Dimethylacetamide → Tert-butyl (6-(2-(dimethylamino)thiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate

HRID 40344Notes

Reaction equation

HRID 40344 reaction equation
Br[C:2]1[S:6][C:5]([N:7]([CH3:9])[CH3:8])=[N:4][CH:3]=1.[Cl-].[Li+].C([Mg+])(C)C.[Cl-].CC(N(C)C)=O.Cl[C:24]1[CH:25]=[CH:26][C:27]2[N:28]([C:30]([CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[N:31][N:32]=2)[N:29]=1>C1COCC1.[Cl-].[Zn+2].[Cl-].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].CC(P(C(C)(C)C)[C-]1C=CC=C1)(C)C.C1C=CC([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)=CC=1.[Fe+2]>[CH3:8][N:7]([CH3:9])[C:5]1[S:6][C:2]([C:24]2[CH:25]=[CH:26][C:27]3[N:28]([C:30]([CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[N:31][N:32]=3)[N:29]=2)=[CH:3][N:4]=1

Participants

9

Reactant 4

HCID 31374DimethylacetamideHCID 124485555-bromo-N,N-dimethyl-1,3-thiazol-2-amineHCID 57691389tert-Butyl ((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)carbamateHCID 178461732HCID 178461732, compound

Product 1

HCID 57691069Tert-butyl (6-(2-(dimethylamino)thiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamateYield 71.9%

Reagents, catalysts & solvents 4

HCID 3007855ZincchlorideCatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 129828017Ditert-butyl(cyclopenta-2,4-dien-1-yl)phosphane;iron(2+);(2,3,4,5-tetraphenylcyclopenta-1,4-dien-1-yl)benzeneCatalystHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 5-bromo-N,N-dimethylthiazol-2-amine (0.73 g, 3.53 mmol) in anhydrous THF (9 mL) was added isopropylmagnesium lithium chloride (1.0 M in THF, 4.8 mL, 4.8 mmol) at −40° C. The solution was stirred for twenty minutes followed by the dropwise addition of zinc chloride (0.5 M in THF, 10 mL, 5.2 mmol). The mixture was brought to room temperature and stirred for thirty minutes followed by the addition of dimethylacetamide (12 mL), Pd2(dba)3, (0.32 g, 0.35 mmol), Q-Phos (0.34 g, 0.56 mmol), and tert-butyl (6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (0.29 g, 1.0 mmol). The mixture was stirred at 50° for two hours then was quenched with saturated ammonium chloride and purified by MPLC chromatography (eluted with a gradient of 0 to 10% (1:10:90 NH4OH:MeOH:DCM) in DCM) to yield the product as a light orange solid (0.27 g, 71%).

Workup

  1. customwas brought to room temperature
  2. stirringstirred for thirty minutes
  3. stirringThe mixture was stirred at 50° for two hours
  4. customthen was quenched with saturated ammonium chloride
  5. custompurified by MPLC chromatography (
  6. washeluted with a gradient of 0 to 10% (1:10:90 NH4OH:MeOH:DCM) in DCM)

Sources & evidence

ORD record
ord-0f44932409b3402eb79f92912b3bf384
Source dataset
uspto-grants-2013_09
Patent number
US08524900B2

Reaction notes

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