Potassium Phosphate, Tribasic → 4-(((3aS,4R,5R,6aS)-2-(2-hydroxy-2-methylpropanoyl)-4-methyloctahydrocyclopenta[c]pyrrol-5-yl)amino)-6-(6-(methylcarbamoyl)-3-pyridinyl)pyrrolo[1,2-b]pyridazine-3-carboxamide

HRID 877740Notes

Reaction equation

HRID 877740 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@@H:11]3[CH2:24][C@@H:14]4[CH2:15][N:16]([C:18](=[O:23])[C:19]([OH:22])([CH3:21])[CH3:20])[CH2:17][C@@H:13]4[C@H:12]3[CH3:25])=[C:8]([C:26]([NH2:28])=[O:27])[CH:7]=[N:6][N:5]2[CH:29]=1.[CH3:30][NH:31][C:32](=[O:48])[C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][N:34]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O>[OH:22][C:19]([CH3:20])([CH3:21])[C:18]([N:16]1[CH2:17][C@@H:13]2[C@@H:12]([CH3:25])[C@H:11]([NH:10][C:9]3[C:4]4[N:5]([CH:29]=[C:2]([C:36]5[CH:35]=[N:34][C:33]([C:32](=[O:48])[NH:31][CH3:30])=[CH:38][CH:37]=5)[CH:3]=4)[N:6]=[CH:7][C:8]=3[C:26]([NH2:28])=[O:27])[CH2:24][C@@H:14]2[CH2:15]1)=[O:23]

Participants

5

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 44119560N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamideHCID 682908626-bromo-4-(((3aS,4R,5R,6aS)-2-(2-hydroxy-2-methylpropanoyl)-4-methyloctahydrocyclopenta[c]pyrrol-5-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide

Product 1

HCID 682918074-(((3aS,4R,5R,6aS)-2-(2-hydroxy-2-methylpropanoyl)-4-methyloctahydrocyclopenta[c]pyrrol-5-yl)amino)-6-(6-(methylcarbamoyl)-3-pyridinyl)pyrrolo[1,2-b]pyridazine-3-carboxamideYield 52.1%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
90 °C

Procedure

A mixture of 6-bromo-4-(((3aS,4R,5R,6aS)-2-(2-hydroxy-2-methylpropanoyl)-4-methyloctahydrocyclopenta[c]pyrrol-5-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (32 mg, 0.055 mmol), N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide (29.0 mg, 0.111 mmol) and 2.0 M aqueous K3PO4 (0.111 mL, 0.221 mmol) in dimethylformamide (1 mL) was heated to 90° C. under nitrogen for 1 h. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 0-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (14.9 mg, 52% yield). 1H NMR (500 MHz, 1:1 mixture of methanol-d4/chloroform-d) d 8.93 (d, J=2.0 Hz, 1H), 8.28-8.08 (m, 3H), 8.04 (d, J=1.5 Hz, 1H), 7.28 (d, J=1.5 Hz, 1H), 4.45-4.19 (m, 2H), 4.03-3.91 (m, 1H), 3.77-3.56 (m, 2H), 3.10-2.99 (m, 3H), 2.96-2.79 (m, 2H), 2.53-2.32 (m, 1H), 1.87-1.75 (m, 1H), 1.66-1.54 (m, 1H), 1.51-1.35 (m, 6H), 1.22 (d, J=6.4 Hz, 3H); MS (ES+) m/z: 520.2 (M+H); LC retention time: 1.135 min (analytical HPLC Method I).

Workup

  1. customThe crude material was purified via preparative LC/MS with the following conditions
  2. customa 5-minute hold
  3. additionFractions containing the desired product
  4. customdried via centrifugal evaporation

Sources & evidence

ORD record
ord-abf846e0b7d24d0fa94ba7a698ea6a1b
Source dataset
uspto-grants-2015_03
Patent number
US08987268B2

Reaction notes

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