1,2,3,6-四氢邻苯二甲酰亚胺 | 85-40-5

• 物质功能分类: 医药中间体
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异吲哚及其衍生物
• 中文名称: 1,2,3,6-四氢邻苯二甲酰亚胺
• 中文别名: 四氢邻苯二甲酰亚胺；顺式-1,2,3,6-四氢吩胺；顺式-1,2,3,6-四氢邻苯二甲酰亚胺；四氢酞酰亚胺；1,2,3,6-四氢邻苯二甲；四氢化邻苯二甲酰亚胺
• 英文名称: 1,2,3,6-tertahydrophthalimide
• 英文别名: 1,2,3,6-tetrahydrophthalimide；3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione；tetrahydrophthalimide；cis-1,2,3,6-tetrahydrophthalimide；4-cyclohexene-1,2-dicarboximide；3a,4,7,7a-tetrahydroisoindole-1,3-dione
• CAS: 85-40-5；27813-21-4
• 化学式: C₈H₉NO₂
• mdl: MFCD12974310
• 分子量: 151.165
• InChiKey: CIFFBTOJCKSRJY-UHFFFAOYSA-N

物化性质

• 熔点：
  129-133 °C(lit.)
• 沸点：
  273.17°C (rough estimate)
• 密度：
  1.2023 (rough estimate)
• 颜色/状态：
  Crystals from ethanol
• 溶解度：
  In water, 4.18X10+4 mg/L at 25 °C (est)
• 蒸汽压力：
  1.19X10-7 mm Hg at 25 °C (est)
• 分解：
  When heated to decomposition it emits toxic vapors of /Nitrogen oxides/
• 保留指数：
  1470

计算性质

• 辛醇/水分配系数(LogP)：
  0.2
• 重原子数：
  11
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  46.2
• 氢给体数：
  1
• 氢受体数：
  2

ADMET

代谢

... 五种可能的灭菌丹代谢物：1,2,3,6-四氢酞酰亚胺（THPI）、顺式-3-羟基-1,2,3,6-四氢酞酰亚胺（C3）、顺式-5-羟基-1,2,3,6-四氢酞酰亚胺（C5）、反式-3-羟基-1,2,3,6-四氢酞酰亚胺（T3）和反式-5-羟基-1,2,3,6-四氢酞酰亚胺（T5）...

... Five possible metabolites of captan: 1,2,3,6-tetrahydrophthalimide (THPI), cis-3-hydroxy-1,2,3,6-tetrahydrophthalimide (C3), cis-5hydroxy-1,2,3,6-tetrahydrophthalimide (C5), trans-3-hydroxy-1,2,3,6-tetrahrahydrophthalimide (T3), and trans-5-hydroxy-1,2,3,6-tetrahydrophthalimide (T5) ...

来源:Hazardous Substances Data Bank (HSDB)

代谢

四氢邻苯二甲酰亚胺（85405）（THPI）和2-硫代噻唑烷-4-羧酸（TTCA）作为职业暴露于克菌丹（133062）的生物监测潜在参数的研究。雄性Wistar大鼠口服给予400、814和1250 mg/kg，以及腹腔注射20、50和75 mg/kg。在代谢笼中收集48小时的尿液。从八名喷洒克菌丹的男性果农和六名未暴露的男性中收集尿液点样。毛细管气相色谱结合质谱或硫选择性检测适用于大鼠和人类尿液中THPI和TTCA的定性和定量测定。THPI和TTCA的累积尿排泄量约占克菌丹投递剂量的5%。在未暴露的受试者中，使用目前可用的技术无法检测到THPI或TTCA。职业暴露于克菌丹导致尿液中TTCA和THPI的排泄可被检测到。作者认为THPI和TTCA作为职业暴露于克菌丹的生物监测参数具有前景。

The use of tetrahydrophthalimide (85405) (THPI) and 2-thiothiazolidine-4-carboxylic-acid (TTCA) as potential parameters for the biological monitoring of occupational exposure to captan (133062). Male Wistar-rats were treated orally with 400, 814, and 1250 mg/kg and intraperitoneally with 20, 50 and 75mg/kg. Urine was collected for 48 hours in metabolism cages. Urine spot samples were collected from eight male fruit growers after spraying captan and from six nonexposed men. Capillary gas chromatography in combination with mass or sulfur selective detection was suitable for the qualitative and quantitative determination of THPI and TTCA in rat and human urine. The cumulative urinary excretion of THPI and TTCA accounted for about 5% of the delivered dose of captan. In nonexposed subjects, neither THPI nor TTCA could be detected using the currently available techniques. Occupational exposure to captan resulted in detectable excretion of both TTCA and THPI in urine. The authors conclude that THPI and TTCA have promise as parameters for the biological monitoring of occupational exposure to captan.

来源:Hazardous Substances Data Bank (HSDB)

代谢

向大鼠喂食54%的LD50剂量的克菌丹，在血液中产生了2种代谢物：四氢酞亚胺和四氢酞酸。

Feeding 54% LD50 dose of captan to rats produced 2 metabolites in the blood: tetrahydrophthalimide and tetrahydrophthalic acid.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 副作用

生殖毒素 - 对生殖系统有毒性的化学物质，包括对后代造成缺陷以及对男性或女性生殖功能的损害。生殖毒性包括发育效应。参见生殖毒性风险评估指南。

Reproductive Toxin - A chemical that is toxic to the reproductive system, including defects in the progeny and injury to male or female reproductive function. Reproductive toxicity includes developmental effects. See Guidelines for Reproductive Toxicity Risk Assessment.

来源:Haz-Map, Information on Hazardous Chemicals and Occupational Diseases

毒理性

• 解毒与急救

/SRP:/ 立即急救：将患者从接触物质中移开。确保已经进行了充分的去污处理。如果患者停止呼吸，开始人工呼吸，最好使用需求阀复苏器、袋阀面罩装置或口袋面罩，按训练操作。根据需要执行心肺复苏。立即用缓慢流动的水冲洗受污染的眼睛。不要催吐。如果发生呕吐，让患者前倾或置于左侧（如果可能的话，头部向下）以保持呼吸道畅通，防止吸入。保持患者安静，维持正常体温。获取医疗救助。 /二硫代氨基甲酸酯及其相关化合物/

/SRP:/ Immediate first aid: Remove patient from contact with the material. Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand-valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR as necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Dithiocarbamates and Related Compounds/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 基本治疗：建立专利气道（如有需要，使用口咽或鼻咽气道）。如有必要，进行吸痰。观察呼吸不足的迹象，如有必要，进行辅助通气。通过非重复呼吸面罩以10至15升/分钟的速度给予氧气。监测休克并视必要进行治疗……。预见并治疗癫痫发作……。对于眼睛污染，立即用水冲洗眼睛。在运输过程中，用0.9%的生理盐水（NS）连续冲洗每只眼睛……。不要使用催吐剂。对于摄入，如果患者能够吞咽、有强烈的干呕反射且不流口水，则用水冲洗口腔，并给予5毫升/千克，最多200毫升的水进行稀释。给予活性炭……。 /二硫代氨基甲酸盐及相关化合物/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Dithiocarbamates and Related Compounds/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 高级治疗：对于无意识或严重呼吸困难的病人，考虑进行口咽或鼻咽插管以控制气道。如果出现脑水肿的迹象，使用中度过度通气（每分钟20次呼吸）。监测心率和必要时治疗心律失常...开始静脉输注D5W /SRP: "保持开放"，最小流量/。如果出现低血容量的迹象，使用0.9%盐水（NS）或乳酸钠林格液（LR）。对于伴有低血容量迹象的低血压，谨慎给予液体。如果病人在正常血容量下出现低血压，考虑使用血管加压药。注意液体过载的迹象...用地西泮或劳拉西泮治疗癫痫...使用丙美卡因氢氯化物协助眼部冲洗... /二硫代氨基甲酸盐及其相关化合物/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or is in severe respiratory distress. Use moderate hyperventilation (rate of 20 respirations per minute) if signs of cerebral edema are present. Monitor cardiac rhythm and treat arrhythmias if necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Consider vasopressors if patient is hypotensive with a normal fluid volume. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Dithiocarbamates and Related Compounds/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 人类毒性摘录

/生物监测/研究了在荷兰果园使用灭菌剂（133062）的26名水果种植者通过皮肤和呼吸道接触灭菌剂对尿液中四氢酞酰亚胺（85405）（THPI）水平的影响。工人们使用拖拉机牵引的风送喷雾器来处理果园。个人空气样本用于评估杀虫剂颗粒浓度。使用皮肤垫来测量皮肤接触。使用高效液相色谱法分析皮肤垫和空气样本中的灭菌剂水平。收集尿液样本并通过化学离子化和质谱的气相色谱法分析THPI。总皮肤接触估计是基于皮肤垫接触外推到全身接触，并与特定身体部位的皮肤垫接触估计进行比较。皮肤接触最高的是额头，其次是手腕和脖子。平均喷雾持续时间为211分钟，标准差为84分钟。每次喷雾处理的灭菌剂量从1.7到22.5公斤不等。呼吸道接触灭菌剂并未发现对尿液中THPI有贡献；然而，从脚踝和脖子上的皮肤垫接触估计与尿液中THPI有明显的关联。其他因素，如拖拉机上使用驾驶室、混合和装载时戴手套以及使用橡胶靴，也与尿液中THPI高度相关。作者得出结论，基于实证研究的皮肤接触数据可以更好地与生物监测相联系，而不是基于总皮肤剂量的估计。

/BIOMONITORING/ The contribution of dermal and respiratory exposure to captan (133062) to levels of tetrahydrophthalimide (85405) (THPI) in urine was studied among 26 fruit growers applying captan in orchards in the Netherlands. The workers used an air blast sprayer pulled by a tractor to treat an orchard. Personal air samples were used to assess pesticide particle concentrations. Skin pads were used to measure dermal exposure. Skin pads and air samples were analyzed for captan levels using high performance liquid chromatography. Urine samples were collected and analyzed for THPI by gas chromatography with chemical ionization and mass spectrometry. Estimates of total dermal exposure were based on extrapolation to total body exposures from skin pad exposures and compared to estimates based on exposure of skin pads on specific body areas. The highest dermal exposure was on the forehead, followed by the wrists and neck. Average air spraying duration was 211 minutes with a standard deviation of 84 minutes. The amount of captan handled per spraying varied from 1.7 to 22.5 kilograms. Respiratory exposure to captan was not found to contribute to urinary THPI; however, a clear association with urinary THPI was found from the estimations of exposure on the skin pads from the ankles and neck. Other factors such as use of a cabin on the tractor, wearing of gloves during mixing and loading, and the use of rubber boots also correlated very well in THPI in the urine. The authors conclude that dermal exposure data can be better linked to biological monitoring based on empirical findings as gathered in a pilot study rather than on estimates of total skin dose.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

给大鼠口服TPI，剂量为230毫克/千克，并观察(14)C。治疗后48小时，75%的(14)C通过尿液排出，15%通过粪便排出。

TPI given orally to rats in dosage of 230 mg/kg & (14)C observed. 75% (14)C excreted in urine and 15% in feces 48 hr after treatment.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  Xn
• 危险类别码：
  R20/21
• WGK Germany：
  2
• RTECS号：
  GW4635000
• 海关编码：
  2925190090
• 安全说明：
  S61
• 包装等级：
  II
• 危险类别：
  8
• 危险品运输编号：
  UN 2922 8/PG 2
• 危险性防范说明：
  P280
• 危险性描述：
  H302,H317

制备方法与用途

化学性质：白色结晶性粉末。

生产方法：将顺丁烯二酸酐加入反应釜中，加热至完全熔融后，在搅拌下缓慢加入溶剂苯，继续搅拌并升温至100～110℃。随后通入C4馏分或丁二烯进行双烯加成反应。反应完成后，将溶剂苯蒸出，并通过冷凝器冷却回收循环使用。最后，经过抽滤和干燥处理，即可得到成品。顺丁烯二酸酐的转化率可达100%。

反应信息

• 作为反应物：
  描述：

  1,2,3,6-四氢邻苯二甲酰亚胺 在 三氯异氰尿酸 、 sodium hydroxide 作用下， 以 水 为溶剂， 反应 1.5h， 以69%的产率得到cis-2-aminocyclohex-4-enecarboxylic acid
  参考文献：
  名称：

  三卤代异氰脲酸介导的羧酰胺和环状酰亚胺的便捷霍夫曼反应

  摘要：

  通过与三氯或三溴异氰脲酸和三溴异氰脲酸反应，已开发出一种在单个容器中简单、有效且经济适用的方法，用于将芳香族和脂肪族羧酰胺转化为少一个碳原子的伯胺（霍夫曼反应），产率为 38-89%。氢氧化钠的乙腈水溶液。在相同的反应条件下，环状酰亚胺产生氨基酸（69-83%）。三卤代异氰脲酸的作用是原位生成N-卤代酰胺，这是霍夫曼反应的关键中间体。该方法的可扩展性通过邻苯二甲酰亚胺以 77% 的产率转化为邻氨基苯甲酸的多克级规模得到证明。

  DOI：

  10.1016/j.tetlet.2021.153422
• 作为产物：
  描述：

  alkaline earth salt of/the/ methylsulfuric acid 在 氨 作用下， 以74%的产率得到1,2,3,6-四氢邻苯二甲酰亚胺
  参考文献：
  名称：

  受阻α-酰基亚胺离子的烯烃环化

  摘要：

  立体控制的NaBH 4 / H⊕-还原3,4-顺式-双取代的N-烯基酰亚胺1-5导致仲羟基内酰胺。叔羟基内酰胺是通过将MeMgCl加到酰亚胺2和4中形成的。羟基内酰胺的HCOOH环化通过立体选择性α-酰基亚胺闭环提供多环哌啶。伴随的同步和逐步环化途径在叔α-酰基亚胺离子反平面添加到Me取代的烯烃8c和11c中起作用。

  DOI：

  10.1016/0040-4020(82)85067-9