CN102453044B - Method for preparing biapenem by using micro-reaction technology - Google Patents
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Abstract
The present invention provides a method for preparing biapenem by using a micro-reaction technology. The method is characterized in that: the preparation process is performed in a micro-reactor. During the development process of the micro-reaction technology, positive input and accelerating research of the industry provide important effects. The micro-reaction technology is a new technology field, which meets the industry requirements of green chemistry, energy saving and emission reduction, low cost and high efficiency, and the social development requirements. The micro-reaction technology focusedly studies a modern manufacturing technology of the micro-reactor, micro heat transfer characteristics of the micro-reactor, micro extraction characteristics of the micro-reactor, transfer and reaction characteristics of a multiphase system in the micro-reactor, an application of the traditional chemical reaction in the micro-reactor, and the micro-reaction technology conversion of the projects with the hazardous or bad conditions, wherein the micro-reaction technology conversion of the projects can not be achieved by using the traditional chemical engineering technology.
Description
Technical field
The present invention relates to the preparation field of medicine, a kind of method of utilizing micro-reaction technology to prepare biapenem is provided especially.
Background technology
Biapenem (Biapenem) is by injection 1 Beta-methyl carbapenem antibiotic of Japanese Lederle company and American Cyanamid Company's exploitation, goes on the market in Japan's approval in March, 2002, just carries out phase ii clinical trial in the U.S. at present.Biapenem is the same with meropenem, has has a broad antifungal spectrum, feature that anti-microbial activity is strong.Biapenem all has stronger anti-microbial activity to gram positive organism, gram-negative bacteria (comprising the Pseudomonas aeruginosa of resistance), anerobe etc.; Stable to β-lactamase; Stability to DHP-1 is strong compared with Yi meter Pei Nan.The carbapenem veriety having gone on the market compared with other, biapenem renal toxicity is almost nil, can be individually dosed, and without central nervous system toxicity, can not bring out epileptic seizures, can be used for the treatment of bacterial meningitis.Biapenem is stronger 2～4 times than imipenum to suppressing Pseudomonas aeruginosa and anerobe, suppresses drug-resistant pseudomonas aeruginosa stronger 4～8 times than meropenem, more effective than ceftazime to acinetobacter calcoaceticus, anerobe.Clinically be applicable to treat chronic bronchitis secondary infection, pneumonia, pulmonary suppuration disease, pyelonephritis, complicacy urocystitis, peritonitis and adnexitis.
In the past in 10 years, the synthetic technology of 1 beta-methyl carbon penicillenic bicyclic system of chirality has had very large breakthrough, the development of the production technology of the key intermediate of this carbapenem veriety, for the production of imitated medicine and semi-synthetic raw material provides more spacious income space, also promote turning to of original new drug.But along with development and the competition of synthetic technology are further fierce, biapenem price declines gradually in the world, and the focus that reduces costs, improves international competitiveness forwards follow-up technique naturally to; As, recrystallization under the docking of female ring and side chain, catalytic hydrogenation deprotection, acetone condition.
While carrying out above-mentioned subsequent technique production according to traditional processing method, there is following problem:
1. technique is simpler, and the space that can enhance competitiveness is very little.
2. solvent usage quantity is larger, serious environment pollution.
3. yield is lower, wastes raw material.
4. because heat release in reaction process is larger, by product is more, and more dangerous.
5. repeatedly reaction on a small quantity, raises the cost.
Microreactor is a kind of pipeline reactor of continuous flow in essence.It comprises the needed mixing tank of chemical unit, interchanger, reactor, controller etc.But its line size is far smaller than conventional tubular reactor, microreactor inside is that a lot of microtubules that are 10～500 μ m by diameter are formed in parallel, and has great specific surface area.The advantage of bringing is thus great heat exchange efficiency and mixing efficiency.Can realize the accurate control to temperature of reaction and reaction mass was mixed with accurate proportioning moment.
Summary of the invention
The object of the present invention is to provide a kind of method of utilizing micro-reaction technology to prepare biapenem, to solve long reaction time, by product is many, the problem that yield is low.
The present invention specifically provides a kind of method of utilizing micro-reaction technology to prepare biapenem, it is characterized in that: preparation process is carried out in microreactor, and concrete preparation process is as follows:
---pack the first deposit portion of microreactor reactive system into 4.88g (4R, 5S, 6S)-3-bis-benzenephosphonic acid oxygen base-6-[(R)-1-hydroxyethyl]-4-methyl carbon mould-2-alkene-2-p-nitrophenyl ester (2) and 30ml anhydrous acetonitrile low-grade fever dissolve anhydrous acetonitrile;
---pack the second deposit portion of microreactor reactive system into 1.14g 6-sulfydryl-(6,7-dihydro-5H-pyrazoles [1,2-a] [1,2,4] (3), 1.2ml diisopropylethylamine and 30ml anhydrous acetonitrile make 6-sulfydryl-(6,7-dihydro-5H-pyrazoles [1,2-a] [1 in triazole, 2,4] in triazole, dissolve (3);
---by the pipe connecting of microreactor, the reactive material of the first deposit portion of reactive system and the second deposit portion is sent into reacting part reaction and obtain product 1, wherein, reactant is at the flow velocity of pipe connecting inside that 4～8ml/ divides, temperature is that-5 ℃～0 ℃, pressure are that 7bar～10bar, reactant are 1.2min～2.5min in the time of reacting part internal stops;
---1 decompression of described product is removed to acetonitrile and obtain residue, then residue is dissolved in to ethyl acetate, and water and the washing of 0.1M phosphoric acid buffer, use again saturated sodium-chloride and anhydrous magnesium sulfate drying organic layer, decompression obtains white solid after removing ethyl acetate, and wherein white solid is target product;
In the present invention, utilize micro-reaction technology to improve the butt-joint process of the synthetic middle key intermediate of biapenem, enhance productivity.
As shown in Figure 1, although this reaction is gentleer, the reaction times is longer for traditional butt-joint process, and by product is more, and reaction efficiency is lower, and heat release is not serious, but whole process needs cooling.
While utilizing microreactor to dock reaction in the present invention, can regulate by flow velocity key intermediate and the side chain (6 of biapenem, 7-dihydro-6-sulfydryl-5H-pyrazolo [1,2-a] [1,2,4] triazole muriate 6,7-dihydro-6-sulfydryl-5h-pyrazolo [1,2-a] [1,2,4] triazole muriate) in reactor mix stop time be 1.2min～2.5min, effectively prevented side reaction; Increase specific surface area by the diameter that regulates microchannel, improve key intermediate and the side chain (6 of biapenem, 7-dihydro-6-sulfydryl-5H-pyrazolo [1,2-a] [1,2,4] triazole muriate 6,7-dihydro-6-sulfydryl-5h-pyrazolo [1,2-a] [1,2,4] triazole muriate) mixing efficiency; Can effectively conduct heat in microchannel, without specially cooling, can suitably take if desired cooling measure, but its temperature can accurately regulate and control.
In the present invention, utilize micro-reaction technology to shorten biapenem synthesis technique, significantly reduce costs.
In traditional technique, the key intermediate of biapenem accomplishs without any letup to the synthetic of biapenem, and this is also to reducing costs the step that contribution is larger.But the synthetic technique of phosphoric acid ester has a problem that traditional technology is impassable.The feature of this reaction is; Speed of response is very fast, and heat release is serious, temperature control difficulty, but post-reaction treatment is easier to.In phosphoryl chloride and ketone carbonyl reaction process, produce a large amount of heats, local temperature can reach 40～50 degree, easily produces a large amount of by products, lowers the temperature particularly important.
In the present invention, this reaction is forwarded in microreactor as shown in Figure 2, its temperature effectively reduces the generation of by product within being easy to and being controlled at exactly-5 ± 1 degree, has shortened the time of reaction, improves yield and purity, enhances productivity.
The present invention utilizes micro-reaction technology of gas one liquid one solid reaction system to enhance productivity, and greatly alleviates problem of environmental pollution.
Traditional catalytic hydrogenation directly adopts hydrogen, and pilot scale and large production are that fund input is large to the having relatively high expectations of equipment; Relate to excess hydrogen, have potential safety hazard, waste a large amount of hydrogen; Heavy metal reclaims and processes the potential problem of environmental pollution of initiation.There is common above-mentioned drawback in the reaction of the catalytic hydrogenation deprotection group of the key intermediate of biapenem, as shown in Figure 3, be thermopositive reaction, but thermal discharge is little simultaneously, and reaction enthalpy is little, restive reaction conditions and minimizing by product.
Nearly all gas phase reaction process all inevitably needs active catalyst.Industrially be applied in fixed bed reaction the small-particle that contains a small amount of catalytic material as weighting material; What in fluidized-bed reactor, apply is the active catalyst powder disperseing at reactor inner height; To the reaction of residence time section, conventionally use Web materials (majority is precious metal) as catalyzer.Due to many-sided reason, in microreactor, cannot adopt the catalyzer of these traditional forms.In the micro-reactive system of gas-liquid-solid three-phase, should guarantee the dispersion of gas in liquid in whole reaction, also require the intrinsic larger net contact area of gas-liquid simultaneously, will be also the key factor of guaranteeing that reaction is carried out smoothly along the low pressure of reaction channel in addition.Many experimental studies show, directly adopt simple microchannel catalytic structure layer as reactor, and its performance is just very superior.
The micro-reactive system of gas-liquid-solid three-phase adopting in the present invention is the FRX system of Syrris company of Britain, it easy and simple to handle, and gas-liquid-solid contact area is larger, can control reflection channel pressure, also can Reaction time shorten, its artwork is as shown in Figure 4.
The present invention has improved recrystallization condition, improves reaction efficiency, reduces solvent usage quantity, reduces costs, and energy saving and pollution alleviation, realizes Green Chemistry.
The crude product of biapenem need to be with a large amount of acetone recrystallizations (10g biapenem need nearly 3000ml acetone), and this has increased production cost simultaneously undoubtedly, has had a strong impact on the safety case of Working environment, severe contamination ambient air and soil.In addition, the yield of recrystallization is lower, so the Main Bottleneck of biapenem raising international competitiveness when this step is reacted.Compared with conventional preparation method, in microreactor, carry out recrystallization without complicated process.The good microcosmic mixed characteristic of microreactor makes nano particle have higher monodispersity; Also can change operational condition to regulate product dispersity.In preparation process, divide two-way to inject micro mixer the solution of solid and the recrystallization solution pump that adds equivalent respectively and carry out short mix, reaction, just can directly synthesize the nano-solid with good single dispersing characteristic, the method is simple, good quality of product, stable, reliable.
The batch process of biapenem is changed into continuity technique by the present invention, tentatively realizes mini factory (miniplant).
People generally believe that the major cause of large-scale production process complexity comes from separation and circulation loop system, and chemical reaction process is relatively simple.Therefore, mini factory requires the product that obtains single, or separating unit in process is relatively simple.Environmental standard, safety and process control should be more considered in the design of modern factories, rather than only consider throughput, and these are consistent with the thought of mini factory just.The present invention, by the continuous production of microreactor, preferentially improves technical process, avoids complicated circulation and separation system, the security of raising process and turndown ratio, system is airtight, reduces and pollutes, easy to maintenance, easy to clean, also can be used as the mini factory of discardable intermittent type.
The concrete following advantage of method provided by the invention:
1, regulate key intermediate and the side chain (6 of microchannel flow velocity biapenem, 7-dihydro-6-sulfydryl-5H-pyrazolo [1,2-a] [1,2,4] triazole muriate 6,7-dihydro-6-sulfydryl-5h-pyrazolo [1,2-a] [1,2,4] triazole muriate) time of retaining in reactor, reduces side reaction.
2, reduce the heat producing in phosphoryl chloride and ketone carbonyl reaction process, reduce side reaction.
3,, in the gas-liquid-solid phase reaction of catalytic hydrogenation deprotection, Optimization Technology, reduces hydrogen usage quantity, improves yield.
4,, in the recrystallization of biapenem crude product, reduce the usage quantity of acetone.
5, utilize microreactor, realize the continuous production of biapenem.
It is a kind of brand-new trial that the present invention utilizes micro-reaction technology to produce biapenem, is also a kind of innovation of Green Chemistry.Adopt micro-reaction technology, can allow reactant pass through fully mixing of miniflow, uniformly transfer heat, expansion area of dissipation, minimizing reaction times, solvent, reduce by product, improves yield.
Accompanying drawing explanation
Reaction formula when Fig. 1 is traditional butt-joint process;
Fig. 2 is reaction formula when butt-joint process in microreactor;
Fig. 3 is the reaction formula of the catalytic hydrogenation deprotection group of biapenem key intermediate;
Fig. 4 is the artwork while using microreactor;
Embodiment
Embodiment 1
Utilize micro-reaction technology to synthesize (4R, 5S, 6S)-3-[(6,7-dihydro-5H-pyrazoles [1,2-a] in [1,2,4] triazole-6-yl)]-sulphur-6-[(R)-1-hydroxyethyl]-4-methyl carbon mould-2-alkene-2-p-nitrophenyl ester (1)
This reaction is to utilize microchannel reaction system (FRX 100, Syrris) to carry out.The first deposit portion of reactive system packs 4.88g (8.0mmol) (4R into, 5S, 6S)-3-bis-benzenephosphonic acid oxygen base-6-[(R)-1-hydroxyethyl]-4-methyl carbon mould-2-alkene-2-p-nitrophenyl ester (2) and 30ml anhydrous acetonitrile low-grade fever be compound (4R, 5S, 6S)-3-bis-benzenephosphonic acid oxygen base-6-[(R)-1-hydroxyethyl] dissolving of-4-methyl carbon mould-2-alkene-2-p-nitrophenyl ester (2).The second deposit portion of reactive system packs 1.14g (8.0mmol) 6-sulfydryl-(6 into, 7-dihydro-5H-pyrazoles [1,2-a] (3), 1.2ml (8.8mmol) diisopropylethylamine and 30ml anhydrous acetonitrile make its dissolving in [1,2,4] triazole.Microchannel mixing portion is that the volume of reacting part is 1ml.The first and second deposit portions all connect from different pumps, by connected pipe connecting, the reagent of deposit portion and solvent are sent into reacting part.The equal 15cm of pipe connecting is long.At this moment the flow velocity of pipe connecting internal-response thing is that 8ml/ divides, temperature is that 0 ℃, pressure are that 10bar, reactant are 1.2 minutes in the time of reacting part internal stops.Acetonitrile is removed in the product decompression obtaining, and residue is dissolved in ethyl acetate, water, the washing of 0.1M phosphoric acid buffer, and with saturated sodium-chloride and anhydrous magnesium sulfate drying organic layer, decompression obtains white solid 3.1g after removing ethyl acetate, and wherein white solid is target product, and its yield is 75%.
Embodiment 2
Utilize micro-reaction technology to synthesize (4R, 5S, 6S)-3-[(6,7-dihydro-5H-pyrazoles [1,2-a] in [1,2,4] triazole-6-yl)]-sulphur-6-[(R)-1-hydroxyethyl]-4-methyl carbon mould-2-alkene-2-p-nitrophenyl ester (1)
This reaction is to utilize microchannel reaction system (FRX 100, Syrris) to carry out.The first deposit portion of reactive system packs 4.88g (8.0mmol) (4R into, 5S, 6S)-3-bis-benzenephosphonic acid oxygen base-6-[(R)-1-hydroxyethyl]-4-methyl carbon mould-2-alkene-2-p-nitrophenyl ester (2) and 30ml anhydrous acetonitrile low-grade fever be compound (4R, 5S, 6S)-3-bis-benzenephosphonic acid oxygen base-6-[(R)-1-hydroxyethyl] dissolving of-4-methyl carbon mould-2-alkene-2-p-nitrophenyl ester (2).The second deposit portion of reactive system packs 1.14g (8.0mmol) 6-sulfydryl-(6 into, 7-dihydro-5H-pyrazoles [1,2-a] (3), 1.2ml (8.8mmol) diisopropylethylamine and 30ml anhydrous acetonitrile make its dissolving in [1,2,4] triazole.Microchannel mixing portion is that the volume of reacting part is 1ml.The first and second deposit portions all connect from different pumps, by connected pipe connecting, the reagent of deposit portion and solvent are sent into reacting part.The equal 15cm of pipe connecting is long.By flow velocity set that 6ml/ divides for, temperature is that subzero 5 ℃, pressure are that 8bar, reactant are 1.7 minutes in the time of reacting part internal stops, acetonitrile is removed in the product decompression obtaining, residue is dissolved in ethyl acetate, water, the washing of 0.1M phosphoric acid buffer, and with saturated sodium-chloride and anhydrous magnesium sulfate drying organic layer, decompression obtains white solid 2.5g after removing ethyl acetate, and wherein the solid of white is target product, and its yield is 62%.
Embodiment 3
Utilize micro-reaction technology to synthesize (4R, 5S, 6S)-3-[(6,7-dihydro-5H-pyrazoles [1,2-a] in [1,2,4] triazole-6-yl)]-sulphur-6-[(R)-1-hydroxyethyl]-4-methyl carbon mould-2-alkene-2-p-nitrophenyl ester (1)
This reaction is to utilize microchannel reaction system (FRX 100, Syrris) to carry out.The first deposit portion of reactive system packs 4.88g (8.0mmol) (4R into, 5S, 6S)-3-bis-benzenephosphonic acid oxygen base-6-[(R)-1-hydroxyethyl]-4-methyl carbon mould-2-alkene-2-p-nitrophenyl ester (2) and 30ml anhydrous acetonitrile low-grade fever be compound (4R, 5S, 6S)-3-bis-benzenephosphonic acid oxygen base-6-[(R)-1-hydroxyethyl] dissolving of-4-methyl carbon mould-2-alkene-2-p-nitrophenyl ester (2).The second deposit portion of reactive system packs 1.14g (8.0mmol) 6-sulfydryl-(6 into, 7-dihydro-5H-pyrazoles [1,2-a] (3), 1.2ml (8.8mmol) diisopropylethylamine and 30ml anhydrous acetonitrile make its dissolving in [1,2,4] triazole.Microchannel mixing portion is that the volume of reacting part is 1ml.The first and second deposit portions all connect from different pumps, by connected pipe connecting, the reagent of deposit portion and solvent are sent into reacting part.The equal 15cm of pipe connecting is long.By flow velocity set that 4ml/ divides for, temperature is that subzero 5 ℃, pressure are that 7bar, reactant are 2.5 minutes in the time of reacting part internal stops, acetonitrile is removed in the product decompression obtaining, residue is dissolved in ethyl acetate, water, the washing of 0.1M phosphoric acid buffer, and with saturated sodium-chloride and anhydrous magnesium sulfate drying organic layer, decompression obtains white solid 2.3g after removing ethyl acetate, and wherein the solid of white is target product, and yield is 58%.
Claims (2)
1. utilize micro-reaction technology to prepare a method for biapenem, it is characterized in that: preparation process is carried out in microreactor, concrete preparation process is as follows:
---pack the first deposit portion of microreactor reactive system into 4.88g (4R, 5S, 6S)-3-bis-benzenephosphonic acid oxygen base-6-[(R)-1-hydroxyethyl]-4-methyl carbon mould-2-alkene-2-p-nitrophenyl ester (2) and 30ml anhydrous acetonitrile low-grade fever dissolve anhydrous acetonitrile;
---pack the second deposit portion of microreactor reactive system into 1.14g6-sulfydryl-(6,7-dihydro-5H-pyrazoles [1,2-a] [1,2,4] (3), 1.2ml diisopropylethylamine and 30ml anhydrous acetonitrile make 6-sulfydryl-(6,7-dihydro-5H-pyrazoles [1,2-a] [1 in triazole, 2,4] in triazole, dissolve (3);
---by the pipe connecting of microreactor, the reactive material of the first deposit portion of reactive system and the second deposit portion is sent into reacting part reaction and obtain product 1, wherein, reactant is at the flow velocity of pipe connecting inside that 4～8ml/ divides, temperature is that-5 ℃～0 ℃, pressure are that 7bar～10bar, reactant are 1.2min～2.5min in the time of reacting part internal stops;
---1 decompression of described product is removed to acetonitrile and obtain residue, then residue is dissolved in to ethyl acetate, and water and the washing of 0.1M phosphoric acid buffer, use again saturated sodium-chloride and anhydrous magnesium sulfate drying organic layer, decompression obtains white solid after removing ethyl acetate, and wherein white solid is target product;
The volume of described reacting part is 1ml.
2. according to utilizing micro-reaction technology to prepare the method for biapenem described in claim 1, it is characterized in that: the length of described pipe connecting is 15cm.
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| CN105713059A (en) * | 2016-01-05 | 2016-06-29 | 浙江朗华制药有限公司 | Method for synthesizing zidovudine azide intermediate by using microchannel reactor |
| CN105566326B (en) * | 2016-02-16 | 2018-03-30 | 江苏华旭药业有限公司 | A kind of synthetic method of Panipenem intermediate |
| CN105601661B (en) * | 2016-03-22 | 2019-04-23 | 南京曙光精细化工有限公司 | The method for preparing mercaptosilane coupling agents using pathway reaction device |
| CN113149989A (en) * | 2017-02-22 | 2021-07-23 | 浙江瑞博制药有限公司 | Method for preparing medicine and medicine intermediate by continuous solid-liquid-gas three-phase reaction |
| CN109988168A (en) * | 2019-05-07 | 2019-07-09 | 重庆天地药业有限责任公司 | A method of southern crude product is trained using micro passage reaction synthesizing imine |
| CN118162064B (en) * | 2024-05-15 | 2024-08-30 | 济南大学 | Continuous production device and method for meropenem parent nucleus intermediate |
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| CN1927867A (en) * | 2005-09-08 | 2007-03-14 | 上海医药工业研究院 | Synthesis method of biapenem |
| CN101284839A (en) * | 2008-06-02 | 2008-10-15 | 河北科技大学 | Method and device for preparing superfine amorphousn cefuroxime axetil |
| CN100497349C (en) * | 2006-01-26 | 2009-06-10 | 江苏先声药物研究有限公司 | Improved Biapenem preparation method |
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Patent Citations (4)
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| US3907786A (en) * | 1973-09-04 | 1975-09-23 | Bristol Myers Co | 7-{8 {60 -(2-aminomethyl-1,4-cyclohexadienyl)acetamido{9 -3-heterocyclic-thiomethyl-3-cephem-4-carboxylic acids and salts |
| CN1927867A (en) * | 2005-09-08 | 2007-03-14 | 上海医药工业研究院 | Synthesis method of biapenem |
| CN100497349C (en) * | 2006-01-26 | 2009-06-10 | 江苏先声药物研究有限公司 | Improved Biapenem preparation method |
| CN101284839A (en) * | 2008-06-02 | 2008-10-15 | 河北科技大学 | Method and device for preparing superfine amorphousn cefuroxime axetil |
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