Phosgene → 4-[Bis-(3-methyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carboxylic acid benzyl-hydroxy-amide

HRID 251131Notes

Reaction equation

HRID 251131 reaction equation
[CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:33](Cl)(Cl)=[O:34].Cl.[CH2:38]([NH:45][OH:46])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C1(C)C=CC=CC=1>[CH2:38]([N:45]([OH:46])[C:33]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:8][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:11][CH2:12]1)=[O:34])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1

Participants

6

Reactant 4

HCID 6371PhosgeneHCID 81531Diisopropylethylamine2×HCID 11332622N-benzylhydroxylamine hydrochlorideHCID 58996965Bis-(3-methyl-pyridin-2-ylmethyl)-piperidin-4-yl-amine

Product 1

HCID 589972414-[Bis-(3-methyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carboxylic acid benzyl-hydroxy-amideYield 77%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

To a solution of COMPOUND 249 (0.115 g, 0.37 mmol) in toluene (4 mL) was added DIPEA (0.16 mL, 0.92 mmol) followed by phosgene solution (20% in toluene, 0.20 mL, 0.44 mmol). The resultant mixture was stirred at room temperature for 90 minutes then concentrated under reduced pressure. The residue was dissolved in DMF (4 mL) and treated with DIPEA (0.60 mL, 3.44 mmol) followed by N-benzylhydroxylamine hydrochloride (0.194 g, 1.22 mmol) and the resultant mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was partitioned between CH2Cl2 (50 mL) and saturated aqueous NaHCO3 (15 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×15 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by radial chromatography on silica gel (1 mm plate, 25:1:1 CH2Cl2-MeOH—NH4OH) provided 131 mg (74%) of COMPOUND 272 as a white solid. 1H NMR (CDCl3) δ 1.64-1.76 (m, 2H), 1.918-1.96 (m, 2H), 2.08 (s, 6H), 2.68-2.79 (m, 3H), 3.81 (s, 4H), 4.20 (d, 2H, J=13.2 Hz), 4.30 (s, 2H), 6.81 (s, 1H), 7.08 (dd, 2H, J=7.5, 4.8 Hz), 7.27-7.38 (m, 7H), 8.32 (d, 2H, J=3.6 Hz); 13C NMR (CDCl3) δ 18.35, 27.54, 46.12, 54.86, 57.74, 59.70, 122.87, 127.94, 128.68, 129.35, 133.88, 136.61, 138.59, 146.15, 157.28, 164.68; ES-MS m/z 460 (M+H). Anal. Calcd. For C27H33N5O2.0.2CH2Cl2: C, 68.55; H, 7.06; N, 14.70. Found: C, 68.85; H, 7.21; N, 14.79.

Workup

  1. concentrationthen concentrated under reduced pressure
  2. dissolutionThe residue was dissolved in DMF (4 mL)
  3. concentrationThe mixture was concentrated
  4. customthe residue was partitioned between CH2Cl2 (50 mL) and saturated aqueous NaHCO3 (15 mL)
  5. customThe phases were separated
  6. extractionthe aqueous phase was extracted with CH2Cl2 (3×15 mL)
  7. dry with materialThe combined organic extracts were dried (Na2SO4)
  8. concentrationconcentrated
  9. customPurification of the crude material by radial chromatography on silica gel (1 mm plate, 25:1:1 CH2Cl2-MeOH—NH4OH)

Sources & evidence

ORD record
ord-61921e5f29d84c8c9bc6549bb9bd89d3
Source dataset
uspto-grants-2011_01
Patent number
US07863293B2

Reaction notes

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