N,N,N',N'-Tetramethylethylenediamine → tert-butyl 2-((6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(hydroxy)methyl)pyrrolidine-1-carboxylate

HRID 1773680Notes

Reaction equation

HRID 1773680 reaction equation
[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(CCN(C)C)C.N[C@H](C(O)=O)C[SeH].[Li]CCCC.[CH3:33][C:34]1[C:38]([C:39]2[CH:40]=[C:41]([CH:58]=[O:59])[C:42]3[N:46]=[C:45]([O:47][CH2:48][CH3:49])[N:44](C(OC(C)(C)C)=O)[C:43]=3[CH:57]=2)=[C:37]([CH3:60])[O:36][N:35]=1>CC1OCCC1>[CH3:33][C:34]1[C:38]([C:39]2[CH:40]=[C:41]([CH:58]([OH:59])[CH:12]3[CH2:11][CH2:10][CH2:9][N:8]3[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[C:42]3[N:46]=[C:45]([O:47][CH2:48][CH3:49])[NH:44][C:43]=3[CH:57]=2)=[C:37]([CH3:60])[O:36][N:35]=1

Participants

6

Reactant 4

HCID 8037N,N,N',N'-TetramethylethylenediamineHCID 643455N-Boc-pyrrolidineHCID 117601313tert-butyl 6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-formyl-1H-benzo[d]imidazole-1-carboxylateHCID 178511841HCID 178511841, compound

Product 1

HCID 117601830tert-butyl 2-((6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(hydroxy)methyl)pyrrolidine-1-carboxylateYield 30%

Reagents, catalysts & solvents 1

HCID 73012-MethyltetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

N-Boc-pyrrolidine (150 mg, 0.39 mmol) and TMEDA (0.2 mL, 158 mg, 1.36 mmol) was dissolved in dry MeTHF (2.6 mL) under Ar and cooled to −78° C. Sec-BuLi (1.4M, 0.97 mL, 1.36 mmol) was added dropwise and the reaction was allowed to stir at −78° C. for 40 mins. tert-butyl 6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-formyl-1H-benzo[d]imidazole-1-carboxylate (150 mg, 0.39 mmol) was dissolved in MeTHF (0.5 mL) and added dropwise via syringe to the reaction and allowed to stir at −78° C. for 10 minutes. The reaction was quenched with water and extracted three times with EtOAc, combined organic layers were washed once with brine, concentrated, and purified by reverse-phase HPLC to give tert-butyl 2-((6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(hydroxy)methyl)pyrrolidine-1-carboxylate (53 mg, 30%) as a white powder. The solid (50 mg, 0.11 mmol) was dissolved in EtOH (5 mL) and HCl (1 mL) and heated for 12 hours at 65° C. The reaction was cooled and concentrated to afford the desired product as a white powder.

Workup

  1. additionadded dropwise via syringe to the reaction
  2. stirringto stir at −78° C. for 10 minutes
  3. customThe reaction was quenched with water
  4. extractionextracted three times with EtOAc
  5. washwere washed once with brine
  6. concentrationconcentrated
  7. custompurified by reverse-phase HPLC

Sources & evidence

ORD record
ord-d6ab5a9fb1c847fb81b0518020a8a052
Source dataset
uspto-grants-2016_02
Patent number
US09255089B2

Reaction notes

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