Binap, (A+-)- → 4-((4,5-dimethylthiazol-2-yl)methylamino)-6-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyridazin-3(2H)-one

HRID 530820Notes

Reaction equation

HRID 530820 reaction equation
[CH3:1][C:2]1[N:3]=[C:4]([CH2:8][NH2:9])[S:5][C:6]=1[CH3:7].Br[C:11]1[C:12](=[O:31])[N:13]([CH3:30])[N:14]=[C:15]([O:17][CH2:18][C@H:19]2[CH2:21][C@@H:20]2[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][N:23]=2)[CH:16]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(O[Na])(C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][C:2]1[N:3]=[C:4]([CH2:8][NH:9][C:11]2[C:12](=[O:31])[N:13]([CH3:30])[N:14]=[C:15]([O:17][CH2:18][C@H:19]3[CH2:21][C@@H:20]3[C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][N:23]=3)[CH:16]=2)[S:5][C:6]=1[CH3:7]

Participants

7

Reactant 4

HCID 634876Binap, (A+-)-HCID 24261647(Dimethyl-1,3-thiazol-2-yl)methanamineHCID 904192134-bromo-6-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl) methoxy)-2-methylpyridazin-3(2H)-oneHCID 178418730sodium 2-methylpropan-2-olate

Product 1

HCID 904544034-((4,5-dimethylthiazol-2-yl)methylamino)-6-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyridazin-3(2H)-one

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
85 °C

Procedure

A mixture of (4,5-dimethylthiazol-2-yl)methanamine (28 mg, 0.2 mmol), 4-bromo-6-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyridazin-3(2H)-one (73 mg, 0.2 mmol), Pd2(dba)3 (18 mg, 0.02 mmol), BINAP (18 mg, 0.03 mmol) and t-BuONa (38 mg, 0.4 mmol) in toluene (4 mL) under N2 was heated at 85° C. for 4 h. filtered and concentrated to give crude product which was purified by Pre-HPLC to give the title compound 6 as a oil. 1H NMR (400 MHz, CD3OD) δ 7.92 (d, 1H), 7.14 (dd, 1H), 7.02 (d, 1H), 5.66 (s, 1H), 4.45 (d, 2H), 4.05-4.01 (m, 1H), 3.92-3.88 (m, 1H), 3.71 (s, 3H), 3.51 (s, 3H), 2.18 (s, 3H), 2.15 (s, 3H), 1.95-1.90 (m, 1H), 1.63-1.58 (m, 1H), 1.06-1.01 (m, 1H), 0.91-0.86 (m, 1H), LCMS m/z (M+H) 428.1 found, 428.1 required.

Workup

  1. filtrationfiltered
  2. concentrationconcentrated
  3. customto give crude product which
  4. customwas purified by Pre-HPLC

Sources & evidence

ORD record
ord-efa2d834a94d42f1843976873b938da9
Source dataset
uspto-grants-2016_05
Patent number
US09353104B2

Reaction notes

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