Hydrochloric Acid → 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

HRID 1893700Notes

Reaction equation

HRID 1893700 reaction equation
[CH3:1][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:36])[C:25]([O:29][CH2:30][CH:31](OC)OC)=[CH:26][CH:27]=4)[N:22]=[C:21]([C:37]4[N:38]=[C:39]([NH:42][CH:43]([CH3:45])[CH3:44])[S:40][CH:41]=4)[CH:20]=3)[CH2:15][N:14]2[C:46](=[O:62])[CH:47]([NH:52][C:53]([O:55][CH:56]2[CH2:61][CH:60]3[CH:58]([CH2:59]3)[CH2:57]2)=[O:54])[C:48]([CH3:51])([CH3:50])[CH3:49])=[O:12])[CH2:7][CH:6]1[CH2:8][CH3:9])=[O:4].Cl.[NH:64]1[CH2:69][CH2:68][O:67][CH2:66][CH2:65]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(O)(=O)C.O>[CH3:1][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:36])[C:25]([O:29][CH2:30][CH2:31][N:64]5[CH2:69][CH2:68][O:67][CH2:66][CH2:65]5)=[CH:26][CH:27]=4)[N:22]=[C:21]([C:37]4[N:38]=[C:39]([NH:42][CH:43]([CH3:44])[CH3:45])[S:40][CH:41]=4)[CH:20]=3)[CH2:15][N:14]2[C:46](=[O:62])[CH:47]([NH:52][C:53]([O:55][CH:56]2[CH2:57][CH:58]3[CH:60]([CH2:59]3)[CH2:61]2)=[O:54])[C:48]([CH3:50])([CH3:51])[CH3:49])=[O:12])[CH2:7][CH:6]1[CH2:8][CH3:9])=[O:4]

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 8083MorpholineHCID 516892Sodium BicarbonateHCID 5049666Sodium triacetoxyborohydrideHCID 766049481-({1-[2-(Bicyclo[3.1.0]hex-3-yloxycarbonylamino)-3,3-dimethylbutyryl]-4-[8-chloro-7-(2,2-dimethoxyethoxy)-2-(2-isopropylaminothiazol-4-yl)-quinolin-4-yloxy]pyrrolidine-2-carbonyl}amino)-2-ethylcyclopropanecarboxylic acid methyl ester

Product 1

HCID 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 esterYield 50%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolvent2×HCID 962WaterSolvent

Conditions

Temperature
60 °C

Procedure

1-({1-[2-(Bicyclo[3.1.0]hex-3-yloxycarbonylamino)-3,3-dimethylbutyryl]-4-[8-chloro-7-(2,2-dimethoxyethoxy)-2-(2-isopropylaminothiazol-4-yl)-quinolin-4-yloxy]pyrrolidine-2-carbonyl}amino)-2-ethylcyclopropanecarboxylic acid methyl ester (23.6 g, 26 mmol) was dissolved in glacial acetic acid (200 ml) and 1.4N HCl in H2O (75 ml) was added to the solution. The mixture was stirred at 60° C. for 1 h. The mixture was concentrated to remove the solvents, followed by co-evaporation with toluene (×2) to remove residual acetic acid. The residue was then dissolved in EtOAc (500 ml) and sat. NaHCO3 aqueous solution while monitoring CO2 evolution. The organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was further dried under high vacuum for 1 h and used without further purification in the next step. The crude material was dissolved in CH2Cl2 (360 ml) and morpholine (3.4 g, 39 mmol) and sodium triacetoxyborohydride (7.2 g, 34 mmol) were added to the mixture at 0° C. Then glacial acetic acid (0.47 g, 7.8 mmol) was added dropwise to the mixture. The reaction was complete in 10 min at 0° C. Saturated aqueous NaHCO3 solution was added to quench the reaction. After stirring for another 20 min, the organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography to give 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 as a yellow solid (12 g, 50% yield). LCMS found 924.63 [M+H]+.

Workup

  1. concentrationThe mixture was concentrated
  2. customto remove the solvents
  3. customto remove residual acetic acid
  4. dissolutionThe residue was then dissolved in EtOAc (500 ml)
  5. washThe organic layer was washed with brine
  6. dry with materialdried (Na2SO4)
  7. concentrationconcentrated in vacuo
  8. customThe residue was further dried under high vacuum for 1 h
  9. customused without further purification in the next step
  10. dissolutionThe crude material was dissolved in CH2Cl2 (360 ml)
  11. waitThe reaction was complete in 10 min at 0° C
  12. customto quench
  13. customthe reaction
  14. stirringAfter stirring for another 20 min
  15. washthe organic layer was washed with brine
  16. dry with materialdried (Na2SO4)
  17. concentrationconcentrated in vacuo
  18. customThe residue was purified by silica gel chromatography

Sources & evidence

ORD record
ord-97f7a20cb9c7450398b4c46c8bb66a58
Source dataset
uspto-grants-2013_08
Patent number
US08513186B2

Reaction notes

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