Hydrochloric Acid → 1-({1-[2-(Bicyclo[3.1.0]hex-3-yloxycarbonylamino)-3,3-dimethyl-butyryl]-4-[8-chloro-2-(2-isopropylamino-thiazol-4-yl)-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-pyrrolidine-2-carbonyl}-amino)-2-ethyl-cyclopropanecarboxylic acid

HRID 1893701Notes

Reaction equation

HRID 1893701 reaction equation
C[O:2][C:3]([C:5]1([NH:10][C:11]([CH:13]2[CH2:17][CH:16]([O:18][C:19]3[C:28]4[C:23](=[C:24]([Cl:38])[C:25]([O:29][CH2:30][CH2:31][N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)=[CH:26][CH:27]=4)[N:22]=[C:21]([C:39]4[N:40]=[C:41]([NH:44][CH:45]([CH3:47])[CH3:46])[S:42][CH:43]=4)[CH:20]=3)[CH2:15][N:14]2[C:48](=[O:64])[CH:49]([NH:54][C:55]([O:57][CH:58]2[CH2:63][CH:62]3[CH:60]([CH2:61]3)[CH2:59]2)=[O:56])[C:50]([CH3:53])([CH3:52])[CH3:51])=[O:12])[CH2:7][CH:6]1[CH2:8][CH3:9])=[O:4].[Li+].[OH-].CO.Cl>C1COCC1.O>[CH:60]12[CH2:61][CH:62]1[CH2:63][CH:58]([O:57][C:55]([NH:54][CH:49]([C:50]([CH3:53])([CH3:52])[CH3:51])[C:48]([N:14]1[CH2:15][CH:16]([O:18][C:19]3[C:28]4[C:23](=[C:24]([Cl:38])[C:25]([O:29][CH2:30][CH2:31][N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)=[CH:26][CH:27]=4)[N:22]=[C:21]([C:39]4[N:40]=[C:41]([NH:44][CH:45]([CH3:46])[CH3:47])[S:42][CH:43]=4)[CH:20]=3)[CH2:17][CH:13]1[C:11]([NH:10][C:5]1([C:3]([OH:4])=[O:2])[CH2:7][CH:6]1[CH2:8][CH3:9])=[O:12])=[O:64])=[O:56])[CH2:59]2

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 887MethanolHCID 3939Lithium HydroxideHCID 766051261-({1-[2-(Bicyclo[3.1.0]hex-3-yloxycarbonylamino)-3,3-dimethylbutyryl]-4-[8-chloro-2-(2-isopropylaminothiazol-4-yl)-7-(2-morpholin-4-yl-ethoxy)quinolin-4-yloxy]pyrrolidine-2-carbonyl}-amino)-2-ethyl-cyclopropanecarboxylic acid methyl ester

Product 1

HCID 866327961-({1-[2-(Bicyclo[3.1.0]hex-3-yloxycarbonylamino)-3,3-dimethyl-butyryl]-4-[8-chloro-2-(2-isopropylamino-thiazol-4-yl)-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-pyrrolidine-2-carbonyl}-amino)-2-ethyl-cyclopropanecarboxylic acidYield 93%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 8028TetrahydrofuranSolvent

Procedure

1-({1-[2-(Bicyclo[3.1.0]hex-3-yloxycarbonylamino)-3,3-dimethylbutyryl]-4-[8-chloro-2-(2-isopropylaminothiazol-4-yl)-7-(2-morpholin-4-yl-ethoxy)quinolin-4-yloxy]pyrrolidine-2-carbonyl}-amino)-2-ethyl-cyclopropanecarboxylic acid methyl ester (12 g, 13 mmol) was dissolved in THF (200 ml), LiOH (11 g, 260 mmol) in H2O (200 ml) was added, followed by MeOH (200 ml). The mixture was kept stirring at room temperature for 20 h. Upon completion of the reaction, 4 N HCl in H2O was added to adjust pH to 7 at 0° C. The mixture was extracted with EtOAc (2×400 ml). The combined organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo to give 1-({1-[2-(bicyclo[3.1.0]hex-3-yloxycarbonylamino)-3,3-dimethyl-butyryl]-4-[8-chloro-2-(2-isopropylamino-thiazol-4-yl)-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-pyrrolidine-2-carbonyl}-amino)-2-ethyl-cyclopropanecarboxylic acid as a yellow solid (11 g, 93% yield). LCMS found 911.52[M+H]+.

Workup

  1. additionwas added
  2. customto adjust pH to 7 at 0° C
  3. extractionThe mixture was extracted with EtOAc (2×400 ml)
  4. washThe combined organic layer was washed with brine
  5. dry with materialdried (Na2SO4)
  6. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-dd65e50a31cf4b7984d3559a7f163d56
Source dataset
uspto-grants-2013_08
Patent number
US08513186B2

Reaction notes

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