Water → 1-[1-(2,4-difluorobenzyl)-3-({[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-5-yl]ethanone

HRID 2377101Notes

Reaction equation

HRID 2377101 reaction equation
[F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14](OC)=[O:15])[CH:13]=[C:8]2[C:7]([CH2:18]SC2C=CC=CC=2)=[CH:6]1.[CH3:31][C:32]1([CH3:39])[O:36][C@H:35]([CH2:37][OH:38])[CH2:34][O:33]1.[CH3:40]CN(C(C)C)C(C)C.O>CN(C=O)C>[F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14](=[O:15])[CH3:40])[CH:13]=[C:8]2[C:7]([CH2:18][O:38][CH2:37][C@@H:35]2[CH2:34][O:33][C:32]([CH3:39])([CH3:31])[O:36]2)=[CH:6]1

Participants

6

Reactant 4

HCID 962WaterHCID 81531DiisopropylethylamineHCID 736056(R)-SolketalHCID 691988651h-Pyrrolo[2,3-c]pyridine-5-carboxylic acid,1-[(2,4-difluorophenyl)methyl]-3-[(phenylthio)methyl]-,methyl ester

Product 1

HCID 691996921-[1-(2,4-difluorobenzyl)-3-({[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-5-yl]ethanoneYield 88.1%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
40 °C

Procedure

To a solution of methyl 3-(chloromethyl)-1-(2,4-difluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (3 mL, 0.197M in CH2Cl2, 0.591 mmol) [prepared as described in step 2 of example 40] in anhydrous DMF (5 mL) was added (R)-(−)-2,2-dimethyl-1,3-dioxolane-4-methanol (2.955 mmol, 0.37 mL, 5.0 eq.) followed by i-Pr2NEt (0.407 g, 3.14 mmol, 0.55 mL, 4 eq.). The mixture, under nitrogen, was placed in an oil bath and the bath was warmed to 40° C. After stirring for 24 hours (40° C.) the reaction was judged to be complete by HPLC-MS analysis. Water (0.5 mL) was added and after 45 minutes the volatiles were removed in vacuo (ca. 2 torr) to give a golden yellow oil. The crude material was purified by chromatography on a column of silica gel (40 mm OD, 100 g, 230-400 mesh, packed with CH2Cl2, eluted with CH2Cl2-EtOAc 70:30 v/v, 1.0 L, 1.0 L, 25 mL fractions) using the flash technique. Fractions were combined to afford 0.224 g (85%) of 1-[1-(2,4-difluorobenzyl)-3-({[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-5-yl]ethanone as a colorless oil. TLC (Merck, CH2Cl2:EtOAc 50:50, UV-+, cerium molybdate-+): Rf=0.26. LC-MS (Eclipse XDB-C8, 0.8 mL/min, gradient 80:20 to 5:95H2O (+0.1% HOAc):CH3CN—5 minutes, APCI, +mode): RT—3.456 min, m/e=447.20 (M+H+, base).

Workup

  1. customThe mixture, under nitrogen, was placed in an oil bath
  2. customwere removed in vacuo (ca. 2 torr)
  3. customto give a golden yellow oil
  4. customThe crude material was purified by chromatography on a column of silica gel (40 mm OD, 100 g, 230-400 mesh, packed with CH2Cl2, eluted with CH2Cl2-EtOAc 70:30 v/v, 1.0 L, 1.0 L, 25 mL fractions)

Sources & evidence

ORD record
ord-60a8e87523d14974992a34618b73ef1c
Source dataset
uspto-grants-2008_12
Patent number
US07468375B2

Reaction notes

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