CN112707919A - 利用石墨烯负载铜催化剂合成3-去氨甲酰基头孢呋辛酸的方法 - Google Patents
利用石墨烯负载铜催化剂合成3-去氨甲酰基头孢呋辛酸的方法 Download PDFInfo
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- 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
- C07D501/06—Acylation of 7-aminocephalosporanic acid
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Abstract
本发明涉及医药合成技术领域,具体涉及一种利用石墨烯负载铜催化剂合成3‑去氨甲酰基头孢呋辛酸的方法。在石墨烯负载铜催化剂的作用下,呋喃铵盐与7‑氨基头孢烷酸发生酰胺化反应,再加入碱液,发生水解反应,过滤,滤液析晶得到3‑去氨甲酰基头孢呋辛酸。本发明大幅缩短了目标化合物的合成步骤,且避免了三氯氧磷或五氯化磷等酰胺化试剂的使用,降低了目标产物中反式异构杂质的含量,提高了产物收率,并且催化剂回收率高,减少了石墨烯负载铜催化剂的用量,具有工艺操作简单,成本低,安全性可靠的特点。
Description
技术领域
本发明涉及医药合成技术领域,具体涉及一种利用石墨烯负载铜催化剂合成3-去氨甲酰基头孢呋辛酸的方法。
背景技术
3-去氨甲酰基头孢呋辛酸是合成头孢呋辛酸的中间产物。目前,该化合物的合成方法是先将7-氨基头孢烷酸(7-ACA)与N-甲氧亚氨基呋喃乙酰氯(SMIF-Cl)在7位上酰胺化缩合,然后水解去掉3位上的乙酰基得到。其中,7位上的酰胺化缩合反应是工艺合成的关键。该合成方法使用SMIF-Cl作为酰胺化试剂,存在以下问题:1、SMIF-Cl的合成工序繁琐且路线较长,需要先将呋喃铵盐合成呋喃乙酸,再与酰化试剂酰化合成SMIF-Cl,最后经酰胺化合成目标产物。2、SMIF-Cl合成过程中使用三氯氧磷或五氯化磷做酰化试剂,造成呋喃铵盐上Z型甲氧亚胺基(C=N-OR)在酸性环境中极易发生异构化,生成E型异构体杂质且很难除去。3、由于SMIF-Cl的活泼性较高,室温下极易发生分解,不适合长期储存,给生产造成较大困难。4、合成温度为-20~-40℃,工艺能耗较高,且产生大量废水和磷酸盐固体微废。
如中国专利CN102702231A公开一种3-去氨甲酰基-头孢呋辛酸的制备方法:(1)将7-ACA溶于水或甲醇溶液中配制7-ACA溶液,水解反应,得7-DACA溶液;(2)将酰氯化试剂溶于溶剂中,加入助溶剂,然后加入SMIA,反应后过滤,加水或旋蒸除去过量的酰氯化试剂,然后真空旋蒸,加入均相化试剂溶解,制得SMIF-Cl溶液;(3)向7-DACA溶液中加入均相化试剂,然后滴加SMIF-Cl溶液,调pH值,保温反应,得反应液;(4)将反应液经脱色后,调pH值,然后加入纯化水,养晶,过滤,真空干燥,即得。
中国专利CN111440196A公开一种镍基催化合成3-去氨甲酰基头孢呋辛酸的方法,将2-呋喃基-2-甲氧亚氨基乙酸和镍基催化剂置于反应装置中,再加入溶剂,搅拌均匀得到第一混合物;将3-氨基头孢烷酸溶解在氢氧化钠溶液中得到第二混合物;将所述第二混合物加入所述第一混合物中,进行第一反应,再向中加入碱液,进行第二反应,得到3-去氨甲酰基头孢呋辛酸。该专利采用的催化剂为镍基有机化合物,市场价格偏贵,由该催化剂合成的3-去氨甲酰基头孢呋辛酸在人体内容易形成金属元素残留物,影响身体健康,且该专利的催化剂回收率低。
发明内容
本发明的目的是提供一种石墨烯负载铜催化剂合成3-去氨甲酰基头孢呋辛酸的方法,在石墨烯负载铜催化剂的作用下,避免了呋喃铵盐的异构化,降低了产物中反式异构体杂质的含量,提高了产物收率,石墨烯负载铜催化剂的回收率高。
本发明解决其技术问题所采取的技术方案是:
所述的利用石墨烯负载铜催化剂合成3-去氨甲酰基头孢呋辛酸的方法:在石墨烯负载铜催化剂的作用下,呋喃铵盐与7-氨基头孢烷酸发生酰胺化反应,再加入碱液,发生水解反应,过滤,滤液析晶得到3-去氨甲酰基头孢呋辛酸。
其中:
呋喃铵盐与7-氨基头孢烷酸的摩尔比为1.1~1.3:1。
石墨烯负载铜催化剂的用量为呋喃铵盐质量的30~55%。
酰胺化反应温度为10~30℃,优选25~30℃;酰胺化反应时间为2~8h,优选4~6h。
水解反应温度为-20~-10℃,水解反应时间为10~20min,优选15min。
本发明所述的利用石墨烯负载铜催化剂合成3-去氨甲酰基头孢呋辛酸的方法,具体包括:
(1)将呋喃铵盐和石墨烯负载铜催化剂置于反应装置中,再加入溶剂,搅拌得到第一混合物;
(2)将7-氨基头孢烷酸溶解在氢氧化钠溶液中得到第二混合物;
(3)将第二混合物加入第一混合物中,进行酰胺化反应;之后再加入碱液进行水解反应,过滤,滤液析晶得到3-去氨甲酰基头孢呋辛酸。
其中:
溶剂为甲苯、丙酮、四氢呋喃、N,N-二甲基甲酰胺或二氯甲烷,优选四氢呋喃或N,N-二甲基甲酰胺。
溶剂与呋喃铵盐的用量比为3~10:1,其中溶剂以ml计,呋喃铵盐以g计。
氢氧化钠溶液与7-氨基头孢烷酸的质量比为1.6~3:1,氢氧化钠溶液为15wt.%的氢氧化钠水溶液。
碱液为15wt.%的氢氧化钠溶液,碱液与7-氨基头孢烷酸的质量比为1.6~3:1;加入碱液的目的是为了水解除去甲酰基,为酯的水解。
滤液中加入10wt.%盐酸进行析晶,过滤得到的滤饼为石墨烯负载铜催化剂,经二氯甲烷洗涤、干燥,循环利用。
将呋喃铵盐和石墨烯负载铜催化剂置于反应装置中,该装置是密闭的,需预先干燥。
本发明石墨烯负载铜催化剂中铜的负载量为石墨烯质量的15~20wt.%,其制备方法如下:
将20~25g氧化石墨分散在10L蒸馏水中,超声处理形成分散液,搅拌10~15min,加入氢氧化钠溶液调节pH值至10,再加入24~26g抗坏血酸,搅拌20~30min,形成反应液;将7~8g硫酸铜溶于0.5L蒸馏水中,制得硫酸铜溶液,再将该硫酸铜溶液缓慢滴加至反应液中,于100~110℃下反应1.5~2小时。反应结束后向其中加入蒸馏水,静置分层,保留下层溶液,先后用蒸馏水、无水乙醇溶液分别洗涤离心3次,得到的固体于50~55℃下真空干燥10~12小时,得到石墨烯负载铜催化剂。
本发明的反应方程式为:
本发明的有益效果如下:
本发明采用的石墨烯负载铜催化剂,具体地为氧化石墨烯和铜纳米粒子形成的空间立体结构催化剂。氧化石墨烯上丰富的羧基所提供的酸性微环境,促进了呋喃铵盐在温和的环境下在石墨烯表面形成呋喃羧酸分子结构,继而通过铜纳米粒子的催化,与7-氨基头孢烷酸7位上的氨基发生酰胺化反应构建碳氮键,最终得到酰胺化产物。本发明将铜元素负载于石墨烯上,形成铜元素和石墨烯共催化,具有高效和循环利用高的特点,且分离方法简单,不易产生残留,洁净、环保、综合成本低。
本发明以呋喃铵盐为起始原料,在石墨烯负载铜催化剂的作用下,一步催化呋喃铵盐直接与7-ACA上的氨基进行酰胺化反应,再加入碱液进行水解反应,合成3-去氨甲酰基头孢呋辛酸。该方法大幅度缩短了目标化合物的合成步骤,且避免了三氯氧磷或五氯化磷等酰胺化试剂的使用,避免了呋喃铵盐上Z型甲氧亚胺基(C=N-OR)发生异构化,目标产物中反式异构杂质的含量降低至0.05%以下,提高了产物收率,纯度可达到99%以上,并且催化剂回收率高,能够循环使用,减少了石墨烯负载铜催化剂的用量,具有工艺操作简单,成本低,安全性可靠的特点。
附图说明
图1为本发明石墨烯负载铜催化剂中石墨烯的结构示意图;
图2为本发明实施例1中3-去氨甲酰基头孢呋辛酸产品的氢谱图。
具体实施方式
以下结合实施例对本发明做进一步描述。
实施例1
向密闭的预先干燥好的反应容器内,加入22.6g(0.121mol,1.1equiv.)呋喃铵盐和10g石墨烯负载铜催化剂,再加入150mL二氯甲烷后,在室温下充分搅拌30分钟,得到第一混合物;将30g(0.11mol)7-氨基头孢烷酸溶解在50g 15wt.%的氢氧化钠水溶液中得到第二混合物;将第二混合物缓慢加入第一混合物中,在20℃下继续反应4h。然后,降温至-20℃后加入50g 15wt.%氢氧化钠溶液,继续反应20min,过滤,过滤得到的滤饼为石墨烯负载铜催化剂,经二氯甲烷洗涤、干燥,循环利用。滤液继续滴加10wt.%盐酸析晶,过滤得到37.2g3-去氨甲酰基头孢呋辛酸;产率为88.6%,反式异构杂质含量为0.01%,纯度为99.3%。催化剂回收率为99.6wt.%。3-去氨甲酰基头孢呋辛酸的氢谱图如图2所示:1H NMR(600MHz,(CD3)2SO,δppm):9.77(d,J=7.8Hz,1H),7.84(dd,J=1.8Hz,J=0.6Hz,1H),6.70(dd,J=4.2Hz,J=0.6Hz,1H),6.64-6.63(m,1H),5.76-5.74(m,1H),5.14(d,J=4.8Hz,1H),4.29-4.22(m,2H),3.89(s,3H),3.58(dd,J=48.6Hz,J=18Hz,2H).
实施例2
向密闭的预先干燥好的反应容器内,加入53.6g(0.288mol,1.2equiv.)呋喃铵盐和20g石墨烯负载铜催化剂,再加入300mL丙酮后,在室温下充分搅拌30分钟,得到第一混合物;将65g(0.24mol)7-氨基头孢烷酸溶解在110g 15wt.%的氢氧化钠水溶液中得到第二混合物;将第二混合物缓慢加入第一混合物中,在25℃下继续反应5h。然后,降温至-10℃后加入110g15wt.%氢氧化钠溶液,继续反应10min,过滤,过滤得到的滤饼为石墨烯负载铜催化剂,经二氯甲烷洗涤、干燥,循环利用。滤液继续滴加10wt.%盐酸析晶,过滤得到85.8g 3-去氨甲酰基头孢呋辛酸;产率为94.3%,反式异构杂质含量为0.03%,纯度为99.2%。催化剂回收率为99.7wt.%。
实施例3
向密闭的预先干燥好的反应容器内,加入58.0g(0.312mol,1.3equiv.)呋喃铵盐和25g石墨烯负载铜催化剂,再加入200mLN,N-二甲基甲酰胺后,在室温下充分搅拌30分钟,得到第一混合物;将65g(0.24mol)7-氨基头孢烷酸溶解在130g 15wt.%的氢氧化钠水溶液中得到第二混合物;将第二混合物缓慢加入第一混合物中,在10℃下继续反应8h。然后,降温至-10℃后加入130g 15wt.%氢氧化钠溶液,继续反应10min,过滤,过滤得到的滤饼为石墨烯负载铜催化剂,经二氯甲烷洗涤、干燥,循环利用。滤液继续滴加10wt.%盐酸析晶,过滤得到84.5g 3-去氨甲酰基头孢呋辛酸;产率为92.9%,反式异构杂质含量为0.01%,纯度为99.1%。催化剂回收率为99.7wt.%。
实施例4
向密闭的预先干燥好的反应容器内,加入58.0g(0.312mol,1.3equiv.)呋喃铵盐和30g石墨烯负载铜催化剂,再加入250mL四氢呋喃后,在室温下充分搅拌30分钟,得到第一混合物;将65g(0.24mol)7-氨基头孢烷酸溶解在120g 15wt.%的氢氧化钠水溶液中得到第二混合物;将第二混合物缓慢加入第一混合物中,在30℃下继续反应2h。然后,降温至-15℃后加入120g 15wt.%氢氧化钠溶液,继续反应10min,过滤,过滤得到的滤饼为石墨烯负载铜催化剂,经二氯甲烷洗涤、干燥,循环利用。滤液继续滴加10wt.%盐酸析晶,过滤得到83.2g 3-去氨甲酰基头孢呋辛酸;产率为91.4%,未检测到反式异构杂质,纯度为99.4%。催化剂回收率为99.6wt.%。
对比例1
不添加石墨烯负载铜催化剂,其余步骤同实施例1。得到0g 3-去氨甲酰基头孢呋辛酸;产率为0wt.%,反应不进行。
对比例2
不添加石墨烯负载铜催化剂,其余步骤同实施例2。得到0g 3-去氨甲酰基头孢呋辛酸;产率为0wt.%,反应不进行。
本发明实施例1~4中所述的石墨烯负载铜催化剂中铜的负载量为石墨烯质量的20wt.%,其制备方法如下:
将20g氧化石墨分散在10L蒸馏水中,超声处理形成分散液,搅拌10min,加入氢氧化钠溶液调节pH值至10,再加入25g抗坏血酸,搅拌25min,形成反应液;将8g硫酸铜溶于0.5L蒸馏水中,制得硫酸铜溶液,再将该硫酸铜溶液缓慢滴加至反应液中,于110℃下反应1.5小时。反应结束后向其中加入蒸馏水,静置分层,保留下层溶液,先后用蒸馏水、无水乙醇溶液分别洗涤离心3次,得到的固体于50℃下真空干燥10小时,得到石墨烯负载铜催化剂。
Claims (10)
1.一种利用石墨烯负载铜催化剂合成3-去氨甲酰基头孢呋辛酸的方法,其特征在于:在石墨烯负载铜催化剂的作用下,呋喃铵盐与7-氨基头孢烷酸发生酰胺化反应,再加入碱液,发生水解反应,过滤,滤液析晶得到3-去氨甲酰基头孢呋辛酸。
2.根据权利要求1所述的利用石墨烯负载铜催化剂合成3-去氨甲酰基头孢呋辛酸的方法,其特征在于:呋喃铵盐与7-氨基头孢烷酸的摩尔比为1.1~1.3:1。
3.根据权利要求1所述的利用石墨烯负载铜催化剂合成3-去氨甲酰基头孢呋辛酸的方法,其特征在于:石墨烯负载铜催化剂的用量为呋喃铵盐质量的30~55%。
4.根据权利要求1所述的利用石墨烯负载铜催化剂合成3-去氨甲酰基头孢呋辛酸的方法,其特征在于:酰胺化反应温度为10~30℃,酰胺化反应时间为2~8h。
5.根据权利要求1所述的利用石墨烯负载铜催化剂合成3-去氨甲酰基头孢呋辛酸的方法,其特征在于:水解反应温度为-20~-10℃,水解反应时间为10~20min。
6.根据权利要求1~5任一所述的利用石墨烯负载铜催化剂合成3-去氨甲酰基头孢呋辛酸的方法,其特征在于:将呋喃铵盐和石墨烯负载铜催化剂加入溶剂,搅拌得到第一混合物;将7-氨基头孢烷酸溶解在氢氧化钠溶液中得到第二混合物;将第二混合物加入第一混合物中,进行酰胺化反应;之后再加入碱液进行水解反应,过滤,滤液析晶得到3-去氨甲酰基头孢呋辛酸。
7.根据权利要求6所述的利用石墨烯负载铜催化剂合成3-去氨甲酰基头孢呋辛酸的方法,其特征在于:溶剂为甲苯、丙酮、四氢呋喃、N,N-二甲基甲酰胺或二氯甲烷。
8.根据权利要求7所述的利用石墨烯负载铜催化剂合成3-去氨甲酰基头孢呋辛酸的方法,其特征在于:溶剂与呋喃铵盐的用量比为3~10:1,其中溶剂以ml计,呋喃铵盐以g计。
9.根据权利要求6所述的利用石墨烯负载铜催化剂合成3-去氨甲酰基头孢呋辛酸的方法,其特征在于:氢氧化钠溶液与7-氨基头孢烷酸的质量比为1.6~3:1,氢氧化钠溶液为15wt.%的氢氧化钠水溶液。
10.根据权利要求6所述的利用石墨烯负载铜催化剂合成3-去氨甲酰基头孢呋辛酸的方法,其特征在于:滤液中加入10wt.%盐酸进行析晶,过滤得到的滤饼为石墨烯负载铜催化剂,循环利用。
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