CN102690266B - Method for preparing ertapenem sodium - Google Patents
Method for preparing ertapenem sodium Download PDFInfo
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- CN102690266B CN102690266B CN201110258264.3A CN201110258264A CN102690266B CN 102690266 B CN102690266 B CN 102690266B CN 201110258264 A CN201110258264 A CN 201110258264A CN 102690266 B CN102690266 B CN 102690266B
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- ertapenem
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- ertapenem intermediate
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- 238000000034 method Methods 0.000 title claims abstract description 45
- 229960002818 ertapenem sodium Drugs 0.000 title abstract 4
- 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 abstract 4
- JUZNIMUFDBIJCM-ANEDZVCMSA-N Invanz Chemical compound 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 108
- 229960002770 ertapenem Drugs 0.000 claims abstract description 108
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 49
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims abstract description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 46
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 41
- 238000006243 chemical reaction Methods 0.000 claims description 37
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- 238000000967 suction filtration Methods 0.000 claims description 29
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 23
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 23
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 19
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 16
- 239000002253 acid Substances 0.000 claims description 14
- 229910052799 carbon Inorganic materials 0.000 claims description 14
- 125000006502 nitrobenzyl group Chemical group 0.000 claims description 13
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 229960000583 acetic acid Drugs 0.000 claims description 11
- 239000012362 glacial acetic acid Substances 0.000 claims description 11
- 239000003513 alkali Substances 0.000 claims description 10
- OKDQKPLMQBXTNH-UHFFFAOYSA-N n,n-dimethyl-2h-pyridin-1-amine Chemical compound CN(C)N1CC=CC=C1 OKDQKPLMQBXTNH-UHFFFAOYSA-N 0.000 claims description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- 239000000706 filtrate Substances 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- -1 methoxy-benzyl Chemical group 0.000 claims description 7
- 239000012046 mixed solvent Substances 0.000 claims description 7
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical group CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 claims description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 5
- 230000002829 reductive effect Effects 0.000 claims description 5
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 5
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 4
- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 238000005119 centrifugation Methods 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- 239000010452 phosphate Substances 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 4
- 239000011591 potassium Substances 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- BGNGWHSBYQYVRX-UHFFFAOYSA-N 4-(dimethylamino)benzaldehyde Chemical compound CN(C)C1=CC=C(C=O)C=C1 BGNGWHSBYQYVRX-UHFFFAOYSA-N 0.000 claims description 3
- 239000011260 aqueous acid Substances 0.000 claims description 3
- 238000001556 precipitation Methods 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- 229940043279 diisopropylamine Drugs 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 229940045641 monobasic sodium phosphate Drugs 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims 1
- 239000003054 catalyst Substances 0.000 claims 1
- 239000003610 charcoal Substances 0.000 claims 1
- DAGQYUCAQQEEJD-UHFFFAOYSA-N tris(2-methylpropyl)phosphane Chemical compound CC(C)CP(CC(C)C)CC(C)C DAGQYUCAQQEEJD-UHFFFAOYSA-N 0.000 claims 1
- 230000009286 beneficial effect Effects 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 37
- 239000000047 product Substances 0.000 description 35
- 238000003756 stirring Methods 0.000 description 35
- 238000005984 hydrogenation reaction Methods 0.000 description 21
- 230000004224 protection Effects 0.000 description 21
- 238000001291 vacuum drying Methods 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 11
- 238000001035 drying Methods 0.000 description 9
- 239000012535 impurity Substances 0.000 description 9
- 125000002619 bicyclic group Chemical group 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 150000004678 hydrides Chemical class 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000010792 warming Methods 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 5
- 239000011259 mixed solution Substances 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 4
- 239000000284 extract Substances 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 239000011574 phosphorus Substances 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 229910017053 inorganic salt Inorganic materials 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000000630 rising effect Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 2
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 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
- JUZNIMUFDBIJCM-YZLSNGRKSA-N C[C@H](C([C@@H]([C@H]1C)N2C(C(O)=O)=C1S[C@@H](C1)CN[C@@H]1C(Nc1cc(C(O)=O)ccc1)=O)C2=O)O Chemical compound C[C@H](C([C@@H]([C@H]1C)N2C(C(O)=O)=C1S[C@@H](C1)CN[C@@H]1C(Nc1cc(C(O)=O)ccc1)=O)C2=O)O JUZNIMUFDBIJCM-YZLSNGRKSA-N 0.000 description 1
- 229910004373 HOAc Inorganic materials 0.000 description 1
- CJLNQTFMWROSFX-WUSBCXHWSA-N O[C@H](C)C1C2C(C=CN2C1=O)C.[S] Chemical compound O[C@H](C)C1C2C(C=CN2C1=O)C.[S] CJLNQTFMWROSFX-WUSBCXHWSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
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
- C07D477/02—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
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a method for preparing ertapenem sodium. In the method provided by the invention, an undried ertapenem intermediate is directly subjected to catalytic hydrogenation, or an ertapenem intermediate which is dried to a water content of 5-65% at 20-30 DEG C is subjected to catalytic hydrogenation, thereby preparing the ertapenem sodium. The method provided by the invention is beneficial to simply and efficiently preparing high-quality ertapenem sodium.
Description
Technical field
The present invention relates to a kind of method of preparing carbapenem antibiotic, be specifically related to a kind of method of preparing ertapenem.
Background technology
Ertapenem (ertapenem; as shown in Equation 1) be a kind of carbapenem antibiotic with broad spectrum antibacterial performance; developed jointly by Merck & Co., Inc. and Astrazeneca AB; its chemistry (4R by name; 5R; 6S)-3-[(3S; 5S)-5-[(3-carboxyl phenyl) formamyl] pyrrolidin-3-yl] sulphur-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-formic acid, concrete structure formula is as follows:
Ertapenem (as shown in Equation 2) is as the activeconstituents of ertapenem preparation, its synthetic extensive concern that is subject to.
The synthetic of ertapenem carries out according to following route conventionally:
Particularly, carry out condensation reaction by 1 beta-methyl carbon penicillenic parent nucleus MAP and side chain ES ', obtain protected ertapenem intermediate PE ', then react and slough protection by hydro-reduction, obtain ertapenem (formula 2) through aftertreatment.Wherein, R
1for allyl group, substituted benzyl; R
2for allyloxycarbonyl, substituted benzyl oxygen carbonyl or H
2 +cl
-; R
3for H, allyl group or substituted benzyl.
The synthetic line of current existing ertapenem comprises following several:
1, synthetic by the ertapenem intermediate PE ' of three protection structure types
In U.S. Pat 5478820, the technical scheme of the synthetic ertapenem of ertapenem intermediate PE ' of following two kind of three protection structure type is disclosed: 1) R
1, R
3for allyl group, R
2for allyloxycarbonyl; 2) R
1, R
2for to nitrobenzyl, R
3for allyloxycarbonyl.
2, synthetic by the ertapenem intermediate PE ' of two protection structure types
In PCT patent application WO9802439, R is disclosed
1, R
2for to nitrobenzyl, R
3for two technical schemes of protecting the ertapenem intermediate PE ' of structure types to synthesize ertapenems of H.
3, protect the ertapenem intermediate PE ' of structure type synthetic by list
In U.S. Pat 6504027, R is disclosed
1for to nitrobenzyl, R
2for H
2 +cl
-, R
3for single technical scheme of protecting the ertapenem intermediate PE ' of structure type to synthesize ertapenem of H.
Obviously, the preparation technology of ertapenem has experienced from the development course of three protections, two protection, single protection.From " Atom economy " angle of Green Chemistry; in chemical building-up process; synthetic method and technique should be designed to be transformed in final product as much as possible all raw material used in reaction process, and single protected mode is the most rational beyond doubt.
But, in U.S. Pat 6504027, the preparation method of disclosed ertapenem adopts the mode of one kettle way to prepare ertapenem by MAP, although need not isolate ertapenem intermediate PE ', but by unnecessary alkali in reaction, the inorganic salt that generate, two phenoxy group phosphonic acids and other impurity have all been brought hydrogenation into, like this, in order to remove unnecessary alkali and two phenoxy group phosphonic acids, need to increase extraction treatment step, strengthen the difficulty of aftertreatment, can in crude product, introduce inorganic salt simultaneously, affect product purity and content, so impurity this step before hydrogenation must be removed as far as possible, the quality of the efficient and the finished product that react with assurance subsequent hydrogenation, and the mode of one kettle way be unfavorable for effective removal of impurity.
Therefore first isolate highly purified ertapenem intermediate, then carry out hydrogenation, be conducive to obtain simply, efficiently high-quality ertapenem.
Summary of the invention
The inventor finds under study for action, preparing in the process of ertapenem intermediate (be called for short PE), due to reaction solution is poured in aqueous acid, the precipitation water content obtaining is higher, in general, prepare after compound, after drying and dehydrating, be conducive to the preservation of compound, but ertapenem intermediate is more responsive to ratio of specific heat, in the time of heat drying, if drying conditions is improper, time of drying is long, can cause ertapenem intermediate to decompose serious, cause the impurity in products of further reaction to increase, purity drop.In addition, the extensive material of applying in industrial production, even if be dried for a long time, its inside is also difficult to complete drying (reaching the water content of < 5%).
Therefore, the object of the invention is, for overcoming the prepared shortcoming that impurity in products content is high and purity is low, provide a kind of new method of preparing ertapenem.
The object of the invention is to be achieved through the following technical solutions.
Prepare a method for ertapenem, described method comprises that the ertapenem intermediate shown in following general formula PE is passed through to catalytic hydrogenation obtains ertapenem:
Wherein R
1for carboxyl-protecting group, be selected to nitrobenzyl, adjacent nitrobenzyl, to methoxy-benzyl, allyl group or TMS, preferably R
1for to nitrobenzyl;
The ertapenem intermediate that wherein said ertapenem intermediate is undried, or at 20～30 ℃, to be dried to water content be 5～65 % by weight, and preferred water content is the ertapenem intermediate of 40～65 % by weight.
Preferably, the reaction system of described catalytic hydrogenation comprises: the 1) mixed solvent of organic solvent and water, and wherein said organic solvent is selected from tetrahydrofuran (THF), DMF, N, one or more in N-N,N-DIMETHYLACETAMIDE and N-Methyl pyrrolidone, are preferably tetrahydrofuran (THF); And the volume ratio of described organic solvent and water is 1.05～1.5: 1, is preferably 1.05～1.2: 1; 2) catalyzer, is selected from one or more in palladium charcoal, zinc powder, tetrakis triphenylphosphine palladium, preferably palladium charcoal, more preferably 7.5 % by weight palladium charcoals; And 3) basifier, preferably supercarbonate, for example sodium bicarbonate.
Preferably, in described reaction system, the volume/mol ratio of mixed solvent and ertapenem intermediate is 10～30: 1, is preferably 16: 1; And/or the mol ratio of basifier and ertapenem intermediate is 3～4: 1; And/or the mass ratio of ertapenem intermediate and catalyzer is 1.7～3: 1, be preferably 2.4: 1.The mole number of described ertapenem intermediate PE is identical with carbapenem parent nucleus MAP mole number, is considered as carbapenem parent nucleus MAP 100% and is converted into ertapenem intermediate PE; The quality of described ertapenem intermediate is water-free quality.
Preferably, described catalytic hydrogenation condition comprises: pressure is 10-17 normal atmosphere; Temperature is 15～20 ℃; Time is 30min～120min, preferably 60～90min.
In a preferred embodiment, method provided by the invention comprises the following steps: 1) prepare the ertapenem intermediate shown in general formula PE; 2) catalytic hydrogenation step 1) the ertapenem intermediate prepared.
Preferably, described step 1) in the method for ertapenem intermediate of preparation comprise the carbapenem parent nucleus shown in following formula M AP reacted under alkali existence with the ertapenem side chain shown in following general formula E S:
Wherein R
1representation carboxy protecting group, is selected to nitrobenzyl, adjacent nitrobenzyl, to methoxy-benzyl, allyl group or TMS; Preferably R
1for to nitrobenzyl.
Preferably, described step 1) in alkali be selected from diisopropyl ethyl amine, Diisopropylamine, tetramethyl guanidine, triethylamine, diethylamine, 4-N, one or more in N-Dimethylamino pyridine, preferably tetramethyl guanidine and 4-N, the mixture of N-Dimethylamino pyridine, the mol ratio of described alkali and MAP is preferably 3～4: 1, more preferably 3.3～3.5: 1.
Preferably, in described step 1) reaction in add reductive agent, described reductive agent is selected from organophosphorus reagent, as three normal-butyl phosphorus, triphenyl phosphorus, triisobutyl phosphorus, preferably three normal-butyl phosphorus.
Preferably, described step 1) reaction complete after, first to splashing into acid in reaction solution, to regulate reaction solution pH be 6.5～7.5, then this reaction solution is splashed in aqueous acid, making pH value of solution is 5.5～5.9; Described acid is one or more in Glacial acetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, potassium primary phosphate, SODIUM PHOSPHATE, MONOBASIC, formic acid, tosic acid, sulfonic acid, phenylformic acid, succsinic acid, oxalic acid and trifluoroacetic acid preferably, more preferably Glacial acetic acid and/or potassium primary phosphate.
Preferably, described step 1) in also comprise by suction filtration or centrifugation gained reaction precipitation, obtain the ertapenem intermediate shown in formula PE; Or, the dry ertapenem intermediate obtaining at 20～30 ℃, making its water content is 5～65 % by weight, is preferably 40～65 % by weight.
Preferably, described method further comprising the steps of 3): described step 2) reaction complete after, be first 5.5～6.0 to splashing into acid for adjusting pH in reaction solution, suction filtration, use dichloromethane extraction filtrate, the water that obtains adds gac suction filtration after filtering, in-20～-10 ℃ equal-volume than the mixed solvent of methyl alcohol and Virahol in crystallization.In above-mentioned last handling process, first to drip acid for adjusting pH and be in order removing and the dark oil thing of palladium complexing, then by suction filtration, most of palladium complex is removed.
Visible; the method of preparing ertapenem provided by the invention; can be directly below 85% by water content; especially single protection ertapenem intermediate of 5～65% (is the ertapenem intermediate of undried; or the ertapenem intermediate under room temperature in dry so far water content ranges) carry out hydrogenation; not only can greatly simplify the operation, also help and improve purity and reduce costs, be conducive to obtain simply, efficiently high-quality product ertapenem.The present invention finds by research, and by minimum the foreign matter content of intermediate PE undried direct hydrogenation products therefrom ertapenem, thereby product purity is the highest.Hydrogenation again after intermediate PE being carried out to vacuum-drying at 20～30 ℃ of room temperatures, can increase the foreign matter content of products therefrom, but the amplitude that foreign matter content increases is little, thereby product purity changes little.But along with the rising of drying temperature, as intermediate PE carried out to hydrogenation again after vacuum-drying under the temperature condition higher than 35 ℃, products therefrom impurity obviously increases, and purity is less than 90%.Visible, by intermediate PE undried direct hydrogenation, or hydrogenation again after being dried at 20～30 ℃, can obviously reduce the impurity of hydrogenated products ertapenem and improve product purity.
Embodiment
Referring to specific embodiment, the present invention is described.It will be appreciated by those skilled in the art that these embodiment are only for the present invention is described, the scope that it does not limit the present invention in any way.
The raw material 1 beta-methyl carbon penicillenic bicyclic mother nucleus MAP using in following embodiment can be purchased from Kang Rui bio tech ltd of Handan City, or in reference US4933333 or CN100347175, disclosed method is synthetic obtains; Ertapenem side chain ES can be purchased from Tianjin Jingye Fine Chemical Industry Co., Ltd., or the J.Org.Chem.2002 such as reference Karel M.J.Brands, and in 67,4771-4776, disclosed method is synthetic obtains.
Moisture determination method in following embodiment is that karl-Fischer reagent is measured, method for detecting purity reference Karel M.J.Brands etc., J.Org.Chem.2002,67, disclosed method in 4771-4776, described purity is the HPLC area % purity with standard control.
Other experimental techniques in following embodiment, if no special instructions, are ordinary method.Other chemical feedstockss, the reagent material etc. that in following embodiment, use, if no special instructions, be commercially available purchase product.
embodiment 1
With the ertapenem intermediate of 1 beta-methyl carbon penicillenic bicyclic mother nucleus MAP and the single protection of ertapenem side chain ES reaction preparation structure, concrete operation step is as follows:
A. in 500ml four-hole bottle, first lead to N
2, add 100ml dimethyl formamide (DMF), be cooled to 0 ℃, add again 11.6g MAP, then add 6.48g side chain ES, drip 0.3g tri-n-butyl phosphine, stir complete molten after, be cooled to-50 ℃, be added dropwise to 8.1g tetramethyl guanidine (TMG), add 0.35g4-N, N-Dimethylamino pyridine (DMAP), keep system temperature-50 ℃～-40 ℃, reaction 3h.
B. be added dropwise to the saturated KH of 20ml
2pO
4the aqueous solution, pH is about 6.5～7.5 ,-40 ℃ and stirs 30min, is warming up to 10 ℃.
C. solution step B being obtained is slowly added dropwise in the hydrochloric acid soln of 1000ml 1%, and making pH value of solution is 5.5～5.9, and finish and stir 30min, suction filtration, frozen water washed twice, obtains PE wet product 34g, and measuring its purity is 98.6%, moisture 65%.
embodiment 2
Ertapenem intermediate PE by catalytic hydrogenation list protection structure prepares ertapenem, and concrete operation step is as follows:
A. 7g palladium charcoal (7.5%) is joined in 80ml pure water and stirred.
The PE wet product (moisture 65%) of the undried B. embodiment 1 being obtained is dissolved in 210ml tetrahydrofuran (THF) (THF), complete molten after, join 60ml water and (contain 5g NaHCO
3, with MAP mol ratio be 3 equivalents) in.
C. solution step B being obtained joins in the solution that steps A obtains, and 15～20 ℃, under 1.7MPa, hydrogenation 90min.
D. aftertreatment: pour out hydride, with 20% salt acid for adjusting pH to 5.8, suction filtration, filtrate is used the cold CH of 300ml
2cl
2extraction once, separates organic phase, and water layer filters, and adds 3g gac, stirs 10min, suction filtration.
E. in the solution obtaining to step D, be added dropwise to 250ml methyl alcohol, and then be added dropwise to 250ml Virahol, be cooled to-10 ℃, stir 30min, then be cooled to-15 ℃, drip methanol/isopropanol (1: 1) mixed solution 500ml, add and stir 30min, suction filtration, acetone drip washing filter cake, vacuum-drying, obtain 4.88g ertapenem white solid, yield 50.3% (in MAP), purity: 97.1%.
embodiment 3
With the ertapenem intermediate of 1 beta-methyl carbon penicillenic bicyclic mother nucleus MAP and the single protection of ertapenem side chain ES reaction preparation structure, concrete operation step is as follows:
A. in 500ml four-hole bottle, first lead to N
2add 100ml dimethyl formamide (DMF), be cooled to 0 ℃, then add 11.6g MAP, then add 6.48g side chain ES, add 0.3g tri-n-butyl phosphine, stir complete molten after, be cooled to-50 ℃, add 7.9g 4-N, N-Dimethylamino pyridine (DMAP), keeps system temperature-50 ℃～-40 ℃, reaction 3h.
B. be added dropwise to 1.2g Glacial acetic acid, add 20ml water, pH is about 6.5～7.5 ,-40 ℃ and stirs 30min, is warming up to 10 ℃.
C. solution step B being obtained is slowly added dropwise to the KH of 1000ml 3%
2pO
4in the aqueous solution, making pH value of solution is 5.5～5.9, finish and stir 30min, and suction filtration, frozen water washed twice, obtains PE wet product 30g, and measuring its purity is 98%, moisture 60%.
embodiment 4
Ertapenem intermediate PE by catalytic hydrogenation list protection structure prepares ertapenem, and concrete operation step is as follows:
A. 7g palladium charcoal (7.5%) is joined in 80ml pure water and stirred.
The PE wet product (moisture 60%) of the undried B. embodiment 3 being obtained is dissolved in 160ml N-Methyl pyrrolidone (NMP), complete molten after, join 60ml water and (contain 5g NaHCO
3, with MAP mol ratio be 3 equivalents) in.
C. solution step B being obtained joins in the solution that steps A obtains, and 15～20 ℃, under 1.0MPa, hydrogenation 120min.
D. aftertreatment: pour out hydride, with 20% salt acid for adjusting pH to 6.0, suction filtration, filtrate extracts once with 300ml cold ethyl acetate, separates organic phase, and water adds 3g gac, stirs 10min, suction filtration.
E. in the solution obtaining to step D, be added dropwise to 250ml methyl alcohol, and then be added dropwise to 250ml Virahol, be cooled to-10 ℃, stir 30min, then be cooled to-20 ℃, drip methanol/isopropanol (1: 1) mixed solution 500ml, add and stir 30min, suction filtration, acetone drip washing filter cake, vacuum-drying, obtain 4.83g ertapenem white solid, yield 49.8% (in MAP), purity 97.3%.
embodiment 5
With the ertapenem intermediate of 1 beta-methyl carbon penicillenic bicyclic mother nucleus MAP and the single protection of ertapenem side chain ES reaction preparation structure, concrete operation step is as follows:
A. in 500ml four-hole bottle, first lead to N
2, add 100ml dimethyl formamide (DMF), be cooled to 0 ℃, add again 11.6g MAP, then add 6.15g side chain ES, add 0.3g tri-n-butyl phosphine, stir complete molten after, be cooled to-50 ℃, be added dropwise to 7.6g tetramethyl guanidine (TMG), add 0.35g 4-N, N-Dimethylamino pyridine (DMAP), keep system temperature-50 ℃～-40 ℃, reaction 3h.
B. be added dropwise to 1.2g Glacial acetic acid, add 20ml water, pH is about 6.5～7.5 ,-40 ℃ and stirs 30min, is warming up to 10 ℃.
C. solution step B being obtained is slowly added dropwise to the KH of 1000ml 3%
2pO
4in the aqueous solution, making pH value of solution is 5.5～5.9, finish and stir 30min, and centrifugation, frozen water washed twice, obtains PE wet product 19.8g, and measuring its purity is 98%, moisture 40%.
embodiment 6
Ertapenem intermediate PE by catalytic hydrogenation list protection structure prepares ertapenem, and concrete operation step is as follows:
A. 5g palladium charcoal (7.5%) is joined in 80ml pure water and stirred.
The PE wet product (moisture 40%) of the undried B. embodiment 5 being obtained is dissolved in 160ml tetrahydrofuran (THF) (THF), complete molten after, join 60ml water and (contain 5g NaHCO
3, with MAP mol ratio be 3 equivalents) in.
C. solution step B being obtained joins in the solution that steps A obtains, and 15～20 ℃, under 1.5MPa, hydrogenation 90min.
D. aftertreatment: pour out hydride, with 20% salt acid for adjusting pH to 5.5, suction filtration, filtrate is used the cold dichloromethane extraction of 300ml once, separates organic phase, and water layer filters, and adds 3g gac, stirs 10min, suction filtration.
E. in the solution obtaining to step D, be added dropwise to 250ml methyl alcohol, and then be added dropwise to 250ml Virahol, be cooled to-10 ℃, stir 30min, then be cooled to-15 ℃, drip methanol/isopropanol (1: 1) mixed solution 500ml, add and stir 30min, suction filtration, acetone drip washing filter cake, vacuum-drying, obtain 4.90g ertapenem white solid, yield is 50.5% (in MAP), purity: 97.2%.
embodiment 7
With the ertapenem intermediate of 1 beta-methyl carbon penicillenic bicyclic mother nucleus MAP and the single protection of ertapenem side chain ES reaction preparation structure, concrete operation step is as follows:
A. in 500ml four-hole bottle, first lead to N
2, add 100ml dimethyl formamide (DMF), be cooled to 0 ℃, add again 11.6g MAP, then add 6.25g side chain ES, add 0.3g triphenylphosphine, stir complete molten after, be cooled to-50 ℃, be added dropwise to 7.6g tetramethyl guanidine (TMG), add 0.35g 4-N, N-Dimethylamino pyridine (DMAP), keep system temperature-50 ℃～-40 ℃, reaction 3h.
B. be added dropwise to 1.2g Glacial acetic acid, add 20ml water, pH is about 6.5～7.5 ,-40 ℃ and stirs 30min, is warming up to 10 ℃.
C. solution step B being obtained is slowly added dropwise in the HOAc aqueous solution of 1000ml 1.3%, and making pH value of solution is 5.5～5.9, and finish and stir 30min, suction filtration, frozen water washed twice, obtains PE wet product 42.5g, and measuring its purity is 98.2%, moisture 72%.
embodiment 8
Ertapenem intermediate PE by catalytic hydrogenation list protection structure prepares ertapenem, and concrete operation step is as follows:
A. 7g palladium charcoal (7.5%) is joined in 130ml pure water and stirred.
PE wet product (moisture 72%) 42.5g of the undried B. embodiment 7 being obtained is dissolved in 320ml tetrahydrofuran (THF) (THF), complete molten after, join 136ml water and (contain 5g NaHCO
3, with MAP mol ratio be 3 equivalents) in.
C. solution step B being obtained joins in the solution that steps A obtains, and 15～20 ℃, under 1.7MPa, hydrogenation 90min.
D. aftertreatment: pour out hydride, with 20% salt acid for adjusting pH to 5.9, suction filtration, filtrate is used the cold dichloromethane extraction of 300ml once, separates organic phase, and water layer filters, and adds 3g gac, stirs 10min, suction filtration.
E. in the solution obtaining to step D, be added dropwise to 500ml Virahol, be cooled to-10 ℃, then drip 500ml Virahol, add and stir 30min, suction filtration, acetone drip washing filter cake, vacuum-drying, obtain 5.1g ertapenem white solid, yield 52.6% (in MAP), purity 96.8%.
embodiment 9
With the ertapenem intermediate of 1 beta-methyl carbon penicillenic bicyclic mother nucleus MAP and the single protection of ertapenem side chain ES reaction preparation structure, concrete operation step is as follows:
A. in 500ml four-hole bottle, first lead to N
2, add 100ml dimethyl formamide (DMF), be cooled to 0 ℃, add again 11.6g MAP, then add 6.15g side chain ES, add 0.3g tri-n-butyl phosphine, stir complete molten after, be cooled to-50 ℃, be added dropwise to 8.3g diisopropyl ethyl amine (DIPEA), add 0.35g 4-N, N-Dimethylamino pyridine (DMAP), keep system temperature-50 ℃～-40 ℃, reaction 3h.
B. be added dropwise to 1.2g Glacial acetic acid, add 20ml water, pH is about 6.5～7.5 ,-40 ℃ and stirs 30min, is warming up to 10 ℃.
C. solution step B being obtained is slowly added dropwise to the NaH of 1000ml 3%
2pO
4in the aqueous solution, making pH value of solution is 5.5～5.9, finishes and stirs 30min, suction filtration, frozen water washed twice, obtain PE wet product 36g, measuring its purity is 97.8%, moisture 67%, at 20～30 ℃ of room temperatures, intermediate PE is carried out after vacuum-drying, obtain PE wet product 27.7g, measuring its purity is 96.6%, moisture 57%.
embodiment 10
Ertapenem intermediate PE by catalytic hydrogenation list protection structure prepares ertapenem, and concrete operation step is as follows:
A. 4g palladium charcoal (10%) is joined in 45ml pure water and stirred.
B. at 20～30 ℃ of the room temperatures that embodiment 9 obtained, vacuum drying PE wet product (moisture 57%) 27.7g is dissolved in 100ml tetrahydrofuran (THF) (THF), complete molten after, join 50ml water and (contain 6.6g NaHCO
3, with MAP mol ratio be 4 equivalents) in.
C. solution step B being obtained joins in the solution that steps A obtains, and 15～20 ℃, under 1.7MPa, hydrogenation 90min.
D. aftertreatment: pour out hydride, with Glacial acetic acid adjusting pH to 5.8, suction filtration, filtrate extracts once with the cold primary isoamyl alcohol of 300ml, separates organic phase, and water layer filters, and adds 3g gac, stirs 10min, suction filtration.
E. in the solution obtaining to step D, be added dropwise to 250ml methyl alcohol, and then be added dropwise to 250ml Virahol, be cooled to-10 ℃, stir 30min, then be cooled to-15 ℃, drip methanol/isopropanol (1: 1) mixed solution 500ml, add and stir 30min, suction filtration, acetone drip washing filter cake, vacuum-drying, obtain 4.8g ertapenem white solid, yield 49.5% (in MAP), purity 90.2%.
embodiment 11
With the ertapenem intermediate of 1 beta-methyl carbon penicillenic bicyclic mother nucleus MAP and the single protection of ertapenem side chain ES reaction preparation structure, concrete operation step is as follows:
A. in 500ml four-hole bottle, first lead to N
2, add 100ml dimethyl formamide (DMF), be cooled to 0 ℃, add again 23.2g MAP, then add 12.3g side chain ES, add 0.6g tri-n-butyl phosphine, stir complete molten after, be cooled to-50 ℃, be added dropwise to 17g tetramethyl guanidine (TMG), add 0.7g 4-N, N-Dimethylamino pyridine (DMAP), keep system temperature-50 ℃～-40 ℃, reaction 3h.
B. be added dropwise to 2.4g Glacial acetic acid, add 40ml water, pH is about 6.5～7.5 ,-40 ℃ and stirs 30min, is warming up to 10 ℃.
C. solution step B being obtained is slowly added dropwise to the KH of 2000ml 3%
2pO
4in the aqueous solution, making pH value of solution is 5.5～5.9, finish and stir 30min, and centrifugation, frozen water washed twice, obtains PE wet product 34g, and measuring its purity is 98%, moisture 30%.
embodiment 12
Ertapenem intermediate PE by catalytic hydrogenation list protection structure prepares ertapenem, and concrete operation step is as follows:
A. 7g palladium charcoal (5%) is joined in 320ml pure water and stirred.
The PE wet product (moisture 30%) of the undried B. embodiment 11 being obtained is dissolved in 640ml tetrahydrofuran (THF) (THF), complete molten after, join 240ml water and (contain 10g NaHCO
3, with MAP mol ratio be 3 equivalents) in.
C. solution step B being obtained joins in the solution that steps A obtains, and 15～20 ℃, under 1.7MPa, hydrogenation 60min.
D. aftertreatment: pour out hydride, with Glacial acetic acid adjusting pH to 5.8, suction filtration, filtrate extracts once with 900ml cold ethyl acetate, separates organic phase, and water adds 6g gac, suction filtration after stirring 10min.
E. in the solution obtaining to step D, be added dropwise to 1000ml methyl alcohol, and then be added dropwise to 1000ml Virahol, be cooled to-10 ℃, stir 30min, then be cooled to-20 ℃, drip methanol/isopropanol (1: 1) mixed solution 2000ml, add and stir 30min, suction filtration, acetone drip washing filter cake, vacuum-drying, obtain 9.1g ertapenem white solid, yield 47% (in MAP), purity 97.2%.
embodiment 13
Drying temperature and time to the prepared intermediate PE of embodiment 1 are studied.Following table 1 is purity and the water content after dry prepared intermediate PE different time at having provided 20～30 ℃.
Table 1
| Time of drying | Intermediate PE weight | Water content | Purity |
| 0h | 34g | 65％ | 98.6％ |
| 4h | 28.1g | 57％ | 96.6％ |
| 6h | 26.2g | 54％ | 95.3％ |
| 10h | 19.1g | 36％ | 94.7％ |
| 12h | 17.3g | 30％ | 94.3％ |
| 14h | 13g | 7％ | 93.3％ |
| 20h | 11.5g | 2％ | 93％ |
Above result shows, at 20～30 ℃ of room temperatures, intermediate PE carried out after vacuum-drying, and the purity of intermediate PE can reduce, but the amplitude of purity drop is little.
embodiment 14
The present embodiment provides the ertapenem intermediate PE of single protection structure of the different moisture content that dry different time obtains under condition of different temperatures of preparing with reference to above-described embodiment preparation method by catalytic hydrogenation to prepare ertapenem.Following table 2 provides part representative result data.
As can be known from the results of Table 2, by minimum the foreign matter content of prepared intermediate PE undried direct hydrogenation products therefrom ertapenem, thereby product purity is the highest, how many purity and the yield impacts on product of water content are little, can obtain high-quality product ertapenem.Hydrogenation again after intermediate PE being carried out to vacuum-drying at 20～30 ℃ of room temperatures, can increase the foreign matter content of products therefrom, but the amplitude that foreign matter content increases is little, thereby the variation of product purity is also little.But along with the rising of drying temperature, as intermediate PE carried out to hydrogenation again after vacuum-drying at the temperature higher than 35 ℃, products therefrom impurity obviously increases, and purity is less than 90%.Visible, by intermediate PE undried direct hydrogenation, or hydrogenation again after being dried at 20～30 ℃, can obviously reduce the impurity of hydrogenated products ertapenem and improve product purity.
Table 2
Claims (17)
1. a method of preparing ertapenem, is characterized in that, described method comprises that the ertapenem intermediate shown in following general formula PE is passed through to catalytic hydrogenation obtains ertapenem:
Wherein R
1for carboxyl-protecting group, be selected to nitrobenzyl, adjacent nitrobenzyl, to methoxy-benzyl;
The ertapenem intermediate that wherein said ertapenem intermediate is undried, or at 20～30 ℃, be dried to the ertapenem intermediate that water content is 5～65 % by weight;
Wherein, the reaction system of described catalytic hydrogenation comprises:
1) mixed solvent of organic solvent and water; Wherein said organic solvent is selected from one or more in tetrahydrofuran (THF), DMF, N,N-dimethylacetamide and N-Methyl pyrrolidone; And the volume ratio of described organic solvent and water is 1.05～1.5:1;
2) palladium catalyst charcoal; And
3) basifier.
2. method according to claim 1, is characterized in that, described organic solvent is tetrahydrofuran (THF); And the volume ratio of described organic solvent and water is 1.05～1.2:1.
3. method according to claim 1 and 2, is characterized in that, described basifier is supercarbonate.
4. method according to claim 1 and 2, is characterized in that, in described reaction system, the volume/mol ratio of mixed solvent and ertapenem intermediate is 10～30:1; And/or the mol ratio of basifier and ertapenem intermediate is 3～4:1; And/or the mass ratio of ertapenem intermediate and catalyzer is 1.7～3:1.
5. method according to claim 4, is characterized in that, in described reaction system, the volume/mol ratio of mixed solvent and ertapenem intermediate is 16:1; And/or the mass ratio of ertapenem intermediate and catalyzer is 2.4:1.
6. method according to claim 1 and 2, is characterized in that, described catalytic hydrogenation condition comprises: pressure is 10-17 normal atmosphere; Temperature is 15～20 ℃; Time is 30min～120min.
7. method according to claim 6, is characterized in that, the time of described catalytic hydrogenation is 60～90min.
8. method according to claim 1 and 2, is characterized in that, said method comprising the steps of:
1) prepare the ertapenem intermediate shown in general formula PE;
2) catalytic hydrogenation step 1) the ertapenem intermediate prepared.
9. method according to claim 8, it is characterized in that, the method for the ertapenem intermediate of preparing in described step 1) comprises reacts with the ertapenem side chain shown in following general formula E S the carbapenem parent nucleus shown in following formula M AP under alkali exists:
Wherein R
1representation carboxy protecting group, is selected to nitrobenzyl, adjacent nitrobenzyl, to methoxy-benzyl.
10. method according to claim 9, it is characterized in that, alkali in described step 1) is selected from diisopropyl ethyl amine, Diisopropylamine, tetramethyl guanidine, triethylamine, diethylamine, 4-N, one or more in N-Dimethylamino pyridine, and the mol ratio of described alkali and MAP is 3～4:1.
11. methods according to claim 10, is characterized in that, the alkali in described step 1) is tetramethyl guanidine and 4-N, the mixture of N-Dimethylamino pyridine, and the mol ratio of described alkali and MAP is preferably 3.3～3.5:1.
12. methods according to claim 9, is characterized in that, in the reaction of described step 1), add reductive agent, and described reductive agent is selected from tri-n-butyl phosphine, triphenylphosphine, tri isobutyl phosphine.
13. methods according to claim 12, is characterized in that, described reductive agent is tri-n-butyl phosphine.
14. methods according to claim 9, is characterized in that, after the reaction of described step 1) completes, first to splashing into acid in reaction solution, to regulate reaction solution pH be 6.5～7.5, then this reaction solution is splashed in aqueous acid, and making pH value of solution is 5.5～5.9; Described acid is selected from one or more in Glacial acetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, potassium primary phosphate, SODIUM PHOSPHATE, MONOBASIC, formic acid, tosic acid, sulfonic acid, phenylformic acid, succsinic acid, oxalic acid and trifluoroacetic acid.
15. methods according to claim 14, is characterized in that, described acid is Glacial acetic acid and/or potassium primary phosphate.
16. methods according to claim 9, is characterized in that, also comprise by suction filtration or centrifugation gained reaction precipitation in described step 1), obtain the ertapenem intermediate shown in formula PE; Or, the dry ertapenem intermediate obtaining at 20～30 ℃, making its water content is 5～65 % by weight.
17. methods according to claim 9, is characterized in that, described method also comprises:
3) when described step 2) reaction complete after, be first 5.5～6.0 to splashing into acid for adjusting pH in reaction solution, suction filtration, use dichloromethane extraction filtrate, the water that obtains adds gac suction filtration after filtering, in-20～-10 ℃ equal-volume than the mixed solvent of methyl alcohol and Virahol in crystallization.
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| CN103772389B (en) * | 2012-10-25 | 2015-12-16 | 浙江医药股份有限公司新昌制药厂 | A kind of preparation method of ertapenem intermediate |
| WO2014082226A1 (en) * | 2012-11-28 | 2014-06-05 | 上海创诺医药集团有限公司 | Purification method of ertapenem sodium |
| CN103848832A (en) * | 2012-11-28 | 2014-06-11 | 上海创诺医药集团有限公司 | Purification method of ertapenem sodium |
| CN103159770A (en) * | 2013-03-22 | 2013-06-19 | 成都自豪药业有限公司 | Crystal form of ertapenem monosodium salt |
| CN106279175A (en) * | 2016-08-12 | 2017-01-04 | 上海龙翔生物医药开发有限公司 | A kind of preparation method of Ertapenem Sodium |
| CN114105988B (en) * | 2022-01-24 | 2022-04-29 | 深圳市海滨制药有限公司 | Synthetic method of ertapenem sodium |
| CN114849702B (en) * | 2022-05-26 | 2024-05-10 | 西安凯立新材料股份有限公司 | Palladium-carbon catalyst for hydrogenation synthesis of ertapenem sodium, and preparation method and application thereof |
| CN117801020A (en) * | 2024-03-01 | 2024-04-02 | 山东安弘制药有限公司 | Preparation method of carbapenem double-ring mother nucleus |
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| WO2010124531A1 (en) * | 2009-04-30 | 2010-11-04 | 石药集团中奇制药技术（石家庄）有限公司 | Intermediates of carbapenem, compositions containing them and preparation methods thereof |
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| CN1829716A (en) * | 2003-12-09 | 2006-09-06 | (株)中外制药 | A new method for preparing imipenem |
| WO2008012830A1 (en) * | 2006-07-28 | 2008-01-31 | Hetero Drugs Limited | Soup faropenem free acid |
| CN101935321A (en) * | 2010-07-20 | 2011-01-05 | 深圳市海滨制药有限公司 | Method for synthesizing 1 beta methyl carbapenem antibiotic |
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| CN102690266A (en) | 2012-09-26 |
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