Cesium carbonate → Ethyl 1-(5-(2-(3-ethylureido)-7-(4-methylpyridin-2-yl)benzothiazol-5-yl)pyrimidin-2-yl)-4-methylpiperidine-4-carboxylate

HRID 712255Notes

Reaction equation

HRID 712255 reaction equation
Br[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][C:26]([CH3:34])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)[CH:3]=1.B1(B2OCC(C)(C)CO2)OCC(C)(C)CO1.C([O-])(=O)C.[K+].Cl[C:57]1[CH:62]=[C:61]([CH3:63])[CH:60]=[CH:59][N:58]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[CH2:15]([NH:14][C:12]([NH:11][C:8]1[S:9][C:10]2[C:2]([C:57]3[CH:62]=[C:61]([CH3:63])[CH:60]=[CH:59][N:58]=3)=[CH:3][C:4]([C:17]3[CH:22]=[N:21][C:20]([N:23]4[CH2:24][CH2:25][C:26]([CH3:34])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:27][CH2:28]4)=[N:19][CH:18]=3)=[CH:5][C:6]=2[N:7]=1)=[O:13])[CH3:16]

Participants

7

Reactant 5

HCID 10796Cesium carbonateHCID 772482-Chloro-4-methylpyridineHCID 517044Potassium AcetateHCID 2734316Bis(neopentyl glycolato)diboronHCID 86663956Ethyl 1-(5-(7-bromo-2-(3-ethylureido)benzo[d]thiazol-5-yl)pyrimidin-2-yl)-4-methylpiperidine-4-carboxylate2×

Product 1

HCID 86663970Ethyl 1-(5-(2-(3-ethylureido)-7-(4-methylpyridin-2-yl)benzothiazol-5-yl)pyrimidin-2-yl)-4-methylpiperidine-4-carboxylateYield 3.1%

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
80 °C

Procedure

To a solution of ethyl 1-(5-(7-bromo-2-(3-ethylureido)benzothiazol-5-yl)pyrimidin-2-yl)-4-methylpiperidine-4-carboxylate (Intermediate 4) (0.5 g, 0.91 mmol) in DMSO (5 mL) was added bis(neopentylglycolato)diboron (0.41 g, 1.82 mmol) and potassium acetate (0.18 g, 1.82 mmol). The reaction was degassed by purging N2 for 15 min followed by addition of dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium (II) (0.07 g, 0.091 mmol) and again degassed for 10-15 min then heated up to 80° C. for 2 h. After completion of reaction (TLC as well as MS monitoring), the reaction was cooled to rt followed by addition of 2-chloro-4-methylpyridine (0.23 g, 1.37 mmol) and an aqueous solution of Cs2CO3 (0.45 g, 1.37 mmol, dissolved in minimum amount of water). The reaction was degassed by purging N2 for 15 min followed by addition of tetrakis (triphenylphosphine)palladium(0) (0.11 g, 0.091 mmol) and again degassed for 10-15 min then heated up to 80° C. for 16 h. After reaction completion, 100 mL of ice-cold water was added then extracted with EtOAc (3×150 mL) and the combined organic layer was washed with brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified over 100-200 M silica-gel using 1.50% MeOH: DCM to obtain a beige solid, which was further purified through preperative-HPLC to obtain the desired product as an off-white solid (0.016 g, 3%).

Workup

  1. customThe reaction was degassed
  2. customby purging N2 for 15 min
  3. customagain degassed for 10-15 min
  4. customAfter completion of reaction (TLC as well as MS monitoring), the reaction
  5. temperaturewas cooled to rt
  6. customThe reaction was degassed
  7. customby purging N2 for 15 min
  8. customagain degassed for 10-15 min
  9. temperaturethen heated up to 80° C. for 16 h
  10. customAfter reaction completion, 100 mL of ice-cold water
  11. additionwas added
  12. extractionthen extracted with EtOAc (3×150 mL)
  13. washthe combined organic layer was washed with brine
  14. dry with materialdried over Na2SO4
  15. filtrationfiltered
  16. customevaporated under reduced pressure
  17. customThe crude residue was purified over 100-200 M silica-gel
  18. customDCM to obtain a beige solid, which
  19. customwas further purified through preperative-HPLC

Sources & evidence

ORD record
ord-ca21846c681144a09ed964ca23e1a224
Source dataset
uspto-grants-2015_11
Patent number
US09181234B2

Reaction notes

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