Nitrogen → HCID 86696436, compound

HRID 870730Notes

Reaction equation

HRID 870730 reaction equation
C([Li])CCC.N#N.[C:8]([O:12][C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH2:20][NH:21][C:22]1[CH:23]=[CH:24][C:25]2[N:26]([C:28](Br)=[CH:29][N:30]=2)[N:27]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>C1COCC1>[C:8]([O:12][C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH2:20][NH:21][C:22]1[CH:23]=[CH:24][C:25]2[N:26]([CH:28]=[CH:29][N:30]=2)[N:27]=1)=[O:14])([CH3:11])([CH3:9])[CH3:10]

Participants

5

Reactant 3

HCID 947NitrogenHCID 86696435HCID 86696435, compoundHCID 178418339Butyllithium

Product 1

HCID 86696436HCID 86696436, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

1.6 M n-butyl lithium in hexanes (5.8 mL, 9.3 mmol) was rapidly syringed into a stirred, colorless, N2 blanketed solution of (S)-2-[(3-bromo-imidazo[1,2-b]pyridazin-6-ylamino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (1.8 g, 4.6 mmol) in anhydrous THF (100 mL) held at −73° C. The reaction solution immediately turned brown in color and was allowed to stir for 5 minutes. The generated aryl lithium was quenched by the careful addition of saturated aqueous NH4Cl (2 mL). The reaction solution was partitioned between brine and ethyl acetate, the extract dried (CaSO4), and the crude product flash chromatographed (silica gel, eluted with 10% (v/v methanol/ethyl acetate) and crystallized from ethyl acetate/heptane to provide S)-2-(imidazo[1,2-b]pyridazin-6-ylaminomethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as 1.5 g of off white powder, mp. 161-162° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.40 (s, 9H) 1.72-1.95 (m, 4H) 3.10-3.22 (m, 1H) 3.28 (br. s., 2H) 3.41-3.53 (m, 1H) 3.92-4.05 (m, 1H) 6.65 (d, J=9.60 Hz, 1H) 6.96 (br. s., 1H) 7.36 (d, J=0.76 Hz, 1H) 7.66 (d, J=9.60 Hz, 2H). 13C NMR (100 MHz, DMSO-d6) δ ppm 23.15, 28.13, 43.14, 45.96, 46.36, 55.57, 56.15, 78.30, 112.50, 116.01, 125.26, 130.32, 135.78, 153.75. LRMS (ESI) m/z 318.3 [(M+H)]+, calc'd for C16H23N6O2: 317.36.

Workup

  1. customheld at −73° C
  2. customThe generated aryl lithium was quenched by the careful addition of saturated aqueous NH4Cl (2 mL)
  3. customThe reaction solution was partitioned between brine and ethyl acetate
  4. dry with materialthe extract dried (CaSO4)
  5. customthe crude product flash chromatographed
  6. wash(silica gel, eluted with 10% (v/v methanol/ethyl acetate) and crystallized from ethyl acetate/heptane to provide S)-2-(imidazo[1,2-b]pyridazin-6-ylaminomethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as 1.5 g of off white powder, mp. 161-162° C

Sources & evidence

ORD record
ord-e8dc012d0e7f479480ca85bb2df67950
Source dataset
uspto-grants-2015_03
Patent number
US08969565B2

Reaction notes

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