CN104031069A - Preparation method of cefquinome sulfate - Google Patents
Preparation method of cefquinome sulfate Download PDFInfo
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- CN104031069A CN104031069A CN201410209739.3A CN201410209739A CN104031069A CN 104031069 A CN104031069 A CN 104031069A CN 201410209739 A CN201410209739 A CN 201410209739A CN 104031069 A CN104031069 A CN 104031069A
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- KYOHRXSGUROPGY-OFNLCGNNSA-N (6r,7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-8-oxo-3-(5,6,7,8-tetrahydroquinolin-1-ium-1-ylmethyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;hydrogen sulfate Chemical compound OS(O)(=O)=O.N([C@@H]1C(N2C(=C(C[N+]=3C=4CCCCC=4C=CC=3)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 KYOHRXSGUROPGY-OFNLCGNNSA-N 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 78
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 67
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 66
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 claims abstract description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 25
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 claims abstract description 18
- HSHGZXNAXBPPDL-HZGVNTEJSA-N 7beta-aminocephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C([O-])=O)N2C(=O)[C@@H]([NH3+])[C@@H]12 HSHGZXNAXBPPDL-HZGVNTEJSA-N 0.000 claims abstract description 17
- 239000012043 crude product Substances 0.000 claims abstract description 17
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 16
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims abstract description 14
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims abstract description 9
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 claims abstract description 9
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims abstract description 9
- 235000010262 sodium metabisulphite Nutrition 0.000 claims abstract description 9
- 239000002253 acid Substances 0.000 claims abstract description 7
- 235000011114 ammonium hydroxide Nutrition 0.000 claims abstract description 7
- 239000002612 dispersion medium Substances 0.000 claims abstract description 7
- 239000005051 trimethylchlorosilane Substances 0.000 claims abstract description 7
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 3
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 3
- 239000011230 binding agent Substances 0.000 claims abstract description 3
- 239000007809 chemical reaction catalyst Substances 0.000 claims abstract description 3
- 238000003756 stirring Methods 0.000 claims description 122
- 238000010792 warming Methods 0.000 claims description 20
- 239000000706 filtrate Substances 0.000 claims description 14
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 claims description 12
- -1 amino cefquinome Chemical compound 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 8
- 229950009592 cefquinome Drugs 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 239000006185 dispersion Substances 0.000 claims description 3
- 238000006386 neutralization reaction Methods 0.000 claims description 3
- 239000000284 extract Substances 0.000 claims description 2
- 238000002386 leaching Methods 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 239000003607 modifier Substances 0.000 claims description 2
- 230000001681 protective effect Effects 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 239000000758 substrate Substances 0.000 claims description 2
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 claims 1
- 239000011259 mixed solution Substances 0.000 abstract description 11
- 239000013078 crystal Substances 0.000 abstract description 10
- 239000000243 solution Substances 0.000 abstract description 9
- 150000002148 esters Chemical class 0.000 abstract description 6
- 239000000047 product Substances 0.000 abstract description 5
- 238000001914 filtration Methods 0.000 abstract description 4
- 238000005406 washing Methods 0.000 abstract description 4
- 239000002932 luster Substances 0.000 abstract description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 abstract 1
- 229940113088 dimethylacetamide Drugs 0.000 abstract 1
- 239000002270 dispersing agent Substances 0.000 abstract 1
- 230000003472 neutralizing effect Effects 0.000 abstract 1
- 239000003223 protective agent Substances 0.000 abstract 1
- 229940001584 sodium metabisulfite Drugs 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- 230000003068 static effect Effects 0.000 description 28
- 238000000605 extraction Methods 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 238000001291 vacuum drying Methods 0.000 description 10
- 239000012065 filter cake Substances 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 239000007787 solid Substances 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
- 230000003115 biocidal effect Effects 0.000 description 4
- YWKJNRNSJKEFMK-PQFQYKRASA-N (6r,7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-8-oxo-3-(5,6,7,8-tetrahydroquinolin-1-ium-1-ylmethyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound N([C@@H]1C(N2C(=C(C[N+]=3C=4CCCCC=4C=CC=3)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 YWKJNRNSJKEFMK-PQFQYKRASA-N 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- 229930186147 Cephalosporin Natural products 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 229940124587 cephalosporin Drugs 0.000 description 2
- 150000001780 cephalosporins Chemical class 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical compound NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 229950003476 aminothiazole Drugs 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 208000004396 mastitis Diseases 0.000 description 1
- 231100000637 nephrotoxin Toxicity 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- UBCKGWBNUIFUST-YHYXMXQVSA-N tetrachlorvinphos Chemical compound COP(=O)(OC)O\C(=C/Cl)C1=CC(Cl)=C(Cl)C=C1Cl UBCKGWBNUIFUST-YHYXMXQVSA-N 0.000 description 1
- 238000003809 water extraction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/38—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof
- C07D501/46—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof with the 7-amino radical acylated by carboxylic acids containing hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/12—Separation; Purification
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a preparation method of cefquinome sulfate, which starts from 7-ACA and takes hexamethyldisilazane as a protective agent with tetrahydroquinoline in dichloromethane, trimethylchlorosilane is used as a reaction catalyst, diethylaniline is used as a polarity regulator of the reaction system, dimethyl acetamide is used as a dispersion medium of tetrahydroquinoline to react, 25 percent ammonia water is dripped to grow crystals after the reaction is completed, light yellow intermediate 7-ACQ is obtained after acetone washing and filtering, the intermediate 7-ACQ and AE active ester react in an inert organic solution by using a small amount of ethanol as a dispersant and sodium metabisulfite as an antioxidant, neutralizing continuously generated acid by using triethylamine as an acid-binding agent, washing and filtering a mixed solution of dichloromethane and ethanol after reaction, extracting pure water for multiple times, adjusting pH with sulfuric acid, controlling temperature and crystallizing to obtain a crude product, and then washing, filtering and recrystallizing the crude product to obtain refined cefquinome sulfate; the product has the advantages of high conversion rate, high purity, good color and luster and the like.
Description
(1) technical field
The present invention relates to a kind of preparation method of Cefquinome sulfate.
(2) background technology
Cynnematin because of the advantages such as it is efficient, wide spectrum, low toxicity, resistance to enzyme be a class important substance on current microbiotic market, since meaning people profit people Broyzn in 1948 finds cynnematin, its development is quite rapid, up to the present oneself has developed nearly 60 kinds (not comprising ester derivative and various preparation), and its kind quantity occupies each antibiotic first place.
According to the feature of its anti-microbial effect feature and clinical application, cynnematin generally can be divided into for four generations, and its pharmacological property is referring to table 1.
Table 1: four generation head embrace rhzomorph antimicrobial active comparison
| ? | Anti-G+ | Anti-G- | Enzyme stability | The nephrotoxin | Indication |
| A generation | By force | A little less than | Poor | High | The staphylococcus aureus of resistance infects |
| Two generations | Stronger | Stronger | Slightly stable | Low toxicity | Gram-negative bacteria |
| Three generations | Stronger | By force | Stable | Nontoxic | Life-threatening severe infections treatment |
| Four generations | Stronger | By force | Highly stable | Nontoxic | Multiple and height resistant organism treatment |
Cefquinome has another name called Cefquinome, HOE 111, commodity are called gram hundred spies (Cobactan), the 1st animal specific cephalosporin analog antibiotic of German Hoechst Roussel Vet company research and development listing, belong to the 4th generation cephalosporin analog antibiotic. its vitriol was ratified listing in 1993 first in Germany.
Cefquinome sulfate is that a kind of brand-new aminothiazole oxidation of ketones imines cynnematin has good broad spectrum antibiotic activity to many Gram-positives and gram negative bacterium, its unique bullet-shaped bipolarity molecular structure can see through G-mycetocyte wall fast and arrive site of action, its side effect is simultaneously little, residual low, and there is stable resistance to karyomit(e) and plasmid-encoded β-lactamase, therefore welcome by veterinary clinic worker.
Cefquinome sulfate is suitable for drug administration by injection, absorb fast, peak time is short, bioavailability is higher, can reach higher tissue concentration in lung, mammary tissue, the current medicine for animals council of Yi Bei European Union (CVMP) ratifies the clinical treatment for diseases such as the respiratory tract bacterial infection of pig, ox and mammitis of cow.
(3) summary of the invention
It is high that the object of the invention is to provide transformation efficiency, the preparation method of product purity, coloury Cefquinome sulfate.
The technical solution used in the present invention is:
A preparation method for Cefquinome sulfate, described method comprises:
(1) take 7-amino-cephalosporanic acid (7-ACA) and tetrahydroquinoline is reaction substrate, in methylene dichloride, take hexamethyldisilazane as protective material, take trimethylchlorosilane as reaction catalyst, using Diethyl Aniline as reaction system polar modifier, using the dispersion medium of N,N-DIMETHYLACETAMIDE as tetrahydroquinoline, react, after reacting completely, drip 25% ammoniacal liquor growing the grain, after acetone filter wash, obtain the amino cefquinome (7-ACQ) of intermediate 7-; Described 7-amino-cephalosporanic acid: tetrahydroquinoline: the consumption mol ratio of Iodotrimethylsilane is 1:2～3:1.5～2;
(2) mol ratio is 1:1.2～1.5 the amino cefquinome of 7-and MEAM be take ethanol as dispersion agent in methylene dichloride, Sodium Pyrosulfite is that antioxidant reacts, the acid that the triethylamine of usining constantly produces as acid binding agent neutralization reaction, after reaction finishes, with after methylene dichloride and alcohol mixeding liquid filter wash (washing+filtration), getting filtrate extracts with pure water, the water merging is first adjusted pH3.9 ± 0.1 with sulfuric acid, add gac and stir decolouring, cross leaching filtrate and with sulfuric acid, adjust pH1.9 ± 0.1 again, control temperature and obtain sulfuric acid head at 20 ± 2 ℃ of crystallizatioies
Spore quinoline oxime crude product, the Cefquinome sulfate after crude product must be refined after filter wash recrystallization again.
The reaction the present invention relates to is as follows:
Concrete, in step (1), 7-amino-cephalosporanic acid be take methylene dichloride as dispersion medium, and tetrahydroquinoline be take N,N-DIMETHYLACETAMIDE as dispersion medium.
Preferably, in step (2), sulfuric acid is adjusted behind pH1.9 ± 0.1, first controls temperature and stirs 15-30min at 5 ± 2 ℃, is then warming up to 20 ± 2 ℃, stirring and crystallizing.
Further, the molar ratio of the 7-amino-cephalosporanic acid/hexamethyldisilazane described in step (1) is 1:1.15～1.45; The molar ratio of described 7-amino-cephalosporanic acid/Diethyl Aniline is 1:1.5～2.
Concrete, described method can be as follows:
Reaction (1): add methylene dichloride (reaction medium) and hexamethyldisilazane (ammonia amido, hydroxyl protection) in reactor, stir.Add 7-ACA and a small amount of trimethylchlorosilane (catalyst).Be warming up to 58 ± 2 ℃, stir back flow reaction 12 hours.Be cooled to 5 ± 2 ℃, add Diethyl Aniline, stir.Add Iodotrimethylsilane, stir 30 minutes.Be warming up to 18 ± 2 ℃, stirring reaction 2.5 hours.Be cooled to 8 ± 2 ℃, add tetrahydrofuran (THF), stir 30 minutes.Add tetrahydroquinoline and N,N-DIMETHYLACETAMIDE to mix liquid, react 6 hours.Above-mentioned reaction solution is turned to still.Add methylene dichloride, stir.Be cooled to 5 ± 2 ℃, drip Virahol and sherwood oil, stir 30 minutes.Filter sherwood oil filter wash 3 times, obtain light yellow solid thing.20wt%H
2sO
4stirring and dissolving at 18 ± 2 ℃.Static layering, water intaking phase.Solvent is added 20 ℃ of water, stirs extraction 10 minutes.Static layering, abandons solvent phase.Merge water, be cooled to 5 ± 2 ℃, drip 25% ammoniacal liquor growing the grain.Continue to drip 5 ± 2 ℃ of acetone temperature controls, stir growing the grain.Filter, use aqueous acetone solution filter wash, then use acetone filter wash 3 times.Put 40 ℃ of following vacuum-dryings, obtain light yellow intermediate 7-ACQ (7-ACA yield is about 1.18-1.4 relatively).
Reaction (2): add methylene dichloride and a small amount of ethanol (dispersion agent) in reactor.Add 7-ACQ+AE active ester+Sodium Pyrosulfite (oxidation inhibitor), stir.Be cooled to 5 ± 2 ℃, add triethylamine (acid that neutralization reaction produces), stir 30 minutes.Be warming up to 10 ± 2 ℃, continue stirring reaction 3 hours.Filter, with methylene dichloride and alcohol mixeding liquid filter wash.Get filtrate temperature adjustment to 20 ± 2 ℃, add water and stir extraction repeatedly.Merge water.Add ethyl acetate agitator treating 15 minutes.Static layering, water intaking phase.Be cooled to 10 ± 2 ℃, stir and add acetone.Drip 40wt%H
2sO
4, adjust pH=3.9 ± 0.1.Add gac, stir decolouring.Filter, use aqueous acetone solution filter wash.Get filtrate and be cooled to 5 ± 2 ℃, stir.Add 40wt%H
2sO
4, then adjust pH=1.9 ± 0.1.5 ± 2 ℃ of temperature controls, stir 30 minutes.Be warming up to 20 ± 2 ℃, add a little crystal seed, stirring and crystallizing 1.5 hours.Drip acetone and be cooled to 5 ± 2 ℃, survey and adjust pH=1.8 ± 0.1, continue to stir growing the grain.Filter, use acetone filter wash.Filter cake is put 40 ℃ of following vacuum-dryings, obtains quinoline oxime crude product (the about 0.75-0.95 of 7-ACQ yield relatively).
Product purification: add purified water and ethyl acetate in reactor.Add quinoline oxime crude product and Sodium Pyrosulfite, stir.Be cooled to 8 ± 2 ℃, add triethylamine, stir molten clear.Static layering, water intaking phase.Ethyl acetate is added 20 ℃ of water extractions 15 minutes.Static layering, abandons ethyl acetate phase.Merge water, be cooled to 8 ± 2 ℃, add acetone and use 40wt%H
2sO
4adjust pH=3.9 ± 0.1.Add gac, stir decolouring.Filter, use aqueous acetone solution filter wash.Filtrate is cooled to 5 ± 2 ℃, stirs.Add 40wt%H
2sO
4, adjust pH=1.8 ± 0.1.5 ± 2 ℃ of temperature controls, stir 30 minutes, are warming up to 20 ± 2 ℃, add a little crystal seed, stirring and crystallizing 1.5 hours.Drip acetone, be cooled to 5 ± 2 ℃, survey and adjust pH=1.65 ± 0.1.Continue to stir growing the grain 1 hour.Filter, use acetone filter wash 3 times.Filter cake is put 40 ℃ of following vacuum-dryings, must refine quinoline oxime (crude product yield approximately 0.95 relatively).
Beneficial effect of the present invention is mainly reflected in: adopt the inventive method, transformation efficiency is high, product purity, color and luster good (white or off-white color), and suitability for industrialized is produced.
(4) embodiment
Below in conjunction with specific embodiment, the present invention is described further, but protection scope of the present invention is not limited in this:
Embodiment 1:7-ACQ's is synthetic
In 300L reactor, add methylene dichloride 90KG (68L)+hexamethyldisilazane 19.5KG (25L), stir.Add 7-ACA25KG+ trimethylchlorosilane 0.22KG (0.25L).Be warming up to 58 ± 2 ℃, stir back flow reaction 12 hours.Be cooled to 5 ± 2 ℃, add Diethyl Aniline 25KG (27L), stir.Add Iodotrimethylsilane 30KG (21.5L), stir 30 minutes.Be warming up to 18 ± 2 ℃, stirring reaction 2.5 hours.Be cooled to 8 ± 2 ℃, add tetrahydrofuran (THF) 4.5KG (5L), stir 30 minutes.Add tetrahydroquinoline 26KG (23L)+N,N-DIMETHYLACETAMIDE 47KG (50L), react 6 hours.Above-mentioned reaction solution is proceeded to 500L reactor.Add methylene dichloride 150KG (113L), stir.Be cooled to 5 ± 2 ℃, drip Virahol 25KG (32L).Drip sherwood oil 100KG (154L), stir 30 minutes.Filter, use sherwood oil 20KG (30.5L) filter wash 3 times, obtain light yellow solid thing.In 300L reactor, add 20wt%H
2sO
460KG (55L).Add above-mentioned light yellow solid thing, stirring and dissolving at 18 ± 2 ℃.Static layering, water intaking phase.Solvent is added 20 ℃ of water 5KG, stirs extraction 10 minutes.Static layering, abandons solvent phase.Merge water, to 300L reactor, be cooled to 5 ± 2 ℃, drip 25% ammoniacal liquor:
Drip 9KG (8L) for the 1st time, add crystal seed a little, stirring and crystallizing 20 minutes;
Drip 7KG (6.2L), stirring and crystallizing 15 minutes the 2nd time;
Drip 5KG (4.5L), stirring and crystallizing 15 minutes the 3rd time;
The 4th drips (about 3KG), adjusts pH=2.9 ± 0.1, continues stirring and crystallizing 30 minutes;
Drip acetone 25KG (32L).5 ± 2 ℃ of temperature controls, stir growing the grain 1 hour.Filter, with acetone 56KG (71L)+water 20KG mixed solution filter wash.Use acetone 20KG (25L) filter wash 3 times, filter cake is put 40 ℃ of following vacuum-dryings again, obtains light yellow intermediate 7-ACQ35KG (7-ACA yield is about 1.4 relatively).
Embodiment 2:7-ACQ's is synthetic
In 300L reactor, add methylene dichloride 90KG (68L)+hexamethyldisilazane 17KG (21.8L), stir.Add 7-ACA25KG+ trimethylchlorosilane 0.22KG (0.25L).Be warming up to 58 ± 2 ℃, stir back flow reaction 12 hours.Be cooled to 5 ± 2 ℃, add Diethyl Aniline 20.4KG (22L), stir.Add Iodotrimethylsilane 27.3KG (19.5L), stir 30 minutes.Be warming up to 18 ± 2 ℃, stirring reaction 2.5 hours.Be cooled to 8 ± 2 ℃, add tetrahydrofuran (THF) 4.5KG (5L), stir 30 minutes.Add tetrahydroquinoline 24.2KG (17.4L)+N,N-DIMETHYLACETAMIDE 43.8KG (46.6L), react 6 hours.Above-mentioned reaction solution is proceeded to 500L reactor.Add methylene dichloride 150KG (113L), stir.Be cooled to 5 ± 2 ℃, drip Virahol 25KG (32L).Drip sherwood oil 100KG (154L), stir 30 minutes.Filter, use sherwood oil 20KG (30.5L) filter wash 3 times, obtain light yellow solid thing.In 300L reactor, add 20wt%H
2sO
460KG (55L).Add above-mentioned light yellow solid thing, stirring and dissolving at 18 ± 2 ℃.Static layering, water intaking phase.Solvent is added 20 ℃ of water 5KG, stirs extraction 10 minutes.Static layering, abandons solvent phase.Merge water, to 300L reactor, be cooled to 5 ± 2 ℃, drip 25% ammoniacal liquor:
Drip 9KG (8L) for the 1st time, add crystal seed a little, stirring and crystallizing 20 minutes;
Drip 7KG (6.2L), stirring and crystallizing 15 minutes the 2nd time;
Drip 5KG (4.5L), stirring and crystallizing 15 minutes the 3rd time;
The 4th drips (about 3KG), adjusts pH=2.9 ± 0.1, continues stirring and crystallizing 30 minutes;
Drip acetone 25KG (32L).5 ± 2 ℃ of temperature controls, stir growing the grain 1 hour.Filter, with acetone 56KG (71L)+water 20KG mixed solution filter wash.Use acetone 20KG (25L) filter wash 3 times, filter cake is put 40 ℃ of following vacuum-dryings again, obtains light yellow intermediate 7-ACQ29.6KG (7-ACA yield is about 1.18 relatively).
Embodiment 3:7-ACQ's is synthetic
In 300L reactor, add methylene dichloride 90KG (68L)+hexamethyldisilazane 21.5KG (27.5L), stir.Add 7-ACA25KG+ trimethylchlorosilane 0.22KG (0.25L).Be warming up to 58 ± 2 ℃, stir back flow reaction 12 hours.Be cooled to 5 ± 2 ℃, add Diethyl Aniline 27.2KG (29.5L), stir.Add Iodotrimethylsilane 36.4KG (26L), stir 30 minutes.Be warming up to 18 ± 2 ℃, stirring reaction 2.5 hours.Be cooled to 8 ± 2 ℃, add tetrahydrofuran (THF) 4.5KG (5L), stir 30 minutes.Add tetrahydroquinoline 36.4KG (32L)+N,N-DIMETHYLACETAMIDE 56.4KG (60L), react 6 hours.Above-mentioned reaction solution is proceeded to 500L reactor.Add methylene dichloride 150KG (113L), stir.Be cooled to 5 ± 2 ℃, drip Virahol 25KG (32L).Drip sherwood oil 100KG (154L), stir 30 minutes.Filter, use sherwood oil 20KG (30.5L) filter wash 3 times, obtain light yellow solid thing.In 300L reactor, add 20wt%H
2sO
460KG (55L).Add above-mentioned light yellow solid thing, stirring and dissolving at 18 ± 2 ℃.Static layering, water intaking phase.Solvent is added 20 ℃ of water 5KG, stirs extraction 10 minutes.Static layering, abandons solvent phase.Merge water, to 300L reactor, be cooled to 5 ± 2 ℃, drip 25% ammoniacal liquor:
Drip 9KG (8L) for the 1st time, add crystal seed a little, stirring and crystallizing 20 minutes;
Drip 7KG (6.2L), stirring and crystallizing 15 minutes the 2nd time;
Drip 5KG (4.5L), stirring and crystallizing 15 minutes the 3rd time;
The 4th drips (about 3KG), adjusts pH=2.9 ± 0.1, continues stirring and crystallizing 30 minutes;
Drip acetone 25KG (32L).5 ± 2 ℃ of temperature controls, stir growing the grain 1 hour.Filter, with acetone 56KG (71L)+water 20KG mixed solution filter wash.Use acetone 20KG (25L) filter wash 3 times, filter cake is put 40 ℃ of following vacuum-dryings again, obtains light yellow intermediate 7-ACQ33.5KG (7-ACA yield is about 1.34 relatively).
Embodiment 4: Cefquinome sulfate crude product is synthetic
1) in 500L reactor, add methylene dichloride 240KG (180L), add ethanol 32KG (40L).2) add 7-ACQ30KG+AE active ester 30KG+ Sodium Pyrosulfite 0.2KG, stir.3) be cooled to 5 ± 2 ℃, add triethylamine 15KG (20.5L), stir 30 minutes.4) be warming up to 10 ± 2 ℃, stirring reaction 3 hours.5) filter, with methylene dichloride 70KG (53L)+ethanol 6.4KG (8L) mixed solution filter wash.6) filtrate is injected 500L reactor, and temperature adjustment to 20 ± 2 ℃, add water 50KG, stirs extraction 20 minutes.7) static layering, water intaking phase.8) methylene dichloride adds water 25KG mutually again, stirs extraction 20 minutes.9) static layering, water intaking phase.10) methylene dichloride adds water 15KG mutually again, stirs extraction 15 minutes.11) static layering, water intaking phase.12) merge above-mentioned steps 7) and 9) water, add ethyl acetate 55KG (61L) agitator treating 15 minutes.13) static layering, water intaking phase.14) ethyl acetate is added to above-mentioned steps 11) water, extraction is stirred 15 minutes.15) static layering, water intaking phase.16) combining step 13) and step 15) water, be cooled to 10 ± 2 ℃, stir and to add acetone 95KG (120L).17) drip 40wt%H
2sO
4, adjust pH=3.9 ± 0.1 (about 2L=2.5KG).18) add gac 3KG, stir decolouring 40 minutes.19) filter, with acetone 24KG (30L)+water 10L mixed solution filter wash.20) filtrate is injected 500L reactor, is cooled to 5 ± 2 ℃, stirs.21) add 40wt%H
2sO
420KG (16.2L), then (another standby 5KG) adjusts pH=1.9 ± 0.1.22) temperature control is 5 ± 2 ℃, stirs 30 minutes.23) be warming up to 20 ± 2 ℃, add a little crystal seed, stirring and crystallizing 1.5 hours.24) drip acetone 160KG (203L).25) be cooled to 5 ± 2 ℃, survey and adjust pH=1.8 ± 0.1.26) continue to stir growing the grain 1 hour.27) filter, with acetone 79KG (100L) filter wash.28) filter cake is put 40 ℃ of following vacuum-dryings, obtains Cefquinome sulfate crude product 28.5KG (7-ACQ yield approximately 0.95 relatively).
Embodiment 5: Cefquinome sulfate crude product is synthetic
1) in 500L reactor, add methylene dichloride 240KG (180L), add ethanol 32KG (40L).2) add 7-ACQ30KG+AE active ester 26KG+ Sodium Pyrosulfite 0.2KG, stir.3) be cooled to 5 ± 2 ℃, add triethylamine 15KG (20.5L), stir 30 minutes.4) be warming up to 10 ± 2 ℃, stirring reaction 3 hours.5) filter, with methylene dichloride 70KG (53L)+ethanol 6.4KG (8L) mixed solution filter wash.6) filtrate is injected 500L reactor, and temperature adjustment to 20 ± 2 ℃, add water 50KG, stirs extraction 20 minutes.7) static layering, water intaking phase.8) methylene dichloride adds water 25KG mutually again, stirs extraction 20 minutes.9) static layering, water intaking phase.10) methylene dichloride adds water 15KG mutually again, stirs extraction 15 minutes.11) static layering, water intaking phase.12) merge above-mentioned steps 7) and step 9) water, add ethyl acetate 55KG (61L) agitator treating 15 minutes.13) static layering, water intaking phase.14) ethyl acetate is added to above-mentioned steps 11) water, extraction is stirred 15 minutes.15) static layering, water intaking phase.16) combining step 13) and step 15) water, be cooled to 10 ± 2 ℃, stir and to add acetone 95KG (120L).17) drip 40wt%H
2sO
4, adjust pH=3.9 ± 0.1 (about 2L=2.5KG).18) add gac 3KG, stir decolouring 40 minutes.19) filter, with acetone 24KG (30L)+water 10L mixed solution filter wash.20) filtrate is injected 500L reactor, is cooled to 5 ± 2 ℃, stirs.21) add 40wt%H
2sO
420KG (16.2L), then (another standby 5KG) adjusts pH=1.9 ± 0.1.22) temperature control is 5 ± 2 ℃, stirs 30 minutes.23) be warming up to 20 ± 2 ℃, add a little crystal seed, stirring and crystallizing 1.5 hours.24) drip acetone 160KG (203L).25) be cooled to 5 ± 2 ℃, survey and adjust pH=1.8 ± 0.1.26) continue to stir growing the grain 1 hour.27) filter, with acetone 79KG (100L) filter wash.28) filter cake is put 40 ℃ of following vacuum-dryings, obtains Cefquinome sulfate crude product 22.5KG (7-ACQ yield approximately 0.95 relatively).
Embodiment 6: Cefquinome sulfate crude product is synthetic
1) in 500L reactor, add methylene dichloride 240KG (180L), add ethanol 32KG (40L).2) add 7-ACQ30KG+AE active ester 32.6KG+ Sodium Pyrosulfite 0.2KG, stir.3) be cooled to 5 ± 2 ℃, add triethylamine 15KG (20.5L), stir 30 minutes.4) be warming up to 10 ± 2 ℃, stirring reaction 3 hours.5) filter, with methylene dichloride 70KG (53L)+ethanol 6.4KG (8L) mixed solution filter wash.6) filtrate is injected 500L reactor, and temperature adjustment to 20 ± 2 ℃, add water 50KG, stirs extraction 20 minutes.7) static layering, water intaking phase.8) methylene dichloride adds water 25KG mutually again, stirs extraction 20 minutes.9) static layering, water intaking phase.10) methylene dichloride adds water 15KG mutually again, stirs extraction 15 minutes.11) static layering, water intaking phase.12) merge above-mentioned steps 7) and step 9) water, add ethyl acetate 55KG (61L) agitator treating 15 minutes.13) static layering, water intaking phase.14) ethyl acetate is added to above-mentioned steps 11) water, extraction is stirred 15 minutes.15) static layering, water intaking phase.16) combining step 13) and step 15) water, be cooled to 10 ± 2 ℃, stir and to add acetone 95KG (120L).17) drip 40wt%H
2sO
4, adjust pH=3.9 ± 0.1 (about 2L=2.5KG).18) add gac 3KG, stir decolouring 40 minutes.19) filter, with acetone 24KG (30L)+water 10L mixed solution filter wash.20) filtrate is injected 500L reactor, is cooled to 5 ± 2 ℃, stirs.21) add 40wt%H
2sO
420KG (16.2L), then (another standby 5KG) adjusts pH=1.9 ± 0.1.22) temperature control is 5 ± 2 ℃, stirs 30 minutes.23) be warming up to 20 ± 2 ℃, add a little crystal seed, stirring and crystallizing 1.5 hours.24) drip acetone 160KG (203L).25) be cooled to 5 ± 2 ℃, survey and adjust pH=1.8 ± 0.1.Continue to stir growing the grain 1 hour.26) filter, with acetone 79KG (100L) filter wash.27) put 40 ℃ of following vacuum-dryings, obtain Cefquinome sulfate crude product 27.3KG (7-ACQ yield approximately 0.91 relatively).Embodiment 7: product purification
In 500L reactor, add purified water 75KG+ ethyl acetate 55KG (61L).Add Cefquinome sulfate crude product 25KG+ Sodium Pyrosulfite 0.2KG, stir.Be cooled to 8 ± 2 ℃, add triethylamine 10KG (14L), stir molten clear.Static layering, water intaking phase.Ethyl acetate is added 20 ℃ of water 10KG extractions 15 minutes.Static layering, abandons ethyl acetate phase.Merge water, be cooled to 8 ± 2 ℃, add acetone 95KG (120L).Use 40wt%H
2sO
4adjust pH=3.9 ± 0.1 (about 2KG).Add gac 3KG, stir decolouring 40 minutes.Filter, with acetone 24KG (30L)+water 10KG mixed solution filter wash.Filtrate is injected 500L reactor, is cooled to 5 ± 2 ℃, stirs.Add 40wt%H
2sO
420KG (16.2L), adjusts pH=1.8 ± 0.1.5 ± 2 ℃ of temperature controls, stir 30 minutes, are warming up to 20 ± 2 ℃, add a little crystal seed, stirring and crystallizing 1.5 hours.Drip acetone 160KG (203L) and be cooled to 5 ± 2 ℃, survey and adjust pH=1.65 ± 0.1, continue to stir growing the grain 1 hour.Filter, with acetone 20KG filter wash 3 times (25L), filter cake is put 40 ℃ of following vacuum-dryings, obtains refining (white or off-white color) Cefquinome sulfate 23.75KG (HPLC detects purity more than 99%) (crude product yield approximately 0.95 relatively).
Claims (5)
1. a preparation method for Cefquinome sulfate, is characterized in that described method comprises:
(1) take 7-amino-cephalosporanic acid and tetrahydroquinoline as reaction substrate, in methylene dichloride, take hexamethyldisilazane as protective material, take trimethylchlorosilane as reaction catalyst, using Diethyl Aniline as reaction system polar modifier, the dispersion medium that the N,N-DIMETHYLACETAMIDE of take is tetrahydroquinoline, react, after reacting completely, drip 25% ammoniacal liquor growing the grain, after acetone filter wash, obtain the amino cefquinome of intermediate 7-; Described 7-amino-cephalosporanic acid: tetrahydroquinoline: the consumption mol ratio of Iodotrimethylsilane is 1:2～3:1.5～2;
(2) mol ratio is 1:1.2～1.5 the amino cefquinome of 7-and MEAM be take ethanol as dispersion agent in methylene dichloride, Sodium Pyrosulfite is that antioxidant reacts, the acid that the triethylamine of usining constantly produces as acid binding agent neutralization reaction, after reaction finishes, with after methylene dichloride and alcohol mixeding liquid filter wash, getting filtrate extracts with pure water, the water merging is first adjusted pH3.9 ± 0.1 with sulfuric acid, add gac and stir decolouring, cross leaching filtrate and with sulfuric acid, adjust pH1.9 ± 0.1 again, control temperature and obtain Cefquinome sulfate crude product at 20 ± 2 ℃ of crystallizatioies, Cefquinome sulfate after crude product must be refined after filter wash recrystallization again.
2. the method for claim 1, is characterized in that in step (1), 7-amino-cephalosporanic acid be take methylene dichloride as dispersion medium, and tetrahydroquinoline be take N,N-DIMETHYLACETAMIDE as dispersion medium.
3. the method for claim 1, is characterized in that in step (2), sulfuric acid is adjusted behind pH1.9 ± 0.1, first controls temperature and stirs 15-30min at 5 ± 2 ℃, is then warming up to 20 ± 2 ℃, stirring and crystallizing.
4. the method for claim 1, the molar ratio that it is characterized in that the 7-amino-cephalosporanic acid/hexamethyldisilazane described in step (1) is 1:1.15～1.45.
5. the method for claim 1, the molar ratio that it is characterized in that the 7-amino-cephalosporanic acid/Diethyl Aniline described in step (1) is 1:1.5～2.
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| CN108802211A (en) * | 2018-04-19 | 2018-11-13 | 佛山市南海东方澳龙制药有限公司 | The liquid phase detection method of related substances in a kind of Cefquinome sulfate breast injection |
| CN113801142A (en) * | 2021-10-28 | 2021-12-17 | 重庆医药高等专科学校 | Preparation method of cefquinome sulfate intermediate 7-amino cefquinome |
| CN113976069A (en) * | 2021-10-28 | 2022-01-28 | 重庆医药高等专科学校 | Production system of cefquinome sulfate intermediate 7-amino cefquinome |
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