Baclofen Powder CAS 1134-47-0

105g (0.75mol) of para-chlorobenzaldehyde, 400ml of deionized water, 137g (1.05mol) of ethyl acetoacetate, stirred at 15~20 ℃, slowly dropped 13.2g (0.1 mol) of diammonium hydrogen phosphate in 132ml of aqueous solution, and after dripping, stirred for 5h with heat preservation, filtered, washed the solid with proper amount of water, dried for 4h at 45~55 ℃ to obtain white solid intermediate II, which is directly used in the next step.

420ml (30N) of aqueous solution of intermediate II and potassium hydroxide is stirred for hydrolysis reaction at 85~90 ℃ for 2h, and the end point of thin-layer identification reaction (developing agent: ethyl acetate-petroleum ether=2:3) is identified. After the reaction is completed, it is cooled to room temperature. 400ml of dichloromethane and 500ml of deionized water are added, stirred for 20min, and then placed for layering. The organic layer is discarded for recycling. The pH of the water layer is adjusted to 1~2 with 6M hydrochloric acid, and then placed for filtration. The solid is washed with appropriate amount of water, 157g of white solid intermediate III was obtained by drying under vacuum at 55-60 ℃ for 5h, with yield of 86.4%, mp: 166.5~167.3 ℃,

1H-NMR(500MHz,CDCl3/TMS,ppm)： δ 12.09 (s, 1H), 7.27～7.48 (m, 4H), 3.31～3.54 (m, 1H), 2.47～2.74(m, 4H).

150g (0.618mol) of intermediate III and 44.6g (0.742mol) of urea were stirred at 130~140 ℃ for 11h, and the end point of the reaction was identified by TLC (developing agent: ethyl acetate - methanol=5:3). After the reaction, the reaction was completed, cooled to room temperature, solidified, the solid was washed with proper amount of water, toluene recrystallized, and dried at 55~60 ℃ for 5h under vacuum, 130g of white solid intermediate III was obtained, with a yield of 94.2%, mp: 160.1~161.2 ℃, 1H-NMR (500MHz, CDCl3/TMS, ppm): δ 6.41(s, 1H), 7.23～7.45(m, 4H), 3.24～3.45 (m, 1H), 2.30～2.49(m, 4H) .

120g (0.537mol) of intermediate IV and 600ml (15N) of sodium hydroxide aqueous solution are stirred for hydrolysis reaction at 65~70 ℃ for 1.5h, and the end point of thin-layer identification reaction (developing agent: ethyl acetate-methanol=3:1) is identified. After the reaction is completed, the reaction is cooled to room temperature, 500ml of toluene and 700ml of deionized water are added, stirred for 20min, and then placed for layering. The organic layer is discarded for recycling, and the pH of the water layer is adjusted to 2~3 with concentrated hydrochloric acid, then placed for filtration, and the solid is washed with proper amount of water, Dry for 5h under vacuum 55~60 ℃ to obtain 116g of white solid intermediate V, yield 89.5%, mp: 170.0~170.9 ℃, 1H-NMR (500MHz, CDCl3/TMS, ppm): δ 6.03 (s, 2H), 7.46～7.66 (m, 4H), 3.31～3.52 (m, 1H), 2.51～2.65(m, 4H).

The intermediate V 110g (0.455mol), 3.6g (0.03mol) of sodium sulfamate and 60ml (9%~12%) of freshly prepared sodium hypobromate solution are stirred for 1.5h at - 5~0 ℃, slowly heated to 20~30 ° C and stirred for 20min, then heated again to 50~55 ° C, kept at this temperature and stirred for 20min, and the end point of thin-layer identification reaction (developing agent: n-butanol - glacial acetic acid - water (4:1:1), after the reaction is completed, cooled to room temperature, and the pH is adjusted to 6~7 with concentrated hydrochloric acid, After standing for 5h, centrifugation, recrystallization of the crude product with isopropanol-water (1:4), drying for 6h under vacuum at 55-60 ℃, 77.2g of white solid baclofen conforming to clinical use was obtained, Baclofen powder with a yield of 79.4%, mp: 206.1~207.4 ℃, HPLC content of 99.6%, 1H-NMR (500MHz, CDCl3/TMS, ppm): δ： 8.56 (s,1H, CO2H),7.37～7.24(m,4H),3.32-3.28 (m,1H),3.26 (dd,J=15.8, 7.5Hz,1H),3.1/5 (dd, J=15.8,12Hz,1H),2.66 (dd, J=12.8,8.3Hz,1H),2.55 (dd,J=12.8,9Hz,1H),MS：m/z (M+)214.