2-Hydroxyisobutyric acid → 6-(2-amino-5-pyrimidinyl)-4-(((3aS,4R,5R,6aS)-2-(2-hydroxy-2-methylpropanoyl)-4-methyloctahydrocyclopenta[c]pyrrol-5-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide

HRID 877738Notes

Reaction equation

HRID 877738 reaction equation
OC(C(F)(F)F)=O.Br[C:9]1[CH:10]=[C:11]2[C:16]([NH:17][C@@H:18]3[CH2:25][C@@H:21]4[CH2:22][NH:23][CH2:24][C@@H:20]4[C@H:19]3[CH3:26])=[C:15]([C:27]([NH2:29])=[O:28])[CH:14]=[N:13][N:12]2[CH:30]=1.[OH:31][C:32]([CH3:37])([CH3:36])[C:33](O)=[O:34].C(N(CC)C(C)C)(C)C.CC1(C)C(C)(C)OB([C:55]2[CH:56]=[N:57][C:58]([NH2:61])=[N:59][CH:60]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:61][C:58]1[N:59]=[CH:60][C:55]([C:9]2[CH:10]=[C:11]3[C:16]([NH:17][C@@H:18]4[CH2:25][C@@H:21]5[CH2:22][N:23]([C:33](=[O:34])[C:32]([OH:31])([CH3:37])[CH3:36])[CH2:24][C@@H:20]5[C@H:19]4[CH3:26])=[C:15]([C:27]([NH2:29])=[O:28])[CH:14]=[N:13][N:12]3[CH:30]=2)=[CH:56][N:57]=1

Participants

8

Reactant 5

HCID 116712-Hydroxyisobutyric acidHCID 62657Potassium Phosphate, TribasicHCID 81531DiisopropylethylamineHCID 177502122-Aminopyrimidine-5-boronic acid, pinacol esterHCID 867078986-bromo-4-(((3aS,4R,5R,6aS)-4-methyloctahydrocyclopenta[c]pyrrol-5-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide TFA salt

Product 1

HCID 867079006-(2-amino-5-pyrimidinyl)-4-(((3aS,4R,5R,6aS)-2-(2-hydroxy-2-methylpropanoyl)-4-methyloctahydrocyclopenta[c]pyrrol-5-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamideYield 66%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 6228DimethylformamideSolvent

Procedure

A mixture of 6-bromo-4-(((3aS,4R,5R,6aS)-4-methyloctahydrocyclopenta-[c]pyrrol-5-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide TFA salt from Step 2 of Example 59 (22 mg, 0.045 mmol), 2-hydroxy-2-methylpropanoic acid (5.1 mg, 0.049 mmol), (benzotriazol-1-yloxy)tris(dimethylamine)phosphonium hexafluorophosphate (21.7 mg, 0.049 mmol) and N,N-diisopropylethylamine (0.023 mL, 0.134 mmol) in N,N-dimethylformamide (1 mL) was stirred at room temperature for 2 h. 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (19.8 mg, 0.089 mmol), 2.0 M aqueous K3PO4 (0.089 mL, 0.179 mmol) and PdCl2(dppf) (3.27 mg, 4.47 mmol) was added. The reaction vial was sealed under nitrogen and heated to 90° C. 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 0.05% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA; 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 mg, 66% yield). 1H NMR (500 MHz, 1:1 mixture of methanol-d4/chloroform-d) d 8.64 (s, 1H), 8.13 (s, 1H), 7.98 (s, 1H), 7.86 (d, J=2.0 Hz, 1H), 7.08 (d, J=2.0 Hz, 1H), 4.35-4.13 (m, 1H), 4.10-3.89 (m, 1H), 3.79-3.49 (m, 3H), 2.95-2.88 (m, 1H), 2.85-2.75 (m, 1H), 2.45-2.20 (m, 1H), 1.78-1.69 (m, 1H), 1.62-1.52 (m, 1H), 1.52-1.36 (m, 6H), 1.21 (d, J=6.9 Hz, 3H); MS (ES+) m/z: 479.2 (M+H); LC retention time: 1.135 min (analytical HPLC Method I).

Workup

  1. customThe reaction
  2. customvial was sealed under nitrogen
  3. temperatureheated to 90° C. for 1 h
  4. customThe crude material was purified via preparative LC/MS with the following conditions
  5. waitGradient: 0-100% B over 25 minutes
  6. customa 5-minute hold
  7. additionFractions containing the desired product
  8. customdried via centrifugal evaporation

Sources & evidence

ORD record
ord-ff38a47b61a34b698b68bcb6fd69813b
Source dataset
uspto-grants-2015_03
Patent number
US08987268B2

Reaction notes

Loading…