(-)-二氢异可待因 | 795-38-0

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 吗啡烷
• 中文名称: (-)-二氢异可待因
• 英文名称: dihydro-isocodeine
• 英文别名: Dihydroisocodein；Dihydroisocodeine；(4R,4aR,7R,7aR,12bS)-9-methoxy-3-methyl-2,4,4a,5,6,7,7a,13-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-ol
• CAS: 795-38-0
• 化学式: C₁₈H₂₃NO₃
• 分子量: 301.386
• InChiKey: RBOXVHNMENFORY-KEMUOJQUSA-N

物化性质

• 熔点：
  199-200°
• 溶解度：
  可溶于氯仿（轻微，超声处理）、DMSO（轻微）、乙酸乙酯（轻微）

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  22
• 可旋转键数：
  1
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  41.9
• 氢给体数：
  1
• 氢受体数：
  4

ADMET

毒理性

• 在妊娠和哺乳期间的影响

哺乳期使用概要：哺乳期间母亲口服阿片类药物可能会导致婴儿昏睡和严重的中枢神经系统抑制。与可待因类似，药代遗传学可能在阿片类药物导致的中枢神经系统抑制程度中发挥作用。新生儿似乎对即使是很小的阿片类镇痛药剂量都非常敏感。在一项案例中，一名母亲服用二氢可待因为咳嗽治疗，可能导致其新生儿出现严重的呼吸抑制。一旦母亲的乳汁开始分泌，最好使用非阿片类镇痛药来控制疼痛，并将母亲的氢吗啡酮摄入量限制在2到3天内的低剂量，并密切监测婴儿。如果婴儿表现出过度昏睡（比平时更甚）、哺乳困难、呼吸问题或肢体无力，应立即联系医生。由于关于哺乳期间使用二氢可待因的已发表经验很少，可能更倾向于使用其他药物，特别是在哺乳新生儿或早产儿时。 ◉ 对哺乳婴儿的影响：一名妇女在分娩后第一天开始每天两次服用二氢可待因滴剂（5.28毫克）治疗咳嗽。一天后，她的哺乳婴儿难以唤醒，并且哺乳情况不佳。婴儿出现了心动过缓、低血糖和血氧饱和度为85%。在医院观察24小时后，所有症状都得到了解决。这些症状可能是由乳汁中的二氢可待因引起的。 ◉ 对泌乳和乳汁的影响：阿片类药物可以增加血清催乳素水平。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。

◉ Summary of Use during Lactation:Maternal use of oral narcotics during breastfeeding can cause infant drowsiness, and severe central nervous system depression. Like codeine, pharmacogenetics probably plays a role in the extent of central nervous system depression. Newborn infants seem to be particularly sensitive to the effects of even small dosages of narcotic analgesics. Dihydrocodeine possibly caused severe respiratory depression in one newborn infant whose mother was taking the drug for cough. Once the mother's milk comes in, it is best to provide pain control with a nonnarcotic analgesic and limit maternal intake of hydromorphone to 2 to 3 days at a low dosage with close infant monitoring. If the baby shows signs of increased sleepiness (more than usual), difficulty breastfeeding, breathing difficulties, or limpness, a physician should be contacted immediately. Because there is little published experience with dihydrocodeine during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. ◉ Effects in Breastfed Infants:A woman began taking dihydrocodeine drops for cough twice daily (5.28 mg) beginning on the first day postpartum. One day later, her breastfed infant was difficult to arouse and was not breastfeeding well. The infant had bradycardia, hypoglycemia, and an oxygen saturation of 85%. After 24 hours in the hospital, all symptoms resolved. The symptoms were possibly caused by dihydrocodeine in milk. ◉ Effects on Lactation and Breastmilk:Narcotics can increase serum prolactin. However, the prolactin level in a mother with established lactation may not affect her ability to breastfeed.

来源:Drugs and Lactation Database (LactMed)

反应信息

• 作为反应物：
  描述：

  (-)-二氢异可待因 在 戴斯-马丁氧化剂 作用下， 以 二氯甲烷 为溶剂， 反应 2.5h， 以83%的产率得到二氢可待因酮
  参考文献：
  名称：

  Total Synthesis of Dihydrocodeine and Hydrocodone via a Double Claisen Rearrangement and C-10/C-11 Closure Strategy

  摘要：

  Dihydrocodeine and hydrocodone were synthesized from bromobenzene in 16 and 17 transformations, respectively. The key steps involved the toluene dioxygenase-mediated dihydroxylation of bromobenzene by whole-cell fermentation with E. coli JM109(pDTG601A), Kazmaier-Claisen rearrangement of glycinate ester, Claisen rearrangement to set the C-13 quaternary center, and C-10-C-11 closure. Experimental procedures are provided for the key steps.

  DOI：

  10.1055/s-0032-1318114
• 作为产物：
  描述：

  二氢可待因酮 在 aluminum isopropoxide 、 甲苯 作用下， 生成 (-)-二氢异可待因
  参考文献：
  名称：

  REACTIONS OF ALKOXIDES WITH CERTAIN HYDROGENATED ALKALOIDS OF THE MORPHINE SERIES

  摘要：

  DOI：

  10.1021/jo01144a007

文献信息

• Enantioselective Synthesis of (−)-Dihydrocodeinone: A Short Formal Synthesis of (−)-Morphine¹^,
  作者：Kathlyn A. Parker、Demosthenes Fokas

  DOI：10.1021/jo0513008

  日期：2006.1.1

  applied in an asymmetric synthesis of (−)-dihydrocodeinone. A chiral cyclohexenol (R-32), from the CBS reduction of the enone, is the source of chirality. The first key step, tandem closure in which stereochemistry is controlled by geometric constraints, (−)-15b → (+)-16, was followed by an unprecedented reductive hydroamination, completing the synthesis of (−)-dihydroisocodeine ((−)-17) in 13 steps from

  吗啡生物碱的自由基环化方法已用于（-）-二氢可待因酮的不对称合成中。手性环己烯醇（R - 32），是通过CBS烯酮的还原得到的，是手性的来源。第一个关键步骤是串联闭合，其中立体化学受几何约束（-）- 15b →（+）- 16的控制，随后进行了空前的还原性加氢胺化反应，完成了（-）-二氢异可待因（（-）- 17）从市售材料中分13步进行。
• Biotransformations of morphine alkaloids by fungi: N-demethylations, oxidations, and reductions
  作者：Vigi Chaudhary、Hannes Leisch、Alena Moudra、Blake Allen、Vincenzo De Luca、D. Phillip Cox、Tomáš Hudlický

  DOI：10.1135/cccc2009025

  日期：——

  Morphine alkaloids and some of its derivatives (morphine, codeine, thebaine, oripavine, hydrocodone, and oxycodone) were subjected to fermentations with six fungal strains. The alkaloids were transformed to a variety of products via biological oxidations, reductions, and oxidative demethylations. The strain Cunninghamella echinulata proved to be the most effective for demethylations of all of the above compounds, except for morphine. The time profile of the conversion of 3-[¹⁴CH₃]thebaine to 3-[¹⁴CH₃]northebaine by C. echinulata cultures was also determined.

  吗啡生物碱及其一些衍生物（吗啡、可待因、鸦片碱、欧洲罂粟碱、羟考酮和羟麻醉酮）被用六株真菌进行发酵。这些生物碱通过生物氧化、还原和氧化去甲基反应转化为各种产物。其中，Cunninghamella echinulata 菌株被证明对上述所有化合物的去甲基反应最为有效，除了吗啡。还确定了C. echinulata 培养物中3-[¹⁴CH₃]鸦片碱转化为3-[¹⁴CH₃]诺鸦片碱的时间进程。
• [EN] COMPOSITIONS AND METHODS FOR THE TREATMENT OF PAIN AND DEPENDANCE DISORDERS<br/>[FR] COMPOSITIONS ET MÉTHODES DE TRAITEMENT DE LA DOULEUR ET DE TROUBLES DE LA DÉPENDANCE
  申请人：RIPPLE THERAPEUTICS CORP

  公开号：WO2021024039A1

  公开（公告）日：2021-02-11

  Provided herein are (e.g., controlled release) compositions for the treatment of acute or chronic diseases or disorders. Described herein are processable opioid conjugates. Also described herein are compositions and methods for the treatment of central nervous system (CNS) diseases or disorders including chronic pain (e.g., cancer pain), acute pain, opioid addiction, alcohol addiction, alcohol dependence, opioid-induced constipation, and narcotic depression. Said compositions and methods comprise opioid agonists and/or opioid antagonists, which demonstrate CNS activity and/or other desirable activities. Injection of said compositions subcutaneously or intraspinally provides therapeutic benefit to individuals suffering from CNS diseases or disorders

  本文提供了用于治疗急性或慢性疾病或障碍的（例如，控释）组合物。本文描述了可加工的阿片类结合物。本文还描述了用于治疗中枢神经系统（CNS）疾病或障碍的组合物和方法，包括慢性疼痛（例如，癌症疼痛）、急性疼痛、阿片类成瘾、酒精成瘾、酒精依赖、阿片类引起的便秘和麻醉性抑郁症。所述组合物和方法包括表现出CNS活性和/或其他理想活性的阿片类激动剂和/或阿片类拮抗剂。将所述组合物皮下或脊髓内注射可为患有中枢神经系统疾病或障碍的个体提供治疗益处。
• Studies on Morphine Alkaloids. II. Indolinocodeine. I. A New Skeletal Rearrangement of 14-Bromocodeine
  作者：Shigenobu Okuda、Sadao Yamaguchi、Kyosuke Tsuda

  DOI：10.1248/cpb.13.1092

  日期：——

  Neopine (III), isoneopine (XXII) and indolinocodeine (XVII) were isolated from the sodium borohydride reduction mixture of 14-bromocodeinone (I) or 14-bromocodeine (II). The structures of new compounds, XVII and XXII, were elucidated. Hydroindole structure is comprised in XVII instead of hydroisoquinoline skeleton in codeine. The reaction mechanisms for production of the above three compounds were also discussed.

  新化合物 Neopine (III)、isoneopine (XXII) 和 indolinocodeine (XVII) 是从 14-溴可待因酮 (I) 或 14-溴可待因 (II) 的氢化钠还原混合物中分离出来的。新化合物 XVII 和 XXII 的结构得到了阐明。XVII 中包含的氢吲哚结构取代了可待因中的氢异喹啉骨架。同时，还讨论了上述三种化合物的生成反应机制。
• Formal synthesis of (−)-morphine from d-glucal based on the cascade Claisen rearrangement
  作者：Hiroki Tanimoto、Ryosuke Saito、Noritaka Chida

  DOI：10.1016/j.tetlet.2007.11.037

  日期：2008.1

  The formal synthesis of (−)-morphine is described. The C-ring in morphine was prepared in an optically pure form from d-glucal using Ferrier’s carbocyclization reaction, and the vicinal tertiary and quaternary stereocenters in the C-ring were stereoselectively generated in a one-step reaction based on the cascade sequential Claisen rearrangement of an allylic vicinal diol derivative. After the one-step

  描述了（-）-吗啡的形式合成。吗啡中的C环是使用Ferrier的碳环化反应以光学纯净的形式由d-葡萄糖制备而来的，C环中的邻位三级和四级立体中心是根据级联顺序Claisen重排在一步反应中立体选择性生成的烯丙基邻二醇的衍生物。一步形成二苯并呋喃结构后，分子内的Friedel-Crafts型反应有效地构建了ABCE-菲呋喃骨架。引入甲苯磺酰胺功能，然后进行还原环化，得到（-）-二氢异可待因，这是已知的（-）-吗啡合成中间体。