Diisopropylamine → HCID 68232116, compound

HRID 869180Notes

Reaction equation

HRID 869180 reaction equation
C(NC(C)C)(C)C.[Li]CCCC.[Si:13]([O:20][CH2:21][C:22]1[S:26][CH:25]=[N:24][CH:23]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].Cl[C:28]1[N:33]=[N:32][C:31]([N:34]([CH2:42][C:43]2([C:47]3[C:52]([F:53])=[CH:51][CH:50]=[CH:49][N:48]=3)[CH2:46][CH2:45][CH2:44]2)[C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:30][CH:29]=1>[Br-].[Zn+2].[Br-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>[Si:13]([O:20][CH2:21][C:22]1[S:26][C:25]([C:28]2[N:33]=[N:32][C:31]([N:34]([CH2:42][C:43]3([C:47]4[C:52]([F:53])=[CH:51][CH:50]=[CH:49][N:48]=4)[CH2:46][CH2:45][CH2:44]3)[C:35](=[O:41])[O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[CH:30][CH:29]=2)=[N:24][CH:23]=1)([C:16]([CH3:19])([CH3:17])[CH3:18])([CH3:14])[CH3:15]

Participants

8

Reactant 4

HCID 7912DiisopropylamineHCID 59361608HCID 59361608, compoundHCID 86686131HCID 86686131, compoundHCID 178418339Butyllithium

Product 1

HCID 68232116HCID 68232116, compoundYield 73.9%

Reagents, catalysts & solvents 3

HCID 10421208Zinc bromideCatalystHCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

To a stirring mixture of THF (2000 mL) and diisopropylamine (79.3 mL, 0.56 mol) at −78° C. was added n-BuLi (244 mL, 0.56 mol) dropwise. After stirring for 20 min at −78° C., a solution of 5-((t-butyldimethylsilyloxy)methyl)thiazole (110.9 g, 0.49 mol in 300 mL of THF) was added dropwise to the reaction mixture while maintaining a temperature less than −70° C. After the addition was complete, the reaction was stirred for an additional 30 min and a solution of zinc bromide (126.6 g, 0.56 mol in 300 mL of THF) was added dropwise to the reaction mixture while maintaining a temperature less than −65° C. The reaction was warmed to 0° C., stirred for 30 min, and added to a stirring mixture of t-butyl 6-chloropyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (100 g, 0.26 mol), tetrakis(triphenylphosphine)palladium(0) (56 g, 0.05 mol), and THF (2000 mL) heated to 80° C. The reaction mixture was stirred overnight at 80° C. The reaction was concentrated and then slurried in ethyl acetate and brine. The resultant solid was filtered off, and the filtrate was dried over sodium sulfate, concentrated, and purified twice by silica gel chromatography (EtOAc/hexanes) to afford 112.5 g of t-butyl 6-(5-((tert-butyldimethylsilyloxy)methyl)thiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate as a dark oil.

Workup

  1. temperaturewhile maintaining a temperature less than −70° C
  2. additionAfter the addition
  3. stirringthe reaction was stirred for an additional 30 min
  4. temperaturewhile maintaining a temperature less than −65° C
  5. temperatureThe reaction was warmed to 0° C.
  6. stirringstirred for 30 min
  7. temperatureheated to 80° C
  8. stirringThe reaction mixture was stirred overnight at 80° C
  9. concentrationThe reaction was concentrated
  10. filtrationThe resultant solid was filtered off
  11. dry with materialthe filtrate was dried over sodium sulfate
  12. concentrationconcentrated
  13. custompurified twice by silica gel chromatography (EtOAc/hexanes)

Sources & evidence

ORD record
ord-c4513aee5d3d46a1bdd6f42ac5f5c9fd
Source dataset
uspto-grants-2015_03
Patent number
US08969346B2

Reaction notes

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