Potassium trimethylsilanolate → 2-[4-(4-{4-amino-7,7-dimethyl-7H-pyrimido[4,5-b][1,4]oxazin-6-yl}phenyl)bicyclo[2.2.2]octan-1-yl]propanoic acid

HRID 908117ノート

反応式

HRID 908117 の反応式
[NH2:1][C:2]1[C:11]2[N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]45[CH2:25][CH2:24][C:21]([CH:26]([CH3:31])[C:27]([O:29]C)=[O:28])([CH2:22][CH2:23]4)[CH2:20][CH2:19]5)=[CH:14][CH:13]=3)[C:8]([CH3:33])([CH3:32])[O:7][C:6]=2[N:5]=[CH:4][N:3]=1.C[Si](C)(C)[O-].[K+]>C1COCC1.CS(C)=O.CC#N.O>[NH2:1][C:2]1[C:11]2[N:10]=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([C:18]45[CH2:23][CH2:22][C:21]([CH:26]([CH3:31])[C:27]([OH:29])=[O:28])([CH2:20][CH2:19]4)[CH2:24][CH2:25]5)=[CH:16][CH:17]=3)[C:8]([CH3:32])([CH3:33])[O:7][C:6]=2[N:5]=[CH:4][N:3]=1

参加物

5

反応物 2

HCID 23668039Potassium trimethylsilanolateHCID 25258353methyl 2-{4-[4-(4-amino-7,7-dimethyl-7H-pyrimido[4,5-b][1,4]oxazin-6-yl)phenyl]bicyclo[2.2.2]oct-1-yl}propanoate2 回

生成物 1

HCID 250161682-[4-(4-{4-amino-7,7-dimethyl-7H-pyrimido[4,5-b][1,4]oxazin-6-yl}phenyl)bicyclo[2.2.2]octan-1-yl]propanoic acid収率 21.2%

試薬・触媒・溶媒 2

HCID 8028Tetrahydrofuran溶媒HCID 86584666DMSO MeCN water溶媒

反応条件

温度
100 °C

実験手順

A mixture of methyl 2-{4-[4-(4-amino-7,7-dimethyl-7H-pyrimido[4,5-b][1,4]oxazin-6-yl)phenyl]bicyclo[2.2.2]oct-1-yl}propanoate (Intermediate 18; 220 mg, 0.49 mmol) and potassium trimethylsilanolate (315 mg, 2.45 mmol) in THF (5 mL) was heated in a microwave for 35 mins at 100° C. and was then stirred at ambient temperature for 2 days. The solvent was removed under reduced pressure and the residue partitioned between 2M HCl (20 mL) and EtOAc (50 mL) and the aqueous phase was further extracted with EtOAc (50 mL). The organic extracts were combined, dried (MgSO4) and concentrated to leave a gum. This was dissolved in DMSO/MeCN/H2O (7:2:1) and separated by reverse phase chromatography eluting 5-95% water-acetonitrile 0.2% TFA, providing the title compound (45 mg, 0.104 mmol, 21%) as a white solid; 1H NMR δ 1.01 (d, 3H), 1.49-1.55 (m, 3H), 1.62 (s, 6H), 1.64-1.69 (m, 3H), 1.78-1.81 (m, 6H), 2.12 (q, 1H), 7.05 (s, 1H), 7.40 (d, 2H), 7.65 (d, 2H), 7.99 (s, 1H); MS m/e MH+ 435.

後処理

  1. customThe solvent was removed under reduced pressure
  2. customthe residue partitioned between 2M HCl (20 mL) and EtOAc (50 mL)
  3. extractionthe aqueous phase was further extracted with EtOAc (50 mL)
  4. dry with materialdried (MgSO4)
  5. concentrationconcentrated
  6. customto leave a gum
  7. customseparated by reverse phase chromatography
  8. washeluting 5-95% water-acetonitrile 0.2% TFA

出典と根拠

ORDレコード
ord-688399fa0f9947b4be8617faafc097aa
出典データセット
uspto-grants-2011_09
特許番号
US08017603B2

反応ノート

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