盐酸特比萘芬合成工艺的研究
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摘要
皮肤真菌感染发病率高,病程长,目前治疗药物虽多,但疗效高、复发率低、毒副反应小者甚少。30年前推出的灰黄霉素因疗效差而停用。酮康唑则长时间治疗时毒副反应严重。新三唑类如伊曲康唑、氟康唑虽疗效高,副反应低,但其价格昂贵难以普遍应用,而特比萘芬抗菌谱广,抗菌作用强,外用或短疗程口服可以治愈绝大部分皮肤真菌病,且复发率低、副作用少、安全性高,是治疗甲癣及皮肤癣病的首选药物。
盐酸特比萘芬是一种丙烯胺类抗真菌药,具有广谱抗真菌活性,而且抗菌作用强,既可杀菌又可抑菌,其MIC与MFC几乎相等,可广泛地应用于治疗各类皮肤真菌病尤其是甲真菌病。特比萘芬是目前唯一的既可外用又可口服的杀真菌药,它对多数致病真菌均有作用,其中最敏感者为皮肤癣菌;其作用特点为:1.药物具有亲脂性;2.药物杀菌力强;3.不作用于细胞色素氧化酶CYP450;4.独特的化学结构具有强亲角质性,能够有效减少脚气复发,且副作用轻微。
制备盐酸特比芬萘芬药品,首先要有盐酸特比萘芬原料药,本研究的目的就是对已有文献的盐酸特比萘芬的合成路线进行研究,根据原料来源情况和实际操作的难易程度等选用了如下的路线:即从原料N-甲基-N-萘甲胺出发,以甲醇做溶剂,与环氧氯丙烷反应得中间体I,中间体I在碱性条件下生成中间体Ⅱ,中间体Ⅱ在BuLi及BF3-Et2O存在下与叔丁基乙炔反应,得到中间体Ⅲ,进而被脱水、成盐、重结晶可得化合物盐酸特比萘芬,此路线合成出的盐酸特比萘芬不仅产率高,可达到57.3%,比传统工艺提高10%,成本低,而且合成中所用的化学试剂均为工业级的常用试剂。
Terbinafine hydrochloride is especially at present only both may the external use and be possible to take orally compared to the naphthalene fragrance kills the fungus medicine, it has the function to the most pathogenesis fungus, in which sensitivity for the skin ringworm fungus ; Its function characteristic is: 1. medicines have lipophilic ; 2. medicine bactericidal power;3. does not affect in cytochrome oxidase CYP450, high selective action in real membrane squalene epoxidation enzyme;4. unique chemical constitutions have strongly kiss the cutin, can with the trouble department full union, and stores up in the skin in-depth。
In the secure aspect, especially has following merit compared to the terbinafine hydrochloride: 1. liver toxicity are low ; 2. does not affect the internal secretion;3. does not affect other medicine metabolism; 4. side effects are slight。
The skin fungus infection disease incidence rate is high, the course of an illness is long, although at present treats the medicine many, but the curative effect high, the recurrence rate low, poisonous side reaction small are really few。30 years ago promote the griseofulvin stops using because of the curative effect difference。Then alkone Kang Zuo time long treatment course treatment the poisonous side reaction is serious.Although new triazole as for example Iraq Qu Kang Zuo, fluorine Kang Zuo the curative effect is high, the side reaction is low, but its price raises generally applies with difficulty, but is especially profuse the terbinafine hydrochloride the antibacterial spectrum to be broader than, the resist bacteria affects strongly, the external use or the short treatment course oral administration may cure the major part dermatomycosis, also the recurrence rate low, the side effect few, the security is high, treats the first choice medicine which the onychomycosis and skin ringworm get sick。
This article goal was to had the literature especially to conduct the research compared to the terbinafine hydrochloride process of synthesis, determined embarked from raw material N- the methyl - N- naphthalene methylamine, made the solvent by the methyl alcohol, instead earned the intermediate with the epichlorohydrine I, the intermediate I produced the intermediateⅡunder the alkalinity condition。The intermediateⅡresponded in BuLi and under the BF3-Et2O existence with uncle butyl-acetylene, obtains the intermediateⅢ; Then dehydrates, the salifying, the heavy crystal may result in the goal compound terbinafine hydrochlorid, this route synthesizes not only the terbinafine hydrochlorid the production rate is especially higher, the cost is low, moreover synthesizes the chemical reagent relative toxicity which uses to be small。
盐酸特比萘芬是一种丙烯胺类抗真菌药,具有广谱抗真菌活性,而且抗菌作用强,既可杀菌又可抑菌,其MIC与MFC几乎相等,可广泛地应用于治疗各类皮肤真菌病尤其是甲真菌病。特比萘芬是目前唯一的既可外用又可口服的杀真菌药,它对多数致病真菌均有作用,其中最敏感者为皮肤癣菌;其作用特点为:1.药物具有亲脂性;2.药物杀菌力强;3.不作用于细胞色素氧化酶CYP450;4.独特的化学结构具有强亲角质性,能够有效减少脚气复发,且副作用轻微。
制备盐酸特比芬萘芬药品,首先要有盐酸特比萘芬原料药,本研究的目的就是对已有文献的盐酸特比萘芬的合成路线进行研究,根据原料来源情况和实际操作的难易程度等选用了如下的路线:即从原料N-甲基-N-萘甲胺出发,以甲醇做溶剂,与环氧氯丙烷反应得中间体I,中间体I在碱性条件下生成中间体Ⅱ,中间体Ⅱ在BuLi及BF3-Et2O存在下与叔丁基乙炔反应,得到中间体Ⅲ,进而被脱水、成盐、重结晶可得化合物盐酸特比萘芬,此路线合成出的盐酸特比萘芬不仅产率高,可达到57.3%,比传统工艺提高10%,成本低,而且合成中所用的化学试剂均为工业级的常用试剂。
Terbinafine hydrochloride is especially at present only both may the external use and be possible to take orally compared to the naphthalene fragrance kills the fungus medicine, it has the function to the most pathogenesis fungus, in which sensitivity for the skin ringworm fungus ; Its function characteristic is: 1. medicines have lipophilic ; 2. medicine bactericidal power;3. does not affect in cytochrome oxidase CYP450, high selective action in real membrane squalene epoxidation enzyme;4. unique chemical constitutions have strongly kiss the cutin, can with the trouble department full union, and stores up in the skin in-depth。
In the secure aspect, especially has following merit compared to the terbinafine hydrochloride: 1. liver toxicity are low ; 2. does not affect the internal secretion;3. does not affect other medicine metabolism; 4. side effects are slight。
The skin fungus infection disease incidence rate is high, the course of an illness is long, although at present treats the medicine many, but the curative effect high, the recurrence rate low, poisonous side reaction small are really few。30 years ago promote the griseofulvin stops using because of the curative effect difference。Then alkone Kang Zuo time long treatment course treatment the poisonous side reaction is serious.Although new triazole as for example Iraq Qu Kang Zuo, fluorine Kang Zuo the curative effect is high, the side reaction is low, but its price raises generally applies with difficulty, but is especially profuse the terbinafine hydrochloride the antibacterial spectrum to be broader than, the resist bacteria affects strongly, the external use or the short treatment course oral administration may cure the major part dermatomycosis, also the recurrence rate low, the side effect few, the security is high, treats the first choice medicine which the onychomycosis and skin ringworm get sick。
This article goal was to had the literature especially to conduct the research compared to the terbinafine hydrochloride process of synthesis, determined embarked from raw material N- the methyl - N- naphthalene methylamine, made the solvent by the methyl alcohol, instead earned the intermediate with the epichlorohydrine I, the intermediate I produced the intermediateⅡunder the alkalinity condition。The intermediateⅡresponded in BuLi and under the BF3-Et2O existence with uncle butyl-acetylene, obtains the intermediateⅢ; Then dehydrates, the salifying, the heavy crystal may result in the goal compound terbinafine hydrochlorid, this route synthesizes not only the terbinafine hydrochlorid the production rate is especially higher, the cost is low, moreover synthesizes the chemical reagent relative toxicity which uses to be small。
引文
[1] 张文娟,肖德秀,刘彦梅,等 . 特比萘芬软膏治疗浅部真菌病临床试验. 中国新药与临床杂志,2000,19(7):25-27
[2] 王爱平,李若瑜,王端礼 . 特比萘芬治疗真菌病现状 . 中国新药与临床杂志,2000,19(7):4-7
[3] 郭宁如,吴绍熙 . 抗浅部真菌病药特比萘芬的研究进展. 中国新药杂志,1995,4(3):1-4
[4] 新一代抗真菌药——兰美抒 . 中国药典, 2002, (6):64
[5] 李林峰. 从治疗整体观评价新一代皮肤抗真菌药——特比萘芬. 中国新药杂志,1995,4(5):19-21
[6] 国家食品药品监督管理局药品行政保护公告第 166 号(终止公告 )
[7] 国家食品药品监督管理局发布的盐酸特比萘芬原料的国家药品标准:WS1-(X-196)-2004Z
[8] 国家食品药品监督管理局发布的盐酸特比萘芬片的国家药品标准:WS1-(X-119)-2004Z
[9] 国家食品药品监督管理局发布的盐酸特比萘芬凝胶的国家药品标准:WS1-(X-226)-2004Z
[10] 国 家 食 品 药 品 监 督 管 理 局 发 布 的 盐 酸 特 比 萘 芬 乳 膏的国家药品标准:WS1-(X-115)-2004Z
[11] 国 家 食 品 药 品 监 督 管 理 局 发 布 的 盐 酸 特 比 萘 芬 喷 雾剂的国家药品标准:WS1-(X-077)-2003Z
[12] STUETZ ANTON Canadian Patent 1157023 - 1983-11-15
[13] NAKAGAWA SUSUMU BANYU PHARMAC(JP) ,EP0421302 - 1991-04-10
[14] NAKAGAWA SUSUMU (JP); ASAI AKIRA (JP); US5231183 - 1993-07-27
[15] KARIMIAN KHASHAYAR (CA); LEUNG-TOUNG REGIS C H S (CA); US Patent 5817875 - 1998-10-06
[16] KAKALIK IVAN (SK); OREMUS VLADIMIR (SK); WO 01/77064 - 2001-10-18
[2] 王爱平,李若瑜,王端礼 . 特比萘芬治疗真菌病现状 . 中国新药与临床杂志,2000,19(7):4-7
[3] 郭宁如,吴绍熙 . 抗浅部真菌病药特比萘芬的研究进展. 中国新药杂志,1995,4(3):1-4
[4] 新一代抗真菌药——兰美抒 . 中国药典, 2002, (6):64
[5] 李林峰. 从治疗整体观评价新一代皮肤抗真菌药——特比萘芬. 中国新药杂志,1995,4(5):19-21
[6] 国家食品药品监督管理局药品行政保护公告第 166 号(终止公告 )
[7] 国家食品药品监督管理局发布的盐酸特比萘芬原料的国家药品标准:WS1-(X-196)-2004Z
[8] 国家食品药品监督管理局发布的盐酸特比萘芬片的国家药品标准:WS1-(X-119)-2004Z
[9] 国家食品药品监督管理局发布的盐酸特比萘芬凝胶的国家药品标准:WS1-(X-226)-2004Z
[10] 国 家 食 品 药 品 监 督 管 理 局 发 布 的 盐 酸 特 比 萘 芬 乳 膏的国家药品标准:WS1-(X-115)-2004Z
[11] 国 家 食 品 药 品 监 督 管 理 局 发 布 的 盐 酸 特 比 萘 芬 喷 雾剂的国家药品标准:WS1-(X-077)-2003Z
[12] STUETZ ANTON Canadian Patent 1157023 - 1983-11-15
[13] NAKAGAWA SUSUMU BANYU PHARMAC(JP) ,EP0421302 - 1991-04-10
[14] NAKAGAWA SUSUMU (JP); ASAI AKIRA (JP); US5231183 - 1993-07-27
[15] KARIMIAN KHASHAYAR (CA); LEUNG-TOUNG REGIS C H S (CA); US Patent 5817875 - 1998-10-06
[16] KAKALIK IVAN (SK); OREMUS VLADIMIR (SK); WO 01/77064 - 2001-10-18