诺孕酯的合成工艺及其生物活性研究
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摘要
诺孕酯做为新一代孕激素,研究已表明,在药理、药效、毒性、临床等方面,其安全性、稳定性均优于第二代孕激素左炔诺孕酮和第三代孕激素去氧孕烯和孕二烯酮,已广泛用作口服避孕药、痤疮治疗药和妇女激素替代疗法治疗更年期综合症。目前,我国每年都需要从国外大量进口。
本文采用左炔诺孕酮双酯化以及双酯酸水解工艺,最终成功合成了诺孕酯,突破了国外对该产品产业化的技术壁垒。与文献报道的合成方法相比,该方法不仅具有反应条件温和、易于控制、选择性高、无二次污染等优点,同时提高了诺孕酯产品收率。
首先,本文系统研究了微生物发酵、环合氢化、锂氨、沃氏氧化、炔化水解、双酯化、酸水解及肟化反应在多种因素作用和影响下反应的最佳条件。解决了有立体障碍的17位羟基酰化的关键技术问题,产物的质量和收率均有较大幅度的提高。在此基础上确定了诺孕酯最有效的合成方法。
合成产物左炔诺孕酮、重要的中间体及终产物诺孕酯,经高压液相色谱确认纯度后,与Ortho公司诺孕酯样品进行紫外光谱、红外光谱、质子核磁共振、碳核磁共振、质谱等波谱分析,确证化学结构无误,质量与国外样品基本一致。在诺孕酯合成的基础上,本文对诺孕酯的生物医学特性进行了初步的研究。本文研究结果对工业化设计具有重要的理论和实际意义。
As a new generation progesterone product, norgestimate is superior to the second-generation progesterone product levonorgestrel and the third-generation progesterone products-desogestrel and gestodene in terms of pharmacological, pharmacodynamic, toxicological and clinical aspects, as well as its safety and stability profiles. It is widely used as an oral contraceptive, acne therapy, and hormone replacement therapy for menopausal symptoms in women. At present, a significant amount of the products needs to be imported from foreign countries every year. In this paper, a process of di-esterification of levonorgesterol and hydrolysis of di-ester acids is adopted, and finally norgestimate is successfully synthesized, thus making a breakthrough on the foreign technical barrier in product commercialization. As compared with the synthetic methods reported in literature, the method not only has such advantages as reaction conditions mild, control easy, selectivity high and no secondary contamination, but also improves the recovery rate of norgestimate product at the same time.
First, this paper investigates the optimal conditions for the reactions under actions and effects of multiple factors in microbial fermentation, cyclization and hydrogenation, lithium ammonium, wolf oxidation, alkyne hydrolysis, di-esterization, acid hydrolysis and oximization reactions; and solved the key technical issues in 17-hydroxy-acylation with stereoscopic barriers. The quality and recovery rate of the product are both greatly improved. On this basis is established the most effective synthetic method for norgestimate.
The substances prepared in this paper such as Levonorgestrel, key intermediates and final product, after purity qualification with HPLC, was subjected to analyze by UV,IR,HNMR,CNMR and Mass. When analyzing concurrently with Ortho’s Norgestimate specimen, the data obtained from analytical sample is identical to authentic, so thus the chemical structure and the quality of tittle compound are proved concretly.
On the basis of norgestimate synthesis, the bio-medical characteristics of norgestimate are preliminarily studied in this paper. The findings in the paper have important theoretical and practical significance for the industrialization designs.
本文采用左炔诺孕酮双酯化以及双酯酸水解工艺,最终成功合成了诺孕酯,突破了国外对该产品产业化的技术壁垒。与文献报道的合成方法相比,该方法不仅具有反应条件温和、易于控制、选择性高、无二次污染等优点,同时提高了诺孕酯产品收率。
首先,本文系统研究了微生物发酵、环合氢化、锂氨、沃氏氧化、炔化水解、双酯化、酸水解及肟化反应在多种因素作用和影响下反应的最佳条件。解决了有立体障碍的17位羟基酰化的关键技术问题,产物的质量和收率均有较大幅度的提高。在此基础上确定了诺孕酯最有效的合成方法。
合成产物左炔诺孕酮、重要的中间体及终产物诺孕酯,经高压液相色谱确认纯度后,与Ortho公司诺孕酯样品进行紫外光谱、红外光谱、质子核磁共振、碳核磁共振、质谱等波谱分析,确证化学结构无误,质量与国外样品基本一致。在诺孕酯合成的基础上,本文对诺孕酯的生物医学特性进行了初步的研究。本文研究结果对工业化设计具有重要的理论和实际意义。
As a new generation progesterone product, norgestimate is superior to the second-generation progesterone product levonorgestrel and the third-generation progesterone products-desogestrel and gestodene in terms of pharmacological, pharmacodynamic, toxicological and clinical aspects, as well as its safety and stability profiles. It is widely used as an oral contraceptive, acne therapy, and hormone replacement therapy for menopausal symptoms in women. At present, a significant amount of the products needs to be imported from foreign countries every year. In this paper, a process of di-esterification of levonorgesterol and hydrolysis of di-ester acids is adopted, and finally norgestimate is successfully synthesized, thus making a breakthrough on the foreign technical barrier in product commercialization. As compared with the synthetic methods reported in literature, the method not only has such advantages as reaction conditions mild, control easy, selectivity high and no secondary contamination, but also improves the recovery rate of norgestimate product at the same time.
First, this paper investigates the optimal conditions for the reactions under actions and effects of multiple factors in microbial fermentation, cyclization and hydrogenation, lithium ammonium, wolf oxidation, alkyne hydrolysis, di-esterization, acid hydrolysis and oximization reactions; and solved the key technical issues in 17-hydroxy-acylation with stereoscopic barriers. The quality and recovery rate of the product are both greatly improved. On this basis is established the most effective synthetic method for norgestimate.
The substances prepared in this paper such as Levonorgestrel, key intermediates and final product, after purity qualification with HPLC, was subjected to analyze by UV,IR,HNMR,CNMR and Mass. When analyzing concurrently with Ortho’s Norgestimate specimen, the data obtained from analytical sample is identical to authentic, so thus the chemical structure and the quality of tittle compound are proved concretly.
On the basis of norgestimate synthesis, the bio-medical characteristics of norgestimate are preliminarily studied in this paper. The findings in the paper have important theoretical and practical significance for the industrialization designs.
引文
[1]D.W.Hahn ,Allen,G.O.and J.L McGuire ,The pharmaceutical profile of norgestimate, Contraception ,1977,16(5):541～553
[2]Hahn,D.W.Allen,G.O and J.L McGuire , The progestational component of a new combination oral contracetive,The pharmcologist ,1976,18:250
[3]M.E.Hull and K.S.Moghissi ,Effects of norgestimate in combination with ethinyl estradiol ,Adv ConTracepT, 1986,2:71～77
[4] Audrey Phillips ,Do Won Hahn,et al. A comparison of the potencies and activities of progestogens used in contraceptives ,contraception 1987,36(2):181～183
[5]Mohammad Mohsenion, Effects of norgestimate in combination with ethinyl estradiol on cervical mucus ,Contraception, 1981,24(2):173
[6]MilanR.Henzl, M.D.,Ph.D., Norgestimate ,J.Reprod Med,2001,46(7):647～661
[7]M.D.,Ph,D.Jl, Pharmacologic and pharmacokinetic characteristics of norgestimate and its metabolites, Am.J.Obstet.Gynec,1990,163(6-2):2127～31
[8]]McGuire Prescribing information: Otrho-Prefest Estradiol/norgestimate tablets. Raritan(NJ): Otrho-Mcneil pharmaceutical Inc.1999
[9]Samuel F.Sisenwine, The conversion of norgestimate in female rhesus monkeys,Contraception ,1977,15(1):25
[10]Howard S.Weintraub, Disposition of norgestimate in the presence and absence of ethinyl estradiol, J Pharm sci, 1978,67(10) 1406
[11]Stephen madden and David J.Back,Metabolism of norgestimate ,J.Steroid. Biochem. Mol.Biol, 1991, 38(4) 497～503
[12] Kevin B, Biotransformation of norgestimate in women,Contraception,1984,29(1):19～29
[13]Monique P.Curran and Antonal.wagstaf,Estradiol and Norgestimate,Drugs Aging ,2001,18(11):863～885
[14]F.G.Dayton , Biotransformation,The Pharmacologist, 1976,18:153
[15]曹路敏等 ,左旋高诺酮及醋酸左旋高诺酮肟的安全性实验,同济医科大学学报,1987,16(2):93～96
[16]A.Phillips ,et al. Relative binding affinity of norgestimate and other progestins for human sex hormone binding globulin ,Steroids, 1990,55:373
[17]A.Phillips, Progestation and androgenic receptor binding affinitie and in vivo activities , Contraception, 1990,41(4):399
[18]H.Juchem,et al.Receptor binding of norgestimate-a new orally active synthetic progestational compound, Contraception, 1993,47:283
[19]Ronald T.Burkman, Accrual of women’s health benefits,Am. J.obstet Gynecol,2001,185(2suppl) :S1～31
[20] W.Kuhnz, Comparative of progestational activity,Contraception, 1995,51(2):131-139
[21]A.Phillips, The selectivity of a new progestin ,Acta Obstet Gynec Scand Suppl, 1990,152:21-24
[22]Herbert Kuhl, Comparative pharmacology of newer progestogens, Drugs ,1996 51(2)188-215
[23]Geoffrey P.Redmono , Norgestimate and ethinyl estradiol in the treatment of acne vulgaris , Obstetrics Gynecology,1997,89(4):612～615
[24]Stephen L.Corson ,Efficacy and clinical profile of a new oral contraceptive containing norgestimate,Acta Ostet Gynec Scand Suppl, 1990,152:25
[25] Benno Runnebaum, New progestogens in oral contraceptives, Am.J.Obstet.Gynec,1987,157(4):1059
[26] Ronald A .Chen, MD,Clinical aspects of three new progestogens, Am.J.Obstet.Gynec,1989,160(5):1296
[27]Harald Becker,Supportive European data on a new oral contraceptive ,Acta Ostct Gynec Scand Suppl, 1990,152:33
[28]Smith.H., Totally synthetic hormones, J.C.S., 1964,44:72
[29]Take da Chem.,Syntheses of racemic and optically active 13β-ethylgonanes,Pharm.Bull,.1965,13(11):1289
[30] 韩 广 甸 , 我 国 全 合 成 避 孕 甾 体 药 物 的 发 展 , 中 国 医 药 工 业 杂志,1976,8:231-235
[31]Rufer C, Totalsynthese von optisch aktiven 13 –?thyl gonan derivaten ,Liebigs Ann Chem, 1967,702:141～ 148
[32]上海有机化学研究所甾体激素组 ,D-18-甲基炔诺酮及 D-18-甲基二烯炔诺酮的全合成,化学学报,1979,37(1):1-8
[33] Arvin Pranlal Shroff, Piscataway,N.J.,3-Oximesofd-17a-ethynyl-19- norttesterone esters and method [P]US: 4027019 ,1977-05-31
[34] Julien Warnant, Novel process for the preparation of 3-oximes of steroids [P] US 4186128, 1980-1-29
[35]Qinjian Zhao and Zhensu Li,Preparative separation and properties of (E)-and (Z)-Steroidal α,β-unsaturated ketoximes,Journal of Chromatography,1993,635;342-345
[2]Hahn,D.W.Allen,G.O and J.L McGuire , The progestational component of a new combination oral contracetive,The pharmcologist ,1976,18:250
[3]M.E.Hull and K.S.Moghissi ,Effects of norgestimate in combination with ethinyl estradiol ,Adv ConTracepT, 1986,2:71～77
[4] Audrey Phillips ,Do Won Hahn,et al. A comparison of the potencies and activities of progestogens used in contraceptives ,contraception 1987,36(2):181～183
[5]Mohammad Mohsenion, Effects of norgestimate in combination with ethinyl estradiol on cervical mucus ,Contraception, 1981,24(2):173
[6]MilanR.Henzl, M.D.,Ph.D., Norgestimate ,J.Reprod Med,2001,46(7):647～661
[7]M.D.,Ph,D.Jl, Pharmacologic and pharmacokinetic characteristics of norgestimate and its metabolites, Am.J.Obstet.Gynec,1990,163(6-2):2127～31
[8]]McGuire Prescribing information: Otrho-Prefest Estradiol/norgestimate tablets. Raritan(NJ): Otrho-Mcneil pharmaceutical Inc.1999
[9]Samuel F.Sisenwine, The conversion of norgestimate in female rhesus monkeys,Contraception ,1977,15(1):25
[10]Howard S.Weintraub, Disposition of norgestimate in the presence and absence of ethinyl estradiol, J Pharm sci, 1978,67(10) 1406
[11]Stephen madden and David J.Back,Metabolism of norgestimate ,J.Steroid. Biochem. Mol.Biol, 1991, 38(4) 497～503
[12] Kevin B, Biotransformation of norgestimate in women,Contraception,1984,29(1):19～29
[13]Monique P.Curran and Antonal.wagstaf,Estradiol and Norgestimate,Drugs Aging ,2001,18(11):863～885
[14]F.G.Dayton , Biotransformation,The Pharmacologist, 1976,18:153
[15]曹路敏等 ,左旋高诺酮及醋酸左旋高诺酮肟的安全性实验,同济医科大学学报,1987,16(2):93～96
[16]A.Phillips ,et al. Relative binding affinity of norgestimate and other progestins for human sex hormone binding globulin ,Steroids, 1990,55:373
[17]A.Phillips, Progestation and androgenic receptor binding affinitie and in vivo activities , Contraception, 1990,41(4):399
[18]H.Juchem,et al.Receptor binding of norgestimate-a new orally active synthetic progestational compound, Contraception, 1993,47:283
[19]Ronald T.Burkman, Accrual of women’s health benefits,Am. J.obstet Gynecol,2001,185(2suppl) :S1～31
[20] W.Kuhnz, Comparative of progestational activity,Contraception, 1995,51(2):131-139
[21]A.Phillips, The selectivity of a new progestin ,Acta Obstet Gynec Scand Suppl, 1990,152:21-24
[22]Herbert Kuhl, Comparative pharmacology of newer progestogens, Drugs ,1996 51(2)188-215
[23]Geoffrey P.Redmono , Norgestimate and ethinyl estradiol in the treatment of acne vulgaris , Obstetrics Gynecology,1997,89(4):612～615
[24]Stephen L.Corson ,Efficacy and clinical profile of a new oral contraceptive containing norgestimate,Acta Ostet Gynec Scand Suppl, 1990,152:25
[25] Benno Runnebaum, New progestogens in oral contraceptives, Am.J.Obstet.Gynec,1987,157(4):1059
[26] Ronald A .Chen, MD,Clinical aspects of three new progestogens, Am.J.Obstet.Gynec,1989,160(5):1296
[27]Harald Becker,Supportive European data on a new oral contraceptive ,Acta Ostct Gynec Scand Suppl, 1990,152:33
[28]Smith.H., Totally synthetic hormones, J.C.S., 1964,44:72
[29]Take da Chem.,Syntheses of racemic and optically active 13β-ethylgonanes,Pharm.Bull,.1965,13(11):1289
[30] 韩 广 甸 , 我 国 全 合 成 避 孕 甾 体 药 物 的 发 展 , 中 国 医 药 工 业 杂志,1976,8:231-235
[31]Rufer C, Totalsynthese von optisch aktiven 13 –?thyl gonan derivaten ,Liebigs Ann Chem, 1967,702:141～ 148
[32]上海有机化学研究所甾体激素组 ,D-18-甲基炔诺酮及 D-18-甲基二烯炔诺酮的全合成,化学学报,1979,37(1):1-8
[33] Arvin Pranlal Shroff, Piscataway,N.J.,3-Oximesofd-17a-ethynyl-19- norttesterone esters and method [P]US: 4027019 ,1977-05-31
[34] Julien Warnant, Novel process for the preparation of 3-oximes of steroids [P] US 4186128, 1980-1-29
[35]Qinjian Zhao and Zhensu Li,Preparative separation and properties of (E)-and (Z)-Steroidal α,β-unsaturated ketoximes,Journal of Chromatography,1993,635;342-345