CN116332936A - Preparation method of p-aminobenzyl ertapenem sodium and application thereof in preparation research - Google Patents
Preparation method of p-aminobenzyl ertapenem sodium and application thereof in preparation research Download PDFInfo
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- CN116332936A CN116332936A CN202111596551.5A CN202111596551A CN116332936A CN 116332936 A CN116332936 A CN 116332936A CN 202111596551 A CN202111596551 A CN 202111596551A CN 116332936 A CN116332936 A CN 116332936A
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- ertapenem
- sodium
- aminobenzyl
- nitrobenzyl
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- 229960002818 ertapenem sodium Drugs 0.000 title claims abstract description 37
- -1 p-aminobenzyl ertapenem sodium Chemical compound 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims description 24
- 125000003396 thiol group Chemical group [H]S* 0.000 claims abstract description 10
- VOLRSQPSJGXRNJ-UHFFFAOYSA-N 4-nitrobenzyl bromide Chemical compound [O-][N+](=O)C1=CC=C(CBr)C=C1 VOLRSQPSJGXRNJ-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229960002770 ertapenem Drugs 0.000 claims abstract description 8
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 claims abstract description 8
- 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 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 3
- 239000003513 alkali Substances 0.000 claims abstract 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 11
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 238000005984 hydrogenation reaction Methods 0.000 claims description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 238000010511 deprotection reaction Methods 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims 3
- 230000000397 acetylating effect Effects 0.000 claims 1
- 239000003153 chemical reaction reagent Substances 0.000 claims 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims 1
- 235000015497 potassium bicarbonate Nutrition 0.000 claims 1
- 239000011736 potassium bicarbonate Substances 0.000 claims 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims 1
- 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 abstract description 21
- 239000012535 impurity Substances 0.000 abstract description 13
- 238000000034 method Methods 0.000 abstract description 12
- 238000002347 injection Methods 0.000 abstract description 7
- 239000007924 injection Substances 0.000 abstract description 7
- 239000000843 powder Substances 0.000 abstract description 7
- 150000001875 compounds Chemical class 0.000 abstract description 4
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 abstract 2
- 239000002585 base Substances 0.000 abstract 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 10
- 229940079593 drug Drugs 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 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 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- SBMSLRMNBSMKQC-UHFFFAOYSA-N pyrrolidin-1-amine Chemical compound NN1CCCC1 SBMSLRMNBSMKQC-UHFFFAOYSA-N 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 description 1
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- ASSMPDZEDVTRKG-UHFFFAOYSA-N 4-(bromomethyl)aniline Chemical compound NC1=CC=C(CBr)C=C1 ASSMPDZEDVTRKG-UHFFFAOYSA-N 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- IWKLVDHQOMKMCX-HJXLNUONSA-N [Na].O[C@H]1CN[C@H](C(O)=O)C1 Chemical compound [Na].O[C@H]1CN[C@H](C(O)=O)C1 IWKLVDHQOMKMCX-HJXLNUONSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000002924 anti-infective effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000036457 multidrug resistance Effects 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- RZXMPPFPUUCRFN-UHFFFAOYSA-N p-toluidine Chemical compound CC1=CC=C(N)C=C1 RZXMPPFPUUCRFN-UHFFFAOYSA-N 0.000 description 1
- HHXMXAQDOUCLDN-RXMQYKEDSA-N penem Chemical compound S1C=CN2C(=O)C[C@H]21 HHXMXAQDOUCLDN-RXMQYKEDSA-N 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
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
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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
- C07D207/04—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 no double bonds between ring members or between ring members and non-ring members
- C07D207/10—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 no double bonds between ring members or between ring members and non-ring members 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
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- 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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- 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
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- 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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Abstract
Description
技术领域technical field
本发明涉及一种碳青霉烯类抗生素杂质的制备方法，属药物化学领域。The invention relates to a preparation method of carbapenem antibiotic impurities, belonging to the field of medicinal chemistry.
背景技术Background technique
厄他培南钠由默克公司开发，分别于2001年11月和2002年4月在美国和欧洲上市，
2005年在中国上市。厄他培南钠是一种碳青霉烯类抗生素，其结构式为：
药品的合成过程中，不可避免的会有杂质的产生，药品中的杂质对于用药存在着一定的安全隐患，目前国内外对药品审批过程中的杂质研究要求越来越高，厄他培南钠品种在美国药典中对已知的18个杂质进行了控制，原研公司默克在文献（J.Org.Chem.2005,70,7479-7487）中对制备工艺中的主要杂质进行了分析，特别提及了对氨基苄基厄他培南钠的产生途径：中间体A在氢解时，产生中间态化合物Ⅰ，进一步的加氢会产生中间态化合物Ⅱ，化合物Ⅱ从而转变为厄他培南钠以及化合物Ⅲ，化合物Ⅲ进一步转化为对氨基甲苯，路线如下。但在这个过程中，厄他培南钠结构中的吡咯烷胺作为亲核试剂可能与化合物Ⅲ进行反应，从而产生杂质对氨基苄基厄他培南钠。During the synthesis process of drugs, there will inevitably be impurities. The impurities in drugs have certain safety hazards for drug use. At present, the requirements for impurity research in the drug approval process are getting higher and higher at home and abroad. Ertapenem Sodium The 18 known impurities are controlled in the United States Pharmacopoeia, and the original research company Merck analyzed the main impurities in the preparation process in the literature (J.Org.Chem.2005, 70, 7479-7487), especially The production path of p-aminobenzyl ertapenem sodium is mentioned: when intermediate A is hydrogenated, intermediate compound I will be produced, and further hydrogenation will produce intermediate compound II, which will be transformed into ertapenem Sodium and compound III, compound III is further converted into p-aminotoluene, the route is as follows. However, in this process, the pyrrolidinamine in the structure of ertapenem sodium may react with compound III as a nucleophile, thereby producing the impurity p-aminobenzyl ertapenem sodium.
对氨基苄基厄他培南钠既美国药典厄他培南钠品种中控制的已知杂质O，限度为＜0.1%，目前无该化合物的合成文献报道。Para-aminobenzyl ertapenem sodium is a known impurity O controlled in the USP ertapenem sodium variety, the limit is <0.1%, and there is no synthesis literature report of this compound at present.
由于厄他培南钠结构的特性，导致其稳定性差，低温保存时亦会有明显的降解，同时由于厄他培南钠的结构中还含有两个羧基，故直接采取对氨基苄溴与厄他培南钠进行合成较为困难，由此开发一条稳定的、易于操作的对氨基苄基厄他培南钠的合成制备路线对于厄他培南钠的质量研究和控制具有重要意义。Due to the structural characteristics of ertapenem sodium, its stability is poor, and it will be significantly degraded when stored at low temperature. At the same time, because the structure of ertapenem sodium also contains two carboxyl groups, it is necessary to directly take p-aminobenzyl bromide and ertapenem sodium. It is difficult to synthesize tapenem sodium, so developing a stable and easy-to-operate synthetic preparation route of p-aminobenzyl ertapenem sodium is of great significance for the quality research and control of ertapenem sodium.
发明内容Contents of the invention
分析厄他培南钠的结构并结合文献报道的合成路线可知，其主要采取MAP与厄他培南侧链进行缩合反应，然后加氢脱保护制得。路线如下：Analyzing the structure of ertapenem sodium and combining with the synthetic route reported in the literature, it can be seen that it is mainly prepared by condensation reaction between MAP and ertapenem side chain, followed by hydrogenation and deprotection. The route is as follows:
厄他培南侧链的制备则采取L-羟脯氨酸为原料，先经对硝基苄酯的保护，再成活性酯，硫代，氨解得到。路线如下：The preparation of the side chain of ertapenem uses L-hydroxyproline as the raw material, and it is firstly protected by p-nitrobenzyl ester, then converted into active ester, thiolated, and aminolyzed to obtain it. The route is as follows:
基于对侧链合成路线的分析，发明人曾尝试采取L-羟脯氨酸钠与对硝基苄溴进行反应后，套用侧链后续的工艺合成对硝基苄基侧链，但是由于基团的改变，加之成活性酯的制备过程对水分要求极高，采取该路线得到的对硝基苄基侧链收率极低，且工艺稳定性差。Based on the analysis of the side chain synthesis route, the inventor once tried to take L-hydroxyproline sodium and p-nitrobenzyl bromide to react, and then apply the subsequent process of the side chain to synthesize the p-nitrobenzyl side chain, but due to the In addition, the preparation process of the active ester has extremely high requirements on moisture, and the yield of the p-nitrobenzyl side chain obtained by taking this route is extremely low, and the process stability is poor.
由此，发明人通过对厄他培南侧链结构的进一步分析，开发了一条稳定的，易于操作的对氨基苄基厄他培南钠制备方法。路线如下：Therefore, the inventors have developed a stable and easy-to-operate method for preparing p-aminobenzyl ertapenem sodium through further analysis of the side chain structure of ertapenem. The route is as follows:
首先将厄他培南侧链的巯基通过乙酰基进行保护制得中间体1，然后加氢脱去对硝基苄酯获得中间体2，中间体2与对硝基苄溴在弱碱的作用下缩合制得中间体3，中间体3在碱的作用下脱去巯基的乙酰基保护制得对硝基苄基侧链，对硝基苄基侧链与MAP反应后加氢脱保护并还原硝基为氨基，即制得目标化合物对氨基苄基厄他培南钠。First, the mercapto group of the ertapenem side chain is protected by an acetyl group to obtain intermediate 1, and then the p-nitrobenzyl ester is hydrogenated to obtain intermediate 2, and intermediate 2 and p-nitrobenzyl bromide are reacted with a weak base The intermediate 3 is obtained by condensation under the action of a base, and the acetyl group protection of the mercapto group is removed by the intermediate 3 under the action of a base to obtain a p-nitrobenzyl side chain, and the p-nitrobenzyl side chain is reacted with MAP, then hydrogenated, deprotected and reduced The nitro group is an amino group, and the target compound p-aminobenzyl ertapenem sodium is obtained.
制备过程中，若不将侧链的巯基进行保护，直接脱去对硝基苄酯后与对硝基苄溴进行反应，则会由于巯基的反应活性强，制得的产物中含有大量的巯基和吡咯烷胺同时与对硝基苄溴作用的二取代物。In the preparation process, if the sulfhydryl group of the side chain is not protected, and the p-nitrobenzyl ester is directly removed and reacted with p-nitrobenzyl bromide, the resulting product will contain a large amount of sulfhydryl groups due to the strong reactivity of the sulfhydryl group. And pyrrolidinamine and p-nitrobenzyl bromide at the same time as the two substituents.
中间体2与对硝基苄溴反应过程中的缚酸剂极其重要，采用氢氧化钠、氢氧化钾等强碱，巯基的乙酰基保护会遭到破坏，从而产生大量的二取代物，即使采取碳酸盐或者有机弱碱，反应也会产生大量的二取代物，通过大量的试验对比，发明人发现采用无机弱碱碳酸氢盐在乙腈中50-55℃反应，效果较好，产物纯度可达75%以上。The acid-binding agent in the reaction process between intermediate 2 and p-nitrobenzyl bromide is extremely important. If strong bases such as sodium hydroxide and potassium hydroxide are used, the protection of the acetyl group of the mercapto group will be destroyed, thereby producing a large amount of secondary substitutes. Taking carbonates or organic weak bases, the reaction will also produce a large number of secondary substitutions. Through a large number of test comparisons, the inventors have found that using inorganic weak base bicarbonate to react in acetonitrile at 50-55 ° C has a better effect and product purity. Up to 75% or more.
采用本发明的路线制备对氨基苄基厄他培南钠，除中间体3的收率略微偏低，其他步骤收率均＞90%，中间体纯度均＞98%，目标物对氨基苄基厄他培南钠纯度＞97%，符合药品杂质研究时的定量定性纯度要求。Using the route of the present invention to prepare p-aminobenzyl ertapenem sodium, except for the slightly low yield of intermediate 3, the yields of other steps are all >90%, the purity of the intermediates are all >98%, and the target p-aminobenzyl The purity of ertapenem sodium is >97%, meeting the quantitative and qualitative purity requirements for drug impurity research.
将采取本工艺制备得到的对氨基苄基厄他培南钠作为杂质对照品采取外标法对不同工艺制备得到的厄他培南钠冻干粉针注射剂进行了检测，对氨基苄基厄他培南钠均＜0.1%。The p-aminobenzyl ertapenem sodium prepared by this process was used as the impurity reference substance to detect the ertapenem sodium freeze-dried powder injection prepared by different processes by using the external standard method, and the p-aminobenzyl ertapenem sodium Penem sodium was <0.1%.
具体实施方式Detailed ways
实施例1：中间体1的制备Embodiment 1: the preparation of intermediate 1
将厄他培南侧链60g，乙酸酐16ml，吡啶200ml加入三口瓶中，15-20℃搅拌反应4小时，加水2000ml，搅拌析晶1小时，抽滤，滤饼加水1000ml打浆2次，抽滤，滤饼40℃干燥，得中间体1干品65.1g，收率99.3%，纯度＞99%。Add 60g of ertapenem side chain, 16ml of acetic anhydride, and 200ml of pyridine into a three-neck flask, stir and react at 15-20°C for 4 hours, add 2000ml of water, stir and crystallize for 1 hour, filter with suction, add 1000ml of water to the filter cake, beat twice, pump After filtration, the filter cake was dried at 40°C to obtain 65.1 g of intermediate 1 as a dry product, with a yield of 99.3% and a purity of >99%.
实施例2：中间体2的制备Embodiment 2: the preparation of intermediate 2
将65.1g中间体1，纯化水325.5ml，碳酸氢钠35.9g，乙腈390.6ml，5%钯碳（含水约70%）52.1g加入高压釜中，保温20℃，保持压力1.2MPa加氢8小时，出料，抽滤，滤饼水洗，滤液用醋酸调节pH至5-6，加盐至饱和，加乙酸乙酯1400ml，搅拌10分钟，静置10分钟，抽滤，注意此时不要将水中过量的盐加入到抽滤漏斗中，滤饼抽干后，乙酸乙酯洗涤2次，40℃干燥，得中间体2干品37.6g，收率91.3%，纯度＞99%。Put 65.1g of intermediate 1, 325.5ml of purified water, 35.9g of sodium bicarbonate, 390.6ml of acetonitrile, and 52.1g of 5% palladium carbon (about 70% water) into the autoclave, keep the temperature at 20°C, and keep the pressure at 1.2MPa for hydrogenation 8 hours, discharging, suction filtration, filter cake washed with water, the filtrate was adjusted to pH 5-6 with acetic acid, added salt to saturation, added 1400ml of ethyl acetate, stirred for 10 minutes, left to stand for 10 minutes, and suction filtered. Excess salt in water was added to the suction filter funnel, and the filter cake was drained, washed twice with ethyl acetate, and dried at 40°C to obtain 37.6 g of intermediate 2 as a dry product, with a yield of 91.3% and a purity of >99%.
实施例3：中间体3的制备Embodiment 3: the preparation of intermediate 3
将37.6g中间体2，乙腈376ml，碳酸氢钠30.8g，对硝基苄溴25.1g加入到三口瓶中，50-55℃搅拌反应12小时，抽滤，滤液30℃减压浓缩至干，得油状物46.9g，收率86.6%，纯度75.7%。Add 37.6g of intermediate 2, 376ml of acetonitrile, 30.8g of sodium bicarbonate, and 25.1g of p-nitrobenzyl bromide into a three-necked flask, stir and react at 50-55°C for 12 hours, filter with suction, and concentrate the filtrate to dryness at 30°C under reduced pressure. 46.9 g of oil was obtained, with a yield of 86.6% and a purity of 75.7%.
将油状物过硅胶柱，采用乙酸乙酯-正己烷1:1进行洗脱，收集目标物的过柱液，30℃减压蒸馏，得中间体3干品28.4g，纯度＞98%。The oily substance was passed through a silica gel column, and eluted with ethyl acetate-n-hexane 1:1, the column solution of the target product was collected, and distilled under reduced pressure at 30°C to obtain 28.4 g of intermediate 3 dry product, with a purity of >98%.
实施例4：中间体4的制备Embodiment 4: the preparation of intermediate 4
将28.4g中间体3加入到15-20℃的氢氧化钠水溶液（7.7g+568ml）中，保温15-20℃搅拌反应1.5小时，用醋酸调节pH至5-6，搅拌析晶1小时，抽滤，水洗，40℃干燥，得中间体4干品23.7g，收率92.3%，纯度＞98%。Add 28.4g of intermediate 3 to 15-20°C sodium hydroxide aqueous solution (7.7g+568ml), keep warm at 15-20°C and stir for 1.5 hours, adjust the pH to 5-6 with acetic acid, stir and crystallize for 1 hour, Suction filtration, washing with water, and drying at 40°C yielded 23.7 g of intermediate 4 as a dry product, with a yield of 92.3% and a purity of >98%.
实施例5：中间体5的制备Embodiment 5: the preparation of intermediate 5
将MAP35.1g，DMF280.8ml加入到三口瓶中，降温至-5℃，加入23.7g中间体4，降温至-20℃，滴加四甲基胍10.2g和DMF70.2ml的混合液，保温反应3小时，将反应液加入到1000ml冰水中，加醋酸调节pH至5-6，搅拌析晶1小时，抽滤，水洗，得中间体5湿品，纯度＞98%。Add 35.1g of MAP and 280.8ml of DMF into a three-necked flask, cool down to -5°C, add 23.7g of intermediate 4, cool down to -20°C, add dropwise a mixture of 10.2g of tetramethylguanidine and 70.2ml of DMF, and keep warm After reacting for 3 hours, the reaction solution was added to 1000ml of ice water, acetic acid was added to adjust the pH to 5-6, stirred and crystallized for 1 hour, suction filtered and washed with water to obtain the wet product of Intermediate 5 with a purity of >98%.
实施例6：对氨基苄基厄他培南钠的制备Example 6: Preparation of p-aminobenzyl ertapenem sodium
将中间体5湿品，纯化水263ml，碳酸氢钠15.9g，乙腈351ml，5%钯碳（含水约70%）44g加入高压釜中，保温20℃，保持压力1.2MPa加氢3小时，出料，抽滤，滤饼水洗，滤液用醋酸调节pH至5-6，加0-5℃的异丙醇3000ml，0-5℃保温析晶1小时，抽滤，湿品加水150ml，冻干，得对氨基苄基厄他培南钠29.5g，中间体4至对氨基苄基厄他培南钠两步总收率为82.9%，纯度＞97%。Put the wet product of Intermediate 5, 263ml of purified water, 15.9g of sodium bicarbonate, 351ml of acetonitrile, and 44g of 5% palladium carbon (about 70% water) into the autoclave, keep the temperature at 20°C, keep the pressure at 1.2MPa and hydrogenate for 3 hours. Suction filtration, washing the filter cake with water, adjusting the pH of the filtrate to 5-6 with acetic acid, adding 3000ml of isopropanol at 0-5°C, incubating and crystallizing at 0-5°C for 1 hour, suction filtration, adding 150ml of water to the wet product, and freeze-drying , to obtain 29.5 g of p-aminobenzyl ertapenem sodium, the two-step total yield of intermediate 4 to p-aminobenzyl ertapenem sodium was 82.9%, and the purity was >97%.
实施例7：按照专利CN100384845C中实施例1的制备方案，制得含厄他培南钠、碳酸氢钠以及氢氧化钠的冻干粉针注射剂，采用国家食品药品监督管理局进口药品注册标准（标准号：JX20080052）中有关物质的HPLC条件进行检测，同时使用本专利中描述的工艺制备得到的对氨基苄基厄他培南钠进行外标，冻干粉针注射剂中的对氨基苄基厄他培南钠杂质含量＜0.1%。Example 7: According to the preparation scheme of Example 1 in the patent CN100384845C, a freeze-dried powder injection containing ertapenem sodium, sodium bicarbonate and sodium hydroxide was prepared, and the imported drug registration standard of the State Food and Drug Administration ( Standard No.: JX20080052) for the detection of related substances in HPLC conditions, and at the same time use the p-aminobenzyl ertapenem sodium prepared by the process described in this patent as an external standard, p-aminobenzyl ertapenem sodium in the freeze-dried powder injection Tapenem sodium impurity content <0.1%.
实施例8：按照专利CN103127097B中实施例8的制备方案，制得含保护剂是柠檬酸的厄他培南钠冻干粉针注射剂，采用国家食品药品监督管理局进口药品注册标准（标准号：JX20080052）中有关物质的HPLC条件进行检测，同时使用本专利中描述的工艺制备得到的对氨基苄基厄他培南钠进行外标，冻干粉针注射剂中的对氨基苄基厄他培南钠杂质含量＜0.1%。Example 8: According to the preparation scheme of Example 8 in the patent CN103127097B, ertapenem sodium freeze-dried powder injection containing citric acid as a protective agent was prepared, and the imported drug registration standard of the State Food and Drug Administration was adopted (standard number: JX20080052) for the detection of related substances in HPLC conditions, and at the same time use the p-aminobenzyl ertapenem sodium prepared by the process described in this patent as an external standard, p-aminobenzyl ertapenem in the freeze-dried powder injection Sodium impurity content <0.1%.
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