Cyclobutanol → (R)-1-(4-Fluorophenyl)-6-(6-morpholin-4-yl-pyridine-3-sulfonyl]-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carboxylic acid cyclobutyl ester

HRID 1907312Notes

Reaction equation

HRID 1907312 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21](Cl)=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:24]([C:27]2[CH:28]=[N:29][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:31][CH:32]=2)(=[O:26])=[O:25])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.[CH:39]1([OH:43])[CH2:42][CH2:41][CH2:40]1>C(N(CC)CC)C>[CH:39]1([O:43][C:21]([C@@:19]23[CH2:18][N:17]([S:24]([C:27]4[CH:28]=[N:29][C:30]([N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)=[CH:31][CH:32]=4)(=[O:26])=[O:25])[CH2:16][CH2:15][C:14]2=[CH:13][C:12]2[N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[N:9]=[CH:10][C:11]=2[CH2:20]3)=[O:22])[CH2:42][CH2:41][CH2:40]1

Participants

4

Reactant 2

HCID 76218CyclobutanolHCID 86669993HCID 86669993, compound

Product 1

HCID 66780108(R)-1-(4-Fluorophenyl)-6-(6-morpholin-4-yl-pyridine-3-sulfonyl]-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carboxylic acid cyclobutyl esterYield 18%

Reagents, catalysts & solvents 1

HCID 8471TriethylamineSolvent

Procedure

(R)-1-(4-Fluorophenyl)-6-(6-morpholin-4-yl-pyridine-3-sulfonyl]-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carbonyl chloride (0.12 g), triethylamine (0.11 g) and cyclobutanol (0.24 g) were heated in a microwave apparatus at 110° C. for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue purified by column chromatography on silica gel, eluting with ethyl acetate in dichloromethane (1:4 to 2:3 by volume) followed by preparative reverse-phase HPLC eluting with a mixture of acetonitrile and water containing 0.1% formic acid (1:1 to 4:1 by volume) to give the title compound as a white solid (0.023 g). 1H NMR (400 MHz, CHCl3-d): δ 8.53 (d, 1H), 7.78 (dd, 1H), 7.47-7.35 (m, 3H), 7.19-7.11 (m, 2H), 6.62 (d, 1H), 6.40 (d, 1H), 4.95 (t, 1H), 4.38 (dd, 1H), 3.81 (t, 5H), 3.66 (t, 4H), 3.29 (d, 1H), 2.99-2.90 (m, 1H), 2.57 (d, 1H), 2.48-2.28 (m, 5H), 2.16-2.05 (m, 2H), 1.87-1.77 (m, 1H),1.66-1.52 (m, 1H).

Workup

  1. concentrationThe reaction mixture was concentrated under reduced pressure
  2. customthe residue purified by column chromatography on silica gel
  3. washeluting with ethyl acetate in dichloromethane (1:4 to 2:3 by volume)
  4. washeluting with a mixture of acetonitrile and water containing 0.1% formic acid (1:1 to 4:1 by volume)

Sources & evidence

ORD record
ord-0cdc9d07ace244f2824f2565b34b7310
Source dataset
uspto-grants-2013_12
Patent number
US08598154B2

Reaction notes

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