Trimethylphosphine → HCID 131734133, compound

HRID 716202Notes

Reaction equation

HRID 716202 reaction equation
[F:1][C:2]1[C:3]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([NH:17][C:18]4[CH:19]=[N:20][CH:21]=[CH:22][C:23]=4[N:24]4[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C@@H:25]4[CH3:38])=[N:15][CH:16]=3)[N:13]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.FC1C(C2C=CC3N(C(NC4C=NC=CC=4N4CCC[C@H](NC(=O)OC(C)(C)C)[C@H]4C)=NC=3)N=2)=NC=CC=1.P(C)(C)C.N(C1C=NC=CC=1N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1)=C=S.N(C1C=NC=CC=1N1CCC[C@H](NC(=O)OC(C)(C)C)C1C)=C=S>C1COCC1>[F:1][C:2]1[C:3]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([NH:17][C:18]4[CH:19]=[N:20][CH:21]=[CH:22][C:23]=4[N:24]4[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH:25]4[CH3:38])=[N:15][CH:16]=3)[N:13]=2)=[N:4][CH:5]=[CH:6][CH:7]=1

Participants

7

Reactant 5

HCID 68983TrimethylphosphineHCID 123762280HCID 123762280, compoundHCID 131734134HCID 131734134, compoundHCID 131734135HCID 131734135, compoundHCID 131734136HCID 131734136, compound

Product 1

HCID 131734133HCID 131734133, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

tert-butyl ((2S,3S)-1-(3-((2-(3-fluoropyridin-2-yl)imidazo[1,5-b]pyridazin-7-yl)amino)pyridin-4-yl)-2-methylpiperidin-3-yl)carbamate (first eluting diastereomer) and tert-butyl ((2R,3S)-1-(3-((2-(3-fluoropyridin-2-yl)imidazo[1,5-b]pyridazin-7-yl)amino)pyridin-4-yl)-2-methylpiperidin-3-yl)carbamate (second eluting diastereomer). PMe3 (0.86 mL of 1.0 M solution in THF, 0.86 mmol) was added drop wise to a solution of 3-(azidomethyl)-6-(3-fluoropyridin-2-yl)pyridazine (Preparation XXVIII, 190 mg, 0.82 mmol) in THF (2 mL) at RT. After the reaction mixture stirred for 15 min at RT, it was treated with a suspension of tert-butyl ((3S)-1-(3-isothiocyanatopyridin-4-yl)-2-methylpiperidin-3-yl)carbamate (Preparation XLIX, 288 mg, 0.82 mmol) in THF (2.5 mL) at RT. The resulting mixture was stirred at RT for 15 min; then concentrated to half of its volume. The solution purified by silica gel chromatography (50-100% EtOAc in hexanes followed by 1-3% MeOH in EtOAc) to provide tert-butyl ((3S)-1-(3-((2-(3-fluoropyridin-2-yl)imidazo[1,5-b]pyridazin-7-yl)amino)pyridin-4-yl)-2-methylpiperidin-3-yl)carbamate as an orange amorphous solid. MS (ESI, pos. ion) m/z: 519.1 (M+1). LCMS indicated the presence of 2 peaks with the same mass at about 1:3 ratio. The above obtained orange amorphous solid was dissolved in 10 mL of DMSO and purified on a preparative reverse-phase HPLC (using Prep HPLC method 3) to provide tert-butyl ((2S,3S)-1-(3-((2-(3-fluoropyridin-2-yl)imidazo[1,5-b]pyridazin-7-yl)amino)pyridin-4-yl)-2-methylpiperidin-3-yl)carbamate (first eluting diastereomer) and tert-butyl ((2R,3S)-1-(3-((2-(3-fluoropyridin-2-yl)imidazo[1,5-b]pyridazin-7-yl)amino)pyridin-4-yl)-2-methylpiperidin-3-yl)carbamate (second eluting diastereomer).

Workup

  1. stirringThe resulting mixture was stirred at RT for 15 min
  2. concentrationthen concentrated to half of its volume
  3. customThe solution purified by silica gel chromatography (50-100% EtOAc in hexanes followed by 1-3% MeOH in EtOAc)

Sources & evidence

ORD record
ord-fdfed0ce3e2d48cd89726bf666451660
Source dataset
uspto-grants-2015_11
Patent number
US09187486B2

Reaction notes

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