반응 #2161267

반응 방정식

HOBt

EDCI

NMM

tert-butyl methyl(piperidin-4-yl)carbamate

[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetic acid

→

tert-butyl (1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)methylcarbamate

용매

DMA

반응 조건

후처리

1. 1
   기타the mixture sonicated to a solution
2. 2
   기타The volatiles were removed under high vacuum
3. 3
   기타the residue partitioned between EtOAc (300 mL) and water (100 mL)
4. 4
   기타The aqueous layer was removed
5. 5
   세척the organics washed with NaHCO3 (100 mL), water (100 mL), brine (100 mL)
6. 6
   건조dried over MgSO4
7. 7
   여과filtered

실험 절차

To a suspension of [5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetic acid (3.75 g, 12.06 mmol) in DMA (40 mL) at room temperature was added HOBt (1.79 g, 13.26 mmol), EDCI (2.54 g, 13.26 mmol), NMM (3.31 mL, 30.15 mmol) and tert-butyl methyl(piperidin-4-yl)carbamate (2.84 g, 13.26 mmol) and the mixture sonicated to a solution and stirred for 18 hours at room temperature. The volatiles were removed under high vacuum and the residue partitioned between EtOAc (300 mL) and water (100 mL). The aqueous layer was removed and the organics washed with NaHCO3 (100 mL), water (100 mL), brine (100 mL), dried over MgSO4, filtered and stripped to yield tert-butyl (1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)methylcarbamate as a white solid. This was then taken into DCM (40 mL) and TFA (40 mL) added with stirring and the resulting solution stirred at ambient temperature for 18 hours. The volatiles were removed under vacuum and the residue suspended in DCM (200 mL) and 2 M NaOH added (200 mL) with stirring. The bi phasic solution was then stirred for 15 minutes and the phases separated. The organic layer was dried over MgSO4, filtered and stripped to yield the crude product which was then purified by Biotage flash chromatography (45 M cartridge), eluting with a DCM/MeOH/NH4OH gradient to afford the title compound as a white solid, 4.6 g, 94%. 1H NMR (400 MHz, DMSO-D6) δ ppm 8.52 (d, 2 H), 7.66 (d, 2 H), 7.29 (t, 2 H), 7.15 (t, 2 H), 6.51 (s, 1 H), 5.16 (q, 2 H), 4.04 (d, 1 H), 3.95 (s, 2 H), 3.79 (d, 1 H), 3.07-3.17 (m, 1 H), 2.76-2.89 (m, 1 H), 2.27 (s, 3 H), 1.71-1.86 (m, 2 H), 1.59-1.65 (m, 1 H), 1.18-1.31 (m, 1 H), 1.03-1.14 (m, 1 H); m/z (APCI+) for C23H26N5OF 408.2 (M+H)+.

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