Diisopropylethylamine → 4-[7-(3-Methanesulfonylamino-propoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid (4-isopropoxy-phenyl)-amide

HRID 657241노트

반응식

HRID 657241 반응식
C(O)(C(F)(F)F)=O.C(Cl)(Cl)Cl.C(O[C:17]([N:19]1[CH2:24][CH2:23][CH:22]([C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:35][CH2:36][CH2:37][CH2:38][NH:39][S:40]([CH2:43]C)(=[O:42])=[O:41])=[CH:32][CH:33]=3)[N:28]=[CH:27][N:26]=2)[CH2:21][CH2:20]1)=[O:18])(C)(C)C.[Al].CCN(C(C)C)C(C)C.[N+](C1C=CC(OC(=O)[NH:66][C:67]2[CH:72]=[CH:71][C:70]([O:73][CH:74]([CH3:76])[CH3:75])=[CH:69][CH:68]=2)=CC=1)([O-])=O>C(Cl)Cl.CC(C)=O.C(Cl)(Cl)Cl>[CH:74]([O:73][C:70]1[CH:71]=[CH:72][C:67]([NH:66][C:17]([N:19]2[CH2:20][CH2:21][CH:22]([C:25]3[C:34]4[C:29](=[CH:30][C:31]([O:35][CH2:36][CH2:37][CH2:38][NH:39][S:40]([CH3:43])(=[O:41])=[O:42])=[CH:32][CH:33]=4)[N:28]=[CH:27][N:26]=3)[CH2:23][CH2:24]2)=[O:18])=[CH:68][CH:69]=1)([CH3:76])[CH3:75]

참가 물질

8

반응물 5

HCID 81531DiisopropylethylamineHCID 5359268AluminumHCID 19978452Chloroform trifluoroacetic acidHCID 58769998(4-Isopropoxy-phenyl)-carbamic acid 4-nitrophenyl esterHCID 693027414-[7-(3-Ethanesulfonylamino-propoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid tert-butyl ester

생성물 1

HCID 587706584-[7-(3-Methanesulfonylamino-propoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid (4-isopropoxy-phenyl)-amide

시약·촉매·용매 2

HCID 6212Chloroform용매HCID 21584124Propan-2-one--dichloromethane (1/1)용매

실험 절차

A premixed solution of 1:1 TFA/CHCl3 (80 μL, 539 μmol TFA) was added to 4-[7-(3-ethanesulfonylamino-propoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid tert-butyl ester (38.7 mg, 83.4 μmol), prepared as described in the previous step, and the tightly capped reaction was stirred under air at 100° C. (aluminum block) for 10 min. After cooling to rt, DIEA (117 μL, 709 μmol) was added dropwise, followed by CHCl3 (0.5 mL), and the resulting homogeneous solution was stirred at rt while (4-isopropoxy-phenyl)-carbamic acid 4-nitro-phenyl ester (32.9 mg, 104 μmol), as prepared in Example 1a, was added in one portion. The resulting homogeneous dark yellow solution was stirred at rt overnight, and then directly loaded onto a flash silica column (5:3 DCM/acetone eluent) to afford impure title compound. This material was taken up in EtOAc (2 mL) and washed with 1.0 M NaHCO3 (3×2 mL), 1.0 M NaH2PO4 (2×2 mL), and again 1.0 M NaHCO3 (2×2 mL). One contaminant was removed (apparently protonated DIEA), but another substantially remained (apparently nitrophenol), so the EtOAc layer was directly loaded onto a flash silica column (5:3 DCM/acetone eluent) to afford the title compound as a white foam (16.0 mg, 35%). 1H-NMR (400 MHz, CDCl3) δ 9.13 (s, 1H), 8.06 (d, 1H), 7.32 (d, 1H), 7.27-7.21 (m, 3H), 6.84 (m, 2H), 6.34 (br s, 1H), 4.69 (br t, 1H), 4.48 (heptet, 1H), 4.26 (m, 4H), 3.67 (tt, 1H), 3.42 (q, 2H), 3.13 (td, 2H), 2.97 (s, 3H), 2.21-2.05 (m, 4H), 2.00-1.91 (m, 2H), 1.32 (d, 6H). LC/MS (ESI): calcd mass 541.2, found 542.1 (MH)+. Anal. Calcd for C27H35N5O5S: C, 59.87; H, 6.51; N, 12.93. Found: C, 60.03; H, 6.51; N, 12.78.

후처리

  1. customprepared
  2. customthe tightly capped reaction
  3. customas prepared in Example 1a
  4. additionwas added in one portion

출처 및 근거

ORD 기록
ord-1089123e82b045f089a54fbe51a815ee
출처 데이터셋
uspto-grants-2011_12
특허 번호
US08071768B2

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