Cumylamine → tert-butyl (2R,5S)-2-[(R)-{[tert-butyl(dimethyl)silyl]oxy}{6-[(2-phenylpropan-2-yl)amino]pyridin-3-yl}methyl]-5-[4-(methoxycarbonyl)benzyl]pyrrolidine-1-carboxylate

HRID 1911846Notes

Reaction equation

HRID 1911846 reaction equation
[Si:1]([O:8][C@H:9]([C:33]1[CH:34]=[N+:35]([O-])[CH:36]=[CH:37][CH:38]=1)[C@H:10]1[CH2:14][CH2:13][C@@H:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=2)[N:11]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:40]([NH2:49])([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([CH3:42])[CH3:41].C1(C)C=CC(S(OS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1>FC(F)(F)C1C=CC=CC=1.CCOC(C)=O>[Si:1]([O:8][C@H:9]([C:33]1[CH:34]=[N:35][C:36]([NH:49][C:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([CH3:42])[CH3:41])=[CH:37][CH:38]=1)[C@H:10]1[CH2:14][CH2:13][C@@H:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=2)[N:11]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]

Participants

6

Reactant 3

HCID 68509Cumylamine3×HCID 77773Toluene-p-sulphonic anhydride3×HCID 86670463tert-butyl (2R,5S)-2-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(1-oxidopyridin-3-yl)methyl]-5-[4-(methoxycarbonyl)benzyl]pyrrolidine-1-carboxylate

Product 1

HCID 86670464tert-butyl (2R,5S)-2-[(R)-{[tert-butyl(dimethyl)silyl]oxy}{6-[(2-phenylpropan-2-yl)amino]pyridin-3-yl}methyl]-5-[4-(methoxycarbonyl)benzyl]pyrrolidine-1-carboxylateYield 62%

Reagents, catalysts & solvents 2

HCID 7368(Trifluoromethyl)benzeneSolventHCID 8857Ethyl AcetateSolvent

Procedure

A solution of tert-butyl (2R,5S)-2-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(1-oxidopyridin-3-yl)methyl]-5-[4-(methoxycarbonyl)benzyl]pyrrolidine-1-carboxylate (0.465 g, 0.835 mmol) in trifluorotoluene (15 ml) was cooled to 0° C. Cumylamine (0.282 mL, 2.09 mmol) was added, followed by p-toluenesulfonic anhydride (0.273 g, 0.835 mmol) in 2 portions, 5 minutes apart. After 10 minutes, additional cumylamine (0.282 mL, 2.09 mmol) was added, followed by p-toluenesulfonic anhydride (0.273 g, 0.835 mmol) in 2 portions, 5 minutes apart. After 10 minutes, a third addition of cumylamine (0.282 mL, 2.088 mmol) was carried out, followed by p-toluenesulfonic anhydride (273 mg, 0.835 mmol) in 2 portions, 5 minutes apart. After 10 hours, the reaction was diluted with EtOAc (250 mL) and washed with water (2×50 mL) and brine (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography with 0-100% EtOAc/hexanes to afford tert-butyl (2R,5S)-2-[(R)-{[tert-butyl(dimethyl)silyl]oxy}{6-[(2-phenylpropan-2-yl)amino]pyridin-3-yl}methyl]-5-[4-(methoxycarbonyl)benzyl]pyrrolidine-1-carboxylate (349.1 mg, 62%). LC-MS=674.4 (M+1)+. 1H NMR (600 MHz, CD3OD) δ −0.07 (s, 3H), 0.07 (s, 3H), 0.88 (s, 9H), 1.15-1.92 (m, 20H), 2.75 & 2.46 (2 multiplets, 1H), 3.87 (m, 4H), 4.06 (bs, 1H), 5.31 & 5.12 (2 singlets, 1H), 6.00-6.10 (m, 1H), 7.07 (m, 5H), 7.23 (bs, 1H), 7.36 (bs, 2H), 7.81 (bs, 1H), 7.90 (m, 2H).

Workup

  1. waitAfter 10 minutes
  2. waitAfter 10 hours
  3. washwashed with water (2×50 mL) and brine (50 mL)
  4. dry with materialThe organic layer was dried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue was purified by silica gel chromatography with 0-100% EtOAc/hexanes

Sources & evidence

ORD record
ord-174092c3c8384b42bb24a36b8f761c77
Source dataset
uspto-grants-2013_12
Patent number
US08604038B2

Reaction notes

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