高选择性的治疗良性前列腺增生药物Harnal的合成及工艺研究
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摘要
良性前列腺增生是常见的、多发性的男性老年病之一。由于前列腺增生使尿道狭窄引起排尿障碍，因此良性前列腺增生是老年男性尿急、尿频和排尿困难的主要原因。随着社会的老龄化日趋明显，对其治疗已引起社会的广泛关注。
盐酸坦洛新是由日本山之内公司研究开发的治疗良性前列腺增生的强α_(1A)-肾上腺素能受体拮抗剂，其特点为长效、选择性高、副作用低。1993年在日本上市，商品名Harnal。
文献报道了多条盐酸坦洛新的合成路线，本文通过理论分析和实践尝试，经11步反应(和2步侧链反应)制得目标化合物，总收率达2.2％。其结构经红外、紫外、核磁共振氢谱、质谱等图谱确证。
本文先后考察了7个中间体(TH-1，TH-2，TH-3，TH-4，(R)-TH-5，(R)-TH-6，(R)-1)的合成方法和实验条件，确定了较佳反应条件、提高了收率；改进了重要中间体1-(对-甲氧基苯基)-2-丙胺的合成工艺。
本文还重点做了1-(对-甲氧基苯基)-2-丙胺混旋体的拆分工作，以右旋酒石酸为拆分剂，多次重复成盐、重结晶、碱解，最终得左旋1-(对-甲氧基苯基)-2-丙胺。
Benign Prostatic Hyperplasia (abbreviation: BPH) is common and frequently occurs among elder men. BPH is the main reason of urethral obstruction. So the treatment for BPH has attracted the wide concerns.
Tamsulosin Hydrochloride is a potent and selective 1A-adrenoceptor antagonist from Yamanouchi Co.Ltd in Japan. This drug is clinically used as the medication to ameliorate the dysuria associated with prostatic hypertrophy.
It has been reported that there existed many synthetic routes about the preparation of Tamsulosin Hydrochloride. Through analyzing theoretically and trying practically, the objective compound was synthesized over 11 steps (and 2 sideway steps) operation. The overyield is 2.2%. Its structure was identified by the data of IR, UV-VIS, 1H-NMR, 13C-NMR and MS, et al.
The preparation methods of 7 intermediates (TH-1, TH-2, TH-3, TH-4, (R)-TH-5, (R)-TH-6, (R)-1) were investigated respectively. The 1-(p-methoxyp-henyl)-2-propylamine was improved in the method of synthesis.
In this paper, The resolution of 1-(p-methoxyphenyl)-2-propylamine was emphasized. l-(p-methoxyphenyl)-2-propylamine was formed salt with dextrotartatic acid. Then recrstallation, alkaline hydrolysis and a second preparation of salt were operated in order .The laevo-l-(p-methoxyp-henyl)-2-propylamine could be obtained after repeating the same steps over many times.
盐酸坦洛新是由日本山之内公司研究开发的治疗良性前列腺增生的强α_(1A)-肾上腺素能受体拮抗剂，其特点为长效、选择性高、副作用低。1993年在日本上市，商品名Harnal。
文献报道了多条盐酸坦洛新的合成路线，本文通过理论分析和实践尝试，经11步反应(和2步侧链反应)制得目标化合物，总收率达2.2％。其结构经红外、紫外、核磁共振氢谱、质谱等图谱确证。
本文先后考察了7个中间体(TH-1，TH-2，TH-3，TH-4，(R)-TH-5，(R)-TH-6，(R)-1)的合成方法和实验条件，确定了较佳反应条件、提高了收率；改进了重要中间体1-(对-甲氧基苯基)-2-丙胺的合成工艺。
本文还重点做了1-(对-甲氧基苯基)-2-丙胺混旋体的拆分工作，以右旋酒石酸为拆分剂，多次重复成盐、重结晶、碱解，最终得左旋1-(对-甲氧基苯基)-2-丙胺。
Benign Prostatic Hyperplasia (abbreviation: BPH) is common and frequently occurs among elder men. BPH is the main reason of urethral obstruction. So the treatment for BPH has attracted the wide concerns.
Tamsulosin Hydrochloride is a potent and selective 1A-adrenoceptor antagonist from Yamanouchi Co.Ltd in Japan. This drug is clinically used as the medication to ameliorate the dysuria associated with prostatic hypertrophy.
It has been reported that there existed many synthetic routes about the preparation of Tamsulosin Hydrochloride. Through analyzing theoretically and trying practically, the objective compound was synthesized over 11 steps (and 2 sideway steps) operation. The overyield is 2.2%. Its structure was identified by the data of IR, UV-VIS, 1H-NMR, 13C-NMR and MS, et al.
The preparation methods of 7 intermediates (TH-1, TH-2, TH-3, TH-4, (R)-TH-5, (R)-TH-6, (R)-1) were investigated respectively. The 1-(p-methoxyp-henyl)-2-propylamine was improved in the method of synthesis.
In this paper, The resolution of 1-(p-methoxyphenyl)-2-propylamine was emphasized. l-(p-methoxyphenyl)-2-propylamine was formed salt with dextrotartatic acid. Then recrstallation, alkaline hydrolysis and a second preparation of salt were operated in order .The laevo-l-(p-methoxyp-henyl)-2-propylamine could be obtained after repeating the same steps over many times.
引文
[1] 解红武．良性前列腺增生的药物治疗．天津药学，2002，14(3)15-17
[2] 齐湘，于刚．选择性α：受体阻滞剂治疗良前列腺增生研究进展．医学综述，2000，6(9)：420-421
[3] 翁玲玲，楼荣良．国外正在研制的甾体药物．中国药学杂志，1994，29(3)：174
[4] 张丽霞．α-受体阻断药在治疗良性前列腺增生中的地位和作用．中国药师，2002，5(1)：51-52
[5] George FW, Johnson L, Wilson JD. The effect of a 5 alpha-reductase inhibitor on androgen physiology in the immature male rat. Endocrinology, 1989 Nov; 125(5):2434-8
[6] Andersen JT, Nokel JC, Marshall VR, et al. Finasteride significantly reduces acute urinary retention and need for surgery in patients with symptomatic benign prostatic hyperplasia. Urology, 1997,49:839
[7] Lennart Hansson. General Considerations When Treating Hypertension. Drugs., 1993,46(suppl.2): 37-39
[8] 詹鸣，吕胜启，王玲珑等．两种治疗方法治疗前列腺增生症的疗效比较．临床外科杂志，2000，8(3)：166-168
[9] Wenderoth UK, George FW, Wilson JD. The effect of a 5 alpha-reductase inhibitoron androgen mediated growth of the dog prostate. Endocrinology, 1983, 113 (2):569-73
[10] Brooks JR, Berman C, Primka RL, et al. 5 Alpha-reductase inhibitory and anti androgenic activities of some 4-azasteroids in the rat. Steroids, 1986 Jan;47(1): 15-19
[11] 谭莱茵．良性前列腺增生症药物治疗．医学理论与实践，2002，15(1)：1272-1276
[12] Hemsell DL, Grodin JM, Brenner PF, et al. Plasma precursors of estrogen.Ⅱ. Correlation of the extent of conversion of plasma androstenedione to estrone with age. J Clin Endocrinol Metab, 1974 Mar;38(3):476-9
[13] Kley HK, Nieschlag E, Bidlingmaier F, et al. Kruskemper HL Possible age-dependent influence of estrogens on the binding of testosterone in plasma of adult men. Horm Metab Res., 1974 May;6(3):213-6
[14] 彭司勋主编．药物化学进展(第一卷)．中国医学科技出版社：2000，48
[15] 彭明强．前列腺α1—肾上腺素受体研究进展．国外医学(泌尿系统分)，1998，18(2)：58-60
[16] Brooks JR, Berman C, Garnes D, et al. Prostatic effects induced in dogs by chronic or acute oral administration of 5 alpha-reductase inhibitors. Prostate, 1986;9(1):65-75
[17] Harrison JK, Pearson WR, Lynch KR. Molecular characterization of alpha 1 and alpha 2-adrenoceptors. Trends Pharmacol Sci, 1991 Feb; 12(2):62-7
[18] Yoshiaki soeishi, Miho Kobori, Shin-ichiro Kobayashi,et al. Sensitive method for the determination of tamsulosin in human plasma using high-performance liquid chromato graphy with fluroscene detection. J. Chromatography, 1990,533:291-296
[19] Ewoud J, Van Hoogdalem, Yoshiaki Soeishi, et al. Disposition of the selective α_(1A)-adrenoceptor antagonist tamsulosin in humans: comparison with data from interspecies scaling. J. Pharmaceutical Sci., 1997, 86(10): 1156-1160
[20] Blohm TR, Laughlin ME, Benson HD,et al. Pharmacological induction of 5 alpha-reductase deficiency in the rat: separation of testosterone-mediated and 5 alpha-dihydrotestosterone-mediated effects.Endocrinology, 1986 Sep;119(3):959-66
[21] Lepor H, Gup DI, Baumann M, et al. Laboratory assessment of terazosin and alpha-1 blockade in prostatic hyperplasia. Urology, 1988 Dec;32(6 Suppl):21-6
[22] 蒋伯诚．治疗前列腺增生症的α_1的的阻滞剂．药学进展，1992，16(3)：140-145
[23] Kawabe K, Niijima T. Use of an alpha 1-blocker, YM-12617, in micturition difficulty. Urol Int, 1987;42(4):280-4
[24] Kawabe K, Ueno A, Takimoto Y, et al. Use of an alpha 1-blocker, YM617, in the treatment of benign prostatic hypertrophy. YM617 Clinical Study Group. J Urol, 1990
Oct; 144(4):908-11; discussion 911-2
[25] Kenkichi Koiso MD, Hideyuki Akaza MD, Koji Kikuchi MD, et al. Pharmacokinetics of Tamsulosin Hydrochloride in Patients with Renal Impairment Effects of α_1-acid glycoprotein. J. Clin Pharmcol, 996,36:1029-1038
[26] 戴华成，舒平，李新红等．抗高血压新药YM-12617的合成研究[J]．中国药物化学杂志，1993，3(1)：54-56
[27] Yamanouchi Pharmaceutical Co. Ltd. Phenethylamine derivatives[P]. JP:58 18 353, 1983-02-02
[28] Fred W Hoover and Henry B Hass. Synthesis of paredrine and related compounds[J]. J.Org Chem. 1947, 12:501-505
[29] Kiyoshi Murase, Toshiyase Mase, Hisashi Ica, et al. Absolute configuration of four isomers of 3-formido-4-hydroxy α-[[N-(p-methoxy-methlphenethyl)amino]methyl] benzyl alcohol a potent β-adrenoreceptor stimulant. Chem Pharm Bull. 1978, 26(4): 1123-1129
[30] Shunichiro Sakurai, Kazuya Mitani, shigeki Hashmoto, et al. Novel phenoxyalkylamine Derivatives. Ⅶ. Synthesis and pharmacological Activities of 2-Alkoxy-5-phenoxyalkyl-amino)alkyl]benzenesulfonamide derivatives[J].Chem Pharm Bull, 1992,40(6): 1443-1451
[31] Niigata, Kunihiro, Fujikura, et al. Sulfoamoyl-substituted phenethylamine derivatives, their preparation, and pharmaceutical compositions, containing them. US 4731478 1988-03-15
[32] Willam J Wheeler, Klaus K Schmiege,David C Hunden. The synthesis of the ~14C and ~2H-isotopomers of (R)-N-[2-(2'-ethoxyphenoxyl)-N-2-[3-(4'-methoxy-3'-sulfonamido) phenyl]-propylamine hydrochloride, an α_1-adrenoreceptor antagonist[J]. J. Labelled Compd. Radiopharm, 1989,27(2), 171-180
[33] Nabe koichi, Nishida Yutaka, Nakamichi katsuhiko,et al. Enzymic manufacture of 1-(4-methoxyphenyl)-2-aminopropane as an intermediates for bronchodilator synthesis[P]. JP: 63,273,486. 1988-10-10(CA 110:191287w)
[34] Okada Minorv, Yashida Koichi, Takanobu Kiyoshi. Process for producing optically active benzenesulfonamide derivatives[P]. EP: 257,787.1988-03-02(CA: 109:110020h)
[35] Yamada koichiro, Iwakuma Takeo. Preparation of optically active 1-substituted
2-aminopropane derivatives as intermediates for pharmaceuticals[P] JP: 62,240,651. 1987-10-21 (CA: 109:54469x)
[36] 赵冬梅，赵丽琴，黄慧琴等．1-(4-甲氧基苯基)-2-丙胺的合成[J]．中国医药工业杂志．2001，32 (8) ：367-368
[37] Marcello Allegretti, Valerio Berdini, M Candida Cesta. Onepot, new stereoselective synthesis of endo-tropanamine. Tetrahedron Lett. 2001, 42:4257-4259
[2] 齐湘，于刚．选择性α：受体阻滞剂治疗良前列腺增生研究进展．医学综述，2000，6(9)：420-421
[3] 翁玲玲，楼荣良．国外正在研制的甾体药物．中国药学杂志，1994，29(3)：174
[4] 张丽霞．α-受体阻断药在治疗良性前列腺增生中的地位和作用．中国药师，2002，5(1)：51-52
[5] George FW, Johnson L, Wilson JD. The effect of a 5 alpha-reductase inhibitor on androgen physiology in the immature male rat. Endocrinology, 1989 Nov; 125(5):2434-8
[6] Andersen JT, Nokel JC, Marshall VR, et al. Finasteride significantly reduces acute urinary retention and need for surgery in patients with symptomatic benign prostatic hyperplasia. Urology, 1997,49:839
[7] Lennart Hansson. General Considerations When Treating Hypertension. Drugs., 1993,46(suppl.2): 37-39
[8] 詹鸣，吕胜启，王玲珑等．两种治疗方法治疗前列腺增生症的疗效比较．临床外科杂志，2000，8(3)：166-168
[9] Wenderoth UK, George FW, Wilson JD. The effect of a 5 alpha-reductase inhibitoron androgen mediated growth of the dog prostate. Endocrinology, 1983, 113 (2):569-73
[10] Brooks JR, Berman C, Primka RL, et al. 5 Alpha-reductase inhibitory and anti androgenic activities of some 4-azasteroids in the rat. Steroids, 1986 Jan;47(1): 15-19
[11] 谭莱茵．良性前列腺增生症药物治疗．医学理论与实践，2002，15(1)：1272-1276
[12] Hemsell DL, Grodin JM, Brenner PF, et al. Plasma precursors of estrogen.Ⅱ. Correlation of the extent of conversion of plasma androstenedione to estrone with age. J Clin Endocrinol Metab, 1974 Mar;38(3):476-9
[13] Kley HK, Nieschlag E, Bidlingmaier F, et al. Kruskemper HL Possible age-dependent influence of estrogens on the binding of testosterone in plasma of adult men. Horm Metab Res., 1974 May;6(3):213-6
[14] 彭司勋主编．药物化学进展(第一卷)．中国医学科技出版社：2000，48
[15] 彭明强．前列腺α1—肾上腺素受体研究进展．国外医学(泌尿系统分)，1998，18(2)：58-60
[16] Brooks JR, Berman C, Garnes D, et al. Prostatic effects induced in dogs by chronic or acute oral administration of 5 alpha-reductase inhibitors. Prostate, 1986;9(1):65-75
[17] Harrison JK, Pearson WR, Lynch KR. Molecular characterization of alpha 1 and alpha 2-adrenoceptors. Trends Pharmacol Sci, 1991 Feb; 12(2):62-7
[18] Yoshiaki soeishi, Miho Kobori, Shin-ichiro Kobayashi,et al. Sensitive method for the determination of tamsulosin in human plasma using high-performance liquid chromato graphy with fluroscene detection. J. Chromatography, 1990,533:291-296
[19] Ewoud J, Van Hoogdalem, Yoshiaki Soeishi, et al. Disposition of the selective α_(1A)-adrenoceptor antagonist tamsulosin in humans: comparison with data from interspecies scaling. J. Pharmaceutical Sci., 1997, 86(10): 1156-1160
[20] Blohm TR, Laughlin ME, Benson HD,et al. Pharmacological induction of 5 alpha-reductase deficiency in the rat: separation of testosterone-mediated and 5 alpha-dihydrotestosterone-mediated effects.Endocrinology, 1986 Sep;119(3):959-66
[21] Lepor H, Gup DI, Baumann M, et al. Laboratory assessment of terazosin and alpha-1 blockade in prostatic hyperplasia. Urology, 1988 Dec;32(6 Suppl):21-6
[22] 蒋伯诚．治疗前列腺增生症的α_1的的阻滞剂．药学进展，1992，16(3)：140-145
[23] Kawabe K, Niijima T. Use of an alpha 1-blocker, YM-12617, in micturition difficulty. Urol Int, 1987;42(4):280-4
[24] Kawabe K, Ueno A, Takimoto Y, et al. Use of an alpha 1-blocker, YM617, in the treatment of benign prostatic hypertrophy. YM617 Clinical Study Group. J Urol, 1990
Oct; 144(4):908-11; discussion 911-2
[25] Kenkichi Koiso MD, Hideyuki Akaza MD, Koji Kikuchi MD, et al. Pharmacokinetics of Tamsulosin Hydrochloride in Patients with Renal Impairment Effects of α_1-acid glycoprotein. J. Clin Pharmcol, 996,36:1029-1038
[26] 戴华成，舒平，李新红等．抗高血压新药YM-12617的合成研究[J]．中国药物化学杂志，1993，3(1)：54-56
[27] Yamanouchi Pharmaceutical Co. Ltd. Phenethylamine derivatives[P]. JP:58 18 353, 1983-02-02
[28] Fred W Hoover and Henry B Hass. Synthesis of paredrine and related compounds[J]. J.Org Chem. 1947, 12:501-505
[29] Kiyoshi Murase, Toshiyase Mase, Hisashi Ica, et al. Absolute configuration of four isomers of 3-formido-4-hydroxy α-[[N-(p-methoxy-methlphenethyl)amino]methyl] benzyl alcohol a potent β-adrenoreceptor stimulant. Chem Pharm Bull. 1978, 26(4): 1123-1129
[30] Shunichiro Sakurai, Kazuya Mitani, shigeki Hashmoto, et al. Novel phenoxyalkylamine Derivatives. Ⅶ. Synthesis and pharmacological Activities of 2-Alkoxy-5-phenoxyalkyl-amino)alkyl]benzenesulfonamide derivatives[J].Chem Pharm Bull, 1992,40(6): 1443-1451
[31] Niigata, Kunihiro, Fujikura, et al. Sulfoamoyl-substituted phenethylamine derivatives, their preparation, and pharmaceutical compositions, containing them. US 4731478 1988-03-15
[32] Willam J Wheeler, Klaus K Schmiege,David C Hunden. The synthesis of the ~14C and ~2H-isotopomers of (R)-N-[2-(2'-ethoxyphenoxyl)-N-2-[3-(4'-methoxy-3'-sulfonamido) phenyl]-propylamine hydrochloride, an α_1-adrenoreceptor antagonist[J]. J. Labelled Compd. Radiopharm, 1989,27(2), 171-180
[33] Nabe koichi, Nishida Yutaka, Nakamichi katsuhiko,et al. Enzymic manufacture of 1-(4-methoxyphenyl)-2-aminopropane as an intermediates for bronchodilator synthesis[P]. JP: 63,273,486. 1988-10-10(CA 110:191287w)
[34] Okada Minorv, Yashida Koichi, Takanobu Kiyoshi. Process for producing optically active benzenesulfonamide derivatives[P]. EP: 257,787.1988-03-02(CA: 109:110020h)
[35] Yamada koichiro, Iwakuma Takeo. Preparation of optically active 1-substituted
2-aminopropane derivatives as intermediates for pharmaceuticals[P] JP: 62,240,651. 1987-10-21 (CA: 109:54469x)
[36] 赵冬梅，赵丽琴，黄慧琴等．1-(4-甲氧基苯基)-2-丙胺的合成[J]．中国医药工业杂志．2001，32 (8) ：367-368
[37] Marcello Allegretti, Valerio Berdini, M Candida Cesta. Onepot, new stereoselective synthesis of endo-tropanamine. Tetrahedron Lett. 2001, 42:4257-4259