Sodium Carbonate → Butyl 4-({2-[(tert-butoxycarbonyl)amino]-2-methyl-3-phenylpropoxy}methyl)-6-[(methylsulfonyl)(propyl)amino]pyridine-2-carboxylate

HRID 899449Notes

Reaction equation

HRID 899449 reaction equation
[CH2:1]([C:8]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:27])[CH2:9][O:10][CH2:11][C:12]1[CH:17]=[C:16]([N:18]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:19][CH2:20][CH3:21])[N:15]=[C:14](Cl)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36](=[O:39])([O-])[O-:37].[Na+].[Na+]>C(O)CCC.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl>[C:31]([O:30][C:29]([NH:28][C:8]([CH3:27])([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][O:10][CH2:11][C:12]1[CH:17]=[C:16]([N:18]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:19][CH2:20][CH3:21])[N:15]=[C:14]([C:36]([O:37][CH2:8][CH2:1][CH2:2][CH3:3])=[O:39])[CH:13]=1)=[O:35])([CH3:34])([CH3:33])[CH3:32]

Participants

5

Reactant 2

HCID 10340Sodium CarbonateHCID 58856338Tert-butyl [1-benzyl-2-({2-chloro-6-[(methylsulfonyl)(propyl)amino]pyridin-4-yl}methoxy)-1-methylethyl]carbamate2×

Product 1

HCID 67318238Butyl 4-({2-[(tert-butoxycarbonyl)amino]-2-methyl-3-phenylpropoxy}methyl)-6-[(methylsulfonyl)(propyl)amino]pyridine-2-carboxylate

Reagents, catalysts & solvents 2

HCID 498840Bis(benzonitrile)palladium chlorideCatalystHCID 2631-ButanolSolvent

Conditions

Temperature
100 °C

Procedure

A suspension of tert-butyl [1-benzyl-2-({2-chloro-6-[(methylsulfonyl)(propyl)amino]pyridin-4-yl}methoxy)-1-methylethyl]carbamate (115 mg, 0.22 mmol, intermediate VI), sodium carbonate (70 mg, 0.66 mmol), PdCl2(PhCN)2 (2 mg, 0.004 mmol), 4A sieves and 1-[2-(dicyclohexylphasphanyl)ferrocenyl]ethyldicyclohexylphosphane (11 mg, 0.017 mmol, STREM) in n-butanol (2 ml, degassed with Argon), was purged with CO and stirred at 100° C. for 16 h under 1 atm of CO. The reaction mixture was diluted with dichloromethane, washed with water and brine, dried over sodium sulfate, concentrated in vacuo, azeothroped with toluene, and purified by flash chromatography (silica, 0-35% EtOAc/hexanes) to provide butyl 4-({2-[(tert-butoxycarbonyl)amino]-2-methyl-3-phenylpropoxy}methyl)-6-[(methylsulfonyl)(propyl)amino]pyridine-2-carboxylate as a yellow oil which was dissolved in 1:1 THF:MeOH (1.6 mL) and treated with aq LiOH (0.38 mL, 0.38 mmol, 1N) for 2 h at rt. The reaction mixture was acidified to pH 3-4 with 1N HCl, extracted with dichloromethane, dried over sodium sulfate, concentrated in vacuo, azeothroped with toluene to give 4-({2-[(tert-butoxycarbonyl)amino]-2-methyl-3-phenylpropoxy}methyl)-6-[(methylsulfonyl)(propyl)amino]pyridine-2-carboxylic acid as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.71 (s, 1H), 7.34-7.13 (m, 5H), 4.67 (s, 2H), 4.49 (s, 1H), 3.93 (t, J=7.6 Hz, 2H), 3.72 (A of AB, d, J=9.2 Hz, 1H), 3.62 (B of AB, d, J=9.2 Hz, 1H), 3.17 (A of AB, d, J=13.6 Hz, 1H), 3.05 (s, 3H), 2.90 (13 of AB, d, J=13.6 Hz, 1H), 1.70-1.55 (m, 2H), 1.46 (s, 9H), 1.27 (s, 3H), 0.96 (t, J=7.6 Hz, 3H).

Workup

  1. customwas purged with CO
  2. additionThe reaction mixture was diluted with dichloromethane
  3. washwashed with water and brine
  4. dry with materialdried over sodium sulfate
  5. concentrationconcentrated in vacuo
  6. custompurified by flash chromatography (silica, 0-35% EtOAc/hexanes)

Sources & evidence

ORD record
ord-f8ba6a0da2fe4c0789a74a61cff46bb2
Source dataset
uspto-grants-2008_04
Patent number
US07354942B2

Reaction notes

Loading…