CN1076698A - 半合成青霉素缩合新工艺 - Google Patents
半合成青霉素缩合新工艺 Download PDFInfo
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Abstract
本发明介绍了半合成青霉素缩合新工艺。在与
前体酸盐形成混合酸酐过程中,以叔胺型化合物为催
化剂,采用了立体障碍性大,以及具有更强的推电子
能力基团的化合物氯甲酸异丁酯为活化试剂,有利于
选择性进行反应,缩合反应后经常规方法处理而制得
所需化合物。该工艺稳定,操作简单,重现性好,所用
原材料易得,产品收率高,质量好。
Description
本发明涉及一种半合成青霉素缩合新工艺。
目前国内外对半合成青霉素产品的制备方法研究仍很活跃。关于半合成青霉素缩合工艺方法可分为混合酸酐法、酰氯法、酶缩合法、一步合成法。文献较多的介绍是酰氯法,即6-氨基青霉烷酸盐(简称6-APA)在CH2Cl2中进行甲硅烷化,或其改进的用一种N,O-双-甲硅烷化酰胺作为甲硅烷化介质生成单甲硅烷衍生物,然后再与苯甘氨酸酰氯盐酸盐进行酰化反应(详见CN 85102130A,US4625021)。酰氯盐酸盐的制备,贮运都有一定难度,生产工艺条件要求苛刻,工业化生产有诸多不便。通过试验对比,还是混合酸酐法较经济、安全,三废处理容易解决,适合工业化生产。混合酸酐法的操作过程是由苯甘氨酸或对羟基苯甘氨酸与乙酰乙酸乙酯(或甲酯)在碱存在下所形成的N-(2-乙氧基羧基-1-甲基乙烯基)-D-(-)-α-氨基-苯(或对羟基苯)乙酸钾(或钠),即通称为前体酸盐再与氯甲酸乙酯(或甲酯)形成混合酸酐,低温下与6-APA进行缩合反应,经酸解除去α-氨基保护基,再调PH至等电点,最终产品析出。上述混合酸酐法生产工艺水平不高,如氨苄青霉素三水酸收率一般在70-80%(《中国药学杂志》1992,5,262-265),而其它产品可能还要低一些。近些年来有的厂家采用特戊酰氯成混合酸酐法,小试收率较高,但工艺繁琐,工业化条件要求严格,且需要在-60℃反应,溶媒回收困难,三废处理较难,所用试剂多,反应周期长,能耗高,故生产成本仍然很高。因此进一步简化半合成青霉素工艺,,提高工艺技术水平,降低生产成本,已成为重要的研究课题。
本发明的目的是提供一种半合成青霉素缩合新工艺,该工艺稳定,操作简单,反应条件温和,有利于工业化生产,所用原料易得,明显提高产品收率和纯度,降低生产成本。
本发明的目的是这样实现的:采用纯度高的前体酸盐与氯甲酸异丁酯,于丙酮中以叔胺型化合物为催化剂,形成混合酸酐,再将6-氨基青霉烷酸盐加入混合酸酐中,于低温-15~-40℃下进行缩合反应,反应完毕采用常规方法加盐酸调PH不超过2.0进行水解,萃取出丙酮,水相以氨水调至等电点,晶体烘干即得成品;所用原料重量比是:6-氨基青霉烷酸盐∶前体酸盐∶氯甲酸异丁酯∶丙酮∶叔胺型化合物∶盐酸=1∶1.47-1.63∶0.669-0.739∶14.04∶3.75∶1.13∶1.25∶45.25。
上述前体酸盐为N-(2-乙氧基羧基-1-甲基乙烯基)-D-(-)-α-氨基-苯乙酸钾(或钠),或为N-(2-乙氧基羧基-1-甲基乙烯基)-D-(-)-α-氨基-对羟基苯乙酸钾(或钠)。叔胺型化合物为N-甲基吗啉或N,N-二甲基苄胺。
由于本发明采用具有较强推电子能力基因的氯甲酸异丁酯(iso Butylchlorocarbonace,简称CFT)作为前体酸盐制备混合酸酐的活化试剂,以叔胺型化合物为催化剂,与6-APA的盐进行缩合反应后,经常规处理即得成品,所以所用原料易得,工艺稳定,操作简单,反应条件温和。与现有技术相比,本发明所用活化试剂CFT比氯甲酸乙酯(或甲酯)具有更强推电子能力,且立体障碍性大,更有利于选择性进行缩合反应,CFT具有易溶于水的性质极易清除,故反应完全,重现性好。另外本发明因采用较高纯度前体酸盐,使苯甘氨酸或对羟基苯甘氨酸的α-氨基真正被保护起来,未加保护的α-氨基不能混入前体酸盐中,故能有效地保护β-内酰胺骨架不被破坏,明显提高产品收率。产品收率比现有工艺技术可提高10-12%,其产品纯度也明显提高,质量好。因此,本发明生产成本低,三废处理容易,更有利于工业化生产。
本发明所用前体酸盐的通式为:
其中R为H或-OH,M为K或Na,N为-CH3或-C2H5制成的青霉素衍生物的通式为:
其中R表示一个苯基或其对位由羟基取代,也可以是1,4-环己二烯基。
以下结合实施例对本发明作进一步说明。
实施例1:6-(D-(-)-α-氨基-苯乙酰胺)青霉烷酸
将12.4克N-2-乙氧基羧基-1-甲基乙烯基)-D-(-)-α-氨基-苯乙酸钾和86毫升丙酮配成乳液,将其搅拌冷却后加入0.55毫升N,N-二甲基苄按,5.45毫升氯甲酸异丁酯。继续搅拌冷却至-35℃制成溶液A。另将8克6-APA与56毫升丙酮及30毫升水配成悬浮液,搅拌下控制0-5℃滴加氨水约8毫升调至PH7.8,即全溶为止,降温至-15℃以下制成溶液B。将溶液B加入到搅拌下冷却至-35℃的溶液A中,进行缩合反应半小时,反应完毕加盐酸并升温至0℃调PH1.5左右,水解反应半小时。水解完毕,用甲苯420ml分三次提取丙酮,分离出水相,在0-5℃下用氨水将溶液调至PH2.8,产物很快结晶,搅拌10分钟,然后慢慢加入氨水,将PH调至等电点,3-5℃下放置过夜,次日过滤并水洗,抽干后用10毫升丙酮洗涤、滤净。将产品置于50℃的烘箱中烘干,即得标题化合物。
收率 90%(理论值)
含量 97%(分光光度法)
实施例2:6-(D-(-)-α-氨基-苯乙酰胺)青霉烷酸
将11.7克N-(2-乙氧基羧基-1-甲基乙烯基)-D-(-)-α-氨基-苯乙酸钠和70毫升丙酮及12毫升水配成乳液,将其搅拌冷却后加入0.55毫升N,N-二甲基苄胺至-35℃,再加入5.45毫升氯甲酸异丁酯,搅拌反应冷却至-35℃制成溶液A。另将8克6-APA加入30毫升丙酮和30毫升水中,加氨水制成铵盐得溶液B,降温至-15℃,再加入溶液A进行缩合反应半小时。如例1所述相同的方法处理得到本标题化合物。
收率 85%(理论值的)
含量 97%
实施例3:6-(D-(-)-α-氨基-苯乙酰胺)青霉烷酸
例2所述的相同的方法制得溶液A和B,然后将B按例1的方法加入到A中,经相同方法处理而得到标题化合物。
收率 87%(理论值的)
含量 97%
实施例4:6-(D-(-)-α-氨基-苯乙酰胺)青霉烷酸
将11.7克N-(2-乙氧基羧基-1-甲基乙烯基)-D-(-)-α-氨基-苯乙酸钠和86毫升丙酮配成乳液,将其搅拌冷却后加入0.55毫升N,N-二甲基苄胺至-35℃,再加入5.45毫升氯甲酸异丁酯,继续搅拌冷却至-35℃得溶液A。另按例1的方法制得溶液B,然后将B加入到A中,经相同方法处理而得到标题化合物。
收率 89%(理论值的)
含量 97%
实施例5:6-(D-(-)-α-氨基-苯乙酰胺)青霉烷酸
将12.4克N-(2-乙氧基羧基-1-甲基乙烯基)-D-(-)-α-氨基-苯乙酸钾和70毫升丙酮及12毫升水配成乳液,以下按例1制得溶液A和B,反应后处理而得标题化合物。
收率 88%(理论值的)
含量 97%
实施例6:6-(D-(-)-α-氨基-苯乙酰胺)青霉烷酸
将13.01克N-(2-乙氧基羧基-1-甲基乙烯基)-D-(-)-α-氨基-对羟基苯乙酸钾和86毫升丙酮配成乳液,将其搅拌冷却加入0.55毫升N,N-二甲基苄胺后到-35℃,加入5.45毫升氯甲酸异丁酯。继续搅拌冷却至-35℃制成溶液A。另将8克6-APA与56毫升丙酮及40毫升水配成悬浮液,搅拌下控制0-5℃滴加氨水约8毫升调至PH7.8,即全溶为止,降温至-15℃以下制成溶液B。将溶液B加入到搅拌下冷却至-35℃的溶液A中,进行缩合反应半小时。如例1所述相同的方法,用盐酸水解,氨水调PH5.1,分离处理得到本标题下的化合物。
收率 85%(理论值的)
含量 97%(分光光度法)。
Claims (5)
1、一种半合成青霉素缩合新工艺,其特征是采用纯度高的前体酸盐与氯甲酸异丁酯,于丙酮中以叔胺型化合物为催化剂,形成混合酸酐,再将6-氨基青霉烷酸盐加入混合酸酐中,于低温-15~-40℃下进行缩合反应,反应完毕采用常规方法加盐酸调PH不超过2.0进行水解,萃取出丙酮,水相以氨水调至等电点,晶体烘干即得成品。所用原料重量比是:6-氨基青霉烷酸盐∶前体酸盐∶氯甲酸异丁酯∶丙酮∶叔胺型化合物∶盐酸=1∶1.47-1.63∶0.669-0.739∶14.04∶3.75∶1.13∶1.25∶45.25。
2、根据权利要求1所述的新工艺,其特征是前体酸盐为N-(2-乙氧基羧基-1-甲基乙烯基)-D-(-)-α-氨基-苯乙酸钾(或钠),或为N-(2-乙氧基羧基-1-甲基乙烯基)-D-(-)-α-氨基-对羟基苯乙酸钾(或钠)。
3、根据权利要求1所述的新工艺,其特征是叔胺型化合物为N-甲基吗啉或N,N-二甲基苄胺。
4、根据权利要求1所述的新工艺,其特征是进行缩合反应最佳温度为-25~-35℃。
5、根据权利要求1所述的新工艺,其特征是制成青霉素衍生物的通式为:
其中R表示一个苯基或其对位由羟基取代,也可以是1,4-环己二烯基。
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CN93110174A CN1035435C (zh) | 1993-03-16 | 1993-03-16 | 半合成青霉素缩合新工艺 |
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CN93110174A CN1035435C (zh) | 1993-03-16 | 1993-03-16 | 半合成青霉素缩合新工艺 |
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Cited By (1)
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CN104644629A (zh) * | 2015-01-27 | 2015-05-27 | 华北制药股份有限公司 | 一种注射用氨苄西林钠舒巴坦钠制剂及其制备方法 |
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IT1193836B (it) * | 1979-11-02 | 1988-08-24 | Dobfar Spa | Procedimento per la produzione di acido 6-d-alfa-amino-p-idrossifenilacetamido enicillanico |
GB2240102B (en) * | 1990-01-22 | 1993-10-20 | Biochemie Gmbh | Improvements in or relating to beta lactam production |
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CN104644629A (zh) * | 2015-01-27 | 2015-05-27 | 华北制药股份有限公司 | 一种注射用氨苄西林钠舒巴坦钠制剂及其制备方法 |
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