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 1893685Notes

Reaction equation

HRID 1893685 reaction equation
[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

Participants

8

Reactant 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

Product 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 esterYield 16%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

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]+.

Workup

  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

Sources & evidence

ORD record
ord-b1d7043c55b348c0b36b42a731d0a76a
Source dataset
uspto-grants-2013_08
Patent number
US08513186B2

Reaction notes

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