2-[(二甲基氨基)甲基]-1-(3-甲氧基苯基)环己烷-1-醇 | 2914-77-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 中文名称: 2-[(二甲基氨基)甲基]-1-(3-甲氧基苯基)环己烷-1-醇
• 英文名称: tramadol
• 英文别名: 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol；(1RS,2RS)-2-dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohexanol；2-dimethylaminomethyl-1-(3-methoxyphenyl)cyclohexan-1-ol；Ultram；2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexan-1-ol
• CAS: 2914-77-4
• 化学式: C₁₆H₂₅NO₂
• 分子量: 263.38
• InChiKey: TVYLLZQTGLZFBW-UHFFFAOYSA-N

物化性质

• 沸点：
  406.62°C (rough estimate)
• 密度：
  0.9903 (rough estimate)
• 保留指数：
  1945

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  19
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  32.7
• 氢给体数：
  1
• 氢受体数：
  3

ADMET

毒理性

• 在妊娠和哺乳期间的影响

哺乳期使用概述：曲马多的排泄进入乳汁是低的，其活性代谢物O-去甲基曲马多的排泄量甚至更低。在常规的母体剂量下，排入乳汁的量远少于给予新生儿镇痛的剂量。在哺乳的新生儿中进行的研究没有发现可归因于曲马多的不良反应。然而，一名对曲马多上瘾的妇女的8个月大哺乳婴儿死亡，尽管单独的哺乳暴露可能并不足以导致死亡。尽管曲马多在常规母体剂量下不太可能对哺乳婴儿产生不利影响，但美国食品药品监督管理局和制造商建议在哺乳期间不要使用曲马多。如果使用曲马多，监测婴儿是否出现过度嗜睡（比平时更多）、哺乳困难、呼吸困难或无力，如果出现这些症状，请立即联系医生。 ◉ 对哺乳婴儿的影响：对75名母亲在剖宫产后服用每6小时100毫克曲马多并哺乳的婴儿与75名同龄的匹配婴儿进行了比较。49%服用曲马多的母亲和所有对照组的母亲都在服用其他阿片类药物（主要是奥昔康），分别有61%和58%也在服用非甾体抗炎药（主要是双氯芬酸）。儿科医生检查发现两组在使用神经学和适应能力评分方面没有差异。 一名8个月大的婴儿因意识改变、低氧血症、低血压和低血细胞比容被带到埃及的一家急诊科。在ICU中，婴儿的尿检对曲马多呈阳性，对大麻和阿片类药物呈阴性。两剂纳洛酮改善了她的血气，两天后她的精神状态有所改善。婴儿的父母表示他们对曲马多上瘾，母亲正在哺乳婴儿。婴儿在入院3天后出院。36小时后，婴儿再次出现在急诊科，出现心肺骤停，格拉斯哥昏迷量表评分为4，出现全身性强直-阵挛性癫痫。婴儿在入院3天后因心脏骤停而死亡。母亲表示，在从医院初次出院后，她曾哺乳过婴儿。作者推测，母亲或婴儿可能是超快CYP2D6代谢者，导致活性代谢物水平升高，因为这种变异在地中海血统的人中相对常见。然而，既没有进行基因测试，也没有测量乳汁或婴儿中的曲马多水平。这个案例不能肯定地归因于单纯的哺乳暴露，因为8个月大时症状的突然发作似乎不太可能。更有可能的是，婴儿直接摄入了曲马多。 一家日本医院为产后母亲提供了一种含有曲马多37.5毫克和对乙酰氨基酚325毫克的复合片剂，如果她们要求使用止痛药，则每6小时服用一次，连续服用3天。一项回顾性分析发现，在148名接受该药物的母亲中，所有婴儿都进行了哺乳，没有一个婴儿出现不良反应，如嗜睡、哺乳困难或呼吸问题。相对较低的剂量和短期的治疗可能降低了不良反应的风险。 一项对过去12个月内哺乳的母亲进行的横断面调查确定了142名在哺乳期间服用过一种或多种药物的母亲。其中一名服用曲马多的母亲报告说，她的婴儿出现了嗜睡，这导致她改变了哺乳的时间。 ◉ 对泌乳和乳汁的影响：曲马多可以提高血清催乳素水平。然而，对于已经建立泌乳的母亲来说，催乳素水平可能不会影响她的哺乳能力。 一项随机研究比较了曲马多和萘普生用于剖宫产后疼痛的治疗。患者按照固定的时间表或按需服用药物。各组之间的哺乳率没有差异。 在中国的一项研究中，预定进行剖宫产的女性被随机分配接受静脉患者控制镇痛，使用 sufentanil 或曲马多。曲马多组的产后催乳素水平（348 mcg/L）高于 sufentanil 组（314 mcg/L）。曲马多组的泌乳开始时间（21.4小时）早于 sufentanil 组（25.1小时）。这两个差异在统计学上都是显著的。注射用曲马多在美国不可用。 在塞尔维亚一家医院对接近足月进行剖宫产的女性进行的非随机、非盲法研究中，比较了全身麻醉（n = 284）和脊髓或硬脊膜外麻醉（n = 249）。脊髓麻醉包括12 mg重比重布比卡因和0.01 mg芬太尼；硬脊膜外麻醉包括0.5%等比重布比卡因（每10 cm高度0.5 mg）和0.05 mg芬太尼。全身麻醉包括2.3 mg/kg丙泊酚和1.5 mg/kg琥珀胆碱用于诱导和插管，随后使用麻醉气体混合物和氧气。据报道，在分娩前后，一氧化氮（可能是氧化亚氮）在气体中的比例分别为50%和67%。在某些情况下还使用了七氟醚。在分娩和脐带结扎后，母亲静脉注射

◉ Summary of Use during Lactation:The excretion of tramadol into milk is low and even lower amounts of the active metabolite, O-desmethyltramadol, are excreted. With usual maternal dosage, the amount excreted into breastmilk is much less than the dose that has been given to newborn infants for analgesia. Studies in breastfed newborn infants found no adverse effects attributable to tramadol. However, a death occurred in the 8-month-old breastfed infant of a woman addicted to tramadol, although breastfeeding exposure alone might not have accounted for the death. Although tramadol is unlikely to adversely affect nursing infants with usual maternal dosages, the U.S. Food and Drug Administration and the manufacturer recommend against the use of tramadol during breastfeeding. If tramadol is used, monitor infants for increased sleepiness (more than usual), difficulty breastfeeding, breathing difficulties or limpness, and contact a physician immediately if any of these occur. ◉ Effects in Breastfed Infants:Seventy-five breastfed infants whose mothers were breastfeeding and taking tramadol 100 mg every 6 hours following a cesarean section were compared to 75 matched infants at 2 to 4 days of age. Forty-nine percent of the mothers taking tramadol and all of the control mothers were taking other opiates (primarily oxycodone) and 61% of and 58%, respectively, also were taking a nonsteroidal antiinflammatory agent (primarily diclofenac). Examination by a pediatrician revealed no difference between the groups using the Neurologic and Adaptive Capacity Score. An 8-month-old infant was brought to an emergency department (ED) in Egypt with altered mental status, hypoxia, hypotension and a low hematocrit. In the ICU, the infant had a positive urine drug screen for tramadol and a negative urine test for cannabinoids and opiates. Two doses of naloxone improved her blood gases and 2 days later her mental status had improved. The infant’s parents stated that they were addicted to tramadol and the mother was breastfeeding the infant. The infant was discharged on day 3 after admission. Thirty-six hours later, the infant again presented to the ED with cardiopulmonary arrest, with a 4 on the Glasgow coma scale and generalized clonic-tonic seizures. The infant died from cardiac arrest 3 days after admission. The mother stated that she had breastfed the infant after the initial discharge from the hospital. The author speculates that mother or infant might be an ultra-rapid CYP2D6 metabolizer leading to high levels of the active metabolite, because this variant is relatively prevalent in those of Mediterranean origin. However, neither genetic testing nor measurement of tramadol in milk or the infant were performed. This case cannot definitely be attributed to breastmilk exposure alone, because the sudden onset of the symptoms at 8-months of age seems implausible. It is somewhat more likely that the baby ingested the tramadol directly. A hospital in Japan provided postpartum mothers with a combination tablet containing tramadol 37.5 mg and acetaminophen 325 mg every 6 hours for 3 days if they requested a pain medication. A retrospective analysis found that of 148 mothers who received the drug, all infants were breastfed and none of the infants had an adverse reaction, such as drowsiness, difficulty breastfeeding or breathing problems. The relatively low dose and short duration of therapy may have reduced the risk of adverse reactions. A cross-sectional survey of mothers who had breastfed their infant in the past 12 months identified 142 mothers who had taken one or more medications while nursing. One of the mothers who was taking tramadol reported that her infant developed drowsiness, which caused her to change the time of feeding. ◉ Effects on Lactation and Breastmilk:Tramadol can increase serum prolactin. However, the prolactin level in a mother with established lactation may not affect her ability to breastfeed. A randomized study compared tramadol and naproxen for post-cesarean section pain. Patients received the drugs either on a fixed schedule or as needed. No difference in breastfeeding rates were seen among the groups. In a study in China, women with a scheduled cesarean section were randomized to receive intravenous patient-controlled analgesia with either sufentanil or tramadol. Postpartum prolactin levels were higher in the tramadol group (348 mcg/L) than in the sufentanil group (314 mcg/L). The onset of lactation was sooner in the tramadol group (21.4 hours) than in the sufentanil group (25.1 hours). Both of these difference were statistically significant. Injectable tramadol is not available in the United States. A nonrandomized, nonblinded study in a Serbian hospital of women near term who underwent cesarean section compared general anesthesia (n = 284) to spinal or epidural anesthesia (n = 249). Spinal anesthesia consisted of hyperbaric bupivacaine 12 mg and fentanyl 0.01 mg; epidural anesthesia consisted of isobaric bupivacaine 0.5% (0.5 mg per 10 cm height) and fentanyl 0.05 mg. General anesthesia consisted of propofol 2.3 mg/kg and succinylcholine 1.5 mg/kg for induction and intubation, followed by an anesthetic gas mixture and oxygen. Reportedly, nitric oxide (possibly nitrous oxide) was 50% of the gas before delivery and 67% after delivery. Sevoflurane was also used in some cases. After delivery and cord clamping, mothers received fentanyl 3 mcg/kg and rocuronium 0.5 mg/kg intravenously for placental delivery. After surgery, neuromuscular block reversal was performed with neostigmine and atropine. All patients received 1 mg/kg of diclofenac every 8 h for 24 hours after delivery and 98% of general anesthesia patients also received 100 mg of tramadol and 78.5% received acetaminophen 1 gram. No regional anesthesia patients received tramadol or acetaminophen. Patients receiving one of the regional anesthetic protocols established lactation sooner (56% and 29% after 18 and 24 hours, respectively), while 86% of women receiving general anesthesia did not establish lactation until 36 to 48 hours after surgery. A randomized, double-blind study was performed in pregnant women scheduled for cesarean section under spinal anesthesia with bupivacaine and fentanyl. Patients received either 100 mg diclofenac (n = 100), 100 mg tramadol (n = 100) or placebo (glycerin suppositories) n = 100, all given as rectal suppositories every 8 hours for the first 24 hours after surgery. The time to initiate breastfeeding was significantly shorter among mothers who received tramadol than a placebo, 1.7 vs 4.1 hours with breastfeeding support and 3.7 vs 6.2 hours without support. Diclofenac was slightly more effective than tramadol among mothers who received no support (3.5 vs 3.7 hours).

来源:Drugs and Lactation Database (LactMed)

安全信息

• 海关编码：
  2922509090

反应信息

• 作为反应物：
  描述：

  2-[(二甲基氨基)甲基]-1-(3-甲氧基苯基)环己烷-1-醇 在 potassium hydroxide 作用下， 以 乙二醇 为溶剂， 反应 28.0h， 生成 去甲苯胺环醇/(-)-O-去甲基曲马多
  参考文献：
  名称：

  [EN] A PROCESS FOR PREPARATION OF O-DESMETHYLTRAMADOL AND SALTS THEREOF
  [FR] PROCÉDÉ DE PRÉPARATION DE D'O-DESMÉTHYLTRAMADOL ET DE SELS DE CELUI-CI

  摘要：

  本发明涉及一种通过钾氢氧化物介导的相转移条件下的曲马多去甲基化制备O-去甲基曲马多的方法。

  公开号：

  WO2019053494A1
• 作为产物：
  描述：

  (+/-)-tramadol hydrochloride 在 SR-30D polymer 作用下， 以 水 为溶剂， 反应 4.0h， 生成 2-[(二甲基氨基)甲基]-1-(3-甲氧基苯基)环己烷-1-醇
  参考文献：
  名称：

  Modified Release Formulations Containing Drug - Ion Exchange Resin Complexes

  摘要：

  提供一种含有涂层药物-离子交换树脂复合物的水性悬浮液，包括由苯丙胺与药用可接受离子交换树脂复合成的核和未涂层的苯丙胺-离子交换树脂复合物。涂层的苯丙胺-离子交换树脂复合物与聚合物混合形成基质。描述了制备涂层复合物和液体悬浮液的方法。

  公开号：

  US20150024059A1
• 作为试剂：
  描述：

  (+/-)-tramadol hydrochloride 、 在 2-[(二甲基氨基)甲基]-1-(3-甲氧基苯基)环己烷-1-醇 作用下， 以 水 为溶剂， 反应 16.08h， 生成 2-[(二甲基氨基)甲基]-1-(3-甲氧基苯基)环己烷-1-醇
  参考文献：
  名称：

  EXTENDED RELEASE ORAL ACETAMINOPHEN/TRAMADOL DOSAGE FORM

  摘要：

  一种口服延时释放剂型的乙酰氨基酚和曲马多，该剂型包括乙酰氨基酚与带有阴离子聚合物形成的曲马多复合物的组合物。曲马多复合物提供曲马多的持续释放，以实现乙酰氨基酚和曲马多的同步释放。

  公开号：

  US20100104638A1

文献信息

• Development of Highly Efficient Resolutions of Racemic Tramadol Using Mandelic Acid
  作者：Graham R. Evans、Paloma Díaz Fernández、James A. Henshilwood、Steve Lloyd、Chris Nicklin

  DOI：10.1021/op0255276

  日期：2002.9.1

  Two methods for the resolution of tramadol are described. One uses the active pharmaceutical ingredient (API), tramadol hydrochloride as input material. The other utilises the crude free base obtained from the Grignard reaction on tramadol Mannich base. Both resolutions use mandelic acid; the cost and process implications of each approach are discussed.

  描述了两种解决曲马多的方法。一种使用活性药物成分 (API)，盐酸曲马多作为输入材料。另一种利用从曲马多曼尼希碱上的格氏反应获得的粗游离碱。两种决议都使用扁桃酸；讨论了每种方法的成本和过程影响。
• Novel Therapeutic Compounds
  申请人：SESHA Ramesh

  公开号：US20120046272A1

  公开（公告）日：2012-02-23

  The present invention describes a series of therapeutically active compounds of formula I, X—Y—Z  (I) that are useful for treating a disorder in a mammal. In the formula I, X and Z, which may be same or different, are independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group or substituted or unsubstituted heterocyclylalkyl; and Y is a linker selected from —O—, —S—, —NH—, —(CH 2 ) n —, —CO—, —CONR a —, —NR a CO—, —NR a COO—, —COO—, —CONR a CO—, —CONR a COO— and —COOCOO—. The compounds are useful to treat neurodegenerative disorders, depression, Alzheimer's disease, cognitive disorders, motor disorders, Parkinson's disease, drug addiction, behavioral disorders, inflammatory disorders, stomach disorders, cancers, acute pain, chronic pain and recurrent pain.

  本发明描述了一系列具有治疗活性的化合物，其化学式为I，X—Y—Z  (I)，适用于治疗哺乳动物中的某种疾病。在化学式I中，X和Z，可以相同也可以不同，独立地选择自取代或未取代的烷基、取代或未取代的烯基、取代或未取代的环烷基、取代或未取代的环烷基烷基、取代或未取代的芳基、取代或未取代的芳基烷基、取代或未取代的杂芳基、取代或未取代的杂芳基烷基、取代或未取代的杂环基团或取代或未取代的杂环烷基；Y是从—O—、—S—、—NH—、—(CH2)n—、—CO—、—CONRa—、—NRaCO—、—NRaCOO—、—COO—、—CONRaCO—、—CONRaCOO—和—COOCOO—中选择的连接基团。这些化合物适用于治疗神经退行性疾病、抑郁症、阿尔茨海默病、认知障碍、运动障碍、帕金森病、药物成瘾、行为障碍、炎症性疾病、胃病、癌症、急性疼痛、慢性疼痛和复发性疼痛。
• [EN] SALTS OF TRAMADOL AND DIFLUNISAL AND THEIR CRYSTAL FORM IN THE TREATMENT OF PAIN<br/>[FR] SELS DE TRAMADOL ET DIFLUNISAL ET LEUR FORME CRISTALLINE DANS LE TRAITEMENT DE LA DOULEUR
  申请人：ESTEVE LABOR DR

  公开号：WO2010145800A1

  公开（公告）日：2010-12-23

  The present invention relates to tramadol-diflunisal salts, processes for preparation of the same and their uses as medicaments or in pharmaceutical formulations, more particularly for the treatment of pain.

  本发明涉及曲马多-地氟尼索盐，其制备方法以及其作为药物或在制药配方中的用途，更具体地用于治疗疼痛。
• Efficient chemoselective addition of Grignard reagents to carbonyl compounds in 2-methyltetrahydrofuran
  作者：Weihui Zhong、Yaotiao Wu、Xingxian Zhang

  DOI：10.3184/030823409x460939

  日期：2009.6

  Compared with tetrahydrofuran (THF) as a solvent for the addition reactions between Grignard reagents and carbonyl compounds 2-methyltetrahydrofuran affords the corresponding adducts in higher yields with higher chemoselectivities. Moreover, 2-methyltetrahydrofuran can be readily recycled and reused, which lowers the cost of the process and makes the reaction greener.

  与作为格氏试剂和羰基化合物之间加成反应的溶剂的四氢呋喃 (THF) 相比，2-甲基四氢呋喃以更高的收率和更高的化学选择性提供相应的加合物。此外，2-甲基四氢呋喃易于回收再利用，降低了工艺成本，使反应更环保。
• 一种盐酸曲马多杂质C的制备方法
  申请人：深圳市祥根生物医药有限公司

  公开号：CN114292199A

  公开（公告）日：2022-04-08

  本发明公开了一种盐酸曲马多杂质C的制备方法，属于药物合成领域。该方法通过间溴苯甲醚在正丁基锂拔溴作用下与2‑（N,N‑二甲基氨基甲基）环己酮反应，再经过对甲苯磺酸选择性的脱水，得到该杂质，本发明提供的合成方法操作简单，经济高效，缩短了制备周期，可为曲马多的质量研究提供充足测试样品，具有重要的应用价值。