1-Hydroxybenzotriazole → (2beta,3alpha,5alpha)-3-hydroxy-2-(4-{[(2S)-1-(isoquinolin-3-ylcarbonyl)pyrrolidin-2-yl]carbonyl}piperazin-1-yl)androstan-17-one

HRID 244257Notes

Reaction equation

HRID 244257 reaction equation
[OH:1][C@@H:2]1[C@@H:19]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH2:18][C@@:17]2([CH3:26])[CH:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:27])[CH2:3]1.[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[C:30]([C:38]([N:40]2[CH2:47][CH2:46][CH2:45][C@H:41]2[C:42](O)=[O:43])=[O:39])[N:29]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[OH:1][C@@H:2]1[C@@H:19]([N:20]2[CH2:21][CH2:22][N:23]([C:42]([C@@H:41]3[CH2:45][CH2:46][CH2:47][N:40]3[C:38]([C:30]3[N:29]=[CH:28][C:37]4[C:32]([CH:31]=3)=[CH:33][CH:34]=[CH:35][CH:36]=4)=[O:39])=[O:43])[CH2:24][CH2:25]2)[CH2:18][C@@:17]2([CH3:26])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:27])[CH2:3]1

Participants

8

Reactant 5

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 2724699PyBOPHCID 674234501-(isoquinolin-3-ylcarbonyl)-L-prolineHCID 86660495(2beta,3alpha)-3-Hydroxy-2-(piperazin-1-yl)androstan-17-one

Product 1

HCID 86660503(2beta,3alpha,5alpha)-3-hydroxy-2-(4-{[(2S)-1-(isoquinolin-3-ylcarbonyl)pyrrolidin-2-yl]carbonyl}piperazin-1-yl)androstan-17-one

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

To a solution of compound 23 (356 mg, 0.95 mmol) in anhydrous DMF (5 mL) at room temperature under an atmosphere of argon were added 1-(isoquinolin-3-ylcarbonyl)-L-proline (335 mg, 1.2 mmol), PyBOP (647 mg, 1.2 mmol), HOBt (168 mg, 1.2 mmol), and DIPEA (662 μL, 3.8 mmol). The solution was subsequently stirred overnight at room temperature. The resulting solution was then poured into water and extracted with EtOAc (2×30 mL), washed with brine, dried with MgSO4 and evaporated to dryness. Purification by two successive flash chromatography procedures using (DCM/MeOH: 95:5) and (Hexanes/Acetone: 1:1) respectively yielded 302 mg (50%) of compound 43. 1H NMR (CDCl3) δ: 0.84 and 0.86 (2s, 18-CH3), 0.89 and 0.90 (2s, 19-CH3), 0.70-2.30 (residual CH and CH2), 2.35-2.85 (broad m, 2×CH2N, 16β-CH and 2α-CH), 3.10-4.27 (broad m, 2×CH2NCO, CH2N of proline, and 3β-CH), 5.10 and 5.88 (2m, NCHCO of proline), 7.58 (m, CH of quinoline), 7.76 (m, CH of quinoline), 7.84 (t, J=8.3 Hz, CH of quinoline), 7.98 (t, J=8.7 Hz, CH of quinoline), 8.02 and 8.12 (2d, J=8.6 Hz, CH of quinoline), 8.21 and 8.24 (2d, J=8.9 Hz, CH of quinoline).

Workup

  1. extractionextracted with EtOAc (2×30 mL)
  2. washwashed with brine
  3. dry with materialdried with MgSO4
  4. customevaporated to dryness
  5. customPurification by two successive flash chromatography procedures

Sources & evidence

ORD record
ord-8b3108b36bb240b28e4d057dc933c1dd
Source dataset
uspto-grants-2014_02
Patent number
US08653054B2

Reaction notes

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