CN113354679A - 一种二硬脂酰磷脂酰甘油钠的制备工艺 - Google Patents
一种二硬脂酰磷脂酰甘油钠的制备工艺 Download PDFInfo
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- CN113354679A CN113354679A CN202110754813.XA CN202110754813A CN113354679A CN 113354679 A CN113354679 A CN 113354679A CN 202110754813 A CN202110754813 A CN 202110754813A CN 113354679 A CN113354679 A CN 113354679A
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- benzyloxy
- sodium
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- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- FVJZSBGHRPJMMA-IOLBBIBUSA-N PG(18:0/18:0) Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@@H](O)CO)OC(=O)CCCCCCCCCCCCCCCCC FVJZSBGHRPJMMA-IOLBBIBUSA-N 0.000 title claims abstract description 21
- 239000011734 sodium Substances 0.000 title claims abstract description 16
- 229910052708 sodium Inorganic materials 0.000 title claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims description 58
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 29
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 17
- 239000003153 chemical reaction reagent Substances 0.000 claims description 15
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical group OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims description 11
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 10
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 claims description 10
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- -1 5- (benzyloxy) -2- (4-nitro-phenoxy) -2-oxo-1, 3, 2-dioxaphosphorinane Chemical compound 0.000 claims description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 8
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- 238000004821 distillation Methods 0.000 claims description 5
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- UDIPIOHLDFSMLR-UHFFFAOYSA-N 2-phenylmethoxypropane-1,3-diol Chemical compound OCC(CO)OCC1=CC=CC=C1 UDIPIOHLDFSMLR-UHFFFAOYSA-N 0.000 claims description 4
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- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 4
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Classifications
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/10—Phosphatides, e.g. lecithin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
- C07F9/6574—Esters of oxyacids of phosphorus
- C07F9/65742—Esters of oxyacids of phosphorus non-condensed with carbocyclic rings or heterocyclic rings or ring systems
Abstract
本发明涉及一种二硬脂酰磷脂酰甘油钠(DSPGNa)的制备工艺,本发明路线以中间的磷氧键为中心,将该化合物拆分成两个片段的对接。我们将甘油端先连接到磷氧键上,再连接中间体7,尽可能提高价格较为昂贵的中间体7的利用率。
Description
技术领域
本发明涉及合成领域,具体涉及一种二硬脂酰磷脂酰甘油钠的制备工艺。
背景技术
Bangham教授于1965年最早发现了脂质体(liposome),脂质体技术也被喻为“生物导弹”技术或***靶向给药技术。随着脂质体技术的推广,脂质体作为一种新型的药物载体,具有低毒性,较长的体内循环时间,靶向性,缓释等优点,在药物定向输送方面越来越受到人们的重视。
脂质体的组成:类脂质(磷脂)及附加剂。
1.磷脂类:包括天然磷脂和合成磷脂二类。磷脂的结构特点为一个磷酸基和一个季铵盐基组成的亲水性基团,以及由两个较长的烃基组成的亲脂性基团。天然磷脂以卵磷脂(磷脂酰胆碱,PC)为主,来源于蛋黄和大豆,显中性。合成磷脂主要有DPPC(二棕榈酰磷脂酰胆碱)、DPPE(二棕榈酰磷脂酰乙醇胺)、DSPC(二硬脂酰磷脂酰胆碱)、DSPG(二硬脂酰磷脂酰甘油)等,其均属氢化磷脂类,具有性质稳定,抗氧化性强,成品稳定等特点,是国外首选的辅料。
2.胆固醇:胆固醇与磷脂是共同构成细胞膜和脂质体的基础物质。胆固醇具有调节膜流动性的作用,故可称为脂质体“流动性缓冲剂”。
天然磷脂是生物膜的主要成分,几乎存在于所有有机体细胞。按照磷脂的化学结构的不同,磷脂可以分为甘油磷脂与鞘氨醇磷脂。其中甘油磷脂是由三部分组成,分别是甘油骨架,脂肪酸,含羟基的亲水头基。鞘氨醇磷脂与甘油磷脂的区别只在于用鞘氨醇取代了甘油。天然磷脂一般是从大豆或蛋黄中分离提取的,也有通过加工,酶修饰或半合成得到磷脂化合物,但是上述方法得到的磷脂是各类磷脂的混合物或者是一类磷脂的同系物,均不是单一的、高纯度的磷脂,其应用有一定的局限性。
二硬脂酰磷脂酰甘油钠(DSPGNa)是制备脂质体的重要辅料之一,不同于天然磷脂DSPGNa属于合成磷脂,具有确定化学成分。由于其独特的结构和理化性质,在一些关键制剂的开发中起了极为重要的作用,其中,最为的代表即是脂质体药物安必素Ambisome(注射用两性霉素B脂质体),适用于念珠菌、曲霉菌、隐球菌等深部真菌感染的患者。两性霉素B是深度真菌感染的药,但其对肾脏有很大的毒性。两性霉素脂质体B很大程度是解决了这一问题,因肾损伤或药物毒性而不能使用有效剂量的两性霉素B的患者,或已经接受过两性霉素B治疗无效的患者均可使用。脂质体药物安必素Ambisome所用磷脂材料包括:DSPG(二硬脂酰磷脂酰甘油)、HSPC(氢化大豆卵磷脂)、CHO(高纯胆固醇)。鉴于DSPGNa在脂质体研究方面越来越广泛应用,市场需求量大,开发适合工业生产前景的二硬脂酰磷脂酰甘油钠DSPGNa合成方法有着重要的意义。
文献Journal of Biological Chemistry(1958),232,895-901.(By Baer,Erich;Buchnea,Dmytro)中首次提到了DSPGNa的制备方法。以三氯氧磷(POCl3)、D-α,β-二醇、D-丙酮缩甘油为主要原料,先将等摩尔的D-α,β-二醇、吡啶,冰浴下保持0℃,滴加至等摩尔的三氯氧磷溶液中,滴加完毕后,升温至室温,搅拌1.0hr。降温至10℃,滴加等摩尔的D-丙酮缩甘油、吡啶,滴加完毕后,升温至室温,搅拌2.5hr,滴加等摩尔的水,分别用2N冰硫酸溶液、饱和碳酸钠溶液、水处理,减压浓缩得粗品。粗品分散在丙酮溶液中,-85℃下处理2.0hr,离心得二油酰-L-α-甘油基磷酰基-L-甘油。
二油酰-L-α-甘油基磷酰基-L-甘油加入氧化铂作催化剂、乙醇做溶剂,常压氢化,得到粗品,丙酮精制得到二硬脂酰-L-α-甘油基磷酰基-L-甘油。
该路线看似简便,但我们在尝试采用与上述路线类似的方法直接将中间体7[(2S)-3-羟基-1,2-丙烷二基二硬脂酸酯]与中间体4(丙酮缩甘油)分步进行偶联时,发现可能由于三氯氧磷的反应活性较高,与羟基反应时的选择性较差,即使摩尔比控制在1:1,也使会发生磷酰氯同时与多个醇偶联的情况,导致产品为多种磷脂的混合物,我们发现中间体9粗品纯度仅在40-50%之间,通过质谱检测分析,粗品中混有多种磷脂成份。其中最大的杂质(在总杂质中占比55-65%),MS(EI+):m/e=933.5,与下面的化合物10的结构相吻合,应该为单硬脂酰双甘油杂质;另外还有一个主要杂质(在总杂质中占比20-30%),MS(EI+):m/e=1493.7,与下面的化合物11的结构相吻合,应该为双硬脂酰单甘油杂质;有一个非主要杂质(在总杂质中占比5-10%),MS(EI+):m/e=1311.83,与下面的化合物12的结构相吻合,应该为双硬脂酰杂质。中间体5的提纯较为困难,目前只能通过柱层析分离纯化后,进行下一步的反应。针对磷酰氯活性过高所带来的副反应,我们先后采取了降低反应温度、控制滴加速度、增大反应体系等手段,希望能将该反应控制在磷酸二酯阶段,但都以失败告终。因此通过POCl3逐步取代其分子中的氯来合成磷酸二酯的方法,虽然很直接,但并不是一种行之有效的方法。
另外我们发现酸性条件下脱丙叉保护基也会有副反应产生,我们参考文献S.Pedatella et al./Carbohydrate Research 343(2008)31–38中的水解条件:90%TFA,室温3.0hr进行了水解反应,发现产品中有15-20%是由于分子结构中一侧的硬脂酸链发生断裂,生成了副产物13溶血磷脂(LSPG),同时检测到副产物14硬脂酸。我们尝试用稍弱一些的冰醋酸进行脱丙叉反应,但是需要加热至80℃以上,反应才能进行,且副反应仍然不可避免。
合成路线如下:
中间体9中含有的杂质结构如下:
产品1酸降解杂质的结构如下:
2015年,Shigeki Sano等利用Still-Gennari试剂[O,O'双(2,2,2-三氟乙基)磷乙酸甲酯],通过Horner-Wadsworth-Emmons(HWE)反应高效构建酯型甘油磷脂酸(PA)、磷脂酰乙醇胺(PE)和磷脂酰胆碱(PC)。HWE反应是Wittig反应的改进,反应用稳定的膦酸酯碳负离子,代替磷叶立德,与醛、酮反应生成烯烃,产物主要为E-型烯烃,该反应中产生的二烃磷酸盐通常是作为副产物处理,但在用于磷脂类化合物的合成中,则是主要的目标产物。根据此文献,我们尝试使用Still-Gennari试剂合成DSPGNa,我们发现Still-Gennari试剂中的三氟乙醇基(CF3CH2O-)是一个比较合适的离去基团,与醇反应选择性较好,可以实现与不同的醇逐步进行偶联,操作简单,所得中间体17纯度可以达到85-90%,可直接用于下一步反应,但是在脱去丙叉基团时,酸性降解的杂质仍然不可避免。Still-Gennari试剂中使用的三氟乙醇基为制备磷酸二酯拓宽了新的思路。
合成路线如下:
发明内容
本发明的目的在于针对以上技术问题,提供一种合成路线简单、生产成本低、高收率、高纯度的二硬脂酰磷脂酰甘油钠(DSPGNa)的制备工艺。
本发明的技术方案如下:
一种二硬脂酰磷脂酰甘油钠(DSPGNa)的制备工艺,反应方程式为:
制备中间体19(R=TFE)[5-(苄氧基)-2-(2,2,2-三氟乙氧基)-2-氧代-1,3,2-二氧磷杂环己烷]的反应方程式:
具体步骤为:
1.制备中间体19(R=TFE):中间体22三氯氧磷与化合物23(2-苄氧基-1,3-丙二醇)在有机碱试剂的存在下发生二取代反应,与三氟乙醇在有机碱试剂的存在下发生单取代反应,得到中间体19,减压蒸馏获得纯品,有机碱可以是DBU(1,8-二氮杂二环十一碳-7-烯)、DIEA(N,N-二异丙基乙胺)、TEA(三乙胺)等;制备中间体19(R=p-NP):中间体22三氯氧磷与化合物23(2-苄氧基-1,3-丙二醇)在有机碱试剂的存在下发生二取代反应,与4-硝基-苯酚(p-NP)在有机碱试剂的存在下发生单取代反应,得到中间体19,,减压蒸馏获得纯品,有机碱可以是DBU(1,8-二氮杂二环十一碳-7-烯)、DIEA(N,N-二异丙基乙胺)、TEA(三乙胺)等;
2.制备中间体20:中间体7[(2S)-3-羟基-1,2-丙烷二基二硬脂酸酯]与中间体19[5-(苄氧基)-2-(2,2,2-三氟乙氧基)-2-氧代-1,3,2-二氧磷杂环己烷],摩尔比1:1投料,在有机碱试剂的存在下发生缩合反应得到中间体20(R)-3-{[5-(苯甲酰氧基)-2-氧代-1,3,2-二氧杂膦-2-基]氧基}丙烷-1,2-二硬脂酸二乙酯,有机碱试剂可以是DBU、DIEA、TEA等;
3.制备中间体21:中间体20在类似三氟化硼、三氯化铟(InCl3)、四氯化锡(SnCl4)、氯化锌(ZnCl2)等路易斯酸的催化下开环,得到中间体21(2R)-3-{[2-(苯甲酰氧基)-3-羟丙氧基]-羟基-磷酰氧基}丙烷-1,2-二硬脂酸二乙酯;
4.制备化合物1:中间体21在三甲基碘硅烷(TMSI)作用下脱去苄基(Bzl),甲醇钠成钠盐即得到目标化合物1。
本发明的有益效果是:根据该化合物的结构,以中间的磷氧键为中心,将该化合物拆分成两个片段的对接。我们将甘油端先连接到磷氧键上,再连接中间体7,尽可能提高价格较为昂贵的中间体7的利用率。
另外甘油端的是以二取代的连接方式,这样整个中间体19中仅裸露出一个活性离去端,这使得中间体7的连接更为纯净。中间体20的开环采用路易斯酸催化开环,其可能的机理:三氟化硼***作为Lewis酸中心,使得O上电荷偏移,造成P-O键极性变大,在这种情况下亲核试剂进攻位阻较小的磷氧键,发生取代反应生成化合物21。这样的开环条件较为温和,几乎不会影响到另一侧的硬脂酰磷酰键。最后保护基苄基的脱除,可以通过氢化,也可以用三甲基碘硅烷,从安全的角度考虑,我们更倾向于使用三甲基碘硅烷。
路易斯酸催化开环机理如下(以三氟化硼***为例):
三氯氧磷是一种较为常用的化工原料,价廉易得。我们通过基团修饰的方式将其改造为中间体19的结构形式。中间体19中的二取代的结构给后面的反应带来了很多便利条件,使我们避免了活性太高造成的副反应;另外整个反应过程中,没有酸碱的介入,反应较为温和,副反应较少,所得粗品进行简单的精制即可达到药用辅料标准;产品的制备工艺也相对简单,均为常规操作,仅在制备中间体19时,终产品需要通过减压蒸馏进行提纯。
具体实施方式
实施例1:二硬脂酰磷脂酰甘油钠(DSPGNa)的制备
1.1中间体20的制备
物料:
操作:称取中间体7 10.00g 16.00mmol、中间体19 5.22g 16mmol和100ml甲苯混合均匀,冰水浴冷却,反应液温度控制在0-10℃,将DBU 4.87g和10ml甲苯制成的溶液慢慢滴加至反应液中,控制在10-15min滴完,将反应液温度升至室温20-30℃,搅拌反应2.0-3.0hr,反应结束后,过滤除去沉淀,得有机相,有机相用1%盐酸溶液、饱和氯化钠溶液充分洗涤,所得有机相用无水硫酸钠干燥后,减压浓缩至干得白色固体12.83g,为产品中间体20,收率:94.21%。产品纯度:95.42%
HPLC条件:
用十八烷基硅烷键合硅胶为填充剂(4.6mm×250mm,5μm)或效能相当的色谱柱;以水-冰醋酸(100:0.1)为流动相A,以甲醇为流动相B,按下表进行梯度洗脱;流速为每分钟1.0ml;检测器为CAD检测器,雾化温度为35℃;柱温为30℃,进样量为10μl。
梯度表如下表:
时间(min) | 流动相A(%) | 流动相B(%) |
0 | 50 | 50 |
10 | 50 | 50 |
40 | 15 | 85 |
45 | 15 | 85 |
46 | 50 | 50 |
55 | 50 | 50 |
供试品溶液:取本品约10mg,精密称定,置20ml量瓶中,加甲醇溶解,稀释至刻度,摇匀,作为供试品溶液。
测定方法:按面积归一化法计算,主峰面积百分比不得少于95%。
1.2中间体21的制备
操作:
称取中间体20 10.00g 11.76mmol,加入100ml甲苯混合均匀,冰水浴冷却,反应液温度控制在0-10℃,将三氟化硼***溶液(47%)0.18g和10ml甲苯制成的溶液慢慢滴加至反应液中,控制在5-10min滴完,将反应液温度升至室温20-30℃,搅拌反应7.0-8.0hr,反应结束后,有机相用1%NaHCO3溶液、饱和氯化钠溶液充分洗涤,所得有机相用无水硫酸钠干燥后,减压浓缩至干得白色固体9.21g,为产品中间体21,收率:90.19%。产品纯度:91.08%
HPLC条件:
用十八烷基硅烷键合硅胶为填充剂(4.6mm×250mm,5μm)或效能相当的色谱柱;以水-冰醋酸(100:0.1)为流动相A,以甲醇为流动相B,按下表进行梯度洗脱;流速为每分钟1.0ml;检测器为CAD检测器,雾化温度为35℃;柱温为30℃,进样量为10μl。
梯度表如下表:
时间(min) | 流动相A(%) | 流动相B(%) |
0 | 50 | 50 |
10 | 50 | 50 |
40 | 15 | 85 |
45 | 5 | 95 |
46 | 50 | 50 |
55 | 50 | 50 |
供试品溶液:取本品约10mg,精密称定,置20ml量瓶中,加甲醇溶解,稀释至刻度,摇匀,作为供试品溶液。
测定方法:按面积归一化法计算,主峰面积百分比不得少于90%。
1.3产品1的制备
物料:
操作:
称取中间体21 10.00g 11.50mmol,加入100ml甲苯混合均匀,冰盐浴冷却,反应液温度控制在-10-0℃,将三甲基碘硅烷溶液4.60g和10ml甲苯制成的溶液慢慢滴加至反应液中,控制在10-20min滴完,将反应液温度升至10-20℃,搅拌反应0.5-1.0hr,反应结束后,加入含有甲醇钠0.62g的甲醇溶液5ml,有白色固体析出,过滤,干燥,得白色固体8.16g,为产品1,收率:88.54%。产品纯度:97.76%
HPLC条件:
用C8(4.6mm×250mm,5μm)或效能相当的色谱柱;以10mmol/L醋酸铵缓冲液(冰醋酸调节pH至4.0)为流动相A,以甲醇为流动相B,按下表进行梯度洗脱;流速为每分钟1.0ml;检测器为CAD检测器,雾化温度为35℃;柱温为30℃,进样量为10μl。
梯度表如下表:
时间(min) | 流动相A(%) | 流动相B(%) |
0 | 40 | 60 |
10 | 40 | 60 |
40 | 10 | 90 |
45 | 10 | 90 |
46 | 40 | 60 |
55 | 40 | 60 |
供试品溶液:取本品约10mg,精密称定,置20ml量瓶中,加甲醇溶解,稀释至刻度,摇匀,作为供试品溶液。
测定方法:按面积归一化法计算,主峰面积百分比不得少于95%。
19(R=TFE)[5-(苄氧基)-2-(2,2,2-三氟乙氧基)-2-氧代-1,3,2-二氧磷杂环己烷]按实施例3方法制备。
实施例2:二硬脂酰磷脂酰甘油钠(DSPGNa)的制备
2.1中间体20的制备
物料:
操作:
称取中间体7 10.00g 16.00mmol、中间体19 5.84g 16mmol和100ml二氯甲烷混合均匀,冰水浴冷却,反应液温度控制在0-10℃,将三乙胺3.24g和10ml二氯甲烷制成的溶液慢慢滴加至反应液中,控制在10-15min滴完,将反应液温度升至室温20-30℃,搅拌反应2.0-3.0hr,反应结束后,过滤除去沉淀,得有机相,有机相用1%盐酸溶液、饱和氯化钠溶液充分洗涤,所得有机相用无水硫酸钠干燥后,减压浓缩至干得白色固体12.83g,为产品中间体20,收率:94.21%。产品纯度:96.32%
HPLC条件:
用十八烷基硅烷键合硅胶为填充剂(4.6mm×250mm,5μm)或效能相当的色谱柱;以水-冰醋酸(100:0.1)为流动相A,以甲醇为流动相B,按下表进行梯度洗脱;流速为每分钟1.0ml;检测器为CAD检测器,雾化温度为35℃;柱温为30℃,进样量为10μl。
梯度表如下表:
时间(min) | 流动相A(%) | 流动相B(%) |
0 | 40 | 60 |
10 | 40 | 60 |
45 | 5 | 95 |
50 | 5 | 95 |
51 | 40 | 60 |
60 | 40 | 60 |
供试品溶液:取本品约10mg,精密称定,置20ml量瓶中,加甲醇溶解,稀释至刻度,摇匀,作为供试品溶液。
测定方法:按面积归一化法计算,主峰面积百分比不得少于95%。
2.2中间体21的制备
物料:
操作:
称取中间体20 10.00g 11.75mmol,加入100ml四氢呋喃(THF)混合均匀,冰水浴冷却,反应液温度控制在0-10℃,将四氯化锡0.33g和10ml THF制成的溶液慢慢滴加至反应液中,控制在5-10min滴完,将反应液温度升至室温20-30℃,搅拌反应7.0-8.0hr,反应结束后,有机相用1%NaHCO3溶液、饱和氯化钠溶液充分洗涤,所得有机相用无水硫酸钠干燥后,减压浓缩至干得白色固体9.08g,为产品中间体21,收率:88.92%。
产品纯度:92.07%
HPLC条件:
用十八烷基硅烷键合硅胶为填充剂(4.6mm×250mm,5μm)或效能相当的色谱柱;以水-冰醋酸(100:0.1)为流动相A,以甲醇为流动相B,按下表进行梯度洗脱;流速为每分钟1.0ml;检测器为CAD检测器,雾化温度为35℃;柱温为30℃,进样量为10μl。
梯度表如下表:
时间(min) | 流动相A(%) | 流动相B(%) |
0 | 30 | 70 |
10 | 30 | 70 |
45 | 10 | 90 |
50 | 10 | 90 |
51 | 30 | 70 |
60 | 30 | 70 |
供试品溶液:取本品约10mg,精密称定,置20ml量瓶中,加甲醇溶解,稀释至刻度,摇匀,作为供试品溶液。
测定方法:按面积归一化法计算,主峰面积百分比不得少于90%。
2.3产品1的制备
物料:
操作:
称取中间体21 10.00g 11.50mmol,加入100ml甲苯混合均匀,冰盐浴冷却,反应液温度控制在-10-0℃,将三甲基碘硅烷溶液4.60g和10ml甲苯制成的溶液慢慢滴加至反应液中,控制在10-20min滴完,将反应液温度升至10-20℃,搅拌反应0.5-1.0hr,反应结束后,加入含有甲醇钠0.62g的甲醇溶液5ml,有白色固体析出,过滤,干燥,得白色固体7.95g,为产品1,收率:86.26%。产品纯度:98.13%
HPLC条件:同实施例1中(1.3)
19(R=p-NP)[5-(苄氧基)-2-(4-硝基-苯氧基)-2-氧代-1,3,2-二氧磷杂环己烷]按实施例4方法制备。
实施例3:19(R=TFE)[5-(苄氧基)-2-(2,2,2-三氟乙氧基)-2-氧代-1,3,2-二氧磷杂环己烷]的制备
操作:
称取中间体23 11.88g 65.22mmol、DBU29.98g 195.66mmol和200ml二氯甲烷混合均匀,冰水浴冷却,反应液温度控制在0-5℃,将三氯氧磷中间体22 10.00g 65.22mmol和20ml二氯甲烷制成的溶液慢慢滴加至反应液中,控制在20-30min滴完,将反应液温度升至室温20-30℃,搅拌反应0.5-1.0hr,反应结束后,冰水浴冷却,反应液温度控制在0-5℃,将三氟乙醇6.52g 65.22mmol和10ml二氯甲烷制成的溶液慢慢滴加至反应液中,控制在10-20min滴完,将反应液温度升至室温20-30℃,搅拌反应0.5-1.0hr,过滤除去沉淀,得二氯甲烷溶液,减压蒸除有机相后,减压蒸馏,130-140℃/5mmHg,收集馏分,得无色油状液体15.5g,为产品中间体19,收率:72.86%。产品纯度:98.74%
HPLC条件:
用十八烷基硅烷键合硅胶为填充剂(4.6mm×250mm,5μm)或效能相当的色谱柱;以水-冰醋酸(100:0.1)为流动相A,以甲醇为流动相B,按下表进行梯度洗脱;流速为每分钟1.0ml;检测器为CAD检测器,雾化温度为35℃;柱温为30℃,进样量为10μl。
梯度表如下表:
时间(min) | 流动相A(%) | 流动相B(%) |
0 | 95 | 5 |
10 | 95 | 5 |
45 | 80 | 20 |
50 | 80 | 20 |
51 | 95 | 5 |
60 | 95 | 5 |
供试品溶液:取本品约40mg,精密称定,置20ml量瓶中,加甲醇溶解,稀释至刻度,摇匀,作为供试品溶液。
测定方法:按面积归一化法计算,主峰面积百分比不得少于95%。
实施例4:19(R=p-NP)[5-(苄氧基)-2-(4-硝基-苯氧基)-2-氧代-1,3,2-二氧磷杂环己烷]的制备
物料:
操作:
称取中间体23 11.88g 65.22mmol、DBU29.98g 195.66mmol和200ml二氯甲烷混合均匀,冰水浴冷却,反应液温度控制在0-5℃,将三氯氧磷中间体22 10.00g 65.22mmol和20ml二氯甲烷制成的溶液慢慢滴加至反应液中,控制在20-30min滴完,将反应液温度升至室温20-30℃,搅拌反应0.5-1.0hr,反应结束后,冰水浴冷却,反应液温度控制在0-5℃,将4-硝基-苯酚9.07g 65.22mmol和10ml二氯甲烷制成的溶液慢慢滴加至反应液中,控制在10-20min滴完,将反应液温度升至室温20-30℃,搅拌反应0.5-1.0hr,过滤除去沉淀,得二氯甲烷溶液,减压蒸除有机相后,减压蒸馏,155-160℃/5mmHg,收集馏分,得无色油状液体17.8g,为产品中间体19,收率:74.72%。产品纯度:99.04%HPLC条件:
用十八烷基硅烷键合硅胶为填充剂(4.6mm×250mm,5μm)或效能相当的色谱柱;以水-冰醋酸(100:0.1)为流动相A,以甲醇为流动相B,按下表进行梯度洗脱;流速为每分钟1.0ml;检测器为CAD检测器,雾化温度为35℃;柱温为30℃,进样量为10μl。
梯度表如下表:
时间(min) | 流动相A(%) | 流动相B(%) |
0 | 90 | 10 |
10 | 90 | 10 |
35 | 30 | 70 |
40 | 30 | 70 |
41 | 90 | 10 |
50 | 90 | 10 |
供试品溶液:取本品约20mg,精密称定,置20ml量瓶中,加甲醇溶解,稀释至刻度,摇匀,作为供试品溶液。
测定方法:按面积归一化法计算,主峰面积百分比不得少于97%。
对比实施例1:
按CN103864840A中DSPG合成方法,具体步骤为:
将(R)-1,2-甘油二硬脂酸-甘油-3-磷脂酸5.0g(7.09mmol)、500ml氯仿-吡啶混合溶液(氯仿:吡啶=2:1),降温至0-5℃,滴加2,2-二甲基-4-甲醇-1,3-二氧戊环0.94g(7.11mmol),保持同温度下搅拌5.0hr,升温至30℃继续搅拌20hr。停止反应,用1N盐酸溶液调节pH=2,150ml饱和氯化钠溶液洗涤3次,有机层减压浓缩至干。浓缩物加入20%HAc溶液20ml,60℃搅拌2.0hr,饱和NaHCO3溶液调节pH=7,氯仿250ml*3萃取,100ml饱和氯化钠溶液洗涤3次,有机层减压浓缩至干得粗品。粗品4.5g用450g硅胶(100-200目),展开剂氯仿:甲醇:水=30:6:1进行柱层析纯化,得产品DSPG2.76g,收率:49.95%,产品纯度:97.82%
HPLC条件:同实施例1中(1.3)
我们将对比实施例1与实施例实验的结果相比较,可以发现实施例中产品收率较高,且避免了繁琐的柱层析纯化,使得生产更便捷。
Claims (6)
2.如权利要求1所述二硬脂酰磷脂酰甘油钠(DSPGNa)的制备工艺,其特征在于,制备中间体19(R=TFE)[5-(苄氧基)-2-(2,2,2-三氟乙氧基)-2-氧代-1,3,2-二氧磷杂环己烷]的反应方程式:
具体步骤为:
制备中间体19(R=TFE):中间体22三氯氧磷与化合物23(2-苄氧基-1,3-丙二醇)在有机碱试剂的存在下发生二取代反应,与三氟乙醇在有机碱试剂的存在下发生单取代反应,得到中间体19(R=TFE)5-(苄氧基)-2-(2,2,2-三氟乙氧基)-2-氧代-1,3,2-二氧磷杂环己烷],减压蒸馏获得纯品;制备中间体19(R=p-NP):中间体22三氯氧磷与化合物23(2-苄氧基-1,3-丙二醇)在有机碱试剂的存在下发生二取代反应,与4-硝基-苯酚(p-NP)在有机碱试剂的存在下发生单取代反应,得到中间体19(R=p-NP)5-(苄氧基)-2-(4-硝基-苯氧基)-2-氧代-1,3,2-二氧磷杂环己烷,减压蒸馏获得纯品。
3.如权利要求1所述二硬脂酰磷脂酰甘油钠(DSPGNa)的制备工艺,其特征在于,制备中间体20(R)-3-{[5-(苯甲酰氧基)-2-氧代-1,3,2-二氧杂膦-2-基]氧基}丙烷-1,2-二硬脂酸二乙酯:中间体7[(2S)-3-羟基-1,2-丙烷二基二硬脂酸酯]与中间体19 5-(苄氧基)-2-(2,2,2-三氟乙氧基)-2-氧代-1,3,2-二氧磷杂环己烷或5-(苄氧基)-2-(4-硝基-苯氧基)-2-氧代-1,3,2-二氧磷杂环己烷摩尔比1:1投料,在有机碱试剂的存在下发生缩合反应得到中间体20。
4.如权利要求1所述二硬脂酰磷脂酰甘油钠(DSPGNa)的制备工艺,其特征在于,制备中间体21:中间体20在类似三氟化硼、三氯化铟(InCl3)、四氯化锡(SnCl4)、氯化锌(ZnCl2)等路易斯酸的催化下开环,得到中间体21。
5.如权利要求1所述二硬脂酰磷脂酰甘油钠(DSPGNa)的制备工艺,其特征在于,制备化合物1:中间体21(2R)-3-{[2-(苯甲酰氧基)-3-羟丙氧基]-羟基-磷酰氧基}丙烷-1,2-二硬脂酸二乙酯在三甲基碘硅烷(TMSI)作用下脱去苄基(Bzl),甲醇钠成钠盐即得到目标化合物1。
6.如权利要求2或3所述二硬脂酰磷脂酰甘油钠(DSPGNa)的制备工艺,其特征在于,有机碱为DBU(1,8-二氮杂二环十一碳-7-烯)、DIEA(N,N-二异丙基乙胺)、TEA(三乙胺)中的一种或数种。
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