Citric Acid → (S)-3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-(1-(2,6-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(pyridin-2-yl)propanamide

HRID 1098270Notes

Reaction equation

HRID 1098270 reaction equation
C[Al](C)C.[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11].[Si:12]([O:19][CH:20]1[CH2:23][N:22]([CH2:24][C@H:25]([O:30][C:31]2[N:36]=[CH:35][N:34]=[C:33]3[N:37]([C:40]4[C:45]([Cl:46])=[CH:44][CH:43]=[CH:42][C:41]=4[Cl:47])[N:38]=[CH:39][C:32]=23)[C:26](OC)=[O:27])[CH2:21]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.O.C(Cl)Cl>[Si:12]([O:19][CH:20]1[CH2:21][N:22]([CH2:24][C@H:25]([O:30][C:31]2[N:36]=[CH:35][N:34]=[C:33]3[N:37]([C:40]4[C:41]([Cl:47])=[CH:42][CH:43]=[CH:44][C:45]=4[Cl:46])[N:38]=[CH:39][C:32]=23)[C:26]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]=2)=[O:27])[CH2:23]1)([C:15]([CH3:17])([CH3:18])[CH3:16])([CH3:13])[CH3:14]

Participants

8

Reactant 4

HCID 311Citric AcidHCID 104392-AminopyridineHCID 16682925TrimethylaluminumHCID 66813287(S)-methyl 3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-(1-(2,6-dichlorophenyl)-1H-pyrazolo [3,4-d]pyrimidin-4-yloxy)propanoate

Product 1

HCID 57504717(S)-3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-(1-(2,6-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(pyridin-2-yl)propanamideYield 68.2%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 1140TolueneSolvent2×HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

Trimethylaluminium (0.362 mL, 0.72 mmol) was added to a solution of pyridin-2-amine (68.1 mg, 0.72 mmol) in toluene (8 mL) at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 20 mins and then (S)-methyl 3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-(1-(2,6-dichlorophenyl)-1H-pyrazolo [3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate BJ1) (200 mg, 0.36 mmol) in toluene (4 mL) was added. The reaction mixture was allowed to warm to room temperature and then heated at reflux under nitrogen for 4 hours. The reaction mixture was allowed to cool to room temperature and the concentrated. The residue was neutralised to pH 7 with citric acid (1M, aq) and then diluted with water and DCM (50 mL). The organic layer was separated and the aqueous layer re-extracted with DCM (30 mL). The combined organics were dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane to afford the product (151 mg, 67.9%).

Workup

  1. temperatureto warm to room temperature
  2. temperatureheated
  3. temperatureat reflux under nitrogen for 4 hours
  4. temperatureto cool to room temperature
  5. customThe organic layer was separated
  6. extractionthe aqueous layer re-extracted with DCM (30 mL)
  7. dry with materialThe combined organics were dried (MgSO4)
  8. filtrationfiltered
  9. customevaporated
  10. customThe crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane

Sources & evidence

ORD record
ord-12ee198cf38c436d818851e0e27f7e82
Source dataset
uspto-grants-2012_03
Patent number
US08143263B2

Reaction notes

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