N,N,N',N'-Tetramethylethylenediamine → tert-butyl 3-(2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)-3-hydroxypiperidine-1-carboxylate

HRID 1923314Notes

Reaction equation

HRID 1923314 reaction equation
[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=1.CN(CCN(C)C)C.[Li]CCCC.[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][CH2:41][C:40](=[O:44])[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>C1COCC1>[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][CH2:41][C:40]([C:7]2[N:8]([CH3:11])[C:9]3[C:5]([N:6]=2)=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=[C:2]([Cl:1])[N:10]=3)([OH:44])[CH2:39]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]

Participants

6

Reactant 4

HCID 8037N,N,N',N'-TetramethylethylenediamineHCID 2756825Tert-butyl 3-oxopiperidine-1-carboxylateHCID 715006872-Chloro-9-methyl-6-(4-morpholinyl)-9H-purineHCID 178418339Butyllithium

Product 1

HCID 59605825tert-butyl 3-(2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)-3-hydroxypiperidine-1-carboxylateYield 81%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-30 °C

Procedure

To a mixture of 2-chloro-9-methyl-6-morpholin-4-yl-9H-purine (3.5 g, 13.8 mmol) and TMEDA (3.1 mL, 20.7 mmol) in THF (100 mL) at −78° C. was added n-BuLi (8.3 mL, 2.5 M in hexanes, 20.7 mmol). The resulting mixture was allowed to warm to −30° C. over 45 min then cooled back to −78° C. before the addition of a solution of 3-oxo-piperidine-1-carboxylic acid tert-butyl ester (4.1 g, 20.7 mmol) in THF (10 mL). The reaction mixture was warmed to r.t. and stirred for 2 h then quenched with H2O and extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was triturated with Et2O and unreacted starting material removed by filtration. The resulting residue was purified by column chromatography (Si—PCC, EtOAc:cyclohexane, 30-80%) then triturated with cyclohexane affording 3-(2-Chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (5.0 g, 81%). LCMS (method A): RT 3.50 min [M+H]+ 453.3

Workup

  1. temperatureThe reaction mixture was warmed to r.t.
  2. customthen quenched with H2O
  3. extractionextracted with EtOAc
  4. washThe combined organic phases were washed with brine
  5. dry with materialdried (Na2SO4)
  6. concentrationconcentrated in vacuo
  7. customThe resulting residue was triturated with Et2O
  8. customremoved by filtration
  9. customThe resulting residue was purified by column chromatography (Si—PCC, EtOAc:cyclohexane, 30-80%)
  10. customthen triturated with cyclohexane

Sources & evidence

ORD record
ord-cd4c35d04e43405f899bcdb56cace91c
Source dataset
uspto-grants-2012_05
Patent number
US08173650B2

Reaction notes

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