p-Toluenesulfonic acid → 1532533-72-4

HRID 1747703Notes

Reaction equation

HRID 1747703 reaction equation
[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:22]([C:24]3[O:25][C:26]4[C:31]([C:32](=[O:41])[C:33]=3[C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=3)=[CH:30][C:29]([F:42])=[CH:28][CH:27]=4)[CH3:23])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH:18]([CH3:20])[CH3:19])=[C:13]([F:21])[CH:12]=3)[C:3]=12.[C:43]1([CH3:53])[CH:48]=[CH:47][C:46]([S:49]([OH:52])(=[O:51])=[O:50])=[CH:45][CH:44]=1>C(O)(C)C>[CH3:53][C:43]1[CH:44]=[CH:45][C:46]([S:49]([OH:52])(=[O:51])=[O:50])=[CH:47][CH:48]=1.[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:22]([C:24]3[O:25][C:26]4[C:31]([C:32](=[O:41])[C:33]=3[C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=3)=[CH:30][C:29]([F:42])=[CH:28][CH:27]=4)[CH3:23])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH:18]([CH3:19])[CH3:20])=[C:13]([F:21])[CH:12]=3)[C:3]=12

Participants

4

Reactant 2

HCID 6101p-Toluenesulfonic acidHCID 72950888Umbralisib

Product 1

HCID 867078281532533-72-4Yield 95.5%

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Procedure

To (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one (22.7 g, 39.69 mmol) in isopropanol (600 ml), p-toluenesulphonic acid (8.30 g, 43.66 mmol) was added and refluxed for 1 h. The reaction mixture was concentrated, co-distilled with petroleum ether and dried. To the residue water (300 ml) was added and stirred for 30 min. The solid was filtered, washed with petroleum ether and dried under vacuum to afford the title compound as off-white solid (28.2 g, 95%). MP: 138-141° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.11 (s, 1H), 7.85 (dd, J=8.0, 3.0 Hz, 1H), 7.80 (d, J=8.2 Hz, 2H), 7.51 (dd, J=9.3, 4.3 Hz, 1H), 7.45 (dd, J=7.5, 3.1 Hz, 1H), 7.42-7.31 (m, 3H), 7.29 (m, 2H), 7.22 (d, J=8.0 Hz, 2H), 7.16 (t, J=8.3 Hz, 1H), 7.08 (dt, J=8.5, 2.5 Hz, 1H), 6.97 (br s, 1H), 6.88 (br s, 1H), 6.11 (q, J=7.2 Hz, 1H), 4.67 (quintet, J=6.0 Hz, 1H), 2.36 (s, 3H), 2.03 (d, J=7.1 Hz, 3H), 1.43 (d, J=6.0 Hz, 6H). Mass: 572.4 (M++1-PTSA). Enantiomeric excess: 93.4% as determined by HPLC on a chiralpak AD-H column, enriched in the fast eluting isomer (retention time=12.35 min.)

Workup

  1. temperaturerefluxed for 1 h
  2. concentrationThe reaction mixture was concentrated, co-distilled with petroleum ether
  3. customdried
  4. additionTo the residue water (300 ml) was added
  5. filtrationThe solid was filtered
  6. washwashed with petroleum ether
  7. customdried under vacuum

Sources & evidence

ORD record
ord-b8721c5c434240f3b841a10308bdab18
Source dataset
uspto-grants-2015_10
Patent number
US09150579B2

Reaction notes

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