WO2023137874A1 - 一种氘代医药中间体的制备方法 - Google Patents

一种氘代医药中间体的制备方法 Download PDF

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WO2023137874A1
WO2023137874A1 PCT/CN2022/084712 CN2022084712W WO2023137874A1 WO 2023137874 A1 WO2023137874 A1 WO 2023137874A1 CN 2022084712 W CN2022084712 W CN 2022084712W WO 2023137874 A1 WO2023137874 A1 WO 2023137874A1
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deuterated
pharmaceutical intermediate
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methanol
ethanol
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PCT/CN2022/084712
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黄才古
黄铁强
王帅
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广州谷森制药有限公司
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    • 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
    • C07D207/267—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atom
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • the invention belongs to the field of drug synthesis, in particular to a method for synthesizing a deuterated pharmaceutical intermediate D.
  • coronavirus SARS-CoV-2 is a new strain of coronavirus that has never been found in humans before. It was first discovered and reported in 2019. It is still prevalent in many countries around the world and has not been well controlled in many countries and regions.
  • 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 the long protein chain into parts required for its self-replication. Its structure is: 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 this compound has achieved better pharmacokinetic properties than the oral anti-new coronavirus drugs developed by Pfizer and Merck on the basis of comparable virus antibacterial activity. At present, Shanghai Goosen Pharmaceutical Co., Ltd. is preparing to conduct clinical trials for the treatment of new coronavirus patients. Once successful, the market prospect is very huge. Moreover, Shanghai Gusen Pharmaceutical Co., Ltd. has applied for an invention patent (application number CN202111234708X) for the above-mentioned novel deuterated cyano compounds.
  • the deuterated pharmaceutical intermediate D is the key intermediate for the synthesis of the above-mentioned novel deuterated cyano compounds, and its preparation process will also have a great impact on the quality and cost of the final product.
  • the chemical formula of the deuterated pharmaceutical intermediate D is:
  • the present invention provides a preparation method of a deuterated pharmaceutical intermediate D.
  • the preparation process route of the present invention is simple, low in cost, high in yield and purity, and suitable for industrial production.
  • the catalyst is selected from at least one of Pd/C, PtO 2 , and Raney nickel, preferably Raney nickel.
  • the solvent is selected from a deuterated solvent, a non-deuterated solvent or a combination of a deuterated solvent and a non-deuterated solvent.
  • the solvent is selected from deuterated solvents.
  • the deuterated solvent is selected from heavy water, deuterated alcohols, deuterated esters, deuterated hydrocarbons, deuterated ethers.
  • the deuterated solvent is selected from at least one of heavy water, deuterated methanol-d1, deuterated methanol-d4, deuterated ethanol-d1, deuterated ethanol-d6, deuterated isopropanol-d1 and deuterated isopropanol-d8, including but not limited to any mixed solvent in the above listed solvents.
  • the solvent is selected from water, alcohols, esters, hydrocarbons, ethers, preferably at least one of methanol, ethanol, tetrahydrofuran, ethyl acetate, and methyl tetrahydrofuran, including but not limited to any mixed solvent in the solvents listed above.
  • compound B and/or the catalyst need to be pretreated before the reaction.
  • the treatment method is washing with a deuterated solvent
  • the deuterated solvent is at least one selected from heavy water, deuterated alcohols, deuterated esters, deuterated hydrocarbons, and deuterated ethers.
  • the deuterated solvent used in the above treatment method is at least one selected from deuterated methanol-d1, deuterated methanol-d4, deuterated ethanol-d1, deuterated ethanol-d6, deuterated isopropanol-d1, deuterated isopropanol-d8, and heavy water.
  • the reaction temperature is 25-100°C, preferably 30-60°C.
  • reaction conversion rate and selectivity are high, which greatly improves the reaction yield and deuterium abundance, reduces costs, and the yield can reach about 90%, and the product purity and deuterium abundance all reach more than 99%;
  • reaction efficiency is high, the reaction temperature is low, multiple steps are carried out at normal temperature, the energy consumption is low, and the reaction operation is simple;
  • the synthesis route of the present invention has mild conditions, convenient post-treatment, and is more suitable for industrial production.
  • Figure 1 is the H NMR spectrum of deuterated pharmaceutical intermediate D.
  • Fig. 2 is the mass spectrogram of deuterated pharmaceutical intermediate D.
  • the Raney nickel in embodiment 1 is replaced by Pd/C, PtO 2 and/or heavy water is replaced with deuterated methanol-d1, deuterated methanol-d4, deuterated ethanol-d1, deuterated ethanol-d6, deuterated isopropanol-d1, deuterated isopropanol-d8;
  • the deuterated solvent is selected from methanol, ethanol, tetrahydrofuran, ethyl acetate, and methyl tetrahydrofuran; D can also be successfully prepared, with a purity of 98-99%, a deuterium abundance of 99-99.5%, and a yield of 88-92%.

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

一种氘代医药中间体D的制备方法，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。该方法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

一种氘代医药中间体的制备方法 技术领域
本发明属于药物合成领域，具体涉及一种氘代医药中间体D的合成方法。
背景技术
新型冠状病毒SARS-CoV-2是以前从未在人体中发现的冠状病毒新毒株，2019年首次被发现并报道，至今仍然在全球多个国家流行肆虐，并在很多国家区域并未得到很好的控制。
人感染了冠状病毒后常见体征有呼吸道症状、发热、咳嗽、气促和呼吸困难等。在较严重病例中，感染可导致肺炎、严重急性呼吸综合征、肾衰竭，甚至死亡，而且目前对于新型冠状病毒所致疾病没有特异治疗方法。
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 PCTCN2022084712-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 PCTCN2022084712-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 PCTCN2022084712-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，故在此路线基础上进行优化。
发明内容
基于此，本发明提供了一种氘代医药中间体D的制备方法，本发明的制备工艺路线简单、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 PCTCN2022084712-appb-000004
在其中一些实施例中，所述催化剂选自Pd/C、PtO 2、雷尼镍中至少一种， 优选雷尼镍。
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和/或催化剂进行预处理。
优选地，所述处理方式为氘代溶剂洗涤，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。
优选地，上述处理方式使用的氘代溶剂选自氘代甲醇-d1、氘代甲醇-d4、氘代乙醇-d1、氘代乙醇-d6、氘代异丙醇-d1、氘代异丙醇-d8、重水中的至少一种。
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氘代医药中间体D的合成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
实施例1中间体D的合成
Figure PCTCN2022084712-appb-000005
化学式：C 13H 20D 2N 2O 5
分子量：288.34
将化合物B(1.0g，3.24mmol)加入到25mL的氢化反应釜中，加入氘代甲醇-d4(10.0mL，10V)，加入用重水处理后的雷尼镍(50mg，5wt％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，滤饼用乙酸乙酯进行淋洗。滤液经减压浓缩移除溶剂，所得粗品经柱层析(二氯甲烷/甲醇＝100/1)纯 化得到0.84g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)。
将实施例1中的雷尼镍替换为Pd/C、PtO 2；和/或重水替换为氘代甲醇-d1、氘代甲醇-d4、氘代乙醇-d1、氘代乙醇-d6、氘代异丙醇-d1、氘代异丙醇-d8；氘代甲醇-d4替换为重水、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等所有氘代有机溶剂中至少一种，非氘代溶剂选自甲醇、乙醇、四氢呋喃、乙酸乙酯、甲基四氢呋喃；亦能顺利制备得到D，纯度98～99％，氘丰度99-99.5％，收率88-92％。
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 (10)

  1. 一种氘代医药中间体D的合成方法，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 PCTCN2022084712-appb-100001
  2. 根据权利要求1所述的氘代医药中间体D的合成方法，其特征在于：所述催化剂选自Pd/C、PtO 2、雷尼镍中的至少一种。
  3. 根据权利要求1-2任一项所述的氘代医药中间体D的合成方法，其特征在于：所述催化剂选自雷尼镍。
  4. 根据权利要求1-3所述的氘代医药中间体D的合成方法，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。
  5. 根据权利要求4所述的氘代医药中间体D的合成方法，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。
  6. 根据权利要求4所述的氘代医药中间体D的合成方法，其特征在于：所述溶剂选自水、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。
  7. 根据权利要求1-6任一项所述的氘代医药中间体D的合成方法，其特征在于：反应前需要对化合物B和/或催化剂进行预处理。
  8. 根据权利要求7所述的氘代医药中间体D的合成方法，其特征在于：所述处理方式为氘代溶剂洗涤，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。
  9. 根据权利要求8所述的氘代医药中间体D的合成方法，其特征在于：所述氘代溶剂选自氘代甲醇-d1、氘代甲醇-d4、氘代乙醇-d1、氘代乙醇-d6、氘代异丙醇-d1、氘代异丙醇-d8、重水中的至少一种。
  10. 根据权利要求1-9任一项所述的氘代医药中间体D的合成方法，其特征在于：反应温度为25～100℃。
PCT/CN2022/084712 2022-01-19 2022-04-01 一种氘代医药中间体的制备方法 WO2023137874A1 (zh)

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