Diisopropylethylamine → HCID 69199041, compound

HRID 2377104Notes

Reaction equation

HRID 2377104 reaction equation
Cl[CH2:2][C:3]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[N:5]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2F)[CH:4]=1.[CH3:25][C:26]1([CH3:33])[O:30][C@H:29]([CH2:31][OH:32])[CH2:28][O:27]1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:25][C:26]1([CH3:33])[O:30][C@H:29]([CH2:31][O:32][CH2:2][C:3]2[C:11]3[C:6](=[CH:7][N:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=3)[N:5]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH:4]=2)[CH2:28][O:27]1

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 736056(R)-SolketalHCID 59855821HCID 59855821, compound

Product 1

HCID 69199041HCID 69199041, compoundYield 83%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
40 °C

Procedure

To a solution of methyl 3-(chloromethyl)-1-(2,4-difluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (7.43 mL, 0.197M in CH2Cl2, 1.4645 mmol)) [prepared as described in step 2 of example 40] in anhydrous DMF (10 mL) was added (R)-(−)-2,2-Dimethyl-1,3-dioxolane-4-methanol (7.32 mmol, 0.91 mL, 5 eq.) followed by i-Pr2NEt (5.86 mmol, 1.02 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 and the volatiles were removed in vacuo (ca. 2 torr) to give a golden yellow oil. The crude material was diluted with EtOAc (40 mL) and washed with water (4×20 mL) and brine (20 mL). The organic phase was separated, dried (Na2SO4), and concentrated in vacuo to afford the target compound, which was purified by chromatography on a column of silica gel (40 mm OD, 150 g, 230-400 mesh, packed with CH2Cl2, eluted with CH2Cl2-EtOAc-MeOH 70:30:2 v/v, 2.0 L, 25 mL fractions) using the flash technique. Fractions were combined to afford 0.520 g (83%) of methyl 3-({[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}methyl)-1-(4-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate. LC-MS (Eclipse XDB-C8, 0.8 mL/min, gradient 80:20 to 5:95H2O (+0.1% HOAc):CH3CN—5 minutes, ESI, +mode): RT-2.98 min, m/e=429.1 (M+H+, base). 1H-NMR (300 MHz, CDCl3): o=1.38 (s, 3H), 1.42 (s, 3H), 3.53 (m, 2H), 3.72 (m, 1H), 4.04 (m, 4H), 4.27 (m, 1H), 4.78 (q, 2H), 5.38 (s, 2H), 7.05 (t, 2H), 7.17 (m, 2H), 7.32 (s, 1H), 8.56 (s, 1H), 8.77 (s, 1H).

Workup

  1. customThe mixture, under nitrogen, was placed in an oil bath
  2. customthe volatiles were removed in vacuo (ca. 2 torr)
  3. customto give a golden yellow oil
  4. washwashed with water (4×20 mL) and brine (20 mL)
  5. customThe organic phase was separated
  6. dry with materialdried (Na2SO4)
  7. concentrationconcentrated in vacuo
  8. customto afford the target compound, which
  9. customwas purified by chromatography on a column of silica gel (40 mm OD, 150 g, 230-400 mesh, packed with CH2Cl2, eluted with CH2Cl2-EtOAc-MeOH 70:30:2 v/v, 2.0 L, 25 mL fractions)

Sources & evidence

ORD record
ord-c870ffcfd4fd40fd841d453966d680bb
Source dataset
uspto-grants-2008_12
Patent number
US07468375B2

Reaction notes

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