CN101555252B - Synthetic method of antibiotic cefoxitin - Google Patents
Synthetic method of antibiotic cefoxitin Download PDFInfo
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- CN101555252B CN101555252B CN2009100277901A CN200910027790A CN101555252B CN 101555252 B CN101555252 B CN 101555252B CN 2009100277901 A CN2009100277901 A CN 2009100277901A CN 200910027790 A CN200910027790 A CN 200910027790A CN 101555252 B CN101555252 B CN 101555252B
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- cefoxitin
- synthetic method
- methoxyl group
- acid
- antibiotic
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- 229960002682 cefoxitin Drugs 0.000 title claims abstract description 78
- 238000010189 synthetic method Methods 0.000 title claims abstract description 23
- 230000003115 biocidal effect Effects 0.000 title claims abstract description 19
- WZOZEZRFJCJXNZ-ZBFHGGJFSA-N cefoxitin Chemical compound N([C@]1(OC)C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)CC1=CC=CS1 WZOZEZRFJCJXNZ-ZBFHGGJFSA-N 0.000 title 1
- GNWUOVJNSFPWDD-XMZRARIVSA-M Cefoxitin sodium Chemical compound [Na+].N([C@]1(OC)C(N2C(=C(COC(N)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)CC1=CC=CS1 GNWUOVJNSFPWDD-XMZRARIVSA-M 0.000 claims abstract description 46
- 239000002253 acid Substances 0.000 claims abstract description 33
- 229960000603 cefalotin Drugs 0.000 claims abstract description 28
- 239000007787 solid Substances 0.000 claims abstract description 28
- VUFGUVLLDPOSBC-XRZFDKQNSA-M cephalothin sodium Chemical compound [Na+].N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC(=O)C)C([O-])=O)C(=O)CC1=CC=CS1 VUFGUVLLDPOSBC-XRZFDKQNSA-M 0.000 claims abstract description 24
- 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 19
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000003960 organic solvent Substances 0.000 claims abstract description 12
- WRJWRGBVPUUDLA-UHFFFAOYSA-N chlorosulfonyl isocyanate Chemical compound ClS(=O)(=O)N=C=O WRJWRGBVPUUDLA-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000006198 methoxylation reaction Methods 0.000 claims abstract description 9
- 230000021235 carbamoylation Effects 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims abstract description 5
- 229930013930 alkaloid Natural products 0.000 claims abstract description 3
- 150000003797 alkaloid derivatives Chemical class 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 50
- 238000006243 chemical reaction Methods 0.000 claims description 40
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 26
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 238000012545 processing Methods 0.000 claims description 15
- 230000000694 effects Effects 0.000 claims description 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- 239000003513 alkali Substances 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 9
- 239000012346 acetyl chloride Substances 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 238000005917 acylation reaction Methods 0.000 claims description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- -1 methoxyl group Chemical group 0.000 claims description 6
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 6
- 235000017550 sodium carbonate Nutrition 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 238000005815 base catalysis Methods 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 claims description 3
- 230000010933 acylation Effects 0.000 claims description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 150000003222 pyridines Chemical class 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-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
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 2
- 235000015320 potassium carbonate Nutrition 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 10
- 238000009776 industrial production Methods 0.000 abstract description 4
- 239000002351 wastewater Substances 0.000 abstract description 3
- AJYXPNIENRLELY-UHFFFAOYSA-N 2-thiophen-2-ylacetyl chloride Chemical compound ClC(=O)CC1=CC=CS1 AJYXPNIENRLELY-UHFFFAOYSA-N 0.000 abstract 1
- MTRNNCLQPVCDLF-UHFFFAOYSA-N benzyl-[2-(benzylazaniumyl)ethyl]azanium;diacetate Chemical compound CC(O)=O.CC(O)=O.C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 MTRNNCLQPVCDLF-UHFFFAOYSA-N 0.000 abstract 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 abstract 1
- 238000000926 separation method Methods 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 54
- 238000003756 stirring Methods 0.000 description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- 238000005406 washing Methods 0.000 description 23
- 239000012065 filter cake Substances 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- 238000001914 filtration Methods 0.000 description 12
- 239000006210 lotion Substances 0.000 description 12
- 230000002194 synthesizing effect Effects 0.000 description 12
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 235000019371 penicillin G benzathine Nutrition 0.000 description 9
- 238000001291 vacuum drying Methods 0.000 description 9
- 238000005516 engineering process Methods 0.000 description 7
- 230000007062 hydrolysis Effects 0.000 description 7
- 238000006460 hydrolysis reaction Methods 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 239000012452 mother liquor Substances 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 238000010792 warming Methods 0.000 description 6
- 229930186147 Cephalosporin Natural products 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 229940124587 cephalosporin Drugs 0.000 description 4
- 150000001780 cephalosporins Chemical class 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- DQOABIAZCQDDJP-UHFFFAOYSA-N C(CCC)[ClH]O Chemical group C(CCC)[ClH]O DQOABIAZCQDDJP-UHFFFAOYSA-N 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- 230000018044 dehydration Effects 0.000 description 3
- 238000006297 dehydration reaction Methods 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000009413 insulation Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- LALCDSDHLXWTTL-UHFFFAOYSA-N 2-chloro-n-(oxomethylidene)benzenesulfonamide Chemical class ClC1=CC=CC=C1S(=O)(=O)N=C=O LALCDSDHLXWTTL-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- JPOPGVDJJMEDRZ-UHFFFAOYSA-N S(=O)(=O)(N=C=O)N=C=O.[Br] Chemical compound S(=O)(=O)(N=C=O)N=C=O.[Br] JPOPGVDJJMEDRZ-UHFFFAOYSA-N 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000011017 operating method Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- MOVMEFHWBOWMFU-UHFFFAOYSA-N 2-chloroacetyl isocyanate Chemical compound ClCC(=O)N=C=O MOVMEFHWBOWMFU-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- LXWBXEWUSAABOA-UHFFFAOYSA-N Cephamycin-C Natural products S1CC(COC(N)=O)=C(C(O)=O)N2C(=O)C(OC)(NC(=O)CCCC(N)C(O)=O)C21 LXWBXEWUSAABOA-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- LXWBXEWUSAABOA-VXSYNFHWSA-N cephamycin C Chemical compound S1CC(COC(N)=O)=C(C(O)=O)N2C(=O)[C@@](OC)(NC(=O)CCC[C@@H](N)C(O)=O)[C@H]21 LXWBXEWUSAABOA-VXSYNFHWSA-N 0.000 description 1
- 150000003946 cyclohexylamines Chemical class 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
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- 238000011161 development Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000006213 oxygenation reaction Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
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- Cephalosporin Compounds (AREA)
Abstract
The invention relates to a synthetic method of antibiotic cefoxitin. 7-ACA is taken as a starting material and firstly reacts with thiopheneacetyl chloride, cephalothin acid is obtained by separation;the cephalothin acid is not purified, and the methoxylation is directly carried out on the cephalothin acid to obtain an intermediate A which introduces methoxy on the position of 7, the intermediate A obtains 7-alpha-methoxy cephalothin cyclohexylamine salt under the action of cyclohexylamine; the 7-alpha-methoxy cephalothin cyclohexylamine salt reacts with benzathine diacetate under the catalys ation of solid alkaloid to obtain 7-alpha-methoxy-3-deacetoxy cephalothin benzathine salt; and the carbamylation is carried out under the action of chlorosulfonyl isocyanate to obtain the cefoxitin. The synthetic method has the advantages that compared with the prior art, the synthetic method simplifies the operation process, has high product yield, reduces the production cycle, eliminates the discharge of waste water containing organic solvent and reduces the production cost. The product quality is stable, and the synthetic method is applicable to the large-scale industrial production.
Description
Technical field
The invention relates to a kind of synthetic method of cephalosporins cefoxitin, belong to the antibiotic medicine preparing technical field.
Background technology
Cefoxitin (Cefoxitin), by the s-generation cephalosporin analog antibiotic of U.S. Merck company development, its antimicrobial spectrum equilibrium, similar to second generation cephalosporin, but owing to contain 7 a α-methoxyl group on its structure, significantly reduced the hydrolysis destruction of the β-Nei Xiananmei in the bacterium to it, therefore stable to β-Nei Xiananmei, its resistance problem is than little many of other s-generation cephalo product.At present because drug-resistance of bacteria constantly rises, thereby the cefoxitin that is different from the first-generation and third generation cephalosporin has caused people's attention once more.
The cefoxitin chemistry is by name: (6R, 7S)-3-carboxamide oxygen methyl-7-oxygenation base-8-oxo-7-[2-(2-thiazolyl) acetamido]-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid.Its chemical structural formula is as follows:
The present synthetic method of bibliographical information cefoxitin all is that the 7-ACA with 7-ACA or carboxy protective is a raw material; It is raw material with the cephamycin C that document is also arranged, and owing to raw material is not easy to obtain, and reaction scheme is long, yield is low, cost is high, is difficult to suitability for industrialized production, does not therefore have using value.
The synthetic technology difficulty of cefoxitin acid is bigger, though domestic have certain progress in its synthetic technology research, cost is still higher, and quality is not good enough.Therefore it is simple to research and develop technology, low cost, and high quality, and be suitable for the synthetic technology of large-scale industrial production, become the task of top priority.
Summary of the invention
The invention provides a kind of synthetic method that is more suitable for large-scale industrial production, cefoxitin that quality product is higher.Be intended to overcome the above-mentioned defective of existing in prior technology.
Technical scheme of the present invention: this method comprises following processing step:
(1), 7-ACA is dissolved in the organic solvent, add alkali, drip thiophen acetyl chloride generation acylation, obtain cephalothin acid, the temperature of acylation reaction is-20～50 ℃, and optimum temps is-10～25 ℃;
(2), resulting cephalothin acid in the step (1) is not purified, directly under the effect of t-butyl hypochlorate and sodium methylate, carry out methoxylation, obtain the intermediate A of introducing methoxyl group at 7, intermediate A obtains 7-α-methoxyl group cefoxitin cyclohexylamine salt under the hexahydroaniline effect; The temperature of intermediate A and hexahydroaniline reaction is 20～50 ℃, and optimum temps is 35～45 ℃;
(3), with resulting 7-α-methoxyl group cefoxitin cyclohexylamine salt in the step (2) under the solid biologic base catalysis, with the effect of benzyl star diacetate, obtain 7-α-methoxyl group-3-and remove acetoxyl group cefoxitin benzyl star salt, temperature of reaction is-60～50 ℃, and optimum temps is-10～40 ℃;
(4), go acetoxyl group cefoxitin benzyl star salt in acetone, under the chlorosulfonic acid isocyanate effect, to carry out carbamylation resulting 7-α-methoxyl group-3-in the step (3), obtain cefoxitin, temperature of reaction is-80～20 ℃, and optimum temps is-50～10 ℃.
Advantage of the present invention: 7-ACA at first with the thiophen acetyl chloride effect, separate to obtain cephalothin acid.Change the organic phase reaction into from original water react, and change single step reaction into, not only simplified operating procedure, improved the single step yield, also shortened the production cycle, got rid of the discharge of wastewater that contains organic solvent, reduced production cost by original two steps reaction.Three step process from cyclohexylamine salt to benzyl star salt, used solid biologic base catalysis technology, substituted conventional chemical method.Not only simplify operating procedure, improved the yield and the drug effect of single step, reduced side effect; Also shortened the production cycle, got rid of organic solvent, reduced the discharge of wastewater that contains organic solvent, effectively reduced energy consumption and material consumption, reached energy-saving and emission-reduction, reduced production costs.And used solid biologic alkali can be reused more than 500 batches, has reduced productive expense.The present invention compares with existing technological line, has that processing condition are simple, easy to operate, product yield is high, an advantage of constant product quality and suitable large-scale industrial production.
Embodiment:
Synthetic method of antibiotic cefoxitin comprises following processing step:
(1), 7-ACA is dissolved in the organic solvent, add alkali, drip thiophen acetyl chloride generation acylation, obtain cephalothin acid, the temperature of acylation reaction is-20～50 ℃, and optimum temps is-10～25 ℃;
(2), resulting cephalothin acid in the step (1) is not purified, directly under the effect of t-butyl hypochlorate and sodium methylate, carry out methoxylation, obtain the intermediate A of introducing methoxyl group at 7, intermediate A obtains 7-α-methoxyl group cefoxitin cyclohexylamine salt under the hexahydroaniline effect; The temperature of intermediate A and hexahydroaniline reaction is 20～50 ℃, and optimum temps is 35～45 ℃;
(3), with resulting 7-α-methoxyl group cefoxitin cyclohexylamine salt in the step (2) under the solid biologic base catalysis, with the effect of benzyl star diacetate, obtain 7-α-methoxyl group-3-and remove acetoxyl group cefoxitin benzyl star salt, temperature of reaction is-60～50 ℃, and optimum temps is-10～40 ℃;
(4), go acetoxyl group cefoxitin benzyl star salt in acetone, under the chlorosulfonic acid isocyanate effect, to carry out carbamylation resulting 7-α-methoxyl group-3-in the step (3), obtain cefoxitin, temperature of reaction is-80～20 ℃, and optimum temps is-50～10 ℃.
Organic solvent is N in the described processing step (1), dinethylformamide (DMF), N, the mixture of one or more in N-N,N-DIMETHYLACETAMIDE (DMAC), acetonitrile, tetrahydrofuran (THF), methylene dichloride, ethylene dichloride, chloroform, the acetone, preferably methylene dichloride; Add 7-ACA and alkali mol ratio be 1: 1-1: 6, preferably 1: 1.2, the mol ratio that adds 7-ACA and drip thiophen acetyl chloride be 1: 1-1: 6, preferably 1: 1.1, add 7-ACA and organic solvent weight ratio be 1: 3-1: 20, preferably 1: 5.
Alkali in the described processing step (1) is sodium hydroxide, potassium hydroxide, salt of wormwood, yellow soda ash, sodium bicarbonate, pyridine, ammoniacal liquor, Trimethylamine 99, triethylamine, N, one or more in the N dimethylamine yl pyridines.
Methoxylation reagent in the described step (2) is t-butyl hypochlorate and sodium methylate, and the temperature of methoxylation is-85～0 ℃, and optimum temps is-80～-50 ℃; The weight ratio of described cephalothin acid and t-butyl hypochlorate is 1: 0.28-1: 1, and preferably 1: 0.38, the weight ratio of cephalothin acid and sodium methylate was 1: 0.4-1: 1 preferably 1: 0.6.
Catalyzer in the described processing step (3) is an alkaloid, the weight ratio of described 7-α-methoxyl group cefoxitin cyclohexylamine salt and solid biologic alkali is 1: 0.1-1: 1, preferably 1: 0.17, the weight ratio of 7-α-methoxyl group cefoxitin cyclohexylamine salt and benzyl star diacetate is 1: 0.3-1: 1, and preferably 1: 0.45.
Isocyanic ester in the described processing step (4) is bromine sulfonyl isocyanate, Sulfuryl chloride isocyanate, chloroacetyl isocyanate, chloro-phenyl-sulfonylisocyanates, dichloro-acetyl isocyanic ester; wherein preferably Sulfuryl chloride isocyanate carries out carbamylation; described chlorosulfonic acid isocyanate accounts for 7-α-methoxyl group-3-, and to go the weight ratio of acetoxyl group cefoxitin benzyl star salt be 1: 0.3-1: 1, and preferably 1: 0.56.
Acetone in the described processing step (4) is reaction solvent, reaction solvent also comprises N, the mixture of one or more in dinethylformamide (DMF), N,N-dimethylacetamide (DMAC), acetonitrile, tetrahydrofuran (THF), methylene dichloride, ethylene dichloride, the chloroform, preferably acetone.
Synthetic route is as follows:
Synthesizing of embodiment 1 cephalothin acid
In flask, add 40g 7-amino-cephalosporanic acid (7-ACA), 17.2g triethylamine, methylene dichloride 240mL, temperature control 0-10 ℃, stir down and drip thiophen acetyl chloride 27.2g, dropwised in three hours.
Insulation reaction is 5 hours then, after reaction finishes, filters filtering solid, filter cake 100mL washed with dichloromethane.Merging filtrate and washing lotion, evaporate to dryness promptly get cephalothin acid 56g, yield 1.4%.Filtrate and the washing lotion that merges can be directly used in next step reaction in the actual production.
Synthesizing of 7-α-methoxyl group cefoxitin cyclohexylamine salt
In flask, add 60g cephalothin acid, tetrahydrofuran (THF) 200mL, methylene dichloride 500mL, stir 10min, cephalothin acid is dissolved fully.To-85 ℃, add the 50g solid sodium methylate with cooled with liquid nitrogen in batches.Temperature control-80--85 ℃, reacted one hour, drip tertiary butyl hypochlorous acid 50g, drip and finish reaction two hours.After reaction finishes, slowly add the 30ml concentrated hydrochloric acid, add fashionable heat release, be warmed up to-60-65 ℃, stir 10min.Slowly the sodium chloride aqueous solution 200ml of adding 5% is warmed up to 0 ℃, stirs 10min, standing demix.Water layer 50ml dichloromethane extraction, the combined dichloromethane layer.
Dichloromethane layer adds the 10g anhydrous sodium sulphate, stirs the 30min dehydration, when moisture content filters less than 0.5% the time.Filtrate decompression concentrates, and up to residue 120ml-150ml, temperature is controlled at 15-20 ℃, slowly drips the 20g hexahydroaniline, about 40min of time, the about 6-7 of PH.Be cooled to about 0 ℃ insulated and stirred 2h.Filter filtering solid, filter cake 100mL washing with acetone.Under 50 ℃, vacuum-drying 3-4h obtains 7-α-methoxyl group cefoxitin cyclohexylamine salt 68.7g, yield 1.145.
Synthesizing of 7-α-methoxyl group-3-deacetyled cefoxitin benzathine
In flask, add 60g 7-α-methoxyl group cefoxitin cyclohexylamine salt, 500mL pure water, 100mL ethyl acetate, be warming up to 40 ℃, stir 30min, 7-α-methoxyl group cefoxitin cyclohexylamine salt is dissolved fully.Add solid biologic alkaline catalysts 10g, drip 10% ammoniacal liquor control PH8-9, react about 2h, constant until pH value.Reaction is kept under 40 ℃ after finishing, and adds 30g benzyl star diacetate in batches, and the solution becomes muddiness has solid to separate out.Be cooled to 10-15 ℃, insulated and stirred 1.5h, cooling is about-5 ℃ then, stirs 2h.Filter filtering solid, filter cake 100mL washing with acetone.Under 50 ℃, vacuum-drying 3-4h obtains 7-α-methoxyl group-3-deacetyled cefoxitin benzathine 46.8g, yield 0.78.
Synthesizing of cefoxitin acid
In flask, add 50g 7-α-methoxyl group-3-deacetyled cefoxitin benzathine, 500mL ethyl acetate, be cooled to-40--45 ℃, stir 30min, in 50-60min, add the 30g Sulfuryl chloride isocyanate.Check reaction end with HPLC behind the 60min, when raw material 7-α-methoxyl group-3-deacetylate cefoxitin＜1.0%, react completely.
Reaction adds the 150ml pure water after finishing fast, is incubated 10-12 ℃, stirs 60min, checks the hydrolysis terminal point with HPLC.Hydrolysis is warming up to 20-25 ℃ after finishing, and filters the benzyl star hydrochloride that generates, and filter cake washs with the 30mL ethyl acetate.Sodium chloride aqueous solution 150ml adding 5% in mother liquor that merges and the washing lotion stirs 10min, standing demix.Ethyl acetate layer adds 3% aqueous sodium carbonate 500ml, control PH6-7.Stir 10min, standing demix, ethyl acetate layer extracts with the 50ml pure water, combining water layer.Water layer adds the 5g gac and stirs decolouring 20min, filters filter cake 20mL pure water washing.Merge mother liquor and washing lotion and be cooled to 10 ℃, the hydrochloric acid with 10% is regulated pH value, and pH value is stabilized in 1.9-2.1, stirs 2h.Filter, the filtering solid, filter cake washs with the 100mL pure water.Under 50 ℃, vacuum-drying 3-4h obtains cefoxitin acid 31.5g, yield 0.63.
Synthesizing of embodiment 2 cephalothin acids
In flask, add 40g 7-amino-cephalosporanic acid (7-ACA), 30.2gN, N dimethylamine yl pyridines, ethyl acetate 250mL, temperature control 0-10 ℃, stir down and drip thiophen acetyl chloride 27.2g (0.17mol), dropwised in three hours.
Insulation reaction is 5 hours then, after reaction finishes, filter, and the filtering solid, filter cake washs with the 100mL ethyl acetate.Merging filtrate and washing lotion, evaporate to dryness promptly get cephalothin acid 52g, yield 1.3%.Filtrate and the washing lotion that merges can be directly used in next step reaction in the actual production.
Synthesizing of 7-α-methoxyl group cefoxitin cyclohexylamine salt
In flask, add 60g cephalothin acid, DMF200mL, methylene dichloride 500mL, stir 10min, cephalothin acid is dissolved fully.To-95 ℃, add 17% 290g methanol solution of sodium methylate with cooled with liquid nitrogen.Temperature control-90--95 ℃, reacted one hour, drip tertiary butyl hypochlorous acid 50g, drip and finish reaction two hours.After reaction finishes, slowly add the 30ml concentrated hydrochloric acid, add fashionable heat release, be warmed up to-60--65 ℃, stir 10min.Slowly the sodium chloride aqueous solution 200ml of adding 5% is warmed up to 0 ℃, stirs 10min, standing demix.Water layer 50ml dichloromethane extraction, the combined dichloromethane layer.
Dichloromethane layer adds the 10g anhydrous sodium sulphate, stirs the 30min dehydration, when moisture content filters less than 0.5% the time.Filtrate decompression concentrates, and up to residue 120ml-150ml, temperature is controlled at 15-20 ℃, slowly drips the 20g hexahydroaniline, about 40min of time, the about 6-7 of PH.Be cooled to about 0 ℃ insulated and stirred 2h.Filter filtering solid, filter cake 100mL washing with acetone.Under 50 ℃, vacuum-drying 3-4h obtains 7-α-methoxyl group cefoxitin cyclohexylamine salt 63.2g, yield 1.05.
Synthesizing of 7-α-methoxyl group-3-deacetyled cefoxitin benzathine
In flask, add 60g 7-α-methoxyl group cefoxitin cyclohexylamine salt, 500mL pure water, 100mL ethyl acetate, be warming up to 40 ℃, stir 30min, 7-α-methoxyl group cefoxitin cyclohexylamine salt is dissolved fully.Add solid biologic alkaline catalysts 10g, drip 10% sodium bicarbonate control PH8-9, react about 2h, constant until pH value.Reaction is kept under 40 ℃ after finishing, and adds 30g benzyl star diacetate in batches, and the solution becomes muddiness has solid to separate out.Be cooled to 10-15 ℃, insulated and stirred 1.5h, cooling is about-5 ℃ then, stirs 2h.Filter filtering solid, filter cake 100mL washing with acetone.Under 50 ℃, vacuum-drying 3-4h obtains 7-α-methoxyl group-3-deacetyled cefoxitin benzathine 40.2g, yield 0.67.
Synthesizing of cefoxitin acid
In flask, add 50g 7-α-methoxyl group-3-deacetyled cefoxitin benzathine, 500mLTHF, be cooled to-40--45 ℃, stir 30min, in 50-60min, add 35g bromine sulfonyl isocyanate.Check reaction end with HPLC behind the 60min, when raw material 7-α-methoxyl group-3-deacetylate cefoxitin＜1.0%, react completely.
Reaction adds the 150ml pure water after finishing fast, is incubated 10-12 ℃, stirs 60min, checks the hydrolysis terminal point with HPLC.Hydrolysis is warming up to 20-25 ℃ after finishing, and adds the 600ml ethyl acetate, filters the benzyl star hydrochloride that generates, filter cake 30mL ethyl acetate washing.Sodium chloride aqueous solution 150ml adding 5% in mother liquor that merges and the washing lotion stirs 10min, standing demix.Ethyl acetate layer adds 3% aqueous sodium carbonate 500ml, control PH6-7.Stir 10min, standing demix, ethyl acetate layer extracts with the 50ml pure water, combining water layer.Water layer adds the 5g gac and stirs decolouring 20min, filters filter cake 20mL pure water washing.Merge mother liquor and washing lotion and be cooled to 10 ℃, the hydrochloric acid with 10% is regulated pH value, and pH value is stabilized in 1.9-2.1, stirs 2h.Filter, the filtering solid, filter cake washs with the 100mL pure water.Under 50 ℃, vacuum-drying 3-4h obtains cefoxitin acid 29.1g, yield 0.58.
Synthesizing of embodiment 3 cephalothin acids
In flask, add 40g 7-amino-cephalosporanic acid (7-ACA), 15.4g Trimethylamine 99, methylene dichloride 250mL, temperature control 0-10 ℃, stir down and drip thiophen acetyl chloride 27.2g (0.17mol), dropwised in three hours.
Insulation reaction is 5 hours then, after reaction finishes, filter, and the filtering solid, filter cake washs with the 100mL ethyl acetate.Merging filtrate and washing lotion, evaporate to dryness promptly get cephalothin acid 55g, yield 1.375%.Filtrate and the washing lotion that merges can be directly used in next step reaction in the actual production.
Synthesizing of 7-α-methoxyl group cefoxitin cyclohexylamine salt
In flask, add 60g cephalothin acid, methyl alcohol 200mL, methylene dichloride 500mL, stir 10min, cephalothin acid is dissolved fully.To-85 ℃, add the 50g solid sodium methylate with cooled with liquid nitrogen in batches.Temperature control-80--85 ℃, reacted one hour, drip tertiary butyl hypochlorous acid 50g, drip and finish reaction two hours.After reaction finishes, slowly add 50ml formic acid, add fashionable heat release, be warmed up to-60--65 ℃, stir 10min.Slowly the sodium chloride aqueous solution 200ml of adding 5% is warmed up to 0 ℃, stirs 10min, standing demix.Water layer 50ml dichloromethane extraction, the combined dichloromethane layer.
Dichloromethane layer adds the 10g anhydrous sodium sulphate, stirs the 30min dehydration, when moisture content filters less than 0.5% the time.Filtrate decompression concentrates, and up to residue 120ml-150ml, temperature is controlled at 15-20 ℃, slowly drips the 20g hexahydroaniline, about 40min of time, the about 6-7 of PH.Be cooled to about 0 ℃ insulated and stirred 2h.Filter filtering solid, filter cake 100mL washing with acetone.Under 50 ℃, vacuum-drying 3-4h obtains 7-α-methoxyl group cefoxitin cyclohexylamine salt 63.2g, yield 1.05.
Synthesizing of 7-α-methoxyl group-3-deacetyled cefoxitin benzathine
In flask, add 60g 7-α-methoxyl group cefoxitin cyclohexylamine salt, 500mL pure water, 100mL ethyl acetate, be warming up to 60 ℃, stir 30min, 7-α-methoxyl group cefoxitin cyclohexylamine salt is dissolved fully.Add solid biologic alkaline catalysts 10g, drip 10% sodium bicarbonate control PH8-9, react about 2h, constant until pH value.Reaction is kept under 40 ℃ after finishing, and adds 30g benzyl star diacetate in batches, and the solution becomes muddiness has solid to separate out.Be cooled to 10-15 ℃, insulated and stirred 1.5h, cooling is about-5 ℃ then, stirs 2h.Filter filtering solid, filter cake 100mL washing with acetone.Under 50 ℃, vacuum-drying 3-4h obtains 7-α-methoxyl group-3-deacetyled cefoxitin benzathine 33.6g, yield 0.56.
Synthesizing of cefoxitin acid
In flask, add 50g 7-α-methoxyl group-3-deacetyled cefoxitin benzathine, 500mLTHF, be cooled to-40--45 ℃, stir 30min, in 50-60min, add 46g chloro-phenyl-sulfonylisocyanates.Check reaction end with HPLC behind the 60min, when raw material 7-α-methoxyl group-3-deacetylate cefoxitin＜1.0%, react completely.
Reaction adds the 150ml pure water after finishing fast, is incubated 10-12 ℃, stirs 60min, checks the hydrolysis terminal point with HPLC.Hydrolysis is warming up to 20-25 ℃ after finishing, and adds the 600ml ethyl acetate, filters the benzyl star hydrochloride that generates, filter cake 30mL ethyl acetate washing.Sodium chloride aqueous solution 150ml adding 5% in mother liquor that merges and the washing lotion stirs 10min, standing demix.Ethyl acetate layer adds 3% aqueous sodium carbonate 500ml, control PH6-7.Stir 10min, standing demix, ethyl acetate layer extracts with the 50ml pure water, combining water layer.Water layer adds the 5g gac and stirs decolouring 20min, filters filter cake 20mL pure water washing.Merge mother liquor and washing lotion and be cooled to 10 ℃, the hydrochloric acid with 10% is regulated pH value, and pH value is stabilized in 1.9-2.1, stirs 2h.Filter, the filtering solid, filter cake washs with the 100mL pure water.Under 50 ℃, vacuum-drying 3-4h obtains cefoxitin acid 20.4g, yield 0.408.
Claims (13)
1. synthetic method of antibiotic cefoxitin is characterized in that this method comprises following processing step:
(1), 7-amino-cephalosporanic acid is dissolved in the organic solvent, add alkali, drip thiophen acetyl chloride generation acylation, obtain cephalothin acid, the temperature of acylation reaction is-20～50 ℃;
(2), resulting cephalothin acid in the step (1) is not purified, directly under the effect of t-butyl hypochlorate and sodium methylate, carry out methoxylation, obtain the intermediate A of introducing methoxyl group at 7, intermediate A obtains 7-α-methoxyl group cefoxitin cyclohexylamine salt under the hexahydroaniline effect; The temperature of intermediate A and hexahydroaniline reaction is 20～50 ℃;
(3), with resulting 7-α-methoxyl group cefoxitin cyclohexylamine salt in the step (2) under the solid biologic base catalysis, with the effect of benzyl star diacetate, obtain 7-α-methoxyl group-3-and remove acetoxyl group cefoxitin benzyl star salt, temperature of reaction is-60～50 ℃;
(4), go acetoxyl group cefoxitin benzyl star salt in acetone, under the chlorosulfonic acid isocyanate effect, to carry out carbamylation resulting 7-α-methoxyl group-3-in the step (3), obtain cefoxitin, temperature of reaction is-80～20 ℃.
2. a kind of synthetic method of antibiotic cefoxitin according to claim 1 is characterized in that the temperature of acylation reaction in the described step (1) is-10～25 ℃.
3. a kind of synthetic method of antibiotic cefoxitin according to claim 1 is characterized in that the temperature of middle intermediate A of described step (2) and hexahydroaniline reaction is 35～45 ℃.
4. a kind of synthetic method of antibiotic cefoxitin according to claim 1 is characterized in that the temperature of reaction described in the described step (3) is-10～40 ℃.
5. a kind of synthetic method of antibiotic cefoxitin according to claim 1 is characterized in that the temperature of reaction described in the described step (4) is-50～10 ℃.
6. a kind of synthetic method of antibiotic cefoxitin according to claim 1, it is characterized in that the organic solvent in the described processing step (1) is N, the mixture of one or more in dinethylformamide (DMF), N,N-dimethylacetamide (DMAC), acetonitrile, tetrahydrofuran (THF), methylene dichloride, ethylene dichloride, chloroform, the acetone; Add 7-amino-cephalosporanic acid and alkali mol ratio be 1: 1-1: 6, the mol ratio that adds 7-amino-cephalosporanic acid and drip thiophen acetyl chloride be 1: 1-1: 6, add 7-amino-cephalosporanic acid and organic solvent weight ratio be 1: 3-1: 20.
7. a kind of synthetic method of antibiotic cefoxitin according to claim 6 is characterized in that the organic solvent in the described processing step (1) is a methylene dichloride.
8. a kind of synthetic method of antibiotic cefoxitin according to claim 1, it is characterized in that, alkali in the described processing step (1) is sodium hydroxide, potassium hydroxide, salt of wormwood, yellow soda ash, sodium bicarbonate, pyridine, ammoniacal liquor, Trimethylamine 99, triethylamine, N, one or more in the N dimethylamine yl pyridines.
9. a kind of synthetic method of antibiotic cefoxitin according to claim 1 is characterized in that, the methoxylation reagent in the described step (2) is t-butyl hypochlorate and sodium methylate, and the temperature of methoxylation is-85～0 ℃; The weight ratio of described cephalothin acid and t-butyl hypochlorate is 1: 0.28-1: 1, and the weight ratio of cephalothin acid and sodium methylate is 1: 0.4-1: 1.
10. a kind of synthetic method of antibiotic cefoxitin according to claim 9 is characterized in that, the temperature of methoxylation is-80～-50 ℃ in the described step (2).
11. a kind of synthetic method of antibiotic cefoxitin according to claim 1, it is characterized in that, catalyzer in the described processing step (3) is an alkaloid, the weight ratio of described 7-α-methoxyl group cefoxitin cyclohexylamine salt and solid biologic alkali is 1: 0.1-1: 1, and the weight ratio of 7-α-methoxyl group cefoxitin cyclohexylamine salt and benzyl star diacetate is 1: 0.3-1: 1.
12. a kind of synthetic method of antibiotic cefoxitin according to claim 1, it is characterized in that, in the described processing step (4), described chlorosulfonic acid isocyanate accounts for 7-α-methoxyl group-3-, and to go the weight ratio of acetoxyl group cefoxitin benzyl star salt be 1: 0.3-1: 1.
13. a kind of synthetic method of antibiotic cefoxitin according to claim 12, it is characterized in that, in the described processing step (4), described chlorosulfonic acid isocyanate accounts for 7-α-methoxyl group-3-, and to go the weight ratio of acetoxyl group cefoxitin benzyl star salt be 1: 0.56.
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| CN101914105A (en) * | 2010-08-24 | 2010-12-15 | 广东省石油化工研究院 | Preparation method of cephalotin acid |
| CN102295654B (en) * | 2011-08-10 | 2012-07-04 | 江西新先锋医药有限公司 | Cefoxitin compound and composition thereof |
| CN104230956B (en) * | 2012-04-24 | 2016-07-06 | 齐鲁安替（临邑）制药有限公司 | A kind of preparation method of cefoxitin |
| CN102633819A (en) * | 2012-04-24 | 2012-08-15 | 齐鲁安替（临邑）制药有限公司 | Preparation method of cefoxitin |
| CN103012437B (en) * | 2012-12-04 | 2015-08-05 | 山东鑫泉医药有限公司 | The preparation method of antibacterial drugs cefoxitin acid |
| CN102936614B (en) * | 2012-12-07 | 2015-04-01 | 苏州中联化学制药有限公司 | Synthesis method of 7-alpha-methoxy-3-deacetylcephalothin benzathine |
| CN104072521A (en) * | 2014-06-27 | 2014-10-01 | 广东省石油化工研究院 | Preparation method for cefoxitin acid |
| CN104402909B (en) * | 2014-11-12 | 2017-03-15 | 盐城开元医药化工有限公司 | A kind of synthetic method of cefoxitin acid |
| CN105218563A (en) * | 2015-11-02 | 2016-01-06 | 四川清山绿水实业发展有限公司 | A kind of synthetic method of antibacterial drugs cefoxitin acid |
| CN105254650A (en) * | 2015-11-02 | 2016-01-20 | 四川清山绿水实业发展有限公司 | Synthesis method of antibacterial drug cefoxitin |
| CN110204556B (en) * | 2019-07-16 | 2020-09-18 | 重庆医药高等专科学校 | Preparation method of (RS) -methoxy cefoxitin |
| CN112094280A (en) * | 2020-09-09 | 2020-12-18 | 苏州盛达药业有限公司 | Preparation method of cefoxitin derivative |
| CN113583024A (en) * | 2021-08-30 | 2021-11-02 | 浙江国邦药业有限公司 | Synthesis method of key intermediate of cefoxitin sodium |
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