CN102453044A - Method for preparing biapenem by using micro-reaction technology - Google Patents
Method for preparing biapenem by using micro-reaction technology Download PDFInfo
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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 little 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, characteristics that anti-microbial activity is strong.Biapenem all has stronger anti-microbial activity to gram positive organism, gram-negative bacteria (comprising drug-fast Pseudomonas aeruginosa), anerobes etc.; Stable to β-Nei Xiananmei; Stability to DHP-1 is strong than Yi Mipeinan.Than other carbapenem verieties that has gone on the market, the biapenem renal toxicity is almost nil, can be individually dosed, and do not have cns toxicity, and can not bring out epileptic seizures, can be used for the treatment of bacterial meningitis.Biapenem is stronger 2～4 times than imipenum with anerobes to suppressing Pseudomonas aeruginosa, and the inhibition drug-resistant pseudomonas aeruginosa is stronger 4～8 times than meropenem, and is more effective than ceftazime to acinetobacter calcoaceticus, anerobes.The clinical secondary infection of treatment chronic bronchitis, pneumonia, pulmonary suppuration disease, pyelonephritis, complicacy urocystitis, peritonitis and the adnexitis of being applicable to.
In the past in 10 years; The synthetic technology of 1 beta-methyl carbon penicillenic bicyclic system of chirality has had very big breakthrough; The development of the production technology of the key intermediate of this carbapenem veriety; For the production of copying medicine and semi-synthetic raw material provides more spacious income space, also promoted turning to of original new drug.But along with the development and the competition of synthetic technology are fierce further, the biapenem price descends gradually in the world, and the focus that reduces cost, improves international competitiveness forwards follow-up technology naturally to; As, recrystallization under the butt joint of female ring and side chain, catalytic hydrogenation deprotection, the acetone condition.
Carry out above-mentioned subsequent technique when producing according to traditional process method, following problem arranged:
1. technology is simpler, and the space that can enhance competitiveness is very little.
2. the solvent usage quantity is bigger, serious environment pollution.
3. yield is lower, wastes raw material.
4. because of heat release in the reaction process is bigger, by product is more, and hazardous.
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 drum, unit or the like.But its line size is far smaller than conventional tubular reactor, and microreactor inside is to be that a lot of microtubules of 10～500 μ m are formed in parallel by diameter, and great specific surface area is arranged.The advantage of bringing thus is great heat exchange efficiency and mixing efficiency.Can realize mixing with precise proportioning moment to the accurate control of temperature of reaction with to reaction mass.
Summary of the invention
The object of the present invention is to provide a kind of method of utilizing little 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 little reaction technology to prepare biapenem, it is characterized in that: the preparation process is carried out in microreactor, and concrete preparation process is following:
---with the first deposit portion of microreactor reactive system pack into 4.88g (4R, 5S, 6S)-3-two benzenephosphonic acid oxygen base-6-[(R)-1-hydroxyethyl]-4-methyl carbon mould-2-alkene-2-p-nitrophenyl ester (2) and 30ml anhydrous acetonitrile and low-grade fever make the anhydrous acetonitrile dissolving;
---with the second deposit portion of microreactor reactive system pack into 1.14g 6-sulfydryl-(6,7-dihydro-5H-pyrazoles [1,2-a] [1; 2; 4] in the triazole (3), 1.2ml diisopropylethylamine and 30ml anhydrous acetonitrile and make the 6-sulfydryl-(6,7-dihydro-5H-pyrazoles [1,2-a] [1; 2,4] (3) dissolving in the triazole;
---pipe connecting through microreactor is sent the RM of the first deposit portion of reactive system and the second deposit portion into the reacting part reaction and is obtained product 1; Wherein, reactant is that 4～8ml/ branch, temperature are that-5 ℃～0 ℃, pressure are that 7bar～10bar, reactant are 1.2min～2.5min in the time of reacting part internal stops at the inner flow velocity of pipe connecting;
---acetonitrile is removed in described product 1 decompression got residue; Then residue is dissolved in ETHYLE ACETATE; And water and the washing of 0.1M phosphoric acid buffer; Use saturated sodium-chloride and anhydrous magnesium sulfate drying organic layer again, decompression obtains white solid after removing ETHYLE ACETATE, and wherein white solid is title product;
Utilize little reaction technology to improve the butt joint technology of the synthetic middle key intermediate of biapenem among the present invention, enhance productivity.
Traditional butt joint technology is as shown in Figure 1, though this reaction is gentle, the reaction times is longer, and by product is more, and reaction efficiency is lower, and heat release is not serious, but whole process need be lowered the temperature.
Utilize microreactor to dock when reaction among the present invention, can through flow velocity regulate biapenem key intermediate and side chain (6,7-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 drum, mixing the time that stops is 1.2min～2.5min, has effectively prevented side reaction; Diameter through regulating the microchannel increases specific surface area, and the key intermediate of raising biapenem and side chain (6,7-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 the microchannel, need not specially to lower the temperature, and can suitably take cooling measure in case of necessity, but its temperature can be regulated and control accurately.
Utilize little reaction technology to shorten the biapenem synthesis technique among the present invention, significantly reduce cost.
The key intermediate of biapenem accomplishs without any letup to the synthetic of biapenem in traditional technology, and this also is to the bigger step of contribution that reduces cost.But the synthetic technology of SULPHOSUCCINIC ACID ESTER has a problem that traditional technology is impassable.The characteristics of this reaction are; Speed of response is very fast, and heat release is serious, and temperature control is difficult, but post-reaction treatment is easier to.In phosphoryl chloride and ketone carbonyl reaction process, produce great amount of heat, local temperature can reach 40～50 degree, is easy to generate a large amount of by products, and it is particularly important to lower the temperature.
Among the present invention this reaction is forwarded in the microreactor as shown in Figure 2ly, its temperature is easy to and is controlled at exactly within-5 ± 1 degree, has effectively reduced the generation of by product, has shortened the time of reaction, improves yield and purity, enhances productivity.
The present invention utilizes little reaction technology of gas one liquid one solid reaction system to enhance productivity, and alleviates problem of environmental pollution greatly.
Traditional catalytic hydrogenation directly adopts hydrogen, and it is that fund input is big to the having relatively high expectations of equipment that pilot scale and big is produced; Relate to excess hydrogen, have potential safety hazard, waste a large amount of hydrogen; Heavy metal reclaims and handles initiation potential problem of environmental pollution.There is common above-mentioned drawback in the reaction of the catalytic hydrogenation deprotection group of the key intermediate of biapenem, and is as shown in Figure 3, be thermopositive reaction simultaneously, but thermal discharge is little, and reaction enthalpy is little, restive reaction conditions and minimizing by product.
Nearly all gas phase reaction process all inevitably needs active catalyst.The small-particle that will contain a small amount of catalytic material in the industry is applied in the fixed bed reaction as weighting material; What use in the fluidized-bed reactor is at reactor drum inner height dispersive active catalyst powder; To the reaction of residence time section, use Web materials (majority is a precious metal) usually as catalyzer.Owing to many-sided reason, can't adopt the catalyzer of these traditional forms in the microreactor.In the little reactive system of gas-liquid-solid three-phase, should guarantee the dispersion of gas in liquid in entire reaction, also require the intrinsic bigger net contact area of gas-liquid simultaneously, will also be to guarantee to react the key factor of carrying out smoothly along the low pressure of reaction channel in addition.Many experimental studies show, directly adopt simple microchannel catalytic structure layer as reactor drum, and its performance is just very superior.
The little reactive system of the gas-liquid-solid three-phase that adopts among the present invention is the FRX system of Britain Syrris company, it easy and simple to handle, and gas-liquid is affixed, and to touch area bigger, can control the reflection channel pressure, also can shorten the reaction times, and its artwork is as shown in Figure 4.
The present invention has improved the recrystallization condition, improves reaction efficiency, reduces the solvent usage quantity, reduces cost, and energy saving and pollution alleviation is realized Green Chemistry.
The bullion of biapenem need be used a large amount of acetone recrystallization (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 this goes on foot the main bottleneck of biapenem raising international competitiveness when reacting.Compare with conventional preparation method, in microreactor, carry out recrystallization and need not complicated process.The good microcosmic mixed characteristic of microreactor makes nano particle have higher monodispersity; Also can change operational condition to regulate the product dispersity.In the preparation process; Divide two-way to inject micro mixer with the recrystallization solution that adds equivalent with pump solid solution respectively and carry out short mix, reaction; Just can directly synthesize the nano-solid with good single dispersing characteristic, this method is simple, good quality of product, stable, reliable.
The present invention changes into continuity technology with the batch process of biapenem, tentatively realizes mini factory (miniplant).
People generally believe that the complicated major cause of large-scale production process comes from separation and circulation loop system, and chemical reaction process is simple relatively.Therefore, the product that the requirement of mini factory obtains is single, or the separating unit in the process is simple relatively.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 preferentially improves technical process through the continuous production of microreactor, avoids complicated circulation and separation system; The security of raising process and turndown ratio, system is airtight, reduces and pollutes; Easy to maintenance, convenience for washing also can be used as the mini factory of discardable intermittent type.
Advantage below method provided by the invention is concrete:
1, regulate microchannel flow velocity biapenem key intermediate and side chain (6,7-dihydro-6-sulfydryl-5H-pyrazolo [1,2-a] [1; 2,4] the triazole muriate 6,7-dihydro-6-sulfydryl-5h-pyrazolo [1; 2-a] [1; 2,4] time that triazole muriate) in reactor drum, retains, reduce side reaction.
2, reduce the heat that produces in phosphoryl chloride and the ketone carbonyl reaction process, reduce side reaction.
3, in the gas-liquid-solid phase reaction of catalytic hydrogenation deprotection, optimize technology, reduce the hydrogen usage quantity, improve yield.
4, in the recrystallization of biapenem bullion, 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 little reaction technology to produce biapenem, also is a kind of innovation of Green Chemistry.Adopt little reaction technology, can let reactant pass through miniflow thorough mixing, uniformly transfer heat, expansion area of dissipation, minimizing reaction times, solvent reduce by product, improve yield.
Description of drawings
Reaction formula when Fig. 1 is traditional butt joint technology;
Fig. 2 is the reaction formula when docking technology in the microreactor;
Fig. 3 is the reaction formula of the catalytic hydrogenation deprotection group of biapenem key intermediate;
Fig. 4 is the artwork when using microreactor;
Embodiment
Embodiment 1
Utilize little reaction technology synthetic (4R, 5S, 6S)-3-[(6, in 7-dihydro-5H-pyrazoles [1,2-a] [1,2, the 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) carry out.4.88g (the 8.0mmol) (4R that packs into of the first deposit portion of reactive system; 5S; 6S)-3-two benzenephosphonic acid oxygen base-6-[(R)-1-hydroxyethyl]-4-methyl carbon mould-2-alkene-2-p-nitrophenyl ester (2) and 30ml anhydrous acetonitrile and low-grade fever be compound (4R; 5S, 6S)-3-two benzenephosphonic acid oxygen base-6-[(R)-the 1-hydroxyethyl]-4-methyl carbon mould-2-alkene-2-p-nitrophenyl ester (2) dissolving.The second deposit portion of reactive system packs into, and 1.14g (8.0mmol) 6-sulfydryl-(6, (3), 1.2ml (8.8mmol) diisopropylethylamine and 30ml anhydrous acetonitrile make its dissolving in 7-dihydro-5H-pyrazoles [1,2-a] [1,2, the 4] triazole.The microchannel mixer is that the volume of reacting part is 1ml.The first and second deposit portions all connect with different pumps, through the pipe connecting that links to each other the reagent and the solvent of deposit portion 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/ branch, temperature are 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 that obtains, and residue is dissolved in ETHYLE 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 ETHYLE ACETATE, and wherein white solid is a title product, and its yield is 75%.
Embodiment 2
Utilize little reaction technology synthetic (4R, 5S, 6S)-3-[(6, in 7-dihydro-5H-pyrazoles [1,2-a] [1,2, the 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) carry out.4.88g (the 8.0mmol) (4R that packs into of the first deposit portion of reactive system; 5S; 6S)-3-two benzenephosphonic acid oxygen base-6-[(R)-1-hydroxyethyl]-4-methyl carbon mould-2-alkene-2-p-nitrophenyl ester (2) and 30ml anhydrous acetonitrile and low-grade fever be compound (4R; 5S, 6S)-3-two benzenephosphonic acid oxygen base-6-[(R)-the 1-hydroxyethyl]-4-methyl carbon mould-2-alkene-2-p-nitrophenyl ester (2) dissolving.The second deposit portion of reactive system packs into, and 1.14g (8.0mmol) 6-sulfydryl-(6, (3), 1.2ml (8.8mmol) diisopropylethylamine and 30ml anhydrous acetonitrile make its dissolving in 7-dihydro-5H-pyrazoles [1,2-a] [1,2, the 4] triazole.The microchannel mixer is that the volume of reacting part is 1ml.The first and second deposit portions all connect with different pumps, through the pipe connecting that links to each other the reagent and the solvent of deposit portion are sent into reacting part.The equal 15cm of pipe connecting is long.Setting flow velocity for 6ml/ branch, 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 that obtains, and residue is dissolved in ETHYLE 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 ETHYLE ACETATE, and wherein the solid of white is a title product, and its yield is 62%.
Embodiment 3
Utilize little reaction technology synthetic (4R, 5S, 6S)-3-[(6, in 7-dihydro-5H-pyrazoles [1,2-a] [1,2, the 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) carry out.4.88g (the 8.0mmol) (4R that packs into of the first deposit portion of reactive system; 5S; 6S)-3-two benzenephosphonic acid oxygen base-6-[(R)-1-hydroxyethyl]-4-methyl carbon mould-2-alkene-2-p-nitrophenyl ester (2) and 30ml anhydrous acetonitrile and low-grade fever be compound (4R; 5S, 6S)-3-two benzenephosphonic acid oxygen base-6-[(R)-the 1-hydroxyethyl]-4-methyl carbon mould-2-alkene-2-p-nitrophenyl ester (2) dissolving.The second deposit portion of reactive system packs into, and 1.14g (8.0mmol) 6-sulfydryl-(6, (3), 1.2ml (8.8mmol) diisopropylethylamine and 30ml anhydrous acetonitrile make its dissolving in 7-dihydro-5H-pyrazoles [1,2-a] [1,2, the 4] triazole.The microchannel mixer is that the volume of reacting part is 1ml.The first and second deposit portions all connect with different pumps, through the pipe connecting that links to each other the reagent and the solvent of deposit portion are sent into reacting part.The equal 15cm of pipe connecting is long.Setting flow velocity for 4ml/ branch, 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 that obtains, and residue is dissolved in ETHYLE 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 ETHYLE ACETATE, and wherein the solid of white is a title product, and yield is 58%.
Claims (3)
1. method of utilizing little reaction technology to prepare biapenem, it is characterized in that: the preparation process is carried out in microreactor, and concrete preparation process is following:
---with the first deposit portion of microreactor reactive system pack into 4.88g (4R, 5S, 6S)-3-two benzenephosphonic acid oxygen base-6-[(R)-1-hydroxyethyl]-4-methyl carbon mould-2-alkene-2-p-nitrophenyl ester (2) and 30ml anhydrous acetonitrile and low-grade fever make the anhydrous acetonitrile dissolving;
---with the second deposit portion of microreactor reactive system pack into 1.14g 6-sulfydryl-(6,7-dihydro-5H-pyrazoles [1,2-a] [1; 2; 4] in the triazole (3), 1.2ml diisopropylethylamine and 30ml anhydrous acetonitrile and make the 6-sulfydryl-(6,7-dihydro-5H-pyrazoles [1,2-a] [1; 2,4] (3) dissolving in the triazole;
---pipe connecting through microreactor is sent the RM of the first deposit portion of reactive system and the second deposit portion into the reacting part reaction and is obtained product 1; Wherein, reactant is that 4～8ml/ branch, temperature are that-5 ℃～0 ℃, pressure are that 7bar～10bar, reactant are 1.2min～2.5min in the time of reacting part internal stops at the inner flow velocity of pipe connecting;
---acetonitrile is removed in described product 1 decompression got residue; Then residue is dissolved in ETHYLE ACETATE; And water and the washing of 0.1M phosphoric acid buffer; Use saturated sodium-chloride and anhydrous magnesium sulfate drying organic layer again, decompression obtains white solid after removing ETHYLE ACETATE, and wherein white solid is title product.
2. according to the said method of utilizing little reaction technology to prepare biapenem of claim 1, it is characterized in that: the volume of said reacting part is 1ml.
3. according to the said method of utilizing little reaction technology to prepare biapenem of claim 1, it is characterized in that: the length of said pipe connecting is 15cm.
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Cited By (5)
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| CN105566326A (en) * | 2016-02-16 | 2016-05-11 | 顾伟 | Panipenem midbody synthesis method |
| CN105601661A (en) * | 2016-03-22 | 2016-05-25 | 南京曙光精细化工有限公司 | Method for preparing mercaptosilane coupling agent by using channel reactor |
| 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 |
| CN108276409A (en) * | 2017-02-22 | 2018-07-13 | 浙江瑞博制药有限公司 | The method that serialization solid-liquid-gas three phase reaction prepares drug and pharmaceutical intermediate |
| 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 |
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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 |
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| CN108276409A (en) * | 2017-02-22 | 2018-07-13 | 浙江瑞博制药有限公司 | The method that serialization solid-liquid-gas three phase reaction prepares drug and pharmaceutical intermediate |
| CN108276409B (en) * | 2017-02-22 | 2022-09-20 | 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 |
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| CN102453044B (en) | 2014-06-18 |
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