CN108912146A - A kind of synthetic method of Ceftiofur intermediate and Ceftiofur - Google Patents
A kind of synthetic method of Ceftiofur intermediate and Ceftiofur Download PDFInfo
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- CN108912146A CN108912146A CN201810960409.6A CN201810960409A CN108912146A CN 108912146 A CN108912146 A CN 108912146A CN 201810960409 A CN201810960409 A CN 201810960409A CN 108912146 A CN108912146 A CN 108912146A
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- amino
- acid
- ceftiofur
- synthetic method
- carbonyl
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- ZBHXIWJRIFEVQY-IHMPYVIRSA-N ceftiofur Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC(=O)C1=CC=CO1 ZBHXIWJRIFEVQY-IHMPYVIRSA-N 0.000 title claims abstract description 49
- 229960005229 ceftiofur Drugs 0.000 title claims abstract description 49
- 238000010189 synthetic method Methods 0.000 title claims abstract description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 43
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims abstract description 28
- 238000006243 chemical reaction Methods 0.000 claims abstract description 28
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims abstract description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000007787 solid Substances 0.000 claims abstract description 23
- HCDVGJKQJLETMV-YKOKWACPSA-N C1C(=C(N2[C@H](S1)C(C2=O)N)C(=O)O)C(C(=O)C3=CC=CO3)S Chemical compound C1C(=C(N2[C@H](S1)C(C2=O)N)C(=O)O)C(C(=O)C3=CC=CO3)S HCDVGJKQJLETMV-YKOKWACPSA-N 0.000 claims abstract description 22
- 238000001914 filtration Methods 0.000 claims abstract description 21
- 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 18
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000003054 catalyst Substances 0.000 claims abstract description 14
- 239000012065 filter cake Substances 0.000 claims abstract description 14
- 235000019253 formic acid Nutrition 0.000 claims abstract description 14
- 229910021536 Zeolite Inorganic materials 0.000 claims abstract description 12
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000000706 filtrate Substances 0.000 claims abstract description 12
- 239000010457 zeolite Substances 0.000 claims abstract description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 21
- 239000002253 acid Substances 0.000 claims description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- 230000015572 biosynthetic process Effects 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- 238000003786 synthesis reaction Methods 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 6
- -1 2- furyl-carbonyl Chemical group 0.000 claims description 5
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 239000008213 purified water Substances 0.000 claims description 4
- 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 claims description 3
- 239000003610 charcoal Substances 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 238000013517 stratification Methods 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 229910000498 pewter Inorganic materials 0.000 claims description 2
- 239000010957 pewter Substances 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000010583 slow cooling Methods 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 14
- 238000004519 manufacturing process Methods 0.000 abstract description 12
- 239000000047 product Substances 0.000 abstract description 5
- 239000002904 solvent Substances 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 239000002585 base Substances 0.000 description 10
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 6
- 125000002541 furyl group Chemical group 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 229910015900 BF3 Inorganic materials 0.000 description 4
- 238000006555 catalytic reaction Methods 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 150000002240 furans Chemical class 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 229930186147 Cephalosporin Natural products 0.000 description 2
- 239000005864 Sulphur Substances 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 229940124587 cephalosporin Drugs 0.000 description 2
- 150000001780 cephalosporins Chemical class 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- UNWSCLFRWCYCHG-UHFFFAOYSA-N ethyl acetate;trifluoroborane Chemical compound FB(F)F.CCOC(C)=O UNWSCLFRWCYCHG-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical compound NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- RFLHUYUQCKHUKS-JUODUXDSSA-M Ceftiofur sodium Chemical compound [Na+].S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC(=O)C1=CC=CO1 RFLHUYUQCKHUKS-JUODUXDSSA-M 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 241000009328 Perro Species 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 229960004467 ceftiofur sodium Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- WCZBUQIZTSIQFE-UHFFFAOYSA-N furan;thiophene Chemical compound C=1C=COC=1.C=1C=CSC=1 WCZBUQIZTSIQFE-UHFFFAOYSA-N 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000000643 oven drying Methods 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- COFDRZLHVALCDU-LICLKQGHSA-N s-(1,3-benzothiazol-2-yl) (2e)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoethanethioate Chemical compound N=1C2=CC=CC=C2SC=1SC(=O)/C(=N/OC)C1=CSC(N)=N1 COFDRZLHVALCDU-LICLKQGHSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 231100000004 severe toxicity Toxicity 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 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
- C07D501/36—Methylene radicals, substituted by sulfur atoms
-
- 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
- C07D501/04—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
- C07D501/06—Acylation of 7-aminocephalosporanic acid
-
- 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)
Abstract
The invention belongs to chemosynthesis technical fields, and in particular to a kind of Ceftiofur intermediate 7- amino -3- [(2- furyl-carbonyl)-sulfidomethyl] -3- cephem -4- carboxylic acid and Ceftiofur synthetic method.This method comprises the following steps：7-amino-cephalosporanic acid, thio-furan formic acid, solid base catalyst γ-Al are successively put into reaction kettle2O2‑O22‑Na+With zeolite and water, it is stirred to react 1.5-2.5h at room temperature, filtering, filtrate adjust pH to 5.5-6.5, filtering with appropriate hydrochloric acid, filter cake washes to obtain white solid, is dried in vacuo to obtain 7- amino -3- [(2- furyl-carbonyl)-sulfidomethyl] -3- cephem -4- carboxylic acid.This method takes water as a solvent, and reduces production cost and the product yield and purity produced are all higher, be conducive to the popularization of industrialized production.
Description
Technical field
The invention belongs to chemosynthesis technical fields, and in particular to the synthesis of a kind of Ceftiofur intermediate and Ceftiofur
Method.
Background technique
The chemical formula of Ceftiofur:C19H17N5O7S3, chemical name：(6R, 7R) -7- [2- (thiazolamine -4- base) -
(Z) -2- (methoxy imino) acetamido] -3- [(2- furyl carbonyl) sulfidomethyl] -3- cephem -4- carboxylic acid, structural formula
For：
。
Ceftiofur (Ceftiofur) is first third generation cephalosporin analog antibiotic dedicated for animal, by
Pharmacia & Upjohn is succeeded in developing.Since its antibacterial activity is strong, Pharmacokinetic Characteristics are excellent, toxic side effect is small, residual
It is low, it is widely used in the treatment of the bacteriosis such as ox, sheep, pig, dog, chicken all over the world.Ceftiofur is production hydrochloric acid cephalo
The pro-drug of thiophene furan or ceftiofur sodium can also be used separately as product.
7- amino -3- [(2- furyl-carbonyl)-sulfidomethyl] -3- cephem -4- carboxylic acid is the important of synthesis Ceftiofur
Intermediate, structural formula are.7- amino -3- [(2- furans
Base-carbonyl)-sulfidomethyl] -3- cephem -4- carboxylic acid purchase on the market it is relatively difficult, usually oneself synthesis.
Currently, the synthetic method of the intermediate of Ceftiofur reported in the literature is mainly the following：
United States Patent (USP) 5,387,679 reports the method being condensed under non-aqueous conditions, wherein 7-amino-cephalosporanic acid and heterocycle sulphur
Alcohol is condensed in the presence of the compound of boron trifluoride and dialkyl carbonate, is provided and is closed for cephalosporins
At intermediate.When this method is applied to the condensation of 7-amino-cephalosporanic acid and furyl -2- carbonyl mercaptan, reaction mixture
It associates with several impurity, is unable to get separation in last purification step.Later, after testing several times, I
Find that the stability of the furyl -2- carbonyl mercaptan of solid form is bad because furyl -2- carbonyl mercaptan belongs to heterocycle sulphur
Carbonyl acid rather than heterocyclic thiol class.The reflex action of thionic acid and mercaptan are dissimilar, therefore cannot be by United States Patent (USP) 5,387,679
Condition for the present invention.
Patent CN102234289A discloses a kind of 7- amino -3- [2- (furyl carbonyl) sulfidomethyl] -3- cephem -4-
The preparation method of carboxylic acid, specially：Under room temperature, in clean and dry reaction flask, ethyl acetate 20ml, 1ml third are put into
Acid opens stirring, then puts into 7-ACA15g, put into the ethyl acetate solution of the furans -2- carbothiolic acid of above-mentioned preparation.Heating
To 43-45 DEG C, 21ml boron trifluoride ethyl acetate is added.43-45 DEG C is maintained to react 2 hours.It is down to room temperature, is added
0.1gEDTA-2Na and 0.1g sodium pyrosulfite.Start to be slowly added dropwise 11% hydrochloric acid 15ml, reaction 1.0 in ice bath into feed liquid
Hour, filtering.Above-mentioned filter cake is suspended in 50ml tap water.It is 3.3-3.5 with 10% ammonium hydroxide adjustment pH value.It is stirred at room temperature
1 hour.It is separated by filtration, originally water washing 3 times, finally uses acetone washing 3 times, obtain powdered loose off-white color product, 35-
40 DEG C of oven dryings obtain Ceftiofur intermediate 7- amino -3- [2- (furyl carbonyl) sulfidomethyl] -3- cephem -4- carboxylic
Sour 18.3g, yield 97%, HPLC purity are 95%.With 7-amino-cephalosporanic acid in boron trifluoride ethyl acetate network in this method
It closes and is reacted under the catalysis of object with furans -2- carbothiolic acid, obtain intermediate through soda acid purification process, the intermediate that this method obtains is pure
Degree is high, still, after intermediate synthesizes, needs first finally to be used acetone washing 3 times, the production cycle with originally water washing 3 times
Long, consumption organic solvent-acetone is more, and acetone cannot recycle use, and plant area is caused to pollute, and high production cost is not suitable for industry
Change mass production.
A kind of 7- amino -3- [2- (furyl carbonyl) sulfidomethyl] -3- cephem -4- is disclosed in patent CN1639169A
The preparation method of carboxylic acid.Specially：Vulcanized sodium (54.6g) is added in water (600ml), at a temperature of 20 DEG C, 1.0
Furyl -2- dicarbonyl chloride (50.0g) is added in hour.Ethyl acetate is added thereto, is adjusted to the pH of material with hydrochloric acid
1.0.Organic layer is separated, is dried, filtered with anhydrous sodium sulfate, the furyl -2- carbonyl mercaptan in ethyl acetate is obtained.?
Ethyl acetate (350ml) is added in another flask, is passed through boron triflouride gas (124.0g) thereto.By 7- at 10.0 DEG C
Amino-cephalosporanic acid (91.0g) is added in the boron trifluoride solution, and furyl -2- carbonyl mercaptan is then added in ethyl acetate
In solution (made above).After stirring 4-5 hours at 30-40 DEG C, reaction is completed.After completion of the reaction, it will mix
Object is poured into ice cold water.Add ammonium hydroxide that the pH of solution is adjusted to 3.45-3.55.The solid of precipitating is filtered and is mixed with ethyl acetate
Object washing is closed, 7- amino -3- (2- furyl carbonyl) sulfidomethyl is obtained] -3- cephem -4- carboxylic acid (110.0g), HPLC is pure
Degree is 98-99%（CN1639169A embodiment 1）.In this method, 7-amino-cephalosporanic acid is under the catalysis of boron trifluoride etherate
With furans -2- carbonyl thiol reaction, intermediate is obtained through alkali process, the method high income, but boron trifluoride etherate and three
Boron fluoride gas catalysis operation difficulty in industrial production is big, has relatively high risk, because boron trifluoride has asphyxiating,
Moisture is met in air to hydrolyze immediately, the fluoride smog of severe toxicity is generated when decomposition, so the security requirement to operator
It is high.
Summary of the invention
In order to solve the above technical problems, the present invention provides a kind of synthetic method of Ceftiofur intermediate, the present invention
Using solid base catalyst γ-Al2O2-O22-Na+It, should with the condensation of zeolite catalysis 7-amino-cephalosporanic acid and thio-furan formic acid
Method production is simple, highly-safe, obtains product purity up to 99.2%, and yield is up to 99.0%.
The present invention is realized by following technical solutions：
A kind of synthetic method of Ceftiofur intermediate, the Ceftiofur intermediate are 7- amino -3- [(2- furyl-carbonyl
Base)-sulfidomethyl] -3- cephem -4- carboxylic acid, include the following steps：
7-amino-cephalosporanic acid, thio-furan formic acid, solid base catalyst γ-Al are successively put into reaction kettle2O2-O22-Na+With
Zeolite and water, are stirred to react 1.5-2.5h at room temperature, and filtering, filtrate adjust pH to 5.5-6.5, filtering, filter cake with appropriate hydrochloric acid
White solid is washed to obtain, 7- amino -3- [(2- furyl-carbonyl)-sulfidomethyl] -3- cephem -4- carboxylic acid is dried in vacuo to obtain.
Reaction equation is as follows：
。
In the synthetic method of above-mentioned Ceftiofur intermediate, the reaction dissolvent is water, the quality of the reaction dissolvent
It is 10-15 times of 7-amino-cephalosporanic acid quality.
In the synthetic method of above-mentioned Ceftiofur intermediate, the reaction dissolvent is water, the quality of the reaction dissolvent
It is 12.5 times of 7-amino-cephalosporanic acid quality.
In the synthetic method of above-mentioned Ceftiofur intermediate, the matter of the 7-amino-cephalosporanic acid and thio-furan formic acid
Amount is than being 1:1.3-1.7.
In the synthetic method of above-mentioned Ceftiofur intermediate, the matter of the 7-amino-cephalosporanic acid and thio-furan formic acid
Amount is than being 1:1.5.
In the synthetic method of above-mentioned Ceftiofur intermediate, the 7-amino-cephalosporanic acid and solid base catalyst γ-
Al2O2-O22-Na+Mass ratio be 1:0.05-0.10.
In the synthetic method of above-mentioned Ceftiofur intermediate, the γ-Al2O2-O22-Na+Preparation method be：It is filling
Have in the reaction flask of blender, 100g γ-Al is added2O3, stirring is opened, under nitrogen protection, is heated to 300 DEG C, heat preservation
12g metallic sodium is added in 45min, continues to stir 2h, slow cooling obtains blue or pewter powder catalyst γ-Al2O2-
O22-Na+。
In the synthetic method of above-mentioned Ceftiofur intermediate, the mass ratio of the 7-amino-cephalosporanic acid and zeolite is 1:
0.025-0.05。
In the synthetic method of above-mentioned Ceftiofur intermediate, the reaction time is 2h.
The synthetic method of the Ceftiofur of the synthetic method of Ceftiofur intermediate comprising preceding claim, step
It is as follows：
（1）The synthesis of 7- amino -3- [(2- furyl-carbonyl)-sulfidomethyl] -3- cephem -4- carboxylic acid
7-amino-cephalosporanic acid, thio-furan formic acid, solid base catalyst γ-Al are successively put into reaction kettle2O2-O22-Na+With
Zeolite and water, are stirred to react 1.5-2.5h at room temperature, and filtering, filtrate adjust pH to 5.5-6.5, filtering, filter cake with appropriate hydrochloric acid
White solid is washed to obtain, 7- amino -3- [(2- furyl-carbonyl)-sulfidomethyl] -3- cephem -4- carboxylic acid is dried in vacuo to obtain；
（2）The preparation of Ceftiofur
By 7- amino -3- [(2- furyl-carbonyl)-sulfidomethyl] -3- cephem -4- carboxylic acid adding into dichloromethane, stirring
- 5 DEG C are cooled to, triethylamine is slowly added dropwise at -5-0 DEG C of holding, 0.5-1.5h is added, and addition finishes, and is slowly added to AE- activity
Water is then added in ester, and after keeping 5-7 DEG C of reaction 3.5h, stratification separates water phase, organic to be added to purified water, stirring
15min separates water phase, is washed after merging water phase with methylene chloride, and water phase adds active 30 min of carbon decoloring, filters, filtrate is at 5 DEG C
PH value is adjusted to 2.5 with 4N hydrochloric acid solution, is filtered, filter cake is dissolved with (0-5 DEG C) of acetone, is added active carbon decoloring, is filtered out activity
Charcoal, by cold water（0-5℃）It is slowly dropped to crystallization in acetone soln, is filtered, is washed, it is dry, obtain Ceftiofur.
Compared with prior art, beneficial effects of the present invention are as follows：
（1）The synthetic method of 7- amino -3- [(2- furyl-carbonyl)-sulfidomethyl] -3- cephem -4- carboxylic acid of the invention, with
Water is solvent, reduces production cost and the product yield and purity produced are all higher, be conducive to pushing away for industrialized production
Extensively.
（2）The synthesis side of 7- amino -3- [(2- furyl-carbonyl)-sulfidomethyl] -3- cephem -4- carboxylic acid of the invention
In method, purification process is simple, washing, with short production cycle at low cost without using acetone and other organic solvent, is conducive to industry
Change mass production.
（3）The synthesis side of 7- amino -3- [(2- furyl-carbonyl)-sulfidomethyl] -3- cephem -4- carboxylic acid of the invention
In method, without using being the big gas of the big toxicity of the operation difficulties such as boron trifluoride etherate and boron triflouride gas, production difficulty
It is small, it is at low cost.
Specific embodiment
The present invention will be further explained combined with specific embodiments below, so that those skilled in the art knows more about
The present invention, but be not intended to limit the present invention.
Embodiment 1 Ceftiofur intermediate 7- amino -3- [(2- furyl-carbonyl)-sulfidomethyl] -3- cephem -4- carboxylic
The synthesis of acid
20kg7- amino-cephalo-alkanoic acid, 30kg thio-furan formic acid, 1kg solid base catalyst are successively put into 500L reaction kettle
γ-Al2O2-O22-Na+With 0.5kg zeolite and 250kg water, it is stirred to react 2h at room temperature, filtering, filtrate are adjusted with appropriate 6N hydrochloric acid
PH to 6, filtering, filter cake wash to obtain white solid, are dried in vacuo to obtain 7- amino -3- [(2- furyl-carbonyl)-sulfidomethyl] -3-
Cephem -4- carboxylic acid 37.1kg, yield 99.1%, purity 99.3%（HPLC）.
Embodiment 2 Ceftiofur intermediate 7- amino -3- [(2- furyl-carbonyl)-sulfidomethyl] -3- cephem -4- carboxylic
The synthesis of acid
20kg7- amino-cephalo-alkanoic acid, 30kg thio-furan formic acid, 2kg solid base catalyst are successively put into 500L reaction kettle
γ-Al2O2-O22-Na+With 1kg zeolite and 250kg water, it is stirred to react 2h, filtering, the appropriate 6N salt acid for adjusting pH of filtrate at room temperature
To 6, filtering, filter cake washes to obtain white solid, is dried in vacuo to obtain 7- amino -3- [(2- furyl-carbonyl)-sulfidomethyl] -3- head
Spore alkene -4- carboxylic acid 37.2kg, yield 99.2%, purity 99.4%（HPLC）.
Embodiment 3 Ceftiofur intermediate 7- amino -3- [(2- furyl-carbonyl)-sulfidomethyl] -3- cephem -4- carboxylic
The synthesis of acid
20kg7- amino-cephalo-alkanoic acid, 30kg thio-furan formic acid, 2kg solid base catalyst are successively put into 500L reaction kettle
γ-Al2O2-O22-Na+With 1kg zeolite and 250kg water, it is stirred to react 2h, filtering, the appropriate 6N salt acid for adjusting pH of filtrate at room temperature
To 6.5, filtering, filter cake washes to obtain white solid, is dried in vacuo to obtain 7- amino -3- [(2- furyl-carbonyl)-sulfidomethyl] -3-
Cephem -4- carboxylic acid 37.3kg, yield 99.4%, purity 99.2%（HPLC）
Embodiment 4
（1）The synthesis of Ceftiofur intermediate 7- amino -3- [(2- furyl-carbonyl)-sulfidomethyl] -3- cephem -4- carboxylic acid
20kg7- amino-cephalo-alkanoic acid, 30kg thio-furan formic acid, 2kg solid base catalyst are successively put into 500L reaction kettle
γ-Al2O2-O22-Na+With 1kg zeolite and 250kg water, it is stirred to react 2h, filtering, the appropriate 6N salt acid for adjusting pH of filtrate at room temperature
To 5.5, filtering, filter cake washes to obtain white solid, is dried in vacuo to obtain 7- amino -3- [(2- furyl-carbonyl)-sulfidomethyl] -3-
Cephem -4- carboxylic acid 37.1kg, yield 99.1%, purity 99.2%（HPLC）
（2）The synthesis of Ceftiofur
7- amino -3- [(2- furyl-carbonyl)-sulfidomethyl] -3- cephem -4- carboxylic acid 20kg is added to 300kg dichloromethane
In alkane, stirring is cooled to -5 DEG C, 11.9 kg of triethylamine is slowly added dropwise at -5-0 DEG C of holding, about 1h is added, and addition finishes, slowly
2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester 24.7kg is added, water 10kg is then added, after keeping 5-7 DEG C of reaction 3.5h, stratification separates water phase, has
Machine is added to 20kg purified water, stirs 15min, separates water phase, is washed after merging water phase with methylene chloride 15L, water phase adds activity
30 min of charcoal 2.5kg decoloration.Filter, filtrate adjusts pH value to 2.5 with 4N hydrochloric acid solution at 5 DEG C, filter, filter cake with acetone (
0-5 DEG C) 25kg dissolution, add active carbon 1.0kg to decolourize, active carbon is filtered out, by 100kg cold water（About 5 DEG C）It is slowly dropped to acetone
Crystallization in solution.Filtering, purified water rinsing, 40 DEG C of dryings of filter cake obtain 26.3k g, yield:85.7%, purity 98.1%
（HPLC）.
Claims (10)
1. a kind of synthetic method of Ceftiofur intermediate, the Ceftiofur intermediate is 7- amino -3- [(2- furyl-carbonyl
Base)-sulfidomethyl] -3- cephem -4- carboxylic acid, which is characterized in that include the following steps：
7-amino-cephalosporanic acid, thio-furan formic acid, solid base catalyst γ-Al are successively put into reaction kettle2O2-O22-Na+With
Zeolite and water, are stirred to react 1.5-2.5h at room temperature, and filtering, filtrate adjust pH to 5.5-6.5, filtering, filter cake with appropriate hydrochloric acid
White solid is washed to obtain, 7- amino -3- [(2- furyl-carbonyl)-sulfidomethyl] -3- cephem -4- carboxylic acid is dried in vacuo to obtain.
2. the synthetic method of Ceftiofur intermediate according to claim 1, which is characterized in that the reaction dissolvent is
Water, the quality of the reaction dissolvent are 10-15 times of 7-amino-cephalosporanic acid quality.
3. the synthetic method of Ceftiofur intermediate according to claim 1, which is characterized in that the reaction dissolvent is
Water, the quality of the reaction dissolvent are 12.5 times of 7-amino-cephalosporanic acid quality.
4. the synthetic method of Ceftiofur intermediate according to claim 1, which is characterized in that the 7- amino cephalo alkane
The mass ratio of acid and thio-furan formic acid is 1:1.3-1.7.
5. the synthetic method of Ceftiofur intermediate according to claim 1, which is characterized in that the 7- amino cephalo alkane
The mass ratio of acid and thio-furan formic acid is 1:1.5.
6. the synthetic method of Ceftiofur intermediate according to claim 1, which is characterized in that the 7- amino cephalo alkane
Acid and solid base catalyst γ-Al2O2-O22-Na+Mass ratio be 1:0.05-0.10.
7. the synthetic method of Ceftiofur intermediate according to claim 1, which is characterized in that the γ-Al2O2-O22-
Na+Preparation method be：In the reaction flask equipped with blender, 100g γ-Al is added2O3, stirring is opened, under nitrogen protection,
300 DEG C are heated to, 45min is kept the temperature, 12g metallic sodium is added, continues to stir 2h, slow cooling obtains blue or pewter
Powder catalyst γ-Al2O2-O22-Na+。
8. the synthetic method of Ceftiofur intermediate according to claim 1, which is characterized in that the 7- amino cephalo alkane
The mass ratio of acid and zeolite is 1:0.025-0.05.
9. the synthetic method of Ceftiofur intermediate according to claim 1, which is characterized in that the reaction time is
2h。
10. the synthetic method of the Ceftiofur of the synthetic method comprising any Ceftiofur intermediate of claim 1-9,
It is characterized in that, steps are as follows：
（1）The synthesis of 7- amino -3- [(2- furyl-carbonyl)-sulfidomethyl] -3- cephem -4- carboxylic acid
7-amino-cephalosporanic acid, thio-furan formic acid, solid base catalyst γ-Al are successively put into reaction kettle2O2-O22-Na+With
Zeolite and water, are stirred to react 1.5-2.5h at room temperature, and filtering, filtrate adjust pH to 5.5-6.5, filtering, filter cake with appropriate hydrochloric acid
White solid is washed to obtain, 7- amino -3- [(2- furyl-carbonyl)-sulfidomethyl] -3- cephem -4- carboxylic acid is dried in vacuo to obtain；
（2）The preparation of Ceftiofur
By 7- amino -3- [(2- furyl-carbonyl)-sulfidomethyl] -3- cephem -4- carboxylic acid adding into dichloromethane, stirring
- 5 DEG C are cooled to, triethylamine is slowly added dropwise at -5-0 DEG C of holding, 0.5-1.5h is added, and addition finishes, and is slowly added to AE- activity
Water is then added in ester, and after keeping 5-7 DEG C of reaction 3.5h, stratification separates water phase, organic to be added to purified water, stirring
15min separates water phase, is washed after merging water phase with methylene chloride, and water phase adds active 30 min of carbon decoloring, filters, filtrate is at 5 DEG C
PH value is adjusted to 2.5 with 4N hydrochloric acid solution, is filtered, filter cake is dissolved with (0-5 DEG C) of acetone, is added active carbon decoloring, is filtered out activity
Charcoal, by cold water（0-5℃）It is slowly dropped to crystallization in acetone soln, is filtered, is washed, it is dry, obtain Ceftiofur.
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| US20020065412A1 (en) * | 2000-11-27 | 2002-05-30 | Uthira Kumar | Cephalosporin compound and a process for its preparation |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20020065412A1 (en) * | 2000-11-27 | 2002-05-30 | Uthira Kumar | Cephalosporin compound and a process for its preparation |
Non-Patent Citations (2)
| Title |
|---|
| 曾裕建等: "头孢噻呋钠的制备", 《中国抗生素杂志》 * |
| 朱阳等: "头孢噻呋的合成", 《中国医药工业杂志》 * |
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