CN108753898A - 一种米索前列醇酸的制备方法及其用途 - Google Patents
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- OJLOPKGSLYJEMD-URPKTTJQSA-N methyl 7-[(1r,2r,3r)-3-hydroxy-2-[(1e)-4-hydroxy-4-methyloct-1-en-1-yl]-5-oxocyclopentyl]heptanoate Chemical compound CCCCC(C)(O)C\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)OC OJLOPKGSLYJEMD-URPKTTJQSA-N 0.000 claims abstract description 18
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- HHBZJXGYROTGEG-ZHACJKMWSA-N methyl 7-[2-[(e)-4-hydroxy-4-methyloct-1-enyl]-5-oxocyclopenten-1-yl]heptanoate Chemical compound CCCCC(C)(O)C\C=C\C1=C(CCCCCCC(=O)OC)C(=O)CC1 HHBZJXGYROTGEG-ZHACJKMWSA-N 0.000 description 1
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P31/00—Preparation of compounds containing a five-membered ring having two side-chains in ortho position to each other, and having at least one oxygen atom directly bound to the ring in ortho position to one of the side-chains, one side-chain containing, not directly bound to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having at least one oxygen atom bound in gamma-position to the ring, e.g. prostaglandins
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Abstract
本发明提供一种米索前列醇酸的制备方法及其用途，公开了一种高效制备米索前列醇酸的方法，通过将米索前列醇在生物酶的作用下水解制得，使得反应专一，副产物少，操作简单，工艺稳定，重现性好，且产物稳定，降低了成本，使米索前列醇酸商业化生产和批量化供应得以实现。
Description
技术领域
本发明涉及米索前列醇药物制造技术领域，具体地涉及米索前列醇药物制造过程中的质量控制技术。
背景技术
米索前列醇是经过人工合成的前列腺素(prostaglandin，PG) E1的衍生物,其结构如下式II所示：
它能抑制胃酸分泌,保护胃黏膜,用于治疗急性胃、十二指肠溃疡。此外，它还具有保护细胞、促进平滑肌的收缩等功效,特别是在终止早、中、晚期妊娠和产后出血,促进宫颈成熟、诱导分娩等方面效果明显，目前被广泛应用于临床工作中。
米索前列醇酸是米索前列醇体内的代谢产物，也是米索前列醇药物或其制剂的重要杂质之一，其可用于米索前列醇在体内吸收、代谢等毒理药理研究，还可以用于米索前列醇制剂稳定性及质量控制等方面的研究。
生物酶作为生物催化剂具有高度的区域选择性,特别适合于一般化学方法难以实现的多功能化合物的合成,能很好地避免多取代产物等副产物的产生。另外还具有催化反应条件温和、无环境污染等优越性,已被广泛应用于食品、造纸、皮革、洗涤剂、化工材料和医药合成等诸多领域,其中,药物合成一直是酶研究领域的热点。
到目前为止，国内外尚无文献或专利报道米索前列醇酸的合成。笔者亦尝试过化学方法合成米索前列醇酸，但均未成功。经过进一步的研究，发现了一种生物酶催化高效合成米索前列醇酸的方法。即通过将米索前列醇在生物酶的作用下水解制得。本发明具有反应物廉价、反应专一化，所的产物稳定等特点。
发明内容
为此，本发明所要解决的技术问题是：提供米索前列醇酸的制备方法及其用途。
于是，本发明提供了以下技术方案：
一种米索前列醇酸的制备方法，包括以下步骤：
将米索前列醇溶解在溶剂中，在生物酶作用下，加入碱，反应完全后经柱层析纯化制得米索前列醇酸。
作为优选实施方式，该方法中所述的溶剂为：N，N-二甲基甲酰胺、N，N-二甲基乙酰胺、1,4-二氧六环、四氢呋喃、乙腈、丙酮、水中的一种或几种的组合。
作为优选实施方式，该方法中所述的生物酶为：脂肪酶、猪肝酯酶PLE(Pig LiverEsterase)、猪胰脂肪酶、酵母脂肪酶和Lipozym 435脂肪酶中的一种。
作为优选实施方式，该方法中所述的碱为磷酸氢二钾、磷酸氢二钠、碳酸钾、碳酸钠、碳酸氢钠、三乙胺、N,N-二异丙基乙胺、4- 二甲氨基吡啶、吡啶中的一种，且碱与米索前列醇的物质的量比为： (0.1～1):1。
作为优选实施方式，该方法中反应温度控制在10～40℃，优选 37℃。
本发明的另一方面，提供米索前列醇酸在制备米索前列醇的原料药或制剂中用于质量控制的用途。
具体地，所述米索前列醇酸用作米索前列醇或其衍生物药物中杂质或有关物质检查的对照品或标准品。
本发明公开了一种高效制备米索前列醇酸的方法，通过将米索前列醇在生物酶的作用下水解制得，使得反应专一，副产物少，操作简单，工艺稳定，重现性好，且产物稳定，降低了成本，使米索前列醇酸商业化生产和批量化供应得以实现。
附图说明
图1为实施例1中米索前列醇酸的MS谱图。
图2为实施例1中米索前列醇酸的1HNMR谱图。
图3为实施例2中米索前列醇酸的杂质含量测定结果图。
图4为实施例3中米索前列醇酸的杂质含量测定结果图。
具体实施方式
下面结合实施例进一步阐明本发明的内容，但本发明的保护范围并不仅仅局限于这些实施例。本发明所述的百分比除特别注明外，均为重量百分比。说明书中所描述的数值范围，如计量单位或百分比，均是为了提供明白无误的书面参考。本领域熟练技术人员在实践本专利时，基于本发明的教导和原则，使用在此范围之外或有别于单个数值的温度、浓度、数量等，仍然可以得到预期的结果。
术语及定义：
“杂质”：任何影响药物纯度的物质均称为杂质，一般而言，杂质是指在生产和储存过程中引进或产生的活性药物物质以外的其他化学物质。本领域技术人员公知，可以利用光谱方法和通过其它物理方法识别次要产物、副产物和附加试剂(总称为“杂质”)，于是杂质与色谱中的峰位置(或薄层色谱板上的斑点)有关(Strobel，H.A.； Heineman，W.R.，Chemical Instrumentation：Asystematic Approach， 3rd.(Wiley&Sons：NewYork1989))。此后，杂质可以通过其在所述色谱中的位置被识别出来，色谱中的位置通常用样品注射到柱上和特定的组分经检测器流出之间的时间以分钟计算，被称为“保留时间”。这一时间段基于使用仪器的条件和许多其它因素每天变化。为减轻这样变化对杂质准确鉴别的影响，专业人员使用“相对保留时间”(或相对保留值)来鉴别杂质。杂质的相对保留值是其保留时间除以参考标记物(例如对照品或参比标准品)的保留时间的比值。
“对照品”与“标准品”：制药领域的研发人员都知道，相当纯态的化合物可用作“标准品”或“对照品”。对照品一般系指用于鉴别、检查、含量测定和校正检定仪器性能的标准物质，而标准品系通常指用于生物检定、抗生素或生物药品中含量或效价测定的标准物质。本发明中对二者不做严格区分。标准品可用于定性分析，也用于定量测定未知混合物中待检测化合物的含量。在采用相同技术分析已知浓度的标准品的溶液以及未知混合物时，标准品是“外标物”。化合物在混合物中的含量可以通过比较检测器响应值大小来测定。
实施例1米索前列醇酸的制备
往100mL单口瓶中加入米索前列醇(3.82g,10mmol,1.0eq)，再加入四氢呋喃(40mL)及水(10mL)使其溶解，然后加入猪肝酯酶PLE(200mg,15000U/g)及碳酸氢钠(168mg，2mmol，0.2eq)，于37℃搅拌反应24小时。离心除去猪肝酯酶，反应液浓缩。再向反应瓶中加入35mL水，用乙酸调节pH≈6，然后用50mL乙酸乙酯萃取，分液。水相再用30mL乙酸乙酯萃取两次。合并有机相，再用无水硫酸钠干燥，浓缩，柱层析分离得到黄色油状物，纯度98％，即为米索前列醇酸。
测得米索前列醇酸的MS谱图参看附图1(MS(m/z)：367(M-H) +)；测得米索前列醇酸的1HNMR谱图参看附图2，1HNMR数据如下：
1H NMR(400MHz,DMSO-d6)：δ5.53(m,1H),5.36 (m,1H),3.89(m,1H),2.56(d,J＝8Hz,1H),2.25(m,1H), 1.97-2.09(m,4H),1.84(t,J＝8Hz,2H),1.36-1.43(m,4H), 1.16-1.27(m,12H),1.02(s,3H),0.86(t,J＝8Hz,3H)。
实施例2米索前列醇酸用作米索前列醇药物中杂质含量测定的对照品
测试条件及方法：
米索前列醇酸的杂质含量测定结果图参见附图3，具体数据如下表所示。
Area Percent Report
实施例3：米索前列醇酸用作米索前列醇药物中杂质含量测定的标准品
测试条件及方法：
米索前列醇酸的杂质含量测定结果图参见附图4，图中，A为米索前列醇酸，B为米索前列醇。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (9)
1.一种米索前列醇酸的制备方法，包括以下步骤：
将米索前列醇溶解在溶剂中，在生物酶作用下，加入碱，反应完全后经柱层析纯化制得米索前列醇酸。
2.根据权利要求1所述的米索前列醇酸的制备方法，其特征在于该方法中所述的溶剂为：N，N-二甲基甲酰胺、N，N-二甲基乙酰胺、1,4-二氧六环、四氢呋喃、乙腈、丙酮、水中的一种或几种的组合。
3.根据权利要求1或2所述的米索前列醇酸的制备方法，其特征在于该方法中所述的生物酶为：脂肪酶、猪肝酯酶PLE(Pig Liver Esterase)、猪胰脂肪酶、酵母脂肪酶和Lipozym435脂肪酶中的一种。
4.根据权利要求3所述的米索前列醇酸的制备方法，其特征在于该方法中所述的碱为磷酸氢二钾、磷酸氢二钠、碳酸钾、碳酸钠、碳酸氢钠、三乙胺、N,N-二异丙基乙胺、4-二甲氨基吡啶、吡啶中的一种，且碱与米索前列醇的物质的量比为：(0.1～1):1。
5.根据权利要求4所述的米索前列醇酸的制备方法，其特征在于该方法中所述碱与米索前列醇的物质的量比为：0.2:1。
6.根据权利要求4所述的米索前列醇酸的制备方法，其特征在于该方法中反应温度控制在10～40℃。
7.根据权利要求6所述的米索前列醇酸的制备方法，其特征在于该方法中反应温度控制在37℃。
8.米索前列醇酸在制备米索前列醇的原料药或制剂中用于质量控制的用途。
9.根据权利要求8所述米索前列醇酸的用途，其特征在于：所述米索前列醇酸用作米索前列醇或其衍生物药物中杂质或有关物质检查的对照品或标准品。
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