CN110698478A - 一种厄他培南单钠盐的合成方法 - Google Patents

一种厄他培南单钠盐的合成方法 Download PDF

Info

Publication number
CN110698478A
CN110698478A CN201810747154.5A CN201810747154A CN110698478A CN 110698478 A CN110698478 A CN 110698478A CN 201810747154 A CN201810747154 A CN 201810747154A CN 110698478 A CN110698478 A CN 110698478A
Authority
CN
China
Prior art keywords
monosodium salt
ertapenem
ertapenem monosodium
synthesis method
intermediate product
Prior art date
Legal status (The legal status 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 status listed.)
Granted
Application number
CN201810747154.5A
Other languages
English (en)
Other versions
CN110698478B (zh
Inventor
申理滔
喻林
唐红伟
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wuhan QR Pharmaceuticals Co Ltd
Original Assignee
Wuhan QR Pharmaceuticals Co Ltd
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 Wuhan QR Pharmaceuticals Co Ltd filed Critical Wuhan QR Pharmaceuticals Co Ltd
Priority to CN201810747154.5A priority Critical patent/CN110698478B/zh
Publication of CN110698478A publication Critical patent/CN110698478A/zh
Application granted granted Critical
Publication of CN110698478B publication Critical patent/CN110698478B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
    • C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
    • C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
    • C07D477/20—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
    • C07D477/02—Preparation
    • C07D477/06—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
    • C07D477/08—Modification of a carboxyl group directly attached in position 2, e.g. esterification
    • 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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明提供了一种厄他培南钠盐的合成方法。其包括以下步骤：将培南母核MAP与厄他培南侧链反应生成中间产物；将上述中间产物进行氢化脱保护、成盐制得厄他培南单钠盐粗品，再经过析晶纯化的方法，即可精制得到厄他培南单钠盐，该合成方法催化剂成本低，操作简单，适合工业化生产。

Description

一种厄他培南单钠盐的合成方法
技术领域
本发明涉及药物化学领域，具体涉及一种厄他培南单钠盐的合成方法。
背景技术
厄他培南钠(ertapenem sodium)为美国默克制药公司开发的新型广谱碳青霉烯类抗生素，其化学名称为：[4R,5S,6S]-3-[[(3S,5S)-5-[[(3-羧基苯基)氨基]-3-吡咯烷基]硫基]-6-[(1R)-1-羟基乙基]-4-甲基-7-氧-1-氮杂二环[3.2.0]庚-2-烯-2-羧酸单钠盐。该产品具有强效的抗菌活性，抗菌谱广，是肺炎等深度感染症状的一线治疗选择药物。
目前，国内已有多家公司致力于厄他培南的研发，主要的合成方法有两种。一种是Merck的第一代制备方法，通过双保护的中间体脱保护后得到厄他培南(WO2013121279，US20110288290,US20090312539等)；另一种方法是：通过单保护的中间体脱保护后得到厄他培南(WO201238979,CN201010188533)，但是两种方法中均采用Pd/C做催化剂，成本高、收率较低。
发明内容
本发明的目的在于克服现有技术厄他培南成本较高、提供一种厄他培南钠盐的制备新方法。其具体的合成路线如下所示：
Figure BDA0001724647660000021
该合成路线包括以下步骤：
步骤(1)将式(Ⅰ)所示的培南母核MAP与式(Ⅱ)的厄他培南侧链于溶剂及碱中发生对接反应，生成中间产物；及
步骤(2)将上述中间产物以雷尼镍为催化剂、碳酸氢钠作为碱化剂进行氢化脱保护制得厄他培南钠盐，即[4R,5S,6S]-3-[[(3S,5S)-5-[[(3-羧基苯基)氨基]-3-吡咯烷基]硫基]-6-[(1R)-1-羟基乙基]-4-甲基-7-氧-1-氮杂二环[3.2.0]庚-2-烯-2-羧酸单钠盐。
优选的，步骤(1)中所述的碱为二异丙基胺、三乙胺、二异丙基乙基胺、乙二胺中的至少一种。
优选的，步骤(1)的反应温度为-30～-10℃。
优选的，步骤(1)中所述的溶剂为四氢呋喃、N-甲基吡咯烷酮、二氯甲烷、乙腈中的至少一种。
优选的，步骤(2)中所述的催化剂为雷尼镍，其用量为5％～20％。
用上述制备方法合成厄他培南单钠盐，收率大大提高，同时降低了成本，简化了操作步骤；所需试剂价格低廉，且对环境友好。
具体实施方式
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。此外，应理解，在阅读了本发明所记载的内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本发明所限定的范围。
实施例1
在-30℃条件下，将带有保护基的培南母核MAP与等摩尔当量的厄他培南侧链于溶剂四氢呋喃及三乙胺中发生对接反应，生成中间产物；将上述中间产物以10％的雷尼镍为催化剂、碳酸氢钠作为碱化剂进行氢化脱保护制得厄他培南单钠盐粗品，再经过析晶纯化的方法，即可精制得到厄他培南单钠盐，即[4R,5S,6S]-3-[[(3S,5S)-5-[[(3-羧基苯基)氨基]-3-吡咯烷基]硫基]-6-[(1R)-1-羟基乙基]-4-甲基-7-氧-1-氮杂二环[3.2.0]庚-2-烯-2-羧酸单钠盐，产率为71.3％。
实施例2
在-20℃条件下，将式Ⅰ带有保护基的培南母核MAP与式Ⅱ的厄他培南侧链于溶剂二异丙基胺及乙腈中发生对接反应，生成中间产物；将上述中间产物以5％的雷尼镍作为催化剂、碳酸氢钠作为碱化剂进行氢化脱保护制得厄他培南单钠盐粗品，再经过析晶纯化的方法，即可精制得到厄他培南单钠盐，即[4R,5S,6S]-3-[[(3S,5S)-5-[[(3-羧基苯基)氨基]-3-吡咯烷基]硫基]-6-[(1R)-1-羟基乙基]-4-甲基-7-氧-1-氮杂二环[3.2.0]庚-2-烯-2-羧酸单钠盐，产率为67.4％。
实施例3
在-10℃条件下，将式Ⅰ带有保护基的培南母核MAP与式Ⅱ的厄他培南侧链于溶剂二异丙基乙基胺及二氯甲烷中发生对接反应，生成中间产物；将上述中间产物以20％的雷尼镍作为催化剂、碳酸氢钠作为碱化剂进行氢化脱保护制得厄他培南单钠盐粗品，再经过析晶纯化的方法，即可精制得到厄他培南单钠盐，即[4R,5S,6S]-3-[[(3S,5S)-5-[[(3-羧基苯基)氨基]-3-吡咯烷基]硫基]-6-[(1R)-1-羟基乙基]-4-甲基-7-氧-1-氮杂二环[3.2.0]庚-2-烯-2-羧酸单钠盐，产率为75.1％。
实施例4:产品鉴定和质量研究试验
实施例4:产品鉴定和质量研究试验
取实施例1中的样品1克，观察性状为白色至类白色的结晶性粉末。
用色谱法测定样品的含量，样品主峰的保留时间与对照品厄他培南钠盐主峰的保留时间一致。
取少量样品，加水制成0.1g/mL的溶液，pH值为5.5～7.0。
其他杂质含量测试，其中，恶嗪酮≤0.4％，开环降解物≤0.5％，Pro-MABA≤0.5％，除所有特定杂质(恶嗪酮，Pro-MABA，开环降解物，二聚物I+II，二聚物VI，二聚物III，水合二聚物(a+b)，二聚物V)外，其他任一降解杂质≤0.2％，二聚物总量≤1.3％，杂质总量≤3.0％。
高效液相色谱测试该样品，其纯度在97.5％到98.3％之间。
根据上述实验数据可知，由本发明的制备方法得到的厄他培南钠盐收率高、纯度较高，适合工业化生产。

Claims (5)

1.一种厄他培南单钠盐的合成方法，合成路线为
Figure FDA0001724647650000011
所述合成方法包括以下合成步骤：
步骤(1)：将式Ⅰ所示的培南母核MAP与式Ⅱ的厄他培南侧链于溶剂及碱中发生对接反应，生成中间产物；
步骤(2)：将上述中间产物以雷尼镍作为催化剂、碳酸氢钠作为碱化剂进行氢化脱保护制得厄他培南单钠盐粗品，再经过析晶纯化的方法，即可精制得到厄他培南单钠盐，即：[4R,5S,6S]-3-[[(3S,5S)-5-[[(3-羧基苯基)氨基]-3-吡咯烷基]硫基]-6-[(1R)-1-羟基乙基]-4-甲基-7-氧-1-氮杂二环[3.2.0]庚-2-烯-2-羧酸单钠盐。
2.如权利要求1所述的厄他培南单钠盐的合成方法，其特征在于，步骤(1)中所述的碱为二异丙基胺、三乙胺、二异丙基乙基胺、乙二胺中的至少一种。
3.如权利要求1所述的厄他培南单钠盐的合成方法，其特征在于，步骤(1)的反应温度为-30～-10℃。
4.如权利要求1所述的厄他培南单钠盐的合成方法，其特征在于，步骤(1)中所述的溶剂为四氢呋喃、N-甲基吡咯烷酮、二氯甲烷、乙腈中的至少一种。
5.如权利要求1所述的厄他培南单钠盐的合成方法，其特征在于，步骤(2)中所述的雷尼镍用量为5％～20％。
CN201810747154.5A 2018-07-09 2018-07-09 一种厄他培南单钠盐的合成方法 Active CN110698478B (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201810747154.5A CN110698478B (zh) 2018-07-09 2018-07-09 一种厄他培南单钠盐的合成方法

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201810747154.5A CN110698478B (zh) 2018-07-09 2018-07-09 一种厄他培南单钠盐的合成方法

Publications (2)

Publication Number Publication Date
CN110698478A true CN110698478A (zh) 2020-01-17
CN110698478B CN110698478B (zh) 2023-09-08

Family

ID=69192631

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201810747154.5A Active CN110698478B (zh) 2018-07-09 2018-07-09 一种厄他培南单钠盐的合成方法

Country Status (1)

Country Link
CN (1) CN110698478B (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113880839A (zh) * 2021-11-01 2022-01-04 石药集团中诺药业（石家庄）有限公司 一种厄他培南钠粗品的合成新方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100004463A1 (en) * 2008-07-04 2010-01-07 Acs Dobfar S.P.A. Process for synthesizing carbapenem using raney nickel
CN103524507A (zh) * 2012-07-05 2014-01-22 天津九海医药科技有限公司 一种厄他培南钠盐的制备方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100004463A1 (en) * 2008-07-04 2010-01-07 Acs Dobfar S.P.A. Process for synthesizing carbapenem using raney nickel
CN103524507A (zh) * 2012-07-05 2014-01-22 天津九海医药科技有限公司 一种厄他培南钠盐的制备方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
史颖 等: "厄他培南钠的合成研究" *
郭树栋 等: "厄他培南钠的合成" *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113880839A (zh) * 2021-11-01 2022-01-04 石药集团中诺药业（石家庄）有限公司 一种厄他培南钠粗品的合成新方法

Also Published As

Publication number Publication date
CN110698478B (zh) 2023-09-08

Similar Documents

Publication Publication Date Title
US8097719B2 (en) Meropenem intermediate in novel crystalline form and a method of manufacture of meropenem
US9902751B2 (en) Process for the preparation of empagliflozin
CN1139596C (zh) 头孢地尼的胺盐晶体
US20120095210A1 (en) Process for the preparation of beta-lactam antibiotic
WO2008062279A2 (en) An improved process for the preparation of carbapenem antibiotic
US9233963B2 (en) Method for preparing meropenem using zinc powder
CN100497338C (zh) 4－甲基－7－氧－1－氮杂双环[3.2.0]庚－2－烯－2－羧酸类衍生物的制备方法
CN105111117A (zh) 制备截短侧耳素的工艺
WO2006117763A2 (en) A process for the preparation of doripenem
CN110698478B (zh) 一种厄他培南单钠盐的合成方法
CN102702201B (zh) 一种多尼培南中间体化合物、其制备方法和用途以及多尼培南的制备方法
WO2013121279A2 (en) Process to prepare ertapenem
CN110698477A (zh) 一种厄他培南单钠盐的合成方法
CN101805359B (zh) 一种制备高纯度比阿培南的方法
CN102336757A (zh) 一种稳定晶型的美罗培南化合物
CN109096283A (zh) 一种高纯度替比培南酯晶体的制备方法
CN110698480B (zh) 一种厄他培南中间体的合成及纯化方法
CN103524507A (zh) 一种厄他培南钠盐的制备方法
CN102532140B (zh) 一种美罗培南三水合物的制备方法
KR20110062515A (ko) 메로페넴 삼수화물의 제조방법
CN110698479A (zh) 一种厄他培南单钠盐的合成方法
CN114685499A (zh) 一种阿维巴坦钠的制备方法
CN110256464A (zh) 头孢妥仑匹酯开环二聚体的制备方法
KR20170102340A (ko) 포로데신의 제조 방법
CN113929684B (zh) 一种美罗培南中间体及其制备方法

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant