CN107353297A - 一种高效的头孢洛林酯合成方法 - Google Patents
一种高效的头孢洛林酯合成方法 Download PDFInfo
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- CN107353297A CN107353297A CN201710579916.0A CN201710579916A CN107353297A CN 107353297 A CN107353297 A CN 107353297A CN 201710579916 A CN201710579916 A CN 201710579916A CN 107353297 A CN107353297 A CN 107353297A
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Abstract
本发明公开了一种高效的头孢洛林酯合成方法,通过7‑苯乙酰氨‑3‑羟基‑3‑头孢‑4‑羧酸‑二苯甲酯为原料,经氯化,在C‑3位与4‑(4‑吡啶基)‑1,3‑噻唑‑2‑硫醇钠盐反应得到硫醚化合物,脱保护基采用水解去4位二苯甲基和固定化青霉素酶裂解去7位苯乙酰基,再与酰氯化的AE‑活性酯反应进行C‑7位缩合反应,水解,在乙酸中结晶成功制备了头孢洛林酯。本发明本发明提供的方法反应周期短,操作简便,生产成本低,产品质量好,适合工业化生产。
Description
技术领域
本发明涉及一种头孢洛林酯的合成,具体是一种高效的头孢洛林酯合成方法。
背景技术
头孢洛林酯化学名称为:(6R,7R)-7-{(2Z)-2-(乙氧基亚氨基)-2-[5-(磷酰胺基)-1,2,4-噻二唑-3-基]-乙酰氨基}-3-{[4-(1-甲基-4-吡啶)-1,3-噻唑-2-基]硫代}-8-氧代-5-硫杂-1-氮杂双环[4.2.0]辛-2-烯-2-羧酸-一水合物醋酸盐,结构式如下(简称fikg.1):
头孢洛林酯由日本武田制药公司开发,美国Forest Laboratories(Cerexa)公司获得市场授权,于2010年10月29日经美国药品食品管理局批准上市,是头孢洛林的前药(即N-磷酰化头孢洛林),属于第五代头孢菌素类抗菌药。该药用于治疗成人社区获得性细菌性肠炎(CABP)和急性细菌性皮肤和皮肤组织感染(ABSSSI),包括甲氧西林耐受性金黄色酿脓葡萄球菌(MRSA)感染。头孢洛林酯是广谱头孢菌素类抗菌药物,临床前研究和临床研究数据显示头孢洛林酯对包括肺炎链球菌、金黄色葡萄球菌、MRSA在内的大多数耐药革兰阳性菌、革兰阴性厌氧菌、革兰阳性厌氧菌具有较强的抗菌活性,并对耐青霉素肺炎球菌、流感嗜血杆菌、肺炎克雷伯菌、产酸克雷伯菌、大肠杆菌等常见革兰阴性菌也具有杀菌作用,但对铜绿假单胞菌、不动杆菌、产碱杆菌属敏感性低。
目前,对于fikg.1化合物的合成方法,国内文献鲜有报道,武田制药公司已经申请了专利WO0214333、US2004023943、EP1310502、CN1462275对该药物进行保护,主要合成方法如下:
含结构式fikg.2的化合物在注射用水和冰醋酸(注射用水与冰醋酸按照一定体积比1: 1混合)的混合液中溶解,通过超声或加入晶种析晶,得到头孢洛林酯(fikg.1),收率在 65%-70%,同时注射用水可用5%的葡萄糖水溶液及20%的甘露醇水溶液代替,收率在50%-75%;或者,用含结构式fikg.2的化合物先成盐,后在注射用水和冰醋酸(注射用水与冰醋酸按照一定体积比1:1混合)的混合液中溶解,加入晶种析晶,得到头孢洛林酯(fikg.1),成盐剂包括醋酸钠、氨水和醋酸铵,收率在50%左右。专利报道的上述合成方法结晶时间较长,收率较低,如果先转成钠盐再结晶,则可能会造成辅料的浪费,最终影响产品的收率。
有关头孢洛林酯的合成工艺主要有以下几种:
1、中国专利CN01816095“膦酰基头孢烯化合物”报道了头孢洛林酯的合成路线是以 (6R,7R)-7-苯乙酰胺基-3-甲磺酰氧基-8-氧代-5-硫杂-1-氮杂二环[4.2.0]辛-2-烯-2- 甲酸二苯甲酯(2)为起始原料,与化合物(3)通过取代反应得到化合物(4),化合物(4)经过成季铵盐、氨基脱保护、羧基脱保护生成化合物(5),化合物(5)酰化后与稀乙酸混合结晶得到头孢洛林酯(1)。
该路线以3-甲磺酰氧基-头孢为原料,但未公开该化合物的公开步骤;由中国专利CN00802003.5“3-磺酰氧基-3-头孢烯化合物的合成方法”可知,在合成3-磺酰氧基-3- 头孢烯化合物时,常常会副反应产生大量的双键异构体△2-头孢烯化合物,副反应产生△2-头孢烯化合物导致头孢菌素的活性母核△3-头孢烯化合物的纯度和收率降低,给精制工艺带来很大的负荷;且反应中大量应用了五氯化磷或甲醇钠等环境不友好试剂,不利于工业化生产。
2、申请号为20141084251.4的中国专利报道了头孢洛林酯的合成方法:该方法是以 (Z)-2-(5-氨基-1,2,4-噻二唑-3-基)-2-乙氧亚胺基乙酸(式Ⅱ)为原料,先与酸/氯化亚砜在三乙胺作用下反应得到化合物式Ⅲ,其次化合物式Ⅲ与卤代试剂在甲苯中反应得到化合物式Ⅳ,化合物式Ⅳ再与式Ⅴ在三乙胺作用下于四氢呋喃中反应得到化合物式Ⅵ,化合物式Ⅵ在碱的作用下脱保护得到化合物式Ⅶ,化合物式Ⅶ在乙酸乙酯中与PCl5反应,产物经过水解反应得到化合物式Ⅷ,最后化合物式Ⅷ与水、乙酸钠反应,在硫酸与乙酸中成盐得头孢洛林酯(式I),其反应路线如下所示:
其中,R1为三氟乙酰基、三氟丙酰基、三氟甲磺酰基、三氯乙酰基、叔丁氧羰基、乙酰基、对甲苯磺酰基或甲磺酰基。
文献Bioorg.Med.Chem,2003,2427~2437报道了一种头孢洛林酯非水合物前体药的合成方法,以(Z)-2-(5-氨基-1,2,4-噻二唑-3-基)-2-乙氧亚胺基乙酸为原料,先与PCl5反应,合成(Z)-2-(5-二氯磷酰氨基-1,2,4-噻二唑-3-基)-2-乙氧亚胺基乙酰氯,其次将该化合物与7β-氨基-3-[4-(1-甲基-4-吡啶鎓)-2-噻唑硫基]-3-头孢烯-4-羧酸二盐酸化合物反应,最后经水解,与乙酸成盐得到头孢洛林酯前体药物,其合成路线如下:
专利WO0214333以及WO2013034718A1在此基础上分别公开了合成头孢洛林酯的新方法。该两种方法中,在以(Z)-2-(5-氨基-1,2,4-噻二唑-3-基)-2-乙氧亚胺基乙酸为原料的之后合成步骤与以上合成路线类似。
这些合成方法虽然合成路线较短,但是式Ⅴ化合物的市场上没有供应,原料不易得,且反应中大量应用了五氯化磷等环境不友好试剂,不利于工业化生产;还有由于(Z)-2-(5- 二氯磷酰氨基-1,2,4-噻二唑-3-基)-2-乙氧亚胺基乙酰氯中的二氯磷酸酯的活性较强,能在碱性条件下与伯胺发生反应,从而使得获得的化合物3-[4-(1-甲基-4-吡啶鎓)-2-噻唑硫基]-7β-[2-(5-膦酰胺基-1,2,4-噻二唑-3-基)-2(Z)-乙氧基亚氨基乙酰氨基]-3-头孢烯-4-羧酸的副产物较多,进而导致产率降低,不利于工业化生产。
发明内容
本发明的目的在于提供一种高效的头孢洛林酯合成方法,以解决上述背景技术中提出的问题。
为实现上述目的,本发明提供如下技术方案:
步骤一:一种合成头孢洛林酯的中间体化合物式III(Z)-2-(5-取代氨基-1,2,4-噻二唑-3-基)-2-乙氧亚胺基乙酸,其结构式如下所示:
其中,R1选自三氟乙酰基、三氟丙酰基、三氟甲磺酰基、三氯乙酰基、叔丁氧羰基、乙酰基、对甲苯磺酰基、甲磺酰基、对甲氧苄基、三苯甲基或苄基;优选地,R1选自三氟乙酰基、三氟丙酰基或三氟甲磺酰基,其合成方法为:以化合物(Z)-2-(5-氨基-1,2,4- 噻二唑-3-基)-2-乙氧亚胺基乙酸(式II)为原料与酸/氯化亚砜在三乙胺作用下反应得到,其反应式如下所示:
步骤二:7β-[(苯乙酰)氨基]-3-[4-吡啶基-2-噻唑硫基]-3-头孢烯-4-羧酸二苯甲基酯(式Ic)在DMF、碱性试剂条件下,与甲基化试剂反应,加水并酸化析晶,得到7β-[(苯乙酰)氨基]-3-[4-(1-甲基-4-吡啶鎓)-2-噻唑硫基]-3-头孢烯-4-羧酸二苯甲基酯盐酸化物(式Ⅱ);所述甲基化试剂为碳酸二甲酯,碱性试剂为三乙胺;
步骤三:7β-[(苯乙酰)氨基]-3-[4-(1-甲基-4-吡啶鎓)-2-噻唑硫基]-3-头孢烯-4- 羧酸二苯甲基酯盐酸化物(式Ⅱ)用对甲酚脱除二苯甲基,固定化青霉素G酰化酶脱除苯乙酰基,结晶、过滤、真空干燥得到7β-氨基-3-[4-(1-甲基-4-吡啶鎓)-2-噻唑硫基]-3- 头孢烯-4-羧酸内盐化合物(式Ⅲb);
步骤四:在甲基叔丁基醚、石油醚的混合溶剂中,AE-活性酯(式Ⅳa)与三氯氧磷反应得到2-(2-二氯磷酰胺-4-噻唑基)-2-(甲氧亚氨基)乙酸硫代苯并噻唑酯(式Ⅳb);
步骤五:将7β-氨基-3-[4-(1-甲基-4-吡啶鎓)-2-噻唑硫基]-3-头孢烯-4-羧酸内盐化合物(式Ⅲ)和2-(2-二氯磷酰胺-4-噻唑基)-2-(甲氧亚氨基)乙酸硫代苯并噻唑酯(式Ⅳb)在乙醇中滴加三乙胺、DMAP反应缩合,加盐酸水解,然后在乙酸中成盐结晶得到头孢洛林酯(式Ⅴ)。
其合成路线如下所示:
优选地,酸选自三氟乙酸、三氟丙酸、三氟甲磺酸、三氯乙酸、叔丁氧碳酸、乙酸、对甲苯磺酸或甲磺酸.
优选的,所述步骤一中,7-苯乙酰氨基-3-羟基-3-头孢环-4-羧酸二苯甲酯(式Ia)与脱水的二甲基甲酰胺和氯化亚砜、二甲基砜反应,得到7-苯乙酰氨基-3-氯-3-头孢环-4-羧酸二苯甲酯(式Ib),反应完成后,降温冷却,过滤,并用少量清水清洗,得到7-苯乙酰氨基-3-氯-3-头孢环-4-羧酸二苯甲酯(式Ib)湿料,将其混悬于丙酮中,加入4-(4- 吡啶基)-1,3-噻唑-2-硫醇钠盐,并搅拌至溶清,反应完毕后,加水析晶,抽滤、少量水清洗、真空干燥得到7β-[(苯乙酰)氨基]-3-[4-吡啶基-2-噻唑硫基]-3-头孢烯-4-羧酸二苯甲基酯(式Ic)。
更进一步优选的,所述步骤一中,7-苯乙酰氨基-3-羟基-3-头孢环-4-羧酸二苯甲酯 (式Ia):脱水的二甲基甲酰胺:氯化亚砜的用料质量配比为1:5-40:0.3-3:,反应温度为0-30℃,反应时间为2-8小时;7-苯乙酰氨基-3-氯-3-头孢环-4-羧酸二苯甲酯(式 Ib)与2-巯基-4-(4-吡啶基)噻唑的摩尔比为1:1.1~1.2;7-苯乙酰氨基-3-氯-3-头孢环-4-羧酸二苯甲酯(式Ib)与催化剂的质量比为1:0.01~0.03;7-苯乙酰氨基-3-氯-3- 头孢环-4-羧酸二苯甲酯(式Ib)与丙酮的质量体积比为1:3~6;反应温度为40~50℃,反应时间为1~2小时。
优选的,所述步骤二中,将7β-[(苯乙酰)氨基]-3-[4-吡啶基-2-噻唑硫基]-3-头孢烯-4-羧酸二苯甲基酯(式Ic)的DMF溶液与甲基化试剂反应,加入碱性试剂,保温反应完毕后冷却至室温,加水析晶,再用盐酸调pH为1.3~2,继续搅拌析晶,过滤,水洗,得到7β-[(苯乙酰)氨基]-3-[4-(1-甲基-4-吡啶鎓)-2-噻唑硫基]-3-头孢烯-4-羧酸二苯甲基酯盐酸化物(式Ⅱ);所述甲基化试剂为碳酸二甲酯,碱性试剂为三乙胺;7β-[(苯乙酰)氨基]-3-[4-吡啶基-2-噻唑硫基]-3-头孢烯-4-羧酸二苯甲基酯(式Ic)与DMF的质量体积比为1:3;7β-[(苯乙酰)氨基]-3-[4-吡啶基-2-噻唑硫基]-3-头孢烯-4-羧酸二苯甲基酯(式Ic)与甲基化试剂、碱性试剂的摩尔比为1:1.4~1.5:1.5~1.6;DMF与稀盐酸溶液的体积比为1:5~6;反应温度为35~40℃,反应时间为5~6小时。
优选的,在步骤三中,7β-[(苯乙酰)氨基]-3-[4-(1-甲基-4-吡啶鎓)-2-噻唑硫基]-3-头孢烯-4-羧酸二苯甲基酯盐酸化物(式Ⅱ)用对甲酚脱除二苯甲基时,7-苯乙酰氨基-3-氯-3-头孢环-4-羧酸二苯甲酯盐酸化物(式Ⅱ):对甲酚=1:2-10,反应温度为 45-50℃,反应时间为0.5-6小时;反应完全后冷至40℃加入乙酸乙酯继续冷至10℃以下加入2%碳酸氢钠溶液萃取,收集萃取液,待用;7-苯乙酰氨基-3-氯-3-头孢环-4-羧酸二苯甲酯盐酸化物(式Ⅱ):对甲酚:乙酸乙酯:2%碳酸氢钠溶液的质量比=1:2-10:5-15: 10-30。将上述萃取液中加入固定化青霉素G酰化酶IPA-450或IPA-750,用料质量配比为:7-苯乙酰氨基-3-氯-3-头孢环-4-羧酸:固定化青霉素G酰化酶=1:0.65-1;反应温度为 30-37℃,反应时间1-3小时,反应时持续加入2%碳酸氢钠溶液控制pH值在7.0-8.5;反应完成后,结晶、过滤、真空干燥得到7β-氨基-3-[4-(1-甲基-4-吡啶鎓)-2-噻唑硫基]-3-头孢烯-4-羧酸内盐化合物(式Ⅲb)。
优选的,在步骤四中,在甲基叔丁基醚、石油醚的混合溶剂中,加入AE-活性酯(式Ⅳa),随后加入三氯氧磷,加入过程控制反应液温度≤5℃,加完后控温0-5℃反应4-8 小时;向反应液中加水,加入过程控制反应液温度≤5℃,加完后控温0-5℃反应1小时;抽滤,滤饼用石油醚洗涤,在40-50℃真空干燥,得到2-(2-二氯磷酰胺-4-噻唑基)-2-(甲氧亚氨基)乙酸硫代苯并噻唑酯(式Ⅳb);其中AE-活性酯(式Ⅳa)与三氯氧磷、水的摩尔比为1:2:1。
优选的,在步骤五中,所述乙醇的体积为7β-氨基-3-[4-(1-甲基-4-吡啶鎓)-2-噻唑硫基]-3-头孢烯-4-羧酸内盐化合物(式Ⅲ)质量的15-25倍;7β-氨基-3-[4-(1-甲基-4-吡啶鎓)-2-噻唑硫基]-3-头孢烯-4-羧酸内盐化合物(式Ⅲ)、2-(2-二氯磷酰胺-4-噻唑基)-2-(甲氧亚氨基)乙酸硫代苯并噻唑酯(式Ⅳb)、三乙胺和DMAP的反应摩尔比为1: 1.1~1.3:1.05~1.15:0.01~0.02,控制温度5~20℃反应3~5小时;反应液蒸去乙醇,加水,以乙酸乙酯萃取,水层加活性炭脱色,抽滤,将滤液置于冰浴下搅拌,滴加盐酸调至pH2-3,静置,抽滤,真空干燥得白色固体;将其加入水中,滴加2M乙酸钠溶液至全部溶解,加入乙酸,搅拌3h,结晶,抽滤,滤饼用少量水淋洗,真空干燥,得头孢洛林酯(式Ⅴ)。
作为本发明进一步的方案:
与现有技术相比,本发明的有益效果是:本发明改进了头孢洛林酯的合成工艺,以7- 苯乙酰氨-3-羟基-3-头孢-4-羧酸-二苯甲酯为原料,经氯化,在C-3位与4-(4-吡啶基)-1, 3-噻唑-2-硫醇钠盐反应得到硫醚化合物,脱保护基采用水解去4位二苯甲基和固定化青霉素酶裂解去7位苯乙酰基,再与酰氯化的AE-活性酯反应进行C-7位缩合反应,水解,在乙酸中结晶成功制备了头孢洛林酯。优点有,
(1)本发明避免使用价格昂贵毒性大腐蚀性强的五氯化磷、三氟乙酸、碘甲烷、甲醇钠等原料和反应后处理繁琐的难题;反应条件温和,副反应少,提高了纯度,产品纯度为99.8%以上。本发明缩短了工艺步骤,工艺简单、收率高、成本低,产品纯度高,原料廉价易得,适合工业化生产。在脱羧基保护基时用苯酚作溶剂,避免使用价格昂贵腐蚀性强的五氯化磷等原料和反应后处理繁琐的难题;采用了青霉素酶进行氨基保护基团的脱去,替代了原有的三氟乙酸工艺,提高了反应收率,对产品质量有较明显的提高,且酶可以套用300次以上,降低了生产成本,对环境无污染,具有更好的环保性,使工艺符合产业化的要求。
(2)本发明以7-苯乙酰氨-3-羟基-3-头孢-4-羧酸-二苯甲酯为原料先经氯化,C-3位上的氯相对于羟基为更活泼的基团,增加反应活性,更容易与亲核试剂2-巯基-4-(4-吡啶基)噻唑发生取代反应,使硫醚化合物产品收率和纯度更高,外观颜色好,避免了使用甲醇钠等强碱,使生产条件更温和、减少副产物发生、生产工艺更简单、生产成本更低。
(3)C-7位缩合方法有酰氯法、活性酯法及二环己基碳二亚胺(DCC)直接脱水等方法, DCC做缩合剂时,侧链氨基需保护;酰氯法要求无水操作,且需要在低温下进行.本发明采用活性酯法,简化了合成路线,且反应条件温和易于操作,较高收率的形成酰胺键;选择乙醇作溶剂,简化了操作,而且加入DMAP后,加快了反应进程,4h可以定量反应;提高了产率,达到95.2%,HPLC归一化法测产品纯度99%以上。
具体实施方式
下面将对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例1:
1)在20-25℃温度下,在干燥的反应容器内加入三氟乙酸和甲苯,磁力搅拌下,加入氯化亚砜,70℃反应3h,冰水浴降温至0℃,滴加三乙胺(9.34g,0.092mol),滴毕,加入5g(Z)-2-(5-氨基-1,2,4-噻二唑-3-基)-2-乙氧亚氨基乙酸(式II,5g,0.023mol),室温反应4h,冰水浴降温至0℃,滴加50mL水,滴毕,静置分液,水相继续用50mL甲苯萃取,合并有机相,加入无水硫酸钠10g干燥半小时,抽滤,滤液旋干得棕色固体化合物式III,收率:87%。1HNMR(CDCl3),δ(ppm):1.10(3H,t,J=7Hz),3.57(2H,q,J =7Hz),9.15(1H,s),11.0(1H,brs)。向一三口瓶中加入化合物式III,甲苯,磁力搅拌下,加入氯化亚砜,80℃反应3h,将反应液旋干,得棕色固体化合物式,收率96%。 1HNMR(CDCl3),δ(ppm):1.10(3H,t,J=7Hz),3.57(2H,q,J=7Hz),9.15(1H,s)将 221.5g7-苯乙酰氨基-3-氯-3-头孢环-4-羧酸二苯甲酯滤饼(式Ib,测定水分为15.8%,折合干重为0.35mol)其混悬于1200ml丙酮中,加入83.5g4-(4-吡啶基)-1,3-噻唑-2- 硫醇钠盐,反应温度为40~50℃,反应时间为2小时,反应完毕后,加水析晶,抽滤、少量水清洗、真空干燥得到234g7β-[(苯乙酰)氨基]-3-[4-吡啶基-2-噻唑硫基]-3-头孢烯 -4-羧酸二苯甲基酯(式Ic),收率为96%,HPLC纯度为99.2%。
2)将实施例1中制备的228g7β-[(苯乙酰)氨基]-3-[4-吡啶基-2-噻唑硫基]-3-头孢烯-4-羧酸二苯甲基酯(式Ic,0.33mol)和44.6g碳酸二甲酯加入0.5LDMF中,搅拌下滴加50g三乙胺,控温<30℃,滴加完毕后于35~40℃保温反应5小时,反应完毕后冷却至室温,加入2kg水,搅拌析晶,再用盐酸调pH为1.3~1.5,继续搅拌析晶1小时,过滤,水洗,40℃减压干燥得到221.2g7β-[(苯乙酰)氨基]-3-[4-(1-甲基-4-吡啶鎓)-2-噻唑硫基]-3-头孢烯-4-羧酸二苯甲基酯盐酸化物(式Ⅱ,0.3mol),收率:90%,HPLC纯度>99%。
3)将实施例2制得的221g7β-[(苯乙酰)氨基]-3-[4-(1-甲基-4-吡啶鎓)-2-噻唑硫基]-3-头孢烯-4-羧酸二苯甲基酯盐酸化物(式Ⅱ,0.3mol)、1700mL对甲酚加入反应釜中,控制温度在45-50℃,搅拌反应6小时;反应完全后冷至40℃加入2200mL乙酸乙酯继续冷至10℃以下分三批加入1500mL2%碳酸氢钠溶液萃取,收集萃取液,待用;将上述萃取液中加入150g固定化青霉素G酰化酶IPA-750,反应温度为30-37℃,反应时间1-3 小时,反应时持续加入2%碳酸氢钠溶液控制pH值在7.8-8.5。反应毕,冷至室温,滤出 IPA-750。并用少许水洗涤,滤液和洗液冷却到3~5℃,用盐酸调pH值至酸性后析出白色固体,滤过,干燥得115.9g7β-氨基-3-[4-(1-甲基-4-吡啶鎓)-2-噻唑硫基]-3-头孢烯-4- 羧酸内盐化合物(式Ⅲb),收率为95%,HPLC纯度>99%。
4)在反应釜中加入200g的甲基叔丁基醚、200g的石油醚,搅拌,加入170gAE-活性酯(式Ⅳa,含量93%,0.45mol),再分次加入138g三氯氧磷,加入过程控制反应液温度≤5℃,加完后控温0-5℃反应6小时;向反应液中加8.1g水,加入过程控制反应液温度≤5℃,加完后控温0-5℃反应1小时;将反应液抽滤,滤饼用石油醚45g洗涤,在40-50℃真空干燥,得到173.1g2-(2-二氯磷酰胺-4-噻唑基)-2-(甲氧亚氨基)乙酸硫代苯并噻唑酯 (式Ⅳb,0.35mol),摩尔收率77.8%,HPLC含量为94.5%。
5)将101.6g7β-氨基-3-[4-(1-甲基-4-吡啶鎓)-2-噻唑硫基]-3-头孢烯-4-羧酸内盐化合物(式Ⅲb,0.25mol)加入2000ml乙醇中,降温至0℃,滴加三乙胺38.5mL(0.275mol),搅拌30min,加入140.2g2-(2-二氯磷酰胺-4-噻唑基)-2-(甲氧亚氨基)乙酸硫代苯并噻唑酯(式Ⅳb,0.3mol),加入DMAP0.3g(0.0025mol),升温至8~12℃,控温搅拌4h后,蒸去乙醇,加入水2000ml,乙酸乙酯萃去过量的AE-活性酯,水层加活性炭脱色1小时,抽滤,将滤液置于冰浴下搅拌,滴加4mol/L盐酸调至pH3,静置,抽滤,干燥得白色固体。将上述白色固体加入300ml水中,滴加2M乙酸钠溶液至全部溶解,加入600ml乙酸,搅拌3h,结晶,抽滤,滤饼用少量水淋洗,45℃鼓风干燥12h,得白色固体化合物头孢洛林酯(式Ⅴ)171.5g,收率94%,HPLC纯度为99.8%。
1HNMR(DMSO-d6),δ(ppm):1.23(3H,t,J=7Hz),2.28(3H,s),1.91(3H,s),3.3(2H,brs),3.58-3.95(2H,m),4.17(2H,q,J=7Hz),4.34(3H,s),5.32(1H,d,J=5Hz), 5.92(1H,dd,J=5Hz,8Hz),8.51(2H,d,J=6Hz),8.99(3H,m),9.30(1H,m),9.70(1H, d,J=8Hz),11.0(1H,s)。
对于本领域技术人员而言,显然本发明不限于上述示范性实施例的细节,而且在不背离本发明的精神或基本特征的情况下,能够以其他的具体形式实现本发明。因此,无论从哪一点来看,均应将实施例看作是示范性的,而且是非限制性的,本发明的范围由所附权利要求而不是上述说明限定,因此旨在将落在权利要求的等同要件的含义和范围内的所有变化囊括在本发明内。
此外,应当理解,虽然本说明书按照实施方式加以描述,但并非每个实施方式仅包含一个独立的技术方案,说明书的这种叙述方式仅仅是为清楚起见,本领域技术人员应当将说明书作为一个整体,各实施例中的技术方案也可以经适当组合,形成本领域技术人员可以理解的其他实施方式。
Claims (5)
1.一种高效的头孢洛林酯合成方法,其特征在于包括以下步骤:
步骤一:一种合成头孢洛林酯的中间体化合物式III(Z)-2-(5-取代氨基-1,2,4-噻二唑-3-基)-2-乙氧亚胺基乙酸,其中,R1选自三氟乙酰基、三氟丙酰基、三氟甲磺酰基、三氯乙酰基、叔丁氧羰基、乙酰基、对甲苯磺酰基、甲磺酰基、对甲氧苄基、三苯甲基或苄基,其合成方法为:以化合物(Z)-2-(5-氨基-1,2,4-噻二唑-3-基)-2-乙氧亚胺基乙酸(式II)为原料与酸/氯化亚砜在三乙胺作用下反应得到;
步骤二:7β-[(苯乙酰)氨基]-3-[4-吡啶基-2-噻唑硫基]-3-头孢烯-4-羧酸二苯甲基酯(式Ic)在DMF、碱性试剂条件下,与甲基化试剂反应,加水并酸化析晶,得到7β-[(苯乙酰)氨基]-3-[4-(1-甲基-4-吡啶鎓)-2-噻唑硫基]-3-头孢烯-4-羧酸二苯甲基酯盐酸化物(式Ⅱ);所述甲基化试剂为碳酸二甲酯,碱性试剂为三乙胺;
步骤三:7β-[(苯乙酰)氨基]-3-[4-(1-甲基-4-吡啶鎓)-2-噻唑硫基]-3-头孢烯-4-羧酸二苯甲基酯盐酸化物(式Ⅱ)用对甲酚脱除二苯甲基,固定化青霉素G酰化酶脱除苯乙酰基,结晶、过滤、真空干燥得到7β-氨基-3-[4-(1-甲基-4-吡啶鎓)-2-噻唑硫基]-3-头孢烯-4-羧酸内盐化合物(式Ⅲb);
步骤四:在甲基叔丁基醚、石油醚的混合溶剂中,化学名称为2-(5-氨基-1,2,4-噻二唑-3-基)-2(Z)-(甲氧亚氨基)乙酸硫代苯并噻唑酯的活性酯(式Ⅳa)与三氯氧磷反应得到2-(5-二氯磷酰胺-1,2,4-噻二唑-3-基)-2(Z)-(甲氧亚氨基)乙酸硫代苯并噻唑酯(式Ⅳb);
步骤五:将7β-氨基-3-[4-(1-甲基-4-吡啶鎓)-2-噻唑硫基]-3-头孢烯-4-羧酸内盐化合物(式Ⅲb)和2-(5-二氯磷酰胺-1,2,4-噻二唑-3-基)-2(Z)-(甲氧亚氨基)乙酸硫代苯并噻唑酯(式Ⅳb)在乙醇中滴加三乙胺、DMAP反应缩合,加盐酸水解,然后在乙酸中成盐结晶得到头孢洛林酯(式Ⅴ);
所述步骤一中,优选地,R1选自三氟乙酰基、三氟丙酰基或三氟甲磺酰基;
所述步骤二中,将7β-[(苯乙酰)氨基]-3-[4-吡啶基-2-噻唑硫基]-3-头孢烯-4-羧酸二苯甲基酯(式Ic)的DMF溶液与甲基化试剂反应,加入碱性试剂,保温反应完毕后冷却至室温,加水析晶,再用盐酸调pH为1.3~2,继续搅拌析晶,过滤,水洗,干燥得到7β-[(苯乙酰)氨基]-3-[4-(1-甲基-4-吡啶鎓)-2-噻唑硫基]-3-头孢烯-4-羧酸二苯甲基酯盐酸化物(式Ⅱ);
在步骤三中,7β-[(苯乙酰)氨基]-3-[4-(1-甲基-4-吡啶鎓)-2-噻唑硫基]-3-头孢烯-4-羧酸二苯甲基酯盐酸化物(式Ⅱ)用对甲酚脱除二苯甲基时,反应温度为45-50℃,反应时间为0.5-6小时;反应完全后冷至40℃加入乙酸乙酯继续冷至10℃以下加入2%碳酸氢钠溶液萃取,收集萃取液,待用;7β-[(苯乙酰)氨基]-3-[4-(1-甲基-4-吡啶鎓)-2-噻唑硫基]-3-头孢烯-4-羧酸二苯甲基酯盐酸化物(式Ⅱ):对甲酚:乙酸乙酯:2%碳酸氢钠溶液的质量比=1:2-10:5-15:10-30;
在步骤五中,所述乙醇的体积为7β-氨基-3-[4-(1-甲基-4-吡啶鎓)-2-噻唑硫基]-3-头孢烯-4-羧酸内盐化合物(式Ⅲ)质量的15-25倍;7β-氨基-3-[4-(1-甲基-4-吡啶鎓)-2-噻唑硫基]-3-头孢烯-4-羧酸内盐化合物(式Ⅲ)、2-(5-二氯磷酰胺-1,2,4-噻二唑-3-基)-2(Z)-(甲氧亚氨基)乙酸硫代苯并噻唑酯(式Ⅳb)、三乙胺和DMAP的反应摩尔比为1:1.1~1.3:1.05~1.15:0.01~0.02,控制温度5~20℃反应3~5小时;反应液蒸去乙醇,加水,以乙酸乙酯萃取,水层加活性炭脱色,抽滤,将滤液置于冰浴下搅拌,滴加盐酸调至pH2-3,静置,抽滤,真空干燥得白色固体;将其加入水中,滴加2M乙酸钠溶液至全部溶解,加入乙酸,搅拌3小时,结晶,抽滤,滤饼用少量水淋洗,真空干燥,得头孢洛林酯(式Ⅴ)。
2.根据权利要求1所述的一种高效的头孢洛林酯合成方法,其特征在于:所述步骤一中,7-苯乙酰氨基-3-羟基-3-头孢烯-4-羧酸二苯甲酯(式Ia):脱水的二甲基甲酰胺:氯化亚砜的用料质量配比为1:5-40:0.3-3,反应温度为0-30℃,反应时间为2-8小时;7-苯乙酰氨基-3-氯-3-头孢烯-4-羧酸二苯甲酯(式Ib)与4-(4-吡啶基)-1,3-噻唑-2-硫醇钠盐的摩尔比为1:1.1~1.2;7-苯乙酰氨基-3-氯-3-头孢烯-4-羧酸二苯甲酯(式Ib)与丙酮的质量体积比为1:3~6;反应温度为40~50℃,反应时间为1~2小时。
3.根据权利要求1所述的一种高效的头孢洛林酯合成方法,其特征在于:所述步骤二中,7β-[(苯乙酰)氨基]-3-[4-吡啶基-2-噻唑硫基]-3-头孢烯-4-羧酸二苯甲基酯(式Ic)与DMF的质量体积比为1:3;7β-[(苯乙酰)氨基]-3-[4-吡啶基-2-噻唑硫基]-3-头孢烯-4-羧酸二苯甲基酯(式Ic)与甲基化试剂、碱性试剂的摩尔比为1:1.4~1.5:1.5~1.6;DMF与水的体积比为1:5~6;反应温度为35~40℃,反应时间为5~6小时。
4.根据权利要求1所述的一种高效的头孢洛林酯合成方法,其特征在于:在步骤三中,将上述萃取液中加入固定化青霉素G酰化酶IPA-450或IPA-750,用料质量配比为:7β-[(苯乙酰)氨基]-3-[4-(1-甲基-4-吡啶鎓)-2-噻唑硫基]-3-头孢烯-4-羧酸二苯甲基酯盐酸化物(式Ⅱ):固定化青霉素G酰化酶=1:0.65-1;反应温度为30-37℃,反应时间1-3小时,反应时持续加入2%碳酸氢钠溶液控制pH值在7.0-8.5;反应完成后,结晶、过滤、真空干燥得到7β-氨基-3-[4-(1-甲基-4-吡啶鎓)-2-噻唑硫基]-3-头孢烯-4-羧酸内盐化合物(式Ⅲb)。
5.根据权利要求1所述的一种高效的头孢洛林酯合成方法,其特征在于:在步骤四中,在甲基叔丁基醚、石油醚的混合溶剂中,加入化学名称为2-(5-氨基-1,2,4-噻二唑-3-基)-2(Z)-(甲氧亚氨基)乙酸硫代苯并噻唑酯的活性酯(式Ⅳa),随后加入三氯氧磷,加入过程控制反应液温度≤5℃,加完后控温0-5℃反应4-8小时;向反应液中加水,加入过程控制反应液温度≤5℃,加完后控温0-5℃反应1小时;抽滤,滤饼用石油醚洗涤,在40-50℃真空干燥,得到2-(5-二氯磷酰胺-1,2,4-噻二唑-3-基)-2(Z)-(甲氧亚氨基)乙酸硫代苯并噻唑酯(式Ⅳb);其中化学名称为2-(5-氨基-1,2,4-噻二唑-3-基)-2(Z)-(甲氧亚氨基)乙酸硫代苯并噻唑酯的活性酯(式Ⅳa)与三氯氧磷、水的摩尔比为1:2:1。
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