1-Hydroxybenzotriazole → (S)-tert-butyl 2-(6-bromo-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate

HRID 1471109Notes

Reaction equation

HRID 1471109 reaction equation
CCN=C=NCCCN(C)C.Cl.[Br:13][C:14]1[CH:15]=[C:16]([NH2:21])[C:17]([NH2:20])=[CH:18][CH:19]=1.[C:22]([N:29]1[CH2:36][CH2:35][CH2:34][C@H:30]1[C:31](O)=O)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O.C(O)(=O)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]2[N:20]=[C:31]([C@@H:30]3[CH2:34][CH2:35][CH2:36][N:29]3[C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[NH:21][C:16]=2[CH:15]=1

Participants

8

Reactant 4

HCID 757711-HydroxybenzotriazoleHCID 850831,2-Pyrrolidinedicarboxylic acid, 1-(1,1-dimethylethyl) ester, (2S)-HCID 3235934-Bromobenzene-1,2-diamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochloride

Product 1

HCID 56605032(S)-tert-butyl 2-(6-bromo-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylateYield 61.4%

Reagents, catalysts & solvents 3

HCID 176Acetic AcidSolventHCID 962WaterSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
85 °C

Procedure

EDCI.HCl (16.9 g, 88.0 mmol) was added to a mixture of 4-bromobenzene-1,2-diamine (15.0 g, 80.0 mmol), N-Boc-L-proline (18.13 g, 84.0 mmol) and 1-hydroxybenzotriazole (12.28 g, 80.0 mmol) in CH2Cl2 (500 mL) and stirred at ambient conditions for 16 h. The mixture was then diluted with water. The resulting white precipitate was filtered away and the layers were separated. The organic layer was washed with water, dried (brine; Na2SO4), filtered and concentrated in vacuo to provide a brown foam. Acetic acid (300 mL) was added to the foam and the mixture was heated at 85° C. (bath temperature) for 5 h. The volatile component was removed in vacuo and the residue was dissolved in EtOAc, washed with water and the organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The resultant crude material was submitted to flash chromatography (silica gel; 0-37% EtOAc/CH2Cl2). The partially pure material was re-submitted to flash chromatography (silica gel; 20-35% EtOAc/CH2Cl2) to provide (S)-tert-butyl 2-(6-bromo-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (17.98 g, 61.2% yield) as yellow foam. LC-MS retention time 1.23 min; Calcd. for C16H20BrN3O2: 365.07 Found m/z 368.07 [M+H]+. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 min and an analysis time of 4 min where Solvent A was 10% acetonitrile/90% water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (500 MHz, MeOD) δ ppm 7.59-7.75 (m., 1H), 7.38-7.53 (m, 1H), 7.31-7.38 (m, 1H), 5.04-5.09 (m, 0.3H), 4.94-5.00 (m, 0.7H), 3.68-3.76 (m, 1H), 3.50-3.59 (m, 1H), 2.34-2.51 (m., 1H), 1.95-2.12 (m., 3H), 1.47 (br s, 3H), 1.15 (s, 6H).

Workup

  1. filtrationThe resulting white precipitate was filtered away
  2. customthe layers were separated
  3. washThe organic layer was washed with water
  4. dry with materialdried (brine; Na2SO4)
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customto provide a brown foam
  8. customThe volatile component was removed in vacuo
  9. dissolutionthe residue was dissolved in EtOAc
  10. washwashed with water
  11. dry with materialthe organic phase was dried (Na2SO4)
  12. filtrationfiltered
  13. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-667bb8ea3c9049209582ad10a9009a4b
Source dataset
uspto-grants-2015_04
Patent number
US09006455B2

Reaction notes

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