Cesium carbonate → (3R*,4R*)-N-(3,5-dichloropyridin-2-yl)-4'H-1-azaspiro[bicyclo[2.2.1]heptane-3,5'-oxazol]-2'-amine

HRID 2059818ノート

反応式

HRID 2059818 の反応式
[Cl:1][C:2]1[C:3]([N:9]=[C:10]=S)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.Cl.[NH2:14][CH2:15][C@@:16]1([OH:23])[C@H:21]2[CH2:22][N:18]([CH2:19][CH2:20]2)[CH2:17]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(N=C=NC(C)C)(C)C>CN(C)C=O.O.C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:9][C:10]2[O:23][C@@:16]3([C@H:21]4[CH2:22][N:18]([CH2:19][CH2:20]4)[CH2:17]3)[CH2:15][N:14]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1

参加物

8

反応物 4

HCID 10796Cesium carbonateHCID 12734DiisopropylcarbodiimideHCID 233404453,5-Dichloro-2-isothiocyanatopyridineHCID 57516879(3S*,4R*)-3-(aminomethyl)-1-azabicyclo[2.2.1]heptan-3-ol dihydrochloride

生成物 1

HCID 68356205(3R*,4R*)-N-(3,5-dichloropyridin-2-yl)-4'H-1-azaspiro[bicyclo[2.2.1]heptane-3,5'-oxazol]-2'-amine収率 48%

試薬・触媒・溶媒 3

HCID 962Water溶媒HCID 6212Chloroform溶媒HCID 6228Dimethylformamide溶媒

反応条件

温度
80 °C

実験手順

To a solution of 3,5-dichloro-2-isothiocyanatopyridine (57 mg, 0.279 mmol) in N,N-dimethylformamide (2 mL) was added (3S*,4R*)-3-(aminomethyl)-1-azabicyclo[2.2.1]heptan-3-ol dihydrochloride (60 mg, 0.279 mmol). The reaction was treated with cesium carbonate (227 mg, 0.697 mmol) and heated to 80° C. After 2 hours, the reaction was further treated with 1,3-diisopropylcarbodiimide (0.152 mL, 0.976 mmol). The reaction was heated at 80° C. for a further 18 hours and then cooled to room temperature. The reaction was poured into chloroform (20 ml) and water (20 ml). The organic was collected and purified by silica gel chromatography eluting with 5-40% (10% NH4OH/Methanol)/chloroform. The product fractions were collected and concentrated in vacuo followed by trituration in diethyl ether to yield (3R*,4R*)—N-(3,5-dichloropyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine (42 mg, 0.134 mmol, 48%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.91 (s, 1H) 8.16 (d, J=2.26 Hz, 1H) 7.97 (d, J=2.51 Hz, 1H) 3.79 (d, J=10.04 Hz, 1H) 3.58 (d, J=9.79 Hz, 1H) 2.71-2.98 (m, 2H) 2.56-2.71 (m, 4H) 2.37 (dd, J=10.04, 3.76 Hz, 1H) 1.83-2.00 (m, 1H) 1.48 (s, 1H). MS (LC/MS) R.T=1.423; (M+H=312.99).

後処理

  1. temperatureThe reaction was heated at 80° C. for a further 18 hours
  2. temperaturecooled to room temperature
  3. customThe organic was collected
  4. custompurified by silica gel chromatography
  5. washeluting with 5-40% (10% NH4OH/Methanol)/chloroform
  6. customThe product fractions were collected
  7. concentrationconcentrated in vacuo

出典と根拠

ORDレコード
ord-8d0a93693eac4450b19c12e044a4f1bd
出典データセット
uspto-grants-2012_10
特許番号
US08278320B2

反応ノート

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