Hydrochloric Acid → 2,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-N-[1,3,4]thiadiazol-2-yl-benzamide

HRID 1025873Notes

Reaction equation

HRID 1025873 reaction equation
C(OC([C:6]1[S:7][C:8]([NH:11][C:12](=[O:43])[C:13]2[CH:18]=[C:17]([Cl:19])[C:16]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=3[C:27]([N:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]([CH:39]4[CH2:41][CH2:40]4)[CH2:31][CH2:30]3)=[O:28])=[CH:15][C:14]=2[Cl:42])=[N:9][N:10]=1)=O)C.O.O.[OH-].[Li+].Cl>O1CCOCC1.C(OCC)(=O)C>[Cl:42][C:14]1[CH:15]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[C:27]([N:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]([CH:39]3[CH2:40][CH2:41]3)[CH2:31][CH2:30]2)=[O:28])[C:17]([Cl:19])=[CH:18][C:13]=1[C:12]([NH:11][C:8]1[S:7][CH:6]=[N:10][N:9]=1)=[O:43]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 962WaterHCID 168937Lithium hydroxide, monohydrate2×HCID 533111825-{2,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-[1,3,4]thiadiazole-2-carboxylic acid ethyl ester

Product 1

HCID 533111832,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-N-[1,3,4]thiadiazol-2-yl-benzamideYield 33%

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Procedure

To a solution of 0.10 g (0.16 mmol) 5-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-[1,3,4]thiadiazole-2-carboxylic acid ethyl ester (Example 47) in 1 mL dioxane were added 1 mL water and 0.008 g (0.19 mmol) lithiumhydroxide monohydrate. The resulting suspension was stirred for 2 hours at room temperature and then at 80° C. for 5.5 hours. Another 0.001 g (0.024 mmol) lithiumhydroxide monohydrate was added and the reaction mixture was heated for another 1.5 hours at 80° C. After stirring at room temperature for 64 hours the reaction mixture was poured on 1M aqueous hydrochloric acid and ethyl acetate and the layers were separated. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was dissolved in N,N-dimethylformamide, filtered over a syringe microfilter and purified by preparative HPLC (Phenomenex Gemini column) with a gradient of acetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2) to give 0.030 g (33%) of the product as a light yellow solid. MS (ESI): m/z=567.08 [M+H]+.

Workup

  1. waitat 80° C. for 5.5 hours
  2. temperaturethe reaction mixture was heated for another 1.5 hours at 80° C
  3. stirringAfter stirring at room temperature for 64 hours the reaction mixture
  4. customthe layers were separated
  5. extractionThe aqueous layer was extracted three times with ethyl acetate
  6. washThe combined organic layers were washed with brine
  7. dry with materialdried over magnesium sulfate
  8. filtrationfiltered
  9. customevaporated
  10. dissolutionThe residue was dissolved in N,N-dimethylformamide
  11. filtrationfiltered over a syringe microfilter
  12. custompurified by preparative HPLC (Phenomenex Gemini column) with a gradient of acetonitrile

Sources & evidence

ORD record
ord-3cd03d6dd918474098955f2b6322a152
Source dataset
uspto-grants-2014_05
Patent number
US08729091B2

Reaction notes

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