Hydrochloric Acid → [3-(3-{1-[4-Amino-3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-methoxy-6-methylphenyl)azetidin-1-yl]acetonitrile

HRID 1499784Notes

Reaction equation

HRID 1499784 reaction equation
C(OC([N:6]1[CH:10]=[C:9](B2OC(C)(C)C(C)(C)O2)[CH:8]=[N:7]1)C)C.[NH2:20][C:21]1[N:26]=[CH:25][N:24]=[C:23]2[N:27]([CH:31]([C:33]3[C:34]([O:48][CH3:49])=[C:35]([CH:41]4[CH2:44][N:43]([CH2:45][C:46]#[N:47])[CH2:42]4)[C:36]([CH3:40])=[C:37]([Cl:39])[CH:38]=3)[CH3:32])[N:28]=[C:29](Br)[C:22]=12.C(=O)([O-])[O-].[Na+].[Na+].O.Cl.C([O-])(O)=O.[Na+]>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:20][C:21]1[N:26]=[CH:25][N:24]=[C:23]2[N:27]([CH:31]([C:33]3[C:34]([O:48][CH3:49])=[C:35]([CH:41]4[CH2:44][N:43]([CH2:45][C:46]#[N:47])[CH2:42]4)[C:36]([CH3:40])=[C:37]([Cl:39])[CH:38]=3)[CH3:32])[N:28]=[C:29]([C:9]3[CH:10]=[N:6][NH:7][CH:8]=3)[C:22]=12

Participants

9

Reactant 6

HCID 313Hydrochloric AcidHCID 962Water2×HCID 10340Sodium CarbonateHCID 516892Sodium BicarbonateHCID 467367981-(1-Ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 86677710(3-{3-[1-(4-Amino-3-bromo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)acetonitrile2×

Product 1

HCID 136217596[3-(3-{1-[4-Amino-3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-methoxy-6-methylphenyl)azetidin-1-yl]acetonitrile

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
120 °C

Procedure

Into a microwave vial was weighed 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (16 mg, 0.058 mmol) and tetrakis(triphenylphosphine)palladium(0) (3.4 mg, 0.0029 mmol). A solution of (3-{3-[1-(4-amino-3-bromo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)acetonitrile (14 mg, 0.029 mmol, racemic intermediate from Example 125, Step 3) in N,N-dimethylformamide (0.25 mL) was added followed by 2.0 M sodium carbonate in water (73 μL, 0.14 mmol). The resulting mixture was stirred at 120° C. for 5 h. The mixture was filtered and concentrated. To a mixture of the crude coupling product in tetrahydrofuran (0.3 mL) was added 3.0 M hydrochloric acid solution in water (100 μL, 0.3 mmol) and stirred for 2 h at room temperature. The mixture was neutralized with sat. NaHCO3 and extracted with dichloromethane. The organic was dried (MgSO4), filtered, and concentrated. The crude was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 1.0 mg (7.2% for 2 steps) of the desired product. The product was isolated as a racemic mixture. LCMS calculated for C23H25ClN9O (M+H)+: m/z=478.2; Found: 478.1.

Workup

  1. filtrationThe mixture was filtered
  2. concentrationconcentrated
  3. additionTo a mixture of the crude coupling product in tetrahydrofuran (0.3 mL)
  4. stirringstirred for 2 h at room temperature
  5. extractionextracted with dichloromethane
  6. dry with materialThe organic was dried (MgSO4)
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe crude was purified
  10. washeluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min)

Sources & evidence

ORD record
ord-f9abff9ee5f5431aa064d593dc9d1873
Source dataset
uspto-grants-2015_12
Patent number
US09199982B2

Reaction notes

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