CN110698477A - 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

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CN110698477A
CN110698477A CN201810746397.7A CN201810746397A CN110698477A CN 110698477 A CN110698477 A CN 110698477A CN 201810746397 A CN201810746397 A CN 201810746397A CN 110698477 A CN110698477 A CN 110698477A
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monosodium salt
ertapenem
ertapenem monosodium
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申理滔
喻林
唐红伟
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Wuhan QR Pharmaceuticals Co Ltd
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    • 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
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    • 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
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    • C07—ORGANIC CHEMISTRY
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    • 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
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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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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：将带有保护基的培南母核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，再经过树脂纯化的方法，即可精制得到厄他培南单钠盐，该合成方法收率大大提高，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。

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(ertapenem)为美国默克制药公司开发的新型广谱碳青霉烯类抗生素，对DHP-1稳定的培南类抗生素，用于治疗社区获得性混合感染可获满意疗效。本品分别于2001年11月和2002年4月在美国和欧洲上市。该药品目前在国内全部依赖进口，尚无厂家生产。
目前，国内已有多家公司致力于厄他培南的研发，大多采用默克公司的专利中的路线(专利号：US2004/0235817A1)，但是该路线中成本较高、存在安全隐患等问题。
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、存在安全隐患等问题，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：
该合成路线包括以下步骤：
步骤(1)将式(Ⅰ)所示的带有保护基的培南母核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)将上述中间产物以钯-炭作为催化剂、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、二氯甲烷、乙腈中的至少一种。
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；将上述中间产物以钯-炭作为催化剂、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，再经过树脂纯化的方法，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69.3％。
实施例2
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；将上述中间产物以钯-炭作为催化剂、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，再经过树脂纯化的方法，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65.7％。
实施例3
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；将上述中间产物以钯-炭作为催化剂、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，再经过树脂纯化的方法，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64.8％。
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≤0.5％，开环降解物≤0.6％，Pro-MABA≤0.4％，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 FDA0001724470580000011
所述合成方法包括以下合成步骤：
步骤(1)：将式Ⅰ所示的带有保护基的培南母核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)：将上述中间产物以钯-炭作为催化剂、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，再经过树脂纯化的方法，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、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)中所述的树脂至少包括HZPD、XAD树脂中的一种。
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US20060069081A1 (en) * 2004-06-10 2006-03-30 Woo-Baeg Choi Carbapenem antibacterials with gram-negative activity and processes for their preparation
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