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鏂伴椈鍔ㄦ?

澶氬悏缇? 绱㈡媺闈炲凹鐨勫寲瀛﹀悎鎴
2015-05-10 07:05:54

(brand name :Nexavar®, other name BAY 43-9006, Chinese name: 澶氬悏缇? 绱㈡媺闈炲凹, 钑捐帋鐡? wasapproved by US FDA for the treatment of kidney cancer in 2005 and advanced liver cancer in 2007.

Chemical Synthesis of  Sorafenib Tosylate (Nexavar)  澶氬悏缇? 绱㈡媺闈炲凹鐨勫寲瀛﹀悎鎴怽

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

References 鍙傝?鏂囩尞

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)鏂藉嚡缈?鍒樻竻缁?璋㈠辜瀹?绱㈡媺闈炲凹鐨勫埗澶囨柟娉? 鍙戞槑涓撳埄鐢宠? 鍏?紑鍙稢N102311384, 鐢宠?鍙稢N201010212039
5)璧典箻鏈?闄堟灄鎹?璁哥叇,缃楁檽鐕?鍐?簹椋? 瀵圭敳鑻?:閰哥储鎷夐潪灏肩殑鍚堟垚,涓?浗鍖昏嵂宸ヤ笟鏉傚織, 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.

澶氬悏缇? 绱㈡媺闈炲凹鍙婂叾鐢插熀纾洪吀鐩愮殑鍒跺?鏂规硶

鎽樿?:4-锛?-姘ㄥ熀鑻?哀鍩猴級-2-锛堢敳鍩烘皑鐢查叞鍩猴級鍚″暥,涓?-姘?3-锛堜笁姘熺敳鍩猴級鑻?紓姘伴吀閰?缉鍚堛?鍐嶆垚鐩愬緱瀵圭敳鑻?:閰哥储鎷夐潪灏?/p>

鍖栧悎鐗?-(4- 姘ㄥ熀鑻?哀鍩?-N- 鐢插熀鍚″暥-2- 鐢查叞鑳虹殑鍒跺?鏂规硶

绉板彇鍖栧悎鐗?4-姘?-N-鐢插熀 -2-鍚″暥鐢查叞鑳?(4-chloro-N-methyl-2-pyridine carboxamide锛?鍏嬶紝11.72mmol)銆?-鑳哄熀閰?(4-Aminophenol锛?鍏嬶紝18.33mmol)鍙婂彅涓侀唶閽?potassium-t-butoxide锛?.7鍏嬶紝24.06mmol)缃?簬 100姣?崌鍗曢?鐡朵腑锛屽湪瀹ゆ俯涓嬮?姘?皵锛屽姞鍏?15姣?崌 N锛孨-浜岀敳鍩虹敳閰拌兒 (DMF)绉昏嚦 90鈩冧笅鍔犵儹鍙嶅簲 2灏忔椂銆傜?娓╋紝鍔犲叆 65姣?崌鐨勬按锛屽苟浠ヤ箼閰镐箼閰?(20姣?崌 x2)钀冨彇锛屽悎骞舵湁鏈哄眰浠ラケ鍜屾隘鍖栭挔娓呮礂锛屽彇鏈夋満灞傚姞鍏?2鍏嬫棤姘寸~閰搁晛 (MgSO4)骞茬嚗锛岃繃婊わ紝婊ゆ恫娴撶缉锛屽共鐕ワ紝寰?2.69鍏嬫繁瑜愯壊娑蹭綋鍖栧悎鐗?-(4- 姘ㄥ熀鑻?哀鍩?-N- 鐢插熀鍚″暥-2- 鐢查叞鑳恒?

鍖栧悎鐗?4-(4- 姘ㄥ熀鑻?哀鍩?-N- 鐢插熀鍚″暥-2- 鐢查叞鑳虹洂閰哥洂鐨勫埗澶囨柟娉? 

绉板彇鍖栧悎鐗?4-姘?-N-鐢插熀 -2-鍚″暥鐢查叞鑳?(18.8鍏嬶紝110.02mmol)銆?-鑳哄熀閰?18.8鍏嬶紝172.27mmol)鍙婂彅涓侀唶閽?(25.35鍏嬶紝225.91mmol)缃?簬 1鍗囧崟棰堢摱涓?紝鍦ㄥ?娓╀笅閫氭爱姘?(N2)锛屽姞鍏?141DMF绉昏嚦 90鈩冧笅鍔犵儹鍙嶅簲 2灏忔椂銆傜?娓╋紝闄嶈嚦 30鈩冿紝鍦ㄦ爱姘斾笅鍔犲叆 176姣?崌宸ヤ笟绾т笝閰?紝绉昏嚦 5鈩冧笅婊村叆 10姣?崌娴撶洂閰革紝杩囨护锛屽浐浣撳啀浠ュ伐涓氱骇涓欓叜娓呮礂锛岃繃婊わ紝骞茬嚗寰?30鍏嬫贰瑜愯壊鍥轰綋鍖栧悎鐗?4-(4- 姘ㄥ熀鑻?哀鍩?-N- 鐢插熀鍚″暥-2- 鐢查叞鑳虹洂閰哥洂銆?/p>

1H-NMR(DMSO)锛?.78(d锛孞锛?.7Hz锛?H)锛?.22(m锛?H)锛?.39(dd锛孞锛?.0Hz锛?.8Hz锛?H)锛?7.50(d锛孞锛?2.4Hz锛?H)锛?.57(dd锛孞锛?2.0Hz锛?.8Hz锛?H)锛?8.56(d锛孞锛?5.6Hz锛?H)锛?.95(br d锛?H)銆?/p>

绱㈡媺闈炲凹纰辩殑鍒跺?鏂规硶

绉板彇鍖栧悎鐗?-(4- 姘ㄥ熀鑻?哀鍩?-N- 鐢插熀鍚″暥-2- 鐢查叞鑳虹洂閰哥洂 (3.2鍏嬶紝11.72mmol)鍙?4-姘?-3-涓夋盁鐢插熀鑻?熀寮傛鞍閰搁叝 (4-chloro-3-trifluoromethylphenyl isocyanate锛?.60鍏嬶紝11.71mmol)锛岀疆浜?250姣?崌鍗曢?鐡朵腑锛屽湪瀹ゆ俯涓嬮?姘?皵锛屽姞鍏?70姣?崌涔欓吀涔欓叝鍙婃?鍗囦笁涔欒兒锛屽姞鐑?洖娴佸弽搴?5灏忔椂銆傜?娓╋紝鍐峰嵈骞剁疆浜?5鈩冧笅鍔犲叆 70姣?崌鐨勬按缁堟?鍙嶅簲锛屽苟浠ヤ箼閰镐箼閰?(100姣?崌 x2)钀冨彇锛屽悎骞舵湁鏈哄眰浠ラケ鍜屾隘鍖栭挔 (65姣?崌 x2)娓呮礂锛屽彇鏈夋満灞傚姞鍏?3.28鍏嬫棤姘寸~閰搁晛骞茬嚗锛岃繃婊わ紝婊ゆ恫娴撶缉锛屽共鐕?16灏忔椂锛屽緱 3.80鍏嬫贰榛勮?鑹插浐浣撶储鎷夐潪灏肩⒈銆?/p>

绱㈡媺闈炲凹鐢插熀纾洪吀鐩愮殑鍚堟垚鍙嶅簲

绉板彇绱㈡媺闈炲凹纰?(3.57鍏嬶紝7.68mmol)缃?簬 500姣?崌鍗曢?鐡朵腑锛屽湪瀹ゆ俯涓嬮?姘?皵锛屽姞鍏?125姣?崌鐢查唶鍔犵儹鍥炴祦鑷冲叏婧?(榛勮?鑹叉緞娓呮恫 )锛屾淮鍏ュ?鐢插熀鑻?:閰?(p-toluene sulfonic acid锛?.46鍏嬶紝7.68mmol)鍦?15姣?崌鐢查唶涓?紝鍦?70鈩冧笅鍔犵儹鍥炴祦鍙嶅簲 1灏忔椂銆傜?娓╋紝鍐峰嵈骞剁疆浜庡?娓╀笅閫氭爱姘旀悈鎷?16灏忔椂锛岃繃婊わ紝鍥轰綋鍐嶄互涔欓吀涔欓叝 (20姣?崌 )娓呮礂锛岃繃婊わ紝鍥轰綋骞茬嚗 (70鈩?)16灏忔椂锛屽緱 3.9鍏嬫贰鑲よ壊鍥轰綋绱㈡媺闈炲凹绛夌洂绫汇?

1H-NMR(DMSO-d6)锛?.28(s锛?H)锛?.81(d锛孞锛?.7Hz锛?H)锛?.13(d锛孞锛?.4Hz锛?H)锛?7.18(d锛孞锛?.0Hz锛?H)锛?.25(m锛?H)锛?.52(d锛孞锛?.1Hz锛?H), 7.60(d锛孞锛?.1Hz锛?H)锛?.59-7.68(m锛?H)锛?.12(d锛孞锛?.5Hz锛?H)锛?.56(d锛孞锛?.0Hz锛?H)锛?9.00(br d锛?H)锛?.22(s锛?H)锛?.41(s锛?H)銆?/p>

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