88678-31-3

• 常用中文名：利拉萘酯
• 常用英文名：Liranaftate
• CAS号：88678-31-3
• 分子式：C₁₈H₂₀N₂O₂S
• 分子量：328.429
• 相关类别： 原料药 抗生素类药物 其它抗生素类药
• 发布时间：2018-09-30 19:34:24
• 更新时间：2024-01-02 17:13:40
• 广谱抗真菌药

名称

• 中文名: 利拉萘酯
• 英文名: O-(5,6,7,8-tetrahydronaphthalen-2-yl) N-(6-methoxypyridin-2-yl)-N-methylcarbamothioate
• 中文别名: N-(6-甲氧基-2-吡啶基)-N-甲基氨基硫代甲酸(5,6,7,8-四氢)-2-萘酯; 利拉柰酯
• 英文别名: Liranaftatum; Liranaftate; O-(5,6,7,8-Tetrahydro-2-naphthalenyl) (6-methoxy-2-pyridinyl)methylcarbamothioate; M-732; piritetrate; O-(5,6,7,8-Tetrahydronaphthalen-2-yl)-(6-methoxypyridin-2-yl)methylthiocarbamat; Liranaftato; Zefnart; O-(5,6,7,8-Tetrahydronaphthalen-2-yl) (6-methoxypyridin-2-yl)methylcarbamothioate; (6-Methoxy-2-pyridinyl)methylcarbamothioic Acid O-(5,6,7,8-Tetrahydro-2-naphthalenyl) Ester; Carbamothioic acid, N-(6-methoxy-2-pyridinyl)-N-methyl-, O-(5,6,7,8-tetrahydro-2-naphthalenyl) ester; Liranaftate (JAN)

物化性质

• 密度: 1.2±0.1 g/cm3
• 沸点: 462.5±55.0 °C at 760 mmHg
• 熔点: 98.5-99.5ºC
• 分子式: C₁₈H₂₀N₂O₂S
• 分子量: 328.429
• 闪点: 233.5±31.5 °C
• 精确质量: 328.124542
• PSA: 66.68000
• LogP: 5.20
• 外观性状: 白色结晶固体
• 蒸汽压: 0.0±1.1 mmHg at 25°C
• 折射率: 1.642
• 储存条件: -20°C Freezer
• 分子结构:

  1、 摩尔折射率：95.66

  2、 摩尔体积（cm³/mol）：264.8

  3、 等张比容（90.2K）：724.9

  4、 表面张力（dyne/cm）：56.1

  5、 极化率（10-24cm3）：37.92

• 计算化学:

  1.疏水参数计算参考值（XlogP）:无

  2.氢键供体数量:0

  3.氢键受体数量:4

  4.可旋转化学键数量:4

  5.互变异构体数量:无

  6.拓扑分子极性表面积66.7

  7.重原子数量:23

  8.表面电荷:0

  9.复杂度:407

  10.同位素原子数量:0

  11.确定原子立构中心数量:0

  12.不确定原子立构中心数量:0

  13.确定化学键立构中心数量:0

  14.不确定化学键立构中心数量:0

  15.共价键单元数量:1

• 更多:

  1.性状：白色至淡黄色结晶性粉末。

  2.熔点（ºC）：98.5～99.5

  3.溶解性：在丙酮、氯仿中易溶，在甲醇和乙醇中微溶，水中几乎不溶。

生物活性

• 描述: Liranaftate是鲨烯环氧化酶抑制剂,有抗真菌活性。
• 相关类别:
  信号通路 >> 抗感染 >> 真菌
  研究领域 >> 感染
• 参考文献:

  [1]. Oku, Y., et al., [Fungicidal activity of liranaftate against Trichophyton rubrum]. Nihon Ishinkin Gakkai Zasshi, 2002. 43(3): p. 181-7.

  [2]. Oku, Y., N. Takahashi, and K. Yokoyama, [Fungicidal activity of liranaftate against dermatophytes]. Nihon Ishinkin Gakkai Zasshi, 2009. 50(1): p. 9-13.

毒性和生态

CHEMICAL IDENTIFICATION RTECS NUMBER : FD3890000 CHEMICAL NAME : Carbamothioic acid, (6-methoxy-2-pyridinyl)methyl-, O-(5,6,7,8-tetrahydro-2- naphthalenyl) ester CAS REGISTRY NUMBER : 88678-31-3 LAST UPDATED : 199312 DATA ITEMS CITED : 12 MOLECULAR FORMULA : C18-H20-N2-O2-S MOLECULAR WEIGHT : 328.46 HEALTH HAZARD DATA ACUTE TOXICITY DATA TYPE OF TEST : LD50 - Lethal dose, 50 percent kill ROUTE OF EXPOSURE : Oral SPECIES OBSERVED : Rodent - rat DOSE/DURATION : >2 gm/kg TOXIC EFFECTS : Details of toxic effects not reported other than lethal dose value REFERENCE : IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 24,281,1993 TYPE OF TEST : LD50 - Lethal dose, 50 percent kill ROUTE OF EXPOSURE : Intraperitoneal SPECIES OBSERVED : Rodent - rat DOSE/DURATION : >2 gm/kg TOXIC EFFECTS : Liver - other changes Blood - changes in spleen Nutritional and Gross Metabolic - weight loss or decreased weight gain REFERENCE : IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 24,281,1993 TYPE OF TEST : LD50 - Lethal dose, 50 percent kill ROUTE OF EXPOSURE : Subcutaneous SPECIES OBSERVED : Rodent - rat DOSE/DURATION : >2 gm/kg TOXIC EFFECTS : Skin and Appendages - dermatitis, other (after systemic exposure) REFERENCE : IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 24,281,1993 TYPE OF TEST : LD50 - Lethal dose, 50 percent kill ROUTE OF EXPOSURE : Oral SPECIES OBSERVED : Rodent - mouse DOSE/DURATION : >2 gm/kg TOXIC EFFECTS : Details of toxic effects not reported other than lethal dose value REFERENCE : IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 24,281,1993 TYPE OF TEST : LD50 - Lethal dose, 50 percent kill ROUTE OF EXPOSURE : Intraperitoneal SPECIES OBSERVED : Rodent - mouse DOSE/DURATION : >2 gm/kg TOXIC EFFECTS : Lungs, Thorax, or Respiration - respiratory depression Liver - other changes Skin and Appendages - hair REFERENCE : IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 24,281,1993 TYPE OF TEST : LD50 - Lethal dose, 50 percent kill ROUTE OF EXPOSURE : Subcutaneous SPECIES OBSERVED : Rodent - mouse DOSE/DURATION : >2 gm/kg TOXIC EFFECTS : Skin and Appendages - dermatitis, other (after systemic exposure) REFERENCE : IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 24,281,1993 TYPE OF TEST : LD50 - Lethal dose, 50 percent kill ROUTE OF EXPOSURE : Subcutaneous SPECIES OBSERVED : Mammal - dog DOSE/DURATION : >2 gm/kg TOXIC EFFECTS : Skin and Appendages - dermatitis, other (after systemic exposure) REFERENCE : IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 24,281,1993 ** OTHER MULTIPLE DOSE TOXICITY DATA ** TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Subcutaneous SPECIES OBSERVED : Rodent - rat DOSE/DURATION : 5824 mg/kg/26W-I TOXIC EFFECTS : Blood - changes in serum composition (e.g. TP, bilirubin, cholesterol) Blood - changes in leukocyte (WBC) count Biochemical - Metabolism (Intermediary) - lipids including transport REFERENCE : IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 24,287,1993 TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Subcutaneous SPECIES OBSERVED : Mammal - dog DOSE/DURATION : 819 mg/kg/26W-I TOXIC EFFECTS : Endocrine - changes in thymus weight Biochemical - Metabolism (Intermediary) - other proteins Related to Chronic Data - changes in prostate weight REFERENCE : IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 24,287,1993 ** REPRODUCTIVE DATA ** TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Subcutaneous DOSE : 3300 mg/kg SEX/DURATION : female 7-17 day(s) after conception TOXIC EFFECTS : Reproductive - Specific Developmental Abnormalities - musculoskeletal system REFERENCE : IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 24,376,1993 TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Subcutaneous DOSE : 7800 mg/kg SEX/DURATION : female 17-21 day(s) after conception lactating female 21 day(s) post-birth TOXIC EFFECTS : Reproductive - Maternal Effects - other effects Reproductive - Effects on Newborn - growth statistics (e.g.%, reduced weight gain) Liver - changes in liver weight REFERENCE : IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 24,402,1993 TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Subcutaneous DOSE : 6500 mg/kg SEX/DURATION : female 6-18 day(s) after conception TOXIC EFFECTS : Reproductive - Effects on Embryo or Fetus - fetotoxicity (except death, e.g., stunted fetus) Reproductive - Effects on Embryo or Fetus - fetal death REFERENCE : IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 24,422,1993

安全

• RTECS号: FD3890000

制备

主要有四种合成路线和方法:其一是将5,6,7,8-四氢-2-萘酚与N-(6-甲氧基-2-吡啶基)-N-甲基硫代氨基甲酰氯缩合;其二是6-甲氧基-2-甲氨基吡啶与5,6,7,8-四氢-2-萘氧硫酰氯缩合;其三是将N-(6-甲氧基-2-吡啶基)-N-甲基二硫代氨基甲酸钠与2-(2,4-二硝基苯氧基)-5,6,7,8-四氢萘缩合;其四是将中间体N-(6-甲氧基-2-吡啶基)-N-甲基二硫代氨基甲酸-2,4-二硝基苯酯与5,6,7,8-四氢-2-萘酚缩合.推荐方法二的合成方法和路线.

(1).6-甲氧基-2-甲氨基吡啶的制备

在1L的不锈钢高压釜中加入2,6-二氯吡啶270g(1.82mol)、30%甲胺水溶液567g(含甲胺170g)(5.48mol),密闭高压釜,开搅拌升温至135~140 ºC反应3 ~4h,反应过程中釜内压力约为0.8~1.3Mpa.反应毕,冷至60 ºC,加入48%的溶液92ml,加热至100 ºC保持2h.以便除去过量的甲胺(可回收甲胺98%).再将其冷至50 ºC以下,将混合物转移至2L分液漏斗,用苯(270ml*3)提取,合并有机层,用饱和食盐水洗涤,无水Na2SO4干燥,过滤,滤液浓缩除苯,冷至50 ºC加入140ml无水甲醇,得6-氯-2-甲氨基吡啶的甲醇溶液.

在1L高压釜加入6-氯-2-甲氨基吡啶的甲醇溶液和新鲜制备的甲醇钠187g(3.46mol),密闭反应釜#搅拌升温至145~150ºC,保温反应4h(釜内压力大约为1MPa).反应毕,冷至50ºC,加水430ml,剩余物用氯仿(100ml×4)提取,合并氯仿层,减压蒸除氯仿,得油状物6-甲氧基-2-甲氨基吡啶213g,收率84%左右,无需进一步纯化,直接用于下步反应.

(2)5,6,7,8-四氢-2-萘氧硫酰氯的制备

在反应瓶中加入硫光气(纯度95%)12.7g(0.105mol),四氯化碳75ml,搅拌,冰水浴冷却到5 ºC

以下,于1.5~2h内滴加5,6,7,8-四氢-2-萘酚[14.8g(0.100mol)]的NaOH(2mol/L,50ml)溶液,控制滴加过程温度5~6 ºC,滴毕,继续搅拌反应5~15h(用HPLC跟踪,5,6,7,8-四氢-2-萘酚消失,则反

应达终点).反应毕,将反应混合液用水洗,分相,有机相减压蒸除溶剂,得粗品21.5g,进行真空蒸馏,收集106~112 ºC/39.996Pa馏分,得精制品5,6,7,8-四氢-2-萘氧硫酰氯 18g油状物,收率79.5%(中真空蒸馏收率84%).

(3)利拉萘酯的合成

在反应瓶中加粗制6-甲氧基-2-甲氨基吡啶 19.6g(折合0.128mol)、异丙醇250ml、水100ml、无水K2CO3 29.4g,

于室温下1~1.5h内滴加5,6,7,8-四氢-2-萘氧硫酰氯 41.9g(0.128mol)的异丙醇100ml的溶液.滴毕,继续在室温搅拌反应4~5h,当反应瓶产生多量结晶沉淀时反应终了(一般反应5~6h).加水500ml,充分搅拌则析出大量结晶,过滤,滤饼水洗至中性,抽干,干燥,得粗品50g,用无水乙醇200ml重结晶,过滤,滤饼用少量冰冷乙醇洗涤,抽干,干燥得利拉萘酯 31g,收率73.7%,mp97~99 ºC,纯度99.5~99.8%(HPLC法)。(注意：5,6,7,8-四氢-2-萘酚按文献[27,28]制备.)