CN103408588A - 一种(r)-1,2-二硬脂酰基磷脂酰胆碱的制备方法 - Google Patents
一种(r)-1,2-二硬脂酰基磷脂酰胆碱的制备方法 Download PDFInfo
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
本发明公开了一种(R)-1,2-二硬脂酰基磷脂酰胆碱的制备方法,以3-卤代丙烯为原料,在手性催化剂催化下发生氧化反应,将得到(S)-1,2-二醇-3-卤代丙烷与硬脂酸酐或硬脂酰卤加成得到(R)-1,2-二硬脂酰-3-卤代丙烷;之后与3,4-二甲氧苄基磷酸银回流反应,得到(R)-1,2-二硬脂酰-3-(3,4-二甲氧苄氧基)磷酸盐丙烷;将其与相转移催化剂反应脱去磷保护基团,得到(R)-1,2-甘油二硬脂酸-甘油-3-磷脂酸;最后与胆碱对甲苯磺酸盐在无水吡啶中三氯乙腈催化下发生加成反应得到(R)-1,2-二硬脂酰基磷脂酰胆碱。本发明方法步骤简单,反应温和,适合工业化生产。
Description
技术领域
本发明属于医药化工领域,具体涉及一种(R)-1,2-二硬脂酰基磷脂酰胆碱的制备方法。
背景技术
磷脂是生物膜的重要组成部分,其含磷酸根的极性端具有亲水性,两个较长的碳氢链非极性端具有亲脂性,这种独特的理化性质使其能自发在水介质中形成闭合双分子层,成为生物膜骨架,可作为脂质体材料用于制药工业中。然而天然磷脂作为脂质体材料,具有寿命短、易被氧化、稳定性差等缺点,应用受到限制。
二硬脂酰磷脂酰胆碱(1,2-Distearoyl-sn-glycero-3-phosphocholine,DSPC)是一种重要的人工合成磷脂,主要应用于脂质体的制备,是脂质体药物制剂中不可缺少的一种添加性辅料,人工合成的二硬脂酰磷脂酰胆碱纯度高,稳定性好,比天然磷脂有较强的抗氧化能力,制备脂质体效果非常理想。
《磷脂酰胆碱、磷脂酰乙醇胺和磷脂酰甘油的全合成研究》(陈光友,西北大学,硕士学位论文,2006)一文公开了二硬脂酰磷脂酰胆碱的合成方法,以丙三醇为原料,,采用缩酮,3,4-二甲氧苄基分别作为甘油骨架的二羟基和单羟基的保护基,以乙酸水溶液、DDQ作为相应的脱保护试剂。分别采用对甲苯磺酸甲酯、叔丁氧羰基和缩酮作为磷脂头基的保护基,以NaHCO3水溶液、三氟乙酸、乙酸作为相应的脱保护试剂,采用萃取、高真空蒸馏、柱层析、制备薄层层析等方法,先后经过还原、氯化、缩合、双羟基以及单羟基的保护和脱保护、酰化、磷酰化、头基保护、偶联及脱保护等步骤,制备得到二硬脂酰磷脂酰胆碱。该方法以甘油为原料,需要对甘油骨架的二羟基和单羟基进行保护和脱保护,反应步骤繁琐。不适合工业化生产。并且,该法制得消旋的二硬脂酰磷脂酰胆碱,目前尚未文献报道二硬脂酰磷脂酰胆碱的单一光学异构体的制备方法。
发明内容
本发明的目的是在现有技术的基础上,提供一种(R)-1,2-二硬脂酰基磷脂酰胆碱的制备方法,该法步骤简单,反应温和,适合工业化生产。
本发明的目的可以通过以下措施达到:
一种(R)-1,2-二硬脂酰基磷脂酰胆碱的制备方法,其包括如下步骤:
(1)3-卤代丙烯在手性催化剂和氧化剂作用下进行氧化反应,得到(S)-1,2-二醇-3-卤代丙烷,
在步骤(1)中,采用催化量的手性催化剂,其中手性催化剂优选采用氢化奎尼定1,4-(2,3-二氮杂萘)二醚;氧化剂为K2OsO2(OH)4和/或K3Fe(CN)6;优选的氧化剂的用量为3-卤代丙烯摩尔量的2~4倍。该反应的反应溶剂选自叔丁醇的水溶液,优选的叔丁醇和水的体积比为1:1;反应温度为-5℃~5℃,优选0℃;进一步的反应在碱的存在下进行,所述碱选自K2CO3或NaHCO3中的一种或几种;优选的,碱的用量为3-卤代丙烯摩尔量的4~8倍。
上述反应可进一步包括精制步骤:将反应产物水层分离用乙酸乙酯进行萃取,合并有机层,分别用1N KOH,稀盐酸和饱和食盐水洗涤。无水硫酸镁干燥并浓缩得到粗品,使用石油醚和甲醇混和溶剂进行重结晶。
(2)(S)-1,2-二醇-3-卤代丙烷与硬脂酸酐或硬脂酰卤反应,得到(R)-1,2-二硬脂酰-3-卤代丙烷,
在步骤(2)中,反应溶剂采用二氯甲烷,反应温度为30℃~50℃,优选搅拌回流反应,反应在惰性气体保护下进行,所述惰性气体优选采用氮气。其中(S)-1,2-二醇-3-卤代丙烷与硬脂酸酐或硬脂酰卤的摩尔比优选为1:1~3;
步骤(2)反应可进一步包括精制步骤:将反应产物冷却到室温后,倒入无水乙醚。有机层用5%的碳酸氢钠水溶液和饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩得到的粗品用乙醇重结晶。
(3)(R)-1,2-二硬脂酰-3-卤代丙烷与3,4-二甲氧苄基磷酸银反应,得到(R)-1,2-二硬脂酰-3-(3,4-二甲氧苄氧基)磷酸盐丙烷,
在步骤(3)中,反应溶剂采用甲苯,反应温度为100℃~111℃,优选搅拌回流反应;反应在避光条件下进行。
步骤(3)反应可进一步包括精制步骤:将反应产物冷却到室温后过滤,二氯甲烷洗涤,合并有机层减压浓缩,得到的粗品用乙醇重结晶。
(4)(R)-1,2-二硬脂酰-3-(3,4-二甲氧苄氧基)磷酸盐丙烷在相转移催化剂作用下脱去磷的保护基团,得到(R)-1,2-甘油二硬脂酸-甘油-3-磷脂酸,
在步骤(4)中,所述相转移催化剂优选采用二氯二氰基苯醌反应温度为室温;反应溶剂为二氯甲烷和水的混合溶液。其中(R)-1,2-二硬脂酰-3-(3,4-二甲氧苄氧基)磷酸盐丙烷与相转移催化剂的摩尔比优选为1:1~2。本发明所述室温为本领域公知常识,通常指20±5℃。
步骤(4)反应可进一步包括精制步骤:将反应产物过滤,滤液减压浓缩,得到的粗品用丙酮和水重结晶。
(5)(R)-1,2-甘油二硬脂酸-甘油-3-磷脂酸与胆碱对甲苯磺酸盐发生加成反应,得到(R)-1,2-二硬脂酰基磷脂酰胆碱,
在步骤(5)中,加成反应在三氯乙腈催化下进行;(R)-1,2-甘油二硬脂酸-甘油-3-磷脂酸与三氯乙腈的用量比为1:20~30g/mL。加成反应溶剂为无水吡啶;反应温度为40℃~60℃,优选50℃。其中(R)-1,2-甘油二硬脂酸-甘油-3-磷脂酸与胆碱对甲苯磺酸盐的摩尔比优选为1:8~15。
步骤(5)反应可进一步包括精制步骤:将反应产物减压浓缩得粗品,快速柱层析(200-300目GF254硅胶,展开剂CHCl3-CH3OH-H2O,15:5:1)得白色凝胶状物。
本发明的有益效果:
1.以3-卤代丙烯为原料,通过手性催化氧化一步制得单一光学异构体,步骤简单。
2.由于3-卤代丙烯的3位被卤元素取代,与甘油作为原料相比,无需对3位进行羟基的保护和脱保护,简化了反应步骤。
3.本发明采用先进行侧链酰化偶联,再进行磷脂头基的引入,避免了侧链酰化偶联时酰化试剂对磷脂酰基的破坏。
4.本发明采用3,4-二甲氧苄基磷酸银为磷酰化试剂,相比于POCl3反应条件温和,且磷酸羟基保护基3,4-二甲氧苄基相较于3,4-二甲氧苯基更易于脱去,无需采用H2/Pd这种剧烈的条件即可完成脱保护基,更利于工业化应用。
具体实施方式
以下通过实施例说明本发明的具体工艺步骤,但不受实施例限制。
在本发明中所使用的术语,除非另有说明,一般具有本领域普通技术人员通常理解的含义。
下面结合具体实施例并参照数据进一步详细描述本发明。应理解,这些实施例只是为了举例说明本发明,而非以任何方式限制本发明的范围。
在以下实施例中,未详细描述的各种过程和方法是本领域中公知的常规方法。
实施例1、(S)-1,2-二醇-3-碘丙烷的制备
在圆底反应瓶中加入0.08g(0.1mmol)氢化奎尼定1,4-(2,3-二氮杂萘)二醚(DHQD)2PHAL,0.018g(0.05mmol)K2OsO2(OH)4,9.8g(30mmol)K3Fe(CN)6,4.2g(30mmol)K2CO3,2.5g(30mmol)NaHCO3,0.95g(10mmol)和叔丁醇的水溶液100mL(叔丁醇:水=1:1),在0℃下充分搅拌,然后加入3-碘丙烯1.7g(10mmol)反应6小时,加入10g Na2S2O4并继续搅拌30分钟停止反应。将水层分离用乙酸乙酯进行萃取,合并有机层,分别用1N KOH,稀盐酸和饱和食盐水洗涤。无水硫酸镁干燥并浓缩得到粗品,石油醚和甲醇混和溶剂重结晶得到1.58g(S)-1,2-二醇-3-碘丙烷,收率78%。
实施例2、(R)-1,2-二硬脂酰-3-碘丙烷的制备
将硬脂酸酐(0.8g,1.5mmol),(S)-1,2-二醇-3-碘丙烷(0.2g,1mmol)加入到50mL二氯甲烷中,氮气保护在40℃下搅拌回流3小时,停止加热,冷却到室温后,倒入50mL无水乙醚。有机层用10mL5%的碳酸氢钠水溶液和10mL饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩得到的粗品用乙醇重结晶得到0.61g(S)-1,2-二醇-3-碘丙烷,收率83%。
实施例3、(R)-1,2-二硬脂酰-3-(3,4-二甲氧苄氧基)磷酸盐丙烷的制备
在避光条件下将(R)-1,2-二硬脂酰-3-碘丙烷(0.6g,0.8mmol)和3,4-二甲氧苄基磷酸银(1.3g,2.5mmol)加入到50mL甲苯中,回流反应6h停止反应,冷却到室温后过滤,二氯甲烷洗涤,合并有机层减压浓缩,得到的粗品用乙醇重结晶得白色固体0.52g,收率65%。
实施例4、(R)-1,2-甘油二硬脂酸-甘油-3-磷脂酸的制备
将(R)-1,2-二硬脂酰-3-(3,4-二甲氧苄氧基)磷酸盐丙烷(0.5g,0.5mmol)和二氯二氰基苯醌(DDQ)(0.14g,0.6mmol)加入到15mL二氯甲烷和1mL水中,室温搅拌0.5h,过滤,滤液减压浓缩,得到的粗品用丙酮和水重结晶得到0.24g(R)-1,2-甘油二硬脂酸-甘油-3-磷脂酸,收率68%
实施例5、1,2-二硬脂酰基磷脂酰胆碱(DSPC)的制备
将(R)-1,2-甘油二硬脂酸-甘油-3-磷脂酸(0.2g,0.28mmol)加入到60mL无水吡啶中,50℃下加热0.5h,然后加入胆碱对甲苯磺酸盐(0.84g,3mmol)和三氯乙腈5mL,继续在50℃下反应36h,减压浓缩得粗品,快速柱层析(展开剂CHCl3-CH3OH-H2O,15:5:1)得白色凝胶状物0.13g,收率59%。1H-NMR(CDCl3-d6,300MHz)δ(ppm):0.88(t,6H,J=7.6Hz,-CH 3),1.31-1.58(m,60H,CH3-(CH 2 )15-CH2-CO),2.25-2.42(m,4H,CH3-(CH2)15-CH 2 -CO),3.29(s,9H,-N(CH3)3),3.71-3.75(m,2H,-CH 2 -OPO3),3.93-3.97(m,4H,-CH 2 CH 2 N),4.29(d,2H,J=7.1Hz,-CH 2OCO),5.16-5.22(m,1H,-OCOCHCH2);MS(EI)m/e:791.3(M+);Anal.C44H88NO8P.Calcd:C,66.88;H,11.23;N,1.77;Found:C,66.65;H,11.01;N,1.65。
Claims (10)
1.一种(R)-1,2-二硬脂酰基磷脂酰胆碱的制备方法,其特征在于包括如下步骤:
(1)3-卤代丙烯在手性催化剂和氧化剂作用下进行氧化反应,得到(S)-1,2-二醇-3-卤代丙烷,
其中X代表Cl、Br或I;
(2)(S)-1,2-二醇-3-卤代丙烷与硬脂酸酐或硬脂酰卤反应,得到(R)-1,2-二硬脂酰-3-卤代丙烷,
(3)(R)-1,2-二硬脂酰-3-卤代丙烷与3,4-二甲氧苄基磷酸银反应,得到(R)-1,2-二硬脂酰-3-(3,4-二甲氧苄氧基)磷酸盐丙烷,
(4)(R)-1,2-二硬脂酰-3-(3,4-二甲氧苄氧基)磷酸盐丙烷在相转移催化剂作用下脱去磷的保护基团,得到(R)-1,2-甘油二硬脂酸-甘油-3-磷脂酸,
(5)(R)-1,2-甘油二硬脂酸-甘油-3-磷脂酸与胆碱对甲苯磺酸盐发生加成反应,得到(R)-1,2-二硬脂酰基磷脂酰胆碱,
2.根据权利要求1所述的制备方法,其特征在于在步骤(1)中,所述手性催化剂为氢化奎尼定1,4-(2,3-二氮杂萘)二醚;所述氧化剂为K2OsO2(OH)4和/或K3Fe(CN)6。
3.根据权利要求1所述的制备方法,其特征在于在步骤(1)中,反应溶剂选自叔丁醇的水溶液;反应温度为-5℃~5℃;反应在碱的存在下进行。
4.根据权利要求3所述的制备方法,其特征在于反应溶剂中叔丁醇和水的体积比为1:1,所述碱选自K2CO3或NaHCO3中的一种或几种。
5.根据权利要求1所述的制备方法,其特征在于在步骤(2)中,反应溶剂为二氯甲烷,反应温度为30℃~50℃,反应在惰性气体保护下进行。
6.根据权利要求1所述的制备方法,其特征在于在步骤(3)中,反应溶剂为甲苯,反应温度为100℃~111℃;反应在避光条件下进行。
7.根据权利要求1所述的制备方法,其特征在于在步骤(4)中,所述相转移催化剂为二氯二氰基苯醌;反应温度为20℃~30℃;反应溶剂为二氯甲烷和水的混合溶液。
8.根据权利要求1所述的制备方法,其特征在于在步骤(4)中,(R)-1,2-二硬脂酰-3-(3,4-二甲氧苄氧基)磷酸盐丙烷与相转移催化剂的摩尔比为1:1~2。
9.根据权利要求1所述的制备方法,其特征在于在步骤(5)中,加成反应在三氯乙腈催化下进行;反应溶剂为无水吡啶;反应温度为40℃~60℃。
10.根据权利要求9所述的制备方法,其特征在于(R)-1,2-甘油二硬脂酸-甘油-3-磷脂酸与三氯乙腈的用量比为1:20~30g/mL;(R)-1,2-甘油二硬脂酸-甘油-3-磷脂酸与胆碱对甲苯磺酸盐的摩尔比为1:8~15。
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CN103864840A (zh) * | 2014-03-11 | 2014-06-18 | 苏州东南药业股份有限公司 | 一种人工磷脂dspg的制备方法 |
CN105753897A (zh) * | 2016-03-17 | 2016-07-13 | 苏州东南药业股份有限公司 | 一种合成磷脂dppc的制备方法 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH0597876A (ja) * | 1991-10-09 | 1993-04-20 | Kanegafuchi Chem Ind Co Ltd | リン脂質およびその中間体の製造法 |
-
2013
- 2013-06-20 CN CN201310247063.2A patent/CN103408588B/zh active Active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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Non-Patent Citations (3)
Title |
---|
ERICH BAYER ET AL.: "N,N-Dimethylcephalins I. Synthesis of Distearoyl L-α-Glycerylphosphoryl-(N,N-Dimethyl)Ethanolamine", 《THE JOURNAL OF BIOLOGICAL CHEMISTRY》 * |
SHAUKAT ALI ET AL.: "Facile Diacylation of Glycidyl Tosylate. Chiral Synthesis of Symmetric-Chain Glycerophospholipids", 《JOURNAL OF THE ORGANIC CHEMISTRY》 * |
荣国斌等: "《大学基础有机化学》", 31 March 2011, 化学工业出版社 * |
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CN105753897A (zh) * | 2016-03-17 | 2016-07-13 | 苏州东南药业股份有限公司 | 一种合成磷脂dppc的制备方法 |
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