(3S,4S)-4-[(S)-3-(4-Fluoro-benzyl)-piperidin-1-ylmethyl]-tetrahydro-pyran-3-ylamine → 1-{(3S,4S)-4-[(S)-3-(4-fluorobenzyl)-piperidin-1-ylmethyl]-tetrahydro-pyran-3-yl}-3-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea

HRID 1169242Notes

Reaction equation

HRID 1169242 reaction equation
[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][C@@H:14]3[CH2:19][CH2:18][O:17][CH2:16][C@H:15]3[NH2:20])[CH2:8]2)=[CH:4][CH:3]=1.C1([O:29][C:30](=O)[NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]3[N:42]([CH3:43])[N:41]=[N:40][N:39]=3)[CH:33]=2)C=CC=CC=1>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][C@@H:14]3[CH2:19][CH2:18][O:17][CH2:16][C@H:15]3[NH:20][C:30]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]4[N:42]([CH3:43])[N:41]=[N:40][N:39]=4)[CH:33]=3)=[O:29])[CH2:8]2)=[CH:21][CH:22]=1

Participants

4

Reactant 2

HCID 21362442(3S,4S)-4-[(S)-3-(4-Fluoro-benzyl)-piperidin-1-ylmethyl]-tetrahydro-pyran-3-ylamineHCID 22252681phenyl 3-(1-methyl-1H-tetraazol-5-yl)phenylcarbamate

Product 1

HCID 697476451-{(3S,4S)-4-[(S)-3-(4-fluorobenzyl)-piperidin-1-ylmethyl]-tetrahydro-pyran-3-yl}-3-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-ureaYield 23%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

(3S,4S)-4-[(S)-3-(4-Fluoro-benzyl)-piperidin-1-ylmethyl]-tetrahydro-pyran-3-ylamine (44 mg, 143 μmol) and [3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-carbamic acid phenyl ester (47 mg, 158 μmol) were dissolved in acetonitrile (1 mL) and the mixture was stirred at room temperature. After 24 h , the mixture was concentrated, dissolved in ethyl acetate, washed with water, dried (Na2SO4) and concentrated. The residue was purified by reverse phase high pressure liquid chromatography (C18, 10-100% acetonitrile in water, containing 0.05% trifluoroacetic acid), then by flash column chromatography (5% methanol in dichloromethane, containing 0.5% ammonium hydroxide) to provide the product as a glass (16 mg, 23%). 1H NMR (300 mHz, CD3OD) δ7.95 (s, 1H), 7.52 (m, 2H), 7.43 (m, 1H), 7.05 (m, 2H), 6.86 (m, 2H), 4.19 (s, 3H), 3.94 (dd, J=10.7, 4.4 Hz, 1H), 3.87 (bd, 1H), 3.50 (td, J=9.9, 4.4 Hz, 1H), 3.39 (m, 1H), 3.09 (t, J=10.2 Hz, 1H), 2.93 (bd, 1H), 2.85 (bd, 1H), 2.56 (dd, J=12.8, 5.2 Hz, 1H), 2.45 (m, 2H), 2.30 (dd, J=12.4, 6.6 Hz, 1H), 2.04 (bt, 1H), 1.9-1.5 (7H), 1.40 (m, 1H), 0.95 (m, 1H), ESI MS: (M+H)+=508.3 (100%).

Workup

  1. concentrationthe mixture was concentrated
  2. dissolutiondissolved in ethyl acetate
  3. washwashed with water
  4. dry with materialdried (Na2SO4)
  5. concentrationconcentrated
  6. customThe residue was purified by reverse phase high pressure liquid chromatography (C18, 10-100% acetonitrile in water, containing 0.05% trifluoroacetic acid)
  7. additionby flash column chromatography (5% methanol in dichloromethane, containing 0.5% ammonium hydroxide)

Sources & evidence

ORD record
ord-1c53cbd86c7543baaf1398d457bc0cf9
Source dataset
uspto-grants-2003_09
Patent number
US06627629B2

Reaction notes

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