WO2024031838A1 - 一种采用固载镍催化工业化生产氘代医药中间体的方法 - Google Patents

一种采用固载镍催化工业化生产氘代医药中间体的方法 Download PDF

Info

Publication number
WO2024031838A1
WO2024031838A1 PCT/CN2022/126723 CN2022126723W WO2024031838A1 WO 2024031838 A1 WO2024031838 A1 WO 2024031838A1 CN 2022126723 W CN2022126723 W CN 2022126723W WO 2024031838 A1 WO2024031838 A1 WO 2024031838A1
Authority
WO
WIPO (PCT)
Prior art keywords
deuterated
solid
supported nickel
industrial production
pharmaceutical intermediate
Prior art date
Application number
PCT/CN2022/126723
Other languages
English (en)
French (fr)
Inventor
黄才古
黄铁强
王帅
Original Assignee
广州谷森制药有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 广州谷森制药有限公司 filed Critical 广州谷森制药有限公司
Publication of WO2024031838A1 publication Critical patent/WO2024031838A1/zh

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the invention belongs to the field of drug synthesis, and specifically relates to a method for the industrial production of deuterated pharmaceutical intermediate D using solid-supported nickel catalysis.
  • the new deuterated cyano compound is a small molecule 3CL protease inhibitor independently developed by Shanghai Gusen Pharmaceutical Co., Ltd. By inhibiting the main protease, it can prevent the virus from cutting long protein chains into the parts required for self-replication. Its structure for: In vitro experiments have confirmed that it has amazing anti-SARS-CoV-2 activity and can effectively inhibit the replication of the virus. What is even more surprising is that on the basis of equivalent virus antibacterial activity, this compound has achieved better results than those of Pfizer and Merck.
  • the developed oral anti-COVID-19 drug has better pharmacokinetic properties.
  • Shanghai Gusen Pharmaceutical Co., Ltd. is preparing to conduct clinical trials for the treatment of COVID-19 patients. Once successful, the market prospects will be huge.
  • Shanghai Gusen Pharmaceutical Co., Ltd. has applied for an invention patent (application number CN202111234708X) for the above-mentioned new deuterated cyano compounds.
  • Deuterated pharmaceutical intermediate D is a key intermediate for the synthesis of the above-mentioned new deuterated cyano compounds. The quality of its preparation process will also have a great impact on the quality and cost of the final product.
  • the above route uses Pd/C, PtO 2 and Raney Nickel to catalyze the reaction.
  • This type of catalyst has high activity, is flammable and explosive, and is often stored in water. Direct use will bring in hydrogen sources and affect product quality, even after treatment with deuterated solvents. There are still safety hazards and quality risks in use, especially if it cannot be scaled up in production, or equipment modifications are required, which greatly increases the cost. Due to production needs, optimization is carried out on the basis of this route.
  • the present invention provides a method for the industrial production of deuterated pharmaceutical intermediate D using solid-supported nickel catalysis.
  • the preparation process of the present invention is simple, the catalyst is safe and easy to obtain, the cost is low, the yield and purity are high, and it is suitable for industrial production.
  • reaction route is as follows:
  • the catalyst is selected from solid supported nickel.
  • the solid supported nickel main catalyst is nickel.
  • the nickel content is 55 to 70%.
  • the solid-loaded nickel carrier is at least one of diatomite, alumina, silicon oxide, and titanium oxide.
  • the support is selected from alumina.
  • the preparation method of the solid-loaded nickel is as follows: through precipitation and other techniques, the active ingredient nickel is highly dispersed on the carrier, and then through processes such as filtration and washing, drying and roasting, reduction and passivation to form a finished product.
  • the brief flow chart is as follows:
  • the solvent is selected from deuterated solvents, non-deuterated solvents, or a combination of deuterated solvents and non-deuterated solvents.
  • the solvent is selected from deuterated solvents.
  • the deuterated solvent is selected from heavy water, deuterated alcohols, deuterated esters, deuterated hydrocarbons, and deuterated ethers.
  • the deuterated solvent is selected from heavy water, deuterated methanol-d1, deuterated methanol-d4, deuterated ethanol-d1, deuterated ethanol-d6, deuterated isopropanol-d1 and deuterated isopropanol-
  • d8 includes but is not limited to any mixed solvent among the solvents listed above.
  • the solvent is selected from water, alcohols, esters, hydrocarbons, and ethers, preferably at least one of methanol, ethanol, tetrahydrofuran, ethyl acetate, and methyltetrahydrofuran, including but not limited to Mixed solvents in any mixed form among the solvents listed above.
  • compound B needs to be pretreated before the reaction.
  • the treatment method is non-deuterated and deuterated combined solvent washing.
  • the deuterated solvent in the above treatment method is selected from at least one of heavy water, deuterated alcohols, deuterated esters, deuterated hydrocarbons, and deuterated ethers, preferably heavy water;
  • the non-deuterated solvent is selected from At least one selected from water, alcohols, esters, hydrocarbons, and ethers, preferably at least one selected from tetrahydrofuran, ethyl acetate, and methyltetrahydrofuran.
  • the weight ratio of the deuterated solvent to B in the above treatment method is at least 5%.
  • the reaction temperature is 25-100°C, and the preferred reaction temperature is 30-60°C.
  • reaction conversion rate and selectivity in the present invention are high, the reaction yield and deuterium abundance are greatly improved, and the deuterium abundance is reduced.
  • the yield can reach about 90%, and the product purity and deuterium abundance reach more than 99%;
  • reaction efficiency of the present invention is high, the reaction temperature is low, multiple steps are performed at room temperature, and the energy consumption is low,
  • the synthesis route of the present invention has mild conditions, convenient post-processing, and is more suitable for industrial production.
  • Figure 1 shows the hydrogen nuclear magnetic spectrum of deuterated pharmaceutical intermediate D.
  • Figure 2 is the mass spectrum of deuterated pharmaceutical intermediate D.
  • Compound B was pretreated with a tetrahydrofuran/heavy water mixed solvent and then spun dry for later use.
  • the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent in the filtrate.
  • the crude product was crystallized and purified from a mixed solution of methyl tert-butyl ether, petroleum ether and ethyl acetate, and filtered to obtain a white solid with a purity of 99%, a yield of 90%, and a deuterium abundance of 99%.
  • Compound B was pretreated with a mixed solvent of ethyl acetate/deuterated methanol-d1 and then spun dry for later use.
  • the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent in the filtrate.
  • the crude product was crystallized and purified from a mixed solution of methyl tert-butyl ether, petroleum ether and ethyl acetate, and filtered to obtain white solid D, with a purity of 97%, a yield of 88%, and a deuterium abundance of 97%.
  • Compound B was pretreated with a mixed solvent of methyltetrahydrofuran/heavy water and then spun dry for later use.
  • the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent in the filtrate.
  • the crude product was crystallized and purified from a mixed solution of methyl tert-butyl ether, petroleum ether and ethyl acetate, and filtered to obtain white solid D, with a purity of 95%, a yield of 81%, and a deuterium abundance of 96%.
  • Compound B was pretreated with a mixed solvent of ethyl acetate/deuterated ethanol-d1 and then spun dry for later use.
  • the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent in the filtrate.
  • the crude product was crystallized and purified from a mixed solution of methyl tert-butyl ether, petroleum ether and ethyl acetate, and filtered to obtain white solid D, with a purity of 95%, a yield of 83%, and a deuterium abundance of 96%.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Catalysts (AREA)

Abstract

本发明涉及一种采用固载镍催化工业化生产氘代医药中间体D的方法，反应线路条件温和，转化率、选择性高，反应收率、反应效率高、氘丰度高，能耗低，后处理方便，反应操作简单，更适合工业化生产。本发明可以高收率的制备得到中间体D，收率可达到90％左右，并且产品纯度及氘丰度都达到99％以上，达到药用级别。

Description

一种采用固载镍催化工业化生产氘代医药中间体的方法 技术领域
本发明属于药物合成领域，具体涉及一种采用固载镍催化工业化生产氘代医药中间体D的方法。
背景技术
新型氘代氰基类化合物是由上海谷森医药有限公司独自研发的一种小分子3CL蛋白酶抑制剂，通过抑制主蛋白酶，可防止病毒将长蛋白链切割成其自我复制所需的部分，其结构为：
Figure PCTCN2022126723-appb-000001
体外实验证实，其具有惊人的抗SARS-CoV-2活性，能有效抑制病毒的复制，更让人意外的是，该化合物在病毒抑菌活性相当的基础上，实现了比辉瑞、默克所研发的口服抗新冠药更优的药动学特质，目前，上海谷森医药有限公司已经准备进行临床试验用于治疗新冠病毒病患，一旦获得成功，市场前景非常巨大。而且，上海谷森医药有限公司针对上述新型氘代氰基类化合物申请了发明专利(申请号CN202111234708X)。
而氘代医药中间体D是合成上述新型氘代氰基类化合物的关键中间体，其制备工艺的优劣也将对终产品的质量及成本造成较大影响，氘代医药中间体D的化学式为：
Figure PCTCN2022126723-appb-000002
尽管申请人在先专利CN202111234708X报道了氘代医药中间体D及其合成路线，即以化合物B为起始原料，在硼氘化钠和氯化钴的存在下，先经中间体 态C，然后环合得到D。路线如下所示：
Figure PCTCN2022126723-appb-000003
但以上路线未能提供中间体的质量说明，重复后发现中间体氘丰度较低，成本高，不适合放大生产，因生产需要，后续申请人专利CN2022100574053此路线基础上进行优化。路线如下所示：
Figure PCTCN2022126723-appb-000004
以上路线使用Pd/C、PtO 2、雷尼镍催化反应，该类催化剂活性较高，易燃易爆，常在水中保存，直接使用会带入氢源影响产品质量，即使氘代溶剂处理后使用仍存在安全隐患及质量风险，特别是在生产中无法放大，或需要进行设备改造，成本大大增加，因生产需要，故在此路线基础上进行优化。
发明内容
基于此，本发明提供了一种采用固载镍催化工业化生产氘代医药中间体D的方法，本发明的制备工艺路线简单、催化剂安全易得、成本低廉、收率纯度高、适合工业化生产。
具体技术方案如下：
在溶剂中，化合物B在催化剂/氘气的存在下发生氘代还原反应，得中间体D，反应路线如下：
Figure PCTCN2022126723-appb-000005
所述催化剂选自固体负载镍。
所述固体负载镍主催化剂是镍。
所述镍的含量为55～70％。
所述固体负载镍载体为硅藻土、氧化铝、氧化硅、氧化钛中的至少一种。
优选地，所述载体选自氧化铝。
所述固体负载镍制备方法为：通过沉淀等技术，将活性成分镍高度分散在载体上，再经过过滤洗涤、干燥焙烧、还原钝化等工序形成成品。简要流程图如下：
Figure PCTCN2022126723-appb-000006
所述溶剂选自氘代溶剂、非氘代溶剂或者氘代溶剂与非氘代溶剂的组合。
优选地，所述溶剂选自氘代溶剂。
优选地，所述氘代溶剂选自重水、氘代醇类、氘代酯类、氘代烃类、氘代醚类。
优选地，所述氘代溶剂选自重水、氘代甲醇-d1、氘代甲醇-d4、氘代乙醇-d1、氘代乙醇-d6、氘代异丙醇-d1和氘代异丙醇-d8中的至少一种，包括但不限于上述所列溶剂中任何混合形式的混合溶剂。
在其中一些实施例中，所述溶剂选自水、醇类、酯类、烃类、醚类，优选甲醇、乙醇、四氢呋喃、乙酸乙酯、甲基四氢呋喃中的至少一种，包括但不限于上述所列溶剂中任何混合形式的混合溶剂。
优选地，反应前需要对化合物B进行预处理。
优选地，所述处理方式为非氘代和氘代组合溶剂洗涤。
优选地，上述处理方式的氘代溶剂选自重水、氘代醇类、氘代酯类、氘代烃类、氘代醚类中的至少一种，优选重水；所述的非氘代溶剂选自水、醇类、酯类、烃类、醚类中的至少一种，优选四氢呋喃、乙酸乙酯、甲基四氢呋喃中的至少一种。
优选地，上述处理方式的氘代溶剂与B的重量比至少为5％。
优选地，反应温度为25～100℃，优选反应温度为30-60℃。
本发明的氘代医药中间体D制备路线具有以下优点和有益效果：
(1)本发明中反应转化率、选择性高，极大提高了反应收率和氘丰度，降
低成本，收率可达到90％左右，并且产品纯度及氘丰度都达到99％以上；
(2)本发明中反应效率高，反应温度低，多个步骤在常温下进行，能耗低，
反应操作简单；
(3)本发明合成路线条件温和，后处理方便，更适合工业化生产。
附图说明
图1为氘代医药中间体D的核磁氢谱图。
图2为氘代医药中间体D的质谱图。
具体实施方式：
以下结合具体实施例对本发明的采用固载镍催化工业化生产氘代医药中间体D的方法做进一步详细的说明。
以下详细的说明都仅是示例性和解释性的，而非限制性的。
以下实施例，除非另外指出，否则使用的所有溶剂和试剂都是商购得到并且以原样使用。
本文采用了以下缩写:
D 2：氘气
中间体D的合成
Figure PCTCN2022126723-appb-000007
化学式：C 13H 20D 2N 2O 5
分子量：288.34
实施例1
将化合物B用四氢呋喃/重水混合溶剂预处理后旋干备用。
将处理后的B(1.0kg，3.24mol)加入到20L的氢化反应釜中，加入氘代甲醇-d4(5.0L，5V)，加入氧化铝负载镍(镍含量63.5％，300g，30wt％of化合物B)；利用氮气和氘气依次置换2次，最后将氘气保压0.5Mpa；将体系温度升至55℃，保温反应18小时。待反应到终点后，垫入硅藻土过滤，滤饼用甲醇进行淋洗。减压浓缩移除溶剂，所得粗品用10L二氯甲烷溶解。经5L的水进行洗涤1次，收集有机相。将有机相经无水硫酸钠干燥后，过滤，减压浓缩移除滤液中的溶剂。粗品经甲基叔丁基醚、石油醚和乙酸乙酯的混合溶液进行结晶纯化，过滤得到白色固体，纯度99％，收率90％，氘丰度99％。
LC-MS(ESI，m/z，C 13H 20D 2N 2O 5，189.17，[M+1]＝M-100+1)
1H NMR(500MHz,CDCl 3)δ:6.16(s,1H),5.51(d,1H),4.30～4.32(m,1H),3.73(s,3H),2.42～2.48(m,2H),2.10～2.15(m,1H),1.83-1.81(m,2H),1.27(s,9H)。
实施例2
将化合物B用乙酸乙酯/氘代甲醇-d1混合溶剂预处理后旋干备用。
将处理后的B(1.0kg，3.24mol)加入到20L的氢化反应釜中，加入氘代甲醇-d1(5.0L，5V)，加入氧化硅负载镍(镍含量59.5％，300g，30wt％of化合物B)；利用氮气和氘气依次置换2次，最后将氘气保压0.5Mpa；将体系温度升至55℃，保温反应18小时。待反应到终点后，垫入硅藻土过滤，滤饼用甲醇进行淋洗。减压浓缩移除溶剂，所得粗品用10L二氯甲烷溶解。经5L的水进行洗涤1次，收集有机相。将有机相经无水硫酸钠干燥后，过滤，减压浓缩移除滤液中的溶剂。粗品经甲基叔丁基醚、石油醚和乙酸乙酯的混合溶液进行结晶纯化，过滤得到白色固体D，纯度97％，收率88％，氘丰度97％。
实施例3
将化合物B用甲基四氢呋喃/重水混合溶剂预处理后旋干备用。
将处理后的B(1.0kg，3.24mol)加入到20L的氢化反应釜中，加入氘代乙醇-d1(5.0L，5V)，加入硅藻土负载镍(镍含量56.2％，300g，30wt％of化合物B)；利用氮气和氘气依次置换2次，最后将氘气保压0.5Mpa；将体系温度升至55℃，保温反应18小时。待反应到终点后，垫入硅藻土过滤，滤饼用甲醇进行淋洗。减压浓缩移除溶剂，所得粗品用10L二氯甲烷溶解。经5L的水进行洗涤1次，收集有机相。将有机相经无水硫酸钠干燥后，过滤，减压浓缩移除滤液中的溶剂。粗品经甲基叔丁基醚、石油醚和乙酸乙酯的混合溶液进行结晶纯化，过滤得到白色固体D，纯度95％，收率81％，氘丰度96％。
实施例4
将化合物B用乙酸乙酯/氘代乙醇-d1混合溶剂预处理后旋干备用。
将处理后的B(1.0kg，3.24mol)加入到20L的氢化反应釜中，加入氘代乙醇-d1(5.0L，5V)，加入氧化钛负载镍(镍含量69.2％，300g，30wt％of化合物B)；利用氮气和氘气依次置换2次，最后将氘气保压0.5Mpa；将体系温度升至55℃， 保温反应18小时。待反应到终点后，垫入硅藻土过滤，滤饼用甲醇进行淋洗。减压浓缩移除溶剂，所得粗品用10L二氯甲烷溶解。经5L的水进行洗涤1次，收集有机相。将有机相经无水硫酸钠干燥后，过滤，减压浓缩移除滤液中的溶剂。粗品经甲基叔丁基醚、石油醚和乙酸乙酯的混合溶液进行结晶纯化，过滤得到白色固体D，纯度95％，收率83％，氘丰度96％。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。

Claims (12)

  1. 一种采用固载镍催化工业化生产氘代医药中间体D的方法，其特征在于，包括以下步骤：
    在溶剂中，化合物B在催化剂/氘气的存在下发生氘代还原反应，得中间体D，反应路线如下：
    Figure PCTCN2022126723-appb-100001
    所述催化剂选自固体负载镍。
  2. 根据权利要求1所述的一种采用固载镍催化工业化生产氘代医药中间体D的方法，其特征在于：所述固体负载镍主催化剂是镍。
  3. 根据权利要求2所述的一种采用固载镍催化工业化生产氘代医药中间体D的方法，其特征在于：所述镍的含量为55～70％。
  4. 根据权利要求1所述的一种采用固载镍催化工业化生产氘代医药中间体D的方法，其特征在于：所述固体负载镍载体为硅藻土、氧化铝、氧化硅、氧化钛中的至少一种，优选氧化铝。
  5. 根据权利要求1所述的一种采用固载镍催化工业化生产氘代医药中间体D的方法，其特征在于：所述溶剂选自氘代溶剂、非氘代溶剂或者氘代溶剂与非氘代溶剂的组合。
  6. 根据权利要求5所述的一种采用固载镍催化工业化生产氘代医药中间体D的方法，其特征在于：所述氘代溶剂选自重水、氘代醇类、氘代酯类、氘代烃类、氘代醚类中的至少一种，优选重水、氘代甲醇-d1、氘代甲醇-d4、氘代乙醇-d1、氘代乙醇-d6、氘代异丙醇-d1和氘代异丙醇-d8中的至少一种。
  7. 根据权利要求5所述的一种采用固载镍催化工业化生产氘代医药中间体 D的方法，其特征在于：所述非氘代溶剂选自水、醇类、酯类、烃类、醚类中的至少一种，优选甲醇、乙醇、四氢呋喃、乙酸乙酯、甲基四氢呋喃中的至少一种。
  8. 根据权利要求1-7任一项所述的一种采用固载镍催化工业化生产氘代医药中间体D的方法，其特征在于：反应前需要对化合物B进行预处理。
  9. 根据权利要求8所述的一种采用固载镍催化工业化生产氘代医药中间体D的方法，其特征在于：所述处理方式为非氘代和氘代组合溶剂洗涤。
  10. 根据权利要求9所述的一种采用固载镍催化工业化生产氘代医药中间体D的方法，其特征在于：所述的氘代溶剂选自重水、氘代醇类、氘代酯类、氘代烃类、氘代醚类中的至少一种，优选重水；所述的非氘代溶剂选自水、醇类、酯类、烃类、醚类中的至少一种，优选四氢呋喃、乙酸乙酯、甲基四氢呋喃中的至少一种。
  11. 根据权利要求10所述的一种采用固载镍催化工业化生产氘代医药中间体D的方法，其特征在于：氘代溶剂与B的重量比至少为5％。
  12. 根据权利要求1-11任一项所述的一种采用固载镍催化工业化生产氘代医药中间体D的方法，其特征在于：反应温度为25～100℃。
PCT/CN2022/126723 2022-08-08 2022-10-21 一种采用固载镍催化工业化生产氘代医药中间体的方法 WO2024031838A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202210941633.7A CN115340481A (zh) 2022-08-08 2022-08-08 一种采用固载镍催化工业化生产氘代医药中间体的方法
CN202210941633.7 2022-08-08

Publications (1)

Publication Number Publication Date
WO2024031838A1 true WO2024031838A1 (zh) 2024-02-15

Family

ID=83950650

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/126723 WO2024031838A1 (zh) 2022-08-08 2022-10-21 一种采用固载镍催化工业化生产氘代医药中间体的方法

Country Status (2)

Country Link
CN (1) CN115340481A (zh)
WO (1) WO2024031838A1 (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115322065A (zh) * 2022-09-01 2022-11-11 广州谷森制药有限公司 一种采用固载镍与有机碱组合催化工业化生产氘代医药中间体的方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110053943A1 (en) * 2009-06-02 2011-03-03 Vitae Pharmaceuticals, Inc. CARBAMATE AND UREA INHIBITORS OF 11ß-HYDROXYSTEROID DEHYDROGENASE 1
CN114426568A (zh) * 2022-01-11 2022-05-03 安帝康（无锡）生物科技有限公司 2-氧代-3-吡咯烷基丙腈类化合物及其药物组合物和用途

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110053943A1 (en) * 2009-06-02 2011-03-03 Vitae Pharmaceuticals, Inc. CARBAMATE AND UREA INHIBITORS OF 11ß-HYDROXYSTEROID DEHYDROGENASE 1
CN114426568A (zh) * 2022-01-11 2022-05-03 安帝康（无锡）生物科技有限公司 2-氧代-3-吡咯烷基丙腈类化合物及其药物组合物和用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WANG, JIN; GAO, ZHONG-LIANG; SHI, RONG-CHAO: "Synthesis of Carphedon", CHEMICAL REAGENTS, vol. 42, no. 1, 31 January 2020 (2020-01-31), China, pages 100 - 104, XP009552823, ISSN: 0258-3283, DOI: 10.13822/j.cnki.hxsj.2020007061 *

Also Published As

Publication number Publication date
CN115340481A (zh) 2022-11-15

Similar Documents

Publication Publication Date Title
WO2023137874A1 (zh) 一种氘代医药中间体的制备方法
WO2024031838A1 (zh) 一种采用固载镍催化工业化生产氘代医药中间体的方法
WO2024045292A1 (zh) 一种采用固载镍与有机碱组合催化工业化生产氘代医药中间体的方法
CN112300212A (zh) 硼烷-吡啶络合物在制备nk-1受体拮抗剂中的用途
WO2023137876A1 (zh) 一种用于合成新型氘代氰基类化合物的中间体的制备方法
WO2013040750A1 (zh) 制备β-蒿甲醚的方法
WO2020010765A1 (zh) 一种特布他林中间体的合成方法
CN115197232A (zh) 一种环丙烷稠合的氧桥六环类化合物及其合成方法
CN116041326A (zh) 伏诺拉生盐酸盐粗品、精品及富马酸伏诺拉生的制备方法
CN111620788B (zh) 一种制备(2s,3s)-3-氨基-二环[2.2.2]辛烷-2-甲酸酯的方法
JPH0246590B2 (zh)
CN114920764A (zh) 一种三仲丁基硼氢化锂的制备及其在制备抗菌剂中的应用
WO2024060356A1 (zh) 一种经济可行的工业化生产氘代新冠药物关键中间体的方法
CN112552345A (zh) 一种nk-1受体拮抗剂的制备方法
CN103664941B (zh) 一种长春西汀类似物的制备方法
CN116239529B (zh) 一种二氧化碳参与的n-甲基四氢喹啉类生物碱的制备方法
CN106117200B (zh) 预防或治疗关节置换静脉血栓药物阿哌沙班的制备方法
CN115521964B (zh) 一种甾体激素药物中间体的制备方法
CN104292293A (zh) 一种度他雄胺杂质i的制备方法
CN111233763B (zh) 一种1-(4-甲氧基-苄基)-2-甲基-八氢异喹啉的制备方法
CN115785057B (zh) 一种替卡格雷中间化合物及其盐的制备方法
CN115010647B (zh) 一种双环内酰胺类化合物的制备方法
CN115109026A (zh) 一种高ee值左旋沙丁胺醇中间体及盐酸盐的制备方法
CN116751196A (zh) 一种高效合成马拉维诺中间体n-苄基托品胺的方法
CN116283619A (zh) 一种硫酸沙丁胺醇杂质及其制备方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22954780

Country of ref document: EP

Kind code of ref document: A1