Phosphorus oxide (P4O10) → 5-Bromo-2-[2-(2-(R)-methyl-pyrrolidin-1-yl)-ethyl]-1H-benzoimidazole

HRID 10416

Reaction equation

HRID 10416 reaction equation
C(O[C:4](=O)[CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[CH3:12])C.[Br:14][C:15]1[CH:16]=[C:17]([NH2:22])[C:18]([NH2:21])=[CH:19][CH:20]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>CS(O)(=O)=O>[Br:14][C:15]1[CH:20]=[CH:19][C:18]2[NH:21][C:4]([CH2:5][CH2:6][N:7]3[CH2:11][CH2:10][CH2:9][C@H:8]3[CH3:12])=[N:22][C:17]=2[CH:16]=1

Participants

5

Reactant 3

HCID 14812Phosphorus oxide (P4O10)HCID 3235934-Bromobenzene-1,2-diamineHCID 596967383-(2-(R)-Methyl-pyrrolidin-1-yl)-propionic acid ethyl ester

Product 1

HCID 1784189255-Bromo-2-[2-(2-(R)-methyl-pyrrolidin-1-yl)-ethyl]-1H-benzoimidazoleYield 40%

Reagents, catalysts & solvents 1

HCID 6395Methanesulfonic AcidSolvent

Conditions

Temperature
110 °C

Procedure

In a round-bottom flask was charged 3-(2-(R)-methyl-pyrrolidin-1-yl)-propionic acid ethyl ester (5.6 g, 30 mmol), 4-bromo-benzene-1,2-diamine (5.6 g, 30 mmol) and 56 mL of 5% P2O5 in CH3SO3H (Eaton's reagent). After briefly stirring, the homogeneous solution was heated to 110° C. for approximately 24–48 h. The reaction mixture was quenched with ice (˜50 g) and then the pH slowly adjusted to pH >11 with 50% NaOH. The product was extracted with isopropyl acetate (100 mL). The organic layer was then extracted with 5% NaHCO3, H2O and then distilled to dryness. The crude product was purified by column chromatography to provide the title compound (3.7 g). 1H NMR (500 MHz, [(CD3)2SO] δ 1.00 (d, 3H), 1.27 (m, 1H), 1.63 (m, 2H), 1.85 (m, 1H), 2.11 (m, 1H), 2.31 (m, 1H), 2.45 (m, 1H), 2.91–2.99 (m, 2H), 3.09 (m, 1H), 3.19 (m, 1H), 7.24 (m, 1H), 7.43 (d, 1H), 7.66 (s, 1H), some protons were not readily identified due to exchange broadening. 13C NMR (500 MHz, [(CD3)2SO+2 drops DCI] δ 15.3, 21.0, 23.2, 31.0, 48.3, 52.3, 64.3, 115.9, 116.6, 117.9, 128.8, 130.2, 132.2, 151.1 (some 13C peaks were not readily identified due to exchange broadening at 25° C., but were observed under acidic conditions, 2 drops DCI). APPI-MS: (M+1)+ at 308 m/z.

Workup

  1. customThe reaction mixture was quenched with ice (˜50 g)
  2. extractionThe product was extracted with isopropyl acetate (100 mL)
  3. extractionThe organic layer was then extracted with 5% NaHCO3, H2O
  4. distillationdistilled to dryness
  5. customThe crude product was purified by column chromatography

Sources & evidence

ORD record
ord-e1314770786e43798d6d10cde0eaf3fd
Source dataset
uspto-grants-2006_08
Patent number
US07094790B2

Linked notes

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