CN102532139A - Method for preparing tebipenem - Google Patents
Method for preparing tebipenem Download PDFInfo
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- CN102532139A CN102532139A CN2010105777653A CN201010577765A CN102532139A CN 102532139 A CN102532139 A CN 102532139A CN 2010105777653 A CN2010105777653 A CN 2010105777653A CN 201010577765 A CN201010577765 A CN 201010577765A CN 102532139 A CN102532139 A CN 102532139A
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- 238000000034 method Methods 0.000 title claims abstract description 42
- SNUDIPVBUUXCDG-QHSBEEBCSA-N tebipenem pivoxil Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(=O)OCOC(=O)C(C)(C)C)=O)[C@H](O)C)SC(C1)CN1C1=NCCS1 SNUDIPVBUUXCDG-QHSBEEBCSA-N 0.000 title abstract description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 63
- 239000003054 catalyst Substances 0.000 claims abstract description 28
- -1 p-nitrobenzyl tebipenem Chemical compound 0.000 claims abstract description 26
- 229910052751 metal Inorganic materials 0.000 claims abstract description 8
- 239000002184 metal Substances 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 60
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 41
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical group CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 36
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 35
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 32
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 25
- 238000006243 chemical reaction Methods 0.000 claims description 22
- 239000003960 organic solvent Substances 0.000 claims description 20
- 229910052763 palladium Inorganic materials 0.000 claims description 18
- JYYNAJVZFGKDEQ-UHFFFAOYSA-N 2,4-Dimethylpyridine Chemical compound CC1=CC=NC(C)=C1 JYYNAJVZFGKDEQ-UHFFFAOYSA-N 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 13
- 238000002425 crystallisation Methods 0.000 claims description 11
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 11
- 230000008025 crystallization Effects 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 9
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000012046 mixed solvent Substances 0.000 claims description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical class CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- 239000007868 Raney catalyst Substances 0.000 claims description 8
- 150000007530 organic bases Chemical class 0.000 claims description 8
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 claims description 8
- 150000003222 pyridines Chemical class 0.000 claims description 8
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 150000002576 ketones Chemical class 0.000 claims description 6
- GGRHYQCXXYLUTL-UHFFFAOYSA-N chloromethyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OCCl GGRHYQCXXYLUTL-UHFFFAOYSA-N 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 239000007810 chemical reaction solvent Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 229910003445 palladium oxide Inorganic materials 0.000 claims description 2
- HBEQXAKJSGXAIQ-UHFFFAOYSA-N oxopalladium Chemical compound [Pd]=O HBEQXAKJSGXAIQ-UHFFFAOYSA-N 0.000 claims 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 abstract description 8
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- 230000003115 biocidal effect Effects 0.000 abstract description 2
- 239000003513 alkali Substances 0.000 abstract 1
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 abstract 1
- 125000006239 protecting group Chemical group 0.000 abstract 1
- 239000000047 product Substances 0.000 description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- GXXLUDOKHXEFBQ-YJFSRANCSA-N (4r,5s,6s)-3-[1-(4,5-dihydro-1,3-thiazol-2-yl)azetidin-3-yl]sulfanyl-6-[(1r)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)SC(C1)CN1C1=NCCS1 GXXLUDOKHXEFBQ-YJFSRANCSA-N 0.000 description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 22
- 238000001914 filtration Methods 0.000 description 20
- 239000010410 layer Substances 0.000 description 17
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 16
- 238000003756 stirring Methods 0.000 description 15
- 238000002360 preparation method Methods 0.000 description 13
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 12
- 238000001816 cooling Methods 0.000 description 11
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 8
- 150000001298 alcohols Chemical group 0.000 description 7
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 230000003113 alkalizing effect Effects 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical class C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 6
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 5
- 238000005984 hydrogenation reaction Methods 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 150000004685 tetrahydrates Chemical class 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 150000002170 ethers Chemical class 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 230000015556 catabolic process Effects 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
- 238000006731 degradation reaction Methods 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 229910017053 inorganic salt Inorganic materials 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000007142 ring opening reaction Methods 0.000 description 3
- 229950007537 tebipenem pivoxil Drugs 0.000 description 3
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical class C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241000193998 Streptococcus pneumoniae Species 0.000 description 2
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 2
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000007327 hydrogenolysis reaction Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- RZXMPPFPUUCRFN-UHFFFAOYSA-N p-toluidine Chemical compound CC1=CC=C(N)C=C1 RZXMPPFPUUCRFN-UHFFFAOYSA-N 0.000 description 2
- 239000008055 phosphate buffer solution Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- 150000003952 β-lactams Chemical group 0.000 description 2
- PTPXCXBTGGXERT-XHSVMWQWSA-N (4-nitrophenyl)methyl (4r,5s,6s)-3-[1-(4,5-dihydro-1,3-thiazol-2-yl)azetidin-3-yl]sulfanyl-6-[(1r)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(=O)OCC=1C=CC(=CC=1)[N+]([O-])=O)=O)[C@H](O)C)SC(C1)CN1C1=NCCS1 PTPXCXBTGGXERT-XHSVMWQWSA-N 0.000 description 1
- FYZUENZXIZCLAZ-UHFFFAOYSA-N 2-methylhept-2-enoic acid Chemical compound CCCCC=C(C)C(O)=O FYZUENZXIZCLAZ-UHFFFAOYSA-N 0.000 description 1
- 201000001178 Bacterial Pneumonia Diseases 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 206010033078 Otitis media Diseases 0.000 description 1
- 201000007100 Pharyngitis Diseases 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 206010046306 Upper respiratory tract infection Diseases 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002148 esters Chemical group 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- JQPTYAILLJKUCY-UHFFFAOYSA-N palladium(ii) oxide Chemical compound [O-2].[Pd+2] JQPTYAILLJKUCY-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
- 230000002085 persistent effect Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 208000020029 respiratory tract infectious disease Diseases 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 125000004149 thio group Chemical group *S* 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- 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
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a method for preparing carbapenem type antibiotic tebipenem. The method comprises the following steps of: carrying out catalytic hydrogenation on p-nitrobenzyl tebipenem under the presence of an organic alkali reagent and a metal catalyst (such as palladium/carbon) to remove p-nitrobenzyl ester to obtain the tebipenem, and further esterifying the tebipenem to obtain tebipenem ester. The method disclosed by the invention has the advantages of: (1) solving instability of the p-nitrobenzyl tebipenem in a catalytic hydrogenation protective group removal process and improving the yield and purity; and (2) simplifying operation steps, saving troubles of post-treatment and improving efficiency.
Description
Technical Field
The invention belongs to the field of chemistry or pharmaceutical chemistry, and particularly relates to a preparation method of tebipenem, and further relates to a method for obtaining tebipenem ester by esterification of tebipenem.
Technical Field
Tebipenem pivoxil (L-084) is the first oral beta-methylcarbapenem antibiotic product developed by Nippon Ming Zhi Co., Ltd, and is used for treating streptococcus pneumoniae anti-drug strain infection, including persistent otitis media and bacterial pneumonia, especially has strong activity on gram-positive bacteria such as streptococcus pneumoniae and the like, has obvious treatment effect on infantile acquired pneumonia, and has obvious advantages compared with other penem antibiotics. The product has been approved and recommended in japan in 2009 at 4 months for the treatment of ear, nose, throat and upper respiratory tract infections in paediatric patients.
Tebipenem pivoxil
According to the prior literature, there are two main methods for preparing the compound of formula (I) from tebipenem p-nitrobenzyl ester, i.e. the compound of formula (II): one is to reduce and hydrolyze p-nitrobenzyl ester in the presence of phosphate buffer solution/zinc powder to obtain a compound shown in the formula (I), and the other is to reduce p-nitrobenzyl ester by using sodium bicarbonate as an alkalizing agent and palladium/carbon as a catalyst through hydrogenolysis to obtain the compound shown in the formula (I).
EP0632039 patent reports hydrolysis with tetrahydrofuran/phosphate buffer as solvent and zinc dust as reducing agent to give compounds of formula (I) for post-treatment by resin purification. This method has the following problems: the reduced zinc solution is emulsion and a large amount of inorganic salt cannot be removed, the compound in the formula (I) is difficult to separate out crystals from water, and the purification of the product is inconvenient; the reaction conditions are unstable to reaction substrates and products, and can cause beta-lactam ring-opening byproducts and increase impurities; the post-treatment requires column chromatography for separation and purification, which increases the operation difficulty, causes the yield and quality to be reduced, and is difficult to realize industrial production.
J.antitoot.2006, 59 (4): 241-247 reports a preparation method for preparing a compound of formula (I) by catalytic hydrogenation of a compound of formula (II) which is tebipenem p-nitrobenzyl ester, the method comprises the steps of catalytic hydrogenation of deprotected p-nitrobenzyl ester by using sodium bicarbonate as an alkalizing agent and palladium/carbon as a catalyst in a mixed solvent of n-butanol and water, and carrying out post-treatment by acidification and crystallization to obtain a solid. The method overcomes the defect that the zinc reduction hydrolysis operation in EP0632039 causes difficult purification of post-treatment, simplifies the steps of the post-treatment operation, reduces the degradation speed of the product, but also has the following defects: sodium bicarbonate is used as an alkalizing reagent, hydrogenolysis is slow and incomplete, the reaction time needs to be prolonged when the reaction is complete, the product is easy to be degraded in an alkaline environment by ring opening, and the yield and the quality of the product are influenced; hydrochloric acid is needed to be added in the post-treatment process for neutralization and post-crystallization, so that inorganic salt is easy to exceed the standard, degradation and damage of products are caused, and degraded impurities influence the subsequent reaction, increase the purification difficulty of final products and directly influence the yield of the subsequent reaction.
In order to overcome the above disadvantages, the present invention aims to provide a novel process for preparing the compound of formula (I) by catalytic hydrogenation, which process results in the compound of formula (I) being further used for preparing tebipenem ester.
Disclosure of Invention
The invention aims to provide a method for preparing a tebipenem compound (a chemical name of which is (4R, 5S, 6S) -3- [ [1- (4, 5-dihydro-2-thiazolyl) -3-azetidinyl ] thio ] -6- [ (1R) -1-hydroxyethyl ] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid) with high purity and suitable for industrial production by catalytic hydrogenation.
To achieve this object, the present invention provides a process for the preparation of a compound of formula (I), characterized in that: the compound of formula (II) is catalytically hydrogenated in the presence of organic base and metal catalyst to obtain the compound of formula (I),
wherein
The above method may further comprise a crystallization step.
The "metal catalyst" described in the above-mentioned method is a palladium-based catalyst and a Raney nickel (Raney nickel) catalyst, wherein the palladium-based catalyst is selected from three types of catalysts of palladium oxide, palladium black and supported palladium. The "supported palladium" is a supported palladium catalyst, preferably a mixture of palladium and carbon, more preferably activated carbonPalladium catalyst (Pd/C) or palladium hydroxide catalyst (Pd (OH)2and/C), wherein the palladium content is 5-20%, preferably 10%. The weight ratio of the catalyst dosage to the compound of the formula (II) is 0.1: 1-0.5: 1, preferably 0.15: 1-0.3: 1.
The "organic base" mentioned in the above-mentioned method is selected from pyridine, alkyl-substituted pyridine, triethylamine, diisopropylethylamine and the like, and preferably substituted pyridine such as 2, 6-lutidine, 2, 4-lutidine and the like. The molar ratio of the organic base to the compound (II) is 1: 1-6: 1, preferably 4: 1-5: 1.
The above process of the present invention further comprises a reaction solvent selected from organic solvents or aqueous organic solvents, wherein the organic solvent is selected from alcohols or ethers, the alcohols can be lower aliphatic alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, isoamyl alcohol, etc., preferably n-butanol, and the ethers are ethyl ether, isopropyl ether, tetrahydrofuran, dioxane, etc., preferably tetrahydrofuran. The aqueous organic solvent is preferably a mixed solvent of tetrahydrofuran and water, or a mixed solvent of n-butanol and water.
In the crystallization in the above method, the crystallization solvent is selected from a mixture solvent in which an organic solvent and water are miscible, the organic solvent is preferably a lower alcohol and a ketone, the lower alcohol is selected from methanol, ethanol, n-propanol, isopropanol and the like, and the ketone is selected from acetone, butanone, 2-methylisobentanone and the like.
The hydrogenation reaction in the above-mentioned method is carried out at a reaction temperature of usually 0 to 60 ℃ and preferably 20 to 50 ℃. The pressure of the reaction hydrogen is normal pressure to 10MPa, preferably 0.5MPa to 1.5 MPa.
The above process further comprises reacting the compound of formula (I) with chloromethyl pivalate to give tebipenem ester.
In a specific embodiment, the method for preparing the compound of formula (I) of the present invention comprises dissolving the compound of formula (II) in an organic solvent or an aqueous organic solvent system, adding a metal catalyst in a weight ratio of 0.1: 1 to 0.5: 1 (preferably 0.15: 1 to 0.3: 1) to the compound of formula (II) and an organic base in a molar ratio of 1: 1 to 6: 1 (preferably 4: 1 to 5: 1) to the compound of formula (II), placing the mixture in a hydrogenation kettle at a pressure of between normal pressure and 10MPa, stirring and reacting at 0 to 60 ℃ until hydrogen absorption stops, filtering, removing an organic layer, adding an organic solvent miscible with water into a water layer, stirring, cooling, crystallizing, and filtering to obtain the compound of formula (I). The organic solvent is selected from alcohols or ethers, the alcohols can be lower aliphatic hydrocarbon alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, isoamyl alcohol, etc., preferably n-butanol, the ethers are diethyl ether, isopropyl ether, tetrahydrofuran, dioxane, etc., preferably tetrahydrofuran. Wherein the aqueous organic solvent is preferably a mixed solvent of tetrahydrofuran and water, or a mixed solvent of n-butanol and water. The organic solvent is selected from lower alcohols such as methanol, ethanol, n-propanol, isopropanol, etc., and ketones such as acetone, butanone, 2-methyl-isoamyl ketone, etc. Wherein the "organic base" is selected from pyridine, alkyl substituted pyridine, triethylamine, diisopropylethylamine, etc., preferably substituted pyridine such as 2, 6-dimethylpyridine, 2, 4-dimethylpyridine, etc
In the above embodiment, the metal catalyst is preferably Raney nickel (Raney nickel) catalyst, palladium/carbon (Pd/C) or palladium hydroxide/carbon (Pd (OH)2The catalyst comprises 5-20% of palladium, preferably 10%.
In another embodiment, the method for preparing the compound of formula (I) of the present invention comprises dissolving the compound of formula (II) in an alcohol or aqueous alcohol or ether or aqueous ether solvent system, adding a supported palladium catalyst (palladium content is 5-20%) in a weight ratio of 0.1: 1 to 0.5: 1 (preferably 0.15: 1 to 0.3: 1) to the compound of formula (II), placing the substituted pyridine in a hydrogenation kettle at a molar ratio of 1: 1 to 6: 1 (preferably 4: 1 to 5: 1) to the compound of formula (II) in a normal pressure to 10MPa, stirring and reacting at 0-60 ℃ until hydrogen absorption stops, filtering, removing the organic layer, adding an organic solvent miscible with water into the water layer, stirring, cooling, crystallizing, and filtering to obtain the compound of formula (I). The alcohol is selected from lower aliphatic hydrocarbon alcohol such as methanol, ethanol, propanol, isopropanol, n-butanol, and isoamyl alcohol, and the ether is selected from diethyl ether, isopropyl ether, tetrahydrofuran, dioxane, etc., preferably tetrahydrofuran. The substituted pyridine is selected from 2, 6-dimethyl pyridine, 2, 4-dimethyl pyridine, etc. The organic solvent in the water-miscible organic solvent is selected from alcohols such as methanol, ethanol, n-propanol, isopropanol, etc., ketones such as acetone, butanone, 2-methyl-isoamyl ketone, etc.
In the above embodiments, the supported palladium catalyst is preferably palladium on carbon (Pd/C) or palladium hydroxide on carbon (Pd (OH)2catalyst/C), wherein the palladium content is preferably 10%.
In another embodiment, the method for preparing the compound of formula (I) of the present invention comprises dissolving the compound of formula (II) in an alcohol or aqueous alcohol or ether or aqueous ether solvent system, adding Raney nickel catalyst in an amount of 0.1: 1 to 0.5: 1 (preferably 0.15: 1 to 0.3: 1) times by weight of the compound of formula (II), and substituted pyridine in an amount of 1: 1 to 6: 1 (preferably 4: 1 to 5: 1) times by weight of the compound of formula (II), placing in a hydrogenation kettle at a pressure of from normal pressure to 10MPa, stirring and reacting at 0-60 ℃ until hydrogen absorption stops, filtering, removing an organic layer, adding an organic solvent miscible with water into a water layer, stirring, cooling, crystallizing, and filtering to obtain the compound of formula (I). The alcohol is selected from lower aliphatic hydrocarbon alcohol such as methanol, ethanol, propanol, isopropanol, n-butanol, and isoamyl alcohol, and the ether is selected from diethyl ether, isopropyl ether, tetrahydrofuran, dioxane, etc., preferably tetrahydrofuran. The substituted pyridine is selected from 2, 6-dimethyl pyridine, 2, 4-dimethyl pyridine, etc. The organic solvent in the water-miscible organic solvent is selected from alcohols such as methanol, ethanol, n-propanol, isopropanol, etc., ketones such as acetone, butanone, 2-methyl-isoamyl ketone, etc.
In another embodiment, the method for preparing the compound of formula (I) of the present invention comprises dissolving the compound of formula (II) in a mixed solvent system of n-butanol and water, adding a supported palladium catalyst (palladium content is 5-20%) in a weight ratio of 0.15: 1 to 0.3: 1 (preferably 0.15: 1 to 0.3: 1) to the compound of formula (II), stirring and reacting the 2, 6-dimethylpyridine with the compound of formula (II) in a molar ratio of 4: 1 to 5: 1 (preferably 4: 1 to 5: 1) in a 0.5-1.5 MPa hydrogenation reactor at 20-50 ℃ until hydrogen absorption stops, filtering, removing the organic layer, adding acetone to the water layer, stirring, cooling, crystallizing, and filtering to obtain the compound of formula (I).
In the above embodiments, the supported palladium catalyst is preferably palladium on carbon (Pd/C) or palladium hydroxide on carbon (Pd (OH)2catalyst/C), wherein the palladium content is preferably 10%.
The schemes can further comprise the step of reacting the compound shown in the formula (I) in the presence of chloromethyl pivalate to obtain tebipenem pivoxil.
For the preparation of the compounds of formula (II) according to the invention (chemical name: (4R, 5S, 6S) -3- [ [1- (4, 5-dihydro-2-thiazolyl) -3-azetidinyl ] thio ] -6- [ (1R) -1-hydroxyethyl ] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid p-nitrobenzyl ester), reference is made to EP 2039, J.Antibiott.2006, 59 (4): the preparation is carried out by the method described in 241-247, which is incorporated by reference in its entirety.
In the prior art, in the process of preparing the compound shown in the formula (I) by removing a p-nitrobenzyl ester protecting group by using the compound shown in the formula (II) as a substrate, the instability of raw materials and products is increased by using a phosphate buffer solution and a zinc powder system for reduction and removal of the p-nitrobenzyl ester and using sodium bicarbonate as an alkalizing reagent and a palladium/carbon system for catalytic hydrogenation and removal of the p-nitrobenzyl ester.
The method solves the problem of unstable product in the process of preparing tebipenem by removing p-nitrobenzyl ester from the compound shown in the formula (II), and reduces the content of beta-lactam ring-opening degradation impurities; the invention takes 2, 6-dimethyl pyridine or 2, 4-dimethyl pyridine as an alkalizing agent and palladium (or palladium hydroxide)/carbon and Raney nickel as catalysts for catalytic hydrogenation, has a stabilizing effect on raw materials and products, and can play a role of a solubilizer for a mixed solvent system of water and n-butyl alcohol, so that the raw materials are better dissolved, and the reaction is more fully facilitated. The byproducts p-methylaniline and the alkalizing agent 2, 6-lutidine or 2, 4-lutidine are easy to remove in the post-treatment process. The method also solves the problem of overproof inorganic salt in the post-treatment, avoids the trouble of column chromatography required in the post-treatment, greatly improves the yield (more than 85 percent), reduces impurities, obviously improves the quality, is simple and convenient in post-treatment operation, and is suitable for industrial production.
Detailed Description
The following examples are presented to enable one of ordinary skill in the art to more fully understand the present invention and are not intended to limit the invention in any way.
Example 1
Preparation of (4R, 5S, 6S) -3- [ [1- (4, 5-dihydro-2-thiazolyl) -3-azetidinyl ] thio ] -6- [ (1R) -1-hydroxyethyl ] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid (compound of formula (I))
23.30g (45mmol) of p-nitrobenzyl (compound of formula (II)) of (4R, 5S, 6S) -3- [ [1- (4, 5-dihydro-2-thiazolyl) -3-azetidinyl ] thio ] -6- [ (1R) -1-hydroxyethyl ] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate is dissolved in 275ml of n-butanol, 340ml of water and 14.44g (135mmol) of 2, 6-lutidine, 3.50g of 10% palladium on charcoal is added, the mixture is transferred to a 2L reaction vessel, and the reaction solution is reacted at 26 ℃ for about 3 hours under a pressure of 1.1 MPa. Filtering to remove palladium carbon, separating out water layer, cooling acetone 915ml in ice bath, slowly dropping water layer under stirring for crystallization. Filtering to obtain a white-like product, and drying overnight under reduced pressure and vacuum to obtain 17.96g of tetrahydrate of the white-like product (4R, 5S, 6S) -3- [ [1- (4, 5-dihydro-2-thiazolyl) -3-azetidinyl ] thio ] -6- [ (1R) -1-hydroxyethyl ] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid, yield: 87.6 percent. HPLC: 98.62%, m/z: 384.
example 2
Preparation of (4R, 5S, 6S) -3- [ [1- (4, 5-dihydro-2-thiazolyl) -3-azetidinyl ] thio ] -6- [ (1R) -1-hydroxyethyl ] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid (compound of formula (I))
23.30g (45mmol) of p-nitrobenzyl (compound of formula (II)) of (4R, 5S, 6S) -3- [ [1- (4, 5-dihydro-2-thiazolyl) -3-azetidinyl ] thio ] -6- [ (1R) -1-hydroxyethyl ] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate is dissolved in 450ml tetrahydrofuran, 300ml water and 14.44g (135mmol), 2.33g of 10% palladium/carbon is added, the mixture is transferred to a 2L reaction kettle, and the reaction solution is reacted at 35 ℃ for 3 hours under the pressure of 1.5 MPa. Filtering to remove palladium carbon, separating out water layer, cooling with 900ml acetone in ice bath, stirring, and slowly dropping into water layer for crystallization. Filtering the mixture by suction to obtain a white-like product, and drying the white-like product overnight under reduced pressure and vacuum to obtain 18.28g of a tetrahydrate of (4R, 5S, 6S) -3- [ [1- (4, 5-dihydro-2-thiazolyl) -3-azetidinyl ] thio ] -6- [ (1R) -1-hydroxyethyl ] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid, yield: 89.2%, HPLC: 96.78%, m/z: 384.
example 3
Preparation of (4R, 5S, 6S) -3- [ [1- (4, 5-dihydro-2-thiazolyl) -3-azetidinyl ] thio ] -6- [ (1R) -1-hydroxyethyl ] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid (compound of formula (I))
23.30g (45mmol) of p-nitrobenzyl (compound of formula (II)) of (4R, 5S, 6S) -3- [ [1- (4, 5-dihydro-2-thiazolyl) -3-azetidinyl ] thio ] -6- [ (1R) -1-hydroxyethyl ] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate is dissolved in 275ml of n-butanol, 340ml of water and 24.09g (225mmol) of 2, 6-lutidine, 3.50g of 10% palladium hydroxide/carbon is added, and the mixture is transferred to a 2L reaction vessel and reacted at a pressure of 0.7MPa and a temperature of 50 ℃ for 3 hours. Filtering to remove palladium carbon, separating out water layer, cooling with 900ml acetone in ice bath, stirring, and slowly dropping water layer for crystallization. Filtering to obtain a white-like product, and drying overnight under reduced pressure in vacuum to obtain 18.32g of tetrahydrate of the white-like product (4R, 5S, 6S) -3- [ [1- (4, 5-dihydro-2-thiazolyl) -3-azetidinyl ] thio ] -6- [ (1R) -1-hydroxyethyl ] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid, yield: 89.4%, HPLC: 98.87%, m/z: 384.
example 4
Preparation of (4R, 5S, 6S) -3- [ [1- (4, 5-dihydro-2-thiazolyl) -3-azetidinyl ] thio ] -6- [ (1R) -1-hydroxyethyl ] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid (compound of formula (I))
23.30g (45mmol) of p-nitrobenzyl (compound of formula (II)) of (4R, 5S, 6S) -3- [ [1- (4, 5-dihydro-2-thiazolyl) -3-azetidinyl ] thio ] -6- [ (1R) -1-hydroxyethyl ] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate is dissolved in 275ml of n-butanol, 340ml of water and 28.91g (270mmol) of 2, 6-lutidine, 7.0g of 5% palladium hydroxide/carbon is added, the mixture is transferred to a 2L reaction kettle, and the reaction solution is reacted at 20 ℃ for 3 hours under the pressure of 0.5 MPa. Filtering to remove palladium carbon, separating out water layer, cooling acetone 910ml in ice bath, slowly dropping into water layer while stirring, stirring and crystallizing. Filtering the mixture by suction to obtain a white-like product, and drying the white-like product overnight in vacuum under reduced pressure to obtain 17.85g of a tetrahydrate of (4R, 5S, 6S) -3- [ [1- (4, 5-dihydro-2-thiazolyl) -3-azetidinyl ] thio ] -6- [ (1R) -1-hydroxyethyl ] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid, yield: 87.1%, HPLC: 97.62%, m/z: 384.
example 5
Preparation of (4R, 5S, 6S) -3- [ [1- (4, 5-dihydro-2-thiazolyl) -3-azetidinyl ] thio ] -6- [ (1R) -1-hydroxyethyl ] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid (compound of formula (I))
23.30g (45mmol) of p-nitrobenzyl (compound of formula (II)) of (4R, 5S, 6S) -3- [ [1- (4, 5-dihydro-2-thiazolyl) -3-azetidinyl ] thio ] -6- [ (1R) -1-hydroxyethyl ] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate is dissolved in 275ml of n-butanol, 340ml of water and 9.64g (90mmol) of 2, 4-lutidine, 11.65g of 10% palladium/carbon is added, the mixture is transferred to a 2L reaction kettle, and the reaction solution is reacted at a pressure of 1.0MPa and a temperature of 36 ℃ for 3 hours. Filtering to remove palladium carbon, separating out water layer, cooling with 940ml acetone in ice bath, stirring, slowly dropping water layer, and crystallizing. Filtering the mixture by suction to obtain a white-like product, and drying the white-like product overnight under reduced pressure and vacuum to obtain 18.18g of a tetrahydrate of (4R, 5S, 6S) -3- [ [1- (4, 5-dihydro-2-thiazolyl) -3-azetidinyl ] thio ] -6- [ (1R) -1-hydroxyethyl ] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid, yield: 88.7%, HPLC: 96.85%, m/z: 384.
example 6
Preparation of (4R, 5S, 6S) -3- [ [1- (4, 5-dihydro-2-thiazolyl) -3-azetidinyl ] thio ] -6- [ (1R) -1-hydroxyethyl ] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid (compound of formula (I))
23.30g (45mmol) of p-nitrobenzyl (compound of formula (II)) of (4R, 5S, 6S) -3- [ [1- (4, 5-dihydro-2-thiazolyl) -3-azetidinyl ] thio ] -6- [ (1R) -1-hydroxyethyl ] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate is dissolved in 275ml of n-butanol, 340ml of water and 24.08g (225mmol) of 2, 6-lutidine, Raney nickel is added and the mixture is transferred to a 2L reaction vessel, and the reaction solution is reacted at 0.7MPa and room temperature for 4 hours. The catalyst is removed by filtration, the water layer is separated, and acetone 920ml is slowly dropped into the water layer under the cooling and stirring of ice bath, and is stirred for crystallization. Filtering the mixture by suction to obtain a white-like product, and drying the white-like product overnight in vacuum under reduced pressure to obtain 17.44g of a white-like product (4R, 5S, 6S) -3- [ [1- (4, 5-dihydro-2-thiazolyl) -3-azetidinyl ] thio ] -6- [ (1R) -1-hydroxyethyl ] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid tetrahydrate, yield: 85.1%, HPLC: 96.35%, m/z: 384.
example 7 preparation of tebipenem ester
(4R, 5S, 6S) -3- [ [1- (4, 5-dihydro-2-thiazolyl) -3-azetidinyl ] prepared in the above examples 1-6]Thio group]-6- [ (1R) -1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0]26.70g (60mmol) of hept-2-ene-2-carboxylic acid (compound of formula (I)), 27.36g (120mmol) of benzyltriethylammonium chloride and 18.06(120mol) of chloromethyl pivalate were dissolved in DMF60mL and DIPEA 26.40ml (120mol), and the reaction mixture was reacted in a thermostatic water bath at 45 ℃ for 4 hours. Cooling to 5 ℃, adding 120mL of ethyl acetate and 120mL of water into the reaction solution, and adjusting the pH value to 4 by using 1mol/L of citric acid aqueous solution; adding KHCO into the water layer3Adjusting pH to 7.6, extracting with ethyl acetate, mixing organic layers, adding anhydrous magnesium sulfateDrying and evaporating the solvent under reduced pressure to obtain a yellow solid.
Claims (12)
1. A process for preparing a compound of formula (I) characterized in that: the compound of formula (II) is catalytically hydrogenated in the presence of organic base and metal catalyst to obtain the compound of formula (I),
wherein,
2. the process of claim 1, wherein the metal catalyst is palladium, palladium oxide or a mixture thereof with carbon or raney nickel, preferably palladium on carbon, palladium hydroxide on carbon or raney nickel.
3. The process of claim 1 wherein the organic base comprises pyridine, substituted pyridine, triethylamine or diisopropylethylamine.
4. The method of claim 1, wherein the substituted pyridine is 2, 6-lutidine or 2, 4-lutidine.
5. The process according to claim 1, wherein the molar ratio of the organic base to the compound (II) is 1: 1 to 6: 1, preferably 4: 1 to 5: 1.
6. The method of claim 1, further comprising a reaction solvent that is a mixture solvent of an alcohol or an ether and water.
7. The method according to claim 6, wherein the reaction solvent is a mixed solvent of tetrahydrofuran and water, and a mixed solvent of n-butanol and water.
8. The process according to claim 1, wherein the reaction temperature is from 0 to 60 ℃, preferably from 20 to 50 ℃, and/or the reaction hydrogen pressure is from atmospheric pressure to 10MPa, preferably from 0.5MPa to 1.5 MPa.
9. The method of claim 1, further comprising a crystallization step, wherein the crystallization solvent is selected from a mixture solvent in which an organic solvent is miscible with water.
10. The method of claim 9, wherein the organic solvent is a lower alcohol or a ketone.
11. The method of claim 1, wherein the molar ratio of the metal catalyst to the compound of formula (II) is 1: 1 to 6: 1.
12. The process according to any one of claims 1 to 11, further comprising reacting the compound of formula (I) with chloromethyl pivalate to give tebipenem ester.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102824314A (en) * | 2012-09-19 | 2012-12-19 | 山东罗欣药业股份有限公司 | Preparation method of tebipenem pivoxil granules |
| CN104341421A (en) * | 2013-08-03 | 2015-02-11 | 鲁南制药集团股份有限公司 | Tebipenem pivoxil industrial preparation method |
| CN106083858A (en) * | 2016-07-08 | 2016-11-09 | 河南全宇制药股份有限公司 | The preparation method of L-084 |
| CN109096283A (en) * | 2018-09-03 | 2018-12-28 | 成都倍特药业有限公司 | A kind of preparation method of high-purity tebipenem crystalline esters |
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Cited By (4)
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| CN109096283A (en) * | 2018-09-03 | 2018-12-28 | 成都倍特药业有限公司 | A kind of preparation method of high-purity tebipenem crystalline esters |
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