Piperidin-4-ol → HCID 58335500, compound

HRID 1890699Notes

Reaction equation

HRID 1890699 reaction equation
[F-].[K+].[OH:3][CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.F[C:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[N:27]4[N:28]=[C:29]([N:32]5[CH2:36][CH2:35][CH2:34][C@@H:33]5[C:37]5[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=5)[CH:30]=[CH:31][C:26]4=[N:25][CH:24]=3)[N:18]=2)[CH:14]=[CH:13][N:12]=1>CS(C)=O>[F:43][C:39]1[CH:38]=[C:37]([C@H:33]2[CH2:34][CH2:35][CH2:36][N:32]2[C:29]2[CH:30]=[CH:31][C:26]3[N:27]([C:23]([C:19]4[N:18]=[C:17]([C:15]5[CH:14]=[CH:13][N:12]=[C:11]([N:7]6[CH2:8][CH2:9][CH:4]([OH:3])[CH2:5][CH2:6]6)[CH:16]=5)[CH:22]=[CH:21][CH:20]=4)=[CH:24][N:25]=3)[N:28]=2)[CH:42]=[CH:41][CH:40]=1

Participants

5

Reactant 3

HCID 79341Piperidin-4-olHCID 522689Potassium FluorideHCID 58335627HCID 58335627, compound

Product 1

HCID 58335500HCID 58335500, compound

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Procedure

In step 16-4, potassium fluoride (10 g, 175 mmol) and 4-hydroxypiperidine (10.6 g, 105 mmol) were added to a solution of crude (R)-3-(2′-fluoro-2,4′-bipyridin-6-yl)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine (16-3) (16.1 g, 35 mmol) in DMSO (100 mL). The mixture was heated overnight to 120° C. (approx. 14 hours). The mixture was filtered through a celite pad and rinsed with EtOAc (1 L). The filtrate was washed with brine, dried over Na2SO4, filtered and concentrated to give a dark oil. The mixture was purified by column chromatography (silica gel, CH2Cl2/CH3OH, gradient 5% to 15%) to yield (R)-1-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-2,4′-bipyridin-2′-yl)piperidin-4-ol (16-4) which was crashed out from CH2Cl2, filtered and dried under high vacuum. 1H NMR (400 MHz, DMSO, ppm): δ 8.30 (s, 1H), 8.22 (d, 1H, J=5.2 Hz), 8.10-8.24 (bs, 1H), 7.90-7.98 (m, 2H), 7.76-7.86 (bs, 1H), 7.52 (s, 1H), 7.40 (q, 1H, J=7.4 Hz), 7.34 (d, 1H, J=5.2 Hz), 7.04 (t, 1H, J=8 Hz), 6.80-6.94 (bs, 1H), 5.19 (d, 1H, J=8 Hz), 4.71 (d, 1H, J=4 Hz), 4.10-4.18 (m, 2H), 3.93-4.06 (m, 1H), 3.65-3.75 (m, 2H), 3.10-3.20 (m, 2H), 1.98-2.10 (m, 2H), 1.78-1.92 (m, 3H), LC/MS: 536.2 (M+H+), 1.34-1.45 (m, 2H). 13C NMR (400 MHz, DMSO, ppm): 163.53, 161.11, 159.53, 153.95, 151.76, 148.27 (d, J=34.7 Hz), 147.69, 147.10 (d, J=25.6 Hz), 146.92, 137.61, 133.14 (d, J=23.2 Hz), 130.34 (d, J=32.4 Hz), 126.54, 126.04, 121.56, 119.26, 118.75, 113.40 (d, J=83.6 Hz), 112.41 (d, J=86.0), 110.26, 109.86, 103.75, 66.34, 61.24, 48.37, 42.72, 35.12, 33.71, 22.65.

Workup

  1. temperatureThe mixture was heated overnight to 120° C. (approx. 14 hours)
  2. filtrationThe mixture was filtered through a celite pad
  3. washrinsed with EtOAc (1 L)
  4. washThe filtrate was washed with brine
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customto give a dark oil
  9. customThe mixture was purified by column chromatography (silica gel, CH2Cl2/CH3OH, gradient 5% to 15%)

Sources & evidence

ORD record
ord-e747df1c8bfd48eb8887266786fdb234
Source dataset
uspto-grants-2013_08
Patent number
US08507488B2

Reaction notes

Loading…