Ethanol → N,N-diethyl-1-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methanesulfonamide

HRID 1969703Notes

Reaction equation

[CH2:1]([N:3]([CH2:38][CH3:39])[S:4]([CH2:7][CH:8]1[CH2:12][CH:11]([C:13]([NH:15][NH:16][C:17]2[N:18]=[C:19]3[CH:25]=[CH:24][N:23](S(C4C=CC(C)=CC=4)(=O)=O)[C:20]3=[N:21][CH:22]=2)=O)[CH:10]([CH2:36][CH3:37])[CH2:9]1)(=[O:6])=[O:5])[CH3:2].O=S(Cl)Cl.CCO>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>[CH2:1]([N:3]([CH2:38][CH3:39])[S:4]([CH2:7][CH:8]1[CH2:12][CH:11]([C:13]2[N:18]3[C:19]4[CH:25]=[CH:24][NH:23][C:20]=4[N:21]=[CH:22][C:17]3=[N:16][N:15]=2)[CH:10]([CH2:36][CH3:37])[CH2:9]1)(=[O:6])=[O:5])[CH3:2]

Participants

Conditions

Temperature: 80 °C

Procedure

To a mixture of N,N-diethyl-1-(3-ethyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentyl)methanesulfonamide (0.730 g, 1.27 mmol) and TEA (0.529 mL, 3.80 mmol) in 1,4-dioxane (12.7 mL) was added SOCl2 (0.185 mL, 2.53 mmol). The reaction mixture was heated at about 80° C. for about 2 h. The reaction mixture was cooled to ambient temperature and partitioned between saturated aqueous NaHCO3 (30 mL) and DCM (30 mL). The aqueous layer was washed with DCM (2×30 mL). The organic layers were combined, concd under reduced pressure, and purified by silica gel (80 g) chromatography eluting with a gradient of 0-60% MeOH in DCM to give a brown solid. The resulting solid was suspended in Na2CO3 (2 M aqueous, 2 mL), EtOH (2 mL) and 1,4-dioxane (2 mL). The reaction mixture was heated at about 60° C. for about 16 h. The reaction mixture was cooled to ambient temperature and purified by RP-HPLC (Table 1, Method d) to afford N,N-diethyl-1-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methanesulfonamide (0.300 g, 58%) as a tan solid: LC/MS (Table 1, Method b) Rt=1.89 min; MS m/z: 405 (M+H)+. The solid was further purified by using General Procedure AA to give N,N-diethyl-1-((1S,3R,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methanesulfonamide (Table 2, Method 27, Rt=11.8 min, or =negative) (0.021 g, 7%) [Example #1.1]; N,N-diethyl-1-((1R,3S,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methane-sulfonamide (Table 2, Method 27, Rt=11.1 min, or =positive) (0.018 g, 6%) [Example #1.2]; N,N-diethyl-1-((1S,3S,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclo-pentyl)methanesulfonamide (Table 2, Method 27, Rt=10.7 min, or =positive) (0.018 g, 6%) [Example #1.3]; N,N-diethyl-1-((1R,3R,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methanesulfonamide (Table 2, Method 28, Rt=20.1 min, or =negative) (0.031 g, 11%) [Example #1.4]; N,N-diethyl-1-((1S,3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methanesulfonamide (Table 2, Method 27, Rt=12.8 min, or =positive) (0.002 g, 1%) [Example #1.5]; and N,N-diethyl-1-((1R,3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methanesulfonamide (Table 2, Method 27, Rt=12.8 min, or =positive) (0.001 g, 1%) [Example #1.6].

Workup

temperatureThe reaction mixture was cooled to ambient temperature
custompartitioned between saturated aqueous NaHCO3 (30 mL) and DCM (30 mL)
washThe aqueous layer was washed with DCM (2×30 mL)
custompurified by silica gel (80 g) chromatography
washeluting with a gradient of 0-60% MeOH in DCM
customto give a brown solid
temperatureThe reaction mixture was heated at about 60° C. for about 16 h
temperatureThe reaction mixture was cooled to ambient temperature
custompurified by RP-HPLC (Table 1, Method d)

Sources & evidence

ORD record: ord-21980300a92a44ac96e37602bc9c3326
Source dataset: uspto-grants-2013_04
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08426411B2

Reaction notes

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