Carbamate → (3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methyl-N-(pyrimidin-4-yl)piperidine-1-carboxamide

HRID 1969636Notes

Reaction equation

HRID 1969636 reaction equation
[C:1](=[O:4])([O-])[NH2:2].Cl.[CH3:6][C@@H:7]1[CH2:12][CH2:11][NH:10][CH2:9][C@@H:8]1[C:13]1[N:17]2[C:18]3[CH:24]=[CH:23][NH:22][C:19]=3[N:20]=[CH:21][C:16]2=[CH:15][N:14]=1.CC[N:27]([CH:31](C)C)[CH:28]([CH3:30])C.C[C:35]#[N:36]>>[C:13]1([C@@H:8]2[C@H:7]([CH3:6])[CH2:12][CH2:11][N:10]([C:1]([NH:2][C:35]3[CH:30]=[CH:28][N:27]=[CH:31][N:36]=3)=[O:4])[CH2:9]2)[N:17]2[C:18]3[CH:24]=[CH:23][NH:22][C:19]=3[N:20]=[CH:21][C:16]2=[CH:15][N:14]=1

Participants

5

Reactant 4

HCID 276CarbamateHCID 6342Acetonitrile2×HCID 81531DiisopropylethylamineHCID 672171491-((3R,4R)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine hydrochloride

Product 1

HCID 67999614(3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methyl-N-(pyrimidin-4-yl)piperidine-1-carboxamideYield 9%

Conditions

Temperature
70 °C

Procedure

To solution of 4-aminopyrimidine (0.04 g, 0.43 mmol), TEA (0.07 mL, 0.47 mmol) and DMAP (0.006 g, 0.05 mmol), in MeCN (1 mL) at about 0° C. was added phenyl chloroformate (0.05 mL, 0.41 mmol). The reaction mixture was warmed to ambient temperature and stirred for about 3 h. To the reaction mixture was added water (2 mL) and Et2O (5 mL). The organic layer was separated, washed with water (2 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure to provide the crude carbamate. The carbamate was dissolved in MeCN (1 mL) and to it was added a solution of 1-((3R,4R)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine hydrochloride (0.06 g, 0.21 mmol, Example #5 Step J) and DIEA (0.04 mL, 0.21 mmol) in MeCN (1 mL). The reaction mixture was heated to about 70° C. for about 2 h. The solvent was removed under reduced pressure. The crude residue was dissolved in DCM (5 mL) and washed with water (2 mL), brine (3 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The crude material was purified by RP-HPLC (Table 1, Method e) to give (3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methyl-N-(pyrimidin-4-yl)piperidine-1-carboxamide (0.007 g, 9%): LC/MS (Table 1, Method b) Rt=1.40 min; MS m/z 377 (M+H)+.

Workup

  1. customThe solvent was removed under reduced pressure
  2. dissolutionThe crude residue was dissolved in DCM (5 mL)
  3. washwashed with water (2 mL), brine (3 mL)
  4. dry with materialdried over anhydrous MgSO4
  5. filtrationfiltered
  6. customThe crude material was purified by RP-HPLC (Table 1, Method e)

Sources & evidence

ORD record
ord-2a68e081ac8d4703bec0577e598b2d6d
Source dataset
uspto-grants-2013_04
Patent number
US08426411B2

Reaction notes

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