4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole → (3-Dimethylaminomethyl-4-morpholin-4-yl-phenyl)-[5-(1H-pyrazol-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine

HRID 1925003Notes

Reaction equation

HRID 1925003 reaction equation
[N:1]1(C2C=CC(NC3C4N(C=CN=4)C(C4C=CNC(=O)C=4)=CN=3)=CC=2)CCOCC1.C(OC(=O)[N:36]([C:53]1[C:54]2[N:55]([CH:60]=[CH:61][N:62]=2)[C:56](Br)=[CH:57][N:58]=1)[C:37]1[CH:42]=[CH:41][C:40]([N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)=[C:39]([CH2:49][N:50]([CH3:52])[CH3:51])[CH:38]=1)(C)(C)C.CC1(C)C(C)(C)OB([C:72]2[CH:73]=[N:74][NH:75][CH:76]=2)O1.CC([O-])(C)C.[Na+]>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.CN(C=O)C.O>[NH3:1].[CH3:52][N:50]([CH2:49][C:39]1[CH:38]=[C:37]([NH:36][C:53]2[C:54]3[N:55]([CH:60]=[CH:61][N:62]=3)[C:56]([C:72]3[CH:73]=[N:74][NH:75][CH:76]=3)=[CH:57][N:58]=2)[CH:42]=[CH:41][C:40]=1[N:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1)[CH3:51]

Participants

8

Reactant 4

HCID 27740104-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 23676156Sodium t-butoxideHCID 248574474-[8-(4-Morpholin-4-yl-phenylamino)imidazo[1,2-a]pyrazin-5-yl]-1H-pyridin-2-oneHCID 86652631(5-Bromo-imidazo[1,2-a]pyrazin-8-yl)-(3-dimethylaminomethyl-4-morpholin-4-yl-phenyl)-carbamic acid tert-butyl ester

Product 2

HCID 222AmmoniaHCID 59023035(3-Dimethylaminomethyl-4-morpholin-4-yl-phenyl)-[5-(1H-pyrazol-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amineYield 66%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 21962138N,N-Dimethylformamide--water (1/1)Solvent

Procedure

In the same way as described for Compound 85, step 1, using (5-bromo-imidazo[1,2-a]pyrazin-8-yl)-(3-dimethylaminomethyl-4-morpholin-4-yl-phenyl)-carbamic acid tert-butyl ester (54 mg, 0.1024 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (29.8 mg, 0.153 mmol), Pd(PPh3)4 (12 mg, 0.0102 mmol) and NaOtBu (39 mg, 0.41 mmol) in 3:1 DMF/water (4 mL). The reaction mixture is concentrated under reduced pressure and the residue is dissolved in a mixture 1:1 DCM:TFA (drop of water). After stirring the solution at room temperature for 4 hours, ethyl acetate is added and the mixture is basified using sat. NaHCO3. The organic layer is separated, dried over MgSO4, filtered and concentrated in vacuo to afford a crude compound. Purification by silica gel column chromatography eluting with DCM followed by 95:5 DCM:NH3 (7M in MeOH), affords the title compound (28.1 mg, 66%). Conversion into the mesylate salt using 0.1M MsOH (0.67 mL) yields the title compound (26.9 mg, 78%). LCMS: Rt 1.97 min (97%), m/z (APCI) 419 (M+H)+, 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 2.35 (3H, s, MsOH), 2.74-2.89 (10H, m), 3.82 (4H, m), 4.39 (2H, d), 7.42 (1H, d), 7.61 (1H, s), 7.81 (1H, s), 8.08 (1H, d), 8.14-8.26 (4H, m), 9.19 (1H, br s), 9.75 (1H, br s).

Workup

  1. concentrationThe reaction mixture is concentrated under reduced pressure
  2. dissolutionthe residue is dissolved in a mixture 1:1 DCM
  3. additionethyl acetate is added
  4. customThe organic layer is separated
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customto afford a crude compound
  9. customPurification by silica gel column chromatography
  10. washeluting with DCM

Sources & evidence

ORD record
ord-0438427ad26d47c495605bbee3462fdc
Source dataset
uspto-grants-2012_05
Patent number
US08178530B2

Reaction notes

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