Thionyl Chloride → 4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-amine

HRID 1969591Notes

Reaction equation

[S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([NH:20][NH:21][C:22]([C:24]34[CH2:31][CH2:30][C:27]([NH:32]C(=O)OC(C)(C)C)([CH2:28][CH2:29]3)[CH2:26][CH2:25]4)=O)[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].O=S(Cl)Cl>O1CCOCC1>[S:1]([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:22]([C:24]45[CH2:29][CH2:28][C:27]([NH2:32])([CH2:30][CH2:31]4)[CH2:26][CH2:25]5)=[N:21][N:20]=3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:3])=[O:2]

Participants

Conditions

Temperature: 80 °C

Procedure

To a solution of tert-butyl 4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)-bicyclo[2.2.2]octan-1-ylcarbamate (6.1 g, 11.0 mmol, Example #9, Step E), and TEA (6.1 mL, 44.0 mmol) in 1,4-dioxane (110 mL) was added SOCl2 (2.0 mL, 27.5 mmol). The reaction mixture was heated at about 80° C. for about 2 h then cooled to ambient temperature. The reaction mixture was washed with saturated aqueous NaHCO3 (3×50 mL). The layers were separated and the aqueous portion was filtered to give 4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]-octan-1-amine as a brown solid (1.17 g, 24%): LC/MS (Table 1, Method a) Rt=1.28 min; MS m/z: 437 (M+H)+. The remaining filtrate was extracted with EtOAc (10 mL). The combined organic layer was dried over anhydrous MgSO4, filtered, and concd under reduced pressure to afford crude tert-butyl 4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-ylcarbamate (3.5 g). The crude Boc-protected material was dissolved in 1,4-dioxane (38 mL) and HCl (4 N in 1,4-dioxane, 8 mL) was added. The reaction mixture was heated to about 50° C. for about 3 h. The precipitate formed was collected by filtration. The solid was dissolved in DCM (50 mL), and washed with saturated aqueous NaHCO3 (3×20 mL). The layers were separated and the organic portion was dried over anhydrous MgSO4, filtered, and concd under reduced pressure to give additional 4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-amine as a brown solid (2.3 g, 50% over 2 steps): LC/MS (Table 1, Method a) Rt=1.28 min; MS m/z: 437 (M+H)+.

Workup

temperaturethen cooled to ambient temperature
washThe reaction mixture was washed with saturated aqueous NaHCO3 (3×50 mL)
customThe layers were separated
filtrationthe aqueous portion was filtered

Sources & evidence

ORD record: ord-9c1ee868ad4944d28767c37098e63d59
Source dataset: uspto-grants-2013_04
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08426411B2

Reaction notes

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