盐酸坦洛新合成工艺研究
摘要
前列腺增生又叫前列腺肥大,又称良性前列腺增生症,多发于老年男性。现代医学认为：前列腺肥大与内分泌系统有关,是前列腺内层尿道腺和尿道下腺上皮细胞及基质增生,腺泡囊性扩张,结缔组织及平滑肌节样增生所致。
前列腺肥大(BPH)为老年人常见疾病,一般开始于30岁,50岁以上的男性中大约50%、80岁以上大约90%患有前列腺增生。前列腺增生和生活方式有关,西方国家老年男子前列腺增生几率高于东方国家；在中国,城市人口的前列腺增生患病率远远高于农村。
盐酸坦罗新——新型抗前列腺增生药,α-肾上腺素受体阻滞剂,主要用于治疗前列腺增生所致的排尿障碍。
本课题旨在研究一个适合工业化的盐酸坦洛新制备路线和工艺。
1.本论文对文献资料进行了详细的研究,在小试工艺考察的基础上,综合考虑了工业化的基本要求,设计了盐酸坦洛新合成路线。该路线以4-甲氧基苯基丙酮为起始原料,经氯磺化、胺化、加氢还原、成盐、氢化脱苄、游离得中间体一；中间体一与中间体二(溴醚)进行缩合、成盐,得到盐酸坦洛新。
该路线原料价廉易得,反应条件要求低,避免了其它路线存在的原料不易得到、反应条件苛刻、反应选择性差等缺点。
2.本文对设计的合成路线进行了详细的工艺研究。对试剂的选择、溶剂的选择、反应温度、反应时间、原料配比、后处理方法等进行了详细的考察。具有反应条件温和,操作简便、原料易得等适合工业化的特点。
特别是用以工业生产的R—(+)—a—苯乙胺为原料,经过光学诱导催化氢化和氢解两步,得到光学活性中间体R-(-)-5-(2—氨基丙基)-2-甲氧基苯磺酰胺,光学纯度>99.0%,解决了盐酸坦洛新制备的关键技术问题。
本方法以4-甲氧基苯基丙酮为原料,经过氯磺化、胺化、加氢、成盐、氢化脱苄、游离六步反应得中间体一；中间体一与中间体二(溴醚)进行缩合、成盐,共8步反应得到盐酸坦洛新,总收率10.83%。
3.将利用本方法合成的盐酸坦洛新和从中国药品生物制品检定所购买的对照品(100688-200401)进行结构确证,分别进行了：紫外吸收光谱(UV)、红外吸收光谱(IR)、核磁共振谱(NMR)、氢核磁共振谱(1H-NMR)、l3C-NMR共振谱(13C-NMR)、NOESY谱、高分辨质谱(MS)、X-射线衍射谱、热分析(TG-DSC)。证明合成的样品与中检所对照品结构一致、晶型相同,并且为R构型。
4.文中还采用CHIRAICEL OJ-H柱(正相柱)用HPLC对异构体进行了分离、检测,并用S异构体进行对照,得出其光学纯度超过99%的结论。
总之,本课题进行了路线选择、工艺研究、质量研究、试验验证等工作。获得的工艺便于操作,原料便宜易得,收率质量稳定,环境友好,成本低廉的盐酸坦洛新合成工艺；实验所得的成品和对照品进行了光谱等分析,确定结构符合要求；成品质量全检结果稳定合格。
本工艺已经具备了工业化条件,和国内外有关公开报道比较,本文对盐酸坦洛新的工艺研究处于领先水平。
Benign prostatic hyperplasia (BPH) also known as benign prostatic hypertrophy (technically a misnomer), benign enlargement of the prostate (BEP), and adenofibromyomatous hyperplasia, refers to the increase in size of the prostate in elderly men. To be accurate, the process is one of hyperplasia rather than hypertrophy, but the nomenclature is often interchangeable, even amongst urologists.
Adenomatous prostatic growth is believed to begin at approximately age 30 years. An estimated 50% of men have histologic evidence of BPH by age 50 years and 90% by age 80 years. In 40-50% of these patients, BPH becomes clinically significant.
On a microscopic level, BPH can be seen in the vast majority of men as they age, in particular over the age of 70 years, around the world. However, rates of clinically significant, symptomatic BPH vary dramatically depending on lifestyle. Men that lead a western lifestyle have a much higher incidence of symptomatic BPH than men that lead a traditional or rural lifestyle. This is confirmed by research in China showing that men in rural areas have very low rates of clinical BPH, while men living in cities adopting a western lifestyle have a skyrocketing incidence of this condition, though it is still below rates seen in the West.
Tamsulosin is the most common choice for BPH. It relax smooth muscle in the prostate,decreasing the blockage of urine flow.
This paper, we aimed to research a synthetic path and its technics which was suitable for tamsulosin.
1. In this paper, many literatures on Tamsulosin have been studied thoroughly, and the suitable synthetic path have been selected according to lab and industralization. In the synthetic path, Tamsulosin was synthesized using the main materials 4-Methoxyphenylacetone, and was synthesized by chlorosulfonatio, amination, hydrogenation,salify,hydrogenation,dissociation,received intermediated I. Then this intermediated I react with intermediated II which called amidogen ether,received the product tamsulosin. In this synthetic path, the main materials were cheap and facile, and its reaction conditions were moderate, and the disadvantages were avoided comparing with other synthetic paths of which main materials were not facile, and reaction conditions were stern, being short of selectivity.
2. In this paper, the technics was researched thoroughly relating to the selection of reagent, reaction temperature, reaction time, compounding ratio and the methods of upper diaposal. The key side reactions were researched, and the methods of restraining side reactions and removing from by-products were brought up. In this paper the methods for disposing waste were offered. The technical condition was comparatively mature for industrialisation through technical optimization. Especially we use R-(+)-methylbenzylamine and 5-acetonyl-2-methoxybenzenesulfonamide in the presence of reducing agient to obtain high optical purity 1R,2R-2-methoxy-[2-(1-methylbenzylamino)-propyl]-benzensulfonamide(Ⅰ). This intermediate(Ⅰ) hydrogensis of intermediatedⅡto obtain tamsulosin.The process is capable of producing optically active R-(-)tamsulosin of high optical purity (> 99.0%) with hign reaction yield. The whole process involved chlorosulfonatio, amination, hydrogenation,salify,hydrogenation,dissociation,condensation etc. the total yield is 10.83%.
3.The structure of target molecule was determined by UV,IR, MS,13C-NMR,1H-NMR TG-DSC,X-ray,NOESY. Also contrasted control article which from National institute for the control of pharmaceutical and biological products(B.A.100688-200401).
4.The optical purity was determined by HPLC with CHIRAICEL OJ-H.
To sum up, in this paper,many researches were carried out such as synthetic path design, technical research, quality research, lab validation, etc. The acquired technics was simple to operation, its raw materials were cheap and facile, and its yield and quality were steady, it was on terms to enviroment, and its material cost was cheap. The spectral analysis of finished product was carried out comparing with comparative product, which made sure that their structures were accordant. The finished product was proved out through assay. So the technics is suitable for industrialization. The tamsulosin technical research is advanced comparing with other open-eyed papers.
前列腺肥大(BPH)为老年人常见疾病,一般开始于30岁,50岁以上的男性中大约50%、80岁以上大约90%患有前列腺增生。前列腺增生和生活方式有关,西方国家老年男子前列腺增生几率高于东方国家；在中国,城市人口的前列腺增生患病率远远高于农村。
盐酸坦罗新——新型抗前列腺增生药,α-肾上腺素受体阻滞剂,主要用于治疗前列腺增生所致的排尿障碍。
本课题旨在研究一个适合工业化的盐酸坦洛新制备路线和工艺。
1.本论文对文献资料进行了详细的研究,在小试工艺考察的基础上,综合考虑了工业化的基本要求,设计了盐酸坦洛新合成路线。该路线以4-甲氧基苯基丙酮为起始原料,经氯磺化、胺化、加氢还原、成盐、氢化脱苄、游离得中间体一；中间体一与中间体二(溴醚)进行缩合、成盐,得到盐酸坦洛新。
该路线原料价廉易得,反应条件要求低,避免了其它路线存在的原料不易得到、反应条件苛刻、反应选择性差等缺点。
2.本文对设计的合成路线进行了详细的工艺研究。对试剂的选择、溶剂的选择、反应温度、反应时间、原料配比、后处理方法等进行了详细的考察。具有反应条件温和,操作简便、原料易得等适合工业化的特点。
特别是用以工业生产的R—(+)—a—苯乙胺为原料,经过光学诱导催化氢化和氢解两步,得到光学活性中间体R-(-)-5-(2—氨基丙基)-2-甲氧基苯磺酰胺,光学纯度>99.0%,解决了盐酸坦洛新制备的关键技术问题。
本方法以4-甲氧基苯基丙酮为原料,经过氯磺化、胺化、加氢、成盐、氢化脱苄、游离六步反应得中间体一；中间体一与中间体二(溴醚)进行缩合、成盐,共8步反应得到盐酸坦洛新,总收率10.83%。
3.将利用本方法合成的盐酸坦洛新和从中国药品生物制品检定所购买的对照品(100688-200401)进行结构确证,分别进行了：紫外吸收光谱(UV)、红外吸收光谱(IR)、核磁共振谱(NMR)、氢核磁共振谱(1H-NMR)、l3C-NMR共振谱(13C-NMR)、NOESY谱、高分辨质谱(MS)、X-射线衍射谱、热分析(TG-DSC)。证明合成的样品与中检所对照品结构一致、晶型相同,并且为R构型。
4.文中还采用CHIRAICEL OJ-H柱(正相柱)用HPLC对异构体进行了分离、检测,并用S异构体进行对照,得出其光学纯度超过99%的结论。
总之,本课题进行了路线选择、工艺研究、质量研究、试验验证等工作。获得的工艺便于操作,原料便宜易得,收率质量稳定,环境友好,成本低廉的盐酸坦洛新合成工艺；实验所得的成品和对照品进行了光谱等分析,确定结构符合要求；成品质量全检结果稳定合格。
本工艺已经具备了工业化条件,和国内外有关公开报道比较,本文对盐酸坦洛新的工艺研究处于领先水平。
Benign prostatic hyperplasia (BPH) also known as benign prostatic hypertrophy (technically a misnomer), benign enlargement of the prostate (BEP), and adenofibromyomatous hyperplasia, refers to the increase in size of the prostate in elderly men. To be accurate, the process is one of hyperplasia rather than hypertrophy, but the nomenclature is often interchangeable, even amongst urologists.
Adenomatous prostatic growth is believed to begin at approximately age 30 years. An estimated 50% of men have histologic evidence of BPH by age 50 years and 90% by age 80 years. In 40-50% of these patients, BPH becomes clinically significant.
On a microscopic level, BPH can be seen in the vast majority of men as they age, in particular over the age of 70 years, around the world. However, rates of clinically significant, symptomatic BPH vary dramatically depending on lifestyle. Men that lead a western lifestyle have a much higher incidence of symptomatic BPH than men that lead a traditional or rural lifestyle. This is confirmed by research in China showing that men in rural areas have very low rates of clinical BPH, while men living in cities adopting a western lifestyle have a skyrocketing incidence of this condition, though it is still below rates seen in the West.
Tamsulosin is the most common choice for BPH. It relax smooth muscle in the prostate,decreasing the blockage of urine flow.
This paper, we aimed to research a synthetic path and its technics which was suitable for tamsulosin.
1. In this paper, many literatures on Tamsulosin have been studied thoroughly, and the suitable synthetic path have been selected according to lab and industralization. In the synthetic path, Tamsulosin was synthesized using the main materials 4-Methoxyphenylacetone, and was synthesized by chlorosulfonatio, amination, hydrogenation,salify,hydrogenation,dissociation,received intermediated I. Then this intermediated I react with intermediated II which called amidogen ether,received the product tamsulosin. In this synthetic path, the main materials were cheap and facile, and its reaction conditions were moderate, and the disadvantages were avoided comparing with other synthetic paths of which main materials were not facile, and reaction conditions were stern, being short of selectivity.
2. In this paper, the technics was researched thoroughly relating to the selection of reagent, reaction temperature, reaction time, compounding ratio and the methods of upper diaposal. The key side reactions were researched, and the methods of restraining side reactions and removing from by-products were brought up. In this paper the methods for disposing waste were offered. The technical condition was comparatively mature for industrialisation through technical optimization. Especially we use R-(+)-methylbenzylamine and 5-acetonyl-2-methoxybenzenesulfonamide in the presence of reducing agient to obtain high optical purity 1R,2R-2-methoxy-[2-(1-methylbenzylamino)-propyl]-benzensulfonamide(Ⅰ). This intermediate(Ⅰ) hydrogensis of intermediatedⅡto obtain tamsulosin.The process is capable of producing optically active R-(-)tamsulosin of high optical purity (> 99.0%) with hign reaction yield. The whole process involved chlorosulfonatio, amination, hydrogenation,salify,hydrogenation,dissociation,condensation etc. the total yield is 10.83%.
3.The structure of target molecule was determined by UV,IR, MS,13C-NMR,1H-NMR TG-DSC,X-ray,NOESY. Also contrasted control article which from National institute for the control of pharmaceutical and biological products(B.A.100688-200401).
4.The optical purity was determined by HPLC with CHIRAICEL OJ-H.
To sum up, in this paper,many researches were carried out such as synthetic path design, technical research, quality research, lab validation, etc. The acquired technics was simple to operation, its raw materials were cheap and facile, and its yield and quality were steady, it was on terms to enviroment, and its material cost was cheap. The spectral analysis of finished product was carried out comparing with comparative product, which made sure that their structures were accordant. The finished product was proved out through assay. So the technics is suitable for industrialization. The tamsulosin technical research is advanced comparing with other open-eyed papers.
引文
① Andersson K.E. The pharmacological treatment of urinary incontinence. BJU International (1999),84,823-947
② Meconnell JD. Bruskewitz R. Walsh P etc. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with begign prostatic hyperplasia. N Engl J Med.1998;338:557-563
③刘东明,黄翼然,江鱼等.盐酸坦洛新治疗前列腺增生症的临床疗效评估[J].中国男科科学杂志,1998,12(3)：133-135.
④潘慈康.良性前列腺增生症的药物治疗[J].实用医院临床杂志,2005,2(1)：22-23。
③ShuniehiroSakural, KazuyaMitani, Shigeki Hashmoto, Koji, Morikawa etc, Novel Phenoxyalkylamineoevatives.Synthesis and Pharmaeological Activities of 2-Alkoxy-5-[(Phenoxyalkylamino)alklyl benzenesulfonamine Derivatives.Chem.Pharm. Bull.40(6)1443-1445(1992).
⑥.Haj icek, Josef,Slavikova, Marketa. A method of the Preparatio of (R)-(-)-5'2-'2-(2-ethoxyphenoxy)ethylaminopropyl-2-methoxybenzensulphonamide (tamsulosin) WO03/035608A1
⑦藤昌峻,新形邦宏。昭62—114952
⑧Kazuo Imai; Kunihiro Niigata; Takashi Fujikura, all of Saitamaete, Sulfa-substituted Phenethylamine derivatives and proeess of Produeing them.us4703063.
⑨ HAN H,PETERS J,JAROSLAV P,et al. Process for resolution of tamsulosin:WO,03/037850[P].2002210215.
⑩ YASUOI, HIDEO K, KOSHINAKA E, et al. Phenoxyethylamine derivatives.process for preparing the same,and com-position for exhibiting excellent alpha212blocking activity containing the same:EP,0331 943 [P].1989209213.
⑾MINORU O. Process for producing optically active benzenesulfonamide derivates:EP,0 257787[P].1988202203.
[12]加藤羲则；加藤秀榭.JP2000—229901
⒀PATEL M K,SOHANI S,DEODHAR M,et al. An improved process for the preparation of (R) (-) tamsulosin hydrochlo-ride:WO,2004 087 623 [P].2004210214.
⒁]BORUT F,ANTON C,BORUT F,et al. Preparation of R-5-(2-(2-ethoxyphenoxyethylamino) propy1)-2-methoxybenzene-sulphonamide hydrochloride of high chemical:WO,2005 063 702[P].2005207214.
⒂ ]JOSEF H,MARKETA S,ZENTIVA A S,et al. A method of preparation of (R)-(-)-5-(2-aminopropyl)-2-methoxyben-zenesulfonamide:WO,2005 075 415[P].2005208218.
② Meconnell JD. Bruskewitz R. Walsh P etc. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with begign prostatic hyperplasia. N Engl J Med.1998;338:557-563
③刘东明,黄翼然,江鱼等.盐酸坦洛新治疗前列腺增生症的临床疗效评估[J].中国男科科学杂志,1998,12(3)：133-135.
④潘慈康.良性前列腺增生症的药物治疗[J].实用医院临床杂志,2005,2(1)：22-23。
③ShuniehiroSakural, KazuyaMitani, Shigeki Hashmoto, Koji, Morikawa etc, Novel Phenoxyalkylamineoevatives.Synthesis and Pharmaeological Activities of 2-Alkoxy-5-[(Phenoxyalkylamino)alklyl benzenesulfonamine Derivatives.Chem.Pharm. Bull.40(6)1443-1445(1992).
⑥.Haj icek, Josef,Slavikova, Marketa. A method of the Preparatio of (R)-(-)-5'2-'2-(2-ethoxyphenoxy)ethylaminopropyl-2-methoxybenzensulphonamide (tamsulosin) WO03/035608A1
⑦藤昌峻,新形邦宏。昭62—114952
⑧Kazuo Imai; Kunihiro Niigata; Takashi Fujikura, all of Saitamaete, Sulfa-substituted Phenethylamine derivatives and proeess of Produeing them.us4703063.
⑨ HAN H,PETERS J,JAROSLAV P,et al. Process for resolution of tamsulosin:WO,03/037850[P].2002210215.
⑩ YASUOI, HIDEO K, KOSHINAKA E, et al. Phenoxyethylamine derivatives.process for preparing the same,and com-position for exhibiting excellent alpha212blocking activity containing the same:EP,0331 943 [P].1989209213.
⑾MINORU O. Process for producing optically active benzenesulfonamide derivates:EP,0 257787[P].1988202203.
[12]加藤羲则；加藤秀榭.JP2000—229901
⒀PATEL M K,SOHANI S,DEODHAR M,et al. An improved process for the preparation of (R) (-) tamsulosin hydrochlo-ride:WO,2004 087 623 [P].2004210214.
⒁]BORUT F,ANTON C,BORUT F,et al. Preparation of R-5-(2-(2-ethoxyphenoxyethylamino) propy1)-2-methoxybenzene-sulphonamide hydrochloride of high chemical:WO,2005 063 702[P].2005207214.
⒂ ]JOSEF H,MARKETA S,ZENTIVA A S,et al. A method of preparation of (R)-(-)-5-(2-aminopropyl)-2-methoxyben-zenesulfonamide:WO,2005 075 415[P].2005208218.