Diisopropylethylamine → ((3R*,5R*)-5-{Cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-carbamoyl}-piperidin-3-yl)-carbamic acid tert-butyl ester

HRID 1698336ノート

反応式

HRID 1698336 の反応式
C1C2C(COC([N:18]3[CH2:23][C@H:22]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][C@@H:20]([C:32]([OH:34])=O)[CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH:69]1([NH:72][CH2:73][C:74]2[C:82]3[C:77](=[CH:78][CH:79]=[CH:80][CH:81]=3)[N:76]([CH2:83][CH2:84][CH2:85][O:86][CH3:87])[CH:75]=2)[CH2:71][CH2:70]1>C(Cl)Cl.CC#N.C(OCC)(=O)C>[C:28]([O:27][C:25](=[O:26])[NH:24][C@@H:22]1[CH2:21][C@@H:20]([C:32](=[O:34])[N:72]([CH:69]2[CH2:71][CH2:70]2)[CH2:73][C:74]2[C:82]3[C:77](=[CH:78][CH:79]=[CH:80][CH:81]=3)[N:76]([CH2:83][CH2:84][CH2:85][O:86][CH3:87])[CH:75]=2)[CH2:19][NH:18][CH2:23]1)([CH3:29])([CH3:30])[CH3:31]

参加物

7

反応物 4

HCID 81531DiisopropylethylamineHCID 42624899O-(6-Chlorobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphateHCID 57870350trans-5-(Tert-butoxycarbonylamino)-1-(9H-fluoren-9-ylmethoxycarbonyl)piperidine-3-carboxylic acidHCID 59817701cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-amine

生成物 1

HCID 57870326((3R*,5R*)-5-{Cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-carbamoyl}-piperidin-3-yl)-carbamic acid tert-butyl ester

試薬・触媒・溶媒 2

HCID 8857Ethyl Acetate溶媒HCID 21877088Acetonitrile methylene chloride溶媒2 回

実験手順

An ice-cooled mixture of (3R*,5R*)-5-tert-butoxycarbonylamino-piperidine-1,3-dicarboxylic acid 1-(9H-fluoren-9-ylmethyl) ester (93.3 mg, 0.2 mmol), O-(1H-6-chlorobenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU) (91 mg, 0.22 mmol) and ethyldiisopropylamine (17.1 μL, 0.1 mmol) in CH2Cl2/CH3CN 1:1 (2 mL) is stirred for 10 min. Cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-amine (51.7 mg, 0.2 mmol) in CH2Cl2/CH3CN 1:1 (1 mL) is added and the mixture is stirred for 14 h at RT. The mixture is diluted with ethyl acetate, and washed twice with K2CO3 solution. The organic layer is dried over Na2SO4 and evaporated in vacuo. The crude product is treated with CH2Cl2/piperidine 4:1 (5 mL) and stirred for 1 h at RT. After evaporation in vacuo, the residue is purified by preparative HPLC (YMC Pack Pro C18, 10-100% CH3CN+0.1% TFA/H2O+0.1% TFA, flow 20 mL/min). The combined pure fractions are treated with solid K2CO3, CH3CN is removed in vacuo, and the residual aqueous phase is extracted twice with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporated to afford the title compound. MS: 485.5 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 5.33 min.

後処理

  1. stirringthe mixture is stirred for 14 h at RT
  2. washwashed twice with K2CO3 solution
  3. dry with materialThe organic layer is dried over Na2SO4
  4. customevaporated in vacuo
  5. additionThe crude product is treated with CH2Cl2/piperidine 4:1 (5 mL)
  6. stirringstirred for 1 h at RT
  7. customAfter evaporation in vacuo
  8. customthe residue is purified by preparative HPLC (YMC Pack Pro C18, 10-100% CH3CN+0.1% TFA/H2O+0.1% TFA, flow 20 mL/min)
  9. additionThe combined pure fractions are treated with solid K2CO3, CH3CN
  10. customis removed in vacuo
  11. extractionthe residual aqueous phase is extracted twice with CH2Cl2
  12. dry with materialThe combined organic layers are dried (Na2SO4)
  13. customevaporated

出典と根拠

ORDレコード
ord-10796f27e2474be5861e41b3ec9744a9
出典データセット
uspto-grants-2012_04
特許番号
US08163773B2

反応ノート

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