CN101941981B - Catalyst composition and method for preparing faropenem sodium - Google Patents
Catalyst composition and method for preparing faropenem sodium Download PDFInfo
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- CN101941981B CN101941981B CN200910148791.1A CN200910148791A CN101941981B CN 101941981 B CN101941981 B CN 101941981B CN 200910148791 A CN200910148791 A CN 200910148791A CN 101941981 B CN101941981 B CN 101941981B
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- triphenylphosphine
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- KDUOTWOTIWSCEX-UHFFFAOYSA-N CC(C(C1SC(C2OCCC2)=C(C(OCC=C)=O)N11)C1=O)O Chemical compound CC(C(C1SC(C2OCCC2)=C(C(OCC=C)=O)N11)C1=O)O KDUOTWOTIWSCEX-UHFFFAOYSA-N 0.000 description 1
- LNOWBZGDRBPBMJ-IGPRPORTSA-N C[C@H]([C@H](C1SC([C@@H]2OCCC2)=C(C(N=O)=O)N11)C1=O)O Chemical compound C[C@H]([C@H](C1SC([C@@H]2OCCC2)=C(C(N=O)=O)N11)C1=O)O LNOWBZGDRBPBMJ-IGPRPORTSA-N 0.000 description 1
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Abstract
The invention provides a catalyst composition, mainly containing palladium carbon (Pd/C) and triphenylphosphine, wherein the molar ratio of palladium to the triphenylphosphine is 1:2-1:6. The invention also provides a method for preparing faropenem sodium of a formula I, comprising the following step of: performing a reaction of a compound as an intermediate in a formula II and an allyl receptor under the action of a catalyst for removing allyl to produce the faropenem sodium of the formula I. The adopted catalyst for removing the allyl is the catalyst composition containing the palladium carbon (Pd/C) and the triphenylphosphine. The catalyst composition is easy to recover, thereby greatly reducing pollution of the palladium in a product.
Description
Technical field
The present invention relates to a kind of catalyst composition, a concrete aspect of the present invention relates to the preparation method of Faropenem sodium.
Background technology
Tetrakis triphenylphosphine palladium (Pd (PPh
3)
4) be a kind of homogeneous catalyst in organic synthesis field with important use, usually for the various coupling of catalysis, as Suzuki coupling, Stille coupling, Kumada coupling, Negishi coupling, Murahashi coupling, Hiyama coupling and Sonogashira coupling etc.But, at existing use Pd (PPh
3)
4reaction conditions under, this catalyzer can be dissolved in reaction system usually, not easily separates after completion of the reaction, therefore causes the catalyzer of this costliness cannot recycle, sometimes also can cause the heavy metal contamination of product simultaneously.Such as, namely its application in the synthesis of Faropenem sodium is like this.
Faropenem sodium is a kind of new oral antibacterials.This medicine not only can act on the bacterium being in reproductive stage, and also has effect to established bacterium.Its significant advantage also has germicidal action to stationary state bacterium.Compare with penicillin with cephamycin, the antimicrobial spectrum of Faropenem sodium is wider, all demonstrates broad-spectrum antibacterial action for the aerobic and anaerobism gram positive organism except Pseudomonas aeruginosa and most gram-negative bacteria.This medicine is applicable to bacterial respiratory tract infection, urinary tract infection, skin, otorhinolaryngology infection etc.It is high that various toxicity test shows its security, is the choice drug of various grade and moderate infection.
Faropenem sodium is first mould ene-type oral antibiotic in the world, is developed cooperatively, go on the market in June, 1997 in Japan by Suntory and Yamanouchi drugmaker.Faropenem sodium mainly contains two synthesis paths, and difference is to construct pentacyclic method.Article one, the Wittig based on classics reacts, as shown in reaction formula one (see United States Patent (USP) 4997829), another is then two carbonyl linked reactions that development in recent years is got up, (see Masaji lshiguro et al as shown in reaction formula two, J.Antibiotics1988,41,1685).
As shown in reaction formula one, two, in the preparation method of the Faropenem sodium reported at present, in the end remove in allylic step with Pd (PPh
3)
4as removing allylic catalyzer.In the reaction, Pd (PPh
3)
4be dissolved in using the mixed solution of methylene dichloride and acetic acid as in the system of solvent, be difficult to reclaim, be so not only difficult to the catalyzer of this costliness of recycle, also can there is the danger that catalyzed dose of product pollutes, make the heavy metals exceeding standard in product.In addition, Pd (PPh
3)
4catalyst property is unstable, and long-term placement can be gone bad.
Therefore, a kind of inexpensive, catalyzer containing palladium-triphenylphosphine of stablizing, being suitable for reclaiming from reaction system is needed.
Summary of the invention
For above problem, one object of the present invention is to propose a kind of new catalyzer, and it may be used for the above-mentioned many reactions enumerated, and avoids existing Pd (PPh
3)
4shortcoming.
Another object of the present invention improves the preparation method of Faropenem sodium, overcomes in prior art the shortcoming removing allyl group step, produces with the industrialization of implementation faropenem better.
Therefore, one aspect of the present invention provides a kind of catalyst composition, and it mainly comprises palladium carbon and triphenylphosphine, and wherein, the mol ratio of palladium and triphenylphosphine is 1:2 ~ 1:6.
Another aspect of the present invention provides a kind of method for the preparation of Faropenem sodium (compound of formula I), the method comprises makes the compound of formula II react with allyl acceptor removing under allylic catalyst action, method of formation faropenem, the feature of the inventive method is, removes the compatibility that allylic catalyzer is palladium carbon (Pd/C) and triphenylphosphine.
According to the method for the present invention for the preparation of the Faropenem sodium of formula I, wherein, removing in allylic catalyzer, the mol ratio of palladium and triphenylphosphine is 1:2 ~ 1:6.
According to the method for the present invention for the preparation of the Faropenem sodium of formula I, wherein, allyl acceptor be 2 ethyl hexanoic acid sodium, N-methylmorpholine, 5,5-dimethyl-hydroresorcinol, to one or more in benzene sulfinic acid sodium salt.
According to the method for the present invention for the preparation of the Faropenem sodium of formula I, wherein, the solvent of the method employing is one or more in methylene dichloride, normal hexane, Skellysolve A, sherwood oil, tetrahydrofuran (THF), ether, ethyl acetate, toluene, dimethylbenzene.
According to the method for the present invention for the preparation of the Faropenem sodium of formula I, wherein, in the method, temperature of reaction is 0-40 DEG C, and the reaction times is 1-24 hour.
In the method for the invention, owing to adopting palladium carbon (Pd/C) and triphenylphosphine compatibility as removing allylic catalyzer, thus compared with prior art, the present invention has the following advantages: (1) of the present invention to be removed allylic catalyzer and be easy to be separated, by suction filtration and recyclable Pd-C; (2) Pd can be reclaimed with the higher rate of recovery; (3) pollution of Pd in product is decreased.
Embodiment
Catalyst according to the invention is formed by palladium carbon and triphenylphosphine compatibility, and it can be the dosage form that market is easy to get that palladium carbon wherein or title carbon carry palladium (Pd/C).Such as, the palladium content generally sold in the market be about 5% palladium carbon may be used for the present invention.Easy understand, the palladium carbon of other content forms is also applicable.
In catalyst composition of the present invention, its activeconstituents is palladium and triphenylphosphine, so in most of the cases, said composition can only be made up of palladium carbon and triphenylphosphine.But the present invention is not limited thereto, this catalyst composition can also comprise other compositions to introduce new function, such as, in order to promote the dispersion of palladium carbon in reaction system and introduce a small amount of dispersion agent.
The method be carried on by palladium on carbon is known in the art, and its MIN requirement is that palladium is not easily separated from from carbon.
In catalyzer of the present invention, the mol ratio of palladium-triphenylphosphine can be 1:2 ~ 1:6, and for different reactions, its mol ratio can be different.Contriver synthesizes example research with Faropenem sodium, and find that the mol ratio of palladium-triphenylphosphine is preferably 1:2 ~ 1:6, be more preferably 1:3 ~ 1:4, in this case, the mol ratio of 1:4 is best.
When being equipped with catalyst composition of the present invention, the consumption of palladium carbon can regulate according to the size of wherein palladium content, makes the numerical value that the mol ratio of palladium and triphenylphosphine in composition reaches predetermined.
Catalyzer of the present invention may be used for catalysis such as Suzuki coupling, Stille coupling, Kumada coupling, Negishi coupling, Murahashi coupling, Hiyama coupling and Sonogashira coupling etc.Those skilled in the art easily expect, this catalyzer may be used for all needs with Pd (PPh
3)
4make the reaction type of catalyzer.
In another aspect of this invention, provide a kind of method for the preparation of Faropenem sodium (formula I), the method comprises makes formula II midbody compound react with allyl acceptor removing under allylic catalyst action, method of formation faropenem, of the present invention to remove allylic catalyzer be above-mentioned palladium carbon (Pd/C) and the composition of triphenylphosphine.
In the specific embodiment of the present invention, midbody compound (formula II), triphenylphosphine and Pd-C are added successively in dry solvent, then allyl acceptor is added, after stirring for some time, stopped reaction, suction filtration, reclaim Pd-C, add water in reaction solution, be stirred to solid and separated out, and continue to stir, suction filtration, obtain faint yellow solid, this solid is dissolved in as far as possible few water, adds decolorizing with activated carbon, filter, filtrate adds in the acetone of quintuple, places crystallization, obtains Faropenem sodium.
In a kind of embodiment, remove in allylic catalyzer and adopt the Pd-C containing the palladium 10% or Pd-C containing palladium 5%.
In the specific embodiment of the present invention, the solvent used can be alkane, aromatics, ethers, ester class, can be specifically one or more in methylene dichloride, normal hexane, Skellysolve A, sherwood oil, tetrahydrofuran (THF), ether, ethyl acetate, toluene, dimethylbenzene.
In the specific embodiment of the present invention, the allyl acceptor used can be 2 ethyl hexanoic acid sodium, N-methylmorpholine, 5,5-dimethyl-hydroresorcinol, to one or more in benzene sulfinic acid sodium salt etc.
In the specific embodiment of the present invention, after adding allyl acceptor, carry out stirring reaction, wherein temperature of reaction can be 0-40 DEG C, and the reaction times can be 1-24 hour.
Below in conjunction with embodiment, the present invention is specifically described, but the present invention is not limited only to described embodiment.
Embodiment 1
By 10g intermediate, triphenylphosphine 2.0g and 2g Pd-C (containing palladium 10%) adds in dry methylene dichloride 60mL successively, add the ethyl acetate solution 60mL of the 2 ethyl hexanoic acid sodium preparation of 0.5M, stirring at room temperature 8 hours, stopped reaction, suction filtration, reclaim Pd-C, add water 2ml in reaction solution, be stirred to solid to separate out, and continue stirring 0.5 hour, suction filtration, obtain faint yellow solid, this solid is dissolved in as far as possible few water, add activated carbon 0.5g, decolouring 30min, filter, filtrate adds in the acetone of 5 times amount, place crystallization, obtain Faropenem sodium 7.0g, yield is 64.5%.
Embodiment 2
By 10g intermediate, triphenylphosphine 2.0g and 2g Pd-C (containing palladium 10%) adds in dry methylene dichloride 60mL successively, add the ethyl acetate solution 60mL to benzene sulfinic acid sodium salt preparation of 0.5M, 40 DEG C are stirred 3 hours, stopped reaction, suction filtration, reclaim Pd-C, add water 2ml in reaction solution, be stirred to solid to separate out, and continue stirring 0.5 hour, suction filtration, obtain faint yellow solid, this solid is dissolved in as far as possible few water, add activated carbon 0.5g, decolouring 30min, filter, filtrate adds in the acetone of 5 times amount, place crystallization, obtain Faropenem sodium 6.5g, yield is 60.2%.
Embodiment 3
By 10g intermediate, triphenylphosphine 2.0g and 4.2g Pd-C (containing palladium 5%) adds in dry methylene dichloride 60mL successively, add the ethyl acetate solution 60mL of the 2 ethyl hexanoic acid sodium preparation of 0.5M, 25 DEG C are stirred 7 hours, stopped reaction, suction filtration, reclaim Pd-C, add water 2ml in reaction solution, be stirred to solid to separate out, and continue stirring 0.5 hour, suction filtration, obtain faint yellow solid, this solid is dissolved in as far as possible few water, add activated carbon 0.5g, decolouring 30min, filter, filtrate adds in the acetone of 5 times amount, place crystallization, obtain Faropenem sodium 7.0g, yield is 64.5%.
Describing the present invention although above in detail with the preferred embodiment of the present invention, should be appreciated that those skilled in the art can make various distortion and change when not deviating from the spirit and scope of the present invention that claims limit.
Claims (4)
1. for the preparation of a method for the Faropenem sodium of formula I,
Comprise the midbody compound making formula II to react with allyl acceptor in the presence of a catalyst, the Faropenem sodium of production I,
Wherein, described catalyzer is the compatibility of palladium carbon (Pd/C) and triphenylphosphine;
Described allyl acceptor be 2 ethyl hexanoic acid sodium, N-methylmorpholine, 5,5-dimethyl-hydroresorcinol, to one or more in benzene sulfinic acid sodium salt.
2. the method for the Faropenem sodium for the preparation of formula I according to claim 1, is characterized in that, in the catalyst, the mol ratio of palladium and triphenylphosphine is 1:2 ~ 1:6.
3. the method for the Faropenem sodium for the preparation of formula I according to claim 1, it is characterized in that, the solvent that described method adopts is one or more in methylene dichloride, normal hexane, Skellysolve A, sherwood oil, tetrahydrofuran (THF), ether, ethyl acetate, toluene, dimethylbenzene.
4. the method for the Faropenem sodium for the preparation of formula I according to claim 1, is characterized in that, the temperature of reaction of described method is 0-40 DEG C, and the reaction times is 1-24 hour.
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|---|---|---|---|
| CN200910148791.1A CN101941981B (en) | 2009-07-03 | 2009-07-03 | Catalyst composition and method for preparing faropenem sodium |
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| CN200910148791.1A CN101941981B (en) | 2009-07-03 | 2009-07-03 | Catalyst composition and method for preparing faropenem sodium |
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| CN101941981B true CN101941981B (en) | 2015-01-21 |
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| CN105175217A (en) * | 2015-10-21 | 2015-12-23 | 山东盛华电子新材料有限公司 | Method for synthesizing polycyclic aromatic hydrocarbon by directly coupling Grignard reagent of halogenated compounds with halogenated compound by recyclable modified palladium on carbon |
| CN105348037A (en) * | 2015-10-21 | 2016-02-24 | 山东盛华电子新材料有限公司 | Synthetic method of directly coupling aryl halide by aromatic hydrocarbon Grignard reagent in the presence of recycled modified palladium-charcoal |
| CN105237461A (en) * | 2015-10-21 | 2016-01-13 | 山东盛华电子新材料有限公司 | Method for utilizing recyclable modified palladium-charcoal to synthesize heterocyclic compound by directly coupling halogenated compound Grignard reagent to halogenated compound |
| CN108610252B (en) * | 2016-12-12 | 2022-03-08 | 重庆华邦胜凯制药有限公司 | Novel method for isomerizing abamectin A acid |
| CN106824267A (en) * | 2017-01-25 | 2017-06-13 | 江西省汉氏贵金属有限公司 | A kind of Suzuki coupling reactions palladium-carbon catalyst and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0199446A1 (en) * | 1985-03-09 | 1986-10-29 | SUNTORY KABUSHIKI KAISHA, also known as SUNTORY LTD. | Penem compounds, production and use thereof |
| WO2008035153A2 (en) * | 2006-08-02 | 2008-03-27 | Orchid Chemicals & Pharmaceuticals Limited | Process for the preparation of beta-lactam antibiotic |
-
2009
- 2009-07-03 CN CN200910148791.1A patent/CN101941981B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0199446A1 (en) * | 1985-03-09 | 1986-10-29 | SUNTORY KABUSHIKI KAISHA, also known as SUNTORY LTD. | Penem compounds, production and use thereof |
| WO2008035153A2 (en) * | 2006-08-02 | 2008-03-27 | Orchid Chemicals & Pharmaceuticals Limited | Process for the preparation of beta-lactam antibiotic |
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Owner name: HUNAN WARRANT PHARMACEUTICAL CHIRAL PHARMACEUTICAL Free format text: FORMER OWNER: CHANGSHA HUAMEI PHARMACEUTICALRESEARCH INSTITUTE BEIJING WARRANT TIANCHENG TECHNOLOGYCO., LTD. Effective date: 20150414 |
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Effective date of registration: 20150414 Address after: 410331 Liuyang biological medicine Park, Hunan Province Patentee after: Hunan Warrant Pharmaceutical Co., Ltd. Patentee after: Hunan Warner Pharmaceutical Co., Ltd. Address before: 410331 Liuyang biological medicine Park, Hunan Province Patentee before: Hunan Warrant Pharmaceutical Co., Ltd. Patentee before: Changsha Huamei Medicine Research Institute Patentee before: Beijing Warrant Tiancheng Technology Co., Ltd. |
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Address after: 410331 Liuyang biological medicine Park, Hunan Province Patentee after: HUNAN WARRANT PHARMACEUTICAL CO., LTD. Patentee after: Hunan Warner Pharmaceutical Co., Ltd. Address before: 410331 Liuyang biological medicine Park, Hunan Province Patentee before: Hunan Warrant Pharmaceutical Co., Ltd. Patentee before: Hunan Warner Pharmaceutical Co., Ltd. |