1,2-Bis(chlorodimethylsilyl)ethane → 3-[6-(4-Chloro-benzylamino)-pyridazin-3-ylmethyl]-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester

HRID 1367344Notes

Reaction equation

HRID 1367344 reaction equation
Br[C:2]1[N:7]=[N:6][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C([Li])CCC.Cl[Si](C)(C)CC[Si](Cl)(C)C.C([Li])(C)(C)C.C([Cu])#N.[C:40]([O:44][C:45]([N:47]1[C:51]2=[N:52][CH:53]=[CH:54][CH:55]=[C:50]2[C:49]([CH2:56]Cl)=[CH:48]1)=[O:46])([CH3:43])([CH3:42])[CH3:41]>O1CCCC1.CCCCCC.O>[C:40]([O:44][C:45]([N:47]1[C:51]2=[N:52][CH:53]=[CH:54][CH:55]=[C:50]2[C:49]([CH2:56][C:2]2[N:7]=[N:6][C:5]([NH:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)=[CH:4][CH:3]=2)=[CH:48]1)=[O:46])([CH3:43])([CH3:42])[CH3:41]

Participants

10

Reactant 6

HCID 835521,2-Bis(chlorodimethylsilyl)ethaneHCID 21463021tert-Butyl 3-(chloromethyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylateHCID 57619288(6-Bromo-pyridazin-3-yl)-(4-chloro-benzyl)-amineHCID 178418306HCID 178418306, compoundHCID 178418339ButyllithiumHCID 178418546HCID 178418546, compound

Product 1

HCID 576192483-[6-(4-Chloro-benzylamino)-pyridazin-3-ylmethyl]-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl esterYield 23.8%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent4×HCID 8058HexaneSolvent

Procedure

To (6-bromo-pyridazin-3-yl)-(4-chloro-benzyl)-amine (522, 0.560 g, 1.88 mmol) in tetrahydrofuran (45.0 mL), under an atmosphere of nitrogen at −78° C., was added n-butyllithium (2.50 M in hexane, 0.760 mL) slowly. After 10 minutes, 1,2-bis-(chloro-dimethyl-silanyl)-ethane (0.201 g, 0.94 mmol) in tetrahydrofuran (5.0 mL) was added to the reaction. The reaction mixture was allowed to stir at room temperature for 3 hours. The reaction was cooled to −78° C., followed by addition of 1.70 M of tert-butyllithium in hexane (1.20 mL) slowly. The reaction was stirred for 20 minutes, followed by addition of a solution of CuCN.2LiCl (0.6 M in tetrahydrofuran, 3.00 mL) and 3-chloromethyl-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (512, 0.47 g, 1.8 mol) in tetrahydrofuran (10.0 mL). After 30 minutes, the reaction was allowed to warm to room temperature for 10 minutes. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was treated with trifluoroacetic acid (1.0 mL) dissolved in dichloromethane (10.0 mL) for 10 minutes. The reaction was concentrated, poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified with silica gel column chromatography eluting with 60% ethyl acetate in hexane to give the desired compound (523, 0.10 g, 23.8%). MS (ESI) [M+H+]+=450.1.

Workup

  1. temperatureThe reaction was cooled to −78° C.
  2. stirringThe reaction was stirred for 20 minutes
  3. waitAfter 30 minutes
  4. temperatureto warm to room temperature for 10 minutes
  5. extractionextracted with ethyl acetate
  6. dry with materialThe organic layer was dried over anhydrous sodium sulfate
  7. filtrationfiltered
  8. additionThe filtrate was treated with trifluoroacetic acid (1.0 mL)
  9. dissolutiondissolved in dichloromethane (10.0 mL) for 10 minutes
  10. concentrationThe reaction was concentrated
  11. additionpoured into aqueous potassium carbonate
  12. extractionextracted with ethyl acetate
  13. dry with materialThe organic layer was dried over anhydrous sodium sulfate
  14. filtrationfiltered
  15. concentrationThe filtrate was concentrated
  16. custompurified with silica gel column chromatography
  17. washeluting with 60% ethyl acetate in hexane

Sources & evidence

ORD record
ord-976f72ef0700447da6574d56c153b82d
Source dataset
uspto-grants-2011_02
Patent number
US07893075B2

Reaction notes

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