CN103757085A - Cefaclor and synthetic method thereof - Google Patents
Cefaclor and synthetic method thereof Download PDFInfo
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- CN103757085A CN103757085A CN201310629212.1A CN201310629212A CN103757085A CN 103757085 A CN103757085 A CN 103757085A CN 201310629212 A CN201310629212 A CN 201310629212A CN 103757085 A CN103757085 A CN 103757085A
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- cefaclor
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- 229960005361 cefaclor Drugs 0.000 title claims abstract description 136
- 238000010189 synthetic method Methods 0.000 title claims abstract description 8
- QYIYFLOTGYLRGG-GPCCPHFNSA-N cefaclor Chemical compound C1([C@H](C(=O)N[C@@H]2C(N3C(=C(Cl)CS[C@@H]32)C(O)=O)=O)N)=CC=CC=C1 QYIYFLOTGYLRGG-GPCCPHFNSA-N 0.000 title claims abstract 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 102
- 239000013078 crystal Substances 0.000 claims abstract description 56
- 238000000034 method Methods 0.000 claims abstract description 42
- 108090000790 Enzymes Proteins 0.000 claims abstract description 25
- 102000004190 Enzymes Human genes 0.000 claims abstract description 25
- -1 methyl esters salt Chemical class 0.000 claims description 36
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 21
- 239000011541 reaction mixture Substances 0.000 claims description 15
- 239000011259 mixed solution Substances 0.000 abstract description 3
- BHFLUDRTVIDDOR-MRVPVSSYSA-N methyl (2r)-2-amino-2-phenylacetate Chemical class COC(=O)[C@H](N)C1=CC=CC=C1 BHFLUDRTVIDDOR-MRVPVSSYSA-N 0.000 abstract 1
- WKJGTOYAEQDNIA-IOOZKYRYSA-N (6r,7r)-7-[[(2r)-2-amino-2-phenylacetyl]amino]-3-chloro-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;hydrate Chemical compound O.C1([C@H](C(=O)N[C@@H]2C(N3C(=C(Cl)CS[C@@H]32)C(O)=O)=O)N)=CC=CC=C1 WKJGTOYAEQDNIA-IOOZKYRYSA-N 0.000 description 125
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- 239000000243 solution Substances 0.000 description 20
- 230000009466 transformation Effects 0.000 description 20
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 18
- 230000008569 process Effects 0.000 description 17
- 230000035484 reaction time Effects 0.000 description 17
- 239000012535 impurity Substances 0.000 description 13
- 238000005070 sampling Methods 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- 239000000047 product Substances 0.000 description 11
- 108010093096 Immobilized Enzymes Proteins 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 229910021529 ammonia Inorganic materials 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- PJKVFARRVXDXAD-UHFFFAOYSA-N 2-naphthaldehyde Chemical compound C1=CC=CC2=CC(C=O)=CC=C21 PJKVFARRVXDXAD-UHFFFAOYSA-N 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 238000007670 refining Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 description 4
- 230000031018 biological processes and functions Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000010413 mother solution Substances 0.000 description 3
- 108010013491 acyl-CoA-6-aminopenicillanic acid acyltransferase Proteins 0.000 description 2
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- 238000011084 recovery Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 241000606768 Haemophilus influenzae Species 0.000 description 1
- ZGUNAGUHMKGQNY-ZETCQYMHSA-N L-alpha-phenylglycine zwitterion Chemical compound OC(=O)[C@@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-ZETCQYMHSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- 108010073038 Penicillin Amidase Proteins 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- YGBFLZPYDUKSPT-MRVPVSSYSA-N cephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)C[C@H]21 YGBFLZPYDUKSPT-MRVPVSSYSA-N 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
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- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 238000005374 membrane filtration Methods 0.000 description 1
- SZJUWKPNWWCOPG-UHFFFAOYSA-N methyl 2-anilinoacetate Chemical compound COC(=O)CNC1=CC=CC=C1 SZJUWKPNWWCOPG-UHFFFAOYSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 229940124588 oral cephalosporin Drugs 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
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Abstract
The invention provides cefaclor and a synthetic method thereof. The synthetic method of cefaclor comprises that in the presence of an enzyme, cefaclor is generated by forming a reaction mixed solution of 7-ACCA and a D-phenylglycine methyl ester salt derivative and performing reaction, wherein cefaclor crystal seeds are added into the reaction mixed solution, and the crystal seeds are added before cefaclor generated in the reaction is precipitated. The method helps to improve the reaction efficiency, shorten the synthetic period, improve the conversion rate of 7-ACCA and improve the purity of obtained cefaclor.
Description
Technical field
The present invention relates to the synthetic field of cefaclor, especially, relate to a kind of method of biological process the synthesis of cefaclor and the cefaclor being synthesized by the method.
Background technology
Cefaclor chemical name: these product are (6R, 7R)-7-[(R)-2-amino-2-phenylacetylamino)]-3-chloro-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid monohydrate.Cefaclor is s-generation oral cephalosporin.Multiple gram-positive microorganism and Gram-negative bacteria are all had to very strong killing action.Strong 2～4 times compared with S 578 to not producing enzyme streptococcus aureus and pneumococcal anti-microbial effect.Can suppress all hemophilus influenzaes, comprise the bacterial strain to ampicillin-resistant.
At present, the operational path of producing cefaclor both at home and abroad has chemical method and biological process.Current domestic main employing chemical method the synthesis of cefaclor, domestic employing biological process (enzyme process) only have the joint Xinhua-Ken Fu company of DSM.Chemical method be take 7-amino-3-chlorine Cephalosporanic acid (7-ACCA) and in tetrahydrofuran (THF) or acetonitrile equal solvent, is carried out condensation the synthesis of cefaclor as parent nucleus and phenylglycine (need protect amino), then with DMF, beta naphthal equal solvent, forms mixed solution and cefaclor is carried out to purifying make cefaclor bulk drug.Chemical method synthesizes in a large amount of solvents such as tetrahydrofuran (THF), acetonitrile, large to the demand of organic solvent.Reaction process is violent, and the purity of product is low, and organic solvent is residual serious.The generation of " three wastes " is more, and environmental pollution is serious.
It is the short the synthesis of cefaclor of substrate utilization penicillin acidated enzyme that biological process (enzyme process) be take 7-ACCA and Phenylglycine methyl ester (or other derivatives).In CN101090978A, mention and in reaction process, add 7-ACCA and/or PGa, and pH value in reaction is preferably to 6.8～7.2.Although there is no adding of organic solvent in whole process, the impurity producing is more, and products therefrom purifying technique is very complicated.After longer reaction time, transformation efficiency can reach more than 96%, if shorten reaction time, transformation efficiency can significantly reduce.
Summary of the invention
The object of the invention is to provide a kind of cefaclor and synthetic method thereof, and many to solve in prior art in enzyme process the synthesis of cefaclor process impurity, reaction time is long, and cefaclor purity is low, the technical problem of cefaclor separating and purifying method complexity.
For achieving the above object, according to an aspect of the present invention, a kind of cefaclor synthetic method is provided, in the situation that enzyme exists, 7-ACCA forms reaction mixture with D-PG methyl esters salt derivative and reacts generation cefaclor, before cefaclor is separated out, the purity of usining is greater than 50% cefaclor and joins in reaction mixture as crystal seed.
Further, seed concentration >=0.2% (w/v).
Further, seed concentration is 0.5～5% (w/v).
Further, crystal seed added before reaction mixture reacts.
Further, crystal seed adds when reaction mixture reacts.
Further, crystal seed joins in reaction mixture after D-PG methyl esters salt derivative drips.
Further, D-PG methyl esters salt derivative is solution, after reaction starts, in 0～60 minute, in the mode dripping, adds.
Further, D-PG methyl esters salt derivative adds in the mode dripping in 0～30 minute after reaction starts.
Further, pH value in reaction is 6.0～6.5, and temperature is 9～17 ℃.
A kind of cefaclor making as stated above is also provided according to a further aspect in the invention.
Further, cefaclor HPLC content is greater than 99.6%.
The present invention has following beneficial effect:
Method provided by the invention adds cefaclor as the crystal seed of reaction in reaction early stage, has improved reaction efficiency, has shortened synthesis cycle and has improved the transformation efficiency of 7-ACCA, and improved the purity of gained cefaclor.
Method provided by the invention is enzyme process, in reaction process, only needs enzyme catalysis and take water as dissolving phase, and without any organic solvent, environmental protection, circuit is simple, and product yield is high, and purity is high.
Except object described above, feature and advantage, the present invention also has other object, feature and advantage.Below with reference to figure, the present invention is further detailed explanation.
Accompanying drawing explanation
The accompanying drawing that forms the application's a part is used to provide a further understanding of the present invention, and schematic description and description of the present invention is used for explaining the present invention, does not form inappropriate limitation of the present invention.In the accompanying drawings:
Fig. 1 is high performance liquid chromatography (HPLC) figure of the gained cefaclor of the preferred embodiment of the present invention.
Embodiment
Below in conjunction with accompanying drawing, embodiments of the invention are elaborated, but the multitude of different ways that the present invention can be defined by the claims and cover is implemented.
Before cefaclor is separated out, add cefaclor as the crystal seed of reaction, improve the crystallization velocity of cefaclor in reaction process, shortened reaction time greatly.Control the addition manner of D-PG methyl esters salt derivative, improve the solubleness of 7-ACCA in reaction system, reach supersaturation, improve yield and the purity of product.
The present invention includes following steps: in the situation that enzyme exists, 7-ACCA reacts and obtains cefaclor with D-PG methyl esters salt derivative formation reaction mixture, adds crystal seed in reaction mixture, and crystal seed is cefaclor.
In reaction system, 7-ACCA adds with solution form.After 7-ACCA enters reaction system with solid 7-ACCA through dissolving-spread-process reacts.After 7-ACCA adds reaction system with solution form, 7-ACCA is through spreading-react process.Saved the process of dissolving, avoided that 7-ACCA partial concn in reaction system is too high causes reacting inadequate problem.After 7-ACCA solid form adds, the now concentration of 7-ACCA the highest and concentrations and certain region in reaction system.Cefaclor can only generate in the higher region of 7-ACCA concentration, the cefaclor now adding as crystal seed cannot spread or close this region, newly-generated cefaclor also cannot be subject to the attraction of crystal seed at a distance and move out of near immobilized enzyme, and can only separate out on immobilized enzyme nearby.If illustrate that 7-ACCA adds with solid form, even if add cefaclor also cannot prevent being coated and fixed of cefaclor enzyme as crystal.
Cefaclor purity as crystal seed need be greater than 50%, the purity of crystal seed represents wherein impurity content, conventionally in cefaclor, impurity is unreacted intermediate product completely, owing to not knowing which stage that intermediate product is specially reaction produces, thereby can not know after adding, can cause which kind of impact to reaction, thereby purity can not be too low.When impurity is too much, the cefaclor adding as crystal seed can increase the impurity level of reaction system, makes, in reaction process, other unknown side reactions occur, and these side reaction meetings reduce the purity of follow-up gained cefaclor, increase and filter the difficulty of purifying, make this method be unsuitable for industrial applicability.Be preferably cefaclor crystal seed purity and be greater than 90%.
Enzyme used is immobilized enzyme.Immobilized enzyme is vesicular structure, easily adheres to other impurity.Reaction occurs near immobilized enzyme, only have the materials such as 7-ACCA and D-PG methyl esters salt derivative, and the structure of these materials and cefaclor structure differs larger in reaction system, can not be as the crystal seed combination with it of cefaclor.Reacting formed new cefaclor cannot enter in solution rapidly, and now reaction is carried out fast, constantly has new cefaclor to generate.The cefaclor that reaction produces is attached on immobilized enzyme nearby and separates out.Along with the cefaclor that newly produced of exposed enzyme on the being fixed enzyme of reaction covers, in reaction system, unreacted raw material thing cannot approach enzyme and reacts, and along with the prolongation in reaction times, reacts and no longer carries out.Thereby in prior art, enzyme process is longer reaction time.
Add after crystal seed, crystal seed is dispersed in reaction system everywhere.Reaction occurs near immobilized enzyme, and after producing first new cefaclor molecule, the cefaclor hydrate of this new generation can be subject near the molecular force of crystal seed it and attract, and gets off quickly immobilized enzyme and dissolves in reaction system, is incorporated on crystal seed.Along with the carrying out of reaction, repeatedly, crystal seed volume expands this process gradually, and cefaclor is separated out.Adding of crystal seed can be avoided the new cefaclor producing being coated immobilized enzyme.Make the enzyme of immobilized enzyme in whole reaction process can be always exposed, continue the raw material thing in catalystic converter system, make to react and continue to occur.Along with the prolongation in reaction times, reaction is thoroughly carried out, thereby adds shorten reaction time after crystal seed, and the productive rate of gained cefaclor is improved.The cefaclor that the interpolation of crystal seed obtains reaction can be in contact with one another as early as possible crystallization in solution, promotes reaction forward to carry out, and makes sufficient reacting.
In the selection of crystal seed, adopt non-existent material in reaction system can introduce new impurity, for the separation of subsequent products makes trouble.Cefaclor itself is stronger to the material avidity of same structure, thereby can play the effect of crystal seed.Crystal seed herein can all kinds of cefaclors, can be both that water-free cefaclor also can the higher cefaclor (water content can be greater than 20%) of water content.Newly-generated cefaclor is dissolved in reaction system solution separates out again, thereby gained cefaclor water content 9% left and right.But this can't affect the purity of final gained cefaclor.Be preferably the cefaclor obtaining through beta naphthal, DMF separating-purifying.Be that water content is 4.6～6.0% cefaclor.Owing to only containing a water molecules in its molecular structure, the most approaching with newly-generated cefaclor structure, thereby separate out effect optimum.The effect that now crystal seed shortens reaction time is optimum.
The cefaclor that crystal seed cefaclor generates in reaction adds before separating out.Before more preferably reaction occurs in reaction mixture or when reaction occurs, add, now can measure the wherein growing amount of cefaclor by extract real-time reaction mixture and determine whether reaction occurs.Reaction can be the arbitrary period before separating out to cefaclor after reaction starts while occurring.Certainly crystal seed can be also to add in reaction mixture after D-PG methyl esters salt derivative drips.
When in reaction system, the concentration of cefaclor is greater than 40～45mg/ml, cefaclor is separated out.The mode that adds of cefaclor can be both that the some time points before cefaclor is separated out once all add in reaction system, can be also to add in reaction system several times.Be preferably and before cefaclor is separated out, once all add sometime crystal seed.Add in such a way and can make to form fast a plurality of crystal seeds in reaction system, crystal seed is uniformly distributed in reaction system each several part.For separating out of product provides a plurality of sites.Reaction just starts soon, and the optional position of the cefaclor that no matter generated in reaction system, all has nucleus to wait for combination with it in its vicinity, after newly-generated cefaclor is combined with crystal seed, separate out, can further reduce the concentration of cefaclor in reaction system, promote reaction forward to carry out.Can further shorten reaction time.Interpolation concentration >=0.2% (w/v) of preferred crystal seed.By this concentration, add, the crystallization nuclei of q.s can be provided in reaction system, be conducive to further shorten reaction time.But the addition of crystal seed can not be excessive, otherwise reaction system viscosity is excessive, cannot operate.Be preferably 0.5～5% (w/v).In this ratio, add, can avoid the crystal seed of overrich to strengthen reaction system viscosity, reaction cannot smooth and easyly be carried out, can avoid again the waste of crystal seed, can also realize object of the present invention.
Obvious, in enzyme process reaction, add after crystal seed, can react according to conventional process, can play equally the effect of shortening reaction time.Preferably D-PG methyl esters salt derivative is dissolved as to solution, after reaction starts, in 0～60 minute, in the mode dripping, adds.Further, in 0～30 minute, in the mode dripping, add.D-PG methyl esters salt derivative can be the sweet acid methyl ester hydrochloride salt of D-benzene, D-PG methyl esters vitriol, D-PG methyl esters mesylate etc.Because reaction starts rear 0～60 minute 7-ACCA, it is supersaturated solution, now in dropping mode, at the uniform velocity add D-PG methyl esters salt derivative, D-PG methyl esters salt derivative enters reaction system and just reacts with 7-ACCA, near reaction origination point, 7-ACCA concentration reduces, make whole reaction system can dissolve more 7-ACCA, 7-ACCA satiates in reaction system.The amount that 7-ACCA enters reaction system increases, and for improving the productive rate of cefaclor, lays a solid foundation.
During reaction, pH value of reaction system is preferably 5.8～6.6, and more preferably 6.0～6.5.Because pH is greater than 7.0 o'clock cefaclor bad stability, if reaction system maintains higher pH value, the cefaclor that part has generated can decompose again, makes to have some uncertain impurity in system, for later separation, purifies and increases difficulty.When pH value is 6.0～6.5, cefaclor stability newly-generated in reaction system is high, coordinates the effect of crystal seed simultaneously, and newly-generated cefaclor can form crystallization fast, avoids again decomposing, thereby shortens reaction time, improves product yield and purity.The pH value of reaction system can regulate by any common solvent while raising, and is preferably ammoniacal liquor and regulates.PH value control device is easy.Reaction occurrence temperature is preferably 5～25 ℃, more preferably 9～17 ℃.Excess Temperature gained cefaclor can decompose, and the amount of impurity in increase system, for separating-purifying is manufactured difficulty.Temperature is too low can extend the reaction times, reduces enzyme and lives, and makes to react insufficient.Thereby by this preferable reaction temperature.
Enzyme-added for enzyme process prepare enzyme that cefaclor is conventional as: penioillin acylase, penicillin acylase etc. can be used for the synthetic enzyme of cefaclor.The add-on of enzyme routinely technique select, also process choice routinely of the mol ratio of 7-ACCA and D-PG methyl esters salt derivative.
The present invention provides a kind of cefaclor making as stated above on the other hand, and in this cefaclor, impurity HPLC content is less than 0.4%, and cefaclor HPLC content is greater than 99.6%.Illustrate that the cefaclor purity according to said method making is high, purify easy, be suitable for industrial applications.
Embodiment
In following examples, the equal following steps of gained cefaclor are refined, are reclaimed.Enzyme used is that penioillin acylase is purchased from Hu'nan Fulaige Biological Technology Co. Ltd..In following examples, material used, instrument are commercially available.
Refining: with hydrochloric acid, dissolve cefaclor suspension liquid completely, after filtration insolubles, carbon take off, solution is adjusted pH4.0～5.5 with ammoniacal liquor, and 2～15 ℃ of temperature, crystallize out cefaclor, and the solution after crystallization is called crystalline mother solution.The cefaclor wet product that this process obtains is refining cefaclor after drying.
Reclaim: in crystalline mother solution, add a certain amount of beta naphthal or DMF, make cefaclor form corresponding mixture, filter and collect cephalo mixture, add a certain amount of water and dissolving with hydrochloric acid mixture, add ethyl acetate or dichloromethane extraction beta naphthal, after separatory, water is adjusted to pH4.0～5.5 with ammoniacal liquor, obtain the cefaclor wet product of recovery, reclaim after drying cefaclor.The cefaclor reclaiming can as the crystal seed of building-up process.
The weight that drops into 7-ACCA during 7-ACCA transformation efficiency=(residual 7-ACCA weight in the rear solution of 7-ACCA weight-reaction dropping into during reaction)/reaction
The 7-ACCA weight dropping into during the weight yield of cefaclor=refining rear cefaclor weight/reaction
High performance liquid chromatography condition is:
Mobile phase A: take 6.8g potassium primary phosphate, add after the dissolving of 1000ml ultrapure water, with the NaOH solution of 1mol/L, adjust pH to 5.8, with after the water system membrane filtration of aperture 0.22 μ m, degassed about 20 minutes.
Mobile phase B: measure 50ml acetonitrile, the A that joins 450ml mutually in, mix latter degassed about 20 minutes.
Pillar type: Kromasil C185 μ m250mm * 4.6mm.
Embodiment 1
Get 30g (128mmol) 7-ACCA and add 200ml pure water 6mol/L ammonia solvent; pH7.8～8.1 after dissolving; add 2000U penioillin acylase, in 0～10 minute, at the uniform velocity add D-PG methyl ester hydrochloride solution (solution preparation method 28.4g (141mmol) solid adds 60ml pure water).Reaction started after 5 minutes, before in reaction soln, 0.2% (w/v) cefaclor is not separated out, and the disposable cefaclor crystal seed (purity is greater than 90%) that adds.Synthetic pH6.4,15 ℃ of temperature.
Reacting 120 minutes sampling HPLC detects; 7-ACCA concentration is now 0.27mg/ml (referring to Fig. 1); 7-ACCA transformation efficiency 99.6%; screen cloth separating penicillin acyltransferase and cefaclor suspension liquid; after cefaclor suspension liquid is refining, weight is 43.6g; and from crystalline mother solution, use beta naphthal to reclaim cefaclor, and obtaining the cefaclor 2.9g reclaiming, cefaclor gross weight yield is 1.49.
Embodiment 2
Get after 30g (128mmol) 7-ACCA adds 200ml pure water and add 6mol/L ammonia solvent; add 2000U penioillin acylase; in 0～10 minute, at the uniform velocity add D-PG methyl ester hydrochloride solution (solution preparation method 28.4g (141mmol) solid adds 60ml pure water); reaction started after 15 minutes; before in reaction soln, cefaclor is not separated out; the disposable cefaclor 2.9g crystal seed (purity is greater than 90%) that adds beta naphthal recovery in example 1; synthetic pH6.4,15 ℃ of temperature.
Reacting 120 minutes sampling HPLC detects; 7-ACCA concentration is now 0.38mg/ml, 7-ACCA transformation efficiency 99.5%, screen cloth separating penicillin acyltransferase and cefaclor suspension liquid; after cefaclor suspension liquid is refining, weight is 44.50g, and cefaclor weight yield is 1.48.
Embodiment 3
1:1.05 gets 7-ACCA and D-PG methyl ester hydrochloride in molar ratio.7-ACCA adds pure water 6mol/L ammonia solvent; add 12000U penioillin acylase; in 0～30 minute, at the uniform velocity add the D-PG methyl ester hydrochloride aqueous solution; when reaction does not start; dividing adds for 3 times 5% (w/v) cefaclor as crystal seed (purity is greater than 50%); reaction pH5.8,5 ℃ of temperature.
Within 60 minutes, sampling HPLC detects, and 7-ACCA concentration is now 0.18mg/ml, 7-ACCA transformation efficiency 99.7%, and cefaclor gross weight yield is 1.49.
Embodiment 4
1:1.2 gets 7-ACCA and D-PG methyl ester hydrochloride in molar ratio.7-ACCA adds pure water 6mol/L ammonia solvent; add 1200U penioillin acylase; in 0～60 minute, at the uniform velocity add the D-PG methyl ester hydrochloride aqueous solution; reaction started after 5 minutes; before in reaction soln, cefaclor is not separated out; decile adds for four times 0.5% (w/v) cefaclor as crystal seed (purity is greater than 60%), reaction pH6.6,25 ℃ of temperature.
Within 60 minutes, sampling HPLC detects, and 7-ACCA concentration is now 0.20mg/ml, 7-ACCA transformation efficiency 99.7%, and cefaclor gross weight yield is 1.47.
Embodiment 5
1:1.05 gets 7-ACCA and D-PG methyl ester hydrochloride in molar ratio.7-ACCA adds pure water 6mol/L ammonia solvent; add 2000U penioillin acylase; in 0～35 minute, at the uniform velocity add the D-PG methyl ester hydrochloride aqueous solution; after the D-PG methyl ester hydrochloride aqueous solution is added dropwise to complete; disposable 0.7% (w/v) cefaclor that adds is as crystal seed (purity is greater than 80%); reaction pH6,9 ℃ of temperature.
Within 180 minutes, sampling HPLC detects, and 7-ACCA concentration is now 0.62mg/ml, 7-ACCA transformation efficiency 99.2%, and cefaclor gross weight yield is 1.45.
Comparative example 1
Get after 30g (128mmol) 7-ACCA adds 200ml pure water and add 6mol/L ammonia solvent; add 2000U penioillin acylase; in 0～10 minute, at the uniform velocity add D-PG methyl ester hydrochloride solution (solution preparation method 28.4g (141mmol) solid adds 60ml pure water); synthetic pH6.4,15 ℃ of temperature.
Within 120 minutes, sampling HPLC detects, 7-ACCA concentration is now 15.9mg/ml, 7-ACCA transformation efficiency 76.7%, within 180 minutes, sampling HPLC detects, and 7-ACCA concentration is now 14.5mg/ml, 7-ACCA transformation efficiency 79.2%, reacting 360 minutes sampling HPLC detects, 7-ACCA concentration is now 13.2mg/ml, 7-ACCA transformation efficiency 83.5%
Comparative example 2
Get after 30g (128mmol) 7-ACCA adds 200ml pure water and add 6mol/L ammonia solvent; add 2000U penioillin acylase; once D-PG methyl ester hydrochloride solution (solution preparation method 28.4g (141mmol) solid adds 60ml pure water) is added; 7-ACCA separates out very soon; synthetic pH6.4,15 ℃ of temperature.
React 180 minutes materials very thickness that becomes, be difficult to separated with penioillin acylase.
Comparative example 3
1:1.10 gets 7-ACCA and D-PG methyl ester hydrochloride in molar ratio.7-ACCA adds pure water 6mol/L ammonia solvent; add 2000U penioillin acylase, at the uniform velocity add the D-PG methyl ester hydrochloride aqueous solution in 0～30 minute, reaction adds 0.2% (w/v) 7-ACCA as crystal seed while starting the 5th minute; reaction pH5.5,17 ℃ of temperature.
After 7-ACCA adds, find that there is the 7-ACCA that dissolved in a large number at once and again separate out, react 180 minutes materials very thickness that becomes, be difficult to separated with penioillin acylase.
Comparative example 4
1:1.10 gets 7-ACCA and D-PG methyl ester hydrochloride in molar ratio.7-ACCA adds pure water 6mol/L ammonia solvent; add 2000U penioillin acylase, at the uniform velocity add the D-PG methyl ester hydrochloride aqueous solution in 0～70 minute, reaction adds 0.1% (w/v) cefaclor as crystal seed while starting the 5th minute; reaction pH6.8,18 ℃ of temperature.
Within 120 minutes, sampling HPLC detects, 7-ACCA concentration is now 10.9mg/ml, 7-ACCA transformation efficiency 84.3%, within 180 minutes, sampling HPLC detects, 7-ACCA concentration is now 8.7mg/ml, and 7-ACCA transformation efficiency 87.5% reacts 360 minutes sampling HPLC and detects, 7-ACCA concentration is now 2.9mg/ml, 7-ACCA transformation efficiency 95.6%.
Comparative example 5
Press the step the synthesis of cefaclor in CN101090978A.
1:1.10 gets 7-ACCA and D-PG methyl ester hydrochloride in molar ratio.7-ACCA adds pure water to adjust pH7.0 with 6mol/L ammoniacal liquor, and 7-ACCA is dissolved on a small quantity, adds 2000U penioillin acylase, at the uniform velocity adds the D-PG methyl ester hydrochloride aqueous solution, pH7.0,20 ℃ of temperature in 0～120 minute.
React 270 minutes sampling HPLC and detect, 7-ACCA concentration is now 5.92mg/ml, 7-ACCA transformation efficiency 91%, reacting 380 minutes sampling HPLC detects, 7-ACCA concentration is now 1.24mg/ml, 7-ACCA transformation efficiency 97%, and cefaclor gross weight yield is 1.43.Reaction starts 7-ACCA in 200 minutes and does not dissolve completely.
In embodiment 1, gained cefaclor is through our company and third company's experimental verification.The transformation efficiency that 7-ACCA in 120 minutes occurs in reaction is greater than 99%, and cefaclor weight yield is greater than 1.45, beta naphthal or DMF, the residual 10ppm that is all less than of ethyl acetate (or methylene dichloride).Referring to Fig. 1, be the HPLC curve of gained cefaclor, known products therefrom is cefaclor, and purity is high, does not substantially have other impurity to produce.
And do not add in the comparative example 1 of crystal seed, reacting after 180 minutes, the transformation efficiency of 7-ACCA is only 79.2%.
In not controlling the comparative example that adds mode 2 of D-PG methyl esters salt derivative, obtaining cefaclor HPLC content is only 90%, and wherein magazine content is more and complicated.
In comparative example 3, adopt 7-ACCA as crystal seed, after 7-ACCA adds, the 7-ACCA of dissolving separates out again, and the process of impact reaction is difficult to separatedly with penioillin acylase, cannot obtain cefaclor, cannot realize the object of the invention.
According to CN101090978A method reproduction experiment, reacting 7-ACCA transformation efficiency after 270 minutes is only 91%, and reaction time is long, can not realize the object that shortens reaction time.
Therefore method provided by the invention can effectively shorten reaction time, gained cefaclor purity is high, and impurity does not have substantially, is suitable for industrial applicability.
The foregoing is only the preferred embodiments of the present invention, be not limited to the present invention, for a person skilled in the art, the present invention can have various modifications and variations.Within the spirit and principles in the present invention all, any modification of doing, be equal to replacement, improvement etc., within all should being included in protection scope of the present invention.
Claims (11)
1. a cefaclor synthetic method, in the situation that enzyme exists, 7-ACCA forms reaction mixture with D-PG methyl esters salt derivative and reacts generation cefaclor, it is characterized in that, before described cefaclor is separated out, the purity of usining is greater than 50% cefaclor and joins in described reaction mixture as crystal seed.
2. method according to claim 1, is characterized in that, described seed concentration >=0.2% (w/v).
3. method according to claim 2, is characterized in that, described seed concentration is 0.5～5% (w/v).
4. method according to claim 1 and 2, is characterized in that, described crystal seed added before described reaction mixture reacts.
5. method according to claim 1 and 2, is characterized in that, described crystal seed adds when described reaction mixture reacts.
6. method according to claim 5, is characterized in that, described crystal seed joins in described reaction mixture after described D-PG methyl esters salt derivative drips.
7. according to the method described in any one in claim 1 to 6, it is characterized in that, described D-PG methyl esters salt derivative is solution, after reaction starts, in 0～60 minute, in the mode dripping, adds.
8. method according to claim 7, is characterized in that, described D-PG methyl esters salt derivative adds in the mode dripping in 0～30 minute after reaction starts.
9. method according to claim 1, is characterized in that, described pH value in reaction is 6.0～6.5, and temperature is 9～17 ℃.
10. the cefaclor making by the cefaclor synthetic method described in any one in claim 1 to 9.
11. cefaclors according to claim 10, is characterized in that, described cefaclor HPLC content is greater than 99.6%.
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| CN107523603B (en) * | 2017-08-04 | 2020-12-29 | 长沙凯晓生物科技有限公司 | Method for preparing cefaclor by enzyme method |
| CN107604037A (en) * | 2017-10-20 | 2018-01-19 | 苏州中联化学制药有限公司 | A kind of Task-size Controlling method of biological enzyme the synthesis of cefaclor |
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| CN109266713A (en) * | 2018-11-12 | 2019-01-25 | 齐鲁安替制药有限公司 | A kind of preparation method suitable for industrial Cefaclor |
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