CN101456867B - Synthetic method of furbenicillin acid - Google Patents
Synthetic method of furbenicillin acid Download PDFInfo
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- CN101456867B CN101456867B CN200810080290XA CN200810080290A CN101456867B CN 101456867 B CN101456867 B CN 101456867B CN 200810080290X A CN200810080290X A CN 200810080290XA CN 200810080290 A CN200810080290 A CN 200810080290A CN 101456867 B CN101456867 B CN 101456867B
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- 239000002253 acid Substances 0.000 title claims abstract description 39
- 238000010189 synthetic method Methods 0.000 title claims description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- NGHVIOIJCVXTGV-UHFFFAOYSA-N 6beta-amino-penicillanic acid Natural products OC(=O)C1C(C)(C)SC2C(N)C(=O)N21 NGHVIOIJCVXTGV-UHFFFAOYSA-N 0.000 claims abstract description 29
- 239000012074 organic phase Substances 0.000 claims abstract description 26
- NGHVIOIJCVXTGV-ALEPSDHESA-N 6-aminopenicillanic acid Chemical compound [O-]C(=O)[C@H]1C(C)(C)S[C@@H]2[C@H]([NH3+])C(=O)N21 NGHVIOIJCVXTGV-ALEPSDHESA-N 0.000 claims abstract description 23
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 23
- ITIONVBQFUNVJV-UHFFFAOYSA-N Etomidoline Chemical compound C12=CC=CC=C2C(=O)N(CC)C1NC(C=C1)=CC=C1OCCN1CCCCC1 ITIONVBQFUNVJV-UHFFFAOYSA-N 0.000 claims abstract description 20
- 229940006198 sodium phenylacetate Drugs 0.000 claims abstract description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 17
- 150000001335 aliphatic alkanes Chemical class 0.000 claims abstract description 13
- 238000006482 condensation reaction Methods 0.000 claims abstract description 8
- 239000000243 solution Substances 0.000 claims description 56
- 238000003756 stirring Methods 0.000 claims description 32
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- 239000008346 aqueous phase Substances 0.000 claims description 20
- 238000000605 extraction Methods 0.000 claims description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 14
- 229960001701 chloroform Drugs 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 10
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 10
- 238000002425 crystallisation Methods 0.000 claims description 10
- 230000008025 crystallization Effects 0.000 claims description 10
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 9
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- 150000008065 acid anhydrides Chemical class 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 7
- PQLFROTZSIMBKR-UHFFFAOYSA-N ethenyl carbonochloridate Chemical compound ClC(=O)OC=C PQLFROTZSIMBKR-UHFFFAOYSA-N 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 230000032050 esterification Effects 0.000 claims description 6
- 238000005886 esterification reaction Methods 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 5
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 239000000178 monomer Substances 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 4
- 229920002554 vinyl polymer Polymers 0.000 claims description 4
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 3
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 3
- 229940043279 diisopropylamine Drugs 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 239000003921 oil Substances 0.000 claims description 3
- 239000010703 silicon Substances 0.000 claims description 3
- 229910052710 silicon Inorganic materials 0.000 claims description 3
- 235000017550 sodium carbonate Nutrition 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 238000005352 clarification Methods 0.000 claims description 2
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 230000004044 response Effects 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 11
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 239000012071 phase Substances 0.000 abstract description 4
- 239000012535 impurity Substances 0.000 abstract description 2
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 abstract 2
- 230000002194 synthesizing effect Effects 0.000 abstract 2
- 239000013078 crystal Substances 0.000 abstract 1
- 150000002149 estolides Chemical class 0.000 abstract 1
- 229960003424 phenylacetic acid Drugs 0.000 abstract 1
- 239000003279 phenylacetic acid Substances 0.000 abstract 1
- -1 furans alditol Chemical class 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 238000009413 insulation Methods 0.000 description 6
- 238000010792 warming Methods 0.000 description 6
- 238000009833 condensation Methods 0.000 description 5
- 230000005494 condensation Effects 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000008213 purified water Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 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 2
- 229960003311 ampicillin trihydrate Drugs 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 239000001103 potassium chloride Substances 0.000 description 2
- 235000011164 potassium chloride Nutrition 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- FRUAVHAXMXYUGM-NFFDBFGFSA-N (2s,5r,6r)-6-[[(2r)-2-(furan-2-carbonyloxy)-4-methylpentanoyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O([C@H](CC(C)C)C(=O)N[C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=CC=CO1 FRUAVHAXMXYUGM-NFFDBFGFSA-N 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 241000588769 Proteus <enterobacteria> Species 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- PQZTVWVYCLIIJY-UHFFFAOYSA-N diethyl(propyl)amine Chemical compound CCCN(CC)CC PQZTVWVYCLIIJY-UHFFFAOYSA-N 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 229950001615 furbucillin Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000011020 pilot scale process Methods 0.000 description 1
- 229960002292 piperacillin Drugs 0.000 description 1
- WCMIIGXFCMNQDS-IDYPWDAWSA-M piperacillin sodium Chemical compound [Na+].O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C([O-])=O)C(C)(C)S[C@@H]21 WCMIIGXFCMNQDS-IDYPWDAWSA-M 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000017105 transposition Effects 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention relates to a method for synthesizing furbenicillin acid, which comprises the following steps: adding 6-APA into halogenated alkane, and dissolving the 6-APA by an alkalizer to obtain a solution a; dissolving alpha-furanuride sodium phenylacetate in the halogenated alkane, and esterifying the solution to obtain an estolide solution b of alpha-furanuride phenyl acetic acid; and after the solution a and the solution b are subjected to a condensation reaction at a temperature of between 20 DEG C below zero and zero DEC, adjusting pH to be between 5.5 and 6.7 to make the solution split phase, reclaiming an organic phase, adding an extracting agent into a water phase, acidifying and layering the solution, and dripping the extracting agent into the organic phase to separate out furbenicillin acid crystal. The method for synthesizing the furbenicillin acid fully adopts water avoidance reaction, the yield of products reaches more than 78 percent, the purity is improved to more than 90 percent, the content of the total impurities is reduced to below 10 percent, and the method has the advantages of simple production process and stable quality.
Description
Technical field
The present invention relates to a kind of synthetic method of semisynthetic antibiotics, be specifically related to a kind of synthetic method of Furbenicillin Sodium intermediate furbenicillin acid.
Background technology
Furbenicillin (another name Furbencillin, furbenicillin, furbucillin) is the α-urea derivatives of Aminopenicillin, it is a kind of semi-synthetic Broad spectrum antibiotics, effect to Pseudomonas aeruginosa is stronger, extracorporeal bacteria inhibitor test is strong approximately 16 times than Gepcillin, similar to piperacillin, the similar Ampicillin Trihydrate of other anti-microbial effect.Clinical each section that is mainly used in due to the sensitive organisms such as Pseudomonas aeruginosa, intestinal bacteria and Bacillus proteus infects, such as respiratory tract infection, liver and gall infection, urinary tract infections and septicemia etc.
Furbenicillin is the earliest by U.S. Bristol ﹠amp; The development of Mayer company.China develops listing first the seventies in 20th century, it is starting raw material that Taiyuan pharmaceutical factory in 1972 adopts with the furans alditol, the synthesis technique for preparing Furbenicillin sylvite through oximate, molecular transposition, esterification, Ampicillin Trihydrate salify, condensation, furbenicillin acid salify six-step process, for clinical study provides pilot scale sylvite preparation, but because of its quality shakiness, synthetic technological condition harshness, especially one step of esterification, the required equipment precision requirement was too high, be not suitable for suitability for industrialized production, never form standard.Until the nineties in last century, through process modification, employing is a starting raw material with α-Fu Nan uride base sodium phenylacetate, become sodium salt, condensation, furan benzyl acid salify four-step reaction to make the synthesis technique of Furbenicillin Sodium through acid anhydridesization, 6-amino-penicillanic acid (6-APA), just really form industrialization production.
The concrete grammar of above-mentioned production technique is: 1, anhydride reaction: α-Fu Nan uride base sodium phenylacetate, N-methylmorpholine and Vinyl chloroformate react in acetone and make acid anhydrides liquid; 2,6-APA connects the sodium reaction: 6-APA and sodium hydroxide are carried out to reactant salt in the mixed solution of water and acetone; 3, condensation reaction: in the mixed system of water and acetone, the reaction solution of step 2 is poured in the reaction solution of step 1, carried out condensation reaction and make the furbenicillin acid reaction solution; 4, with behind the acetone in methylbenzene extraction step 3 reaction solution, by adding hcl acidifying, sodium hydroxide alkalization, after hcl acidifying, sodium hydroxide alkalization were purified for twice repeatedly again, freeze-drying made Furbenicillin Sodium.
Yet still there is the drawback of following several respects in above-mentioned technology:
1, the solvent phase that uses in the condensation process step is the mixed system of water and organic solvent, because acid anhydrides is avoided water, make the hydrolysis of part acid anhydrides destroy, cause finished product Furbenicillin sodium salt second-rate, content only is about 65% (high performance liquid chromatography), and toxic side effect is big;
2, this technology can not directly obtain the furbenicillin acid solid, and the product condensation is after directly freeze-drying after the extraction several times of alkalization, acidifying, alkalization again, and technology is cumbersome and productive rate is low, only is about 70%, the cost height;
3, the high malicious solvent toluene that uses among the preparation technology causes environmental pollution easily.
Summary of the invention
It is simple to the purpose of this invention is to provide a kind of production process, product purity height, yield height, stay-in-grade furbenicillin acid synthetic method.
Furbenicillin acid synthetic method of the present invention may further comprise the steps:
1) 6-amino-penicillanic acid (6-APA) is added in the halogenated alkane, add basifier under stirring and make its dissolving, treat to obtain solution a after the solution clarification;
2) α-Fu Nan uride base sodium phenylacetate is dissolved in the halogenated alkane, in the presence of catalyzer, adds esterifying agent and carry out esterification, obtain the acid anhydrides solution b of α-Fu Nan uride base toluylic acid;
3) under-20～0 ℃ of condition, solution a is added dropwise to carries out condensation reaction among the solution b, after reaction finishes, adjust pH=5.5～6.7 of reaction solution, make the solution phase-splitting, reclaim organic phase, it is stand-by to leave and take water;
4) add extraction agent at step 3) gained aqueous phase, be acidified to pH=2～3 after the mixing, make standing demix, aqueous phase discarded, it is stand-by to leave and take organic phase;
5) in step 4) gained organic phase, drip extraction agent, stir and separate out crystallization, filter, wash, do drying and obtain furbenicillin acid.
Among the above-mentioned preparation method:
In the step 1), described halogenated alkane is a kind of in methylene dichloride, ethylene dichloride, trichloromethane, the trichloroethane, and described basifier is a kind of in diethylamine, triethylamine, monoisopropylamine, the Diisopropylamine;
Step 2) in, described halogenated alkane is a kind of in methylene dichloride, ethylene dichloride, trichloromethane, the trichloroethane, and described catalyzer is N-methylmorpholine or N-ethylmorpholine, and described esterifying agent is methyl-chloroformate or Vinyl chloroformate;
In the step 3), be the pH value of adjusting reaction solution with a kind of aqueous solution in sodium bicarbonate, yellow soda ash, the sodium hydroxide, the weight percent concentration of its aqueous solution is 5～10%;
In the step 4), described extraction agent is a kind of in vinyl acetic monomer, N-BUTYL ACETATE, trichloromethane, the trichloroethane, and comes acid system to make its layering with a kind of in hydrochloric acid, sulfuric acid, the phosphoric acid, and the concentration of volume percent of the acid of use is 2～10%;
In the step 5), described extraction agent is one or more the arbitrary proportion mixture in normal hexane, sherwood oil, silicon ether, the hexanaphthene.
The concrete synthetic method of furbenicillin acid of the present invention is:
1) the 6-APA adding is accounted in the halogenated alkane of 10～23 times of its weight, add basifier under stirring and makes its dissolving, basifier is 3.3～4: 1 with the amount of substance ratio of 6-APA, treats to obtain solution a after solution is clarified;
2) α-Fu Nan uride base sodium phenylacetate is dissolved in the halogenated alkane that accounts for 14～28 times of its weight, according to α-Fu Nan uride base sodium phenylacetate: esterifying agent: the amount of substance of catalyzer=1: 0.98～1.15: 0.002～0.01 is than adding catalyzer and esterifying agent, esterification 1～2.5h under room temperature obtains the acid anhydrides solution b of α-Fu Nan uride base toluylic acid;
3) under-20～0 ℃ of condition, according to α-Fu Nan uride base sodium phenylacetate: 6-APA=1: the amount of 1.0～1.2 raw material is added dropwise among the solution b than with solution a, condensation reaction 0.5～1.5h, after question response finishes, adjust pH=5.5～6.7 of reaction solution, make the solution phase-splitting, reclaim organic phase, it is stand-by to leave and take water;
4) add the extraction agent that accounts for 6.5～10 times of α-Fu Nan uride base sodium phenylacetate weight at step 3) gained aqueous phase, be acidified to pH=2～3 after the mixing, make standing demix, aqueous phase discarded, it is stand-by to leave and take organic phase;
5) drip extraction agent in step 4) gained organic phase, the consumption volume ratio of extraction agent is 2～5: 5 in its consumption and the step 4), stirs to make and separates out crystallization, after filtration, after the washing, is dried to moisture≤2.5% in 50～55 ℃, obtains furbenicillin acid.
Furbenicillin acid synthetic method of the present invention is to be starting raw material with α-Fu Nan uride base sodium phenylacetate, condensation makes furbenicillin acid in acid anhydridesization, 6-APA one-tenth amine salt, single-phase solvent, this processing method is innovated at the drawback that exists in the existing synthesis technique, all change into and avoid the water reaction from the condensation reaction with 6-APA of being prepared into of acid anhydrides, make product yield improve more than ten percentage point than originally, reach more than 78%.Main is that quality product has had bigger improvement, purity is brought up to (high-efficient liquid phase chromatogram technique analysis) more than 90% by original 65%, total impurities content is reduced to below 10% by original about 40%, also shortened the technological operation program simultaneously, alleviated operator's work load, quality and cost all far are superior to original production process.Simultaneously, synthetic method of the present invention also substitutes high malicious solvent toluene with the low toxicity solvent, has improved Working environment to greatest extent.
Embodiment
Embodiment 1
Add 210kg ethylene dichloride and 16.5kg6-APA in the exsiccant retort, add 27kg triethylamine stirring and dissolving, about 1.5h is molten clear, cools to 0 ℃, is pressed in the high level tank standby.
In another exsiccant retort, add 320kg ethylene dichloride and 21kg α-Fu Nan uride base sodium phenylacetate, order adds 0.09kgN-methylmorpholine and 7.3kg Vinyl chloroformate under room temperature, stir reaction 1.5h down, be cooled to-10 ℃, be added dropwise to the 6-APA amine salt liquid in the high level tank, after dripping off, in-5～0 ℃ of insulation reaction 1h.
Reaction solution is warming up to room temperature, and the aqueous sodium hydroxide solution alkalization with 5% to pH=5.5～6.7 of solution, is left standstill, and makes the solution phase-splitting, reclaims organic phase.Add the 120L vinyl acetic monomer at aqueous phase, drip 9% dilute hydrochloric acid, be acidified to pH=2～3, standing demix, aqueous phase discarded.Organic phase is pressed in the crystallizer, opens and stir, be added dropwise to the 95L normal hexane, about 0.5h drips off.After dropwising, continue to stir 2.5h, crystallization is separated out fully, centrifuging, wash, be dried to moisture≤2.5% in 55 ℃, obtain furbenicillin acid, content 91.25% (high-pressure liquid chromatography) with purified water.Calculate yield 78% with 6-APA.
Embodiment 2
Add 180kg trichloromethane and 16kg6-APA in the exsiccant retort, add 27kg Diisopropylamine stirring and dissolving, about 1.5h is molten clear, cools to 0 ℃, is pressed in the high level tank standby.
In another exsiccant retort, add 370kg trichloromethane and 21kg α-Fu Nan uride base sodium phenylacetate, order adds 0.11kgN-ethyl morpholine and 7.5kg Vinyl chloroformate under room temperature, stir reaction 1.5h down, be cooled to-10 ℃, be added dropwise to the 6-APA amine salt liquid in the high level tank, after dripping off, in-5～0 ℃ of insulation reaction 1h.
Reaction solution is warming up to room temperature, and the aqueous sodium carbonate with 8% alkalizes to the pH=5.5 of solution～6.7, leaves standstill, and makes the solution phase-splitting, reclaims organic phase.Add the 120L vinyl acetic monomer at aqueous phase, the phosphoric acid of dropping 6% is acidified to pH=2～3, standing demix, aqueous phase discarded.Organic phase is pressed in the crystallizer, opens and stir, be added dropwise to the 105L normal hexane, about 0.5h drips off.After dropwising, continue to stir 2.5h, crystallization is separated out fully, centrifuging, purified water washing, drying obtain furbenicillin acid, and content 90.85% (high-pressure liquid chromatography) calculates yield 80% with 6-APA.
Embodiment 3
Add 200kg trichloroethane and 16kg6-APA in the exsiccant retort, add 20kg diethylamine stirring and dissolving, about 1.5h is molten clear, cools to 0 ℃, is pressed in the high level tank standby.
In another exsiccant retort, add 310kg trichloroethane and 21kg α-Fu Nan uride base sodium phenylacetate, order adds 0.18kgN-ethyl morpholine and 7.8kg Vinyl chloroformate under room temperature, stir reaction 1.5h down, be cooled to-10 ℃, be added dropwise to the 6-APA amine salt liquid in the high level tank, after dripping off, in-5～0 ℃ of insulation reaction 1h.
Reaction solution is warming up to room temperature, and the sodium bicarbonate aqueous solution alkalization with 10% to pH=5.5～6.7 of solution, is left standstill, and makes the solution phase-splitting, reclaims organic phase.Aqueous phase adds the 180L trichloromethane, and the sulfuric acid acidation of dropping 3% is to pH=2～3, standing demix, aqueous phase discarded.Organic phase is pressed in the crystallizer, opens and stir, be added dropwise to the 80L sherwood oil, about 0.5h drips off.After dropwising, continue to stir 2.5h, crystallization is separated out fully, centrifuging, purified water washing, drying obtain furbenicillin acid, and content 93.15% (high-pressure liquid chromatography) calculates yield 78% with 6-APA.
Embodiment 4
Add 240kg methylene dichloride and 15.5kg6-APA in the exsiccant retort, add 26kg triethylamine stirring and dissolving, about 1.5h is molten clear, cools to 0 ℃, is pressed in the high level tank standby.
In another exsiccant retort, add 300kg methylene dichloride and 21kg α-Fu Nan uride base sodium phenylacetate, order adds 0.2kgN-methylmorpholine and 7.0kg methyl-chloroformate under room temperature, stir reaction 1.5h down, be cooled to-10 ℃, be added dropwise to the 6-APA amine salt liquid in the high level tank, after dripping off, in-5～0 ℃ of insulation reaction 1h.
Reaction solution is warming up to room temperature, and the aqueous sodium hydroxide solution alkalization with 8% to pH=5.5～6.7 of solution, is left standstill, and makes the solution phase-splitting, reclaims organic phase.Aqueous phase adds the 150L N-BUTYL ACETATE, and the phosphoric acid of dropping 3% is acidified to pH=2～3, standing demix, aqueous phase discarded.Organic phase is pressed in the crystallizer, opens and stir, be added dropwise to 100L silicon ether, about 0.5h drips off.After dropwising, continue to stir 2.5h, crystallization is separated out fully, centrifuging, purified water washing, drying obtain furbenicillin acid, and content 92.03% (high-pressure liquid chromatography) calculates yield 79% with 6-APA.
Embodiment 5
Add 180kg trichloromethane and 15.5kg6-APA in the exsiccant retort, add 27kg diethyl propylamine stirring and dissolving, about 1.5h is molten clear, cools to 0 ℃, and it is standby to be pressed into high level tank.
In another exsiccant retort, add 280kg trichloromethane and 21kg α-Fu Nan uride base sodium phenylacetate, order adds 0.22kgN-methylmorpholine and 7.5kg methyl-chloroformate under room temperature, stir reaction 1.5h down, be cooled to-10 ℃, be added dropwise to the 6-APA amine salt liquid in the high level tank, after dripping off, in-5～0 ℃ of insulation reaction 1h.
Reaction solution is warming up to room temperature, and the aqueous sodium hydroxide solution alkalization with 10% to pH=5.5～6.7 of solution, is left standstill, and makes the solution phase-splitting, reclaims organic phase.Add the 150L N-BUTYL ACETATE at aqueous phase, the hcl acidifying of dropping 9% is to pH=2～3, standing demix, aqueous phase discarded.Organic phase is pressed in the crystallizer, opens and stir, be added dropwise to the 90L normal hexane, about 0.5h drips off.After dropwising, continue to stir 2.5h, crystallization is separated out fully, centrifuging, purified water washing, drying obtain furbenicillin acid, and content 91.50% (high-pressure liquid chromatography) calculates with 6-APA, and yield reaches 78.5%.
Embodiment 6
Add 300kg chloroform and 16kg6-APA in the exsiccant retort, add 28kg triethylamine stirring and dissolving, about 1.5h is molten clear, cools to 0 ℃, is pressed in the high level tank standby.
In another exsiccant retort, add 450kg chloroform and 21kg α-Fu Nan uride base sodium phenylacetate, order adds 0.3kgN-methylmorpholine and 9.1kg Vinyl chloroformate under room temperature, stirring reaction 1.5h, be cooled to-10 ℃, be added dropwise to the 6-APA amine salt liquid in the high level tank, about 20～25min adds, after dripping off, at-5～0 ℃ of insulation reaction 1h.
Reaction solution is warming up to room temperature, and the aqueous sodium hydroxide solution alkalization with 1% to pH=5.5～6.7 of solution, is left standstill, and makes the solution phase-splitting, reclaims organic phase.Add the 150kg N-BUTYL ACETATE at aqueous phase, the hcl acidifying of dropping 9% is to pH=2～3, standing demix, aqueous phase discarded.Organic phase is pressed in the crystallizer, opens and stir, be added dropwise to the 60kg normal hexane, about 0.5h drips off.After dropwising, continue to stir 2.5h, crystallization is separated out fully, centrifuging divides the washing leaching cake of pulling an oar for three times with the 500L pure water, after the drying, filter cake is pulverized sabot, goes in the baking oven in 50～55 ℃ to be dried to moisture below 2.5%, promptly gets furbenicillin acid.Content 94.12% (high-pressure liquid chromatography), in 6-APA, yield 78%.
Claims (5)
1. the synthetic method of a furbenicillin acid may further comprise the steps:
1) 6-APA is added in the halogenated alkane, add basifier under stirring and make its dissolving, treat to obtain solution a after the solution clarification;
2) α-Fu Nan uride base sodium phenylacetate is dissolved in the halogenated alkane, adding esterifying agent methyl-chloroformate or Vinyl chloroformate carry out esterification in the presence of catalyst n-methylmorpholine or N-ethylmorpholine, obtain the acid anhydrides solution b of α-Fu Nan uride base toluylic acid;
3) under-20～0 ℃ of condition, solution a is added dropwise to carries out condensation reaction among the solution b, after reaction finishes, adjust pH=5.5～6.7 of reaction solution, make the solution phase-splitting, reclaim organic phase, it is stand-by to leave and take water;
4) add extraction agent at step 3) gained aqueous phase, be acidified to pH=2～3 after the mixing, make standing demix, aqueous phase discarded, it is stand-by to leave and take organic phase;
5) drip extraction agent in step 4) gained organic phase, stir and separate out crystallization, filtration, washing, drying obtain furbenicillin acid;
Wherein, described basifier is a kind of in diethylamine, triethylamine, monoisopropylamine or the Diisopropylamine, and described extraction agent is a kind of in vinyl acetic monomer, N-BUTYL ACETATE, trichloromethane or the trichloroethane.
2. the synthetic method of furbenicillin acid according to claim 1 may further comprise the steps:
1) the 6-APA adding is accounted in the halogenated alkane of 10～23 times of its weight, add basifier under stirring and makes its dissolving, basifier is 3.3～4: 1 with the amount of substance ratio of 6-APA, treats to obtain solution a after solution is clarified;
2) α-Fu Nan uride base sodium phenylacetate is dissolved in the halogenated alkane that accounts for 14～28 times of its weight, according to α-Fu Nan uride base sodium phenylacetate: esterifying agent: the amount of substance of catalyzer=1: 0.98～1.15: 0.002～0.01 is than adding catalyzer and esterifying agent, esterification 1～2.5h under room temperature obtains the acid anhydrides solution b of α-Fu Nan uride base toluylic acid;
3) under-20～0 ℃ of condition, according to α-Fu Nan uride base sodium phenylacetate: 6-APA=1: the amount of 1.0～1.2 raw material is added dropwise among the solution b than with solution a, condensation reaction 0.5～1.5h, after question response finishes, adjust pH=5.5～6.7 of reaction solution, make the solution phase-splitting, reclaim organic phase, it is stand-by to leave and take water;
4) add the extraction agent that accounts for 6.5～10 times of α-Fu Nan uride base sodium phenylacetate weight at step 3) gained aqueous phase, be acidified to pH=2～3 after the mixing, make standing demix, aqueous phase discarded, it is stand-by to leave and take organic phase;
5) drip extraction agent in step 4) gained organic phase, the consumption volume ratio of extraction agent is 2～5: 5 in its consumption and the step 4), stirs to make and separates out crystallization, after filtration, after the washing, is dried to moisture≤2.5% in 50～55 ℃, obtains furbenicillin acid.
3. the synthetic method of furbenicillin acid according to claim 1 and 2 is characterized in that described halogenated alkane is a kind of in methylene dichloride, ethylene dichloride, trichloromethane, the trichloroethane.
4. the synthetic method of furbenicillin acid according to claim 1 and 2 is characterized in that described extraction agent is one or more the arbitrary proportion mixture in normal hexane, sherwood oil, silicon ether, the hexanaphthene.
5. the synthetic method of furbenicillin acid according to claim 1 and 2, it is characterized in that adjusting the pH value of reaction solution with a kind of aqueous solution in sodium bicarbonate, yellow soda ash, the sodium hydroxide, the weight percent concentration of its aqueous solution is 5～10%, and with a kind of acidifying standing demix that carries out in hydrochloric acid, sulfuric acid, the phosphoric acid, the concentration of volume percent of the acid of use is 2～10%.
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