反応 #41032

反応方程式

Water

(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane

1-(3-chloropropyl)-5-cyclopropyl-2,4(1H,3H)-pyrimidinedione

→

title compound

5-cyclopropyl-1-(3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo-[3.1.0]hex-3-yl}propyl)-2,4(1H,3H)-pyrimidinedione hydrochloride

溶媒

DMF

反応条件

後処理

1. 1
   その他prepared
2. 2
   抽出the solution was extracted with dichloromethane
3. 3
   乾燥The organic phase was dried over Na2SO4
4. 4
   濃縮concentrated in vacuo
5. 5
   その他The crude product was purified by preparative HPLC (column: XTerra Prep MS C18 30×150 mm, 10 uM; mobile phase A: H2O+0.1% formic acid, mobile phase B: acetonitrile+0.1% formic acid, gradient: from 1 to 25% (B) in 10 min, from 25 to 90% in 4.50 min, from 90 to 100% in 0.50 min; flow rate: 40 mL/min; UV wavelength range: 210-400 nm, ionization: ES+ and ES−; mass range: 150-900 amu (ES+))
6. 6
   その他The product thus obtained
7. 7
   洗浄eluted with methanol

実験手順

A mixture of (1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (Prep4, 35 mg, prepared following a similar procedure to that reported in WO 2005080382), 1-(3-chloropropyl)-5-cyclopropyl-2,4(1H,3H)-pyrimidinedione (Prep16, 46 mg) and TEA (0.042 mL) in DMF (0.5 mL) was heated at 100° C. for 24 hours. Water was then added and the solution was extracted with dichloromethane. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by preparative HPLC (column: XTerra Prep MS C18 30×150 mm, 10 uM; mobile phase A: H2O+0.1% formic acid, mobile phase B: acetonitrile+0.1% formic acid, gradient: from 1 to 25% (B) in 10 min, from 25 to 90% in 4.50 min, from 90 to 100% in 0.50 min; flow rate: 40 mL/min; UV wavelength range: 210-400 nm, ionization: ES+ and ES−; mass range: 150-900 amu (ES+)). The product thus obtained was loaded over a SCX cartridge and eluted with methanol to give 54 mg of the formiate of the title compound. To a solution of this material in dichloromethane (1 mL) HCl (1M in Et20, 1 eq) was added, the solvent was evaporated in vacuo and the material thus obtained triturated with Et2O to give 41 mg of the title compound as a white slightly hygroscopic solid.

出典