반응 #166375

반응 방정식

NH4Cl

butyllithium

acetonitrile dry ice

2,2,6,6-tetramethylpiperidine

3,6-dimethoxypyridazine

compound 243

N4-Cyclopentyl-5-iodo-2,4-pyrimidinediamine

→

compound 316

수율 66.5%

N4-Cyclopentyl-5-(3,6-dimethoxy-4-pyridazinyl)-2,4-pyrimidinediamine

수율 66.5%

용매

THF

THF

THF

반응 조건

후처리

1. 1
   기타to stand at 0° C.
2. 2
   기타for 30 min
3. 3
   workup.ADDITIONwas added through a cannula over a period of 30 min
4. 4
   기타was observed fluctuating between −72° C. and -55° C
5. 5
   기타fluctuated between −73° C. and −64° C
6. 6
   기타The cold bath was removed
7. 7
   온도to warm up to rt (20.5° C.)
8. 8
   온도the resulting mixture was heated
9. 9
   온도at reflux for 18 h
10. 10
    추출extracted with ethyl acetate (2×)
11. 11
    건조dried over Na2SO4
12. 12
    농축concentrated in vacuo

실험 절차

A solution of butyllithium (2.5 m solution in hexanes) (7.5 mL, 19 mmol) was added to cold (acetonitrile-dry ice bath, -34° C. internal), stirred 2,2,6,6-tetramethylpiperidine (3.4 mL, 20 mmol). The resulting mixture was allowed to stand at 0° C. (ice-H2O bath) for 30 min. The ice-H2O was then replaced with dry ice-2-propanol bath and the mixture was cooled to −0° C. THF (24 mL) was added. A pre-cooled (ice-H2O bath) solution of 3,6-dimethoxypyridazine (2.40 g, 17 mmol) in THF (40 mL) was added through a cannula over a period of 30 min. The internal temperature was observed fluctuating between −72° C. and -55° C. The resulting mixture was stirred at −70° C. for 1.5 h. A solution of zinc(II) chloride (0.5 M in THF) (34 mL, 17 mmol) was added through a syringe over a period of 15 min. The internal temperature fluctuated between −73° C. and −64° C. The cold bath was removed and the resulting mixture was allowed to warm up to rt (20.5° C.). A solution of compound 243 (1.7 g, 5.7 mmol) and tetrakis(triphenylphosphine)palladium (0.33 g, 0.29 mmol) in THF (20 mL) was added and the resulting mixture was heated at reflux for 18 h. Upon workup, the crude mixture was cooled in an ice-H2O before poured into ice and saturated NH4Cl aqueous solution and extracted with ethyl acetate (2×). The combined organics were combined, dried over Na2SO4, and concentrated in vacuo. The residue was subjected to combi-flash column chromatography (methanol/DCM with Et3N) to give pure compound 316 (1.2 g, 66% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.53 (1 H, s), 7.01 (1 H, s), 6.18-6.38 (3 H, m), 4.35-4.51 (1 H, m, J=7.3, 7.3, 7.3, 7.3, 7.0 Hz), 3.95 (3 H, s), 3.91 (3 H, s), 1.77-1.90 (2 H, m), 1.55-1.69 (2 H, m), 1.35-1.55 (4 H, m). LCMS-ESI (POS), M/Z, M+1: Found 317.2.

출처