CN113880839A - 一种厄他培南钠粗品的合成新方法 - Google Patents
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- 239000012043 crude product Substances 0.000 title claims abstract description 17
- 229960002818 ertapenem sodium Drugs 0.000 title claims abstract description 10
- ZXNAQFZBWUNWJM-HRXMHBOMSA-M ertapenem sodium Chemical compound [Na+].O=C([C@H]1[NH2+]C[C@H](C1)SC=1[C@H](C)[C@@H]2[C@H](C(N2C=1C([O-])=O)=O)[C@H](O)C)NC1=CC=CC(C([O-])=O)=C1 ZXNAQFZBWUNWJM-HRXMHBOMSA-M 0.000 title claims abstract description 10
- 238000001308 synthesis method Methods 0.000 title abstract description 6
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- 238000000034 method Methods 0.000 claims abstract description 16
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- JUZNIMUFDBIJCM-ANEDZVCMSA-N Invanz Chemical group O=C([C@H]1NC[C@H](C1)SC=1[C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)NC1=CC=CC(C(O)=O)=C1 JUZNIMUFDBIJCM-ANEDZVCMSA-N 0.000 claims abstract description 14
- 230000005494 condensation Effects 0.000 claims abstract description 14
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 9
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
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- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
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- 239000000203 mixture Substances 0.000 claims description 2
- HHXMXAQDOUCLDN-RXMQYKEDSA-N penem Chemical compound S1C=CN2C(=O)C[C@H]21 HHXMXAQDOUCLDN-RXMQYKEDSA-N 0.000 claims description 2
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- 230000000844 anti-bacterial effect Effects 0.000 description 2
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
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- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- -1 3-carboxyphenyl Chemical group 0.000 description 1
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010024774 Localised infection Diseases 0.000 description 1
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- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 241000588650 Neisseria meningitidis Species 0.000 description 1
- 108010087702 Penicillinase Proteins 0.000 description 1
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- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
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- 241000191967 Staphylococcus aureus Species 0.000 description 1
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- 102000006635 beta-lactamase Human genes 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
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- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- DHSUYTOATWAVLW-WFVMDLQDSA-N cilastatin Chemical compound CC1(C)C[C@@H]1C(=O)N\C(=C/CCCCSC[C@H](N)C(O)=O)C(O)=O DHSUYTOATWAVLW-WFVMDLQDSA-N 0.000 description 1
- 229960004912 cilastatin Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
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- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
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- 230000004260 plant-type cell wall biogenesis Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
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- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
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Classifications
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- 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
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- 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
本发明公开了一种厄他培南钠粗品的合成新方法。该方法简化了生产操作,提高了总收率,粗品质量符合质量要求。该方法实现了缩合物无需结晶分离,直接用于下步氢化,简化了生产操作,缩短了生产处理时间,降低了缩合物的降解,提高了粗品总收率。本发明按以下步骤进行:将培南母核MAP和厄他培南侧链投入反应釜中,反应完毕后,料液加入到一种有机溶媒和水的混合液中,调pH,经盐水洗涤后,分相,有机相直接用于下一步的氢化工序。后期按现有工艺制备即可得到符合要求的厄他培南钠粗品。
Description
技术领域
本发明涉及的一种厄他培南钠粗品的合成新方法。
背景技术
厄他培南钠(Etapenem sodium),化学名为(4R,5S,6S)-3-[[(3S,5S)-5-[[(3-羧基苯基)氨基甲酰基]吡咯烷-3-基]硫-6-(1-羟基乙基)-4-甲基-7-氧代-1-氮杂双环[3.2.0]庚-2-烯-2-甲酸钠盐,结构式:
厄他培南为美国默克公司和阿斯利康公司共同开发的新型广谱碳青霉烯类抗生素,分别于2001年11月和2002年4月在美国和欧洲批准临床应用,2005年由默沙东公司引进我国。厄他培南具有长效、抗菌活性强和细菌耐药选择性低等特点,较其他药物具有明显的临床治疗优势,为首个被FDA批准用于社区获得性肺炎的碳青霉烯类药物,同时可用于糖尿病并发症足部感染的治疗。厄他培南是通过与青霉素结合蛋白(PBP)结合,干扰细菌细胞壁的合成,导致细菌生长繁殖受抑制,少数出现细胞溶解。厄他培南对大多数青霉素酶、头孢菌素酶和超广谱β-内酰胺酶(ESBLs)稳定,但可被金属酶水解。厄他培南对甲氧西林敏感金葡菌、肺炎链球菌、化脓性链球菌等革兰阳性菌、肠杆菌科细菌具有高度抗菌活性;嗜血杆菌属、卡他莫拉菌、脑膜炎奈瑟球菌等对本品高度敏感,但甲氧西林耐药葡萄球菌、肠球菌属、铜绿假单胞菌、不动杆菌属等细菌对本品耐药。本品对人肾脱氢肽酶-Ⅰ稳定,不需与西司他丁等联合应用。
目前的工艺均为两步法,第一步先制备出缩合物,得到缩合物结晶。第二步再氢化,制得到厄他培南粗品。过程较繁琐,耗时长,而厄他培南中间体及产品均较容易降解,导致杂质偏高,收率也较低。
发明内容
本发明提供了一种厄他培南钠粗品的合成新方法,提高了粗品总收率。
本发明的技术方案如下:
本发明提供一种厄他培南钠粗品的合成方法,含有如下步骤:
(1)将培南母核MAP和厄他培南侧链投入反应釜中,缩合反应完毕,得到缩合液;
(2)缩合液加入到一种有机溶媒和水的混合液中水解,调pH,分相;
(3)有机相经盐溶液洗涤后,分相,有机相直接用于下一步的氢化工序;
(4)氢化反应,结晶。
其中,步骤(1)反应完毕无需结晶,直接将缩合液加入到有机溶剂和水的混合物中水解,缩合物水解完毕直接进入有机相中。
其中,步骤(2)中所述水解所用的有机溶剂为乙酸甲酯、乙酸乙酯、乙酸异丙酯,乙酸丁酯,优选乙酸乙酯。
其中,步骤(3)中所述洗涤有机相的盐溶液为氯化钠溶液。
其中,上述氯化钠溶液的质量百分比为5~15%,优选6-10%,最优选为7-8%。
其中,步骤(3)中所得有机相直接用于后续氢化反应,后处理,制备厄他培南粗品,粗品质量符合要求。
其中,步骤(2)中所述水解的加水体积是缩合液体积的0.8~1.2倍,优选1倍。
其中,步骤(2)中所述水解中加入钯碳,用量为MAP重量的1%,所述钯碳是5%的钯碳。
其中,步骤(2)中所述有机溶媒为四氢呋喃,用量是缩合液体积的0.5~1倍,优选0.8倍。
其中,步骤(4)中所述氢化反应的氢化压力控制0.5~1.0MPa,优选0.8MPa
其中,步骤(4)中所述氢化反应的氢化温度为20~30摄氏度,优选25摄氏度。
其中,步骤(4)中所述氢化反应的氢化时间为1~4小时,优选2小时。
其中,步骤(4)中所述结晶,加入结晶溶剂选自四氢呋喃、丙酮、乙酸乙酯,优选丙酮。
其中,上述丙酮加入体积是氢化液体积的5~8倍,优选6倍。
上述厄他培南钠粗品的合成新方法中,有机相直接用于后续氢化反应,后处理,制备厄他培南粗品,粗品质量符合要求。
具体实施方式
实施例1厄他培南粗品的合成
向干燥洁净的250ml四口瓶中加入150mL甲基吡咯烷酮,再加入培南双环母核,(简称MAP)纯度99%20.0g(33.6mmol,1.0eq),加入侧链16.2g(36.3mmol,1.08eq),一次性加入9.9g(56.8mmol,1.69eq)三乙胺,控温20~25℃反应6h,得到缩合液待用。
将反缩合液倒入量筒,测量体积,按体积折算,加入等1倍体积的水和0.6倍体积的四氢呋喃,加入1g 5%的钯碳,搅拌后加入氢化釜。
控温25℃,保持氢气压力0.8MPa,氢化2小时,得到氢化液。
氢化液过滤除去钯碳,测量体积,加入6倍体积的丙酮结晶,得到白色的厄他培南粗品,纯度98.9%,水分2.1%,产品10.8g,按MAP折算重量收率54%。
Claims (10)
1.一种厄他培南钠粗品的合成方法,含有如下步骤:
(1)将培南母核MAP和厄他培南侧链投入反应釜中,缩合反应完毕,得到缩合液;
(2)缩合液加入到一种有机溶媒和水的混合液中水解,调pH,分相;
(3)有机相经盐溶液洗涤后,分相,有机相直接用于下一步的氢化工序;
(4)氢化反应,结晶。
2.如权利要求1所述的方法,其特征在于步骤(1)反应完毕无需结晶,直接将缩合液加入到有机溶剂和水的混合物中水解,缩合物水解完毕直接进入有机相中。
3.如权利要求1所述的方法,其特征在于步骤(2)中所述水解所用的有机溶剂为乙酸甲酯、乙酸乙酯、乙酸异丙酯,乙酸丁酯,优选乙酸乙酯。
4.如权利要求1所述的方法,其特征在于步骤(3)中所述盐溶液为氯化钠溶液,优选氯化钠溶液的质量百分比为5~15%,优选6-10%,最优选为7-8%。
5.如权利要求1所述的方法,其特征在于步骤(3)中所得有机相直接用于后续氢化反应。
6.如权利要求1所述的方法,其特征在于步骤(2)中水体积是缩合液体积的0.8~1.2倍,优选1倍。
7.如权利要求1所述的方法,其特征在于步骤(2)中所述水解中加入钯碳,用量为MAP重量的1%,所述钯碳是5%的钯碳。
8.如权利要求1所述的方法,其特征在于步骤(2)中所述有机溶媒为四氢呋喃,用量是缩合液体积的0.5~1倍,优选0.8倍。
9.如权利要求1所述的方法,其特征在于步骤(4)中所述氢化反应的氢化压力控制0.5~1.0MPa,优选0.8MPa,或
所述氢化反应的氢化温度为20~30℃,优选25℃,或
所述氢化反应的氢化时间为1~4小时,优选2小时。
10.如权利要求1所述的方法,其特征在于步骤(4)中所述结晶,加入结晶溶剂选自四氢呋喃、丙酮、乙酸乙酯,优选丙酮,进一步优选丙酮加入体积是氢化液体积的5~8倍,优选6倍。
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