CN106046026B - A kind of preparation method of cefteram pivoxil - Google Patents
A kind of preparation method of cefteram pivoxil Download PDFInfo
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- CN106046026B CN106046026B CN201610505011.4A CN201610505011A CN106046026B CN 106046026 B CN106046026 B CN 106046026B CN 201610505011 A CN201610505011 A CN 201610505011A CN 106046026 B CN106046026 B CN 106046026B
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- 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
- C07D501/48—Methylene radicals, substituted by hetero rings
- C07D501/56—Methylene radicals, substituted by hetero rings with the 7-amino radical acylated by carboxylic acids containing hetero rings
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- 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
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- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The present invention relates to a kind of preparation method of cefteram pivoxil, specific method is:Using 7 ACA as raw material, with 5 methyl tetrazoles through BF3Tetrahydrofuran complex catalysis is prepared into 7 MTCA;7 MTCA are reacted with AE active ester is prepared T-2525;T-2525 is prepared into Cefteram sodium salt;Sodium salt after refined carries out esterification with iodometyl pivalate again, obtains cefteram pivoxil.The present invention is easy to operate, and reaction condition is mild, and the product impurity content being prepared is low, and high income is conducive to industrialized production.
Description
Technical field
The present invention relates to antibiotic to synthesize field, more particularly to a kind of preparation method of cefteram pivoxil.
Background information
Cefteram pivoxil is in one kind of early 1990s exploitation listing by Japan folic hill Chemical Co., Ltd.
Oral third-generation cephalosporin, for light yellow or near-white solid, odorless or slightly special stink, bitter;The grade is soluble in second
Nitrile, methanol, chloroform or dilute hydrochloric acid, are soluble in ethyl alcohol, are insoluble in ether, are practically insoluble in water.
The product chemistry is entitled:(6R, 7R) -7- [(Z) -2- (2- amino -4- thiazolyls) -2- (methoxyimino) acetyl ammonia
Base] and -3- [2- (5- methyl -2H- tetrazolium -2- bases) methyl) -8- oxos -5- thia -1- azabicyclos [4,2,0] oct-2-ene -2-
Carboxylic acid pivaloyl oxygen methyl esters
Chemical formula is as follows:
The mechanism of action of this product be block bacteria cell wall row into, have antibacterial action to gram positive bacteria, negative bacterium,
Especially in gram positive bacteria streptococcus, pneumococcus, Escherichia coli, Klebsiella in gram-negative bacteria and
Gonococcus, haemophilus influenzae and anaerobism bacterial ooze hammer category etc. have very strong antibacterial action, in addition to taking orally cephalo preparation in the past
(pioneer No. IV, Cefaclor) insensitive Serratia, indole-positive proteus, Enterobacter, citric acid Pseudomonas etc.
Show good antibacterial action.
It at present about the synthetic method of cefteram pivoxil, has been reported that both at home and abroad, as disclosed in US 5144027
Such as the preparation route of following reaction equation 1,7-ACA passes through BF with 5- methyl tetrazoles in the route3It is prepared by etherate catalysis
It obtains and contains more isomer impurities in 7-MTCA;In addition, when 7-MTCA 2 carboxylation reactions of progress obtain intermediate compound I, due to
The easy moisture absorption of intermediate compound I requires condition of storage stringent;During last 7 bit amino acylation reaction, reaction is also incomplete, causes product
Purity is relatively low.
The preparation method of cepham antibiotics and its intermediate is disclosed in CN 1962666A, reaction route is as reacted
Shown in formula 2:This method is with BF3Gas is catalyst preparation 7-MTCA, but bottled BF3Gas is explosive dangerous material, to industrial metaplasia
Production brings hidden danger;On the other hand since cefteram pivoxil is easily degraded under alkaline environment, impurity isomers is generated,
So the product purity about 96% that T-2525 is obtained in direct carboxylation reaction under the action of alkali compounds DBU, is received
Rate is less than 60%, is unfavorable for industrialized production.
The preparation method of cephalosporin analog antibiotic, for example following 3 institute of reaction equation of this method are disclosed in patent CN 1763046A
Show:D-7ACA is after the acylation of 7 bit aminos, 2 carboxylation reactions, and 3 hydroxyls are using iodide reaction and four nitrogen of 5- methyl
Azoles reacts, and final product is prepared, but this method route is complicated, causes yield relatively low, need to pass through a step column purification, to industrialization
Production brings difficulty.
It is disclosed in synthesis (2014, Chinese antibiotic magazine) document of cefteram pivoxil in addition, stone gram gold is waited
Its preparation method, reaction equation as indicated at 4, utilize BF in this method3.DMC complex compound prepares 7-MTCA, and obtained product is received
Relatively low rate is only 77.8%, purity 98.1%;On the other hand during special logical sequence acid prepares special logical sequence peopentyl ester, sodium methoxide is used
Alkaline reagent is done, alkalinity is too strong, is easy to cause cefteram pivoxil Δ3Isomers generates:
In conclusion cefteram pivoxil is usually using 7-ACA as raw material, through BF3Gas or BF3Ether, carbonic acid diformazan
Ester complex catalysis prepares 7-MTCA, but the 7-MTCA yields that this method obtains are relatively low, and impurity content of isomer is larger (such as formula 1
It is shown), and the refined removing of subsequent reaction is cannot pass through, and then the cefteram pivoxil prepared does not meet standards of pharmacopoeia;Separately
On the one hand, the basic catalysts such as sodium methoxide, DBU are used during T-2525 prepares cefteram pivoxil, easily
Lead to cefteram pivoxil Δ3Isomers generates (as shown in Equation 2), influences product purity, is unfavorable for industrial production.
Invention content
In order to overcome the problems referred above, the present invention realizes the new preparation method of cefteram pivoxil using following technical scheme:
A kind of preparation method of cefteram pivoxil, includes the following steps:
7-ACA is dissolved in tetrahydrofuran by step (1), adds in BF3Tetrahydrofuran complex adds four nitrogen of 5- methyl
Azoles, 20-65 DEG C of temperature control react 3-10h, through being quenched, post-process to obtain 7-MTAC;
The 7-MTCA and 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester that are prepared in step (1) are dissolved in dichloromethane by step (2), and triethylamine, control is added dropwise
10 DEG C of reaction 2-4h of temperature, post processing crystallization obtain T-2525;Molar ratio between the 7-MTCA, 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester, triethylamine
For:1:1-1.5:1-1.8;
The T-2525 prepared in step (2) is dissolved in methanol by step (3), addition sodium iso-octoate, and temperature control -20~
20 DEG C, 0.5~8h is reacted, solvent A is added dropwise after reaction, crystallization post-processes to obtain Cefteram sodium salt;
The Cefteram sodium salt prepared in step (3) is dissolved in solvent B by step (4), is added dropwise iodometyl pivalate, and temperature control-
40~0 DEG C, 0.5~4h is reacted, reaction solution is post-treated, is added dropwise in isopropyl ether, and crystallization obtains cefteram pivoxil;Specifically
Reaction equation is as follows:
Wherein, 7-ACA, 5- methyl tetrazole and BF in step (1)3The molar ratio of tetrahydrofuran complex is 1:1.2-
1.5:2-4;Preferable reaction temperature is 55-65 DEG C, preferred reaction time 3-5h;
Wherein, T-2525 and sodium iso-octoate molar ratio are 1 in step (3):1-2;Solvent A is ether, acetone, acetic acid
One kind in ethyl ester, ethyl alcohol, isopropanol, preferred solvent A are ethyl alcohol;Preferable reaction temperature is 0~10 DEG C, and preferred reaction time is
2-4h;
The molar ratio of Cefteram sodium salt and iodometyl pivalate is 1 in step (4):1-1.5;Solvent B is sub- for dimethyl
One kind in sulfone, n,N-Dimethylformamide, n,N-dimethylacetamide;Preferred solvent B is n,N-dimethylacetamide;It is preferred that
Reaction temperature is -10~0 DEG C, preferred reaction time 1-2h;
Preferably, 7-ACA in step 1:5- methyl tetrazoles:BF3The molar ratio of tetrahydrofuran complex is=1:1.3:
3;7-MTCA in step 2:2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester:The molar ratio of triethylamine is=1:1.2:1.5;T-2525 in step 3:It is different pungent
The molar ratio of sour sodium is=1:1.5;Cefteram sodium salt in step 4:The molar ratio of iodometyl pivalate is=1:1.2.
Beneficial effects of the present invention:
1) using 7-ACA as raw material, with BF3Tetrahydrofuran complex is catalyst preparation 7-MTCA, and obtained 7-MTCA is received
Rate can reach 85%, and more than 99% purity, isomer impurities are less than 0.1%;
2) it is prepared into after Cefteram sodium salt by T-2525 and carries out esterification again Cefteram is prepared
Peopentyl ester increases a step salt-forming reaction, and the sodium salt after refining is reacted with iodometyl pivalate again, and reaction environment is mild, behaviour
It is simple to make step, avoids, using basic catalyst, effectively preventing the generation of degradation impurity, the product yield of preparation can reach
To more than 80%, purity is more than 98.5%, while Δ3Isomer impurities content is less than 0.2%, less than Δ in listing preparation3
(0.5%), it conforms to quality requirements, is conducive to industrialized production.
Abbreviation meaning used in specification and claims is as follows:
7-ACA | 7-amino-cephalosporanic acid |
7-MTCA | Cefteram parent nucleus |
BF3Tetrahydrofuran complex | Boron trifluoride tetrahydrofuran complex compound |
DBU | 1,8- diazabicyclos [5,4,0] hendecene |
TEA | Triethylamine |
D-7ACA | D-7-ACA |
Embodiment:
Below by non-limiting example, the present invention will be described
Embodiment 1
Step (1), by 37g (0.44mol) pentamethyl tetrazoles and 101gBF3Tetrahydrofuran complex (0.74mol) adds
Enter into 1000mL tetrahydrofurans, add 100g 7-ACA (0.368mol), control temperature is reacted 10 hours at 20 DEG C, is added dropwise
700mL water 300mLDCM stirs liquid separation, and water phase adjusts pH=2.9 with 10% ammonium hydroxide, and crystallization obtains 7-MTCA, and 45 DEG C of dry 8h are obtained
To 95g products, yield 87%, purity 99.2%, isomer impurities 0.08%, moisture 0.4%;
Step (2), by 7-MTCA 80g (0.27mol), (0.27mol0 is added to 800mL dichloromethanes to AE active ester 94.5g
In alkane, triethylamine 28.3g (0.27mol) is added dropwise, 10 DEG C of temperature control reacts 4 hours, adds in the extraction liquid separation of 500mL water, water phase salt
Acid is adjusted to pH=2.6, and crystallization obtains T-2525, and 45 DEG C of dry 10h obtain 109g, yield 85%, purity 99.3%, moisture
0.3%;
500mL methanol is cooled to -20 DEG C by step (3), adds in T-2525 100g (0.21mol) and 35g
(0.21mol) sodium iso-octoate, temperature control reaction 8h after, into solution be added dropwise 1800mL diethyl ether solutions, crystallization 1h, filtering, filter cake with
Ether washs, and under the conditions of 55 DEG C, vacuum degree 0.095MPa, is dried in vacuo and obtains Cefteram sodium salt 91.5g, yield 87%,
Purity 99.2%, moisture 0.03%;
800ml n,N-Dimethylformamide is cooled to -40 DEG C by step (4), adds in Cefteram sodium salt 90g
Iodometyl pivalate 43.5g (0.18mol) is added dropwise in (0.18mol), and -40 DEG C of temperature control reacts 4 hours, and dichloro is added in reaction solution
Methane 800ml and purified water 600ml, organic phase are added drop-wise in 2000ml isopropyl ethers, and crystallization 0.5h obtains product;In 45 DEG C, very
Under the conditions of reciprocal of duty cycle 0.095MPa, it is dried to obtain cefteram pivoxil 84.5gg, yield 81%, purity 98.9%, Cefteram
Peopentyl ester Δ3Isomer impurities 0.18%.
Embodiment 2
Step (1), by 40g (0.478mol) pentamethyl tetrazoles and 151gBF3Tetrahydrofuran complex (1.1mol) adds
Enter into 1000mL tetrahydrofurans, add 100g 7-ACA (0.368mol), control temperature is reacted 6 hours at 55 DEG C, is added dropwise
750mL water 350mLDCM stirs liquid separation, and water phase adjusts pH=2.8 with 10% ammonium hydroxide, and crystallization obtains 7-MTCA, and 45 DEG C of dry 8h are obtained
To 103.5g products, yield 95%, purity 99.5%, isomer impurities 0.03%, moisture 0.5%;
Step (2), by 7-MTCA 80g (0.27mol), AE active ester 112g (0.324mol) is added to 800mL dichloromethanes
In alkane, triethylamine 41.4g (0.405mol) g is added dropwise, 10 DEG C of temperature control reacts 4 hours, adds in the extraction liquid separation of 500mL water, and water phase is used
Hydrochloric acid is adjusted to pH=2.6-2.9, and crystallization obtains T-2525, and 45 DEG C of dry 10h obtain 120g, yield 93%, purity
99.3%, moisture 0.3%;
500mL methanol is cooled to 5 DEG C by step (3), adds in T-2525 100g (0.21mol) and 51.5g isooctyl acids
After temperature control reacts 3h, 2100mL ethanol solutions are added dropwise into solution for sodium (0.31mol), and crystallization 1h is filtered, and filter cake is washed with ethyl alcohol
It washs, under the conditions of 55 DEG C, vacuum degree 0.098MPa, vacuum drying obtains Cefteram sodium salt 97g, yield 92.7%, purity
99.4%, moisture 0.06%;
Step (4), by 800mLN, N- dimethylacetamides are cooled to -5 DEG C, add in Cefteram sodium salt 90g (0.18mol),
Iodometyl pivalate 52.2g (0.216mol) is added dropwise, -5 DEG C of temperature control reacts 1 hour, added in reaction solution dichloromethane 800ml and
Purified water 400ml, organic phase are added drop-wise in 2000ml isopropyl ethers, and crystallization 0.5h obtains product, in 45 DEG C, vacuum degree 0.096MPa
Under the conditions of, it is dried to obtain cefteram pivoxil 95.8g, yield 92%, purity 99%, cefteram pivoxil Δ3Isomers
Impurity 0.03%.
Embodiment 3
Step (1), by 46g (0.55mol) pentamethyl tetrazoles and 150g (202g) BF3Tetrahydrofuran complex is added to
In 1000mL tetrahydrofurans, 100g 7-ACA (0.368mol) are added, control temperature is reacted 3 hours at 65 DEG C, and 800mL is added dropwise
Water 300mLDCM stirs liquid separation, and water phase adjusts pH=2.8 with 10% ammonium hydroxide, and crystallization obtains 7-MTCA, and 45 DEG C of dry 8h are obtained
101g products, yield 93%, purity 99.1%, isomer impurities 0.05%, moisture 0.5%;
Step (2), by 7-MTCA 80g (0.27mol), AE active ester 143.5g (0.41mol) is added to 800mL dichloros
In methane, triethylamine 49.5g (0.49mol) is added dropwise, 10 DEG C of temperature control reacts 3 hours, adds in the extraction liquid separation of 500mL water, and water phase is used
Hydrochloric acid is adjusted to pH=2.8, and crystallization obtains T-2525, and 45 DEG C of dry 10h obtain 117.5g, yield 91%, purity 99.3%,
Moisture 0.3%;
500mL methanol is cooled to 20 DEG C by step (3), adds in T-2525 100g (0.21mol) and 70g
After temperature control reacts 0.5h, 2000mL aqueous isopropanols are added dropwise into solution for (0.42mol) sodium iso-octoate, and crystallization 1h is filtered, filter
Cake is washed with isopropanol, and under the conditions of 55 DEG C, vacuum degree 0.097MPa, vacuum drying obtains Cefteram sodium salt 95g, yield
90.8%, purity 99%, moisture 0.02%;
800mL dimethyl sulfoxide (DMSO)s are cooled to 0 DEG C by step (4), add in Cefteram sodium salt 90g (0.18mol), are added dropwise
Iodometyl pivalate 65.3 (0.27mol) g, 0 DEG C of temperature control react 0.5 hour, and dichloromethane 600ml and purifying are added in reaction solution
Water 400ml, organic phase are added drop-wise in 2000ml isopropyl ethers, and crystallization 0.5h obtains product, in 45 DEG C, vacuum degree 0.095MPa conditions
Under, it is dried to obtain cefteram pivoxil 94g, yield 89.5%, purity 99%, cefteram pivoxil Δ3Isomer impurities
0.11%.
Embodiment 4
Step (1), by 40g (0.48mol) pentamethyl tetrazoles and 175gBF3Tetrahydrofuran complex (1.29mol) adds
Enter into 1000mL tetrahydrofurans, add 100g 7-ACA (0.368mol), control temperature is reacted 4 hours at 60 DEG C, is added dropwise
600mL water 4000mLDCM stirs liquid separation, and water phase adjusts pH=2.7 with 10% ammonium hydroxide, and crystallization obtains 7-MTCA, 45 DEG C of dry 8h
Obtain 98g products, yield 90%, purity 99.1%, isomer impurities 0.07%, moisture 0.4%;
Step (2), by 7-MTCA 80g (0.27mol), AE active ester 132g (0.378mol) is added to 850mL dichloromethanes
In alkane, triethylamine 38.2g (0.378mol) g is added dropwise, 10 DEG C of temperature control reacts 4 hours, adds in the extraction liquid separation of 550mL water, and water phase is used
Hydrochloric acid is adjusted to pH=2.7, and crystallization obtains T-2525, and 45 DEG C of dry 10h obtain 118g, yield 91.4%, purity 99%, water
Divide 0.3%;
500mL methanol is cooled to 0 DEG C by step (3), adds in T-2525 100g (0.21mol) and 41.8g isooctyl acids
Sodium (0.252mol) after temperature control reacts 4h, 2100mL ethyl acetate solutions is added dropwise into solution, crystallization 1h, filtering, filter cake is with second
Acetoacetic ester washs, and under the conditions of 55 DEG C, vacuum degree 0.098MPa, vacuum drying obtains Cefteram sodium salt 95g, yield
90.5%, purity 99.2%, moisture 0.06%;
Step (4), by 800mLN, N- dimethylacetylamides are cooled to -10 DEG C, add in Cefteram sodium salt 90g
Iodometyl pivalate 56.6g (0.234mol) is added dropwise in (0.18mol), and -10 DEG C of temperature control reacts 2 hours, and dichloro is added in reaction solution
Methane 750ml and purified water 400ml, organic phase are added drop-wise in 2000ml isopropyl ethers, and crystallization 0.5h obtains product, in 45 DEG C, very
Under the conditions of reciprocal of duty cycle 0.096MPa, it is dried to obtain cefteram pivoxil 94g, yield 90%, purity 99.1%, Cefteram new penta
Ester Δ3Isomer impurities 0.09%.
Embodiment 5
Step (1), by 34g (0.4mol) pentamethyl tetrazoles and 125gBF3Tetrahydrofuran complex (1.29mol) adds in
Into 900mL tetrahydrofurans, 100g 7-ACA (0.368mol) are added, control temperature is reacted 7 hours at 45 DEG C, is added dropwise
600mL water 4000mLDCM stirs liquid separation, and water phase adjusts pH=2.6 with 10% ammonium hydroxide, and crystallization obtains 7-MTCA, 45 DEG C of dry 10h
Obtain 99g products, yield 91%, purity 99.1%, isomer impurities 0.06%, moisture 0.3%;
Step (2), by 7-MTCA 80g (0.27mol), AE active ester 104g (0.297mol) is added to 900mL dichloromethanes
In alkane, triethylamine 43.6g (0.432mol) g is added dropwise, 10 DEG C of temperature control reacts 4 hours, adds in the extraction liquid separation of 650mL water, and water phase is used
Hydrochloric acid is adjusted to pH=2.8, and crystallization obtains T-2525, and 45 DEG C of dry 8h obtain 115g, yield 89%, purity 99%, moisture
0.3%;
500mL methanol is cooled to 10 DEG C by step (3), adds in T-2525 100g (0.21mol) and 48.8g is different pungent
Sour sodium (0.294mol) after temperature control reacts 2h, 2100mL acetone solns is added dropwise into solution, crystallization 1h, filtering, filter cake is with acetone
Washing, under the conditions of 50 DEG C, vacuum degree 0.098MPa, vacuum drying obtains Cefteram sodium salt 95.5g, yield 91%, purity
99%, moisture 0.08%;
Step (4), by 800mLN, N- dimethylacetylamides are cooled to 0 DEG C, add in Cefteram sodium salt 90g
Iodometyl pivalate 47.9g (0.198mol) is added dropwise in (0.18mol), and 0 DEG C of temperature control reacts 1 hour, and dichloromethane is added in reaction solution
Alkane 800ml and purified water 500ml, organic phase are added drop-wise in 2000ml isopropyl ethers, and crystallization 0.5h obtains product, in 45 DEG C, vacuum
It spends under the conditions of 0.096MPa, is dried to obtain cefteram pivoxil 95g, yield 91%, purity 99%, cefteram pivoxil
Δ3Isomer impurities 0.05%.
Claims (8)
1. a kind of preparation method of cefteram pivoxil, which is characterized in that include the following steps:
7-ACA is dissolved in tetrahydrofuran by step (1), adds in BF3Tetrahydrofuran complex adds 5- methyl tetrazoles, control
Warm 55-65 DEG C, 3-10h is reacted, through being quenched, post-processes to obtain 7-MTAC;
The 7-MTCA and 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester that are prepared in step (1) are dissolved in dichloromethane by step (2), and triethylamine, temperature control 10 is added dropwise
DEG C reaction 2-4h, post processing crystallization obtain T-2525;Molar ratio between the 7-MTCA, 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester, triethylamine is:
1:1-1.5:1-1.8;
The T-2525 prepared in step (2) is dissolved in methanol by step (3), addition sodium iso-octoate, 0~10 DEG C of temperature control, instead
2~4h is answered, solvent A is added dropwise after reaction, crystallization post-processes to obtain Cefteram sodium salt;
The Cefteram sodium salt prepared in step (3) is dissolved in solvent B by step (4), is added dropwise iodometyl pivalate, and temperature control -40~
0 DEG C, 0.5~4h is reacted, reaction solution is post-treated, is added dropwise in isopropyl ether, and crystallization obtains cefteram pivoxil;Specific reaction
Formula is as follows:
2. according to a kind of preparation method of cefteram pivoxil described in claim 1, which is characterized in that institute in step (1)
State 7-ACA, 5- methyl tetrazole and BF3The molar ratio of tetrahydrofuran complex is 1:1.2-1.5:2-4.
3. according to a kind of preparation method of cefteram pivoxil described in claim 1, which is characterized in that excellent in step (1)
It is 3-5h to select the reaction time.
4. according to a kind of preparation method of cefteram pivoxil described in claim 1, which is characterized in that institute in step (3)
It is 1 that T-2525, which is stated, with sodium iso-octoate molar ratio:1-2;The solvent A is ether, acetone, ethyl acetate, ethyl alcohol, isopropanol
In one kind.
5. according to a kind of preparation method of cefteram pivoxil described in claim 1, which is characterized in that institute in step (4)
The molar ratio for stating Cefteram sodium salt and iodometyl pivalate is 1:1-1.5;The solvent B is dimethyl sulfoxide (DMSO), N, N- diformazans
One kind in base formamide, n,N-dimethylacetamide.
6. according to a kind of preparation method of cefteram pivoxil described in claim 1, which is characterized in that in step (3)
Preferred solvent A is ethyl alcohol.
7. according to a kind of preparation method of cefteram pivoxil described in claim 1, which is characterized in that excellent in step (4)
It is n,N-dimethylacetamide to select solvent B;Preferable reaction temperature is -10~0 DEG C, preferred reaction time 1-2h.
8. according to a kind of preparation method of cefteram pivoxil described in claim 1, it is characterised in that:7- in step 1
ACA:5- methyl tetrazoles:BF3The molar ratio of tetrahydrofuran complex is=1:1.3:3;7-MTCA in step 2:AE- activity
Ester:The molar ratio of triethylamine is=1:1.2:1.5;T-2525 in step 3:The molar ratio of sodium iso-octoate is=1:1.5;Step
Cefteram sodium salt in rapid 4:The molar ratio of iodometyl pivalate is=1:1.2.
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