Morphine Sulfate

金银花二胺天然产物由Taga等人于1984年从蛇藤（Stephania japonica）中分离出来的诺苏巴南（norhasubanan）类生物碱（Chem Pharm Bull, 1984,32, 4223-4225），其绝对构型是通过其苯甲酰化衍生物的单晶X 射线分析来确证的。虽然蛇藤在传统中药中用于治疗哮喘、发热和消化障碍等疾病，但金银花二胺的生物活性尚不明确。从结构上看，金银花二胺拥有五环骨架，同时包含氮杂[4.3.3]螺桨烷结构，含有四个手性中心，包括一个苄位的季碳中心、两个相邻的顺式三级胺手性中心和一个苄位含氧的季碳手性中心。Marshall Gates等人于1952年首次报道了吗啡（morphine，1）的合成，随后化学家陆续发表了三十多篇相关的合成论文。哈苏班纳生物碱（hasubanonine，2）于1951年由Konto等人完成首次分离，随后人们也报道了很多该分子的合成方法。然而，该系列分子中金银花二胺（3）的合成却并未得到人们的重视。最近，德国慕尼黑大学的Dirk Trauner教授及其团队通过高效的串联过程构建了氮杂[4.3.3]螺桨烷核心骨架结构，由此首次完成了天然产物（+）-金银花二胺的全合成。他们还通过关键Tollens反应和Curtius重排反应构建了空间位阻较大的α-氨基内酯。逆合成分析：全合成路线：萘满酮8的合成和aldol缩合反应的尝试：串联反应构建氮杂[4.3.3]螺桨烷核心骨架：二胺的构建：（+）-金银花二胺的最终合成：合成路线解析：作者在进行消旋体金银花二胺合成的同时，也对手性合成过程进行了探索。他们从烯丙基碳酸酯30出发，尝试合成手性化合物（S）-8，通过钯催化的Tsuji不对称脱羧烯丙基化反应，筛选了包括配体（S）-t-Bu-PHOX在内的诸多反应条件，但是反应结果不是很理想，对映选择性最高只有66%。受到List等人工作的影响，作者在探索优化化合物8 的对映选择性时，尝试了非对称酮的直接官能化反应。他们对底物31进行了一系列的条件优化，最终权衡产率和对映选择性，催化剂B脱颖而出，最佳的反应浓度是0.01mol/L，最佳的温度是15℃，在该条件下，反应以63%的产率和93%的对映选择性得到产物8。催化剂：综上所述，通过高效的串联过程构建了氮杂[4.3.3]螺桨烷核心骨架结构，由此首次完成了天然产物（+）-金银花二胺的全合成。他们还通过关键Tollens反应和Curtius重排反应构建了空间位阻较大的α-氨基内酯。最后，作者阐述了一种不对称合成金银花二胺的方法。在此背景下开发的（R）-8和（S）-8可分别作为合成多种哈苏班纳和吗啡生物碱有价值的中间体。

Multiple drugmakers have had to yank their products in the U.S. this year over manufacturing and quality concerns. A trio of drugmakers have issued separate recalls in the U.S. thanks to string of production flubs, including failed impurity and dissolution specifications and incorrect labelling of infusion bags.The companies behind the product pulls are Dr. Reddy’s Laboratories, Sun Pharma and Zydus Pharmaceuticals, all three of which hail from India. The drugmakers are recalling seizure treatments, painkillers and a chemotherapy drug, respectively, according to the FDA’s online enforcement report, which the regulator uses to catalogue recalls. In the case of Dr. Reddy’s, the company unveiled a voluntary recall on March 13 for one lot of 1,000 mg/100 ml single-dose levetiracetam infusion bags that had been shipped out across the U.S. in early November.  The infusion bags from the suspect batch were incorrectly labeled as 500 mg/100 ml levetiracetam in 0.82% sodium chloride injection, while the aluminum overwrap packaging correctly identifies the product as levetiracetam in 0.75% sodium chloride injection 1,000 mg/100 ml, Dr. Reddy’s explained in its recall notice.Levetiracetam is typically used to treat certain types of seizures when patients are unable to take an oral medication. Although Dr. Reddy’s says there have so far been no reported safety events related to the product pull, patients receiving higher-than-expected doses of the drug by rapid intravenous infusion are at risk of “immediate and serious side effects,” including liver injury, respiratory depression and coma, the company explained. Sun Pharma, for its part, is recalling nearly 10,000 100 mg bottles of morphine sulfate extended-release tablets after the products failed to meet FDA dissolution specifications. The painkillers are part of lot AD16615, which was set to expire in July. The morphine sulfate tablets at issue were distributed nationwide, according to the FDA’s enforcement report.Sun initiated the Class II recall on Feb. 6. The tablets were manufactured by the Indian drugmaker’s subsidiary Ohm Laboratories in New Brunswick, New Jersey.Lastly, Zydus Pharmaceuticals initiated two separate Class II recalls on Feb. 13 covering a whopping 38,871 vials of the chemotherapy injection nelarabine, which were manufactured at the company’s Ahmedabad, India, production facility.The drugmaker issued the recall due to failed impurity and degradation specifications, the FDA’s enforcement report notes.The far-reaching product pull accounts for more than 20 lots of the chemotherapy med, which were set to expire as early as last month or as late as July 2026, depending on the specific batch. Multiple drugmakers have had to yank their products in the U.S. this year, with one recent recall yielding significant interest for its scope and treatment type.Earlier this month, Glenmark Pharma revealed it was recalling some 1.48 million bottles of the generic attention-deficit/hyperactivity disorder (ADHD) drug atomoxetine after detecting unacceptable levels of a possible carcinogen in the product.Atomoxetine—previously sold by Eli Lilly under the brand name Strattera—is a selective norepinephrine reuptake inhibitor (sNRI) independent of the stimulant-based offerings that make up the bulk of ADHD treatment.