-(4-methylbenzoyl)-amino]-propyl}-carbamic acid tert-butyl ester (115 mg, 0.21 mmol, prepared using an identical synthetic sequence to that outlined for Example 12 A–F, except substituting p-toluoyl chloride for 4-chlorobenzoyl chloride in F) and Pd(OH)2 (20 wt. % Pd on carbon, 66 mg) in ethanol (6 mL) was stirred at 50° C., under 60 psi of hydrogen, for 22 h. The catalyst was filtered off and the residue was purified by preparative HPLC (YMC S10 ODS, 30×500 mm, 30 minute gradient from 62–90% aqueous methanol with 0.1% TFA). The appropriate fractions were combined, neutralized with saturated aqueous sodium bicarbonate, and then concentrated in vacuo to remove the methanol. The mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed once each with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to yield the title compound (63 mg, 65%): 1H NMR (CDCl3) δ 10.52 (s, 1H), 7.37–7.35 (m, 3H), 7.27–7.23 (m, 2H), 7.07 (m, 1H), 6.54 (m, 1H), 4.60 (m, 1H), 4.21 (m, 1H), 3.40 (m, 2H), 2.89 (m, 2H), 2.40 (s, 3H), 2.29 (m, 2H), 1.64 (m, 2H), 1.37 (s, 9H), 1.08 (t, 3H, J=7.15 Hz); MS (ESI+) 468.21 (M++H).

Workup

  1. customprepared
  2. filtrationThe catalyst was filtered off
  3. customthe residue was purified by preparative HPLC (YMC S10 ODS, 30×500 mm, 30 minute gradient from 62–90% aqueous methanol with 0.1% TFA)
  4. concentrationconcentrated in vacuo
  5. customto remove the methanol
  6. extractionThe mixture was extracted with ethyl acetate (3×10 mL)
  7. washThe combined organic layers were washed once each with water and brine
  8. dry with materialdried over anhydrous magnesium sulfate
  9. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-c6f2d2f979df40118e3be98bd7937040
Source dataset
uspto-grants-2006_04
Patent number
US07030118B2

Reaction notes

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