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Acetic Acid → (+/-)-2-((2-chloro-5-cyano-3-((4aR,8aR)-1-methylhexahydro-1H-pyrido[3,4-b][1,4]oxazin-6(7H)-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

HRID 921735
ノート
印刷プレビュー

反応式

HRID 921735 の反応式
[Cl:1][C:2]1[C:7]([N:8]2[CH2:17][CH2:16][C@@H:15]3[C@H:10]([O:11][CH2:12][CH2:13][NH:14]3)[CH2:9]2)=[CH:6][C:5]([C:18]#[N:19])=[CH:4][C:3]=1[NH:20][C:21]1[N:26]=[C:25]([NH:27][CH2:28][CH3:29])[C:24]2=[N:30][CH:31]=[C:32]([C:33]#[N:34])[N:23]2[N:22]=1.[CH:35](OC)(OC)OC.CC(O)=O.C=O>CO.CCOC(C)=O.C1COCC1>[Cl:1][C:2]1[C:7]([N:8]2[CH2:17][CH2:16][C@@H:15]3[C@H:10]([O:11][CH2:12][CH2:13][N:14]3[CH3:35])[CH2:9]2)=[CH:6][C:5]([C:18]#[N:19])=[CH:4][C:3]=1[NH:20][C:21]1[N:26]=[C:25]([NH:27][CH2:28][CH3:29])[C:24]2=[N:30][CH:31]=[C:32]([C:33]#[N:34])[N:23]2[N:22]=1
参加物反応条件実験手順後処理出典と根拠反応ノート

参加物

8

反応物 4

HCID 176Acetic AcidHCID 712FormaldehydeHCID 9005Trimethyl orthoformateHCID 86708616(+/-)-2-((2-chloro-5-cyano-3-((4aR,8aR)-hexahydro-1H-pyrido[3,4-b][1,4]oxazin-6(7H)-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

生成物 1

HCID 86708619(+/-)-2-((2-chloro-5-cyano-3-((4aR,8aR)-1-methylhexahydro-1H-pyrido[3,4-b][1,4]oxazin-6(7H)-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
収率 91.7%

試薬・触媒・溶媒 3

HCID 887Methanol溶媒HCID 8028Tetrahydrofuran溶媒HCID 8857Ethyl Acetate溶媒

反応条件

温度
25 °C

実験手順

(+/−)-2-((2-chloro-5-cyano-3-((4aR,8aR)-hexahydro-1H-pyrido[3,4-b][1,4]oxazin-6(7H)-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 371)(13 mg, 0.027 mmol) was taken up in MeOH (0.5 mL) and THF (0.5 mL) and trimethyl orthoformate (0.225 mL, 2.036 mmol), AcOH (6.22 μl, 0.109 mmol), and formaldehyde (2.492 μl, 0.027 mmol) were added. The reaction was stirred at 25° C. for 5 min, then NaCNBH4 (0.271 mL, 0.271 mmol) was added and the reaction stirred at 25° C. 1 hr. The reaction mixture was diluted with EtOAc and washed with sat'd NaHCO3, then brine. The organic layer was dried over Na2SO4, and concentrated. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 20-mM ammonium acetate; Gradient: 50-100% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford (+/−)-2-((2-chloro-5-cyano-3-((4aR,8aR)-1-methylhexahydro-1H-pyrido[3,4-b][1,4]oxazin-6(7H)-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (12.2 mg).

後処理

  1. additionNaCNBH4 (0.271 mL, 0.271 mmol) was added
  2. stirringthe reaction stirred at 25° C
  3. custom1 hr
  4. washwashed with sat'd NaHCO3
  5. dry with materialThe organic layer was dried over Na2SO4
  6. concentrationconcentrated
  7. customThe crude material was purified via preparative LC/MS with the following conditions
  8. waitGradient: 50-100% B over 15 minutes
  9. customa 5-minute hold
  10. additionFractions containing the desired product
  11. customdried via centrifugal evaporation

出典と根拠

ORDレコード
ord-cf9d921000de4bf99a5b3111784cabef
出典データセット
uspto-grants-2016_03
DOI
10.6084/m9.figshare.5104873.v1
特許番号
US09273057B2

反応ノート

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このページの内容参加物反応条件実験手順後処理出典と根拠反応ノート