CN111018932B - 一种甾体化合物9-位脱卤的方法 - Google Patents
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Classifications
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- 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
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- 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
- C07J5/0007—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 not substituted in position 17 alfa
- C07J5/0015—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 not substituted in position 17 alfa not substituted in position 16
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- 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
- C07J5/0061—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 substituted in position 16
- C07J5/0069—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 substituted in position 16 by a saturated or unsaturated hydrocarbon group
- C07J5/0076—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 substituted in position 16 by a saturated or unsaturated hydrocarbon group by an alkyl group
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- 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
- C07J5/0061—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 substituted in position 16
- C07J5/0092—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 substituted in position 16 by an OH group free esterified or etherified
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- 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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Abstract
本发明公开了一种甾体化合物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助剂溶于有机溶剂中，升温至一定温度后滴加三丁基氢化锡，反应一段时间后检测，待反应完全，减压浓缩除去部分溶剂，水析或加入溶剂析晶，过滤得到目标产物11‑羟基酯甾体化合物，母液分层后可回收获得三丁基氧化锡再利用。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，三丁基氧化锡可回收再利用，减少了三废污染，降低了成本。
Description
技术领域
本发明属于医药化工技术领域，尤其涉及一种无铬甾体激素化合物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，一直存在着含铬盐的废水难于处理、成本高等缺点。
专利EP 0994119A1报导将9-溴(碘)取代的布地奈德溶解在四氢呋喃中，以三正丁基锡氢为供氢体，加入少量的偶氮二异丁腈(AIBN)作为催化剂，回流反应l6h，再经精制可得高效抗哮喘药布地奈德反应条件温和，得率88％（式一）。我们尝试用该方法合成16-a 羟基泼尼松龙，却发现几乎全部生成杂质，没有发现目标产物（式二），直接加入过量的三丁基氢化锡不加入偶氮二异丁腈引发剂也产生类似的副产物，没有获得我们希望的目标产物。
发明内容
本发明的目的在于提供一种无保护基的甾体化合物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和产物纯度。
本发明提供一种甾体化合物9-位脱卤的制备方法：
该方法为：将未保护的将9-卤代-11-羟基酯甾体化合物和一定量的助剂溶于有机溶剂中，升温至一定温度后滴加三丁基氢化锡，反应一段时间后检测，待反应完全，减压浓缩除去部分溶剂，水析或加入溶剂析晶，过滤得到目标产物11-羟基酯甾体化合物，母液分层后可回收获得三丁基氧化锡再利用。
所述助剂为有机酸。
发明人分析采用EP 0994119A1提供的方法合成16-a 羟基泼尼松龙几乎全部生成杂质的原因可能是16，17-双羟基的存在容易在该反应条件下生成杂质，所以专利EP0994119A1需要将16，17-双羟基先上保护基，再用三正丁基锡氢脱溴，而无法直接实现无保护的甾体化合物9-位脱卤反应。
本发明的技术方案中，发明人改进了这一工艺，以三丁基锡氢为还原脱卤试剂，取消了自由基引发剂偶氮二异丁腈的使用，加入了少量的有机酸作为助剂以稳定产物，实现了无保护的甾体化合物9-位无铬脱卤反应。
作为优选，有机酸为巯基乙酸、巯基丙酸、巯基丁酸，羟基乙酸，苯甲酸，草酸，甲酸，乙酸中的一种或多种。
进一步优选有机酸为巯基乙酸。
作为优选，所述溶剂为四氢呋喃、2-甲基四氢呋喃、乙醇、异丙醇、丙酮、丁酮、二氯甲烷、N,N-二甲基甲酰胺（DMF）、乙腈、乙酸乙酯等。
进一步优选为四氢呋喃。
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代表氢原子或甲酰基，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：
作为优选，9-卤代-11-羟基酯甾体化合物与三丁基锡氢及助剂的摩尔比为1：(1.0～3.0) ： (0.2～3.0)。
进一步优选为1： (1.0～2.0) ： (0.2～1.0)。
更进一步优选为1：1.2：0.5。
所述反应温度为40℃~105℃，优选为50℃~60℃。
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，三丁基氧化锡可回收再利用，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。
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(0.10 mol, 1.0 equiv)，巯基乙酸4.6g(0.05 mol, 0.5 equiv)，四氢呋喃1500ml升温回流，缓慢滴加三丁基氢化锡29.0g(0.10 mol, 1.0 equiv)，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)移去四氢呋喃约1400ml，搅拌下加入饮用水400ml，降温至0℃，过滤，依次用200ml正庚烷和热水打浆，干燥，得到白色固体11-甲酯醋酸泼尼松龙40.5g，摩尔收率94.3%，HPLC纯度为98.8%。
实施例2
在氮气保护条件下向反应釜中加入式(I)中的9-溴-11-羟基-16-羟基泼尼松龙45.4g(0.10 mol, 1.0 equiv)，巯基丙酸9.2g(0.10 mol, 1.0 equiv)，丙酮1200ml升温回流，缓慢滴加三丁基氢化锡58.0g(0.20 mol, 2.0 equiv)，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)移去丙酮约1100ml，搅拌下加入饮用水400ml，降温至0℃，过滤，依次用200ml正庚烷和热水打浆，干燥，得到白色固体11-羟基-16-羟基泼尼松龙33.7g，摩尔收率89.6%，HPLC纯度为98.6%。
实施例3
在氮气保护条件下向反应釜中加入式(I)中的9-溴-11-苯甲酸酯-16-甲基-21-苯甲酸酯泼尼松龙66.0g(0.10 mol, 1.0 equiv)，羟基乙酸15.2g(0.20 mol, 2.0 equiv)，丁酮1500ml升温回流，缓慢滴加三丁基氢化锡40.6g(0.14 mol, 1.4 equiv)，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)移去丁酮约1350ml，搅拌下加入饮用水500ml，降温至0℃，过滤，依次用200ml正庚烷和热水打浆，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51.5g，摩尔收率88.6%，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(I)中的9-碘-11-甲酸酯-21-醋酸氢化可的松55.8g(0.10 mol, 1.0 equiv)，乙酸12.0g(0.20 mol, 2.0 equiv)，二氯甲烷2000ml升温回流，缓慢滴加三丁基氢化锡58.0g(0.20 mol, 2.0 equiv)，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)移去二氯甲烷约1900ml，搅拌下加入正庚烷500ml，降温至0℃，过滤，依次用200ml正庚烷和热水打浆，干燥，得到白色固体11-甲酸酯-21-醋酸氢化可的松35.0g，摩尔收率81.0%，HPLC纯度为99.4%。
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(0.10 mol, 1.0 equiv)，巯基丁酸36.0g(0.3 mol, 3.0 equiv)，N,N-二甲基甲酰胺(DMF) 300ml，缓慢滴加三丁基氢化锡87.0g(0.30 mol, 3.0 equiv)，升温至105℃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，向反应釜中加入饮用水约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34.0g，摩尔收率76.5%，HPLC纯度为98.1%。
实施例6
在氮气保护条件下向反应釜中加入式(V)中的9-溴-11-羟基-16,17-烯-21-醋酸酯泼尼松龙46.2g(0.10 mol, 1.0 equiv)，苯甲酸24.4g(0.2 mol, 2.0 equiv)，乙腈1000ml，缓慢滴加三丁基氢化锡58.0g(0.20 mol, 2.0 equiv)，升温至70℃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50℃，真空度约为-0.08MPa)移去乙腈约900ml，搅拌下加入饮用水500ml，降温至0℃，过滤，干燥，得到白色固体11-羟基-16,17-烯-21-醋酸酯泼尼松龙34.3g，摩尔收率89.3%，HPLC纯度为98.6%。
上述各实施例中，反应结束水析后的水层可分层后获得三丁基氧化锡再利用，为了避免有机锡对水生生物的毒害，水层可通过正庚烷萃取后排放处理，通过ICP-MS检测发现水层中锡含量少于10 ppm。
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。
对比例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(0.10 mol, 1.0 equiv)，四氢呋喃1500ml升温回流，缓慢滴加三丁基氢化锡29.0g(0.10mol, 1.0 equiv)，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)移去四氢呋喃约1400ml，搅拌下加入饮用水400ml，降温至0℃，过滤，依次用200ml正庚烷和热水打浆，干燥，得到白色固体9-溴-D-高甾烷和D-高甾烷约40克， HPLC比例为15：85。
Claims (5)
1.一种甾体化合物9-位脱卤的方法，其特征在于：将9-卤代-11-羟基酯甾体化合物和一定量的助剂溶于有机溶剂中，升温至一定温度后滴加三丁基氢化锡，反应一段时间后检测，待反应完全，除去部分溶剂，水析或加入溶剂析晶，过滤得到目标产物；其中，所述9-卤代-11-羟基酯甾体化合物的结构式如下所述，
其中： X代表卤素原子，R1代表氢或羟基保护基，R2代表氢或羟基保护基，所述羟基保护基为甲酰基、乙酰基或苯甲酰基；所述助剂为羟基乙酸，苯甲酸，草酸，甲酸，乙酸。
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：9-卤代-11-羟基酯甾体化合物与三丁基氢化锡及助剂的摩尔比为1： (1.0～3.0) ： (0.2～3.0)。
3.根据权利要求2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三丁基氢化锡及助剂的摩尔比为1：1.2：0.5。
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：所述反应温度为40℃~105℃。
5.根据权利要求1所述甾体化合物9-位脱卤的制备方法，其特征在于：所述溶剂为四氢呋喃、2-甲基四氢呋喃、乙醇、异丙醇、丙酮、丁酮、二氯甲烷、N,N-二甲基甲酰胺、乙腈、乙酸乙酯。
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