1-Methylpiperazine → HCID 89815457, compound

HRID 2172321Notes

Reaction equation

HRID 2172321 reaction equation
[CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1F.CC1(C)C(C)(C)OB([C:28]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:29]=2[CH2:30][CH2:31][N:32]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:33]3)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.O1CCOCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:10]2[CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=[CH:14][C:9]=2[C:28]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:29]=2[CH2:30][CH2:31][N:32]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:33]3)[CH2:4][CH2:3]1

Participants

7

Reactant 4

HCID 531671-MethylpiperazineHCID 62657Potassium Phosphate, TribasicHCID 1424144-Bromo-3-fluorobenzotrifluorideHCID 57505885tert-Butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

Product 1

HCID 89815457HCID 89815457, compoundYield 42.9%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 312751,4-DioxaneSolvent

Conditions

Temperature
180 °C

Procedure

A microwave vial charged with 1-methylpiperazine (2.74 ml, 24.69 mmol) and 1-bromo-2-fluoro-4-(trifluoromethyl)benzene (2.000 g, 8.23 mmol) was heated to 180° C. in a microwave reactor for 90 minutes. The reaction mixture was concentrated then transferred to a vial charged with Cl2Pd(AmPhos) (Sigma-Aldrich, St. Louis, Mo., 0.291 g, 0.412 mmol), tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (ASW Medchem, Brunswick, N.J., 2.96 g, 8.23 mmol), and potassium phosphate (8.74 g, 41.2 mmol). 8 mL dioxane and 4 mL water were added, and the reaction mixture was heated to 120° C. for 2 hours. After cooling to rt, the reaction mixture was poured into water and extracted with DCM. The organics were concentrated then purified by reverse phase column chromatography [RediSep Gold C18 150 g, 15 to 100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] yielding tert-butyl 5-(2-(4-methylpiperazin-1-yl)-4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.68 g, 3.53 mmol).

Workup

  1. concentrationThe reaction mixture was concentrated
  2. temperaturethe reaction mixture was heated to 120° C. for 2 hours
  3. temperatureAfter cooling to rt
  4. extractionextracted with DCM
  5. concentrationThe organics were concentrated
  6. customthen purified by reverse phase column chromatography [RediSep Gold C18 150 g, 15 to 100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)]

Sources & evidence

ORD record
ord-b785e95a0f6543549103e9f444c7d41c
Source dataset
uspto-grants-2015_06
Patent number
US09051311B2

Reaction notes

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