Tetrahydrofuran → N4-[3-chloro-4-(3-fluorobenzyloxy)-phenyl]-N6-(3a,4,6,6a-tetrahydrofuro[3,4-d]oxazol-2-yl)-quinazoline-4,6-diamine

HRID 2059765

反応式

HRID 2059765 の反応式
[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH2:28])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.C1C[O:32][CH2:31]C1.[NH2:34][CH:35]1[CH2:39][CH2:38]C[CH:36]1[OH:40]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH:28][C:31]4[O:32][CH:39]5[CH2:38][O:40][CH2:36][CH:35]5[N:34]=4)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1

参加物

5

反応物 3

HCID 8028TetrahydrofuranHCID 143443NoName_4581HCID 53630477Allitinib metabolite M6

生成物 1

HCID 59835147N4-[3-chloro-4-(3-fluorobenzyloxy)-phenyl]-N6-(3a,4,6,6a-tetrahydrofuro[3,4-d]oxazol-2-yl)-quinazoline-4,6-diamine収率 65%

試薬・触媒・溶媒 1

HCID 6344Dichloromethane溶媒

実験手順

N4-[3-Chloro-4-(3-fluorobenzyloxy)-phenyl]-N6-(3a,4,6,6a-tetrahydrofuro[3,4-d]oxazol-2-yl)-quinazoline-4,6-diamine is prepared by adding thioCDI (27 mg, 0.152 mmol) to a stirred solution of N4-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-quinazoline-4,6-diamine (60 mg, 0.152 mmol) in 1:1 THF:DCM (8 mL). After 3 hours, 2-amino-cyclopentanol (30 mg, 0.30 mmol) is added and the reaction mixture stirred for 4 hours. Solvent is removed under reduced pressure and the resulting thiourea is triturated with diethyl ether. The crude thiourea is suspended in THF (10 mL) and 1 M NaOH in water (0.38 mL) is added followed by addition of a 1 M TsCl solution in THF (0.17 mL). After 1 hour, the reaction mixture is diluted with EtOAc and water, and the phases separated. The aqueous phase is extracted with EtOAc and the combined organic extracts are dried (Na2SO4) and concentrated. Purification by column chromatography (10:5:1 EtOAc:Hexanes:MeOH) provides the desired product (50 mg, 65%). MS APCI (+) m/z 506, 508 (M+1, Cl pattern) detected; 1H NMR (400 mHz, CD3CN) δ 8.49 (s, 1H), 8.23 (bs, 1H), 7.94 (s, 1H), 7.73 (m, 2H), 7.59 (m, 2H), 7.45 (m, 1H), 7.35 (d, 1H), 7.29 (d, 1H), 7.19-7.10 (m, 3H), 5.23 (s, 2H), 5.18 (m, 1H), 4.66 (m, 1H), 4.11 (d, 1H), 3.96 (d, 1H), 3.56 (dd, 2H).

後処理

  1. customN4-[3-Chloro-4-(3-fluorobenzyloxy)-phenyl]-N6-(3a,4,6,6a-tetrahydrofuro[3,4-d]oxazol-2-yl)-quinazoline-4,6-diamine is prepared
  2. customSolvent is removed under reduced pressure
  3. customthe resulting thiourea is triturated with diethyl ether
  4. addition1 M NaOH in water (0.38 mL) is added
  5. additionfollowed by addition of a 1 M TsCl solution in THF (0.17 mL)
  6. waitAfter 1 hour
  7. additionthe reaction mixture is diluted with EtOAc and water
  8. customthe phases separated
  9. extractionThe aqueous phase is extracted with EtOAc
  10. dry with materialthe combined organic extracts are dried (Na2SO4)
  11. concentrationconcentrated
  12. customPurification by column chromatography (10:5:1 EtOAc:Hexanes:MeOH)

出典と根拠

ORDレコード
ord-ebada8d2a41c44bebf622b3c15d7db02
出典データセット
uspto-grants-2012_10
特許番号
US08278314B2

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