1,2-Dimethoxyethane → 3-benzothiazol-2-yl-5-[1-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazol-4-yl]-pyridin-2-ylamine

HRID 1926334Notes

Reaction equation

[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:25])=[N:12][CH:13]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:15]=1.I[C:27]1[CH:28]=[N:29][N:30]([CH:32]2[CH2:38][CH:37]3[N:39]([CH3:40])[CH:34]([CH2:35][CH2:36]3)[CH2:33]2)[CH:31]=1.C([O-])([O-])=O.[K+].[K+].COCCOC>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:25])=[N:12][CH:13]=[C:14]([C:27]2[CH:28]=[N:29][N:30]([CH:32]3[CH2:33][CH:34]4[N:39]([CH3:40])[CH:37]([CH2:36][CH2:35]4)[CH2:38]3)[CH:31]=2)[CH:15]=1

Participants

Conditions

Temperature: 80 °C

Procedure

A suspension of 3-benzothiazol-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-ylamine (BB8) (95.6 mg, 0.271 mmol, 1.2 eq), 3-(4-iodopyrazol-1-yl)-8-methyl-8-azabicyclo[3.2.1]octane (69.1 mg, 0.218 mmol, 1.0 eq), (1,1′-bis-(diphenylphosphino)-ferrocene) palladium dichloride (16.0 mg, 0.0219 mmol, 10 mol %), and K2CO3 (92.0 mg, 0.666 mmol, 3 eq) in a 4:1 ratio of DME to H2O (2.5 mL) was evacuated and charged with nitrogen several times, after which the sample was heated in the microwave reactor to 80° C. for 30 min. The reaction mixture was partitioned between EtOAc and water and the layers were separated. The aqueous layer was back extracted with EtOAc (3×) and the combined organic layers were washed with water (1×) and brine (1×), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to dryness. The emulsion that had formed was collected separately and extracted with CH2Cl2 (2×), washed with brine (1×), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. All organics were combined. The crude material was adsorbed onto silica gel and purified by column chromatography on silica gel [10″×0.5″ column, eluting with neat EtOAc→7N NH3(MeOH):EtOAc 2%→3%→5%]. Fractions containing product were pooled and concentrated in vacuo. The product was recrystallized from neat acetonitrile [heated until boiling, cooled to −20° C. for 16 h], giving the title material as a yellow solid. 1H NMR (400 MHz, CDCl3): δ=1.72-1.79 (m, 2H), 2.05 (ddd, J=13.1, 5.8, 3.3 Hz, 2H), 2.13-2.25 (m, 4H), 2.40 (s, 3H), 3.29-3.40 (m, 2H), 4.49-4.63 (m, 1H), 7.12 (br s, 2H), 7.39-7.44 (m, 1H), 7.50 (ddd, J=8.2, 7.2, 1.3 Hz, 1H), 7.71 (s, 1H), 7.72 (s, 1H), 7.92 (dd, J=7.9, 0.6 Hz, 1H), 7.99 (d, J=2.0 Hz, 1H), 8.02 (dd, J=8.1, 0.5 Hz, 1H), 8.32 (d, J=2.0 Hz, 1H). MS (ES+): m/z=417.13 (24) [MH+]. HPLC: tR=2.12 min (ZQ2, polar—5 min).

Workup

customwas evacuated
additioncharged with nitrogen several times
customThe reaction mixture was partitioned between EtOAc and water
customthe layers were separated
extractionThe aqueous layer was back extracted with EtOAc (3×)
washthe combined organic layers were washed with water (1×) and brine (1×)
dry with materialdried over anhydrous Na2SO4
filtrationfiltered
concentrationconcentrated in vacuo to dryness
customThe emulsion that had formed
customwas collected separately
extractionextracted with CH2Cl2 (2×)
washwashed with brine (1×)
dry with materialdried over anhydrous Na2SO4
filtrationfiltered
concentrationconcentrated in vacuo
custompurified by column chromatography on silica gel [10″×0.5″ column
washeluting with neat EtOAc→7N NH3(MeOH)
additionFractions containing product
concentrationconcentrated in vacuo
customThe product was recrystallized from neat acetonitrile [heated until boiling, cooled to −20° C. for 16 h]

Sources & evidence

ORD record: ord-71f63e3c02f44cccb938ea02de1cdba5
Source dataset: uspto-grants-2012_05
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08178668B2

Reaction notes

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