L-Prolinol → 4-{7-[2-(2-Hydroxymethyl-pyrrolidin-1-yl)-ethoxy]-quinazolin-4-yl}-piperidine-1-carboxylic acid (4-pyrrolidin-1-yl-phenyl)-amide

HRID 657267노트

반응식

HRID 657267 반응식
C([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26]OS(C)(=O)=O)=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[NH:32]1[CH2:36][CH2:35][CH2:34][C@H:33]1[CH2:37][OH:38].Cl.[N+](C1C=CC(OC(=O)[NH:51][C:52]2[CH:57]=[CH:56][C:55]([N:58]3[CH2:62][CH2:61][CH2:60][CH2:59]3)=[CH:54][CH:53]=2)=CC=1)([O-])=O>CS(C)=O.O>[N:58]1([C:55]2[CH:56]=[CH:57][C:52]([NH:51][C:6]([N:8]3[CH2:13][CH2:12][CH:11]([C:14]4[C:23]5[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][N:32]6[CH2:36][CH2:35][CH2:34][CH:33]6[CH2:37][OH:38])=[CH:21][CH:22]=5)[N:17]=[CH:16][N:15]=4)[CH2:10][CH2:9]3)=[O:5])=[CH:53][CH:54]=2)[CH2:59][CH2:60][CH2:61][CH2:62]1

참가 물질

6

반응물 3

HCID 640091L-ProlinolHCID 595517384-[7-(2-Methanesulfonyloxy-ethoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid tert-butyl esterHCID 68891845HCID 68891845, 화합물

생성물 1

HCID 732186114-{7-[2-(2-Hydroxymethyl-pyrrolidin-1-yl)-ethoxy]-quinazolin-4-yl}-piperidine-1-carboxylic acid (4-pyrrolidin-1-yl-phenyl)-amide

시약·촉매·용매 2

HCID 679Dimethyl Sulfoxide용매HCID 962Water용매

반응 조건

온도
120 °C

실험 절차

To a solution of 4-[7-(2-methanesulfonyloxy-ethoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid tert-butyl ester (40.6 mg, 0.09 mmol) in DMSO (0.4 mL) was added (S)-(+)-2-pyrrolidinemethanol (90.9 mg, 0.9 mmol). The mixture was stirred at 120° C. overnight and subsequently partitioned between EtOAc and water. The combined organic extracts were washed with brine, dried over Na2SO4 and evaporated. The residue was treated with 50% TFA/CH2Cl2 (8 mL) for 2 h, the solvents (TFA/CH2Cl2) were removed under reduced pressure and half of the residue was re-dissolved in CH2Cl2. DIPEA (55 μL) was added to the above solution, followed by (4-pyrrolidin-1-yl-phenyl)-carbamic acid 4-nitro-phenyl ester hydrochloride (19.6 mg, 0.054 mmol), which was prepared as described in Example 74a. The reaction mixture was stirred for 1 h, diluted with water. The organic phase was collected and the solvents were evaporated. The crude residue was purified by flash column chromatography on silica gel (15% MeOH/EtOAc as eluent) to afford a white solid (10 mg, 40.8% overall yield). 1H NMR (CD3OD) δ 9.03 (s, 1H), 8.35 (d, J=9.44 Hz, 1H), 7.40 (dd, J=9.25 and 2.54 Hz, 1H), 7.34 (d, J=2.48 Hz, 1H), 7.13 (d, J=8.87 Hz, 2H), 6.54 (d, J=8.96 Hz, 2H), 4.29-4.36 (4H), 3.92 (m, 1H), 3.60 (dd, J=10.98 and 4.81 Hz, 1H), 3.52 (dd, J=11.00 and 5.90 Hz, 1H), 3.40 (m, 1H), 3.27 (m, 1H), 3.24 (t, J=6.61 Hz, 4H), 3.15 (td, J=12.57 and 2.55 Hz, 2H), 2.88 (dt, J=13.67 and 5.50 Hz, 1H), 2.71 (m, 1H), 2.47 (m, 1H), 1.90-2.09 (9H), 1.79 (m, 2H), 1.66 (m, 1H). Calcd for C31H41N6O3 (MH+) 545.3, found 545.3.

후처리

  1. customsubsequently partitioned between EtOAc and water
  2. washThe combined organic extracts were washed with brine
  3. dry with materialdried over Na2SO4
  4. customevaporated
  5. additionThe residue was treated with 50% TFA/CH2Cl2 (8 mL) for 2 h
  6. customthe solvents (TFA/CH2Cl2) were removed under reduced pressure and half of the residue
  7. dissolutionwas re-dissolved in CH2Cl2
  8. additionDIPEA (55 μL) was added to the above solution
  9. customwas prepared
  10. stirringThe reaction mixture was stirred for 1 h
  11. customThe organic phase was collected
  12. customthe solvents were evaporated
  13. customThe crude residue was purified by flash column chromatography on silica gel (15% MeOH/EtOAc as eluent)
  14. customto afford
  15. customa white solid (10 mg, 40.8% overall yield)

출처 및 근거

ORD 기록
ord-549ab20e8f534ab69de421646538d6d3
출처 데이터셋
uspto-grants-2011_12
특허 번호
US08071768B2

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