反应详情

温度

5 °C

Add sodium hydride (0.172 g of 60% weight suspension in mineral oil; 2.59 mmol) to a solution of pyrazole (0.183 g; 2.69 mmol) in DMF (5 mL). Cool the mixture to 5° C., stir for 30 min., remove the cooling bath, warm to room temperature and stir for 30 min. Add 3′-(4-chloromethyl-phenyl)-4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl dihydrochloride (0.253 g; 0.540 mmol) in 6 mL of DMF and stir for 20 hr. at room temperature. Quench with a solution of 10% aq. acetic acid (9 mL), add methanol (minimal volume to achieve a homogeneous solution) and add to a 5 gm SCX column (Varian; pre-rinsed with MeOH). Elute the crude product with 2 M ammonia in methanol (18 mL) and concentrate. Purify via chromatography on silica gel eluting 0-10% methanol/dichlormethane to give 4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3′-(4-pyrazol-1-ylmethyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.140 g; 61%). MS (ES+) m/z: 429 (M+H)+. Purify by high pH reverse phase HPLC, and concentrate to give the pure free base. Dissolve the free base in acetonitrile and convert to the hydrochloride salt by adding 1 eq 2 M aq HCl solution. Add water and lyophilize to give the title compound as an off white powder (126 mg). MS (ES): m/z=429 [M+H]+.

1. customremove the cooling bath
2. temperaturewarm to room temperature
3. stirringstir for 30 min
4. customat room temperature
5. customQuench with a solution of 10% aq. acetic acid (9 mL)
6. additionadd methanol (minimal volume
7. additionadd to a 5 gm SCX column (Varian; pre-rinsed with MeOH)
8. washElute the crude product with 2 M ammonia in methanol (18 mL)
9. concentrationconcentrate
10. customPurify via chromatography on silica gel eluting 0-10% methanol/dichlormethane