Diethylamine → (S)-(+)-2-[6-(3-diethylamino-2-methylpropoxy)-2-(3-methoxyphenyl)-4-oxo-4H-quinazolin-3-yl]-N-isopropy-acetamide

HRID 1157463노트

반응식

HRID 1157463 반응식
[CH:1]([NH:4][C:5]([CH2:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH2:20][C@@H:21]([CH3:28])[CH2:22]OS(C)(=O)=O)[CH:15]=2)[N:10]=[C:9]1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=1)=[O:6])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:43]([NH:45][CH2:46][CH3:47])[CH3:44].CCCCCC>C(#N)C>[CH2:43]([N:45]([CH2:46][CH3:47])[CH2:22][C@H:21]([CH3:28])[CH2:20][O:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=1)[N:8]([CH2:7][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[C:17]2=[O:18])[CH3:44]

참가 물질

6

반응물 4

HCID 8021DiethylamineHCID 8058HexaneHCID 11430Potassium CarbonateHCID 59511753(R)-(-)-methanesulfonic acid 3-[3-(isopropylcarbamoylmethyl)-2-(3-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-6-yloxy]-2-methylpropyl ester

생성물 1

HCID 59511766(S)-(+)-2-[6-(3-diethylamino-2-methylpropoxy)-2-(3-methoxyphenyl)-4-oxo-4H-quinazolin-3-yl]-N-isopropy-acetamide수율 65%

시약·촉매·용매 1

HCID 6342Acetonitrile용매

반응 조건

온도
80 °C

실험 절차

To a solution of (R)-(−)-methanesulfonic acid 3-[3-(isopropylcarbamoylmethyl)-2-(3-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-6-yloxy]-2-methylpropyl ester (1.13 g, 2.18 mmol) in anhydrous acetonitrile (40 mL) was added potassium carbonate (1.51 g, 10.95 mmol) followed by diethyl amine (3.20 g, 4.53 mL, 43.80 mmol) and the reaction mixture was heated at 80° C. in a pressure tube. After 2 days (reaction complete by HPLC), the reaction mixture was concentrated in vacuo to dryness and the residue was partitioned between water (100 mL) and ethyl acetate (150 mL). The aqueous layer was extracted with ethyl acetate (5×150 mL) and with dichloromethane (5×100 mL). The combined organic phase was dried (Na2SO4), solvent evaporated in vacuo, and the resulting residue purified by chromatography on silica gel with a gradient of methanol:dichloromethane (1:19, v/v) to methanol:dichloromethane (1:4, v/v) as eluent. The resultant solid was recrystallised from diethyl ether:hexane to afford (S)-(+)-2-[6-(3-diethylamino-2-methylpropoxy)-2-(3-methoxyphenyl)-4-oxo-4H-quinazolin-3-yl]-N-isopropy-acetamide (EXAMPLE 4a) (0.69 g, 1.40 mmol, 65% from (S)-(+)-2-[6-(3-hydroxy-2-methylpropoxy)-2-(3-methoxyphenyl)-4-oxo-4H-quinazolin-3-yl]-N-isopropylacetamide) as a white solid.

후처리

  1. customAfter 2 days (reaction complete by HPLC)
  2. concentrationthe reaction mixture was concentrated in vacuo to dryness
  3. customthe residue was partitioned between water (100 mL) and ethyl acetate (150 mL)
  4. extractionThe aqueous layer was extracted with ethyl acetate (5×150 mL) and with dichloromethane (5×100 mL)
  5. dry with materialThe combined organic phase was dried (Na2SO4), solvent
  6. customevaporated in vacuo
  7. customthe resulting residue purified by chromatography on silica gel with a gradient of methanol:dichloromethane (1:19
  8. customThe resultant solid was recrystallised from diethyl ether

출처 및 근거

ORD 기록
ord-bb0882a78b2349719869f1e47b983b74
출처 데이터셋
uspto-grants-2010_10
특허 번호
US07807686B2

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