Methylamine → Methyl-carbamic acid 4-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl-3'-yl]-benzyl ester hydrochloride

HRID 220597Notes

Reaction equation

HRID 220597 reaction equation
[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:20]([C:21]4[CH:26]=[CH:25][C:24]([CH2:27][OH:28])=[CH:23][CH:22]=4)=[N:19][CH:18]=[CH:17][N:16]=3)[CH2:11][CH2:10]2)[CH:4]=[N:3]1.C([C:36]1[NH:37][CH:38]=CN=1)(C1NC=CN=1)=O.CN.[O:43]1CCCC1.C(Cl)[Cl:49]>>[ClH:49].[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH2:8][N:9]2[CH2:10][CH2:11][N:12]([C:15]3[C:20]([C:21]4[CH:26]=[CH:25][C:24]([CH2:27][O:28][C:38](=[O:43])[NH:37][CH3:36])=[CH:23][CH:22]=4)=[N:19][CH:18]=[CH:17][N:16]=3)[CH2:13][CH2:14]2)[CH:4]=[N:3]1

Participants

6

Reactant 5

HCID 6329MethylamineHCID 6344DichloromethaneHCID 8028TetrahydrofuranHCID 5250894Bis-(1H-imidazol-2-YL)-methanoneHCID 59321924{4-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl-3'-yl]-phenyl}-methanol

Product 1

HCID 68595187Methyl-carbamic acid 4-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl-3'-yl]-benzyl ester hydrochlorideYield 12%

Procedure

Dissolve {4-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-phenyl}-methanol (200 mg, 0.53 mmol) in DCM (5 mL) at room temperature under nitrogen. Add carbonyl diimidazole (94 mg, 0.58 mmol) and stir for 20 hr. Add a solution of methylamine in tetrahydrofuran (2 M, 2 mL, 4.0 mmol) and stir reaction for 2 hr. at room temperature. Quench reaction with water (10 mL) then extract with DCM (2×10 mL), pass through an IST Phase Separator Frit® and concentrate. Purify by low pH reverse phase HPLC, and form the free base by passing through an SCX-2® ion exchange cartridge washing with methanol then eluting with 3 M ammonia in methanol. Dissolve the oil in acetonitrile and convert to the hydrochloride salt by adding 2 M aq HCl solution. Add water and lyophilize to give the title compound as a yellow powder (28 mg, 12%). MS (ES): m/z=436 [M+H]+

Workup

  1. customreaction for 2 hr
  2. customat room temperature
  3. customQuench
  4. customreaction with water (10 mL)
  5. extractionthen extract with DCM (2×10 mL)
  6. concentrationconcentrate
  7. customPurify by low pH reverse phase HPLC
  8. customform the free base
  9. washwashing with methanol
  10. washthen eluting with 3 M ammonia in methanol
  11. dissolutionDissolve the oil in acetonitrile
  12. additionby adding 2 M aq HCl solution

Sources & evidence

ORD record
ord-b523bde9982f40bca6fd8b287252dc5e
Source dataset
uspto-grants-2012_06
Patent number
US08202873B2

Reaction notes

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