Citric Acid → {1-[4-(8-Chloro-2-ethoxy-quinolin-4-yloxy)-2-(1-cyclopropoxysulfonylaminocarbonyl-2-ethyl-cyclopropylcarbamoyl)-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl}-carbamic acid 1-trifluoromethyl-cyclobutyl ester

HRID 1893685ノート

反応式

HRID 1893685 の反応式
[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH2:13][CH3:14])[CH:8]=[C:7]2[O:15][CH:16]1[CH2:20][N:19]([C:21](=[O:39])[CH:22]([NH:27][C:28]([O:30][C:31]2([C:35]([F:38])([F:37])[F:36])[CH2:34][CH2:33][CH2:32]2)=[O:29])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH:18]([C:40]([NH:42][C:43]2([C:48]([OH:50])=O)[CH2:45][CH:44]2[CH2:46][CH3:47])=[O:41])[CH2:17]1.C(N([CH:57]([CH3:59])[CH3:58])C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1([O:87][S:88](=[O:91])(=[O:90])[NH2:89])CC1.C1CCN2C(=NCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[F:38][C:35]([F:36])([F:37])[C:31]1([O:30][C:28](=[O:29])[NH:27][CH:22]([C:21]([N:19]2[CH2:20][CH:16]([O:15][C:7]3[C:6]4[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=4)[N:10]=[C:9]([O:12][CH2:13][CH3:14])[CH:8]=3)[CH2:17][CH:18]2[C:40](=[O:41])[NH:42][C:43]2([C:48]([NH:89][S:88]([O:91][CH:57]3[CH2:59][CH2:58]3)(=[O:90])=[O:87])=[O:50])[CH2:45][CH:44]2[CH2:46][CH3:47])=[O:39])[C:23]([CH3:25])([CH3:26])[CH3:24])[CH2:34][CH2:33][CH2:32]1

参加物

8

反応物 6

HCID 311Citric AcidHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 57785190Cyclopropyl sulfamateHCID 686164141-({4-(8-Chloro-2-ethoxy-quinolin-4-yloxy)-1-[3,3-dimethyl-2-(1-trifluoromethyl-cyclobutoxycarbonylamino)-butyryl]-pyrrolidine-2-carbonyl}-amino)-2-ethyl-cyclopropanecarboxylic acid

生成物 1

HCID 76605009{1-[4-(8-Chloro-2-ethoxy-quinolin-4-yloxy)-2-(1-cyclopropoxysulfonylaminocarbonyl-2-ethyl-cyclopropylcarbamoyl)-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl}-carbamic acid 1-trifluoromethyl-cyclobutyl ester収率 16%

試薬・触媒・溶媒 1

HCID 6228Dimethylformamide溶媒

実験手順

To 1-({4-(8-chloro-2-ethoxy-quinolin-4-yloxy)-1-[3,3-dimethyl-2-(1-trifluoromethyl-cyclobutoxycarbonylamino)-butyryl]-pyrrolidine-2-carbonyl}-amino)-2-ethyl-cyclopropanecarboxylic acid (110 mg, 0.15 mmol) in DMF (3 mL, 0.05 M) was added i-Pr2EtN (90 μL, 0.38 mmol) and HATU (86 mg, 0.23 mmol) and stirred 1 h at rt. To the reaction mixture at rt was added sulfamic acid cyclopropyl ester (46 mg, 0.30 mmol) and DBU (90 μL, 0.60 mmol). The reaction was stirred 17 h at rt, and then added to 5% aq citric acid and extracted with ethyl acetate. The combined organic extracts were washed water, and brine, and subsequently dried over magnesium sulfate. Concentration, followed by purification by reverse phase HPLC and lyophilization gave {1-[4-(8-chloro-2-ethoxy-quinolin-4-yloxy)-2-(1-cyclopropoxysulfonylaminocarbonyl-2-ethyl-cyclopropylcarbamoyl)-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl}-carbamic acid 1-trifluoromethyl-cyclobutyl ester (20 mg, 16% yield) as a white powder. 1H NMR (CD3OD, 500 MHz) δ 9.18 (s, 1H), 7.95 (d, 1H), 7.70 (d, 1H), 7.20 (dd, 1H), 6.48 (s, 1H), 5.4 (br s, 1H), 4.45-4.6 (m, 4H), 4.2-4.3 (m, 2H), 2.58-2.62 (m, 1H), 2.2-2.4 (m, 4H), 1.5-1.7 (m, 4H), 1.43 (t, 3H), 1.2-1.3 (m, 3H) 1.2 (dd, 2H), 1.1-0.9 (m, 13H), 0.85 (m, 2H). LCMS found 846.00 [M+H]+.

後処理

  1. stirringThe reaction was stirred 17 h at rt
  2. extractionextracted with ethyl acetate
  3. washThe combined organic extracts were washed water, and brine
  4. dry with materialsubsequently dried over magnesium sulfate
  5. concentrationConcentration
  6. customfollowed by purification by reverse phase HPLC and lyophilization

出典と根拠

ORDレコード
ord-b1d7043c55b348c0b36b42a731d0a76a
出典データセット
uspto-grants-2013_08
特許番号
US08513186B2

反応ノート

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