Sodium hydride → (4-Bromo-2-fluoro-benzyl)-{5-[1-(4-{3-[N,N-bis-(tert-butoxycarbonyl)aminomethyl]-phenyl)-piperidin-1-yl)-methanoyl]-pyridin-3-yl}-carbamic acid dimethyl-ethyl ester

HRID 489618Notes

Reaction equation

HRID 489618 reaction equation
[C:1]([O:5][C:6](=[O:44])[NH:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:23]=3)[CH2:18][CH2:17]2)=[O:15])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:47][C:48]1[CH:55]=[CH:54][C:51]([CH2:52]Br)=[C:50]([F:56])[CH:49]=1>CN(C)C=O>[CH3:4][C:1]([O:5][C:6](=[O:44])[N:7]([CH2:52][C:51]1[CH:54]=[CH:55][C:48]([Br:47])=[CH:49][C:50]=1[F:56])[C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]([N:16]2[CH2:17][CH2:18][CH:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:23]=3)[CH2:20][CH2:21]2)=[O:15])[CH:13]=1)([CH3:2])[CH3:3]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 27336604-Bromo-2-fluorobenzyl bromideHCID 69027928{5-[1-(4-{3-[N,N-bis-(tert-butoxycarbonyl)aminomethyl]-phenyl}-piperidin-1-yl)methanoyl]-pyridin-3-yl}carbamic acid tert-butyl ester

Product 1

HCID 69033035(4-Bromo-2-fluoro-benzyl)-{5-[1-(4-{3-[N,N-bis-(tert-butoxycarbonyl)aminomethyl]-phenyl)-piperidin-1-yl)-methanoyl]-pyridin-3-yl}-carbamic acid dimethyl-ethyl esterYield 94.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of {5-[1-(4-{3-[N,N-bis-(tert-butoxycarbonyl)aminomethyl]-phenyl}-piperidin-1-yl)methanoyl]-pyridin-3-yl}carbamic acid tert-butyl ester (0.0745 g, 0.1220 mmol) in dimethylformamide (2.0 mL) was added sodium hydride (61% suspension in mineral oil, 0.0216 g, 0.5499 mmol). Deprotonation was allowed to occur over 3 minutes while stirring under inert atmosphere. 4-Bromo-2-fluorobenzyl bromide (0.1559 g, 0.5819 mmol) was added to the anion solution. The mixture was stirred an additional 10 minutes, then quenched with water (5.0 mL). The reaction solution was extracted with ethyl acetate (15 mL), and the organic phase was washed with brine (2×10 mL), dried over magnesium sulfate, filtered, and evaporated to dryness. Purification of the residue on silica gel eluting first with ethyl acetate/methylene chloride/hexane (1:1:2, v/v/v) and then with ethyl acetate and methylene chloride (1:1, v/v) afforded (4-bromo-2-fluoro-benzyl)-{5-[1-(4-{3-[N,N-bis-(tert-butoxycarbonyl)aminomethyl]-phenyl}-piperidin-1-yl)-methanoyl]-pyridin-3-yl}-carbamic acid dimethyl-ethyl ester as a colorless oil (0.0917 g): TLC, 50:50-methylene chloride:ethyl acetate, Rf=0.59. 1H NMR (300 MHz, CDCl3) δ 8.47-8.51 (m, 2H), 7.61 (br s, 1H), 7.07-7.32 (m, 7H), 4.89 (s, 2H), 4.78 (s, 2H), 4.77-4.92 (m partially obscured, 1H), 3.68-3.83 (br m, 1H), 3.09-3.24 (br, m, 1H), 2.70-2.97 (m, 2H), 1.45 (s, 18H), 1.44 (s, 9H), 1.30-2.04 (m partially obscured, 4H); 13C NMR (75 MHz, CDCl3) δ 167.0, 160.4 (d, 250.8), 154.0, 152.7, 148.5, 144.9, 139.0, 138.7, 132.2, 131.9, 130.7, 129.7, 127.9 (d, 3.4), 125.8, 125.7, 125.3, 123.8 (d, 14.5), 121.8 (d, 9.7), 119.3 (d, 24.8), 82.5, 82.2, 49.5, 46.9, 42.6, 32.8 (br), 28.4, 28.2, 28.0; 19F NMR (282 MHz, CDCl3) δ-114.9; MS (CI) m/z 797 (M+H).

Workup

  1. stirringThe mixture was stirred an additional 10 minutes
  2. customquenched with water (5.0 mL)
  3. extractionThe reaction solution was extracted with ethyl acetate (15 mL)
  4. washthe organic phase was washed with brine (2×10 mL)
  5. dry with materialdried over magnesium sulfate
  6. filtrationfiltered
  7. customevaporated to dryness
  8. customPurification of the residue on silica gel eluting first with ethyl acetate/methylene chloride/hexane (1:1:2, v/v/v)

Sources & evidence

ORD record
ord-0209f5f1dea247febfcad4e14f430265
Source dataset
uspto-grants-2005_12
Patent number
US06977263B2

Reaction notes

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