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 2405834Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 2405834
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

Komponenten

7

Edukt 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

Produkt 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 acidAusbeute 50,4 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 6344DichloromethaneLösungsmittelHCID 8471TriethylamineLösungsmittel

Reaktionsbedingungen

Temperatur
0 °C

Versuchsvorschrift

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]+.

Aufarbeitung

  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

Quellen und Nachweise

ORD-Eintrag
ord-4de8ea9cc4a04207bcfa6a7500d18ac0
Quelldatensatz
uspto-grants-2014_08
Patentnummer
US08809267B2

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