Dichloromethane → 1-{4-[4-(1,5-Dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl-3'-yl]-benzyl}-pyrrolidine-2,5-dione hydrochloride

HRID 220602Notes

Reaction equation

HRID 220602 reaction equation
[C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:27][N:28]1[C:32]([CH3:33])=[C:31]([CH2:34][N:35]2[CH2:40][CH2:39][N:38]([C:41]3[C:46]([C:47]4[CH:52]=[CH:51][C:50]([CH2:53]O)=[CH:49][CH:48]=4)=[N:45][CH:44]=[CH:43][N:42]=3)[CH2:37][CH2:36]2)[CH:30]=[N:29]1.N(C(OCC)=O)=NC(OCC)=O.C(Cl)[Cl:68]>>[ClH:68].[CH3:27][N:28]1[C:32]([CH3:33])=[C:31]([CH2:34][N:35]2[CH2:36][CH2:37][N:38]([C:41]3[C:46]([C:47]4[CH:48]=[CH:49][C:50]([CH2:53][N:5]5[C:4](=[O:6])[CH2:3][CH2:2][C:1]5=[O:7])=[CH:51][CH:52]=4)=[N:45][CH:44]=[CH:43][N:42]=3)[CH2:39][CH2:40]2)[CH:30]=[N:29]1

Participants

6

Reactant 5

HCID 6344DichloromethaneHCID 11439SuccinimideHCID 11776TriphenylphosphineHCID 220568ethyl N-ethoxycarbonyliminocarbamateHCID 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 685974391-{4-[4-(1,5-Dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl-3'-yl]-benzyl}-pyrrolidine-2,5-dione hydrochloride

Procedure

Dissolve succinimide (99 mg, 1.0 mmol) in dry DCM (5 mL) under nitrogen. Add triphenylphosphine (408 mg, 1.5 mmol) and stir for 20 min. at room temperature. Add {4-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-phenyl}-methanol (378 mg, 1.0 mmol) and diethyl azodicarboxylate (0.19 mL, 1.1 mmol) and stir for 20 hr. Add water (10 mL), extract with DCM (2×5 mL). Pass the combined DCM extracts through an IST Phase Separator Frit®, concentrate and purify by SCX-2® chromatography washing with methanol then eluting with 2 M ammonia in methanol. Further purify (silica gel chromatography, eluting with 0:100 to 5:95 methanol:DCM), to give the free base as a light yellow oil. Purify again 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 3.5 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 (127 mg, 26%). MS (ES): m/z=460 [M+H]+.

Workup

  1. extractionAdd water (10 mL), extract with DCM (2×5 mL)
  2. concentrationconcentrate
  3. custompurify by SCX-2® chromatography
  4. washwashing with methanol
  5. washthen eluting with 2 M ammonia in methanol
  6. customFurther purify
  7. wash(silica gel chromatography, eluting with 0:100 to 5:95 methanol:DCM)

Sources & evidence

ORD record
ord-34dbc7c7f70049a49487920c3c4b2942
Source dataset
uspto-grants-2012_06
Patent number
US08202873B2

Reaction notes

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