Binap, (A+-)- → (1-(2-(1-(5-Propylpyrimidin-2-yl)piperidin-4-yloxy)benzo[d]thiazol-6-yl)piperidin-4-yl)(pyrrolidin-1-yl)methanone

HRID 1429572Notes

Reaction equation

HRID 1429572 reaction equation
Br[C:2]1[CH:26]=[CH:25][C:5]2[N:6]=[C:7]([O:9][CH:10]3[CH2:15][CH2:14][N:13]([C:16]4[N:21]=[CH:20][C:19]([CH2:22][CH2:23][CH3:24])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)[S:8][C:4]=2[CH:3]=1.[N+]([O-])(O)=O.[NH:31]1[CH2:36][CH2:35][CH:34]([C:37]([N:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)=[O:38])[CH2:33][CH2:32]1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:22]([C:19]1[CH:18]=[N:17][C:16]([N:13]2[CH2:14][CH2:15][CH:10]([O:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([N:31]5[CH2:32][CH2:33][CH:34]([C:37]([N:39]6[CH2:43][CH2:42][CH2:41][CH2:40]6)=[O:38])[CH2:35][CH2:36]5)[CH:26]=[CH:25][C:5]=4[N:6]=3)[CH2:11][CH2:12]2)=[N:21][CH:20]=1)[CH2:23][CH3:24]

Participants

8

Reactant 4

HCID 634876Binap, (A+-)-HCID 23676156Sodium t-butoxideHCID 455957924-(1-Pyrrolidinylcarbonyl)piperidine nitrateHCID 674627936-Bromo-2-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)benzo[d]thiazole

Product 1

HCID 54596883(1-(2-(1-(5-Propylpyrimidin-2-yl)piperidin-4-yloxy)benzo[d]thiazol-6-yl)piperidin-4-yl)(pyrrolidin-1-yl)methanoneYield 13.2%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 1140TolueneSolvent

Conditions

Temperature
80 °C

Procedure

To a degassed solution of 6-bromo-2-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)benzo[d]thiazole (35 mg, 0.081 mmol), piperidin-4-yl(pyrrolidin-1-yl)methanone nitrate salt (39.5 mg, 0.162 mmol), sodium tert-butoxide (31.0 mg, 0.323 mmol), and BINAP (1.0 mg, 1.61 mmol) in toluene (1 mL) was added Pd2(dba)3 (4.5 mg, 5 mmol). The reaction mixture was stirred at 80° C. overnight. The reaction mixture was cooled to rt, diluted with water (3 mL), and extracted with EtOAc (3×4 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The crude product was purified by column chromatography (silica gel, CH2Cl2-EtOAc gradient 0 to 100% EtOAc) to afford (1-(2-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)benzo[d]thiazol-6-yl)piperidin-4-yl)(pyrrolidin-1-yl)methanone (6 mg, 10.66 μmol, 13% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.19 (d, J=2.2 Hz, 2H), 7.57 (dd, J=8.9, 2.3 Hz, 1H), 7.23-7.18 (m, 1H), 7.09-7.03 (m, 1H), 5.47-5.37 (m, 1H), 4.28-4.18 (m, 2H), 3.78-3.62 (m, 4H), 3.58-3.48 (m, 4H), 2.77 (t, J=12.1 Hz, 2H), 2.55-2.46 (m, 1H), 2.45-2.40 (m, 2H), 2.24-2.14 (m, 2H), 2.12-1.82 (m, 10H), 1.64-1.58 (m, 2H), 0.97 (td, J=7.3, 2.5 Hz, 3H). LCMS (m/z)=535 (M+H)+.

Workup

  1. temperatureThe reaction mixture was cooled to rt
  2. extractionextracted with EtOAc (3×4 mL)
  3. dry with materialThe combined organic layers were dried (Na2SO4)
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe crude product was purified by column chromatography (silica gel, CH2Cl2-EtOAc gradient 0 to 100% EtOAc)

Sources & evidence

ORD record
ord-7baf44de2dad4acaab3f5a8f06ce0ddf
Source dataset
uspto-grants-2015_01
Patent number
US08940716B2

Reaction notes

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