CN114044788A - 一种氟骨化醇cd环的制备方法及其应用 - Google Patents
一种氟骨化醇cd环的制备方法及其应用 Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/09—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis
- C07C29/10—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis of ethers, including cyclic ethers, e.g. oxiranes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C35/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring
- C07C35/48—Halogenated derivatives
- C07C35/52—Alcohols with a condensed ring system
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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
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- 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
- C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
- C07C45/29—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups
- C07C45/292—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups with chromium derivatives
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/385—Saturated compounds containing a keto group being part of a ring
- C07C49/487—Saturated compounds containing a keto group being part of a ring containing hydroxy groups
- C07C49/507—Saturated compounds containing a keto group being part of a ring containing hydroxy groups polycyclic
- C07C49/513—Saturated compounds containing a keto group being part of a ring containing hydroxy groups polycyclic a keto group being part of a condensed ring system
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- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
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- 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
Abstract
本发明公开了一种氟骨化醇CD环的制备方法及其应用,涉及医药中间体合成领域。该方法公开了具有如下结构的化合物Ⅶ的制备方法,进而由化合物Ⅶ制备氟骨化醇。本发明的方法利用汇聚法合成,缩短了合成周期,降低了制备的成本;反应收率高,产品质量易于控制;避免使用危险试剂,降低了制备风险,容易实现放大制备。
Description
技术领域
本发明涉及医药中间体合成领域,特别涉及一种氟骨化醇CD环的制备方法及其应用。
背景技术
氟骨化醇是维生素D的类似物,对甲状旁腺机能亢进和骨质疏松症有治疗作用。在多种生物检测系统中,均比骨化三醇表现出更强的生物活性。体外试验中,比较了氟骨化醇与骨化三醇对大鼠成骨细胞株ROB-C26维生素D-反应性基因的激活作用,在加入维生素D后6h检测1α,25(OH)2-D3-24羟化酶mRNA表达水平,发现本品作用比骨化三醇强10倍,其在细胞内的滞留时间更长,能持久激活细胞内的靶基因;对肾切除大鼠的研究结果提示,本品对慢性肾衰引起的继发性甲状旁腺机能亢进和骨营养不良有一定治疗作用,且剂量低于骨化三醇。
对于氟骨化醇,就目前已报道的合成路线来看,其合成方法主要有以下两种:
一是如维生素D类似物那样以类胆固醇为原料,通过多步骤的线性合成,最后利用光反应制备氟骨化醇。如文献Chem.Pharm.Bull.,1982,30,4297报道的合成方法,其合成路线如下(式1):
又如专利US4358406公开了一种氟骨化醇的制备方法,其合成路线如下(式2):
但该方法起始原料昂贵,总收率低,而且都需要光反应开环以及热异构化反应,产品杂质较多,难以纯化。
二是以维生素D2为原料,经过多步骤的线性合成制备氟骨化醇。如日本专利JPH0770053公开了一种氟骨化醇的制备方法,其合成路线如下(式3):
专利US6080879公开了一种氟骨化醇的制备方法,其合成路线如下(式4):
文献Bioorg.Med.Chem.,2000,8,2157报道了一种氟骨化醇的制备方法,其合成路线如下(式5):
该方法路线比较繁琐,反应条件苛刻,合成过程中需使用叔丁基锂,钠汞齐,或者三正丁基锡化氢和二硫化碳等,在放大操作时容易发生危险,而且总收率很低。
发明内容
本发明针对上述现有的氟骨化醇合成中原料昂贵、需要光反应开环以及热异构化反应或需使用叔丁基锂,钠汞齐,或者三正丁基锡化氢和二硫化碳等危险试剂的现象,导致的成本高、安全性低的问题,提供了用于制备氟骨化醇的中间体的制备方法及其应用。
为了实现上述目的,本发明采用的技术方案如下:
本发明的目的之一是提供一种氟骨化醇中间体CD环的制备方法,包括以下步骤:
步骤一:化合物Ⅰ溶于有机溶剂中,在惰性气体保护、低温条件下在烷基锂试剂作用下得到化合物Ⅱ;
步骤二:将步骤一中得到的化合物Ⅱ溶于有机溶剂中,在惰性气体保护、低温条件下在碱性条件下与六氟丙酮反应得到化合物Ⅲ;
步骤三:将步骤二中得到的化合物Ⅲ溶于有机溶剂中,在催化剂条件下于一定温度和压力下经氢化还原得到化合物Ⅳ;
步骤四:将步骤三中得到的化合物Ⅳ溶于有机溶剂中,在常规脱除硅醚保护基条件下得到化合物Ⅴ;
步骤五:将步骤四中得到的化合物Ⅴ溶于机有溶剂中,经氧化反应得到化合物Ⅵ;
步骤六:将步骤五中得到的化合物Ⅵ溶于机有溶剂中,经常规羟基保护反应得到化合物Ⅶ;
其中,化合物Ⅶ的R为羟基保护基,特别是通过含氟无机盐、含氟有机盐、氢氟酸可脱除的保护基。
进一步地,步骤一中所述有机溶剂为乙醚、四氢呋喃、甲基叔丁基醚、二氧六环中的任意一种或几种,优选为四氢呋喃;所述低温条件为-80~-50℃,优选-70℃;所述烷基锂试剂为正丁基锂、正己基锂、叔丁基锂中的至少一种,优选为正丁基锂;所述化合物Ⅰ与烷基锂的摩尔比为1:2~1:6,优选为1:3~1:4。
进一步地,步骤二中所述有机溶剂为乙醚、四氢呋喃、甲基叔丁基醚、二氧六环中的任意一种或几种,优选为四氢呋喃;所述低温条件为-90~-60℃,优选-75℃;所述碱为正丁基锂、LiHMDS、LDA中的任意一种或几种,优选为LDA;所述化合物Ⅱ与碱的摩尔比为1:1~1:6,优选为1:2~1:4;所述化合物Ⅱ与六氟丙酮溶液的体积比为1:1~1:20,优选为1:10。
进一步地,步骤三中所述机溶剂为甲醇、乙醇、异丙醇、乙酸乙酯、四氢呋喃中的任意一种或几种,优选为甲醇或者乙醇;所述催化剂为钯碳、铂碳、钌炭、铑炭中的任意一种或几种,优选为钯碳;所述氢化还原的压力为0.1~1.0MPa,优选0.1~0.5MPa;所述氢化还原的温度为10~60℃,优选室温。
步骤四为常规脱除硅醚保护基的方法。
进一步地,步骤五中所述有机溶剂为正庚烷、二氯甲烷、乙酸乙酯、丙酮、醋酸异丙酯、四氢呋喃、二甲亚砜中的任意一种或几种,优选为二氯甲烷;所述氧化剂为二氯铬酸吡啶盐、氯铬酸吡啶盐、三氧化铬、三氧化硫吡啶中的任意一种或几种,优选为重铬酸吡啶盐;所述化合物Ⅴ与氧化剂的摩尔比值为1:1~1:5,优选为1:2;所述氧化反应的温度为0~40℃,优选为室温。
本发明还提供了上述的氟骨化醇中间体CD环的制备方法制备的化合物Ⅳ、化合物Ⅴ、化合物Ⅵ及化合物Ⅶ中间体在制备氟骨化醇中的应用。
本发明的另一目的是提供一种氟骨化醇的制备方法,该方法的合成路线路线如下:
使用前述方法制备得到化合物Ⅶ,然后化合物Ⅶ与A环进行Wittig-Horner反应,反应后得到保护的氟骨化醇,脱除保护基即可制备得到氟骨化醇。
与现有技术相比,本发明的有益技术效果是:
(1)本发明的方法利用汇聚法合成,简化了反应步骤,缩短了合成周期,降低了制备的成本;
(2)本发明的方法反应收率高,产品质量易于控制,容易放大制备;
(3)本发明的方法避免使用叔丁基锂,钠汞齐,三正丁基锡化氢,二硫化碳等危险试剂,降低了制备风险。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅用以解释本发明,并不用于限定本发明,即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。
实施例
一种氟骨化醇中间体CD环的制备方法,该方法的合成路线如下:
其中,化合物Ⅶ的R为羟基保护基,特别是通过含氟无机盐、含氟有机盐、氢氟酸可脱除的羟基保护基。
化合物Ⅰ通过文献Journal of Medicinal Chemistry,2018,61(15),6658-6673公开的方法制得,其余原料、试剂均通过商业途径获得。
化合物Ⅱ的制备
在3000ml四口瓶中加入化合物Ⅰ(136.0g,275.1mmol),四氢呋喃(1360.0ml),将反应降温到-70℃到-80℃,氩气保护下,滴加正丁基锂(439.0ml,1100.3mmol),保持温度反应1h,水淬灭反应,分离有机相,干燥浓缩干得到粗品,粗品柱层析得产物70.2g,收率78.0%。
化合物Ⅲ的制备
氩气保护下,于1000mL三口瓶中加入化合物Ⅱ(30.0g,89.6mmol),再加入四氢呋喃(300.0ml),将反应降温到-70℃到-80℃,滴加二异丙基氨基锂(358.4ml,358.4mmol),保持温度反应2h,加入饱和六氟丙酮的正己烷溶液(300ml),升温到室温,加水淬灭,分离有机相,干燥浓缩干得到粗品,粗品柱层析得产物40.0g,收率90.0%。饱和六氟丙酮的正己烷溶液的制备:将六氟丙酮的三水合物滴入浓硫酸中,产生的气体用正己烷(-20℃到-40℃)吸收至饱和。
化合物Ⅳ的制备
将化合物Ⅲ(40.0g,79.9mmol)加入到1000mL三口瓶中,加入乙醇(400.0ml),加入醋酸(4.0g,55.5mmol),氩气保护下,加入10%的钯/碳(4.0g),氢气球置换三次后开始氢化反应,室温反应50h,垫硅藻土过滤,将滤液浓缩并柱层析纯化得产物37.1g,收率92.1%。
化合物Ⅴ的制备
将化合物Ⅳ(35.0g,69.4mmol)加入到500mL四氟瓶中,加入丙酮(280ml),加入30%的氢氟酸(138.8g,208.2mmol)的水溶液,室温搅拌36小时。加入饱和碳酸氢钠水溶液,乙酸乙酯萃取,干燥浓缩得到粗品,粗品柱层析得产物24.5g,收率90.3%。
化合物Ⅵ的制备
将化合物Ⅴ(20.0g,51.2mmol)加入到500mL三口瓶中,加入二氯甲烷200ml,加入PDC(38.4g,102.4mol),室温搅拌20小时,反应体系直接干燥浓缩干柱层析得产物17.2g,收率86.3%。
化合物Ⅶ的制备
将化合物Ⅵ(15.0g,38.6mmol)加入到250mL三口瓶中,加入N,N-二甲基甲酰胺(150.0ml),降温到-10℃到-0℃,保持温度滴加TESOTf(30.6g,115.8mol),自然升温到室温,继续搅拌30h,加入水淬灭反应,乙酸乙酯萃取,干燥浓缩得到粗品,粗品柱层析得产物17g,收率90.5%。
Claims (10)
1.一种氟骨化醇中间体CD环的制备方法,其特征在于,包括以下步骤:
步骤一:化合物Ⅰ溶于有机溶剂中,在惰性气体保护、低温条件下在烷基锂试剂作用下得到化合物Ⅱ;
步骤二:将步骤一中得到的化合物Ⅱ溶于有机溶剂中,在惰性气体保护、低温条件下在碱性条件下与六氟丙酮反应得到化合物Ⅲ;
步骤三:将步骤二中得到的化合物Ⅲ溶于有机溶剂中,在催化剂条件下于一定温度和压力下经氢化还原得到化合物Ⅳ;
步骤四:将步骤三中得到的化合物Ⅳ溶于有机溶剂中,在常规脱除硅醚保护基条件下得到化合物Ⅴ;
步骤五:将步骤四中得到的化合物Ⅴ溶于机有溶剂中,经氧化反应得到化合物Ⅵ;
步骤六:将步骤五中得到的化合物Ⅵ溶于机有溶剂中,经常规羟基保护反应得到化合物Ⅶ;
其中,化合物Ⅶ的R为羟基保护基。
2.根据权利要求1所述的氟骨化醇中间体CD环的制备方法,其特征在于:步骤一中所述有机溶剂为乙醚、四氢呋喃、甲基叔丁基醚、二氧六环中的任意一种或几种;所述低温条件为-80~-50℃,所述烷基锂试剂为正丁基锂、正己基锂、叔丁基锂中的至少一种,所述化合物Ⅰ与烷基锂的摩尔比为1:2~1:6。
3.根据权利要求1所述的氟骨化醇中间体CD环的制备方法,其特征在于:步骤二中所述有机溶剂为乙醚、四氢呋喃、甲基叔丁基醚、二氧六环中的任意一种或几种;所述低温条件为-90~-60℃,所述碱为正丁基锂、LiHMDS、LDA中的任意一种或几种,所述化合物Ⅱ与碱的摩尔比为1:1~1:6,所述化合物Ⅱ与六氟丙酮溶液的体积比为1:1~1:20。
4.根据权利要求1所述的氟骨化醇中间体CD环的制备方法,其特征在于:步骤三中所述机溶剂为甲醇、乙醇、异丙醇、乙酸乙酯、四氢呋喃中的任意一种或几种;所述催化剂为钯碳、铂碳、钌炭、铑炭中的任意一种或几种;所述氢化还原的压力为0.1~1.0MPa,所述氢化还原的温度为10~60℃。
5.根据权利要求1所述的氟骨化醇中间体CD环的制备方法,其特征在于:步骤五中所述有机溶剂为正庚烷、二氯甲烷、乙酸乙酯、丙酮、醋酸异丙酯、四氢呋喃、二甲亚砜中的任意一种或几种;所述氧化剂为二氯铬酸吡啶盐、氯铬酸吡啶盐、三氧化铬、三氧化硫吡啶中的任意一种或几种;所述化合物Ⅴ与氧化剂的摩尔比值为1:1~1:5,所述氧化反应的温度为0~40℃。
6.根据权利要求1所述的氟骨化醇中间体CD环的制备方法,其特征在于:化合物Ⅶ的R是通过含氟无机盐、含氟有机盐、氢氟酸可脱除的羟基保护基。
7.一种如权利要求本1-6任一项所述的氟骨化醇中间体CD环的制备方法制备的化合物Ⅶ。
8.如权利要求本1-6任一项所述的氟骨化醇中间体CD环的制备方法制备的化合物Ⅳ、化合物Ⅴ、化合物Ⅵ及化合物Ⅶ中间体在制备氟骨化醇中的应用。
10.根据权利要求9所述氟骨化醇的制备方法,其特征在于:所述化合物Ⅶ采用权利要求1-6任一项所述氟骨化醇中间体CD环的制备方法获得。
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