Trimethylphosphine → tert-butyl ((3R,4R,5S)-4-((tert-butyl(dimethyl)silyl)oxy)-1-(3-((2-(2,6-difluorophenyl)imidazo[1,5-b]pyridazin-7-yl)amino)-4-pyridinyl)-5-methyl-3-piperidinyl)carbamate

HRID 716194Notes

Reaction equation

HRID 716194 reaction equation
P(C)(C)C.[N:5]([CH2:8][C:9]1[N:10]=[N:11][C:12]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=2[F:22])=[CH:13][CH:14]=1)=[N+]=[N-].[Si:23]([O:30][C@@H:31]1[C@@H:36]([CH3:37])[CH2:35][N:34]([C:38]2[CH:43]=[CH:42][N:41]=[CH:40][C:39]=2[N:44]=[C:45]=S)[CH2:33][C@H:32]1[NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>C1COCC1.CCOC(C)=O>[Si:23]([O:30][C@@H:31]1[C@@H:36]([CH3:37])[CH2:35][N:34]([C:38]2[CH:43]=[CH:42][N:41]=[CH:40][C:39]=2[NH:44][C:45]2[N:10]3[N:11]=[C:12]([C:15]4[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=4[F:22])[CH:13]=[CH:14][C:9]3=[CH:8][N:5]=2)[CH2:33][C@H:32]1[NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])([C:26]([CH3:27])([CH3:28])[CH3:29])([CH3:24])[CH3:25]

Participants

6

Reactant 3

HCID 68983TrimethylphosphineHCID 709823613-(Azidomethyl)-6-(2,6-difluorophenyl)pyridazineHCID 131734130tert-butyl ((3R,4R,5S)-4-((tert-butyldimethylsilyl)oxy)-1-(3-isothiocyanatopyridin-4-yl)-5-methylpiperidin-3-yl)carbamate

Product 1

HCID 131734129tert-butyl ((3R,4R,5S)-4-((tert-butyl(dimethyl)silyl)oxy)-1-(3-((2-(2,6-difluorophenyl)imidazo[1,5-b]pyridazin-7-yl)amino)-4-pyridinyl)-5-methyl-3-piperidinyl)carbamateYield 71.6%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

PMe3 (1.0 M solution in THF) (0.95 mL, 0.95 mmol) was added dropwise to a solution of 3-(azidomethyl)-6-(2,6-difluorophenyl)pyridazine (Preparation I, 235 mg, 0.95 mmol) in THF (6.0 mL) at RT. The reaction turned purple and an evolution of gas was observed. The reaction was stirred for 15 min at RT. A solution of tert-butyl ((3R,4R,5S)-4-((tert-butyl(dimethyl)silyl)oxy)-1-(3-isothiocyanato-4-pyridinyl)-5-methyl-3-piperidinyl)carbamate (Preparation XIII, 455 mg, 0.95 mmol) in THF (5.0 mL) was added. After 15 min at RT, the mixture was diluted with EtOAc and washed with brine. The aqueous phase was extracted with EtOAc (2×). The combined organic layers were dried over anh. Na2SO4, filtered and concentrated. The crude material was purified by silica gel chromatography (0-3% MeOH in CH2Cl2) to provide tert-butyl ((3R,4R,5S)-4-((tert-butyl(dimethyl)silyl)oxy)-1-(3-((2-(2,6-difluorophenyl)imidazo[1,5-b]pyridazin-7-yl)amino)-4-pyridinyl)-5-methyl-3-piperidinyl)carbamate (450 mg, 0.68 mmol, 71% yield) as an orange solid. MS (ESI, pos. ion) m/z: 666.3 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 9.76 (s, 1 H), 8.21 (d, J=5.09 Hz, 1 H), 7.77 (d, J=9.39 Hz, 1H), 7.70 (br. s., 1 H), 7.34-7.47 (m, 2 H), 7.05 (t, J=8.12 Hz, 2 H), 6.93 (d, J=5.28 Hz, 1H), 6.51 (d, J=9.39 Hz, 1 H), 4.49 (br. s., 1 H), 3.67 (br. s., 1 H), 3.40 (d, J=10.76 Hz, 1H), 3.14-3.28 (m, 2 H), 2.81 (t, J=10.07 Hz, 1 H), 2.29 (t, J=11.15 Hz, 1 H), 1.89-2.03 (m, 1 H), 1.40 (br. s., 9 H), 0.93 (s, 12 H), 0.11 (d, J=11.15 Hz, 6 H).

Workup

  1. waitAfter 15 min at RT
  2. washwashed with brine
  3. extractionThe aqueous phase was extracted with EtOAc (2×)
  4. dry with materialThe combined organic layers were dried over anh. Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe crude material was purified by silica gel chromatography (0-3% MeOH in CH2Cl2)

Sources & evidence

ORD record
ord-7eb7f76fc9024a92a88071f47a800b8f
Source dataset
uspto-grants-2015_11
Patent number
US09187486B2

Reaction notes

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