CN114195633A - 一种布洛芬杂质f的合成方法 - Google Patents
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- DYNVRFFVBZVRND-UHFFFAOYSA-N 3-[4-(2-methylpropyl)phenyl]propanoic acid Chemical compound CC(C)CC1=CC=C(CCC(O)=O)C=C1 DYNVRFFVBZVRND-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 238000001308 synthesis method Methods 0.000 title claims abstract description 9
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- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims abstract description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000003054 catalyst Substances 0.000 claims abstract description 15
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- VLVILBSSXMZZCB-UHFFFAOYSA-N 1-[4-(2-methylpropyl)phenyl]ethanol Chemical compound CC(C)CC1=CC=C(C(C)O)C=C1 VLVILBSSXMZZCB-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims abstract description 9
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- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical group [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 5
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/10—Preparation of carboxylic acids or their salts, halides or anhydrides by reaction with carbon monoxide
- C07C51/12—Preparation of carboxylic acids or their salts, halides or anhydrides by reaction with carbon monoxide on an oxygen-containing group in organic compounds, e.g. alcohols
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- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/04—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing carboxylic acids or their salts
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- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
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Abstract
本发明公开了一种布洛芬杂质F的合成方法,包括如下步骤:在催化剂和酸的作用下,1‑(4‑异丁基苯基)乙醇与CO进行反应,反应结束后经过后处理得到所述的布洛芬杂质F;所述催化剂由钯催化剂和膦助剂组成。本发明经羰基化和重排化反应,得到布洛芬杂质F的混合物,再经过结晶得到高纯度的布洛芬杂质F,工艺稳定,反应步骤少,操作简便,得到的目标物纯度高,适合用作杂质对照品的合成方法。
Description
技术领域
本发明属于药物杂质标准品的合成技术领域,具体涉及一种布洛芬杂质F的合成方法。
背景技术
布洛芬(Ibuprofen),中文别名拔怒风,是一种芳基烷酸类非甾体抗炎药物,化学名为:2-(4-异丁基苯基)丙酸,化学结构式如下:
作为阿司匹林的替代药物,布洛芬在临床上被广泛使用,可在感冒、风湿和类风湿关节炎等疾病中起到解热消炎和镇痛的作用,且副作用比之小很多,是大部分家庭必备药物的首选。在欧洲药典、中国药典和美国药典等中均记载了布洛芬这一药物品种,同时,也对其有关物质和相关杂质的测定作出了详细的阐述和说明。
布洛芬杂质F,化学名为3-(4-异丁基苯基)丙酸,是布洛芬的同分异构体,也是欧洲药典(EP)规定的杂质,布洛芬杂质F的结构式如下:
药品质量是药品安全性,有效性及稳定性的首要保障,它关系到患者的健康和生命安全,更关乎于社会医疗安全。而杂质研究则是药品质量研究中的重要一环,在进行杂质研究时,其杂质标准品的获取更是一切研究的保证。截止目前,关于布洛芬杂质F的合成方法还非常少。
公开号为CN 112441902 A的中国专利申请公开了一种布洛芬杂质F的合成方法,该合成方法以4-异丁基苯基甲醛为起始原料,依次经过Wittig反应、催化氢化和水解反应得到布洛芬杂质F,该合成方法合成的布洛芬杂质F的纯度较高,不过存在以下缺陷:(1)第一步需要用到Wittig试剂,所用的Wittig试剂成本高并且相对用量大(实施例中摩尔量为醛的三倍),导致整个路线的成本升高;(2)三步反应中有两步都要用到柱层析进行分离,尤其是第三步中的产物酸柱层析困难,增加了后处理的难度,进而限制了反应的规模;(3)反应中要用到大量的碱,会产生大量的废水,对环境不友好。
发明内容
本发明主要目的在于提供一种布洛芬杂质F的合成方法,该合成方法工艺简单,操作方便,产品易于纯化,对环境友好,并且按照该合成方法得到的布洛芬杂质F纯度高,无明显杂质点。
一种布洛芬杂质F的合成方法,包括如下步骤:
在催化剂和酸的作用下,1-(4-异丁基苯基)乙醇与CO进行反应,反应结束后经过后处理得到所述的布洛芬杂质F;
所述催化剂由钯催化剂和膦助剂组成。
反应式如下:
本发明使用1-(4-异丁基苯基)乙醇为原料,在催化剂和酸的作用下依次经羰基化和重排反应,得到布洛芬杂质F的混合物,再经过结晶得到高纯度的布洛芬杂质F,大大缩短了反应步骤,整个路线所用的原料简单易得,并且不用柱层析进行分离,仅仅经过重结晶即可得到高纯度的产物,操作简单。
本发明中,反应所用的钯催化剂可以为零价钯化合物或者二价钯化合物,优选为醋酸钯、氯化钯、二(三苯基膦)二氯化钯、双乙腈氯化钯或四(三苯基膦)钯等化合物,作为进一步的优选,所述的钯催化剂为醋酸钯或四(三苯基膦)钯。
本发明中,所用的膦助剂会对反应结果产生关键性的影响,所用的膦助剂选择磺酸基修饰的膦配体,优选为磺酸基修饰的三苯基膦,例如:3-二苯膦基苯磺酸钠(63995-75-5)、二水合双(对-磺酰苯基)苯基膦化二钾盐、三苯基膦三间磺酸钠盐等,作为优选,所述的膦助剂为三苯基膦三间磺酸钠盐。
作为优选,所述的钯催化剂、膦助剂和1-(4-异丁基苯基)乙醇的物质的量比为1:40~60:4000~5000。
本发明中,所述的酸可以为常见的有机质子酸和无机质子酸,为反应提供酸性环境,作为优选,所述的酸为盐酸、对甲苯磺酸或醋酸;作为进一步的优选,所述的酸为盐酸,浓度为10~20wt%,所述的酸与1-(4-异丁基苯基)乙醇的摩尔比为1:1.1~1.5。
作为优选,反应温度为110~140℃,反应压力为5~7MPa。
作为优选,反应中还加入丙酮。所述的丙酮与1-(4-异丁基苯基)乙醇的质量比为1:0.8~1.2。
本发明的反应结束之后,不需要经过额外的柱层析操作,更适合大量投料,作为优选,所述的后处理包括:
当反应至无压降时,先将反应液浓缩除溶剂,再用碱性溶液调节至弱酸性(pH6~7),静置分层除去水相,然后加入结晶溶剂进行结晶,得到高纯度的3-(4-异丁基苯基)丙酸。
作为进一步的优选,所述的碱性溶液为饱和碳酸氢钠水溶液。
作为进一步的优选,所述的结晶溶剂为环己烷,所述环己烷与浓缩除溶剂后反应液的质量比为1:0.8~1.2。
同现有技术相比,本发明的有益效果体现在:
本发明通过使用1-(4-异丁基苯基)乙醇为原料,经一步羰基化反应及重排反应后,得到布洛芬杂质F的混合物,再经过结晶得到高纯度的布洛芬杂质F。本方法工艺稳定,反应步骤少,操作简便,得到的目标物纯度高,适合用作杂质对照品的合成方法。
附图说明
图1为实施例1中布洛芬杂质F的MS谱图;
图2为实施例1中布洛芬杂质F的1HNMR谱图。
具体实施方式
下面结合实施例来对本发明的上述内容进行进一步的阐释和说明,但本发明并不受其限制。
实施例1:布洛芬杂质F的合成
称取式Ⅰ所示化合物84g,三苯基膦三间磺酸钠2.7g,醋酸钯24mg,混合溶解后转移至1L高压釜中;称取16%盐酸84g,加入高压釜内,丙酮洗涤容器,加入釜内,用量小于100g即可;N2,CO各置换3次,充入CO压力6MPa,温度设置125℃保温反应,直至没有压降。降温泄压出料。经旋转蒸发仪(60℃,-0.09MPa)浓缩除溶剂后的反应液用饱和碳酸氢钠水溶液调节pH至弱酸性(pH试纸检测6-7),静置分层后除去水相,加入与浓缩除溶剂后反应液等质量的环己烷放入60℃水浴中加热15min,后自然降温至25℃,析出后保温30min,再控制结晶条件,得到高纯度的杂质F(产量为27.6g,收率28.1%,HPLC纯度为99.1%)。
产物的MS谱图和1HNMR谱图分别见图1和图2,结构式如下:
采用400M核磁共振仪对化合物进行分析,1H-NMR(400MHz,CDCl3)δ:7.134(2H,d),δ7.090(2H,d),δ2.964(2H,t),δ2.703(2H,t),δ2.464(2H,d),δ1.907-1.805(1H,m),δ0.918(6H,m),羟基是活泼氢在CDCl3中被水交换而没有显现出信号峰。
按照本发明实施例1的反应工艺,虽然最终结晶收率低于CN112441902A的产品收率,但是步骤更短,不用柱层析就能获得高纯度的杂质F,投料量可更高,更适合大规模制备。
实施例2
反应条件与实施例1基本相同,不同之处在于将84g 16%盐酸替换为对甲苯磺酸63g,得到高纯度的布洛芬杂质F 22.2g,收率22.6%,HPLC纯度为99.3%。
实施例3
反应条件与实施例1基本相同,不同之处在于将醋酸钯24mg替换为四(三苯基膦)钯120mg,得到高纯度的布洛芬杂质F 23.9g,收率24.4%,HPLC纯度为99.2%。
对比例1
反应条件与实施例1基本相同,不同之处在于将三苯基膦三间磺酸钠2.7g替换为1.3g三苯基膦,得到高纯度的布洛芬杂质F 0.8g,收率0.8%,HPLC纯度为99.2%。
对比例1的结果表明,三苯基膦三间磺酸钠上的磺酸基团对反应的进行产生了很大的影响。
Claims (10)
1.一种布洛芬杂质F的合成方法,其特征在于,包括如下步骤:
在催化剂和酸的作用下,1-(4-异丁基苯基)乙醇与CO进行反应,反应结束后经过后处理得到所述的布洛芬杂质F;
所述催化剂由钯催化剂和膦助剂组成。
2.根据权利要求1所述的布洛芬杂质F的合成方法,其特征在于,所述的钯催化剂为醋酸钯、氯化钯、二(三苯基膦)二氯化钯、双乙腈氯化钯或四(三苯基膦)钯。
3.根据权利要求1所述的布洛芬杂质F的合成方法,其特征在于,所述的膦助剂为3-二苯膦基苯磺酸钠、二水合双(对-磺酰苯基)苯基膦化二钾盐或三苯基膦三间磺酸钠盐。
4.根据权利要求1所述的布洛芬杂质F的合成方法,其特征在于,所述的钯催化剂、膦助剂和1-(4-异丁基苯基)乙醇的物质的量比为1:40~60:4000~5000。
5.根据权利要求1所述的布洛芬杂质F的合成方法,其特征在于,所述的酸为盐酸、对甲苯磺酸或醋酸。
6.根据权利要求1所述的布洛芬杂质F的合成方法,其特征在于,反应温度为110~140℃,CO的压力为5~7MPa。
7.根据权利要求1所述的布洛芬杂质F的合成方法,其特征在于,反应中还加入丙酮。
8.根据权利要求1所述的布洛芬杂质F的合成方法,其特征在于,所述的后处理包括:
先将反应液浓缩除溶剂,再用碱性溶液调节至弱酸性,静置分层除去水相,然后加入结晶溶剂进行结晶,得到高纯度的布洛芬杂质F。
9.根据权利要求8所述的布洛芬杂质F的合成方法,其特征在于,所述的碱性溶液为饱和碳酸氢钠水溶液。
10.根据权利要求8所述的布洛芬杂质F的合成方法,其特征在于,所述的结晶溶剂为环己烷。
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