甾体化合物的合成研究及结构分析
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摘要
甾体化合物在医学上应用十分广泛,特别是甾体激素类药物,包括肾上腺皮质激素和性激素等是临床医学中重要的一类药物。一些甾体药物具有很强的抗艾滋病毒和抗癌细胞活性等药理作用。近年来,甾体药物在医疗领域的应用范围不断扩大,被广泛用于控制生育领域及治疗风湿病、心血管、人体器官移植、皮肤病、秃头症、痤疮、内分泌失调和老年性疾病等。另外,一些甾体激素也被应用于促进家畜繁殖生长及植物生长等。现在,甾体药物已成为全球产量仅次于抗生素的第二大类药物。本文主要开展了以下三个方面的工作:
1)初步分析研究了大力补(17α-甲基-17β-羟基-雄甾-1,4-二烯-3-酮)的IR、UV、MS、~1H-NMR和~(13)C-NMR谱的特征,对所有的~(13)C-NMR和主要的~1H-NMR谱信号进行了归属,讨论了红外特征吸收峰所对应的官能团的振动形式,探讨了其质谱裂解机理,还对其进行了热重和差热分析,确定了大力补的结构。
2)设计以睾酮(17β-羟基-雄甾-4-烯-3-酮)为原料,经H_2O_2环氧化和盐酸开环两步反应合成了4-氯-睾酮(4-氯-17β-羟基-雄甾-4-烯-3-酮),两步反应连续进行,此反应路线具有绿色环保、操作简单及产率高等优点。并探讨了两步反应的工艺条件。结果表明:较佳的反应条件为,n(H_2O_2):n(NaOH):n(睾酮)=5:1.24:1,n(浓盐酸):n(睾酮)=1:1,反应温度依次为0℃和室温,反应时间依次为20h和3h,4-氯-睾酮的总产率达82.6%,粗产品经重结晶后纯度大于98.6%,反应重复性良好,有较好的应用前景。4-氯-睾酮的结构经IR、MS、~1H-NMR和~(13)C-NMR谱得以表征,并探讨了其质谱裂解机理。
3)报导了2,3-二氯-5,6-二氰基苯醌(DDQ)对4-氯-17α-甲基睾酮的脱氢反应,考察了不同条件下的反应工艺,分析了可能的反应机理和反应副产物。研究结果表明:反应中发现未见文献报道的17-位脱水产物4-氯-17α-甲基-雄甾-1,4,16-三烯-3-酮,却未发现常见的6-位脱氢的甾酮;酸性强弱不同的催化剂可得到不同的主产物;采用对甲苯磺酸(PTS)为催化剂时,反应主要生成4-氯-1,2-脱氢-17α-甲基睾酮;在强酸催化下或通过延长反应时间或升高反应温度,4-氯-1,2-脱氢-17α-甲基睾酮可以通过脱去17-位羟基而在16-位上引入双键生成4-氯-17α-甲基-雄甾-1,4,16-三烯-3-酮;当在60℃反应72h,4-氯-17α-甲基睾酮的用量为8.90mmol,以苯(130mL)为溶剂,催化剂PTS用量为1.9%(摩尔分数),DDQ用量为1.6(摩尔分数)时,4-氯-1,2-脱氢-17α-甲基睾酮的最佳产率为81.0%,4-氯-17α-甲基睾酮的最佳转化率为94.6%,反应重复性良好,有应用前景。产物结构经IR、MS、~1H-NMR和~(13)C-NMR谱得以确定,并分别探讨了它们的质谱裂解机理。
Steroids are widely used in the field of medicine.Especially,steroid hormone,including adrenocortical hormone and sex hormone,is a group of drugs of very considerable clinical medical importance.Some steroid drugs are reported having anti-human immunodeficiency virus(anti-HIV) and anticancer activity.At present,the medical field where Steroid drugs are used is becoming more and more widely.For example,they are employed in birth control and treating rheumatism,angiocardiopathy, dermatonosis,alopecia,acne and endocrine dyscrasia and so on.What is more,some of them can accelerate the reproduction and growth of fowl and plants' growth.Up to now,the amount of steroid drugs is only smaller than that of antibiotics all over the world.The main work of this dissertation comprises three parts:
1)Dianabol(17α-methyl-17β-hydroxy-androst-1,4-dien-3-one)were characterized by UV,IR,MS,~1H and ~(13)C-NMR.In addition,the signal of ~1H and ~(13)C-NMR was adscribed,the relation of the signal of IR spectrum and the functional groups was studied,cleavage mechanism of MS was proposed,the TG-DTA of dianabol was also investigated.
2)A simple two steps for preparing 4-chloro-testosterone from testosterone undergoing hydrogen peroxide epoxidation and concentrated hydrochloric acid ring-opening reaction with total yield 82.6%was reported.The second reaction was employed with no purification of the obtained product.The reaction had several adventage factors,such as,no pollution,simplicity and high yield and so on.The reaction conditions were optimized.4-Chloro-testosterone was characterized by ~1H-NMR, ~(13)C-NMR,IR and MS,cleavage mechanism of MS was proposed.The optimum conditions were,the mole ratio of H_2O_2:NaOH:testosterone and concentrated hydrochloric acid:testosterone were 5:1.24:1 and 1:1 respecticely,the reaction temperature were 0℃and the room temperature, the react time were 20h and 3h in sequence.The purity of the recrystallized crude produce was more than 98.6%.The reaction had good reproducibility.
3)A simple synthetic pathway for 4-chloro-Δ~1-17α-methyltestosterone was performed from 4-chloro-17α-methyltestosterone through dehydrogenation by use of 2,3-dichloro-5,6-dicyanobenzoquinone(DDQ)with yield 81.0%without the normol by-product 6-position dehydrogenated ketones.However,It was surprisingly found that the unexpected 4-chloro-17α-methyl-androst-1,4,16-trien-3-one generated from 17-dehydration. The probable mechanism of dehydrogenation was investigated and the reaction conditions were optimized.Products were characterized by ~1H and ~(13)C-NMR,IR and MS,cleavage mechanism of MS was proposed.The different major product was obtained in the presence of different acidic catalyst.1,2-Dehydrogenation product 4-chloro-Δ~1-17α-methyltestosterone can be eliminated the 17-OH to introduce double in 16-position obtaining 4-chloro-17α-methyl-androst-1,4,16-trien-3-one in strong acid condition or through prolonging the reaction time or though increasing the reaction temperature.4-Chloro-Δ~1-17α-methyltestosterone was the major product in the presence of p-toluene sulfonic acid(PTS). The conversion of 4-chloro-17α-methyltestosterone and the yield of 4-chloro-Δ~1-17α-methyltestosterone were 94.6%and 81.0%respectively under the optimum conditions:8.90mmol 4-chloro-17α-methyltestosterone was dehydrogenated by DDQ(mole fraction 1.6 to 4-chloro-17α-methyltestosterone) under the catalysis of PTS(mole fraction 1.9%to 4-chloro-17α-methyltestosterone)in benzene(130mL)for 72h at 60℃. The reaction had good reproducibility.
1)初步分析研究了大力补(17α-甲基-17β-羟基-雄甾-1,4-二烯-3-酮)的IR、UV、MS、~1H-NMR和~(13)C-NMR谱的特征,对所有的~(13)C-NMR和主要的~1H-NMR谱信号进行了归属,讨论了红外特征吸收峰所对应的官能团的振动形式,探讨了其质谱裂解机理,还对其进行了热重和差热分析,确定了大力补的结构。
2)设计以睾酮(17β-羟基-雄甾-4-烯-3-酮)为原料,经H_2O_2环氧化和盐酸开环两步反应合成了4-氯-睾酮(4-氯-17β-羟基-雄甾-4-烯-3-酮),两步反应连续进行,此反应路线具有绿色环保、操作简单及产率高等优点。并探讨了两步反应的工艺条件。结果表明:较佳的反应条件为,n(H_2O_2):n(NaOH):n(睾酮)=5:1.24:1,n(浓盐酸):n(睾酮)=1:1,反应温度依次为0℃和室温,反应时间依次为20h和3h,4-氯-睾酮的总产率达82.6%,粗产品经重结晶后纯度大于98.6%,反应重复性良好,有较好的应用前景。4-氯-睾酮的结构经IR、MS、~1H-NMR和~(13)C-NMR谱得以表征,并探讨了其质谱裂解机理。
3)报导了2,3-二氯-5,6-二氰基苯醌(DDQ)对4-氯-17α-甲基睾酮的脱氢反应,考察了不同条件下的反应工艺,分析了可能的反应机理和反应副产物。研究结果表明:反应中发现未见文献报道的17-位脱水产物4-氯-17α-甲基-雄甾-1,4,16-三烯-3-酮,却未发现常见的6-位脱氢的甾酮;酸性强弱不同的催化剂可得到不同的主产物;采用对甲苯磺酸(PTS)为催化剂时,反应主要生成4-氯-1,2-脱氢-17α-甲基睾酮;在强酸催化下或通过延长反应时间或升高反应温度,4-氯-1,2-脱氢-17α-甲基睾酮可以通过脱去17-位羟基而在16-位上引入双键生成4-氯-17α-甲基-雄甾-1,4,16-三烯-3-酮;当在60℃反应72h,4-氯-17α-甲基睾酮的用量为8.90mmol,以苯(130mL)为溶剂,催化剂PTS用量为1.9%(摩尔分数),DDQ用量为1.6(摩尔分数)时,4-氯-1,2-脱氢-17α-甲基睾酮的最佳产率为81.0%,4-氯-17α-甲基睾酮的最佳转化率为94.6%,反应重复性良好,有应用前景。产物结构经IR、MS、~1H-NMR和~(13)C-NMR谱得以确定,并分别探讨了它们的质谱裂解机理。
Steroids are widely used in the field of medicine.Especially,steroid hormone,including adrenocortical hormone and sex hormone,is a group of drugs of very considerable clinical medical importance.Some steroid drugs are reported having anti-human immunodeficiency virus(anti-HIV) and anticancer activity.At present,the medical field where Steroid drugs are used is becoming more and more widely.For example,they are employed in birth control and treating rheumatism,angiocardiopathy, dermatonosis,alopecia,acne and endocrine dyscrasia and so on.What is more,some of them can accelerate the reproduction and growth of fowl and plants' growth.Up to now,the amount of steroid drugs is only smaller than that of antibiotics all over the world.The main work of this dissertation comprises three parts:
1)Dianabol(17α-methyl-17β-hydroxy-androst-1,4-dien-3-one)were characterized by UV,IR,MS,~1H and ~(13)C-NMR.In addition,the signal of ~1H and ~(13)C-NMR was adscribed,the relation of the signal of IR spectrum and the functional groups was studied,cleavage mechanism of MS was proposed,the TG-DTA of dianabol was also investigated.
2)A simple two steps for preparing 4-chloro-testosterone from testosterone undergoing hydrogen peroxide epoxidation and concentrated hydrochloric acid ring-opening reaction with total yield 82.6%was reported.The second reaction was employed with no purification of the obtained product.The reaction had several adventage factors,such as,no pollution,simplicity and high yield and so on.The reaction conditions were optimized.4-Chloro-testosterone was characterized by ~1H-NMR, ~(13)C-NMR,IR and MS,cleavage mechanism of MS was proposed.The optimum conditions were,the mole ratio of H_2O_2:NaOH:testosterone and concentrated hydrochloric acid:testosterone were 5:1.24:1 and 1:1 respecticely,the reaction temperature were 0℃and the room temperature, the react time were 20h and 3h in sequence.The purity of the recrystallized crude produce was more than 98.6%.The reaction had good reproducibility.
3)A simple synthetic pathway for 4-chloro-Δ~1-17α-methyltestosterone was performed from 4-chloro-17α-methyltestosterone through dehydrogenation by use of 2,3-dichloro-5,6-dicyanobenzoquinone(DDQ)with yield 81.0%without the normol by-product 6-position dehydrogenated ketones.However,It was surprisingly found that the unexpected 4-chloro-17α-methyl-androst-1,4,16-trien-3-one generated from 17-dehydration. The probable mechanism of dehydrogenation was investigated and the reaction conditions were optimized.Products were characterized by ~1H and ~(13)C-NMR,IR and MS,cleavage mechanism of MS was proposed.The different major product was obtained in the presence of different acidic catalyst.1,2-Dehydrogenation product 4-chloro-Δ~1-17α-methyltestosterone can be eliminated the 17-OH to introduce double in 16-position obtaining 4-chloro-17α-methyl-androst-1,4,16-trien-3-one in strong acid condition or through prolonging the reaction time or though increasing the reaction temperature.4-Chloro-Δ~1-17α-methyltestosterone was the major product in the presence of p-toluene sulfonic acid(PTS). The conversion of 4-chloro-17α-methyltestosterone and the yield of 4-chloro-Δ~1-17α-methyltestosterone were 94.6%and 81.0%respectively under the optimum conditions:8.90mmol 4-chloro-17α-methyltestosterone was dehydrogenated by DDQ(mole fraction 1.6 to 4-chloro-17α-methyltestosterone) under the catalysis of PTS(mole fraction 1.9%to 4-chloro-17α-methyltestosterone)in benzene(130mL)for 72h at 60℃. The reaction had good reproducibility.
引文
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