1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → N-(3-fluoro-4-(2-(4-(morpholine-4-carbonyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(4-fluorophenyl)-2-oxo-3-azabicyclo[3.1.0]hexane-1-carboxamide

HRID 1676356ノート

反応式

HRID 1676356 の反応式
[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH:12]3[C:10]([C:14]([OH:16])=O)([CH2:11]3)[C:9]2=[O:17])=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[NH2:48][C:49]1[CH:78]=[CH:77][C:52]([O:53][C:54]2[CH:59]=[CH:58][N:57]=[C:56]3[CH:60]=[C:61]([C:63]4[CH:68]=[CH:67][C:66]([C:69]([N:71]5[CH2:76][CH2:75][O:74][CH2:73][CH2:72]5)=[O:70])=[CH:65][CH:64]=4)[S:62][C:55]=23)=[C:51]([F:79])[CH:50]=1>ClCCl>[F:79][C:51]1[CH:50]=[C:49]([NH:48][C:14]([C:10]23[CH2:11][CH:12]2[CH2:13][N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]3=[O:17])=[O:16])[CH:78]=[CH:77][C:52]=1[O:53][C:54]1[CH:59]=[CH:58][N:57]=[C:56]2[CH:60]=[C:61]([C:63]3[CH:64]=[CH:65][C:66]([C:69]([N:71]4[CH2:76][CH2:75][O:74][CH2:73][CH2:72]4)=[O:70])=[CH:67][CH:68]=3)[S:62][C:55]=12

参加物

7

反応物 5

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 67347265(4-(7-(4-Amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)phenyl)(morpholino)methanoneHCID 673496483-(4-Fluorophenyl)-2-oxo-3-azabicyclo[3.1.0]hexane-1-carboxylic acid

生成物 1

HCID 67349638N-(3-fluoro-4-(2-(4-(morpholine-4-carbonyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(4-fluorophenyl)-2-oxo-3-azabicyclo[3.1.0]hexane-1-carboxamide収率 23.4%

試薬・触媒・溶媒 1

HCID 6344Dichloromethane溶媒3 回

実験手順

To a stirred solution of 3-(4-fluorophenyl)-2-oxo-3-aza-bicyclo[3.1.0]hexane-1-carboxylic acid (20 mg, 0.085 mmol) in 500 uL of dichloromethane at room temperature under nitrogen was added HOBt (19.5 mg, 0.128 mmol), EDCI (24.5 mg, 0.128 mmol) and DIEA (45 uL, 0.225 mmol). After 15 minutes a solution of (4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)phenyl)(morpholino)methanone (Example 129, Step A, 34 mg, 0.077 mmol) in 500 uL dichloromethane was added by pipet. After stirring overnight, the reaction was diluted to 30 mL with CH2Cl2 and washed 1×30 mL with 10% sodium carbonate solution. The organics were dried (MgSO4), filtered and concentrated. The crude product was loaded onto Biotage 12S column and eluted initially with dichloromethane and then after about 100 mL of elution, switched to 2/98 MeOH/dichloromethane. Pure product containing fractions were pooled and concentrated to a white glass (12 mg, 21% yield). LRMS (APCI pos) m/e 667.4 (M+1). 1H NMR: (CDCl3, 400 MHz): δ 10.52 (s, 1H), 8.50 (d, 1H), 7.83 (m, 1H), 7.82 (s, 1H), 7.80 (s, 2H), 7.54-7.46 (m, 4H), 7.31 (m, 1H), 7.24 (m, 1H), 7.11 (m, 2H), 6.52 (d, 1H), 4.12 (m, 1H), 3.90-3.60 (br m, 8H), 3.78 (d, 1H), 2.81 (m, 1H), 2.05 (m, 1H), 1.39 (m, 1H).

後処理

  1. washwashed 1×30 mL with 10% sodium carbonate solution
  2. dry with materialThe organics were dried (MgSO4)
  3. filtrationfiltered
  4. concentrationconcentrated
  5. washeluted initially with dichloromethane
  6. washafter about 100 mL of elution
  7. additionPure product containing fractions

出典と根拠

ORDレコード
ord-317f5de17a2b441295a2b75c55adcc15
出典データセット
uspto-grants-2011_08
特許番号
US08003662B2

反応ノート

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