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多吉美, 索拉非尼的化学合成
2015-05-10 07:05:54

(brand name :Nexavar®, other name BAY 43-9006, Chinese name: 多吉美, 索拉非尼, 蕾莎瓦) wasapproved by US FDA for the treatment of kidney cancer in 2005 and advanced liver cancer in 2007.

Chemical Synthesis of  Sorafenib Tosylate (Nexavar)  多吉美, 索拉非尼的化学合成

US Patent US7235576, WO2006034796, WO2009111061 and Faming Zhuanli Shenqing(CN102311384) disclosed processes for preparation of sorafenib base and its salt sorafenib tosylate.

References 参考文献

1)Bernd Riedl, Jacques Dumas, Uday Khire, Timothy B. Lowinger, William J. Scott, Roger A. Smith, Jill E. Wood, Mary-Katherine Monahan, Reina Natero, Joel Renick, Robert N. Sibley; Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors; US patent number US7235576
2)Rossetto, pierluigi; Macdonald, peter, lindsay; Canavesi, augusto; Process for preparation of sorafenib and intermediates thereof, PCT Int. Appl., WO2009111061
3)Lögers, michael; gehring, reinhold; kuhn, oliver; matthäus, mike; mohrs, klaus; müller-gliemann, matthias; stiehl, jürgen; berwe, mathias; lenz, jana; heilmann, werner; Process for the preparation of 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-n-methylpyridine-2-carboxamide, PCT Int. Appl.,WO2006034796
4)施凯翔,刘清维,谢幼容,索拉非尼的制备方法, 发明专利申请 公开号CN102311384, 申请号CN201010212039
5)赵乘有,陈林捷,许煦,罗晓燕,冀亚飞; 对甲苯磺酸索拉非尼的合成,中国医药工业杂志, 2007(9): 614-616

Full Experimental Details for the preparation of Sorafenib Tosylate (Nexavar) 

Synthesis of 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline.

A solution of 4-aminophenol (9.60 g, 88.0 mmol) in anh. DMF (150 mL) was treated with potassium tert-butoxide (10.29 g, 91.7 mmol), and the reddish-brown mixture was stirred at room temp. for 2 h. The contents were treated with 4-chloro- N -methyl-2-pyridinecarboxamide (15.0 g, 87.9mmol) and K2CO3 (6.50 g, 47.0 mmol) and then heated at 80°C. for 8 h. The mixture was cooled to room temp. and separated between EtOAc (500 mL) and a saturated NaCl solution (500 mL). The aqueous phase was back-extracted with EtOAc (300 mL). The combined organic layers were washed with a saturated NaCl solution (4×1000 mL), dried (Na2SO4) and concentrated under reduced pressure. The resulting solids were dried under reduced pressure at 35°C. for 3 h to afford 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline as a light-brown solid 17.9 g, 84%):. 1H-NMR (DMSO-d6) δ 2.77 (d, J = 4.8 Hz, 3H), 5.17 (br s, 2H), 6.64, 6.86 (AA’BB’ quartet, J = 8.4 Hz, 4H), 7.06 (dd, J = 5.5, 2.5 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H), 8.44 (d, J = 5.5 Hz; 1H), 8.73 (br d, 1H); HPLC ES-MS m/z 244 ((M+H)+).

Synthesis of 4-{4-[({[4-Chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-methylpyridine-2-carboxamide (sorafenib)

4-(4-Aminophenoxy)-N-methyl-2-pyridinecarboxamide (52.3 kg, 215 mol) is suspended in ethyl acetate (146 kg) and the suspension is heated to approx. 40° C. 4-Chloro-3-trifluoromethylphenyl isocyanate (50 kg, 226 mol), dissolved in ethyl acetate (58 kg), is then added to such a degree that the temperature is kept below 60° C. After cooling to 20° C. within 1 h, the mixture is stirred for a further 30 min and the product is filtered off. After washing with ethyl acetate (30 kg), the product is dried under reduced pressure (50° C., 80 mbar). 93 kg (93% of theory) of the title compound are obtained as colorless to slightly brownish crystals. m.p. 206-208° C. 1H-NMR (DMSO-d6, 500 MHz): δ =2.79 (d, J=4.4 Hz, 3H, NCH3); 7.16 (dd, J=2.5, 5.6 Hz, 1H, 5-H); 7.18 (d, J=8.8 Hz, 2H, 3′-H, 5′-H); 7.38 (d, J=2.4 Hz, 1H, 3-H); 7.60-7.68 (m, 4H, 2′-H, 6′-H, 5″-H, 6″-H); 8.13 (d, J=1.9 Hz, 1H, 2″-H); 8.51 (d, J=5.6 Hz, 1H, 6-H); 8.81 (d, J=4.5 Hz, 1H, NHCH3); 9.05 (br. s, 1H, NHCO); 9.25 (br. s, 1H, NHCO) MS (ESI, CH3CN/H2O): m/e=465 [M+H]+.

Synthesis of Sorafenib Tosylate (Nexavar)

4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N2-methylpyridine-2-carboxamide (sorafenib) (50g, 0.1076 mol) is suspended in ethyl acetate (500 g) and water (10g). The mixture is heated to 69°C within 0.5 h, and a filtered solution of p-toluenesulfonic acid monohydrate (3.26 g, 0.017 mol) in a mixture of water (0.65 g) and ethyl acetate (7.2 g) is added. After filtration a filtered solution of p-toluenesulfonic acid monohydrate (22g, 0.11 mol) in a mixture of ethyl acetate (48 g) and water (4.34 g) is added. The mixture is cooled to 23°C within 2 h. The product is filtered off, washed twice with ethyl acetate (92.5 g each time) and dried under reduced pressure. The sorafenib tosylate (65.5 g, 96% of theory) is obtained as colorless to slightly brownish crystals.

多吉美, 索拉非尼及其甲基磺酸盐的制备方法

摘要:4-(4-氨基苯氧基)-2-(甲基氨甲酰基)吡啶,与4-氯-3-(三氟甲基)苯异氰酸酯缩合、再成盐得对甲苯磺酸索拉非尼

化合物4-(4- 氨基苯氧基)-N- 甲基吡啶-2- 甲酰胺的制备方法

称取化合物 4-氯 -N-甲基 -2-吡啶甲酰胺 (4-chloro-N-methyl-2-pyridine carboxamide,2克,11.72mmol)、4-胺基酚 (4-Aminophenol,2克,18.33mmol)及叔丁醇钾(potassium-t-butoxide,2.7克,24.06mmol)置于 100毫升单颈瓶中,在室温下通氮气,加入 15毫升 N,N-二甲基甲酰胺 (DMF)移至 90℃下加热反应 2小时。离温,加入 65毫升的水,并以乙酸乙酯 (20毫升 x2)萃取,合并有机层以饱和氯化钠清洗,取有机层加入 2克无水硫酸镁 (MgSO4)干燥,过滤,滤液浓缩,干燥,得 2.69克深褐色液体化合物4-(4- 氨基苯氧基)-N- 甲基吡啶-2- 甲酰胺。

化合物 4-(4- 氨基苯氧基)-N- 甲基吡啶-2- 甲酰胺盐酸盐的制备方法  

称取化合物 4-氯 -N-甲基 -2-吡啶甲酰胺 (18.8克,110.02mmol)、4-胺基酚(18.8克,172.27mmol)及叔丁醇钾 (25.35克,225.91mmol)置于 1升单颈瓶中,在室温下通氮气 (N2),加入 141DMF移至 90℃下加热反应 2小时。离温,降至 30℃,在氮气下加入 176毫升工业级丙酮,移至 5℃下滴入 10毫升浓盐酸,过滤,固体再以工业级丙酮清洗,过滤,干燥得 30克淡褐色固体化合物 4-(4- 氨基苯氧基)-N- 甲基吡啶-2- 甲酰胺盐酸盐。

1H-NMR(DMSO):2.78(d,J=4.7Hz,3H),7.22(m,1H),7.39(dd,J=2.0Hz,8.8Hz,2H), 7.50(d,J= 2.4Hz,2H),7.57(dd,J= 2.0Hz,8.8Hz,2H), 8.56(d,J= 5.6Hz,1H),8.95(br d,1H)。

索拉非尼碱的制备方法

称取化合物4-(4- 氨基苯氧基)-N- 甲基吡啶-2- 甲酰胺盐酸盐 (3.2克,11.72mmol)及 4-氯 -3-三氟甲基苯基异氰酸酯 (4-chloro-3-trifluoromethylphenyl isocyanate,2.60克,11.71mmol),置于 250毫升单颈瓶中,在室温下通氮气,加入 70毫升乙酸乙酯及毫升三乙胺,加热回流反应 5小时。离温,冷却并置于 5℃下加入 70毫升的水终止反应,并以乙酸乙酯 (100毫升 x2)萃取,合并有机层以饱和氯化钠 (65毫升 x2)清洗,取有机层加入 3.28克无水硫酸镁干燥,过滤,滤液浓缩,干燥 16小时,得 3.80克淡黄褐色固体索拉非尼碱。

索拉非尼甲基磺酸盐的合成反应

称取索拉非尼碱 (3.57克,7.68mmol)置于 500毫升单颈瓶中,在室温下通氮气,加入 125毫升甲醇加热回流至全溶 (黄褐色澄清液 ),滴入对甲基苯磺酸 (p-toluene sulfonic acid,1.46克,7.68mmol)在 15毫升甲醇中,在 70℃下加热回流反应 1小时。离温,冷却并置于室温下通氮气搅拌 16小时,过滤,固体再以乙酸乙酯 (20毫升 )清洗,过滤,固体干燥 (70℃ )16小时,得 3.9克淡肤色固体索拉非尼等盐类。

1H-NMR(DMSO-d6):2.28(s,3H),2.81(d,J=4.7Hz,3H),7.13(d,J=8.4Hz,2H), 7.18(d,J=9.0Hz,2H),7.25(m,1H),7.52(d,J=8.1Hz,2H), 7.60(d,J=8.1Hz,2H),7.59-7.68(m,3H),8.12(d,J=2.5Hz,1H),8.56(d,J=6.0Hz,1H), 9.00(br d,1H),9.22(s,1H),9.41(s,1H)。


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