l-methylphenidate | 20748-11-2

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: l-methylphenidate
• 英文别名: l-threo-methylphenidate；threo-(-)-Methylphenidate；methyl (2S)-2-phenyl-2-[(2S)-piperidin-2-yl]acetate
• CAS: 20748-11-2
• 化学式: C₁₄H₁₉NO₂
• 分子量: 233.31
• InChiKey: DUGOZIWVEXMGBE-STQMWFEESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.2
• 重原子数：
  17
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  38.3
• 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

哺乳期使用总结：在用于医疗指征的剂量下，有限的证据表明，甲基phenidate在乳汁中的水平非常低，在婴儿血清中检测不到。如果母亲需要服用甲基phenidate，这不是停止哺乳的理由。高剂量的甲基phenidate可能会干扰乳汁生产，尤其是在哺乳期未建立良好的妇女中。 对哺乳婴儿的影响：8名婴儿中有7名，其母亲服用右旋苯丙胺（平均剂量每日25毫克）或甲基phenidate（平均剂量每日52毫克）接受了临床评估。这些婴儿没有药物相关的不良反应，并且按照他们的年龄（平均4.4个月）正常发育。 一名6.4个月大的婴儿主要接受一名每周5天服用甲基phenidate 40毫克两次的母亲的哺乳，持续了5.5周。母亲报告说，婴儿的睡眠、饮食和体重增长正常。这个病人可能是上述同一作者报告中的其中一人。 一名母亲在分娩后5周开始服用舍曲林50毫克/日和甲基phenidate，其婴儿正在哺乳（程度未说明）。剂量从10毫克/日起，使用即释产品，逐渐增加到72毫克/日的缓释产品。14周时，婴儿发育正常，没有喂养困难。6个月和1岁时进行的检查发现孩子没有发育问题。 一名哺乳母亲因ADHD、广泛性焦虑症、边缘型人格障碍和抑郁症服用缓释甲基phenidate（Concerta）36毫克/日和度洛西汀90毫克/日。她部分哺乳（量未说明）约1个月。6个月时，婴儿的发育被认为是正常的，除了由先天性肺气道畸形引起的复发性肺炎。 一名患有发作性睡病的妇女在怀孕期间停用了甲基phenidate，但在怀孕和产后期间继续服用舍曲林100毫克和孕妇维生素。她挤出母乳进行瓶喂，婴儿只喝母乳直到6个月大，7个月大时断奶。当她的小儿13周大时，她恢复了甲基phenidate 10毫克，每日三次。婴儿在6个月大时达到了所有的成长里程碑。 对哺乳和母乳的影响：甲基phenidate降低了血清催乳素，但截至修订日期，尚未找到关于甲基phenidate对乳汁产生影响的的研究。在已建立哺乳的母亲中，催乳素水平可能不会影响她的哺乳能力。 一名15岁女孩已经服用甲基phenidate 54毫克/日的渗透释放片（OROS）2年。开始服用舍曲林50毫克/日治疗抑郁症，并增加到100毫克/日，同时服用0.5毫克/日的氯丙嗪。治疗12周后，学校注意力不集中和头痛促使从OROS产品改为一种改良释放甲基phenidate产品（品牌未指定），剂量为30毫克/日，然后增加到50毫克/日。剂量增加三天后，女孩双侧乳房自发分泌乳汁，随后血清催乳素升高至67.7 mcg/L。停用甲基phenidate和氯丙嗪，但继续使用舍曲林。一周后，乳汁过多完全解决。药物停用15天后，女孩的催乳素水平恢复正常，为19.4 mcg/L。

◉ Summary of Use during Lactation:In dosages prescribed for medical indications, limited evidence indicates that methylphenidate levels in milk are very low and not detectable in infant serum. If methylphenidate is required by the mother, it is not a reason to discontinue breastfeeding. It is possible that large dosages of methylphenidate might interfere with milk production, especially in women whose lactation is not well established. ◉ Effects in Breastfed Infants:Seven of 8 infants, whose mothers were taking either dextroamphetamine (average dosage 25 mg daily) or methylphenidate (average dosage 52 mg daily) were clinically evaluated. The infants had no drug-related adverse reactions and were developing normally for their ages which averaged 4.4 months. One 6.4-month-old infant was mostly breastfed by a mother who had been taking methylphenidate 40 mg twice daily 5 days/week for 5.5 weeks. The mother reported that the infant was sleeping, eating and gaining weight normally. This patient might have been one of those in the report above by the same authors. An infant was being breastfed (extent not stated) by a mother who began taking sertraline 50 mg daily and methylphenidate after 5 weeks postpartum. Dosage was started at 10 mg daily with an immediate-release product and gradually increased to 72 mg daily of an extended-release product. At 14 weeks of age, the infant was developing normally with no feeding difficulties. Examinations at 6 months and 1 year of age found no developmental problems in the child. A nursing mother was taking extended-release methylphenidate (Concerta) 36 mg daily and duloxetine 90 mg daily for ADHD, generalized anxiety disorder, borderline personality disorder, and depression. She partially (amount not stated) breastfed her infant for about 1 month. At 6 months of age, the infant's development was considered to be normal, except for recurrent pneumonia caused by congenital pulmonary airway malformation. A woman with narcolepsy discontinued methylphenidate during pregnancy, but continued sertraline 100 mg and a prenatal vitamin daily during pregnancy and postpartum. She expressed breastmilk for bottle feeding and her infant was fed breastmilk exclusively until 6 months of age, and was weaned at 7 months. When her infant was 13 weeks old, she resumed methylphenidate 10 mg three times daily. The infant met all growth milestones through 6 months of age. ◉ Effects on Lactation and Breastmilk:Methylphenidate reduces serum prolactin, but no studies have been located as of the revision date on the effect of methylphenidate on milk production. The maternal prolactin level in a mother with established lactation may not affect her ability to breastfeed. A 15-year-old girl had been receiving methylphenidate 54 mg daily in an osmotic release tablet (OROS) for 2 years. Sertraline was started for depression at 50 mg daily and increased to 100 mg daily along with haloperidol 0.5 mg daily. After 12 weeks of therapy, inattentiveness at school and headaches prompted a change from the OROS product to a modified-release methylphenidate product (brand not specified) at 30 mg daily, then increasing to 50 mg daily. Three days after the increase in dosage, the girl had spontaneous milk flow from both breasts and subsequently had an elevated serum prolactin of 67.7 mcg/L. Methylphenidate and haloperidol were discontinued, but sertraline was continued. One week later, galactorrhea resolved completely. Fifteen days after drug discontinuation, the girl's prolactin level was in the normal range at 19.4 mcg/L.

来源:Drugs and Lactation Database (LactMed)

反应信息

• 作为反应物：
  描述：

  l-methylphenidate 在 盐酸 作用下， 以 乙醚 为溶剂， 以100%的产率得到(2S,2'S)-(-)-threo-methylphenidate hydrochloride
  参考文献：
  名称：

  对映体纯的叠氮rid中间体与苯基溴化镁的开环反应，不对称合成（S，S）-哌醋甲酯盐酸盐

  摘要：

  在我们合成（S，S）-哌醋甲酯盐酸盐的合成策略中，关键步骤是采用原位形成的叠氮鎓中间体进行开环。用甲磺酸酐处理α-羟基-β-氨基酯可促进叠氮鎓的形成，随后添加苯基溴化镁可产生立体特异性和区域选择性的开环，从而得到相应的α-苯基-β-氨基酯，且其总体结构得以保留。随后的官能团处理，然后进行N-脱保护和环化反应，在目标化合物中生成哌啶环，然后进行酯交换反应，得到（S，S）从1，5-戊二醇仅需8步即可得到）-哌醋甲酯盐酸盐，总收率为15％。这些结果证明了对映体纯的rid啶鎓中间体作为合成立体定义的C-C键的底物的合成效用，并且至关重要的是，该方法提供了通过烯醇化烷基化化学方法无法获得的α-取代-β-氨基酯底物的途径。本文报道的策略可能适用于哌醋甲酯以及差异取代的类似物的所有可能的立体异构体。

  DOI：

  10.1016/j.tet.2019.130713
• 作为产物：
  描述：

  盐酸右哌甲酯 生成 l-methylphenidate
  参考文献：
  名称：

  An efficient large scale resolution of (±)-threo-methylphenidate hydrochloride (Ritalin® hydrochloride)

  摘要：

  An efficient and large scale preparation of (2R,2'R)-(+)-threo-methylphenidate hydrochloride (3) by the resolution of (+/-)-threo-methylphenidate hydrochloride (1) salt with O,O'-dibenzoyl-D-(+)-tartaric acid in the presence of 4-methylmorpholine is described. (C) 1999 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0957-4166(99)00335-3

文献信息

• Method to separate stereoisomers
  申请人：Krsek R. George

  公开号：US20050171155A1

  公开（公告）日：2005-08-04

  A method to resolve the stereoisomers of an optically active compound comprising an amine moiety. The method provides a mixture comprising two stereoisomers of a compound comprising a amine moiety. The method supplies l-fenchyloxyacetic acid, treats the mixture of stereoisomers with that l-fenchyloxyacetic acid, and collects one of those two stereoisomers having greater than a 99 percent enantiomeric excess.

  一种用于解决含有胺基团的光学活性化合物的立体异构体的方法。该方法提供了一个包含一种胺基团的化合物的两个立体异构体的混合物。该方法供应l-芬基氧乙酸，用该l-芬基氧乙酸处理立体异构体的混合物，并收集其中一个具有大于99%对映体过量的立体异构体。
• New Strategic Reactions for Organic Synthesis:  Catalytic Asymmetric C−H Activation α to Nitrogen as a Surrogate for the Mannich Reaction
  作者：Huw M. L. Davies、Chandrasekar Venkataramani、Tore Hansen、Darrin W. Hopper

  DOI：10.1021/ja0290072

  日期：2003.5.1

  activation reactions of methyl aryldiazoacetates are readily induced by the rhodium prolinate catalyst Rh(2)(S-DOSP)(4) (1) or the bridged prolinate catalysts Rh(2)(S-biDOSP)(2) (2a) and Rh(2)(S-biTISP)(2) (2b). The C-H activation of N-Boc-protected cyclic amines demonstrates that the donor/acceptor-substituted carbenoids display remarkable chemoselectivity, which allows for highly regioselective,

  重氮乙酸甲酯的不对称 CH 活化反应很容易被脯氨酸铑催化剂 Rh(2)(S-DOSP)(4) (1) 或桥连脯氨酸催化剂 Rh(2)(S-biDOSP)(2) (2a) 诱导) 和 Rh(2)(S-biTISP)(2) (2b)。N-Boc 保护的环胺的 CH 活化表明供体/受体取代的类卡宾显示出显着的化学选择性，可以实现高度区域选择性、非对映选择性和对映选择性反应。此外，这些反应可以显示出高水平的双立体分化和动力学分辨率。CH 活化是由铑卡宾诱导的 CH 插入引起的。这种化学反应的潜力可以通过非常直接地合成哌醋甲酯来证明。
• Synthesis of methylphenidate analogues and their binding affinities at dopamine and serotonin transport sites
  作者：Huw M.L. Davies、Darrin W. Hopper、Tore Hansen、Quixu Liu、Steven R. Childers

  DOI：10.1016/j.bmcl.2003.12.097

  日期：2004.4

  acid is a very direct method for the synthesis of methylphenidate analogues. By using either dirhodium tetraacetate or dirhodium tetraprolinate derivatives as catalyst, either the racemic or enantioenriched methylphenidate analogues can be prepared. The binding affinities of the methylphenidate analogues to both the dopamine and the serotonin transporters are described. The most notable compounds are the

  用N-Boc-哌啶或N-Boc-吡咯烷进行铑（II）催化的分子间CH插入芳基重氮乙酸甲酯，然后用三氟乙酸脱保护是合成哌醋甲酯类似物的非常直接的方法。通过使用四乙酸二钠吡啶鎓或四脯氨酸四氢吡啶鎓衍生物作为催化剂，可以制备外消旋的或对映体富集的哌醋甲酯类似物。描述了哌醋甲酯类似物与多巴胺和5-羟色胺转运蛋白的结合亲和力。最引人注目的化合物是对5-羟色胺转运蛋白具有高结合亲和力和选择性的赤型-（2-萘基）类似物。
• Low-Temperature Synthesis of Methylphenidate Hydrochloride
  申请人：Huntley C. Frederick M.

  公开号：US20150038720A1

  公开（公告）日：2015-02-05

  The present invention describes a process for the preparation of methylphenidate hydrochloride. The process involves the esterification of ritalinic acid and methanol in the presence of an acid catalyst at a low temperature. The process may optionally involve the addition of an orthoester.

  本发明描述了一种制备盐酸甲基苯丙胺的方法。该过程涉及在低温下，在酸催化剂的存在下，将利他酸和甲醇酯化。该过程可以选择性地涉及正酯的添加。
• [EN] PROCESS FOR THE PREPARATION OF METHYLPHENIDATE AND PHARMACEUTICAL SALTS THEREOF<br/>[FR] PROCÉDÉ DE PRÉPARATION DE MÉTHYLPHÉNIDATE ET DE SES SELS PHARMACEUTIQUES
  申请人：NORAMCO INC

  公开号：WO2015069505A1

  公开（公告）日：2015-05-14

  The present invention is directed to an improved process for the preparation of methylphenidate, stereoisomer, mixture of stereoisomers and pharmaceutically acceptable salts thereof, more particularly, the sulfate and hydrochloride salts of methylphenidate, di-threo-methylphenidate and dexmethylphenidate. Methods of removing or reducing the amount of impurities from the above described process are also disclosed.

  本发明涉及一种改进的甲基苯丙胺、立体异构体、立体异构体混合物及其药学上可接受的盐的制备方法，更具体地说，是甲基苯丙胺、二-反-甲基苯丙胺和右旋甲基苯丙胺的硫酸盐和盐酸盐的制备方法。本发明还揭示了从上述过程中去除或减少杂质的方法。