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 2059818노트

반응식

HRID 2059818 반응식
[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

참가 물질

8

반응물 4

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

생성물 1

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

시약·촉매·용매 3

HCID 962Water용매HCID 6212Chloroform용매HCID 6228Dimethylformamide용매

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온도
80 °C

실험 절차

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).

후처리

  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

출처 및 근거

ORD 기록
ord-8d0a93693eac4450b19c12e044a4f1bd
출처 데이터셋
uspto-grants-2012_10
특허 번호
US08278320B2

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