CN104844622A - 一种新型青霉素衍生物及其制备方法 - Google Patents

一种新型青霉素衍生物及其制备方法 Download PDF

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CN104844622A
CN104844622A CN201510069138.1A CN201510069138A CN104844622A CN 104844622 A CN104844622 A CN 104844622A CN 201510069138 A CN201510069138 A CN 201510069138A CN 104844622 A CN104844622 A CN 104844622A
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derivative
pencillin
preparation
novel
acid salt
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李宁宇
徐玉芳
王俊锋
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and 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
    • C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
    • C07D499/48—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical
    • C07D499/58—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical
    • C07D499/64—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by nitrogen atoms
    • C07D499/70—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by nitrogen atoms with hetero rings as additional substituents on the carbon chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D499/04—Preparation
    • C07D499/08—Modification of a carboxyl radical directly attached in position 2, e.g. esterification

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明公开了一种新型青霉素衍生物及其制备方法，所述的青霉素衍生物为(2S，5R，6R)-3，3-二甲基-7-氧代-6-[2-(2-氨基-4-噻唑基)-2-(甲氧亚氨基)乙酰氨基]-4-硫杂-1-氮杂双环[3.2.0]-庚烷-2-羧酸盐(酯)，它的结构通式为：

Description

一种新型青霉素衍生物及其制备方法
技术领域
本发明涉及一种青霉素衍生物，具体是一种在6位上有2-(2-氨基-4-噻唑基)-2-(甲氧亚氨基)乙酰氨基侧链的青霉菌素衍生物。
背景技术
青霉素是第一种能够治疗人类疾病的抗生素，能破坏细菌的细胞壁并在细菌细胞的繁殖期起杀菌作用，广泛用作为包括人类在内的哺乳动物的抗菌素。在这一技术领域，为了提高青霉菌素抗菌素的效果和安全性，已经从各方面进行过深入的研究，研发出多种青霉菌素衍生物的抗生素，如青霉素V、非奈西林，苯唑西林、氯唑西林、双氯西林、氟氯西林、氨苄西林、阿莫西林、匹氨西林等，至今在临床上广泛应用。
发明内容
本发明的目的在于提供一种新型青霉菌素衍生物的无毒盐和无毒酯，该青霉素衍生物具有宽抗菌谱高杀菌活性，以解决上述背景技术中提出的问题。
为实现上述目的，本发明提供如下技术方案：
一种新型青霉素衍生物，所述的青霉素衍生物为(2S，5R，6R)-3，3-二甲基-7-氧代-6-[2-(2-氨基-4-噻唑基)-2-(甲氧亚氨基)乙酰氨基]-4-硫杂-1-氮杂双环[3.2.0]-庚烷-2-羧酸盐(酯)，它的结构通式为：其中，R是1-6碳烷基或钠、钾、特戊酰氧甲基。
所述的青霉素衍生物的制备方法，包括以下步骤：
(1)羧酸盐制备式化合物：
其中，R1是钠、钾，所用的溶媒是二氯甲烷、丙酮、乙酸乙酯、甲醇、乙醇或DMF；
(2)酯化制备式化合物：
其中，R2是卤族元素，所用的溶媒是二氯甲烷、丙酮乙酸乙酯、甲醇、乙醇或DMF。
与现有技术相比，本发明的有益效果是：本发明的化合物生产工艺成熟，生产成本较低，可以做成各种制剂剂型经注射或口服用于包括人在内的哺乳动物；经动物毒性试验和药效试验，本发明的化合物，杀菌效果明显优于阿莫西林等其它青霉菌素衍生物，且毒副作用更小；抗菌谱广，对G+和G-细菌均有较强杀菌作用，对G+菌的作用尤为显著；本发明具有较高的临床应用价值和市场生产价值。
具体实施方式
下面结合具体实施方式对本专利的技术方案作进一步详细地说明。
实施例1：
二氯甲烷60ml加入100ml四口烧瓶中，加入6-APA2.16g(0.01mol)，搅拌降温至-5℃，滴加入三乙胺1.11g(0.012mol)，再加入AE-活性酯3.85g(0.011mol)，反应2小时，升温至8℃再反应1小时，降温至0℃，搅拌滴加入异辛酸钠二氯甲烷溶液，所述异辛酸钾二氯甲烷溶液的配置方法为：采用异辛酸钾2.18g(0.012mol)溶解入10ml二氯甲烷中；反应1小时，过滤，固体用10ml无水丙酮泡洗三次，抽干，再用5ml无水乙醇淋洗，抽干，40℃下真空干燥，得到白色目标产物(2S，5R，6R)-3，3-二甲基-7-氧代-6-[2-(2-氨基-4-噻唑基)-2-(甲氧亚氨基)乙酰氨基]-4-硫杂-1-氮杂双环[3.2.0]-庚烷-2-羧酸钠 盐3.03g(0.0073mol)，所述白色目标产物经HPLC检测含量超过99％，产率为73％。
实施例2：
二氯甲烷60ml加入100ml四口烧瓶中，加入6-APA2.16g(0.01mol)，搅拌降温至-5℃，滴加入三乙胺1.11g(0.012mol)，再加入AE-活性酯3.85g(0.011mol)，反应2小时，升温至8℃再反应1小时，降温至0℃，搅拌滴加异辛酸钾二氯甲烷溶液，所述异辛酸钾二氯甲烷溶液的配置方法为：采用异辛酸钾2.18g(0.012mol)溶解入10ml二氯甲烷中；反应时间为1小时，过滤，固体用10ml无水丙酮泡洗三次，抽干，再用5ml无水乙醇淋洗，抽干，40℃下真空干燥，得到白色目标产物(2S，5R，6R)-3，3-二甲基-7-氧代-6-[2-(2-氨基-4-噻唑基)-2-(甲氧亚氨基)乙酰氨基]-4-硫杂-1-氮杂双环[3.2.0]-庚烷-2-羧酸钾盐3.28g(0.0075mol)(HPLC检测含量超过99％)，产率75％。
实施例3：
DMF50ml加入200ml四口烧瓶中，加入合成实施例2制备的目标产物钾盐4.37g(0.01mol)，搅拌降温至-10℃，加入溴甲基特戊酰酯2.34g(0.012mol)，反应30分钟，升温至20℃继续反应30分钟，取样层析检测，原料钾盐斑点很微弱时，搅拌加入冰水50ml至反应瓶，终止反应；反应液用乙酸乙酯100ml×3萃取3次，合并乙酸乙酯项，用30ml水反洗1次，有机相加入无水硫酸镁干燥过夜，过滤，用乙酸乙酯洗涤固体，滤干，合并滤液，真空蒸干，得到淡黄色目标产物(2S，5R，6R)-3，3-二甲基-7-氧代-6-[2-(2-氨基-4-噻唑基)-2-(甲氧亚氨基)乙酰氨基]-4-硫杂-1-氮杂双环[3.2.0]-庚烷-2-羧酸特戊酰氧 甲酯1.88g(0.006mol)，所述淡黄色目标产物经HPLC检测含量超过85％，产率60％。
上面对本专利的较佳实施方式作了详细说明，但是本专利并不限于上述实施方式，在本领域的普通技术人员所具备的知识范围内，还可以在不脱离本专利宗旨的前提下作出各种变化。

Claims (2)

1.一种新型青霉素衍生物，其特征在于：所述的青霉素衍生物为(2S，5R，6R)-3，3-二甲基-7-氧代-6-[2-(2-氨基-4-噻唑基)-2-(甲氧亚氨基)乙酰氨基]-4-硫杂-1-氮杂双环[3.2.0]-庚烷-2-羧酸盐(酯)，它的结构通式为：其中，R是1-6碳烷基或钠、钾、特戊酰氧甲基。
2.根据权利要求1所述的新型青霉素衍生物的制备方法，其特征在于，包括以下步骤：
(1)羧酸盐制备式化合物：
其中，R1是钠、钾，所用的溶媒是二氯甲烷、丙酮、乙酸乙酯、甲醇、乙醇或DMF；
(2)酯化制备式化合物：
其中，R2是卤族元素，所用的溶媒是二氯甲烷、丙酮乙酸乙酯、甲醇、乙醇或DMF。
CN201510069138.1A 2015-02-06 2015-02-06 一种新型青霉素衍生物及其制备方法 Pending CN104844622A (zh)

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CN109400630A (zh) * 2018-11-23 2019-03-01 浙江普洛得邦制药有限公司 一种氟氯西林钠的合成方法
CN111024847A (zh) * 2019-12-24 2020-04-17 河北合佳医药科技集团股份有限公司 一种柱前衍生化法测定ae-活性酯纯度的方法

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109400630A (zh) * 2018-11-23 2019-03-01 浙江普洛得邦制药有限公司 一种氟氯西林钠的合成方法
CN109400630B (zh) * 2018-11-23 2021-07-02 浙江普洛得邦制药有限公司 一种氟氯西林钠的合成方法
CN111024847A (zh) * 2019-12-24 2020-04-17 河北合佳医药科技集团股份有限公司 一种柱前衍生化法测定ae-活性酯纯度的方法

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