CN111499677B - 一种甾体激素化合物9-位脱卤的制备方法 - Google Patents
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- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
- C07J5/0053—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa not substituted in position 16
-
- 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
- Y02P20/00—Technologies relating to chemical industry
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
本发明公开了一种甾体激素化合物9‑位脱卤的方法,该方法步骤:将9‑卤代‑11‑羟基酯甾体化合物和一定量的偶氮自由基引发剂溶于有机溶剂中,加入一定量的供氢试剂,升温至一定温度后,反应一段时间后检测,待反应完全,减压浓缩除去部分溶剂,降温析晶,析出固体,过滤得到目标产物11‑羟基酯甾体化合物。本发明操作简单,成本低,避免了金属脱卤剂的使用,减少了三废污染,适用于工业化生产。
Description
技术领域
本发明属于医药化工技术领域,尤其涉及一种甾体激素化合物9-位脱卤的方法。
背景技术
甾体激素类药物(steroid hormone drugs),是指分子结构中含有甾体结构的激素类药物,临床应用较广,主要包括肾上腺皮质激素和性激素两大类。其中肾上腺皮质激素具有抗炎、抗过敏、抑制免疫、增强应激反应、抗内毒素和抗休克等多种药理作用,临床上可用于治疗许多病症,是临床上不可缺少的一类重要药物。在许多皮质激素药物的合成过程中,为了得到11β-羟基甾体化合物,需要对9,11-烯甾体化合物氧化溴羟化,再对9位的卤素进行还原脱卤素反应。工业上常使用二价铬金属还原法,但是这一方法并不绿色环保,一直存在着废水难于处理、成本高等缺点。因此,寻找更加绿色环保的甾体激素化合物9-位脱卤方法,是产品技术再创新的重点。
发明内容
本发明的目的在于提供一种甾体激素化合物9-位脱卤的制备方法,在解决上述技术问题的同时能够提高反应收率。
本发明提供一种甾体激素化合物9-位脱卤的制备方法:
该方法为:将9-卤代-11-羟基酯甾体化合物和一定量的偶氮自由基引发剂溶于有机溶剂中,加入一定量的供氢试剂,升温至一定温度后,反应一段时间后检测,待反应完全,减压浓缩除去部分溶剂,降温析晶,析出固体,过滤得到目标产物11-羟基酯甾体化合物。
所述偶氮自由基引发剂为偶氮二异丁腈(AIBN)、偶氮二异庚腈(ABVN)、偶氮二异丁酸二甲酯(AIBME)、偶氮二异丁咪唑啉盐酸盐(AIBI)、偶氮异丁氰基甲酰胺(V30)、偶氮二苯基甲烷、偶氮异丙苯等,优选为偶氮二异丁腈(AIBN)。
所述供氢试剂为巯基乙酸,巯基丙酸,巯基丁酸,甲酸铵,甲酸及其盐等,优选为巯基乙酸。
所述9-卤代-11-羟基酯甾体化合物(以下通式中X代表卤素原子(氯/溴/碘),R1代表甲酰基,乙酰基,苯甲酰基等羟基保护基,R2代表氢原子或甲酰基,乙酰基,苯甲酰基等羟基保护基),包括但不限于以下分子:
9-卤代-11-羟基酯甾体化合物与偶氮自由基引发剂及供氢试剂的摩尔比为1∶(0.05~1.0)∶(1~5),优选为1∶0.2∶2。
所述反应温度为40℃~105℃,优选为60℃~80℃。
所述溶剂为四氢呋喃,2-甲基四氢呋喃,3-甲基四氢呋喃,1,4-二氧六环,四氢吡喃,环氧己烷,乙二醇二甲醚,乙二醇二乙醚等醚类溶剂,或者单一醚类溶剂与N,N-二甲基甲酰胺(DMF),甲苯,乙腈等溶剂的混合溶剂,优选为2-甲基四氢呋喃的单一溶剂。
相比传统的甾体化合物铬盐脱卤工艺,本发明操作简单,安全性高,未采用金属脱卤剂,减少了三废污染,降低了成本。
具体实施方式
本发明所举的实施例仅是对本发明产品或方法作概括性例示,有助于更好地理解本发明,但并不会限制本发明范围。下述实施例中所述实验方法,如无特殊说明,均为常规方法;所述材料,如无特殊说明,均可从商业途径获得。
所述的9-卤代-11-羟基酯甾体化合物可以通过9,11-烯甾体化合物加入卤化试剂和高氯酸反应制得。
实施例1
在氮气保护条件下向反应釜中加入式(I)中的9-溴-11-甲酯醋酸泼尼松龙50.8g(0.10mol,1.0equiv),偶氮二异丁腈(AIBN)3.3g(0.02mol,0.2equiv),巯基乙酸18.4g(0.20mol,2.0equiv),2-甲基四氢呋喃4000ml升温回流,TLC检测控制反应终点,待反应结束,降低反应釜温度,减压蒸馏(蒸馏温度不超过50℃,真空度约为-0.08MPa)移去2-甲基四氢呋喃约3700ml,降温至0℃,过滤,干燥,得到白色固体11-甲酯醋酸泼尼松龙39.7g,摩尔收率92.3%,HPLC纯度为97.6%。
实施例2
在氮气保护条件下向反应釜中加入式(II)中的9-溴-11-乙酸酯-16-羟基泼尼松龙49.6g(0.10mol,1.0equiv),偶氮二异庚腈(ABVN)7.4g(0.03mol,0.3equiv),巯基丙酸10.5g(0.10mol,1.0equiv),四氢呋喃2000ml升温回流,TLC检测控制反应终点,待反应结束,降低反应釜温度,减压蒸馏(蒸馏温度不超过40℃,真空度约为-0.08MPa)移去四氢呋喃约1800ml,降温至0℃,过滤,干燥,得到白色固体11-乙酸酯-16-羟基泼尼松龙38.1g,摩尔收率91.2%,HPLC纯度为97.8%。
实施例3
在氮气保护条件下向反应釜中加入式(III)中的9-溴-11-苯甲酸酯-16-甲基-21-苯甲酸酯泼尼松龙66.0g(0.10mol,1.0equiv),偶氮二异丁酸二甲酯(AIBME)2.3g(0.01mol,0.1equiv),巯基丁酸24.0g(0.20mol,2.0equiv),3-甲基四氢呋喃3000ml升温回流,TLC检测控制反应终点,待反应结束,降低反应釜温度,减压蒸馏(蒸馏温度不超过50℃,真空度约为-0.08MPa)移去3-甲基四氢呋喃约2800ml,降温至0℃,过滤,干燥,得到白色固体11-苯甲酸酯-16-甲基-21-苯甲酸酯泼尼松龙52.5g,摩尔收率90.3%,HPLC纯度为97.5%。
实施例4
在氮气保护条件下向反应釜中加入式(IV)中的9-碘-11-甲酸酯-21-醋酸氢化可的松55.8g(0.10mol,1.0equiv),偶氮二异丁咪唑啉盐酸盐(AIBI)1.6g(0.005mol,0.05equiv),甲酸铵12.6g(0.20mol,2.0equiv),乙二醇二甲醚1000ml,40℃搅拌反应一段时间,TLC检测控制反应终点,待反应结束,降低反应釜温度,减压蒸馏(蒸馏温度不超过40℃,真空度约为-0.08MPa)移去乙二醇二甲醚约800ml,降温至0℃,过滤,干燥,得到白色固体11-甲酸酯-21-醋酸氢化可的松37.0g,摩尔收率85.6%,HPLC纯度为97.3%。
实施例5
在氮气保护条件下向反应釜中加入式(V)中的6-甲基-9-氯-11-甲酸酯-21-醋酸泼尼松龙47.8g(0.10mol,1.0equiv),偶氮异丁氰基甲酰胺(V30)16.4g(0.1mol,1.0equiv),甲酸钾42g(0.50mol,5.0equiv),四氢呋喃和乙腈各1000ml,升温至回流反应一段时间,TLC检测控制反应终点,待反应结束,降低反应釜温度,减压蒸馏(蒸馏温度不超过40℃,真空度约为-0.08MPa)移去四氢呋喃和乙腈约1800ml,降温至0℃,过滤,干燥,得到白色固体6-甲基-11-甲酸酯-21-醋酸泼尼松龙35.7g,摩尔收率80.5%,HPLC纯度为97.0%。
Claims (6)
1.一种甾体激素化合物9-位脱卤的制备方法,其特征在于:将9-卤代-11-羟基酯甾体化合物和一定量的偶氮自由基引发剂溶于有机溶剂中,加入一定量的供氢试剂,升温至一定温度后反应一段时间待反应完全,减压浓缩除去部分溶剂,降温析晶,析出固体,过滤得到目标产物11-羟基酯甾体化合物;
所述偶氮自由基引发剂为偶氮二异丁腈、偶氮二异庚腈、偶氮二异丁酸二甲酯、偶氮二异丁咪唑啉盐酸盐、偶氮异丁氰基甲酰胺、偶氮二苯基甲烷或偶氮异丙苯;
所述供氢试剂为巯基乙酸、巯基丙酸、巯基丁酸、甲酸铵或甲酸;
所述溶剂为四氢呋喃、2-甲基四氢呋喃或3-甲基四氢呋喃;
所述9-卤代-11-羟基酯甾体化合物的结构式如下:
其中:X代表卤素原子,R1代表甲酰基、乙酰基或苯甲酰基,R2代表氢原子或甲酰基、乙酰基或苯甲酰基。
2.根据权利要求1所述甾体激素化合物9-位脱卤的制备方法,其特征在于:所述偶氮自由基引发剂为偶氮二异丁腈。
3.根据权利要求1所述甾体激素化合物9-位脱卤的制备方法,其特征在于:所述供氢试剂为巯基乙酸。
4.根据权利要求1所述甾体激素化合物9-位脱卤的制备方法,其特征在于:9-卤代-11-羟基酯甾体化合物与偶氮自由基引发剂及供氢试剂的摩尔比为1:0.05~1.0:1~5。
5.根据权利要求1所述甾体激素化合物9-位脱卤的制备方法,其特征在于:所述反应温度为40℃~105℃。
6.根据权利要求1所述甾体激素化合物9-位脱卤的制备方法,其特征在于:所述溶剂为2-甲基四氢呋喃的单一溶剂。
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