Hydrochloric Acid → 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

HRID 1893684Notes

Reaction equation

HRID 1893684 reaction equation
C(OC([NH:8][CH:9]([C:43]([CH3:46])([CH3:45])[CH3:44])[C:10]([N:12]1[CH2:16][CH:15]([O:17][C:18]2[C:27]3[C:22](=[C:23]([Cl:28])[CH:24]=[CH:25][CH:26]=3)[N:21]=[C:20]([O:29][CH2:30][CH3:31])[CH:19]=2)[CH2:14][CH:13]1[C:32]([NH:34][C:35]1([C:40]([OH:42])=[O:41])[CH2:37][CH:36]1[CH2:38][CH3:39])=[O:33])=[O:11])=O)(C)(C)C.Cl.[F:48][C:49]([F:68])([F:67])[C:50]1([O:54][C:55](=[O:66])OC2C=CC([N+]([O-])=O)=CC=2)[CH2:53][CH2:52][CH2:51]1.OS([O-])(=O)=O.[K+]>ClCCl.C(N(CC)CC)C>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:22]=1[N:21]=[C:20]([O:29][CH2:30][CH3:31])[CH:19]=[C:18]2[O:17][CH:15]1[CH2:16][N:12]([C:10](=[O:11])[CH:9]([NH:8][C:55]([O:54][C:50]2([C:49]([F:48])([F:67])[F:68])[CH2:51][CH2:52][CH2:53]2)=[O:66])[C:43]([CH3:44])([CH3:46])[CH3:45])[CH:13]([C:32]([NH:34][C:35]2([C:40]([OH:42])=[O:41])[CH2:37][CH:36]2[CH2:38][CH3:39])=[O:33])[CH2:14]1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 516920Potassium bisulfateHCID 57785522Carbonic acid 4-nitro-phenyl ester 1-trifluoromethyl-cyclobutyl esterHCID 686173651-{[1-(2-Tert-butoxycarbonylamino-3,3-dimethyl-butyryl)-4-(8-chloro-2-ethoxy-quinolin-4-yloxy)-pyrrolidine-2-carbonyl]-amino}-2-ethyl-cyclopropanecarboxylic acid

Product 1

HCID 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 acidYield 50.4%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8471TriethylamineSolvent

Conditions

Temperature
0 °C

Procedure

To 1-{[1-(2-tert-butoxycarbonylamino-3,3-dimethyl-butyryl)-4-(8-chloro-2-ethoxy-quinolin-4-yloxy)-pyrrolidine-2-carbonyl]-amino}-2-ethyl-cyclopropanecarboxylic acid (200 mg, 0.3 mmol) in dichloromethane (4 mL) was added HCl (4N in dioxane) at room temperature. After 2 h, analysis of the reaction mixture by LC-MS showed complete conversion of starting material. At this point, the reaction was cooled to 0° C. and triethylamine (2 mL) was added dropwise, followed by carbonic acid 4-nitro-phenyl ester 1-trifluoromethyl-cyclobutyl ester (300 mg, 1 mmol). The reaction was allowed to warm to room temperature and stirred 14 h. The reaction mixture was then poured into a 1N solution of KHSO4(aq) and extracted with ethyl acetate. The combined organic extracts were washed with 1N KHSO4(aq), water, and brine, and subsequently dried over magnesium sulfate. Concentration, followed by purification by reverse phase HPLC and lyophilization gave 110 mg (50% yield) of 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 as a white powder. LCMS found 727.03 [M+H]+.

Workup

  1. temperatureto warm to room temperature
  2. extractionextracted with ethyl acetate
  3. washThe combined organic extracts were washed with 1N KHSO4(aq), 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-b6bfa491d86e4f1fbc1731b8a5525fa9
Source dataset
uspto-grants-2013_08
Patent number
US08513186B2

Reaction notes

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