CN108276269A - β-氘代丙戊酸的制备方法 - Google Patents
β-氘代丙戊酸的制备方法 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 23
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/06—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid amides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/40—Nitrogen atoms attached in position 8
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
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- Oil, Petroleum & Natural Gas (AREA)
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Abstract
本发明公开了一种β‑氘代丙戊酸的制备方法,依次包括以下步骤:8‑胺基喹啉丙戊酸酰胺在D2O中,以醋酸钯作催化剂,进行分子内丙戊酰基碳骨架β位定向的氘代反应,生成氘代8‑胺基喹啉丙戊酸酰胺,所述氘代反应为在密封状态下进行;氘代8‑胺基喹啉丙戊酸酰胺在有机溶剂中,在碱的作用下,于常压回流条件下进行水解反应,之后再经酸化处理,得到β‑氘代丙戊酸。本发明选择性高,反应后处理简单,原料易得,绿色环保,为高效合成β‑氘代丙戊酸提供了一种高效准确的方法。
Description
技术领域
本发明属氘代药物的合成方法,具体涉及抗癫痫药物β-氘代丙戊酸的制备方法。
背景技术
氘代反应在医药行业中有着广泛的应用。首先,利用氘代反应进行同位素标记的药物因其具有特征的放射性吸收,能够用特定的β核探测器检测追踪该药物在体内的位置,数量及其转变等变化情况,为药理学,药物代谢学等相关学科的理论研究提供了有效可靠的实验依据。其次,在探究一些有机反应的机理方面,将反应物中特定位置的氢进行氘代反应从而可以追踪该氘原子的去向,以此作为依据阐释一些难以研究的有机化学反应机理(Thomas G等,Using Deuterium in Drug Discovery:Leaving the Label in theDrug.J.Med.Chem.2014,57,3595-3611)。
丙戊酸及其盐类在医药行业中有着广泛的应用。丙戊酸本身具有广泛的药理活性,其药物制剂上世纪60年代在美国上市,作为治疗癫痫的抗惊厥药物,也具有治疗躁狂症相关的双相情感障碍和预防治疗偏头痛的作用(Sabbir K等,Anti-fibrotic effects ofvalproic acid role of HDAC inhibition and associatedmechanisms.Epigenomics.2016,8,1087–1101)。其钠盐丙戊酸钠为儿童常用的广谱抗癫痫药物,因其抗癫痫谱广、临床效果好、易于吸收、治疗后病情复发率低等优点也被临床广泛应用(何新苗等,临床应用丙戊酸钠治疗小儿癫痫分析.中国药房,2011,22(28),2624-2626)。然而,丙戊酸具体的药代动力学并未完全阐明,装印权等人的研究中提到,其主要代谢途径可能主要有以下四种:与葡萄糖醛酸相结合,β氧化,w1和w2氧化,其中由β氧化过程得到的β-酮丙戊酸2-丙戊烯酸等是丙戊酸的活性代谢产物(装印权等,丙戊酸钠的药理作用及临床用途,北京医学院学报,1982,14,156-158)。可见,这些代谢过程均涉及到丙戊酸β-C上的氧化脱氢反应,因此利用氘代反应技术,将丙戊酸分子β位的氢进行氘代,利用同位素追踪法探究其在体内的药代动力学过程,在医药领域具有重要的潜在应用价值。
目前,氘代丙戊酸主要有以下几种合成方法:
1、Tsuyoshi Y等人研究饱和脂肪酸的氘代反应(Tsuyoshi Y等,Mild and DirectMultiple Deuterium-Labeling of Saturated Fatty Acids.Adv.Synth.Catal.2016,358,3277-3282)。当催化剂为10%Pd/C或者10%Ru/C时,脂肪酸分子中氢的氘代率为0%;反应式如式1所示:
式1、催化剂为Pd/C或者Ru/C时氘代反应
当10%Pt/C(15mol%)作催化剂时才能得到氘代率较高的全氘代饱和脂肪酸;反应式如式2所示:
式2、全氘代丙戊酸合成路线
此方法需要用到铂催化剂和i-PrOH-d8作氘代试剂,价格昂贵,且对氘代位点无选择性,不能定向氘代丙戊酸分子中重要代谢位点的β-位上的氢原子,不适用于丙戊酸特定代谢位点β位的研究,故此方法适用性有限。
2、以α-氘代1-溴丙烷和氰乙酸乙酯为原料,在丙醇钠、氢氧化钠的作用下,并加热脱羧生成对应的氘代4-氰基庚烷,氘代氢氧化钠水解氰基,并酸化后处理,最终得到多氘代丙戊酸,但是文中仅给出合成路线通式,没有具体的实验操作以及所述多氘代丙戊酸的氘代率(Julie F等,Deuterated 2-Propylpentanoic Acid Compounds,WO 2010/062656A2.);反应式如式3所示:
式3、多氘代丙戊酸合成路线
另外此方法所用的α-氘代1-溴丙烷价格昂贵,原料供应商少,难以直接购买到特定α-氘代的溴丙烷。目前合成α-氘代溴丙烷的方法主要是由丙酸酐为原料,通过氘代四氢铝锂还原再和氢溴酸反应生成(David J等,Ion-Neutral Complexes as Intermediatesin the Decompositions of C5H10O2'+Isomers,J.Am.Chem.Soc.1987,109,7648-7653.);反应式如式4所示:
式4氘代1-溴丙烷合成路线
该方法还原剂氘代氢化铝锂价格也很昂贵,并且该反应需要严格无水无氧体系,反应条件较为苛刻。
发明内容
本发明要解决的技术问题是提供一种产率高、选择性好的β-氘代丙戊酸的制备方法。
为了解决上述技术问题,本发明提供一种β-氘代丙戊酸的制备方法,依次包括以下步骤:
(1)定向氘代反应:
8-胺基喹啉丙戊酸酰胺在D2O(重水)中,以醋酸钯作催化剂,进行分子内丙戊酰基碳骨架β位定向的氘代反应,生成氘代8-胺基喹啉丙戊酸酰胺;
所述氘代反应为在密封状态下进行,反应温度为120~160℃,反应时间为36~60h,8-胺基喹啉丙戊酸酰胺和醋酸钯的摩尔比为1:0.1~0.3;
(2)水解反应:
氘代8-胺基喹啉丙戊酸酰胺在有机溶剂中,在碱的作用下,于常压回流条件下进行水解反应,反应时间为36±2h;氘代8-胺基喹啉丙戊酸酰胺和氢氧化钠的摩尔比为1:8~12;
之后再经酸化处理,得到β-氘代丙戊酸。
作为本发明的β-氘代丙戊酸的制备方法的改进:
所述步骤(2)中的酸化处理为:将水解反应的所得物减压蒸除有机溶剂,加入乙酸乙酯和水进行萃取,合并水相,调节水相pH=2±0.1(用2M HCl进行调节),再用乙醚萃取水相2~4次,合并乙醚相,经洗涤(用饱和食盐水洗涤)、干燥(无水硫酸钠干燥),浓缩(旋蒸浓缩),得到作为最终产物的β-氘代丙戊酸。
作为本发明的β-氘代丙戊酸的制备方法的进一步改进:
所述步骤(2)乙醚萃取所得的水层进行回收:对水层用饱和碳酸氢钠溶液调节pH=7~8,用乙酸乙酯萃取,所得的乙酸乙酯层经洗涤、干燥、抽滤、浓缩,得到8-氨基喹啉。
作为本发明的β-氘代丙戊酸的制备方法的进一步改进:
所述步骤(2)中的有机溶剂为甲醇;
每12mmol的氘代8-胺基喹啉丙戊酸酰胺配用15~20ml的甲醇。
作为本发明的β-氘代丙戊酸的制备方法的进一步改进:
所述步骤(2)中的碱为氢氧化钠;氘代8-胺基喹啉丙戊酸酰胺与氢氧化钠的摩尔比为1:10。
作为本发明的β-氘代丙戊酸的制备方法的进一步改进:
所述步骤(1)中,每15.26mmol的8-胺基喹啉丙戊酸酰胺配用7~10ml重水。
作为本发明的β-氘代丙戊酸的制备方法的进一步改进:
所述步骤(1)中,氘代反应结束后,加入水和乙酸乙酯进行萃取,合并乙酸乙酯层,经洗涤(饱和食盐水洗涤)、干燥(无水硫酸钠干燥)后,浓缩(减压浓缩),浓缩物通过硅胶层析柱分离纯化,洗脱剂为石油醚(PE):乙酸乙酯(EA)=15:1,得到氘代8-胺基喹啉丙戊酸酰胺。
作为本发明的β-氘代丙戊酸的制备方法的进一步改进:
所述步骤(1)中,氘代反应为140℃油浴封管反应48h,8-胺基喹啉丙戊酸酰胺和醋酸钯的摩尔比为1:0.2。
本发明的高效高选择性的β-氘代丙戊酸的制备方法,以易合成的8-胺基喹啉丙戊酸酰胺为原料,反应得到β-氘代丙戊酸。
式5β-氘代丙戊酸的合成路线
本发明的整个过程分为两个步骤进行;本发明以重水作为氘代试剂,8-胺基喹啉丙戊酸酰胺在醋酸钯催化下进行定向氘代,最终脱去8-胺基喹啉基团得到β-氘代丙戊酸,其中,8-胺基喹啉基团作为导向基团。本合成方法选择性高,反应后处理简单,原料易得,绿色环保,为高效合成β-氘代丙戊酸提供了一种高效准确的方法。本发明的合成方法未见文献报道。
具体而言,本发明为β-氘代丙戊酸的合成提供一种新方法,以重水作为氘代试剂,无外加溶剂,8-胺基喹啉丙戊酸酰胺(I)为原料,醋酸钯做催化剂,先定向实现丙戊酰基β位的氘代(II),再进行水解酸化,以高产率高选择性实现β-氘代丙戊酸(III)的合成。
本发明提供的β-氘代丙戊酸的合成方法具有以下特点:
1、本方法为β位定向氘代丙戊酸的合成技术,选择性高,应用面广泛;环境污染小;
2、导向基团8-胺基喹啉反应后结构未发生变化,可以分离纯化重复套用,经济性好;
3、产率高,可达90%以上。
4、此合成方法未见文献报道。
附图说明
下面结合附图对本发明的具体实施方式作进一步详细说明。
图1为β-氘代丙戊酸的1H NMR图谱。
具体实施方式
下面将通过实施例对本发明作进一步的说明。
实施例1、β-氘代丙戊酸的制备方法,依次包括以下步骤:
(1)定向氘代反应:
称取8-胺基喹啉丙戊酸酰胺4.13g(15.26mmol,1eq.),醋酸钯0.68g(3.05mmol,0.2eq.)于封管中,加入8.3ml重水,140℃封管于密封状态下反应48h。
反应结束后加入20ml水,再加入乙酸乙酯(3×30ml)萃取,合并有机相--乙酸乙酯层,用饱和食盐水(30ml)洗,再用无水硫酸钠6g干燥,旋转蒸发仪减压浓缩,浓缩温度为30~40℃,真空度不低于-0.07MPa,浓缩至无明显液滴滴下,浓缩物通过硅胶层析柱分离纯化(洗脱剂为PE:EA=15:1),得到中间产品氘代8-胺基喹啉丙戊酸酰胺3.97g,收率95.6%,丙戊酰基β-位氘代率:91%、90%。
所述柱层析的具体工艺参数如下:
选用装有30g 200-300目硅胶作为层析柱;以石油醚:乙酸乙酯=15:1作为洗脱液;流速为3mL/min;收集第25min~40min的洗脱液;然后经旋转蒸发仪除去溶剂(即,洗脱剂)后,得到氘代8-胺基喹啉丙戊酸酰胺。
(2)水解反应:
称取氘代8-胺基喹啉丙戊酸酰胺3.30g(12mmol,1eq),置于单口瓶中,加入17ml甲醇溶解,再加入氢氧化钠4.80g(120mmol,10eq),回流反应36h(TLC检测反应进行完全)。
反应冷却至室温,减压浓缩除去甲醇(浓缩温度为35~45℃,真空度不低于-0.07MPa,浓缩至无明显液滴滴下),加入乙酸乙酯(30ml)和水(2×30ml)萃取,合并水相,向水相中滴加2M HCl,调节pH=2,再加入乙醚(3×30ml)萃取,合并乙醚层,用饱和食盐水(45ml)洗,无水硫酸钠6g干燥,浓缩(旋转蒸发仪减压浓缩,浓缩温度为30~40℃,真空度不低于-0.07MPa)得到无色液体,为最终产品β-氘代丙戊酸1.71g,收率96.2%,β-位氘代率:91%、90%。1H NMR图谱如图1。
(3)、回收:
步骤2)乙醚萃取产生的水层回收后,用饱和碳酸氢钠溶液调pH=7~8,并用乙酸乙酯(3×20mL)萃取,合并乙酸乙酯层,用饱和食盐水(20mL)洗涤,加无水硫酸钠3g干燥,抽滤,旋转蒸发仪减压浓缩(浓缩温度为30~40℃,真空度不低于-0.07MPa),得到黄色固体8-氨基喹啉1.40g,回收率81%。
以下为不同条件的对比案例:
对比例1-1、将步骤(1)中的140℃封管反应48小时改成25℃封管反应48小时,其余同实施例1,丙戊酰基β-位氘代率:17%、11%。
对比例1-2、将步骤(1)中的140℃封管反应48小时改成60℃封管反应48小时,其余同实施例1,丙戊酰基β-位氘代率:25%、27%。
对比例1-3、将步骤(1)中的140℃封管反应48小时改成回流装置回流反应48小时,其余同实施例1,丙戊酰基β-位氘代率:75%、67%。
对比例1-4、将步骤(1)中的140℃封管反应48小时改成160℃封管反应48小时,其余同实施例1,丙戊酰基β-位氘代率:90%、86%。
对比例1-5、将步骤(1)中的封管反应48小时改成封管反应36小时,其余同实施例1,丙戊酰基β-位氘代率:82%、78%。
对比例1-6、将步骤(1)中的封管反应48小时改成封管反应72小时,其余同实施例1,丙戊酰基β-位氘代率:89%、87%。
对比例1-7、将步骤(1)中的0.2eq.醋酸钯改成0.1eq.,其余同实施例1,丙戊酰基β-位氘代率:56%、49%。
对比例1-8、将步骤(1)中的0.2eq.醋酸钯改成0.3eq.,其余同实施例1,丙戊酰基β-位氘代率:90%、87%。
对比例1-9、在步骤(1)中取消醋酸钯的使用,其余同实施例1,丙戊酰基β-位氘代率:0%。
对比例1-10、将实施例1中的催化剂改为:PdCl2(3.05mmol,0.2eq.);其余同实施例1-1,丙戊酰基β-位氘代率为67%、79%。
对比例1-11、将实施例1中的催化剂改为:Pd(TFA)2(3.05mmol,0.2eq.);其余同实施例1-1,丙戊酰基β-位氘代率为82%、83%%。
实施例2、重复套用
称取实施例1回收得到的8-氨基喹啉(115mg,0.80mmol)和N,N-二甲基-4-氨基吡啶(13mg,0.1mmol)于三颈反应瓶中,在氮气保护下加无水二氯甲烷(10mL),并加三乙胺(135μL,0.96mmol,1.2equiv),将反应体系降温至0℃,滴加丙戊酰氯(130mg,0.80mmol)。反应体系在室温下搅拌反应过夜。加水20mL猝灭反应,用二氯甲烷(3×20mL)萃取,合并二氯甲烷层,无水硫酸钠干燥,抽滤,浓缩,硅胶层析柱分离纯化(石油醚:乙酸乙酯=15:1)得白色固体8-胺基喹啉丙戊酸酰胺195mg,收率90%。
最后,还需要注意的是,以上列举的仅是本发明的若干个具体实施例。显然,本发明不限于以上实施例,还可以有许多变形。本领域的普通技术人员能从本发明公开的内容直接导出或联想到的所有变形,均应认为是本发明的保护范围。
Claims (8)
1.β-氘代丙戊酸的制备方法,其特征在于依次包括以下步骤:
(1)定向氘代反应:
8-胺基喹啉丙戊酸酰胺在D2O中,以醋酸钯作催化剂,进行分子内丙戊酰基碳骨架β位定向的氘代反应,生成氘代8-胺基喹啉丙戊酸酰胺;
所述氘代反应为在密封状态下进行,反应温度为120~160℃,反应时间为36~60h,8-胺基喹啉丙戊酸酰胺和醋酸钯的摩尔比为1:0.1~0.3;
(2)水解反应:
氘代8-胺基喹啉丙戊酸酰胺在有机溶剂中,在碱的作用下,于常压回流条件下进行水解反应,反应时间为36±2h;氘代8-胺基喹啉丙戊酸酰胺和氢氧化钠的摩尔比为1:8~12;
之后再经酸化处理,得到β-氘代丙戊酸。
2.根据权利要求1所述的β-氘代丙戊酸的制备方法,其特征在于:
所述步骤(2)中的酸化处理为:将水解反应的所得物减压蒸除有机溶剂,加入乙酸乙酯和水进行萃取,合并水相,调节水相pH=2±0.1,再用乙醚萃取水相2~4次,合并乙醚相,经洗涤、干燥,浓缩,得到β-氘代丙戊酸。
3.根据权利要求2所述的邻位氘代苯甲酸类化合物的制备方法,其特征是:
所述步骤(2)乙醚萃取所得的水层进行回收:对水层用饱和碳酸氢钠溶液调节pH=7~8,用乙酸乙酯萃取,所得的乙酸乙酯层经洗涤、干燥、抽滤、浓缩,得到8-氨基喹啉。
4.根据权利要求1~3任一所述的β-氘代丙戊酸的制备方法,其特征在于:
所述步骤(2)中的有机溶剂为甲醇;
每12mmol的氘代8-胺基喹啉丙戊酸酰胺配用15~20ml的甲醇。
5.根据权利要求1~3任一所述的β-氘代丙戊酸的制备方法,其特征在于:
所述步骤(2)中的碱为氢氧化钠;氘代8-胺基喹啉丙戊酸酰胺与氢氧化钠的摩尔比为1:10。
6.根据权利要求1~3任一所述的β-氘代丙戊酸的制备方法,其特征在于:
所述步骤(1)中,每15.26mmol的8-胺基喹啉丙戊酸酰胺配用7~10ml重水。
7.根据权利要求1~3任一所述的β-氘代丙戊酸的制备方法,其特征在于:
所述步骤(1)中,氘代反应结束后,加入水和乙酸乙酯进行萃取,合并乙酸乙酯层,经洗涤、干燥后,浓缩,浓缩物通过硅胶层析柱分离纯化,洗脱剂为石油醚:乙酸乙酯=15:1,得到氘代8-胺基喹啉丙戊酸酰胺。
8.根据权利要求1~7任一所述的β-氘代丙戊酸的制备方法,其特征在于:
所述步骤(1)中,氘代反应为140℃油浴封管反应48h,8-胺基喹啉丙戊酸酰胺和醋酸钯的摩尔比为1:0.2。
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