CN1295234C - 一种头孢呋辛酯非对映异构体的分离方法 - Google Patents
一种头孢呋辛酯非对映异构体的分离方法 Download PDFInfo
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Abstract
本发明公开了一种头孢呋辛酯非对映异构体的分离方法。本发明采用盐类添加剂和混合溶剂系统,通过结晶法对头孢呋辛酯非对映异构体实行分离。本发明的分离方法显著简化了操作过程,提高了析出固体的结晶度,一次结晶所获得的(R,R,R)异构体同时具有较为理想的收率和纯度,而且通过该方法,首次获得了(R,R,R)异构体的单晶体,确定了含有半个结晶水的(R,R,R)异构体的晶胞参数、空间群、分子的三维空间结构以及分子在空间通过氢键相互作用的情况。
Description
技术领域
本发明涉及一种药物化合物,具体的说是一种药物化合物的分离方法。
背景技术
头孢呋辛酯是头孢呋辛的前体药物。头孢呋辛是第二代头孢菌素,具有对β-内酰胺酶稳定的特性,对革兰氏阳性菌、革兰氏阴性菌和厌氧菌有广谱抗菌活性,主要用于上、下呼吸道感染、泌尿生殖道感染、皮肤和软组织感染、淋病、耳部感染等的治疗,临床疗效显著,但它在生理pH时易离解,酯溶性差,口服基本不吸收,只能通过制备成钠盐注射进肌体。然而,在头孢呋辛C1位羧基上引入酯基制成头孢呋辛酯后,提高了亲酯性,增加了口服吸收率,避免了头孢呋辛钠的药用缺陷。头孢呋辛酯摄入后,在胃肠酶的作用下水解,分解成头孢呋辛、乙醛和乙酸。释放出来的头孢呋辛再发挥其抗菌作用。引进酯基后得到的头孢呋辛酯不溶于水,略溶于95%乙醇,乙醚,易溶于丙酮、乙酸乙酯和甲醇。头孢呋辛酯含有三个手性碳原子,C6,C7位上碳原子的绝对构型都为R,是头孢呋辛在构建β-内酰胺环的时候形成的,而C1上的不对称碳原子则是头孢呋辛在酯化时由酯化基团带进结构中。因此,头孢呋辛酯存在(R,R,R)和(R,R,S)两种非对映异构体。目前市面上销售的都是无定形的头孢呋辛酯(R,R,R)和(R,R,S)非对映异构体的混合物mR/(mR+mS)=0.48(经HPLC分析),这种市售的头孢呋辛酯的生物利用度往往只有50%,这是由于头孢呋辛酯的水溶性差、在体内容易被酯酶分解成头孢呋辛而降低了其吸收率。残留于体内不被吸收的头孢呋辛累积到一定程度会引起肠胃不适。据相关权威报道,头孢呋辛酯(R,R,R)和(R,R,S)两种构型的非对映异构体在生物体内吸收和生物活性存在明显的差异,其中,(R,R,R)异构体具有较大的溶解度,其水解速率远远低于(R,R,S)异构体,因此,(R,R,R)异构体具有较强的生物利用度和生理活性,以(R,R,R)单一异构体取代临床使用的混合物,将可以提高药物的生物利用度,降低药物的副作用。所以,能否找到一种方便实用的头孢呋辛酯非对映异构体分离方法从而把(R,R,R)与(R,R,S)分开具有重要的意义。
在现有(R,R,R)异构体的分离技术中,Mosher等以甲醇和乙醇为溶剂,获得异构体的分离,得到的(R,R,R)异构体最好收率为94%(未注明纯度),最好纯度为93%(未注明收率)。现将已有的专利报道分离方法总结如下:
1、US 4267320(May 12,1981)
分离的异构体是:(R and S)-1-Acetoxyheptyl(6R,7R)-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylate(头孢呋辛酯,这里的A异构体对应的是1’S6R7R,
B异构体对应1’R6R7R)
报道了两种方法:
(1)取A和B异构体混合物1g(约1∶1),以3ml甲醇溶解并冷却至0℃结晶,放置过夜,获得0.3g的主要为异构体A的晶体(纯度未注明),母液在真空干燥器中挥干,残渣以乙酸乙酯溶解后,经石油醚沉淀得到65∶35(B/A)的固体。
(2)晶种法:
取A和B异构体混合物5.0g,于25℃以7.5ml甲醇溶解,以上述步骤(1)中所得A异构体为晶种,放冷至0℃使固体析出,并放置过夜,过滤,得到1.7g的固体,该固体以30ml甲醇重结晶后,得到相对纯的A异构体1.28g(第一部分)
母液二次结晶,获得0.11g的固体,其中A和B异构体的比率约为1∶1(第二部分)
残余母液真空干燥至残渣呈胶状,加乙酸乙酯并冷却使其固化,再加乙酸乙酯至约15ml,加热使其回流,滤出少量不溶物(0.19g),经测定主要为B异构体。(第三部分)
滤液冷却并缓慢结晶,所得固体经过滤,干燥,共获得0.41g纯度约为80%的B异构体。(第四部分)
所余滤液过滤并干燥,得到0.64g固体,B异构体纯度约为70%。(第五部分)。
2、S 5063224(Nov 5 1991)
报道了三种方法
(1):100g的固体混合物(51/49,S/R),于24℃加甲醇338ml,所得混悬液加热至60℃,并搅拌30分钟,然后放冷至24℃,过滤,从所得滤液中除去溶剂,经HPLC分析,得到纯度为93%的R异构体,剩余部分为S异构体。(注:这里均未说明产率)
(2)生产规模:加360L的甲乙醚至200加仑的不锈钢反应器中,加热至50℃,往其中加入173.2公斤的异构体混合物,并加热至60℃,搅拌1小时后放冷至30℃,过滤,滤渣以氮气流干燥15分钟,往滤渣中加入60L的甲醇,再次过滤,合并两次滤液,滤渣在40℃空气干燥,获得102.2公斤白色S异构体。(产率116%,纯度未说明)
往上述约400L的滤液中加入120L的去离子水,然后溶液冷却至2℃,在该温度下搅拌24小时,过滤获得固态晶体,固体以氮气流干燥15分钟后,再于40℃真空干燥6天,得到结晶型的R异构体无水物63公斤,经分析其中R异构体的纯度约为85%(产率74%)。
(3)取异构体混合物789g,于25℃加甲醇约3.0L,加热至50℃后溶液呈浆状,该温度下搅拌1小时后冷却至25℃,继续搅拌12小时,过滤,白色固体于45℃减压干燥,得到342g的S异构体(产率84%;纯度未说明),上述滤液减压蒸发溶剂,浓缩至600ml,再往溶液中加入600ml乙酸乙酯,最后以减压蒸发除去所有溶剂,得到362.5g的R异构体。(产率94%;纯度未说明)
3、Pol.PL 171244 B1 28Mar 1997,4pp.(Polish).(Poland).
以乙酸乙酯或丙酮溶解异构体混合物,加活性炭脱色,再往其中加入乙醇或正丙醇或异丙醇,然后再加水,过滤固体物,得到S异构体,浓缩滤液,获得R异构体。
现有专利关于头孢呋辛酯非对映异构体分离方法普遍存在R异构体收率低,析出固体结晶度低,实验后处理复杂等问题。
发明内容
本发明的目的在于针对现有头孢呋辛酯非对映异构体分离方法普遍存在一步分离所得到的(R,R,R)异构体的收率和纯度不能同时达到理想的效果、析出固体结晶度低、操作过程复杂等问题,提供一种新的头孢呋辛酯非对映异构体的分离方法,该方法提高了析出固体的结晶度,简化了实验过程,一步分离所得到的(R,R,R)和(R,R,S)异构体同时具有较好的收率和纯度。
本发明通过采用盐类添加剂和混合溶剂系统,通过结晶法对头孢呋辛酯非对映异构体实行分离,其步骤为:
(1)往头孢呋辛酯非对映异构体的混合物中加入丙酮溶解;
(2)再加入盐的水溶液混匀;
(3)冷却结晶;
(4)抽滤得到(R,R,S)固体;
(5)用丙酮和水溶液混合溶剂洗涤抽滤所得的(R,R,S)固体;
(6)蒸发步骤(4)和步骤(5)所得的滤液的混合液;
(7)抽滤得到(R,R,R)固体;
(8)用水洗涤抽滤所得(R,R,R)固体并烘干。
上述步骤(2)所述的盐为NaCl,NH4Cl,KH2PO4,Na2SO4,MgSO4,CaCl2中的一种或几种的混合物。
上述步骤(3)所述的冷却结晶的温度是4℃。
称量所得异构体的收率,用HPLC确定异构体的纯度。一次结晶得到的(R,R,R)异构体收率可达84%(纯度87%),或纯度可达95%(收率66%)。S异构体收率93%(纯度95%)。本发明还可以进一步重结晶得到纯度高达98%的(R,R,R)异构体。
本发明的有益效果:采用本发明的方法分离头孢呋辛酯非对映异构体的混合物,显著简化了操作过程,提高了析出固体的结晶度,一次结晶所获得的(R,R,R)异构体同时具有较为理想的收率和纯度,通过进一步的重结晶可得到纯度更高的活性(R,R,R)异构体。而且,通过该方法,首次获得了(R,R,R)异构体的单晶体,确定了含有半个结晶水的(R,R,R)异构体的晶胞参数、空间群、分子的三维空间结构以及分子在空间通过氢键相互作用的情况。通过与粉末衍射图相对照,证实了文献所报道的头孢呋辛酯α、β晶型均不是严格意义上的同质多晶,经TG-FTIR、DSC、IR、XRD四种方法检测后确认文献报道的头孢呋辛酯β晶型就是结晶型的(R,R,S)异构体,而α晶型则是两种异构体不同含量的混合物。
具体实施方式
实施例
取市售的头孢呋辛酯(RRR)和(RRS)混合物0.400g,边搅拌边滴加4ml丙酮,全溶,再滴加进0.2g NaCl的水溶液5ml,搅拌1h后,在冰箱4℃放置12h,冷却结晶。抽滤,得到(RRS)固体,用丙酮∶水=1∶3洗涤三次,每次3ml。滤液室温下旋转蒸发30min,抽滤,得到(RRR)固体,用水洗涤三次,每次3ml,将上述得到的固体真空干燥24h。
Claims (4)
1、一种头孢呋辛酯非对映异构体的分离方法,其特征在于包括如下步骤:
(1)往头孢呋辛酯非对映异构体的混合物中加入丙酮溶解;
(2)再加入盐的水溶液混匀;
(3)冷却结晶;
(4)抽滤;
(5)用丙酮和水混合溶剂洗涤抽滤所得固体;
(6)蒸发步骤(4)和步骤(5)所得的滤液的混合液;
(7)抽滤。
2、如权利要求1所述的头孢呋辛酯非对映异构体的分离方法,其特征在于包括如下步骤:
(1)往头孢呋辛酯非对映异构体的混合物中加入丙酮溶解;
(2)再加入盐的水溶液混匀;
(3)冷却结晶;
(4)抽滤;
(5)用丙酮和水混合溶剂洗涤抽滤所得固体;
(6)蒸发步骤(4)和步骤(5)所得的滤液的混合液;
(7)抽滤;
(8)用水洗涤抽滤所得固体并烘干。
3、如权利要求1或2所述的头孢呋辛酯非对映异构体的分离方法,其特征在于步骤(2)所述的盐为NaCl、NH4Cl、KH2PO4、Na2SO4、MgSO4、CaCl2中的一种或几种的混合物。
4、如权利要求1或2所述的头孢呋辛酯非对映异构体的分离方法,其特征在于步骤(3)所述的冷却结晶的温度是4℃。
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Publication number | Priority date | Publication date | Assignee | Title |
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GB214509A (en) * | 1923-07-03 | 1924-04-24 | Keeley Ian Goodman | Improvements in or relating to engine-starting devices |
US4267320A (en) * | 1976-02-16 | 1981-05-12 | Glaxo Laboratories Limited | Cephalosporin antibiotics |
US5063224A (en) * | 1990-07-09 | 1991-11-05 | Eli Lilly And Company | R-cefuroxime axetil |
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GB214509A (en) * | 1923-07-03 | 1924-04-24 | Keeley Ian Goodman | Improvements in or relating to engine-starting devices |
US4267320A (en) * | 1976-02-16 | 1981-05-12 | Glaxo Laboratories Limited | Cephalosporin antibiotics |
US5063224A (en) * | 1990-07-09 | 1991-11-05 | Eli Lilly And Company | R-cefuroxime axetil |
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