1,8-Diazabicyclo(5.4.0)undec-7-ene → benzyl trans-3-fluoro-4-{[6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl]amino}pyrrolidine-1-carboxylate

HRID 540259노트

반응식

HRID 540259 반응식
[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[S:15](=[O:23])[CH2:14][CH2:13]1)[NH:6][C:5]2=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N12CCCN=C1CCCCC2.[NH2:63][C@H:64]1[C@H:68]([F:69])[CH2:67][N:66]([C:70]([O:72][CH2:73][C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)=[O:71])[CH2:65]1>CN(C)C=O.O>[F:69][C@H:68]1[C@H:64]([NH:63][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([CH3:1])[CH:3]=3)[N:8]=[C:7]([N:12]3[CH2:18][C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[S:15](=[O:23])[CH2:14][CH2:13]3)[N:6]=2)[CH2:65][N:66]([C:70]([O:72][CH2:73][C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)=[O:71])[CH2:67]1

참가 물질

7

반응물 4

HCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 57970069benzyl (3R,4R)-3-amino-4-fluoropyrrolidine-1-carboxylateHCID 1363367986-Methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4(3H)-one

생성물 1

HCID 86691426benzyl trans-3-fluoro-4-{[6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl]amino}pyrrolidine-1-carboxylate수율 41.8%

시약·촉매·용매 2

HCID 962Water용매HCID 6228Dimethylformamide용매2회

실험 절차

A suspension of 6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4 (5H)-yl)quinazolin-4(3H)-one (600 mg, 1.77 mmol, prepared in analogy to the one in Example 91), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.02 g, 2.3 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (400 mg, 2.6 mmol) in anhydrous N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 minutes. Then a solution of benzyl trans-3-amino-4-fluoropyrrolidine-1-carboxylate (500 mg, 2.1 mmol) in N,N-dimethylformamide (5 mL) was added dropwise. After being heated at 60° C. overnight, the mixture was diluted with water (50 mL), extracted with dichloromethane (50 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography (gradient eluting with 10% to 25% ethyl acetate in dichloromethane) to afford 415 mg of the desired product as a yellow solid (yield was 41.8%).

후처리

  1. temperatureAfter being heated at 60° C. overnight
  2. extractionextracted with dichloromethane (50 mL)
  3. washThe organic layer was washed with brine
  4. dry with materialdried over anhydrous sodium sulfate
  5. concentrationconcentrated in vacuo
  6. customThe residue was purified by flash column chromatography (gradient eluting with 10% to 25% ethyl acetate in dichloromethane)

출처 및 근거

ORD 기록
ord-b2f72a8827314e7cae395c256c5eb4ca
출처 데이터셋
uspto-grants-2014_10
특허 번호
US08871756B2

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