CN114685337B - 一种艾地骨化醇的制备方法 - Google Patents
一种艾地骨化醇的制备方法 Download PDFInfo
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- CN114685337B CN114685337B CN202210434267.6A CN202210434267A CN114685337B CN 114685337 B CN114685337 B CN 114685337B CN 202210434267 A CN202210434267 A CN 202210434267A CN 114685337 B CN114685337 B CN 114685337B
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Classifications
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- A—HUMAN NECESSITIES
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A—HUMAN NECESSITIES
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Abstract
本发明涉及一种药物的合成方法,特别涉及一种艾地骨化醇的制备方法,以25‑羟基胆固醇为起始原料,经氧化、脱氢、异构化、还原、乙酰化保护、脱氢处理、双烯保护、环氧化、脱保护、加成、光照反应制备得到艾地骨化醇,其操作简单,收率高,适合工业化生产。
Description
技术领域
本发明涉及一种药物的合成方法,具体涉及一种艾地骨化醇的制备方法。
背景技术
艾地骨化醇,英文名称eldecalcitol,为白色结晶粉末,对光和空气敏感。微溶于甲醇、乙醇、乙酸乙酯。它是人体内维生素D3最重要的代谢活性产物之一,具有促使小肠吸收钙并调节骨质中无机盐转运等作用;主要用于骨质疏松症;慢性肾功能衰竭病人的肾性骨营养不良,特别是需要长期血液透析的病人;手术后自发性及假性甲状旁腺机减退;维生素D3依赖性佝偻病以及血磷酸盐过少维生素d抗性佝偻病;银屑病等皮肤病;以及其他维生素D缺乏症。
艾地骨化醇作为一种新型活性维生素D类似物,与传统维生素D相比作用持久且利用率高。艾地骨化醇在増强骨密度方面的作用尤为突出,因此被用作治疗骨质疏松症的药物。虽然艾地骨化醇作为治巧骨质疏松的药物一直备受关注。
申请号为201710377709.7的中国专利公开了一种艾地骨化醇的制备方法,将具有式(Ⅰ)结构的A环片段和式(II)结构的CD环片段在催化剂作用下发生偶联,反应完成后萃取干燥,经柱层析分离纯化得到式(III)结构的中间体;将得到的中间体溶解于四氢呋喃溶液中,加入氟化氢吡啶脱除硅醚保护基团,再经纯化、结晶,得艾地骨化醇成品,取得了较高的收率。
申请号为202010325584.5的中国专利公开了一种艾地骨化醇合成方法,以石胆酸、N-溴代丁二酰亚胺、甲醇、盐酸、溴化甲基镁和结晶剂为原料制备而成,大大提高了原材料的转化率,使得相同份数量的原料可产出更多的艾地骨化醇,从而降低生产者的投入成本。
发明内容
为了解决上述问题,本发明制备了一种艾地骨化醇的制备方法,能够高效的完成艾地骨化醇的全合成,过程简单,收率高。
本发明为实现上述目的所采取的技术方案为:
一种艾地骨化醇的制备方法,工艺过程为:
S1、以25-羟基胆固醇为原料,在环己酮溶剂中,异丙醇铝为催化剂,将二级醇氧化为酮后处理得到中间体酮,即为化合物1;
S2、将化合物1与2,3-二氯-5,6-二氰对苯醌混合,进行脱氢反应,经萃取、洗涤、浓缩、提取后,在乙腈溶剂中结晶得到脱氢物,即为化合物2;
S3、以乙醇为溶剂,向其中加入化合物2、乙醇钠和叔丁醇钾,化合物2在叔丁醇钾的作用下重排反应后,经萃取、洗涤、浓缩得到异构体,记为化合物3;
S4、将化合物3溶解于吡啶溶剂中,并加入硼氢化钠,以4-二甲氨基吡啶为催化剂进行反应,化合物3在硼氢化钠作用下选择性还原酮羰基,生成醇,淬灭后,萃取洗涤、浓缩后得到还原产物;
S5、在步骤S4得到的还原产物中加入乙酸酐,还原产物经乙酸酐酰化后,经萃取、洗涤、浓缩、结晶后得到产物酯,记为化合物4;
S6、以正己烷为溶剂,将化合物4与N-溴代丁二酰亚胺混合,并加入偶氮二异丁腈,进行溴代反应,得到1-乙酸酯-25-羟基-7-溴代胆固醇-1-烯;再向其中加入2,4,6-三甲基吡啶,进行脱溴化氢反应,得到1-乙酸酯-25-羟基-胆固醇-1、7-二烯,反应完成后,以甲醇为溶剂,加入氢氧化钾,发生皂化反应,得到化合物5;
S7、化合物5采用4-苯基-1,2,4-***啉-3,5-二酮处理后对双烯进行保护,以N,N-二甲基甲酰胺为溶剂,加入二甲基叔丁基氯硅烷和咪唑进行反应,对羟基进行保护,得到4-苯基-1,2,4-***啉-3,5-二酮保护的共轭二烯烃酯,即为化合物6;
S8、将得到的化合物6用间氯过氧苯甲酸进行处理,氧化未保护的烯烃,得到4-苯基-1,2,4-***啉-3,5-二酮保护的环氧化物,记为化合物7;
S9、以四氢呋喃为溶剂,将加入氟化四丁铵对化合物7进行处理,反应去掉TBS羟基保护基团,然后采用加入1,3-二甲基-2-咪唑啉酮去除4-苯基-1,2,4-***啉-3,5-二酮保护基团,最终得到环氧化物,即为化合物8;
S10、以丙二醇为溶剂,加入化合物8和叔丁醇钾,环氧开环得到羟基丙氧基去氢化合物,记为化合物9;
S11、将化合物9光化开环,经分离纯化后得到产物艾地骨化醇结晶物。
进一步地,一种艾地骨化醇的胶囊,所述胶囊由内容物和囊壳组成,所述内容物由艾地骨化醇、卵磷脂和链甘油三酯组成;所述囊壳由改性聚丙烯树脂、辛酸钠、乙醇、三醋酸甘油酯和二氧化钛组成;
所述改性聚丙烯树脂的制备方法为:以乙醇为溶剂,加入聚丙烯树脂和硫酸铜,加热并搅拌,向其中缓慢滴加甘油,滴加完成后继续搅拌,加热回流得到中间体I;将中间体I与磷酸混合,加入对甲基苯磺酸,加热搅拌,反应完成后减压蒸馏得到改性聚丙烯树脂。
本发明具有如下有益效果:
1.以25-羟基胆固醇为起始原料,经氧化、脱氢、异构化、还原、乙酰化保护、脱氢处理、双烯保护、环氧化、脱保护、加成、光照反应制备得到艾地骨化醇,其操作简单,收率高,适合工业化生产;
2.利用甘油对聚丙烯树脂进行改性,甘油具有一定的润滑性能防止在吞食过程中胶囊粘连在食道上,且甘油性质温和,不会对食道造成伤害;在甘油对聚丙烯树脂改性的基础上将磷酸接枝到甘油改性的聚丙烯树脂上,形成磷酸酯基,促进了药物的溶出,提高了药物的作用效果。
附图说明
图1为本发明中艾地骨化醇制备方法的流程图。
具体实施方式
下面将结合本申请实施例,对本申请实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本申请一部分实施例,而不是全部的实施例。基于本申请中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本申请保护的范围。
实施例1
一种艾地骨化醇的制备方法,具体流程如图1所示,具体工艺过程为:
S1、Oppenauer氧化:以40g 25-羟基胆固醇为原料,在200mL环己酮溶剂中,15.2g异丙醇铝为催化剂,加热至75℃,反应4h,将二级醇氧化为酮后处理得到38.2g中间体酮25-羟基胆甾-4-烯-3-酮,即为化合物1;反应过程如下:
C27H46O2+C6H10O------C27H44O2+C6H12O;
S2、脱氢反应:将38g化合物1与20g2,3-二氯-5,6-二氰对苯醌混合,进行脱氢反应,反应4h,经乙酸乙酯萃取、饱和氯化钠洗涤三次、浓缩、提取后,在乙腈溶剂中结晶得到36.8g脱氢物25-羟基胆甾-1,4-二烯-3-酮,即为化合物2;反应过程如下:
C27H44O2+C8Cl2N2O----C27H42O2+C8H2Cl2N2O;
S3、异构反应:以200mL乙醇为溶剂,向其中加入36g化合物2、15.2g乙醇钠和13.8g叔丁醇钾,反应2h,化合物2在叔丁醇钾的作用下重排反应后,经乙酸乙酯萃取、饱和氯化钠洗涤、浓缩得到34g异构体25-羟基胆甾-1,5-二烯-3-酮,记为化合物3;反应过程如下:
C27H42O2------C27H42O2;
S4、还原反应:将33.5g化合物3溶解于250mL吡啶溶剂中,并加入5.8g硼氢化钠,以3.5g4-二甲氨基吡啶为催化剂,冰浴,反应4h,化合物3在硼氢化钠作用下选择性还原酮羰基,生成醇,淬灭后,萃取洗涤、浓缩后得到32g还原产物25-羟基胆固醇-1-烯,反应过程如下:
4C27H42O2+BH4Na+2H2O--4C27H44O+BNaO2;
S5、乙酰化保护:在步骤S4得到的32g还原产物中加入10mL乙酸酐,回流3h,还原产物经乙酸酐酰化后,经乙酸乙酯萃取、饱和氯化钠洗涤、浓缩、结晶后得到30.2g产物酯,1-乙酸酯-25-羟基胆固醇-1-烯,记为化合物4;反应过程如下:
C27H44O2+C4H6O3----C29H46O3+C2H4O2;
S6、脱氢处理:
溴代反应:以300mL正己烷为溶剂,将30g化合物4与150mL N-溴代丁二酰亚胺混合,并加入15g偶氮二异丁腈,进行溴代反应,保持45℃,反应4h,得到29.5g1-乙酸酯-25-羟基-7-溴代胆固醇-1-烯;反应过程为:
C29H46O3+C4H4BrNO2-----C29H45BrO3+C4H5NO2;
脱溴化氢反应:再向其中加入4.5g 2,4,6-三甲基吡啶,在55℃下进行脱溴化氢反应,反应得到22.3g 1-乙酸酯-25-羟基-胆固醇-1、7-二烯,反应过程为:
C29H45BrO3+C8H11N---C29H44O3+C8H12NBr;
皂化反应:反应完成后,以200mL甲醇为溶剂,加入4g氢氧化钾,发生皂化反应,反应6h,得到18.2g化合物5,即25-羟基胆固醇-1,7-二烯,反应过程为:
C29H44O3+KOH---C27H42O2+C2H3O2K;
S7、保护:
共轭加成:18g化合物5采用6g 4-苯基-1,2,4-***啉-3,5-二酮处理后对双烯进行保护,反应过程为:
C27H42O2+C8H5N3O2---C35H47N3O2;
3位羟基保护:上述反应完成后,以250mL N,N-二甲基甲酰胺为溶剂,加入5g二甲基叔丁基氯硅烷和4.8g咪唑进行反应,对羟基进行保护,得到18.9g 4-苯基-1,2,4-***啉-3,5-二酮保护的共轭二烯烃酯,即为化合物6,反应过程为:
C35H47N3O2+C6H15ClSi+C3H4N2---C41H61N3O2Si+C3H5N2Cl。
S8、环氧化:将得到的18.9g化合物6用15mL间氯过氧苯甲酸在15℃下进行处理,处理2h,氧化未保护的烯烃,得到16.34g 4-苯基-1,2,4-***啉-3,5-二酮保护的环氧化物,记为化合物7,反应过程为:
C41H61N3O2Si+C7H5ClO3----C41H61N3O3Si+C7H5ClO2;
S9、脱保护:以200mL四氢呋喃为溶剂,将加入4.5g氟化四丁铵在15℃下对化合物7进行处理,处理4h,反应去掉TBS羟基保护基团,反应过程为:
C41H61N3O3Si+C16H36FN+H2O-----C16H37O+C6H15FSi+C35H47N3O5。
上述反应完成后,然后采用加入4.2g 1,3-二甲基-2-咪唑啉酮在50℃下反应1.5h,去除4-苯基-1,2,4-***啉-3,5-二酮保护基团,最终得到8.4g环氧化物,即为化合物8,反应过程为:
C35H47N3O5+C5H10N2O---C27H42O3+C13H15N5O3;
S10、加成反应:以150mL丙二醇为溶剂,加入6g化合物8和3g叔丁醇钾,反应4h,环氧开环得到9.6g羟基丙氧基去氢化合物,即1a、25-二羟基-2β-(3-羟基丙氧基)胆固醇-7-烯,记为化合物9,反应过程为:
C27H42O3+C3H8O2----C30H50O5;
S11、光化开环:将9.6g化合物9光化开环,(光照反应条件:XPA光反应仪器内,光照反应10-60min))经分离纯化后得到8.6g产物艾地骨化醇结晶物,总收率为17.6%,反应过程为:
C30H50O5----C30H50O5。
实施例2
一种艾地骨化醇的制备方法,具体流程如图1所示,具体工艺过程为:
S1、Oppenauer氧化:以80g 25-羟基胆固醇为原料,在400mL环己酮溶剂中,30g异丙醇铝为催化剂,加热至85℃,反应6h,将二级醇氧化为酮后处理得到72.4g中间体酮25-羟基胆甾-4-烯-3-酮,即为化合物1;
S2、脱氢反应:将71g化合物1与42g 2,3-二氯-5,6-二氰对苯醌混合,进行脱氢反应,反应6h,经乙酸乙酯萃取、饱和氯化钠洗涤三次、浓缩、提取后,在乙腈溶剂中结晶得到58g脱氢物25-羟基胆甾-1,4-二烯-3-酮,即为化合物2;
S3、异构反应:以350mL乙醇为溶剂,向其中加入58g化合物2、32g乙醇钠和26.8g叔丁醇钾,反应4h,化合物2在叔丁醇钾的作用下重排反应后,经乙酸乙酯萃取、饱和氯化钠洗涤,洗涤三次、浓缩得到51g异构体25-羟基胆甾-1,5-二烯-3-酮,记为化合物3;
S4、还原反应:将51g化合物3溶解于350mL吡啶溶剂中,并加入12g硼氢化钠,以8.5g 4-二甲氨基吡啶为催化剂,冰浴,反应6h,化合物3在硼氢化钠作用下选择性还原酮羰基,生成醇,淬灭后,萃取洗涤、浓缩后得到42g还原产物25-羟基胆固醇-1-烯;
S5、乙酰化保护:在步骤S4得到的42g还原产物中加入25mL乙酸酐,回流5h,还原产物经乙酸酐酰化后,经乙酸乙酯萃取、饱和氯化钠洗涤、浓缩、结晶后得到28.8g产物酯,1-乙酸酯-25-羟基胆固醇-1-烯,记为化合物4;
S6、脱氢处理:
溴代反应:以450mL正己烷为溶剂,将28g化合物4与250mL N-溴代丁二酰亚胺混合,并加入25g偶氮二异丁腈,进行溴代反应,保持50℃,反应4h,得到23g 1-乙酸酯-25-羟基-7-溴代胆固醇-1-烯;
脱溴化氢反应:再向其中加入11g 2,4,6-三甲基吡啶,在60℃下进行脱溴化氢反应,反应得到22.3g 1-乙酸酯-25-羟基-胆固醇-1、7-二烯;
皂化反应:反应完成后,以400mL甲醇为溶剂,加入8g氢氧化钾,发生皂化反应,反应6h,得到18.2g化合物5,即25-羟基胆固醇-1,7-二烯;
S7、保护:
共轭加成:18g化合物5采用14g 4-苯基-1,2,4-***啉-3,5-二酮处理后对双烯进行保护;
3位羟基保护:上述反应完成后,以450mL N,N-二甲基甲酰胺为溶剂,加入12g二甲基叔丁基氯硅烷和12.2g咪唑进行反应,对羟基进行保护,得到16g 4-苯基-1,2,4-***啉-3,5-二酮保护的共轭二烯烃酯,即为化合物6;
S8、环氧化:将得到的16g化合物6用30mL间氯过氧苯甲酸在12℃下进行处理,处理4h,氧化未保护的烯烃,得到15.6g 4-苯基-1,2,4-***啉-3,5-二酮保护的环氧化物,记为化合物7;
S9、脱保护:以450mL四氢呋喃为溶剂,将加入11g氟化四丁铵在12℃下对化合物7进行处理,处理6h,反应去掉TBS羟基保护基团;
上述反应完成后,然后采用加入9.5g 1,3-二甲基-2-咪唑啉酮在55℃下反应2h,去除4-苯基-1,2,4-***啉-3,5-二酮保护基团,最终得到13.2g环氧化物,即为化合物8;
S10、加成反应:以300mL丙二醇为溶剂,加入13g化合物8和6g叔丁醇钾,反应6h,环氧开环得到12.2g羟基丙氧基去氢化合物,即1a、25-二羟基-2β-(3-羟基丙氧基)胆固醇-7-烯,记为化合物9;
S11、光化开环:将12.2g化合物9光化开环,(光照反应条件:XPA光反应仪器内,光照反应40min)经分离纯化后得到10.5g产物艾地骨化醇结晶物,总收率为10.8%。
实施例3
一种艾地骨化醇的胶囊,胶囊由内容物和囊壳组成,内容物由0.0001g艾地骨化醇、0.003g卵磷脂和0.015链甘油三酯组成;囊壳由50g改性聚丙烯树脂、2g辛酸钠、25g乙醇、2g三醋酸甘油酯和2g二氧化钛组成(800粒胶囊);
改性聚丙烯树脂的制备方法为:以80g乙醇为溶剂,加入65g聚丙烯树脂(EudragitL100-55(EL))和5g硫酸铜,加热至120℃并搅拌,向其中缓慢滴加35g甘油,滴加完成后继续搅拌,加热回流得到中间体I,反应过程如下:
将中间体I与35g磷酸混合,加入对5g甲基苯磺酸,加热至110℃搅拌4h,反应完成后减压蒸馏得到改性聚丙烯树脂,反应过程为:
一种艾地骨化醇的胶囊的制备方法,制备过程如下(按如上重量称取各物质):
T1、将艾地骨化醇与卵磷脂和链甘油三酯混合,加热至55℃缓慢搅拌均匀,加热反应1h后停止加热,自然冷却至室温,得到内容物;
T2、将改性聚丙烯树脂、辛酸钠、三醋酸甘油酯和二氧化钛溶解于乙醇溶剂中,加热至45℃搅拌均匀,加热搅拌1.5h后停止加热,真空脱气,低温冷藏,得到囊壳;
T3、将步骤T1制备的内容物和步骤T2制备的囊壳置于胶囊剂中,进行压丸、干燥、检验、包装即得。
对比例1
本对比例为艾地骨化醇的胶囊的制备,与实施例3相比,不对聚丙烯树脂进行改性,直接用市售的聚丙烯树脂(Eudragit L100-55(EL))进行囊壳的制备,其余条件不变,具体操作参照实施例3。
对比例2
本对比例为艾地骨化醇的胶囊的制备,与实施例3相比,将改性聚丙烯树脂更换为中间体I进行囊壳的制备,其余条件不变,具体操作参照实施例3。
对比例3
本对比例为艾地骨化醇的胶囊的制备,与实施例3相比,将改性聚丙烯树脂更换为明胶进行囊壳的制备,其余条件不变,具体操作参照实施例3。
对比例4
本对比例为艾地骨化醇的胶囊的制备,与实施例3相比,在制备囊壳时不加入辛酸钠,其余条件不变,具体操作参照实施例3。
相关测试:
试验分组:选取4月龄200-220g雌性SD大鼠160只,随机分为8组,每组20只,分别为:
(1)空白对照组,实验过程中用蒸馏水替代药物;
(2)阴性对照组,实验过程中用蒸馏水替代药物;
(3)阳性对照组,实验过程中给尼尔雌醇,剂量为1mg/kg;
(4)实施例1组,实验过程中给实施例1胶囊,剂量为5μg/kg;
(5)对比例1组,实验过程中给对比例1胶囊,剂量5μg/kg;
(6)对比例2组,实验过程中给对比例2胶囊,剂量5μg/kg;
(7)对比例3组,实验过程中给对比例3胶囊,剂量5μg/kg;
(8)对比例4组,实验过程中给对比例4胶囊,剂量5μg/kg;
其中,空白对照组保留卵巢,其余各组均摘除卵巢。
实验方法:各组动物口服给药,每天1次,连续给药1个月,将大鼠用10%水合氯醛麻醉,腹部切开皮肤、肌肉,暴露腹腔,腹动脉取血,分离血清,迅速剥离子宫,称取重量。取出右侧胫骨,剔除附着的肌肉及其它组织,保存于70%的乙醇中,以备测定骨密度。
骨密度和固含量测定:
测试结果如表1所示:
表1
由以上结果可以看出,阴性对照组的总骨密度、骨小梁骨密度和皮质骨骨密度低于空白对照组,阳性对照组的总骨密度、骨小梁骨密度和皮质骨骨密度高于空白对照组,实施例1组的总骨密度、骨小梁骨密度和皮质骨骨密度与阳性对照组相当,对比例1-4组总骨密度、骨小梁骨密度和皮质骨骨密度低于实施例3,以上说明采用改性聚丙烯树脂制备的囊壳能够提高药物的吸收,对照实施例3和对比例4的测试数据,发现辛酸钠与改性聚丙烯树脂之间具有协同作用。
去卵巢骨质疏松大鼠骨含量测定结果如表2所示。
表2
由以上结果可知,阴性对照组的总骨含量、骨小梁骨含量和皮质骨骨含量低于空白对照组,阳性对照组的总骨含量、骨小梁骨含量和皮质骨骨含量高于空白对照组,实施例1组的总骨含量、骨小梁骨含量和皮质骨骨含量与阳性对照组相当,高于对比例1-4组。
卵巢骨质疏松大鼠骨钙素含量测定测定结果如表3所示。
表3
由以上结果可知,术前各组骨钙素相当,术后三个月,阴性对照组血清骨钙素含量下降,实施例3和对照组1-4组血清骨钙素含量上升,且实施例3上升幅度较大。
与现有技术相比,在囊壳制备过程中,将常用的明胶用改性聚丙烯树脂替换,有效的缓解了现有技术制备的囊壳对湿、氧敏感药物保护性差、容易在食道粘连、在贮藏过程中存在崩解迟缓及药物溶出度低的问题。为了让药物更好的溶出,在本发明中利用甘油对聚丙烯树脂进行改性,甘油具有一定的润滑性能防止在吞食过程中胶囊粘连在食道上,且甘油性质温和,不会对食道造成伤害;另外为了促进肠道对药物的吸收,在甘油对聚丙烯树脂改性的基础上将磷酸接枝到甘油改性的聚丙烯树脂上,形成磷酸酯基,由于细胞膜主要是由磷脂构成的富有弹性的半透性膜,利用相似相溶的原理,利用改性聚丙烯树脂制备的囊壳更易于与细胞膜间产生相互作用,又因在囊壳的制备过程中还加入了辛酸钠,该物质能够通过与细胞膜相互作用而增加细胞内钙浓度,导致Ca2+/钙调素依赖的肌动蛋白微丝收缩而暂时打开上皮紧密连接,因而能够进一步促进药物的溶出,提高药物的作用效果。
需要说明的是,在本文中,诸如第一和第二等之类的关系术语仅仅用来将一个实体或者操作与另一个实体或操作区分开来,而不一定要求或者暗示这些实体或操作之间存在任何这种实际的关系或者顺序。而且,术语“包括”、“包含”或者其任何其他变体意在涵盖非排他性的包含,从而使得包括一系列要素的过程、方法、物品或者设备不仅包括那些要素,而且还包括没有明确列出的其他要素,或者是还包括为这种过程、方法、物品或者设备所固有的要素。
尽管已经示出和描述了本申请的实施例,对于本领域的普通技术人员而言,可以理解在不脱离本申请的原理和精神的情况下可以对这些实施例进行多种变化、修改、替换和变型,本申请的范围由所附权利要求及其等同物限定。
Claims (4)
1.一种艾地骨化醇在胶囊制备中的应用,其特征在于,所述胶囊由内容物和囊壳组成,所述内容物由艾地骨化醇、卵磷脂和链甘油三酯组成;所述囊壳由改性聚丙烯树脂、辛酸钠、乙醇、三醋酸甘油酯和二氧化钛组成;
所述改性聚丙烯树脂的制备方法为:以乙醇为溶剂,加入聚丙烯树脂和硫酸铜,加热并搅拌,向其中缓慢滴加甘油,滴加完成后继续搅拌,加热回流得到中间体I;将中间体I与磷酸混合,加入对甲基苯磺酸,加热搅拌,反应完成后减压蒸馏得到改性聚丙烯树脂;
所述艾地骨化醇的制备方法为:
S1、以25-羟基胆固醇为原料,在环己酮溶剂中,异丙醇铝为催化剂,将二级醇氧化为酮后处理得到中间体酮,即为化合物1;
S2、将化合物1与2,3-二氯-5,6-二氰对苯醌混合,进行脱氢反应,经萃取、洗涤、浓缩、提取后,在乙腈溶剂中结晶得到脱氢物,即为化合物2;
S3、以乙醇为溶剂,向其中加入化合物2、乙醇钠和叔丁醇钾,化合物2在叔丁醇钾的作用下重排反应后,经萃取、洗涤、浓缩得到异构体,记为化合物3;
S4、将化合物3溶解于吡啶溶剂中,并加入硼氢化钠,以4-二甲氨基吡啶为催化剂进行反应,化合物3在硼氢化钠作用下选择性还原酮羰基,生成醇,淬灭后,萃取洗涤、浓缩后得到还原产物;
S5、在步骤S4得到的还原产物中加入乙酸酐,还原产物经乙酸酐酰化后,经萃取、洗涤、浓缩、结晶后得到产物酯,记为化合物4;
S6、以正己烷为溶剂,将化合物4与N-溴代丁二酰亚胺混合,并加入偶氮二异丁腈,进行溴代反应,溴代反应的条件:温度:45~50℃,得到1-乙酸酯-25-羟基-7-溴代胆固醇-1-烯;再向其中加入2,4,6-三甲基吡啶,进行脱溴化氢反应,脱溴化氢反应的条件:温度:55~60℃,得到1-乙酸酯-25-羟基-胆固醇-1、7-二烯,反应完成后,以甲醇为溶剂,加入氢氧化钾,发生皂化反应,得到化合物5;
S7、化合物5采用4-苯基-1,2,4-***啉-3,5-二酮处理后对双烯进行保护,以N,N-二甲基甲酰胺为溶剂,加入二甲基叔丁基氯硅烷和咪唑进行反应,对羟基进行保护,得到4-苯基-1,2,4-***啉-3,5-二酮保护的共轭二烯烃酯,即为化合物6;
S8、将得到的化合物6用间氯过氧苯甲酸进行处理,氧化未保护的烯烃,得到4-苯基-1,2,4-***啉-3,5-二酮保护的环氧化物,记为化合物7;
S9、以四氢呋喃为溶剂,将加入氟化四丁铵对化合物7进行处理,反应去掉TBS羟基保护基团,然后采用加入1,3-二甲基-2-咪唑啉酮去除4-苯基-1,2,4-***啉-3,5-二酮保护基团,最终得到环氧化物,即为化合物8;
S10、以丙二醇为溶剂,加入化合物8和叔丁醇钾,环氧开环得到羟基丙氧基去氢化合物,记为化合物9;
S11、将化合物9光化开环,经分离纯化后得到产物艾地骨化醇结晶物;
所述聚丙烯树脂型号为 Eudragit L100-55。
2.根据权利要求1所述的一种艾地骨化醇在胶囊制备中的应用,其特征在于,步骤S2中,用乙酸乙酯萃取、饱和氯化钠洗涤。
3.根据权利要求1所述的一种艾地骨化醇在胶囊制备中的应用,其特征在于,步骤S4中在冰浴下发生反应,反应时间4~6h。
4.根据权利要求1所述的一种艾地骨化醇在胶囊制备中的应用,其特征在于,胶囊的制备过程如下:
T1、将艾地骨化醇与卵磷脂和链甘油三酯混合,加热缓慢搅拌均匀,自然冷却至室温,得到内容物;
T2、将改性聚丙烯树脂、辛酸钠、三醋酸甘油酯和二氧化钛溶解于乙醇溶剂中,加热搅拌均匀,真空脱气,低温冷藏,得到囊壳;
T3、将步骤T1制备的内容物和步骤T2制备的囊壳置于胶囊剂中,进行压丸、干燥、检验、包装即得。
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"Process Development for the Practical Production of Eldecalcitol by Linear, Convergent and Biomimetic Syntheses";NOBORU KUBODERA等;Anticancer Research;第32卷;第304页,Figure 2 * |
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