CN106336439A - 一种二丁酰环磷酸腺苷钙的制备方法 - Google Patents
一种二丁酰环磷酸腺苷钙的制备方法 Download PDFInfo
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- RCFZVVHQICKFQW-NGVPHMJWSA-L calcium;[(4ar,6r,7r,7ar)-6-[6-(butanoylamino)purin-9-yl]-2-oxido-2-oxo-4a,6,7,7a-tetrahydro-4h-furo[3,2-d][1,3,2]dioxaphosphinin-7-yl] butanoate Chemical compound [Ca+2].C([C@H]1O2)OP([O-])(=O)O[C@H]1[C@@H](OC(=O)CCC)[C@@H]2N1C(N=CN=C2NC(=O)CCC)=C2N=C1.C([C@H]1O2)OP([O-])(=O)O[C@H]1[C@@H](OC(=O)CCC)[C@@H]2N1C(N=CN=C2NC(=O)CCC)=C2N=C1 RCFZVVHQICKFQW-NGVPHMJWSA-L 0.000 title abstract description 5
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- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
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Abstract
本发明公开了一种二丁酰环磷酸腺苷钙的制备方法,其特征在于,包括如下步骤:(1)将环磷酸腺苷与氢氧化钙按照摩尔比为1:1~1.2加入水中,反应30~40min,过滤去除不容物,向滤液中加入体积为滤液体积的2~3倍的乙醇,待环磷酸腺苷钙盐析出后,过滤,在60~80℃下真空干燥,得到环磷酸腺苷钙;(2)将步骤(1)得到的环磷酸腺苷钙与丁酸酐按照1g:7~12ml加入反应釜中,氮气保护,搅拌反应1~3h;(3)向步骤(2)的反应液中加入3~4倍体积0~4℃水,搅拌30~40min,纳滤反应液,再浓缩截留液,冷冻干燥或喷雾干燥,即得到二丁酰环磷酸腺苷钙。本发明得到的二丁酰环磷酸腺苷钙选择性>90%,反应时间短,反应过程简单环保,适于工业应用。
Description
技术领域
本发明属于生物化工领域,具体涉及从环磷酸腺苷制备环磷酸腺苷钙与丁酸酐发生酰化反应得到产品二丁酰环磷酸腺苷钙的方法。
背景技术
环磷酸腺苷(Cyclic Adenosine-3’,5′-Mconophosphate,简称cAMP)是核苷酸的衍生物,它是人体内具有传递含氮激素作用的重要物质。当含氮激素从某一细胞分泌后随体液运行到靶细胞,作用于细胞膜上的特异受体时,激活细胞膜内的腺苷环化酶,此酶在Mg2+或Ca2+存在的条件下,使细胞中的三磷酸腺苷(ATP)转化为cAMP,再由cAMP激活蛋白质激酶,由蛋白质激酶再激活多种酶系而起强大的生理效应。故称含氮激素为第一信使,cAMP为第二信使。cAMP广泛存在于各种细胞中,对细胞的功能和代谢起着重要的调节作用。由于环磷酸腺苷(cAMP)可参与细胞分化、癌变、逆转等多种生理生化过程,具有重要的调节控制作用,是一种效果明显、毒副作用较小的非强心苷类药物。作为一个心血管药物(美心力),在临床上主要用于治疗心功能不全、心绞痛和心肌梗死,对洋地黄类强心药中毒或不敏感的患者,以及辅助治疗心律失常、慢性肺心病心衰。还用于充血性心力衰竭(CHF)、缺血性心脏病患者围术期、病毒性心肌炎、甲亢、神经系统疾病、肝胆疾病、呼吸系统疾病等疾病的治疗。同时,cAMP可以改善微循环,促进肺组织细胞的代谢,改善供氧对肺组织细胞祈祷保护作用,减少感染,也利于放射性炎症的愈合。
通过化学方法对cAMP的结构进行改造,在分子中加入两个丁酰基,使其具有较好的脂溶性,克服了cAMP使用上的局限性,可通过细胞膜在细胞内发挥作用,在细胞内转变成cAMP,激活蛋白磷酸化酶,增强心肌功能,改善外周血管循环,解除休克时胰岛素分泌的抑制,促进组织对糖的摄取,改善能量代谢;还能对抗机体内磷酸二酯酶的降解作用,作用时间较为持久和迅速,因此具有更广阔的应用前景。如二丁酰环磷腺苷钙,是cAMP的衍生物,参与人体糖、脂肪、蛋白质三大代谢,催化体内最基本的生物化学代谢,使大多数蛋白质和每类产生活性,同时产生大量ATP,改善细胞能量代谢,由扩张血管、转化异常细胞等作用。
传统的二丁酰环磷酸腺苷钙合成方法(CN 103242403A;CN 101020708A)是cAMP与三乙胺按比例投料,溶解后,减压浓缩,加入无水吡啶,振摇脱水,减压抽干,干燥得cAMP-乙胺盐。加入无水吡啶和丁酐,避光反应6-7天,酰化反应完全后用水和乙醚按步骤提取,再用无水乙醇溶解成糖浆状。最后加入氯化钙,减压浓缩至干,加入无水乙醇和乙醚,析出过滤,洗涤,减压干燥,即得二丁酰环磷酸腺苷钙。过程见图1。
传统的合成路线,先做成乙胺盐然后酰化再做成钙盐的途径,不仅工艺繁琐收率低,而且得到的产品质量较差,并且使用吡啶等具有生殖毒性的溶剂,既消耗了成本,又增加了分离难度。
发明内容
本发明所要解决的技术问题是研究一种收率较高,不使用吡啶作溶剂,且工艺简单的制备二丁酰环磷酸腺苷钙的方法。
为解决上述问题,本发明采用的技术方案如下:
一种二丁酰环磷酸腺苷钙的制备方法,包括如下步骤:
(1)将环磷酸腺苷与氢氧化钙按照摩尔比为1:1~1.2加入水中,反应30~40min,过滤去除不容物,向滤液中加入体积为滤液体积的2~3倍的乙醇,待环磷酸腺苷钙盐析出后,过滤,在60~80℃下真空干燥,得到环磷酸腺苷钙;
(2)将步骤(1)得到的环磷酸腺苷钙与丁酸酐按照1g:7~12ml加入反应釜中,氮气保护,搅拌反应1~3h;
(3)向步骤(2)的反应液中加入3~4倍体积0~4℃水,搅拌30~40min,纳滤反应液,再浓缩截留液,冷冻干燥或喷雾干燥,即得到二丁酰环磷酸腺苷钙。
步骤(1)中,环磷酸腺苷与水的质量比为1:5~6,优选1:6。
步骤(2)中,搅拌速度为200~250rpm,优选250rpm。
步骤(2)中,反应温度为120~140℃。
步骤(3)中,纳滤所用的膜截留分子量为300~500Da,纳滤压力为1~2MPa。
上述二丁酰环磷酸腺苷钙的制备方法制备得到的二丁酰环磷酸腺苷钙在本发明的保护范围之内。
上述二丁酰环磷酸腺苷钙在药物制备领域中的应用在本发明的保护范围之内。
有益效果:
1、本发明利用环磷酸腺苷制备成环磷酸腺苷钙盐,后期不需要再用氯化钙与二丁酰环磷酸腺苷置换钙离子。
2、本发明酰化反应过程不需要溶剂,不需要催化剂,高温下即可反应,大大节约了原料的成本。
3、本发明反应时间短,反应选择性高,最后产品的得率也较高。
4、本发明后处理过程采用纳滤只用到纯水,未引入金属离子与有机溶剂。
5、本发明后处理过程中可以联产丁酸盐,作为饲料添加剂。
附图说明
图1为传统的二丁酰环磷酸腺苷钙的合成方法路线图;
图2为本发明二丁酰环磷酸腺苷钙的合成反应路线图;
图3为环磷酸腺苷钙的液相图;
图4为二丁酰环磷酸腺苷钙的液相图;
图5为二丁酰环磷酸腺苷钙的质谱图,
图6为二丁酰环磷酸腺苷钙的1H NMR;(核磁氢谱图,以下为数据分析)
1H NMR(400MHz,CD3OD)δ8.58(s,1H),8.37(s,1H),6.18(s,1H),5.71(d,J=5.6Hz,1H),5.25(ddd,J=9.5,5.6,2.1Hz,1H),4.33–4.17(m,2H),4.08(td,J=10.0,4.9Hz,1H),2.52(t,J=7.4Hz,2H),2.36(t,J=7.4Hz,2H),1.67(dd,J=14.8,7.4Hz,2H),1.57(dd,J=14.8,7.4Hz,2H),0.93(t,J=7.4Hz,3H),0.87(t,J=7.4Hz,3H)。
图7为二丁酰环磷酸腺苷钙的13C NMR;(核磁碳谱图,以下为数据分析)
13C NMR(100MHz,CD3OD)δ174.74(s,1H),174.16(s,1H),153.65(s,2H),152.39(s,1H),150.72(s,1H),144.80(s,2H),123.80(s,1H),91.42(s,2H),77.17(d,J=3.8Hz,2H),74.66(d,J=8.1Hz,2H),74.22(d,J=3.8Hz,2H),67.96(d,J=6.6Hz,2H),39.96(s,2H),36.54(s,2H),19.51(s,2H),19.18(s,3H),13.97(d,J=6.8Hz,6H)。
具体实施方式
根据下述实例,可以更好地理解本发明。然而,实施所描述的内容仅用于说明本发明,而不应当也不会限制权利要求书中所详细描述的本发明。
该方案主要经过两步反应,分别是环磷酸腺苷与氢氧化钙成盐反应以及环磷酸腺苷钙盐与丁酸酐的酰化反应。具体反应方式如下:
实施例1:
准确称量环磷酸腺苷与氢氧化钙于烧杯中,并向烧杯中加入一定量的水,其中环磷酸腺苷与氢氧化钙的摩尔比为1:1.2,环磷酸腺苷与水的质量比1:6,剧烈搅拌30分钟左右,将反应液过滤,去除滤渣。
实施例2:
向上述滤液中,滴加乙醇析晶并剧烈搅拌,乙醇与滤液的体积比为3:1,将析出的环磷酸腺苷钙盐过滤,60~80℃下真空干燥,得产品环磷酸腺苷钙盐,转化率100%,选择性>99%。环磷酸腺苷钙液相图见图3。
实施例3:
酰化反应在三口烧瓶中反应,其中三口烧瓶一口接冷凝管,一口通氮气保护,一口进物料,反应在油浴中加热反应,通过磁力搅拌器进行搅拌。
反应装置如上所示,称量一定量的环磷酸腺苷钙于烧瓶中,并向其中加入一定体积的丁酸酐,其中环磷酸腺苷钙与丁酸酐的质量体积比为1g:10ml,反应分别在120℃,130℃,140℃下反应3h,反应结束后取样检测,转化率和选择性如表1所示。
表1实施例3的选择性和转化率
反应温度 | 转化率 | 选择性 |
120℃ | 63.2% | 87.4% |
130℃ | 89.7% | 92.4% |
140℃ | 97.6% | 94.6% |
实施例4:
反应装置如上所示,称量一定量的环磷酸腺苷钙于烧瓶中,并向其中加入一定体积的丁酸酐,其中环磷酸腺苷钙与丁酸酐的比为1g:7ml,1g:10ml,1g:12ml。反应分别在140℃下反应3h,反应结束后取样检测,转化率和选择性如表2所示。
表2实施例4的选择性和转化率
实施例5:
反应装置如上所示,称量一定量的环磷酸腺苷钙于烧瓶中,并向其中加入一定体积的丁酸酐,其中环磷酸腺苷钙与丁酸酐的质量体积比为1g:15ml,反应分别在140℃下反应1h,2h,3h,反应结束后取样检测,转化率和选择性如表3所示。
表3实施例5的选择性和转化率
反应时间 | 转化率 | 选择性 |
1h | 88.6% | 92.6% |
2h | 98.7% | 96.4% |
3h | 100% | 90.2% |
实施例6:
酰化反应结束后,向反应液中分批加入3倍体积的冰水,剧烈搅拌30min,体系发生水解反应,反应液通过纳滤过程分离丁酸,并将截留液浓缩2~3倍。
纳滤过程在纳滤机中进行,纳滤膜选用截留分子量30~500的膜,型号为DK1812C,纳滤过程中小分量的丁酸溶液透过纳滤膜除去,大分子量的二丁酰环磷酸腺苷钙则被循环回原溶液中。
实施例7:
纳滤过程以及膜如上所述,将之前的下层水溶液倒入纳滤机,开始纳滤,纳滤体系压力为1.5MPa,纳滤原液pH为3.32,浓缩一倍体积后向其中加入纯水,循环此过程至pH为4.52左右且几乎不变,浓缩截留液为最初的纳滤液体积的1/3左右。整个过程液相检测产品,气相检测丁酸,结果如下所示:
各液体 | 体积 | 产品浓度 | 液相纯度 | 产品总量 | 丁酸浓度 | 丁酸总量 | PH |
纳滤液 | 4.2L | 55.65g/L | 97.34% | 233.7g | 40.02g/L | 184.1g | 3.32 |
浓缩液 | 1.4L | 143.5g/L | 96% | 200.9g | 2.79g/L | 3.91g | 4.56 |
滤出液 | 20L | 0.0726g/L | 57% | 1.452g | 8.85g/L | 177g | 3.62 |
洗涤液 | 0.65L | 46.3g/L | 95% | 30.93g | 0.52g/L | 0.34g | 4.74 |
实施例8:
将上述纳滤结束后的液体,进行冷冻干燥或者喷雾干燥,得到的淡黄色固体即为产品(液相纯度为97%),得率为92.23%。取样液相检测见图4,质谱检测见图5,核磁检测见图6和图7。
Claims (7)
1.一种二丁酰环磷酸腺苷钙的制备方法,其特征在于,包括如下步骤:
(1)将环磷酸腺苷与氢氧化钙按照摩尔比为1:1~1.2加入水中,反应30~40min,过滤去除不容物,向滤液中加入体积为滤液体积的2~3倍的乙醇,待环磷酸腺苷钙盐析出后,过滤,在60~80℃下真空干燥,得到环磷酸腺苷钙;
(2)将步骤(1)得到的环磷酸腺苷钙与丁酸酐按照1g:7~12ml加入反应釜中,氮气保护,搅拌反应1~3h;
(3)向步骤(2)的反应液中加入3~4倍体积0~4℃水,搅拌30~40min,纳滤反应液,再浓缩截留液,冷冻干燥或喷雾干燥,即得到二丁酰环磷酸腺苷钙。
2.根据权利要求1所述的二丁酰环磷酸腺苷钙的制备方法,其特征在于,步骤(1)中,环磷酸腺苷与水的质量比为1:5~6。
3.根据权利要求1所述的二丁酰环磷酸腺苷钙的制备方法,其特征在于,步骤(2)中,搅拌速度为200~250rpm。
4.根据权利要求1所述的二丁酰环磷酸腺苷钙的制备方法,其特征在于,步骤(2)中,反应温度为120~140℃。
5.根据权利要求1所述的二丁酰环磷酸腺苷钙的制备方法,其特征在于,步骤(3)中,纳滤所用的膜截留分子量为300~500Da,纳滤压力为1~2MPa。
6.权利要求1~5任一项所述二丁酰环磷酸腺苷钙的制备方法制备得到的二丁酰环磷酸腺苷钙。
7.权利要求6所述的二丁酰环磷酸腺苷钙在药物制备领域中的应用。
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