CN110294770A - A kind of cephalosporanic olefinic salt compound, preparation method and in the method for the compound synthesis Cefquinome - Google Patents
A kind of cephalosporanic olefinic salt compound, preparation method and in the method for the compound synthesis Cefquinome Download PDFInfo
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- 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
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- 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
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- 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
- C07D501/18—7-Aminocephalosporanic or substituted 7-aminocephalosporanic acids
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- 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
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Abstract
The present invention relates to a kind of cephalosporanic olefinic salt compounds, preparation method and in the method for the compound synthesis Cefquinome, the preparation method of cephalosporanic olefinic salt compound of the present invention is to use 7-ACA for starting material, with N, N- hexamethyldisilazane or trim,ethylchlorosilane carry out silanization protection to the amino on C4 carboxyls and the position C7, the acetoxyl group that Iodotrimethylsilane is added after protection to C3 carries out iodo, then 5 are added, 6, 7, 8- tetrahydroquinoline carries out nucleophilic substitution, it is eventually adding organic solvent and carries out crystallization, obtained product and acid ion is at salt, obtain cephalosporanic olefinic salt compound, cephalosporanic olefinic salt compound purity is high of the invention, quality is stablized, high income, it is a kind of new intermediate for synthesizing cephalo product, it is closed with the intermediate and AE active ester one pot reaction At Cefquinome, the solvent for reducing reaction step and using reduces production cost, has prevented and treated environmental pollution.
Description
Technical field
The present invention relates to a kind of cephalosporanic olefinic salt compound, preparation method and with the side of the compound synthesis Cefquinome
Method belongs to field of medicine and chemical technology.
Background technique
Cefquinome (cefquinome), entitled 1- [[(6R, the 7R) -7- [[(2Z)-(2- amino -4- thiazolyl) of chemistry
(methoxy imino) acetyl group] amino] -2- carboxyl -8- oxo -5- thia -1- azabicyclic [4,2,0] oct-2-ene -3- base]
Methyl] -5,6,7,8- tetrahydroquinoline inner salt.Its sulfate (cefquinome sulfate) is that German Hoechst company grinds
The first animal specific forth generation cephalosporins of hair list, at present by European Union's veterinary medicine for 1993 in Germany
The committee (CVMP) approval is used for respiratory system disease bacterium infection, mastitis for milk cows, sow postpartum syndrome and the family of animal
The treatment of bacterial disease in poultry, therapeutic effect are significantly and uneasy to recur after treatment.
Cefquinome is a kind of completely new aminothiazole oxidation of ketones imines cephalosporin, 4 valence nitrogen -5,6 on its position C3,
7,8- tetrahydroquinoline groups make it possess zwitterionic character, and the water solubility with height, this molecular structure can make cephalo quinoline
Oxime quick penetration, the electronegative micro channel of rapid osmotic Gram-negative bacteria outer membrane, to the maximum extent with penicillin fruit albumen
(PBPs) it combines, acylation occurs for beta-lactam open loop and bacterium, inhibits mucopeptide transpeptidase, and the transpeptidation reaction for being catalyzed it is not
It can be carried out, so that the formation of block cell wall, makes thallus lose protective barrier, large quantity of moisture penetrates into thallus in low-permeability environments
It is interior, make cellular swelling, deformation, rupture and dissolution and dies.The water of the beta-lactam of a variety of plasmids and chromosome medium is resisted simultaneously
Solution effect, shows as the low-affinity and high stability of beta-lactamase.
Cefquinome is as a kind of animal specific antibiotic, with antibacterial activity is strong, Pharmacokinetic Characteristics are excellent, malicious pair
The advantages of small, residual is low, bioavilability is high, has a broad antifungal spectrum is acted on, unique characteristic is by people's common concern.As
A kind of new drug for treating animal bacterial infection, Cefquinome have broad application prospects on China's veterinary clinic.
Synthesis report about Cefquinome has more documents and materials both at home and abroad.The primary raw material of synthesis Cefquinome has 7-
ACA or GCLE, 5,6,7,8- tetrahydroquinolines and AE active ester, according to documents and materials, the synthetic route of Cefquinome mainly has three
Item.
Synthetic route one: first synthesizing cefotaxime acid using 7-ACA and AE active ester as raw material, then with 5,6,7,8- tetrahydros
Quinoline reaction generates Cefquinome.
Synthetic route two: using 7-ACA as starting material, first with 5, the reaction of 6,7,8- tetrahydroquinolines is generated among parent nucleus
Then body reacts to obtain final product Cefquinome again with AE active ester.
The reaction equation of synthetic route one, two is shown in Formula II.
Synthetic route three: 7-ACA is replaced to synthesize Cefquinome as starting material using GCLE.The position C3 in GCLE molecular structure
Chloromethyl and 5,6,7,8- tetrahydroquinolines carry out substitution reaction and intermediate are made, then slough the protection of C7 bit amino and C4 carboxyls
Then group is reacted with AE active ester under alkaline condition, Cefquinome is made.The synthetic reaction formula of this route is shown in formula III
The route of above-mentioned synthesis Cefquinome, route of synthesis are different because of starting material difference.Select different startings
Raw material, process route, process conditions and the parameter of synthesis Cefquinome reagent and reaction condition for example used etc. are entirely different,
Its effect also can be different.
Synthetic route one, synthetic route two common ground be all using 7-ACA as starting material, difference is and AE active ester
It is different with 5,6,7,8- tetrahydroquinoline reaction sequence.
In synthetic route one, the C7 bit amino of 7-ACA is first reacted with AE active ester, and cefotaxime acid is made, then exists
Under the action of Iodotrimethylsilane, silanization protections are carried out to C4 carboxyls, then with 5,6,7,8- tetrahydroquinoline necleophilic reactions are obtained
To product Cefquinome.United States Patent (USP) US4845087 is exactly to synthesize Cefquinome using this route.It is used in synthesis process
A large amount of Iodotrimethylsilane and 5, the reagents such as 6,7,8- tetrahydroquinolines, and reaction condition anhydrous and oxygen-free is required, react item
Part is harsh, and reaction system is complicated, and generation impurity is more, and products obtained therefrom purity and color grade do not meet quality requirement.
In synthetic route two, and using 7-ACA as starting material, first its C4 carboxyl and C7 bit amino are protected
Shield, for the C3 position acetoxyl group of 7-ACA with 5 under the action of Iodotrimethylsilane, centre is made in the reaction of 6,7,8- tetrahydroquinolines
Then body reacts to obtain product Cefquinome again with AE active ester.United States Patent (USP) US4667028 uses this synthetic route.
In this synthetic route, large excess of Iodotrimethylsilane has been used to protect C4 position carboxyl in 7-ACA structure and C7
Cost has been significantly greatly increased in amino, and a large amount of by-product is generated in reaction process, increases the tired of subsequent product separating-purifying
Difficulty causes product yield low, of poor quality.
In synthetic route three, it is using GCLE (7-Phenylacetamido-3-chloromethylcephalosporanic acid p-methoxybenzyl ester)
Starting material.It is better than 3 acetyl-o-methyls in 7-ACA structure in view of the reactivity of 3 chloromethyls in GCLE structure, and
C4 carboxyls and C7 bit amino are all protected, so that the nucleophilic substitution of C3 progress is more single-minded.Although this route avoids
Iodotrimethylsilane use, but the subsequent reactions of sloughing that increase the blocking group on C4 and the position C7, reaction route extension,
Complex operation, the chemical raw material used increase, and cause side reaction more, target product yield is relatively low.
Since the raw material of synthesis cephalosporin has special construction, using some special reagents, cause to exist in synthesis
Many side reactions generate more by-product, to cause to isolate and purify difficulty, cause the yield of Cefquinome low.So not only
Make high production cost, and therefore environmental pollution, seeks the novel synthesis that Cefquinome has industrial value than more serious
Technique has great importance.
Summary of the invention
For the various deficiencies for solving synthesis Cefquinome technology, the present invention provides a kind of cephalosporanic olefinic salt compound,
Chemical name is 7- beta-amino -3- (5,6,7,8- tetrahydric quinoline group) methyl -3- cephem -4- carboxylate.
A second object of the present invention is to provide a kind of preparation methods of cephalosporanic olefinic salt compound.
Third object of the present invention is to provide a kind of methods with cephalosporanic olefinic salt compound synthesis Cefquinome.
Cefquinome is prepared by intermediate of cephalosporanic olefinic salt compound provided by the invention, reaction does not need expensive examination
Agent, reaction step is few, is not necessarily to special installation, reaction condition is mildly easily-controllable, high income, can control lower production cost and reduction
Environmental pollution is suitable for industrialized production, and Cefquinome obtained is with high purity, stable product quality.
The present invention is achieved through the following technical solutions:
A kind of cephalosporanic olefinic salt compound, chemical name are 7- beta-amino -3- (5,6,7,8- tetrahydric quinoline group) first
Base -3- cephem -4- carboxylate, structural formula are shown in formula I.
Wherein, X is acid radical anion, the acid radical anion be sulfate radical, acetate, nitrate anion, trifluoroacetic acid root,
One of alkyl azochlorosulfonate, chloride ion, bromide ion or iodide ion；N is 1 or 2；
The cephalosporanic olefinic salt compound is in the form of the free form of Formulas I or hydrate or solvate forms are deposited
?.
The compound described in Formulas I carries out structural identification, and confirming structure by nuclear magnetic resonance, mass spectrum and the measurements such as infrared is formula
I compound represented, following data are by taking compound sulfate as an example.
Nuclear magnetic resonance data is as follows:
1HNMR(500MHz,CDCl3),
δ 3.70,3.79 (d, J=7.5Hz, 2H, SCH2), 4.2 (ABq, J=13.5Hz, 1H N+CH2), 4.57 (ABq, J
=14.0Hz, 1H N+CH2), 5.12 (s, 3H, C-6, β-Lactam), 5.15 (s, 2H, COCH2), 5.41 (dd, J=4.0Hz, J
=8.5Hz, 1H, C-7, β-Lactam), 6.68 (m, 2H, COOCH2),8.48-8.90(m,9H,pyridninum-H)。
13CNMR(500MHz,CDCl3),
δ64.9,164.1,58.7,26.2,121.7,155.0,144.2,142.7,126.1,127.1,140.6,26.5,
28.6,23.0,22.7,161.9,49.1。
Its mass spectrometric data are as follows: MS [M+]444.50,[M++1]445.50。
Its infrared absorption peak data are as follows:
IR(KBr,Max,cm-1): 3416,3180,2948,2920,1775,1675,1612,1585,1455,1244.
A second object of the present invention is to provide a kind of preparation methods of cephalosporanic olefinic salt compound.
The preparation method of cephalosporanic olefinic salt compound of the present invention is to use 7-ACA for starting material, with N, N- hexamethyl
Disilazane or trim,ethylchlorosilane carry out silanization protection to the amino on C4 carboxyls and the position C7, and trimethyl is added after protection
Iodine silane carries out iodo to C3 acetoxyl groups, and 5,6,7,8- tetrahydroquinolines are then added and carry out nucleophilic substitution, finally
Organic solvent is added and carries out crystallization, obtained product and acid ion is at salt, to complete the system of compound shown in formula I
It is standby.
A kind of preparation method of cephalosporanic olefinic salt compound, comprises the following steps that
1) 7-ACA is protected with silylating reagent in organic solvent, obtains the 7-ACA reaction of silanization protection
Liquid；
2) Iodotrimethylsilane is added in the 7-ACA reaction solution protected to silanization and carries out iodide reaction, after obtaining iodo
Reaction solution, the reaction solution after iodo directly carry out in next step without isolation；
3) under the catalysis of organic amine, it is anti-that 5,6,7,8- tetrahydroquinolines progress nucleophilic displacement of fluorine is added to the reaction solution after iodo
It answers, after reaction, sloughs silanization blocking group, solvent is then added, solid is precipitated；
4) solid and acid ion being precipitated are added organic solvent crystallization, Formulas I compound represented can be obtained at salt.
Above-mentioned steps 1), step 2) reaction solution all without isolation, directly progress next step reaction.
Preferably, in step 1), the organic solvent is the mixing of nitrile, alkyl halide hydro carbons or nitrile and alkyl halide hydro carbons
Solvent.
Preferably, the nitrile is selected from acetonitrile；Alkyl halide hydro carbons appointing in methylene chloride, chloroform or carbon tetrachloride
Anticipating, two or more is mixed.
Preferably, in step 1), silylating reagent N, N- hexamethyldisilazane or trim,ethylchlorosilane and triethylamine
Mixing.
Preferably, in step 1), silylating reagent selects N, when N- hexamethyldisilazane, 7-ACA and N, N- hexamethyl
The molar ratio of disilazane be 1:0.5~20, it is preferred that the molar ratio of 7-ACA and N, N- hexamethyldisilazane be 1:0.5~
5。
Preferably, in step 1), when silylating reagent selects the mixing of trim,ethylchlorosilane and triethylamine, 7-ACA: front three
Base chlorosilane: the molar ratio of triethylamine is 1:0.5~10:0.5~10, it is preferred that 7-ACA: trim,ethylchlorosilane: triethylamine
Molar ratio is 1:0.5~5:0.5~5.
Preferably, in step 1), the mass volume ratio of 7-ACA and organic solvent are as follows: 1:(4~20), unit: g/mL is protected
Shield reaction for 0~45 DEG C reaction 1-5 hours.
Preferably, in step 2), the molar ratio of 7-ACA and Iodotrimethylsilane is 1:0.5~20, it is preferred that 7-ACA with
The molar ratio of Iodotrimethylsilane are as follows: 1:0.5~10, iodide reaction are to keep the temperature 0~10 DEG C reaction 3-6 hours.
Preferably, in step 3), organic amine is low-grade aliphatic amine, and preferred organic amine is triethylamine, tri-n-butylamine or positive fourth
Amine.
Preferably, in step 3), 7-ACA: organic amine: the molar ratio of 5,6,7,8- tetrahydroquinolines is 1:0.01~5:0.05
~20, it is preferred that 7-ACA: organic amine: the molar ratio of 5,6,7,8- tetrahydroquinolines is 1:0.01~2:0.5~10.
Preferably, in step 3), nucleophilic substitution is to react 10-20 hours at 0~10 DEG C.
Preferably, it in step 3), sloughs silanization blocking group and carries out sloughing silanization protecting group for alcohols solvent is added
Group.
Preferably, in step 3), be precipitated the solvent that solid is added be one or both of ketone, alkanes or ethers with
Upper mixing.
Preferably, in step 3), ketones solvent is acetone, methyl ethyl ketone or pentanone；Alkane solvents are petroleum ether, hexamethylene
Or heptane；Ether solvent is isopropyl ether or methyl tertiary butyl ether(MTBE).
Preferably, in step 4), salt-forming reaction temperature is -50~100 DEG C, it is preferred that salt-forming reaction temperature is -20~50
℃。
Preferably, in step 4), acid ion be sulfate radical, acetate, nitrate anion, trifluoroacetic acid root, alkyl azochlorosulfonate,
One of chloride ion, bromide ion or iodide ion.
Preferably, in step 4), the solid of precipitation and the molar ratio of acid ion are 1:0.5~50, it is preferred that precipitation
The molar ratio of solid and acid ion is 1:0.5~20.
The preparation method chemical equation of above-mentioned cephalosporanic olefinic salt compound is as shown in formula IV:
Third object of the present invention is to provide a kind of methods with cephalosporanic olefinic salt compound synthesis Cefquinome.
A method of Cefquinome being synthesized with cephalosporanic olefinic salt compound, using Formulas I compound represented as preparation
The intermediate of Cefquinome, this intermediate and AE active ester carry out condensation reaction, after reaction after progress acidizing crystal to obtain the final product
Cefquinome.
A method of Cefquinome is synthesized with cephalosporanic olefinic salt compound, is comprised the following steps that
Using one pot reaction, Formulas I compound represented is put into the mixed solvent of organic solvent or organic solvent and water
In, after being down to certain temperature, AE active ester is added into system and organic amine carries out condensation reaction, end of reaction, by extraction
Separation is added sulfuric acid into feed liquid or hydrochloric acid is acidified, and organic solvent is then added and carries out crystallization, cephalo quinoline can be obtained
Oxime.
In the method for synthesizing Cefquinome, condensation reaction reaction temperature is -100~100 DEG C, it is preferred that condensation reaction temperature
Degree is -50~50 DEG C；
In the method for synthesizing Cefquinome, Formulas I compound represented, AE active ester and sulfuric acid/hydrochloric acid molar ratio are 1:
0.5~10:0.1~50, it is preferable that Formulas I compound represented, AE active ester and sulfuric acid/hydrochloric acid molar ratio be proportion 1:0.5~
5:0.5~2.0.
In the method for synthesizing Cefquinome, organic solvent is that lower alcohols, nitrile, alkyl halide hydro carbons or their mixing are molten
Agent.
Preferably, lower alcohols are methanol, ethyl alcohol, isopropanol, normal propyl alcohol or n-butanol；Nitrile is acetonitrile；Halogenated alkane
Class is two or more any mixing in methylene chloride, chloroform or carbon tetrachloride.
In the method for synthesizing Cefquinome, organic amine used is triethylamine, tri-n-butylamine or n-butylamine.
In the method for synthesizing Cefquinome, crystallization organic solvent is ketone, alkanes or ethers.
Ketone is acetone, methyl ethyl ketone or pentanone；Alkanes are petroleum ether, hexamethylene, n-hexane or normal heptane；Ethers is different
Propyl ether, isopropyl ether, two or more any mixing in methyl tertiary butyl ether(MTBE).
It is shown as a formula V with the reactive chemistry formula of cephalosporanic olefinic salt compound synthesis Cefquinome:
During preparing Cefquinome, without separating intermediate product, reaction can be monitored with HPLC to fully reacting.
The beneficial effects of the present invention are develop the unique new process for preparing Cefquinome.The present invention provides such as Formulas I
Shown in cephalosporanic olefinic salt compound and Cefquinome is prepared by this compound.
Formulas I compound represented passes through Structure identification and determination, and product purity is high, and quality is stablized, and high income is a kind of conjunction
At the new intermediate of cephalo product, Cefquinome is synthesized with AE active ester one pot reaction with the intermediate, reduces reaction
Step and the solvent used, reduce production cost, have prevented and treated environmental pollution.
Cefquinome sulfate crystal form obtained by the present invention is good, good fluidity, and quality meets domestic and international pharmacopoeial requirements.
The present invention is prepared in Cefquinome method, and raw materials used reagent is cheap and easy to get, and process conditions are mildly easily-controllable, reaction letter
Single easy, reaction yield is high, is not necessarily to special installation, is suitble to industrialized production.
Detailed description of the invention
Fig. 1 is the HPLC map of a hydrochloride of compound prepared by embodiment 2；
Fig. 2 is the HPLC map of hydrochloric acid Cefquinome prepared by embodiment 5.
Specific embodiment
Below with reference to embodiment, the present invention is further illustrated, but can not be in this, as to the scope of the present invention
Limitation.
The dihydrochloride of 1 preparation formula I compound represented of embodiment
(1) 27.2g 7-ACA is put into 150ml methylene chloride, is cooled to 0~5 DEG C, 60 minutes used times dropwise addition 50ml
Triethylamine is added dropwise, and 27g trim,ethylchlorosilane is then added dropwise into feed liquid, was added dropwise within the used time 90 minutes, keeps the temperature 0~5 DEG C
Reaction 60 minutes, is filtered to remove solid, is washed with 50ml methylene chloride, merging filtrate；
(2) filtrate after merging is cooled to -10~-5 DEG C, 15ml triethylamine and 50g Iodotrimethylsilane, heat preservation is added
0~10 DEG C is reacted 3 hours.
(3) then into feed liquid be added 5,6,7,8- tetrahydroquinoline of 25g, insulation reaction 12 hours.Then it is dripped into feed liquid
Add isopropanol 800ml, solid is gradually precipitated, stirring is filtered after sixty minutes, isopropanol washing.It drains.
(4) obtained solid is added in 100ml water, concentrated hydrochloric acid 30ml is added, then active carbon is added in solid dissolution
5g, stirring decoloration 30 minutes, filtering.By gained filtrate added drop-wise into 1000ml isopropanol, solid, mistake after stirring 30 minutes is precipitated
Filter, appropriate isopropanol washing, is drained, and is placed in a vacuum drying oven drying at 40 DEG C, is obtained two hydrochloric acid of Formulas I compound represented
Salt about 28g, product purity 96%, molecular structure is as follows:
One hydrochloride of 2 preparation formula I compound represented of embodiment
(1) 27.2g 7-ACA is put into 150ml methylene chloride, is cooled to 0~5 DEG C, 30mlN, N- hexamethyl is added
Then feed liquid is warming up to 45 DEG C of back flow reactions 5 hours by disilazane and 0.1g iodine.
(2) feed liquid is cooled to 0~10 DEG C, is added triethylamine 15ml and 40g Iodotrimethylsilane, and insulation reaction 4 hours.
(3) then into feed liquid be added 5,6,7,8- tetrahydroquinoline of 25g, insulation reaction 15 hours.Then it is dripped into feed liquid
Add isopropanol 800ml, solid is gradually precipitated, stirring is filtered after sixty minutes, appropriate isopropanol washing.It drains.
(4) obtained solid is added in 100ml water, concentrated hydrochloric acid about 10ml is added, adjust material liquid pH 3.5 or so, Gu
Body dissolution.Then active carbon 5g, stirring decoloration 30 minutes, filtering is added.By gained filtrate added drop-wise into 800ml acetone, it is precipitated
Solid, stirring are filtered after 30 minutes, and proper amount of acetone washing is drained, and are placed in a vacuum drying oven drying at 40 DEG C, are obtained Formulas I institute
The a hydrochloride about 26g of the compound shown, product purity 96.8%, molecular structure is as follows:
Fig. 1 is the HPLC map of a hydrochloride compound of preparation.
The preparation of the toluenesulfonate of 3 Formulas I compound represented of embodiment
(1) 27.2g 7-ACA is put into 150ml methylene chloride, is cooled to 0~5 DEG C, 30mlN, N- hexamethyl is added
Disilazane and 0.1g iodine.Then feed liquid is warming up to 45 DEG C of back flow reactions 5 hours.
(2) feed liquid is cooled to 0~10 DEG C, is added triethylamine 15ml and 40g Iodotrimethylsilane, and insulation reaction 4 hours.
(3) then into feed liquid be added 5,6,7,8- tetrahydroquinoline of 25g, insulation reaction 15 hours.Then it is dripped into feed liquid
Add normal butane 800ml, solid is gradually precipitated, stirring is filtered after sixty minutes, appropriate normal butane washing.It drains.
(4) obtained solid is added in 120ml water, p-methyl benzenesulfonic acid about 20g is added, adjust material liquid pH 3.0~
3.5 or so, solid dissolution.Then active carbon 5g, stirring decoloration 30 minutes, filtering is added.By gained filtrate added drop-wise to 1200ml
In acetone, solid is precipitated, stirring is filtered after 30 minutes, and proper amount of acetone washing is drained, and is placed in a vacuum drying oven at 40 DEG C and is done
It is dry, the toluenesulfonate about 22g of Formulas I compound represented is obtained, product purity 95%, molecular structure is as follows:
The preparation of 4 Cefquinome sulfate of embodiment
Resulting Formulas I compound represented sulfate 20g is put into the mixed liquor of 100ml water and 100mlDMF, is dropped
AE active ester 30g is added to 5~10 DEG C in temperature, and n-butylamine about 30ml is then added dropwise, is added dropwise, feed clarification.5 DEG C of heat preservation anti-
It answers 4 hours, sampling HPLC detects qualified to reaction.
Methylene chloride 200ml × 3 is added into feed liquid to wash, retains water phase.40% sulfuric acid is added into gained water phase
20ml, is added active carbon 5g, stirring decoloration 30 minutes, then isopropanol 1500ml is added dropwise into filtrate, solid is precipitated for filtering.
Stirring 60 minutes, filtering, appropriate isopropanol washing drain, are dried under vacuum to moisture≤1.0% at 40 DEG C, obtain white sulfuric acid
Cefquinome about 22g, yield 83%, product purity 98.8%.
Fig. 2 is the HPLC map of the Cefquinome sulfate of preparation.
The preparation of 5 hydrochloric acid Cefquinome of embodiment
By the hydrochloride 15g and AE active ester 20g of Formulas I compound represented made from embodiment 2,200ml is put into
In methylene chloride, it is cooled to 0~5 DEG C, 90 minutes used times dropwise addition triethylamine 20ml is added dropwise, insulation reaction 4 hours.Sampling
HPLC detects qualified to reaction.Then purified water 200ml is added into feed liquid, extracting and demixing after stirring 15 minutes retains water phase.
Active carbon 3g, stirring decoloration 30 minutes, filtering, 30ml water washing filter cake are added into gained water phase.Merging filtrate,
Concentrated hydrochloric acid about 30ml is added into gained filtrate, stirs evenly, feed liquid is added drop-wise in 1800ml acetone, solid, stirring is precipitated
It is filtered after 45 minutes, proper amount of acetone washing drains, is dried under vacuum to moisture≤1.0% at 40 DEG C, obtains white hydrochloride cephalo quinoline
Oxime about 18g, yield 86%, product purity 98.5%.
Claims (10)
1. a kind of cephalosporanic olefinic salt compound, chemical name is 7- beta-amino -3- (5,6,7,8- tetrahydric quinoline group) methyl -
3- cephem -4- carboxylate, structural formula are shown in formula I:
Wherein, X is acid radical anion, and the acid radical anion is sulfate radical, acetate, nitrate anion, trifluoroacetic acid root, alkyl
One of sulfonate radical, chloride ion, bromide ion or iodide ion；N is 1 or 2；The cephalosporanic olefinic salt compound is with the free of Formulas I
Form or hydrate form or solvate forms exist.
2. a kind of preparation method of cephalosporanic olefinic salt compound, comprises the following steps that
1) 7-ACA is protected with silylating reagent in organic solvent, obtains the 7-ACA reaction solution of silanization protection；
2) Iodotrimethylsilane is added in the 7-ACA reaction solution protected to silanization and carries out iodide reaction, the reaction after obtaining iodo
Liquid, the reaction solution after iodo directly carry out in next step without isolation；
3) under the catalysis of organic amine, 5,6,7,8- tetrahydroquinolines is added to the reaction solution after iodo and carry out nucleophilic substitution,
After reaction, silanization blocking group is sloughed, solvent is then added, solid is precipitated；
4) solid and acid ion being precipitated are added organic solvent crystallization, Formulas I compound represented can be obtained at salt.
3. the preparation method of cephalosporanic olefinic salt compound according to claim 2, which is characterized in that in step 1), institute
Stating organic solvent is nitrile, alkyl halide hydro carbons or nitrile and alkyl halide hydro carbons mixed solvent；Preferably, the nitrile is selected from second
Nitrile；Two or more any mixing of alkyl halide hydro carbons in methylene chloride, chloroform or carbon tetrachloride.
4. the preparation method of cephalosporanic olefinic salt compound according to claim 2, which is characterized in that in step 1), silicon
Alkylators are N, the mixing of N- hexamethyldisilazane or trim,ethylchlorosilane and triethylamine.
5. the preparation method of cephalosporanic olefinic salt compound according to claim 4, which is characterized in that in step 1), silicon
Alkylators select N, when N- hexamethyldisilazane, the molar ratio of 7-ACA and N, N- hexamethyldisilazane be 1:0.5~
20, it is preferred that the molar ratio of 7-ACA and N, N- hexamethyldisilazane is 1:0.5~5；Silylating reagent selects trimethyl chlorine
When the mixing of silane and triethylamine, 7-ACA: trim,ethylchlorosilane: the molar ratio of triethylamine is 1:0.5~10:0.5~10, excellent
Choosing, 7-ACA: trim,ethylchlorosilane: the molar ratio of triethylamine is 1:0.5~5:0.5~5.
6. the preparation method of cephalosporanic olefinic salt compound according to claim 2, which is characterized in that in step 1), 7-
The mass volume ratio of ACA and organic solvent are as follows: 1:(4~20), unit: g/mL, protection reaction are small in 0~45 DEG C of reaction 1-5
When.
7. the preparation method of cephalosporanic olefinic salt compound according to claim 2, which is characterized in that in step 2), 7-
The molar ratio of ACA and Iodotrimethylsilane is 1:0.5~10, it is preferred that the molar ratio of 7-ACA and Iodotrimethylsilane are as follows: 1:
0.5~5, iodide reaction is to keep the temperature 0~10 DEG C reaction 3-6 hours.
8. the preparation method of cephalosporanic olefinic salt compound according to claim 2, which is characterized in that in step 3), have
Machine amine is low-grade aliphatic amine, and preferred organic amine is triethylamine, tri-n-butylamine or n-butylamine, 7-ACA: organic amine: 5,6,7,8- tetra-
The molar ratio of hydrogen quinoline is 1:0.01~5:0.05~20, it is preferred that 7-ACA: organic amine: mole of 5,6,7,8- tetrahydroquinolines
Than for 1:0.01~2:0.5~10, nucleophilic substitution is react 10-20 hour at 0~10 DEG C, precipitation solid addition it is molten
Agent is the mixing of one or more of ketone, alkanes or ethers.
9. the preparation method of cephalosporanic olefinic salt compound according to claim 2, which is characterized in that in step 4), at
Reactant salt temperature is -50~100 DEG C, it is preferred that salt-forming reaction temperature is -20~50 DEG C；Acid ion is sulfate radical, acetic acid
One of root, nitrate anion, trifluoroacetic acid root, alkyl azochlorosulfonate, chloride ion, bromide ion or iodide ion, the solid and acid group of precipitation from
The molar ratio of son is 1:0.5~50, it is preferred that the molar ratio of the solid of precipitation and acid ion is 1:0.5~20.
10. a kind of method with cephalosporanic olefinic salt compound synthesis Cefquinome, comprises the following steps that
Using one pot reaction, Formulas I compound represented is put into the in the mixed solvent of organic solvent or organic solvent and water, drop
To certain temperature, AE active ester and organic amine are added into system and carries out condensation reaction, end of reaction, by extraction and separation,
Sulfuric acid is added into feed liquid or hydrochloric acid is acidified, organic solvent is then added and carries out crystallization, Cefquinome can be obtained；
Synthesize Cefquinome method in, condensation reaction reaction temperature be -100~100 DEG C, it is preferred that setting-up point be -
50~50 DEG C；Formulas I compound represented, AE active ester and sulfuric acid/hydrochloric acid molar ratio are 1:0.5~10:0.1~50, it is preferable that
Formulas I compound represented, AE active ester and sulfuric acid/hydrochloric acid molar ratio are proportion 1:0.5~5:0.5~2.0；Organic solvent is
Lower alcohols, nitrile, alkyl halide hydro carbons or their mixed solvent；Lower alcohols be methanol, ethyl alcohol, isopropanol, normal propyl alcohol or
N-butanol；Nitrile is acetonitrile；Alkyl halide hydro carbons is that any two or more in methylene chloride, chloroform or carbon tetrachloride mixes
It closes；Organic amine used is triethylamine, tri-n-butylamine or n-butylamine；Crystallization organic solvent is ketone, alkanes or ethers.
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