Lithium Hexamethyldisilazide → HCID 57504323, compound

HRID 1097987Notes

Reaction equation

HRID 1097987 reaction equation
C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[OH:11][C@@H:12]([CH2:22][O:23][CH:24]([CH3:26])[CH3:25])[C:13]([NH:15][C:16]1[S:20][N:19]=[C:18]([CH3:21])[N:17]=1)=[O:14].Cl[C:28]1[N:33]=[CH:32][N:31]=[C:30]2[N:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[Cl:43])[N:35]=[CH:36][C:29]=12>C1COCC1.CCOC(C)=O>[Cl:43][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[N:34]1[C:30]2[N:31]=[CH:32][N:33]=[C:28]([O:11][C@@H:12]([CH2:22][O:23][CH:24]([CH3:26])[CH3:25])[C:13]([NH:15][C:16]3[S:20][N:19]=[C:18]([CH3:21])[N:17]=3)=[O:14])[C:29]=2[CH:36]=[N:35]1

Participants

6

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 112655704-Chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-D]pyrimidine2×HCID 57504480HCID 57504480, compound2×

Product 1

HCID 57504323HCID 57504323, compoundYield 78%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

A solution of lithium bis(trimethylsilyl)amide (0.82 mL, 0.82 mmol) was added dropwise to a stirred solution of (S)-2-hydroxy-3-isopropoxy-N-(3-methyl-1,2,4-thiadiazol-5-yl)propanamide (Intermediate C9) (200 mg, 0.82 mmol) in anhydrous THF (5 mL) over a period of 3 minutes under nitrogen. The resulting suspension was stirred at ambient temperature for 10 minutes and then a solution of 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B1) in dry THF (1.5 mL) was added dropwise over 1 minute and the reaction heated to 50° C. for 20 hours. The mixture was cooled, diluted with EtOAc (50 mL), washed with water (10 mL) and brine (10 mL). The combined aqueous extracts were acidified with 1M citric acid and extracted with EtOAc (2×20 mL), the combined organic extracts were dried (MgSO4) and evaporated. The resulting residue was purified by flash silica chromatography, eluting with an increasing gradient of 60 to 100% EtOAc in isohexane to afford (2S)-2-[1-(2-chlorophenyl)pyrazolo[4,5-e]pyrimidin-4-yl]oxy-N-(3-methyl-1,2,4-thiadiazol-5-yl)-3-propan-2-yloxypropanamide (300 mg, 78%).

Workup

  1. temperaturethe reaction heated to 50° C. for 20 hours
  2. temperatureThe mixture was cooled
  3. washwashed with water (10 mL) and brine (10 mL)
  4. extractionextracted with EtOAc (2×20 mL)
  5. dry with materialthe combined organic extracts were dried (MgSO4)
  6. customevaporated
  7. customThe resulting residue was purified by flash silica chromatography
  8. washeluting with an increasing gradient of 60 to 100% EtOAc in isohexane

Sources & evidence

ORD record
ord-4e926817ef6f4d4bbe63a87508e8f786
Source dataset
uspto-grants-2012_03
Patent number
US08143263B2

Reaction notes

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