Water → Ethyl 1-[7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperidine-3-carboxylate

HRID 1727031Notes

Reaction equation

HRID 1727031 reaction equation
Br[C:2]1[N:10]([CH2:11][C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[C:9]2[C:8](=[O:20])[N:7]([CH3:21])[C:6](=[O:22])[N:5]([CH3:23])[C:4]=2[N:3]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH:26]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:25]1.O.C(Cl)Cl>CS(C)=O.CCOC(C)=O>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([F:18])[C:12]=1[CH2:11][N:10]1[C:9]2[C:8](=[O:20])[N:7]([CH3:21])[C:6](=[O:22])[N:5]([CH3:23])[C:4]=2[N:3]=[C:2]1[N:24]1[CH2:29][CH2:28][CH2:27][CH:26]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:25]1

Participants

7

Reactant 4

HCID 962WaterHCID 6344DichloromethaneHCID 98969Ethyl nipecotateHCID 6592358-bromo-7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione

Product 1

HCID 57565596Ethyl 1-[7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperidine-3-carboxylateYield 88.3%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

A solution of 8-bromo-7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (6.0 g, 0.015 mol) in 30 mL of DMSO was treated with (+/−)-ethyl piperidine-3-carboxylate (11.7 g, 0.075 mol) and heated at 100° C. for 15 h. The reaction was cooled to room temperature and treated with H2O and CH2Cl2. The layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×). The combined organic layers were washed with H2O, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, Merck 20×20 cm silica gel 60 F254) eluting with 7:3/hexanes:EtOAc to give 6.33 g (88% yield) of the title compound: 1H NMR (CDCl3, 400 MHz) δ 7.20 (dt, 2H, J=8.1, 5.7), 7.14 (t, 1H, J=7.6), 6.98-6.90 (m, 1H), 5.57 (AB quartet, 2H, J=15.7, 5.7), 4.18-4.00 (m, 2H), 3.51 (s, 3H), 3.42 (dd, 1H, J=12.6, 4.0), 3.30 (s, 3H), 3.18 (br d, 1H), 3.06 (dd, 1H, J=12.4, 10.0), 2.91-2.83 (m, 1H), 2.52-2.41 (m, 1H), 2.03-1.92 (m, 1H), 1.75-1.66 (m, 1H), 1.63-1.40 (m, 2H), 1.21 (t, 3H, J=7.1); LRMS (ESI) m/z 478 (M+H+); TLC (hexanes:EtOAc/7:3) Rf=0.20.

Workup

  1. temperatureThe reaction was cooled to room temperature
  2. customThe layers were separated
  3. extractionthe aqueous layer was extracted with CH2Cl2 (2×)
  4. washThe combined organic layers were washed with H2O
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe crude product was purified by flash chromatography (silica gel, Merck 20×20 cm silica gel 60 F254)
  9. washeluting with 7:3/hexanes

Sources & evidence

ORD record
ord-307e7246dde34beaacd9d69fe66fafdc
Source dataset
uspto-grants-2009_02
Patent number
US07495004B2

Reaction notes

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