CN105713011A - 一种原研制品质头孢拉定的制备方法及组合物 - Google Patents
一种原研制品质头孢拉定的制备方法及组合物 Download PDFInfo
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
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Abstract
本发明在KR840002043(B1)和US4235900(A)基础之上公开了一种原研制品质头孢拉定的制备方法，包括：(1)溶剂中加入双氢苯甘氨酸酰氯盐酸盐，降温，加入保护后的7?ADCA，混合后进行缩合反应；(2)反应结束后加入水、盐酸经水解反应，有机相层待用，水层真空蒸馏保留非馏出液；(3)非馏出液结晶过滤，滤液待用，滤饼洗涤干燥得到头孢拉定；(4)合并所述有机相层和所述滤液，回收提取头孢拉定。本发明还公开了原研制品质头孢拉定的组合物。本发明制备的头孢拉定及其组合物达到原研制品质，制备方法简单易行，整个流程反应条件相对温和，原料成本低，污染少，制备得到的头孢拉定组合物质量稳定、质量高。
Description
技术领域
本发明涉及药物化学领域，尤其涉及一种原研制品质头孢拉定的制备方法及组合物。
背景技术
头孢拉定是第一代注射或口服的头孢烯类的β-内酰胺抗生素药物，主药对耐药性金葡萄球菌和肺类克雷伯氏菌有较强的杀菌作用，对溶血性链球菌、肺类球菌、大肠埃希菌、部分变形杆菌均有抗菌作用，具有抗菌谱广、杀菌力强，过敏反应小、对β-内酰胺酶具有较高稳定性等优点。临床上主要用于治疗呼吸道、泌尿道、皮肤及软组织等感染。
头孢拉定的原研公司为百时美施贵宝，根据美国FDA橙皮书数据库可知批准时间为1982.01.01，商标名为VELOSEF(泛捷复)，并在中国上市。
目前头孢拉定原料药的生产主要为化学合成和酶法合成。
酶法合成是采用青霉素转移酰化酶催化反应。如申请号200480018394.8，名称为“制备头孢拉定的方法”的专利申请公开了一种头孢拉定的制备方法，采用在酶的作用下，使7-氨基脱乙酰氧基头孢烷酸(7-ADCA)与活化形式的D-二氢苯基甘氨酸反应得到头孢拉定，此方法避免了环境污染，但由于催化酶价格昂贵，而且选择性很强，且催化效果受气温、湿度、PH值等外部因素的影响很大；同时在反应中还存在产物、副产物对反应的抑制问题，使催化剂的催化性不能达到最大发挥。所以，目前酶法合成头孢拉定并不适用于工业化生产。
化学合成法一般以7-ADCA经四甲基胍(TMG)或DBU(1，8-二氮杂二环[5.4.0]十一碳-7-烯)保护后，与双氢苯甘氨酸经保护后的中间体双氢苯甘氨酸邓钠盐经特戊酰氯制成的混合酸酐缩合、水解、结晶而成。但特戊酰氯属危险化学品，易燃，遇明火、高热或与氧化剂接触，有引起燃烧爆炸的危险，受热或遇水分解放热，放出有毒的腐蚀性烟气，故双氢苯甘氨酸邓钠盐与特戊酰氯合成混合酸酐反应条件苛刻，反应剧烈，不易控制，很容易出现安全隐患。
发明内容
有鉴于现有技术的上述缺陷，本发明所要解决的技术问题是提供一种新型原研制品质头孢拉定的制备方法及组合物。
为实现上述目的，本发明提供了一种原研制品质头孢拉定的制备方法，包括以下步骤：
(1)在二氯甲烷溶剂中，加入双氢苯甘氨酸酰氯盐酸盐，降温至-20℃～-30℃，加入经1,8-二氮杂二环[5,4,0]十一碳-7-烯保护后的7-ADCA，混合后进行缩合反应；
(2)反应结束后，加入水、盐酸经水解反应后体系分层，有机相层待用，水层进行真空蒸馏保留非馏出液；
(3)非馏出液进行结晶，然后过滤，滤液待用，滤饼洗涤干燥后得到头孢拉定；
(4)合并所述有机相层和所述滤液，回收提取头孢拉定。
优选地，所述步骤(1)中的7-ADCA与双氢苯甘氨酸酰氯盐酸盐的质量比为1:1.2。
优选地，所述步骤(1)中的1,8-二氮杂二环[5,4,0]十一碳-7-烯与7-ADCA的质量为1：1.1。
优选地，所述步骤(2)中真空蒸馏直至水溶液中残留的二氯甲烷量小于0.8％w/w。
进一步地，所述步骤(4)中的回收提取工艺包括以下步骤：
(5)将合并液经聚酰胺膜处理浓缩至合并液原始体积的15％～25％，得到浓缩液1，透过液待用；
(6)透过液经聚酰胺膜处理浓缩至透过液原始体积的10％～15％，得到浓缩液2；
(7)将浓缩液1和浓缩液2合并，通过β-萘酚络合提取头孢拉定。
通过上述步骤，浓缩时，避免采用旋转蒸发等方式造成的有效成分的分解，浓缩时，不存在相变，大大降低了能耗，并实现废液中头孢的回收率，实现了资源的循环利用，保护了环境。
本发明还提供了一种原研制品质头孢拉定组合物，按重量计，所述组合物组成如下：
L-精氨酸 400～600份；
头孢拉定 1000份；
所述头孢拉定通过上述制备方法制得。
本发明具有以下有益效果：
(1)本发明头孢拉定的制备方法简单易行，整个流程反应条件相对温和，原料成本低，污染少，制备得到的头孢拉定组合物质量稳定，质量高；
(2)通过将头孢拉定、盐酸、残余的二氯甲烷的混合体系进行真空蒸馏，易形成稳定的头孢拉定水相，避免了溶液中头孢拉定盐酸盐的不可控的结晶，从而避免结晶前过滤不可控结晶步骤导致头孢拉定的降解以及产率的降低，也进一步减少头孢拉定可能存在的二氯甲烷而使产品质量得到改善。
具体实施方式
实施例1(头孢拉定的制备)
(1)加入100g 7-ADCA，二氯甲烷500ml，通入氮气，搅拌，加入120mlN-甲基乙酰胺，加热至45℃，缓慢加入再缓慢加入90g 1,8-二氮杂二环[5,4,0]十一碳-7-烯，恒温回流反应1.5～2小时得到7-ADCA硅脂；
(2)二氯甲烷300ml中加入加入120g双氢苯甘氨酸酰氯盐酸盐，降温至-20℃～-30℃；缓慢滴加0℃的7-ADCA硅脂，维持-5℃～-10℃，缩合反应2小时；
(3)向水解罐中加入500ml水，冷却至2℃，将上步缩合反应后的反应液和140ml的浓盐酸加入至水解罐中，10℃下搅拌15min，静置，分离有机相层待用；水层快速加热至38℃，同时在真空条件下蒸馏，以出去残留的二氯甲烷；当GC色谱显示二氯甲烷浓度为0.7％w/w时，停止蒸馏，得到稳定的头孢拉定澄清溶液(非馏出液)。
(3)非馏出液加入三乙胺调节pH至3.0，加入晶种，继续用三乙胺调节pH至5～5.5，冷却至5℃，静置过夜结晶，得到结晶液。将结晶液过滤，滤液待用，滤饼用水和丙酮洗涤后，真空干燥，得到头孢拉定。
实施例2(头孢拉定的回收)
合并实施例1中的有机相层和所述滤液，将合并液通过0.45μm微孔过滤膜，然后泵入聚酰胺膜装置处理，先浓缩至合并液原始体积的65％～75％，然后再加入现体积的1-2倍的水，再浓缩至合并液原始体积的15％～25％，得到浓缩液1，透过液待用；
透过液泵入聚酰胺膜装置处理，浓缩至透过液原始体积的10％～15％，得到浓缩液2；
将浓缩液1和浓缩液2合并，通过β-萘酚络合方式提取头孢拉定。
实施例3(组合物的制备)
取L-精氨酸、实施例1制备的头孢拉定，重量计，按照L-精氨酸400份，头孢拉定1000份的配比，置于注射用水中，搅拌使其溶解。于QZR-5型喷雾干燥器中喷雾干燥，进口温度105℃～115℃，出口温度50℃～55℃，进料量25～40ml/min，喷头压力0.25～0.40kgf/cm2，与旋风分离器处收集混粉，即得成品。取成品，按分装装量为0.765克(相当于头孢拉定0.5克)进行分装，之后轧盖、包装，即得。
实施例4(组合物的制备)
取L-精氨酸、实施例1制备的头孢拉定，重量计，按照L-精氨酸600份，头孢拉定1000份的配比，置于注射用水中，搅拌使其溶解。于QZR-5型喷雾干燥器中喷雾干燥，进口温度105℃～115℃，出口温度50℃～55℃，进料量25～40ml/min，喷头压力0.25～0.40kgf/cm2，与旋风分离器处收集混粉，即得成品。取成品，按分装装量为0.765克(相当于头孢拉定0.5克)进行分装，之后轧盖、包装，即得。
实施例5
对随机购买的3家已上市(分别计为市售-1、市售-2及市售-3)注射用头孢拉定(0.5g规格)及实施例3随机批次制备的注射用头孢拉定进行质量检测。所得数据见表1。
表1 质量检测结果
以上数据可以看出，在含量均匀度方面，实施例3要大大高于已上市的3家市售品，且具有更低的含水量，说明本发明制备的样品具有较优的质量。
以上详细描述了本发明的较佳具体实施例。应当理解，本领域的普通技术人员无需创造性劳动就可以根据本发明的构思作出诸多修改和变化。因此，凡本技术领域中技术人员依本发明的构思在现有技术的基础上通过逻辑分析、推理或者有限的实验可以得到的技术方案，皆应在由权利要求书所确定的保护范围内。
Claims (6)
1.一种原研制品质头孢拉定的制备方法，其特征在于，包括以下步骤：
(1)在二氯甲烷溶剂中，加入双氢苯甘氨酸酰氯盐酸盐，降温至-20℃～-30℃，加入经1,8-二氮杂二环[5,4,0]十一碳-7-烯保护后的7-ADCA，混合后进行缩合反应；
(2)反应结束后，加入水、盐酸经水解反应后体系分层，有机相层待用，水层进行真空蒸馏保留非馏出液；
(3)非馏出液进行结晶，然后过滤，滤液待用，滤饼洗涤干燥后得到头孢拉定；
(4)合并所述有机相层和所述滤液，回收提取头孢拉定。
2.如权利要求1所述的原研制品质头孢拉定的制备方法，其特征在于，所述步骤(1)中的7-ADCA与双氢苯甘氨酸酰氯盐酸盐的质量比为1:1.2。
3.如权利要求1所述的原研制品质头孢拉定的制备方法，其特征在于，所述步骤(1)中的1,8-二氮杂二环[5,4,0]十一碳-7-烯与7-ADCA的质量比为1：1.1。
4.如权利要求1所述的原研制品质头孢拉定的制备方法，其特征在于，所述步骤(2)中真空蒸馏直至水溶液中残留的二氯甲烷量小于0.8％w/w。
5.如权利要求1所述的原研制品质头孢拉定的制备方法，其特征在于，所述步骤(4)中的回收提取工艺包括以下步骤：
(5)将合并液经聚酰胺膜处理浓缩至合并液原始体积的15％～25％，得到浓缩液1，透过液待用；
(6)透过液经聚酰胺膜处理浓缩至透过液原始体积的10％～15％，得到浓缩液2；
(7)将浓缩液1和浓缩液2合并，通过β-萘酚络合提取头孢拉定。
6.一种原研制品质头孢拉定组合物，其特征在于，按重量计，所述组合物组成如下：
L-精氨酸 400～600份；
头孢拉定 1000份；
所述头孢拉定通过权利要求1-5任一项所述制备方法制得。
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