头孢丙烯的合成

1、中国医药工业杂志ChineseJournalofPharmaceuticals2004,35(7388肖涛1 ,张孝清2 ,曹芳3 ,田春梅3 ,王锦堂1(1.南京工业大学理学院应用化学系,江苏南京210009;2.南京医科大学基础医学院,江苏南京210029;3.南京华威医药科技开发有限公司,江苏南京210036摘要:以7-苯乙酰胺基-3-氯甲基-3-头孢烯-4-羧酸二苯甲酯为起始原料,经7-位酰胺基水解、在DCC作用下与侧链D-2-叔丁氧羰基氨基-2-(4-羟苯基乙酸缩合、3-位氯甲基置换为碘甲基后与三苯膦成内鎓盐,与乙醛进行Wittig反应在3-位形成丙烯基,最后在三氟乙酸作用下脱去7-

2、位侧链氨基和4-位羧基的保护基制得头孢丙烯,总收率16.4%。关键词:头孢丙烯;7-苯乙酰胺基-3-氯甲基-3-头孢烯-4-羧酸二苯甲酯;抗生素;合成中图分类号:R978.1+1文献标识码:A文章编号:1001-8255(200407-0388-03头孢丙烯的合成收稿日期:2003-03-24作者简介:肖涛(1968,男,讲师,博士研究生,专业方向:有机化学的教学,新药及中间体的研究开发。本品可以头孢母核为起始原料,3-位引入丙烯基、7-位脱保护基后引入侧链,最后水解制得17;也有文献8报道通过青霉素的衍生物丙二烯氮杂环丁酮与(Z -丙烯基有机铜试剂成头孢环,在3-位引入(Z -丙烯基后再引入

3、7-位侧链的方法。本文参考文献47,以7-苯乙酰胺基-3-氯甲基-3-头孢烯-4-羧酸二苯甲酯(GCLH ,2为原料,7-位酰胺基水解后,在DCC 作用下与侧链D-2-叔丁氧羰基氨基-2-(4-羟苯基乙酸(10缩合得4,用NaI 将3-位氯甲基置换为碘甲基后与三苯膦成内鎓盐6,6与乙醛进行Wittig 反应在3-位形成丙烯基,最后在三氟乙酸作用下脱去7-位侧链氨基和4-位羧基的保护基得1(图1,总收率16.4%。10的合成可参考文献9:以氯甲酸对硝基苯酯(8与叔丁醇酯化形成活性酯后,用以保护D-对羟基苯甘氨酸的氨基得到(图2,收率52%。实验部分RY-2型熔点仪,温度计未校正;Nicolet

4、170SX 型傅里叶红外光谱仪;Foss Heraeus 型元素分析仪;JMS-D300型质谱仪;Bruker AM-500MHz 型核磁共振仪。2(工业品,浙江永宁制药厂;8、D-对羟基苯甘氨酸(工业品,南京惠尔精细化学品有限公司;其它试剂均为分析纯。fffffffffffffffffffffffffffffffffffffffffSynthesis of BalofloxacinLIU Ming-Liang, LIU Bing-Quan, SUN Lan-Ying, GUO Hui-Yuan*(Institute of Medicinal Biotechnology, Chinese Ac

5、ademy of Medical Sciences, Peking Union Medical College, Beijing 100050A B S T R A C T :Balofloxacin was synthesized from ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylate after boron chelation followed by condensation with 3-methylaminopiperidine and then hydrolysi

6、s with an overall yield of 74.4%. The key intermediate 3-methylaminopiperidine was synthesized in 11.5% overall yield from -butyrolactone via aminolysis, hydrolysis, esterification, condensation with ethyl bromoacetate, cyclization,decarboxylation, reductive amination and debenzylation.K e y W o r d

7、 s :balofloxacin; fluoroquinolone; antibacterial agent; 3-methylaminopiperidine; synthesis中国医药工业杂志ChineseJournalofPharmaceuticals2004,35(7 3890.12mol 中缓慢加入吡啶(10ml ,0.13mol ,搅拌反应1h 。05下分批加入2(42g ,0.08mol ,加毕同温搅拌反应2h 。反应液搅拌下加到-20的甲醇(150ml 中,控制滴加速度控温于-20-15。加毕于-10反应1.5h ,加入冰水(32ml ,停止反应。减压蒸除溶剂,搅拌下向残留油状

8、物中加入乙醚(300ml ,析出固体,过滤,滤饼用少量乙醚洗涤后溶于二氯甲烷(250ml 和水(100ml 中,冰浴搅拌下用饱和碳酸钠溶液调至碱性。室温搅拌30min ,二氯甲烷层用少量水洗后用无水硫酸钠干燥,过滤,减压回收溶剂,残留物干燥,得3(22g ,66.8%,mp 106110。7-D-2-叔丁氧羰基氨基-2-(4-羟苯基乙酰胺基-3-氯甲基-3-头孢烯-4-羧酸二苯甲酯(43(21g ,0.05mol 、如上所得侧链10(20g ,0.08mol 和THF (200ml ,搅拌下加入N , N' -二环己基碳二亚胺(DCC ,15.5g ,0.08mol 。加毕室温搅拌反应

9、3h 。减压回收THF ,残留物搅拌下溶于乙酸乙酯(300ml ,过滤。滤液依次用5%碳酸氢钠溶液、水、1mol/L 盐酸和水洗涤,用无水硫酸钠干燥,过滤后减压回收乙酸乙酯,剩余物于45减压干燥,得4(30g 。叔丁基对硝基苯基碳酸酯(905搅拌下向叔丁醇(19g ,0.25mol 和吡啶(100ml 中缓慢加入8(52g ,0.25mol ,加毕升至室温搅拌反应4h 。过滤,滤液中加入水(15ml 后用乙醚提取,醚层依次用1mol/L 盐酸、饱和碳酸钠溶液和饱和食盐水洗涤。用无水硫酸钠干燥,过滤后减压回收乙醚,残留物中加入乙醇(180ml ,搅拌下加入水(200ml ,析出固体,过滤,滤饼用

10、少量50%乙醇洗涤,于45减压干燥,得9(43.5g ,72.4%,mp 78.580。D-2-叔丁氧羰基氨基-2-(4-羟苯基乙酸(109(43g ,0.18mol 、D-对羟基苯甘氨酸(31g ,0.18mol 、碳酸钠(35g ,0.32mol 、叔丁醇(180ml 和水(120ml 搅拌回流反应1h ,完毕后减压浓缩至剩约1/2,有固体析出。冷至室温,过滤,滤液用1mol/L 盐酸调至pH 56,用少量乙醚提取,水层用1mol/L 盐酸调至pH 1,用乙醚(150ml ×3提取,醚层用无水硫酸钠干燥,过滤,滤液减压回收乙醚。剩余物用石油醚-乙酸乙酯(51重结晶,得10(43.

11、5g ,71.8%,mp 113114。7-氨基-3-氯甲基-3-头孢烯-4-羧酸二苯甲酯(3冰浴搅拌下向二氯甲烷(250ml 和PCl 5(25g,1.15%磷酸二氢铵水溶液(pH 4.4-乙腈(91,其中Z -型 86.69%,E -型7.72%。MS (m /z : 389。1HNMR (D 2O : 1.72(d, 3H , 3.27(d, J =18Hz, 1H ,3.61(d, J =18Hz, 1H , 5.17(d, J =4.5Hz, 1H ,5.22(s,1H , 5.62(d, J =4.5Hz, 1H , 5.73(d, 1H ,6.04(d, 1H ,6.98(d,

12、J =9Hz, 2H ,7.42(d, J =9Hz, 2H 。IR (KBr (cm -1: 3543, 3459, 3391, 32172000, 1759, 1691,1563, 1520, 1460, 1393, 1350, 1268, 1241。元素分析(C 18H 19N 3O 5S H 2O 测定值(计算值,%:C 53.01(53.03, H 5.15(5.13, N 10.31(10.33,S 7.85(7.84。参考文献:Hoshi H, Okumura J. Substituted vinyl cephalosporins P . US:4520022, 1985-05-

13、28; DE: 3402642, 1984-08-02. (CA 1984,101: 191542Naito T, Hoshi H, Aburaki S, et al . Synthesis and structure-activity relationships of a new oral cephalosporin, BMY-28100and related compounds J . J Antibiot (Tokyo , 1987, 40(7:991-1005.Alan GL, Greenford NGW. Preparation of 4-carboxy cepha-losporin

14、s having a 3-vinyl or substituted 3-vinyl group P . US:3769277, 1973-10-30.(CA 1975, 82: 125043Niall GW.3-Vinyl-7-(2,2-disubstituteb acetamino -cepha-losporins.P US: 3994884, 1976(CA 1971, 75: 118328Shiozaki M, Ishida N, Iino K, et al . Cleavage and some modi-fications of the 7-amide group of the ce

15、phamycins J .Tetrahedron , 1980, 36(19: 2735-2740.Yamanaka H, Chiba T, Kawabata K, et al . Studies on -lactam antibiotics synthesis and biological activity of new orally active cephalosporin, cefixime (FK027J . J Antibiot , 1985,38(12: 1738-1751.Aburaki S, Narito Y, Okumura J, et al . Cephalosporin

16、intermediates P . US: 4659812, 1987-04-21. (CA 1987, 107:96507Kant J, Farina V. A stereocontrolled synthesis of cefprozil and cephems via allenylazetidinones J . Tetrahedron Lett ,1992, 33(25: 3563-3566.Anderson CW, McGregor AC. t -Butyloxycarbonylamino acids and their use in peptide synthesis J . J

17、 Am Chem Soc ,1957, 79: 6180-6183.1234567897-D-2-叔丁氧羰基氨基-2-(4-羟苯基乙酰胺基-3-碘甲基-3-头孢烯-4-羧酸二苯甲酯(5如上所得4(29g ,0.04mol 、碘化钠(20g ,0.13mol 和丙酮(500ml 于室温搅拌反应4h 。反应毕减压回收丙酮,残留物中加入乙酸乙酯(500ml ,依次用10%硫代硫酸钠溶液和饱和食盐水洗涤,用无水硫酸钠干燥,过滤后减压回收乙酸乙酯,得半固体状5(29.5g 。碘化7-D-2-叔丁氧羰基氨基-2-(4-羟苯基乙酰胺基-3-甲基-3-头孢烯-4-羧酸二苯甲酯-3-三苯膦内鎓盐(65(28g

18、,0.04mol 和乙酸乙酯(400ml ,搅拌下加入三苯膦(30g ,0.12mol 。加毕室温搅拌反应3h 。过滤,滤液减压浓缩至剩约1/2,冷却后加入乙醚(500ml ,过滤。滤饼用乙醚洗涤,于45减压干燥,得6(32g ,mp 172178。7-D-2-叔丁氧羰基氨基-2-(4-羟苯基乙酰胺基-3-(Z -1-丙烯基-3-头孢烯-4-羧酸二苯甲酯(76(31g ,0.03mol 和氯仿(600ml ,搅拌下加入0.25%氢氧化钠水溶液(600ml 。加毕,室温搅拌反应30min 。有机层用少量水洗后用无水硫酸钠干燥,过滤,滤液待用。另一三口瓶中加入三聚乙醛(30g ,0.68mol ,

19、40滴加10%硫酸(35ml ,通过冷凝管冰水冷却下收集2021馏分,得乙醛22g 。搅拌下转至如上所得的滤液中,室温搅拌反应3h 。减压回收氯仿,残留物于乙醚(150ml 中回流10min ,冷却,过滤,滤饼于45减压干燥。用甲醇-氯仿(81重结晶,得淡黄色固体7(8.5g ,40.9%,mp 122127。头孢丙烯(1二氯甲烷(20ml 、三氟乙酸(20ml 和茴香醚(7ml ,搅拌下加入7(7g ,0.01mol ,室温搅拌反应30min 。减压回收溶剂,残留物中加入乙醇(80ml 和水(100ml ,冰浴搅拌下滴加饱和碳酸氢钠溶液至pH 6.57.0,室温搅拌30min 。过滤,滤饼依

20、次用少量水和乙醇洗涤,P 2O 5室温减压干燥后,用30%甲醇于40重结晶,得1(2.5g ,59.9%,mp 210213。纯度99.8%HPLC 法,流动相:(下转第396页fffffffffffffffffffffffffffffffffffffffff(上接第390页Synthesis of CefprozilXIAO Tao 1 , ZHANG Xiao-Qing 2 , CAO Fang 3 , TIAN Chun-Mei 3 , WANG Jin-Tang 1(1. Dept. of Applied Chemistry, Nanjing University of Chemica

21、l Technology, Nanjing 210009; 2. School of Basic Medical Sciences,Nanjing Medical Unversity, Nanjing 210029; 3. Nanjing Huawei Medicinal Science Development Co. Ltd., Nanjing 210036A B S T R A C T :Cefprozil was synthesized from benzyhydryl 7-phenylacetamido- 3-chloromethyl-3-cephem-4-carboxylate by

22、 hydrolysis, condensation with D-2-(t -butoxycarbonylamino -2-(p -hydroxyphenyl acetic acid, conversion of the 3-chloromethyl group to 3-iodomethyl, Wittig reaction with acetaldehyde and hydrolysis with trifluoroacetic acid in an overall yield of 16.4%.K e y W o r d s :cefprozil; benzyhydryl 7-phenylacetamido-3-chloromethyl-3-cephem-4-carboxylate; antibiotics;synthesisA Convenient Preparation of OximesZHANG Jian-Jun