Triethylamine → methyl 4-(4-(5-amino-6-(1H-benzo[d]imidazol-2-yl)pyrazin-2-yl)-5,6-dihydropyridin-1(2H)-yl)-4-oxobutanoate

HRID 1959440Notes

Reaction equation

HRID 1959440 reaction equation
[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:22])=[N:12][CH:13]=[C:14]([C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH:21]=2)[N:15]=1.Cl[C:24](=[O:31])[CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28].C(N(CC)CC)C>C(Cl)Cl>[NH2:22][C:11]1[N:12]=[CH:13][C:14]([C:16]2[CH2:17][CH2:18][N:19]([C:24](=[O:31])[CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:20][CH:21]=2)=[N:15][C:10]=1[C:2]1[NH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=1

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 73888Butanoic acid, 4-chloro-4-oxo-, methyl esterHCID 667451703-(1H-benzo[d]imidazol-2-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-amine

Product 1

HCID 66745179methyl 4-(4-(5-amino-6-(1H-benzo[d]imidazol-2-yl)pyrazin-2-yl)-5,6-dihydropyridin-1(2H)-yl)-4-oxobutanoate

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of 3-(1H-benzimidazol-2-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-amine (50 mg, 0.12 mmol) in DCM (2 mL) at 0° C. was added methyl 4-chloro-4-oxo-butanoate (19 mg, 15 μL, 0.12 mmol) followed by the addition of triethylamine (50 mg, 69 μL, 0.5 mmol). The reaction mixture was stirred at room temperature for 2 h and then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc, dried (MgSO4), filtered and concentrated. The crude material was dissolved in DMSO and purified by reverse phase HPLC using 1-99% MeOH in H2O to obtain methyl 4-(4-(5-amino-6-(1H-benzo[d]imidazol-2-yl)pyrazin-2-yl)-5,6-dihydropyridin-1(2H)-yl)-4-oxobutanoate, which was re-dissolved in THF (1.0 mL), treated with NaOH (996 μL of 2.5 M, 2.5 mmol) and stirred for 18 h at room temperature. The reaction mixture was then acidified with conc. HCl till pH7 and extracted with DCM. The organic layer was dried (MgSO4), filtered and concentrated. The crude material was purified via reverse phase HPLC using 1-99% MeOH in H2O (0.05% HCl modifier) to obtain 4-(4-(5-amino-6-(1H-benzo[d]imidazol-2-yl)pyrazin-2-yl)-5,6-dihydropyridin-1(2H)-yl)-4-oxobutanoic acid (5 mg, 11%). 1H NMR (400 MHz, MeOD) δ 8.24 (s, 1H), 7.66 (d, J=4.1 Hz, 2H), 7.27 (dd, J=6.0, 3.1 Hz, 2H), 6.68 (d, J=7.9 Hz, 1H), 4.34 (s, 1H), 4.27 (s, 1H), 3.84 (t, J=5.6 Hz, 2H), 2.85 (s, 1H), 2.80-2.65 (m, 3H), 2.56-2.47 (m, 2H). LC/MS m/z 393.0 [M+H]+.

Workup

  1. custompartitioned between EtOAc and water
  2. extractionThe aqueous layer was extracted with EtOAc
  3. dry with materialdried (MgSO4)
  4. filtrationfiltered
  5. concentrationconcentrated
  6. dissolutionThe crude material was dissolved in DMSO
  7. custompurified by reverse phase

Sources & evidence

ORD record
ord-960c73c78fe445019bd041393f9fca2c
Source dataset
uspto-grants-2013_04
Patent number
US08410112B2

Reaction notes

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