1,4-Dioxane → tert-butyl 3-(cyanomethyl)-3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate

HRID 1853011Notes

Reaction equation

HRID 1853011 reaction equation
Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]2[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=2)[N:3]=1.[C:17]([CH2:19][C:20]1([N:31]2[CH:35]=[C:34](B3OC(C)(C)C(C)(C)O3)[CH:33]=[N:32]2)[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21]1)#[N:18].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>CCOC(C)=O.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>[C:17]([CH2:19][C:20]1([N:31]2[CH:35]=[C:34]([C:2]3[N:7]4[CH:8]=[CH:9][N:10]=[C:6]4[CH:5]=[C:4]([C:11]4[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=4)[N:3]=3)[CH:33]=[N:32]2)[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21]1)#[N:18]

Participants

8

Reactant 4

HCID 312751,4-DioxaneHCID 62657Potassium Phosphate, TribasicHCID 67457197tert-butyl 3-(cyanomethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylateHCID 86685297HCID 86685297, compound

Product 1

HCID 53497465tert-butyl 3-(cyanomethyl)-3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylateYield 88.81%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolvent2×HCID 8857Ethyl AcetateSolvent2×

Conditions

Temperature
70 °C

Procedure

In a 5 L 4-necked flask with an overhead mechanical stirrer was added 5-chloro-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (Preparation J; 34.83 g, 149.1 mmol), tert-butyl 3-(cyanomethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-Pyrazol-1-yl)azetidine-1-carboxylate (Preparation F; 86.82 g, 223.6 mmol), and K3PO4 (94.92 g, 447.2 mmol) by powder funnel. Dioxane (745.3 mL, 149.1 mmol) was added to rinse down funnel. Pd(PPh3)4 (17.23 g, 14.91 mmol) was added, followed by 74.5 mL of water. The reaction mixture was slowly heated to 70° C. as measured by an internal temperature probe. After heating for 6 hours, the reaction mixture was cooled to ambient temperature. The reaction mixture was diluted in EtOAc (500 mL) and water (100 mL), and then the resultant solids were filtered out. The solids were washed with EtOAc (2×500 mL) to afford a grey-white solid, which was re-introduced back to the 5 L 4-neck flask and diluted with 1 L of water and 300 mL of EtOAc. This was stirred for 3 hours, and then the solids were isolated by filtration. After washing with EtOAc (2×500 mL), the solids were dried to afford tert-butyl 3-(cyanomethyl)-3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (60.83 g, 132.4 mmol, 88.81% yield). MS (apci) m/z=460.1 (M+H).

Workup

  1. washto rinse down funnel
  2. temperatureAfter heating for 6 hours
  3. temperaturethe reaction mixture was cooled to ambient temperature
  4. filtrationwater (100 mL), and then the resultant solids were filtered out
  5. washThe solids were washed with EtOAc (2×500 mL)
  6. customto afford a grey-white solid, which
  7. additionwas re-introduced back to the 5 L 4-neck flask
  8. customthe solids were isolated by filtration
  9. washAfter washing with EtOAc (2×500 mL)
  10. customthe solids were dried

Sources & evidence

ORD record
ord-e4916476a4fe4c55830e15676c3a2697
Source dataset
uspto-grants-2015_02
Patent number
US08962596B2

Reaction notes

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