N,N,N',N'-Tetramethylethylenediamine → 3-[2-(2-Ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester

HRID 1923329Notes

Reaction equation

HRID 1923329 reaction equation
[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[CH:13][N:14]3[CH3:17])=[C:10]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:9]=2)[C:6]2[CH:24]=[CH:25][CH:26]=[CH:27][C:5]=2[N:4]=1)[CH3:2].CN(CCN(C)C)C.[Li]CCCC.[C:41]([O:45][C:46]([N:48]1[CH2:51][C:50](=[O:52])[CH2:49]1)=[O:47])([CH3:44])([CH3:43])[CH3:42]>C1COCC1>[C:41]([O:45][C:46]([N:48]1[CH2:51][C:50]([C:13]2[N:14]([CH3:17])[C:15]3[C:11]([N:12]=2)=[C:10]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:9]=[C:8]([N:7]2[C:6]4[CH:24]=[CH:25][CH:26]=[CH:27][C:5]=4[N:4]=[C:3]2[CH2:1][CH3:2])[N:16]=3)([OH:52])[CH2:49]1)=[O:47])([CH3:44])([CH3:42])[CH3:43]

Participants

6

Reactant 4

HCID 8037N,N,N',N'-TetramethylethylenediamineHCID 15194043-Oxo-azetidine-1-carboxylic acid tert-butyl esterHCID 596054942-(2-Ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purineHCID 178418339Butyllithium

Product 1

HCID 596058743-[2-(2-Ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-3-hydroxy-azetidine-1-carboxylic acid tert-butyl esterYield 65.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-40 °C

Procedure

To a mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (2.5 g, 6.88 mmol) and TMEDA (1.6 mL, 10.33 mmol) in THF (40 mL) at −78° C. was added n-BuLi (4.1 mL, 2.5 M in hexanes, 10.33 mmol). The resulting mixture was allowed to warm to −40° C. over 30 min then cooled back to −78° C. before the addition of a solution of 3-oxoazetidine-1-carboxylic acid tert-butyl ester (1.8 g, 10.33 mmol) in THF (10 mL). The reaction mixture was warmed to −10° C. over 2 h then quenched with sat, aq. NH4Cl and extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-5%) then recrystallised from iPrOAc and pentane affording 3-[2-(2-Ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester as a cream solid (2.4 g, 64%). LCMS (method A): RT 2.83 min [M+H]+ 535.4

Workup

  1. temperatureThe reaction mixture was warmed to −10° C. over 2 h
  2. customthen quenched
  3. extractionaq. NH4Cl and extracted 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 purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-5%)
  8. customthen recrystallised from iPrOAc and pentane

Sources & evidence

ORD record
ord-7d8a9e88374d43bc8743e8607939149a
Source dataset
uspto-grants-2012_05
Patent number
US08173650B2

Reaction notes

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