CN117126090A - 一种骨化醇类原料药5,6-trans杂质的除杂方法 - Google Patents
一种骨化醇类原料药5,6-trans杂质的除杂方法 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 19
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- MGNNYOODZCAHBA-GQKYHHCASA-N fluticasone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(O)[C@@]2(C)C[C@@H]1O MGNNYOODZCAHBA-GQKYHHCASA-N 0.000 claims 1
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- FBPFZTCFMRRESA-GUCUJZIJSA-N galactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-GUCUJZIJSA-N 0.000 claims 1
- 229950006319 maxacalcitol Drugs 0.000 claims 1
- IMAKHNTVDGLIRY-UHFFFAOYSA-N methyl prop-2-ynoate Chemical compound COC(=O)C#C IMAKHNTVDGLIRY-UHFFFAOYSA-N 0.000 claims 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C45/69—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by addition to carbon-to-carbon double or triple bonds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/92—Naphthofurans; Hydrogenated naphthofurans
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/14—All rings being cycloaliphatic
- C07C2602/24—All rings being cycloaliphatic the ring system containing nine carbon atoms, e.g. perhydroindane
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Abstract
本发明首次公开了一种骨化醇类原料药5,6‑trans杂质的除杂方法，属于有机化学领域。5,6‑trans异构体杂质是含有19位亚甲基骨化醇类原料药的光降解杂质，对于该杂质的去除方法有硅胶柱层析、重结晶、制备液相纯化等，但是以上方法存在杂质去除不彻底、收率低、成本高、产生二次杂质等风险。针对以上问题，本发明根据5,6‑trans异构体杂质特有的顺式共轭双烯结构特征，通过添加一类化学试剂（亲双烯试剂）与该杂质的顺式共轭双烯结构发生狄尔斯‑阿尔德反应（Diels‑Alder反应），利用所得产物与骨化醇类API极性差异，再通过硅胶柱层析等常规手段将该产物去除（图1），从而达到对5,6‑trans异构体杂质的除杂效果。本发明的创新点在于：首次公开了一种化学反应法除骨化醇类原料药中5,6‑trans异构体杂质的方法，该方法有反应条件温和、环境友好、工艺操作简单、除杂效果好、收率高等优点。
Description
技术领域
本发明属于有机化学领域，涉及骨化醇类原料药5,6-trans杂质的除杂方法。
技术背景
骨化醇类药物是一类活性维生素D衍生物，在治疗骨质疏松症、继发性甲状旁腺功能亢进、增生性皮肤病有着广泛应用，另外，骨化醇类药物还发挥各种免疫调节作用和抑制肿瘤细胞的生成的作用。目前在国内外上市的骨化醇类药物有维生素D2、维生素D3、骨化二醇、骨化三醇、度骨化醇、阿法骨化醇、氟骨化醇、马沙骨化醇、卡泊三醇、艾地骨化醇、他卡西醇、西奥骨化醇、帕立骨化醇等品种（式1）。
式1
骨化醇类化合物的基本化学结构和甾体类似，命名也是采用甾体化合物的编号，其结构通式如式2。通式分子母核中一般含有19个碳原子组成，3-位α羟基和三烯结构是该类化合物固定结构特征。其中，含有19位亚甲基结构的骨化醇类原料药中，光降解杂质普遍会出现5,6-trans异构体杂质（式2）。
式2
5,6-trans异构体杂质是含有19位亚甲基骨化醇类原料药的光降解杂质，对于该杂质的去除方法有硅胶柱层析、重结晶、制备液相纯化等，但是以上方法存在杂质去除不彻底、收率低、成本高、产生二次杂质等风险。因此，对于5,6-trans异构体杂质的去除，存在较大难度。
狄尔斯-阿尔德反应（Diels-Alder反应），又称双烯合成（diene synthesis），是共轭双烯与取代烯烃（称为亲双烯体）反应生成取代环己烯。此反应分为两部分，即一部分为提供共轭双烯化合物—双烯体，另一部分为提供不饱和键的化合物—亲双烯体。其中亲双烯体包括：1、双键类亲双烯体：如-C=C-Z 或Z-C=C-Z′(Z 或Z′为-CHO，-COR，-CO2H，-CO2R，-COCl，-COAr，-CN，-NO2，-Ar，-CH2OH，-CH2Cl，-CH2NH2，-CH2CN，-CH2CO2H，-X 或-C=C)；2、叁键类亲双烯体：如-C≡C-Z或Z-C≡C-Z（(Z 或Z′同上）；3、含其它原子的杂亲二烯体：如-CN，-C=N-，-N=N-，O=N 及-C=O 等。
发明内容
针对以上问题，本发明根据5,6-trans异构体杂质特有的顺式共轭双烯结构特征，通过添加一类化学试剂（亲双烯试剂）与该杂质的顺式共轭双烯结构发生Diels-Alder反应，利用所得产物与骨化醇类API极性差异，再通过硅胶柱层析等常规手段将该产物去除，从而达到对5,6-trans异构体杂质的除杂效果。
本发明对5,6-trans异构体杂质的除杂反应通式（式3）如下：该反应只有5,6-trans异构体杂质与亲双烯试剂选择性反应，而API不参与反应。
式3
除杂方法：将含有5,6-trans异构体杂质的骨化醇原料药粗品以有机溶剂一，添加亲双烯试剂，在10~50℃下搅拌反应1~5h，然后经过淬灭、萃取、水洗、干燥等后处理，硅胶柱层析除掉杂质反应产物，得到除掉5,6-trans异构体杂质后的骨化醇原料药。
有机溶剂一可为乙酸乙酯、二氯甲烷、甲苯、丙酮、甲醇、乙醇、异丙醇、甲基叔丁基醚、乙醚、异丙醚、正己烷、正庚烷中的一种或多种组合，根据不同骨化醇类原料药溶解性优选溶剂种类，其中维生素D2、维生素D3、骨化二醇、度骨化醇、阿法骨化醇、氟骨化醇的除杂优选乙酸乙酯，骨化三醇、马沙骨化醇、卡泊三醇、艾地骨化醇、他卡西醇、西奥骨化醇的除杂优选乙醇和乙酸乙酯。
亲双烯试剂可为顺丁烯二酸酐、顺丁烯二酸、顺丁烯二羧酸二甲酯、顺丁烯二羧酸二乙酯、丙烯醛、丙烯酸甲酯、丙烯酸乙酯、丙炔酸甲酯、丙炔酸乙酯、肉桂醛、α,β-不饱和硝基化合物、α,β-不饱和氰基化合物、对苯醌、丁炔二羧酸、丁炔二羧酸二甲酯、丁炔二羧酸二乙酯、偶氮二羧酸酯类、苯炔等含有取代基的不饱和烃类化合物。亲双烯试剂优选顺丁烯二酸酐。亲双烯试剂的摩尔投料比按照除杂之前骨化醇原料药粗品中5,6-trans异构体杂质检测含量而定，可为该杂质含量的2~15倍摩尔当量，优选5倍。
反应温度优选25~30℃，反应时间优选2h。
本发明的创新点在于：首次公开了一种化学反应法除骨化醇类原料药中5,6-trans异构体杂质的方法，该方法有反应条件温和、环境友好、工艺操作简单、除杂效果好、收率高等优点。
附图说明
图1为化学反应法除5,6-trans异构体杂质的工艺流程图
具体实施方式
下面将对本发明实施例中的技术方案进行清楚、完整地描述，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，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，都属于本发明保护的范围。
下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
实施例1
将骨化三醇粗品（1.0g，HPLC检测含5,6-trans杂质0.5%）添加至50mL反应瓶中，添加2mL乙醇和8mL乙酸乙酯搅拌溶清，添加顺丁烯二酸酐6mg，氮气保护下于25~30℃搅拌反应2h，反应完成后添加乙酸乙酯10mL，依次用饱和碳酸氢钠溶液、纯水洗涤，无水硫酸镁干燥，硅胶柱层析纯化，洗脱剂二氯甲烷/甲醇=30:1，得到960mg，收率96%，HPLC检测5,6-trans杂质含量为0.01%。
实施例2
将氟骨化醇粗品（1.0g，HPLC检测含5,6-trans杂质0.45%）添加至50mL反应瓶中，添加10mL乙酸乙酯搅拌溶清，添加顺丁烯二酸酐4mg，氮气保护下于25~30℃搅拌反应2h，反应完成后添加乙酸乙酯10mL，依次用饱和碳酸氢钠溶液、纯水洗涤，无水硫酸镁干燥，硅胶柱层析纯化，洗脱剂二氯甲烷/甲醇=50:1，得到969mg，收率96.9%，HPLC检测5,6-trans杂质含量为0.02%。
实施例3
将阿法骨化醇粗品（1.0g，HPLC检测含5,6-trans杂质0.55%）添加至50mL反应瓶中，添加10mL乙酸乙酯搅拌溶清，添加顺丁烯二酸酐7mg，氮气保护下于25~30℃搅拌反应2h，反应完成后添加乙酸乙酯10mL，依次用饱和碳酸氢钠溶液、纯水洗涤，无水硫酸镁干燥，硅胶柱层析纯化，洗脱剂二氯甲烷/甲醇=80:1，得到958mg，收率95.8%，HPLC检测5,6-trans杂质含量为0.01%。
实施例4
将艾地骨化醇粗品（1.0g，HPLC检测含5,6-trans杂质0.35%）添加至50mL反应瓶中，添加2mL乙醇和8mL乙酸乙酯搅拌溶清，添加顺丁烯二酸酐3.5mg，氮气保护下于25~30℃搅拌反应2h，反应完成后添加乙酸乙酯10mL，依次用饱和碳酸氢钠溶液、纯水洗涤，无水硫酸镁干燥，硅胶柱层析纯化，洗脱剂二氯甲烷/甲醇=25:1，得到975mg，收率97.5%，HPLC检测5,6-trans杂质，未检出该杂质。
实施例5
将度骨化醇粗品（1.0g，HPLC检测含5,6-trans杂质0.63%）添加至50mL反应瓶中，添加2mL乙醇和8mL乙酸乙酯搅拌溶清，添加顺丙烯醛7mg，氮气保护下于25~30℃搅拌反应2h，反应完成后添加乙酸乙酯10mL，依次用纯水、饱和氯化钠溶液洗涤，无水硫酸镁干燥，硅胶柱层析纯化，洗脱剂二氯甲烷/甲醇=50:1，得到955mg，收率95.5%，HPLC检测5,6-trans杂质含量为0.03%。
Claims (4)
1.本发明公开了一种骨化醇类原料药5,6-trans杂质的除杂方法，对5,6-trans异构体杂质的除杂反应通式（式1）如下：
除杂过程为：将含有5,6-trans异构体杂质的骨化醇原料药粗品以有机溶剂一，添加亲双烯试剂，在10~50℃下搅拌反应1~5h，然后经后处理和硅胶柱层析纯化除掉杂质反应产物，得到除掉5,6-trans异构体杂质后的骨化醇原料药。
2.根据权利要求1中所述的一种骨化醇类原料药5,6-trans杂质的除杂方法，其特征在于，所述骨化醇类原料药含有19位亚甲基结构，包括维生素D2、维生素D3、骨化二醇、骨化三醇、度骨化醇、阿法骨化醇、氟骨化醇、马沙骨化醇、卡泊三醇、艾地骨化醇、他卡西醇、西奥骨化醇，但不限于以上品种。
3.根据权利要求1中所述的一种骨化醇类原料药5,6-trans杂质的除杂方法，其特征在于，所述亲双烯试剂可为顺丁烯二酸酐、顺丁烯二酸、顺丁烯二羧酸二甲酯、顺丁烯二羧酸二乙酯、丙烯醛、丙烯酸甲酯、丙烯酸乙酯、丙炔酸甲酯、丙炔酸乙酯、肉桂醛、α,β-不饱和硝基化合物、α,β-不饱和氰基化合物、对苯醌、丁炔二羧酸、丁炔二羧酸二甲酯、丁炔二羧酸二乙酯、偶氮二羧酸酯类、苯炔等含有取代基的不饱和烃类化合物。
4.根据权利要求1中所述的一种骨化醇类原料药5,6-trans杂质的除杂方法，其特征在于，所述有机溶剂一可为乙酸乙酯、二氯甲烷、甲苯、丙酮、甲醇、乙醇、异丙醇、甲基叔丁基醚、乙醚、异丙醚、正己烷、正庚烷中的一种或多种组合。
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