氯唑西林钠的合成

山西大学学报(自然科学版)25(3);224~ 226,2002Journal of Shanxi University(Nat. Sci. Ed. )文章编号;0253- 2395<2002)03-0224-03氯唑西林钠的合成李忠华(山西博康药业有限公司研究室.山西太原030021)摘要:氯唑西袜钠是耐酶 、耐酸的半合成抗生素。以邻氯苯甲醛为原料,经与盐酸羟胺肟化制得邻氯苯甲肟;它与氟气在乙醇中氯化制得邻氟苯甲肟氯的乙醇液，此乙醇液与乙酰乙酸乙酯在正已烷中酯化、水解制得邻氟苯甲异嗯唑酸(5).从邻氯萃甲肟三步收率71.54 %。(5)与POCI,酰化制得邻氰苯甲异嗯唑甲酰氯。所得的酰氯13.2g以丙酮10ml溶解.6-氦基青霉烷酸(6- APA)10g悬浮于水300 ml中,用NaOH溶清.加入丙酮液反应60 min,以醋酸丁酯提取硫酸酸化至pH2.0~pH2.5,醋酸丁酯液中加入5ml甲醇，加入异辛酸钠7.7g的醋酸丁酯液，即析出氯唑西林钠结晶19.2g.收率90.57 %。此方法收率高，成本低,适合于工业化生产。关键词:氟唑西林钠;合成;抗生素中围分类号:O626文献标识码:A0引言氯唑西林钠(Cloxacilin Sodium),化学名为6-[3-(2-氯苯基)-5-甲基-4-异聩唑甲酰胺基]青舞烷酸钠,为一半合成的异聩唑类抗生素。本品对能够产生β一内酰胺酶的革兰氏阳性菌感染是一种酶抑制剂”。从而可用来保护氨苄西林不被β-内酰胺酶破坏,临床上用于治疗如败血症、呼吸道感染、脑膜炎、软组织感染等。本文在参考文献的基础上,以邻氯苯甲醛为起始原料,采用如下的路线合成了氯唑西林钠(8)。- CHO NHrOH_ HCI-CH-NOH.ClzCH,CH.OHCC1-NOHCH.COCH.COC且sCOxGzHsM.Oc-C0016APADMF-CONHy000HCOON■收稿日期:2002-01-31中国煤化工作者简介:李忠华(1967-),女,山西大同人,工程师山西博康药业.YHCN MH G学及合成工艺研究，李忠华:氯唑西林钠的合成.251实验 部分:1.1 3-(2-氧苯基)-5-甲基-4-异噫唑甲酸的制备1.1.1邻氯苯 甲肟2|的制备按文献[]制备得橙色油状液体(2),收率80 %(文献[?'收率79 %)1. 1.2邻氯苯甲肟氯'|的制备(2)(40.0g,0. 26 mol),乙醇80 ml,降温至0 'C,通氯气,约4h后,用淀粉- KI试验测试,如果变蓝,则终点到,制得(3)的溶液不经纯化可直接用于下步反应。1.1.3 3-(2-氯苯基)-5-甲基一4一异聩唑甲酸乙酯(4)的制备上步反应液加入乙酰乙酸乙酯(56.0g,0.43 mol),正己烷80 ml,降温至5C以下,缓慢滴加40 %液碱，当pH=6.5~7.0时，温度突跃上升,保持温度不超过40 C。尔后自然降温至15 C时,用液碱调pH=9~9.5,保温反应5 h,直接用于下步反应。1.1.4 3-(2- 氯苯基)-5-甲基一4一异瞍唑甲酸(5)的制备按文献[}]操作,制得土色固体(5)粗品,用NaOH- HCI重结晶.即得乳黄色结晶粉末(5)43.7 g,收率71.4 %,mp198 C. (文献[)1mp195 C~196 C,收率65 %)。1.2 3-(2-氯苯基)-5-甲基-4-异唔唑甲酰氯(6)的制备(5)(25 g,0.105 mol) ,DMF0.06 g,POCl,(31.6g,0.210 mol),升温回流7 h,自然降温，即得橙色油状(低温固化)酰氯(6)34.2g,收率 93.7 %,含量98. 6 % ,b. p131*/0.5 mm. (文献[7)b. p130*/0.5 mm,收率91 %).1.3 氯唑西林钠(8)的制备aminopenicillanic acid(6- APA)(10 g,0. 05 mol) ,H[O300 ml,Na;HPO,(1 g,0.0I mol),滴加10 %NaOH,使溶液澄清,升温至30 C,滴加(6)(13.2 g,0. 05 mol)与丙酮10 ml的混合液,滴完保温反应60min,同时保持溶液pH在中性,加人醋酸丁酯170 ml,滴加20 %H2SO.至pH=2.0~2.5,分层,水层用30ml醋酸丁酯提取，合并提取液,用50ml盐水洗涤,弃去盐水,醋酸丁酯中加5ml甲醇,升温至50C,加入配制好的异辛酸钠(7.7g,0.046mol)和醋酸丁酯25ml的混合液,静置自然析结晶,2h后过滤,丙酮洗涤,50C干燥得白色粉末结晶[819.2 g,收率90. 6 % ,mp170 C(dep. ),[a]B'+ 166. 65°,含量93. 06 %,[文献[7]mp170 C (dep. ),[x]"+ 163° ,收率87 %]元素分析，CisHnCIN,NaO:S. H2O,实测值(%):C, 47.65; H,4.02;Cl,7. 6;N,8. 6;S,6. 75;Na,5. 1;H2O,3. 81;理论值:C.47. 95;H,4.0;Cl,7. 45;N,8. 85;S,6. 75;Na,4. 85;H20,4. 0。2结果与讨论2.1 邻氧苯甲肟氯(3)的合成改进化合物(3)的制备,文献[2]用盐酸和邻氯苯甲肟反应生成邻氯苯甲肟盐酸盐,通氯气,反应后抽去盐酸，再用乙醇溶解(3)。文献W用二甲基甲酰胺(DMF>作溶剂,反应毕蒸去DMF,再用乙醇溶解(3),操作起来较为繁锁。本文直接加乙醇,通氯反应,简单易行。2.2邻氯苯 甲异唔唑酸(5)的合成改进按文献[3]所给的化合物(5)的制备方法中,回流毕反应液中有许多黑色油状物,这些副产物的生成严重影响(5)的产量和质量,造成这种情况的主要原因是溶剂甲醇的影响,本文用正已烷代替甲醇,使黑色油状物消失,(5)的收率由原来的65%提高到71.4%,(5)也变得疏松,颜色由土色呈乳黄色。2.3 邻氯苯甲异唿唑甲酰氯(6)的合成改进中间体(6)的制备可用SOCI21]. PCI55 POCI3作酰化剂甲SOC1作酷化剂:制冬所得的(6)呈褐色,含量80 %;用PCI;作酰化剂,按文献报道(6)溶解在醋酸丁酯中国煤化工是两相反应，反应速度馒,而且反应不- -定完全。本文用POCl;作酰化剂,反THCNMHG98%~99%.226山西大学学报(自然科学版)25(3) 20022.4氯唑西林钠(8)的合 成改进文献报到的氯唑西林酸可与甲醇醋酸钠[或异辛酸钠["反应制备氯唑西林钠,由于醋酸钠微溶于甲醇,.需补加适量的水,才能配制成溶液(H2O:15 %~17 %),这样使氯唑西林钠的产量降低。直接加异辛酸钠成盐,结晶太细,过滤困难,本文采用在氯唑西林酸的醋酸丁酯液中补加适量甲醇,使醋酸丁酯液的系统水份均相分布,所得的氯唑西林钠晶形好,收率由用甲醇醋酸钠的75%提高到90.57%。参考文献:[1]诸骏仁,金有豫,曹 文庄,等.临床用药须知[M].北京:化学工业出版杜.2001.611.[2]章思规,辛忠.精细有机化工制备手册[M].北京:科学技术文献出版社,1998.704.. [3] LONGIN WALENDZIAK,JERZY LUSZCZEWSKI,ROMAM LOGWINIENKO,et al. 3- phenyl - 5 - methylisoxazole- 4- carboxylie acid and its derivatives [P]. Pol 89716.1977-07 - 30(CA 89 :43387m).[4]上海 医药工业研兖院技术情报站编.有机药物合成手册[M].上海:上海医药工业研究院,1977. 12-115.[5]上海第四制药厂. 氯唑青霉素前体酸既氯工艺改进[J].医药工业.1977.(4-5)33-34.[6] 王汝龙,原正平.化工产品手册●药物[M].北京:化学I业出版社,1998. 11-12.[7] DOYLE F ,PHANSON J C,LONG A A W ,et al. Derivatives of 6- Aminopenicillanic Acid Part VI Pericillins from 3-and 5- Phenylisoxazole -4-carboxylic Acids and their Alkyl and Halogen Derivatives[J].J Chem Soc ,1963, 12:5838-5845.Study on Synthesis of Cloxacillin SodiumLI Zhong-hua(Shanxi Guardian Pharmaceuticals Co. Ltd ,Taisyuan 030021 ,China)Abstract: In the paper, Cloxacillin Sodium, a known antibiotic, was prepared according to followingprocedures :2 - chlorobenzaldehyde oxime(2) was prepared by oximation of 2一chlorbenzaldehyde(1) withhydroxylamine. The solution of(2) in C2H.OH was treated with Cl2 at 0C. The reaction mixture wasstirred with ethyl acetoacetate in hexane at room tepm. for 5h and then refluxed with agua NaOH for 2h togive 3- (2 - chlorophenyl) - 5- methyl - isoxazole - 4 - carboxylic acid(5). 3- (2 - chlorophyenyl)- 5-methyl - isoxazole一4 - carboxylic acid(5) was reflucxed with POC; and DMF for 7 h to give 3- (2一chlorophenyl - 5- methylisoxazole 一4 - - carbonyl -chloride(6). Asolution of 3 - (2 - chlorophenyl -- - 5一methylisoxazole - 4 - carbonyl - chwride(6) in 10 ml acetone was added into the suspension of 6-aminopenicilanic acid(6- APA) in 300ml water. The mixture was stirred vigorously for 60 min and butylacetate was then added. After acidification with H2SO, to pH2.0~ 2.5,the mixture became two layers. Thelayer of hutyl acetate was separated and the aq. layer was extraced. After adding CH2OH,the comhindedbutyl acetate - layer was treated with sodium 2 - ethylhexanoate to obtain cloxacillin sodium.Key Words :cloxcilin sodium ;synthesis ;antibiotic中国煤化工MYHCNMHG