Nitrogen → HCID 58557614, compound

HRID 1969671Notes

Reaction equation

HRID 1969671 reaction equation
[C:1](Cl)(Cl)=[O:2].N#N.[CH2:7]([C@H:9]1[CH2:13][NH:12][CH2:11][C@H:10]1[C:14]1[N:18]2[C:19]3[CH:25]=[CH:24][N:23]([S:26]([C:29]4[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=4)(=[O:28])=[O:27])[C:20]=3[N:21]=[CH:22][C:17]2=[N:16][N:15]=1)[CH3:8].[F:36][C:37]1([F:41])[CH2:40][NH:39][CH2:38]1.Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:36][C:37]1([F:41])[CH2:40][N:39]([C:1]([N:12]2[CH2:11][C@H:10]([C:14]3[N:18]4[C:19]5[CH:25]=[CH:24][N:23]([S:26]([C:29]6[CH:30]=[CH:31][C:32]([CH3:33])=[CH:34][CH:35]=6)(=[O:28])=[O:27])[C:20]=5[N:21]=[CH:22][C:17]4=[N:16][N:15]=3)[C@H:9]([CH2:7][CH3:8])[CH2:13]2)=[O:2])[CH2:38]1

Participants

7

Reactant 5

HCID 947NitrogenHCID 6371PhosgeneHCID 516892Sodium BicarbonateHCID 27582473,3-Difluoroazetidine hydrochlorideHCID 67216364HCID 67216364, compound

Product 1

HCID 58557614HCID 58557614, compoundYield 65%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Conditions

Temperature
0 °C

Procedure

To a solution of phosgene (0.400 mL, 0.761 mmol, 20% in toluene) in DCM (1.5 mL) under a balloon of N2 at about 0° C. were added a solution of 1-((cis)-4-ethylpyrrolidin-3-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.250 g, 0.609 mmol, Example #36, step F) in DCM (5.0 mL) and TEA (0.430 mL, 3.08 mmol). After about 40 min, at about 0° C., a solution of 3,3-difluoroazetidine•hydrochloride (0.095 g, 0.731 mmol, Matrix) and TEA (0.430 mL, 3.08 mmol) in DCM (5.0 mL) were added dropwise and stirred at about 0° C. for about 45 min. Saturated aqueous sodium bicarbonate (2 mL) was added and the layers were separated. The aqueous layer was extracted with DCM (2×30 mL). The combined organic layers were washed with water (25 mL), dried over anhydrous MgSO4, filtered, and concd to give a brown residue. The crude material was purified via flash chromatography on silica gel eluting with a gradient of 0-10% MeOH in DCM to afford (3,3-difluoroazetidin-1-yl)((cis)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)pyrrolidin-1-yl)methanone (0.208 g, 65%) as a brown residue: LC/MS (Table 1, Method a) Rt=2.17 min; MS m/z: 530 (M+H)+.

Workup

  1. customthe layers were separated
  2. extractionThe aqueous layer was extracted with DCM (2×30 mL)
  3. washThe combined organic layers were washed with water (25 mL)
  4. dry with materialdried over anhydrous MgSO4
  5. filtrationfiltered
  6. customconcd to give a brown residue
  7. customThe crude material was purified via flash chromatography on silica gel eluting with a gradient of 0-10% MeOH in DCM

Sources & evidence

ORD record
ord-f01ea1266372444b94d9c89920c1b94d
Source dataset
uspto-grants-2013_04
Patent number
US08426411B2

Reaction notes

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