CN109956958A - A kind of 7- amino -3- methoxy -3- cephem -4- carboxylic acid synthetic method - Google Patents
A kind of 7- amino -3- methoxy -3- cephem -4- carboxylic acid synthetic method Download PDFInfo
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- CN109956958A CN109956958A CN201910263131.1A CN201910263131A CN109956958A CN 109956958 A CN109956958 A CN 109956958A CN 201910263131 A CN201910263131 A CN 201910263131A CN 109956958 A CN109956958 A CN 109956958A
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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
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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
- C07D501/12—Separation; Purification
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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
- C07D501/18—7-Aminocephalosporanic or substituted 7-aminocephalosporanic acids
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Abstract
The invention discloses a kind of 7- amino -3- methoxy -3- cephem -4- carboxylic acid synthetic methods, under organic solvent environment, 7- amino -3- methylol -3- cephem -4- carboxylic acid D-7-ACA is catalyzed by strong protonic acid to be reacted with alkylating reagent, generate 7- amino -3- methoxy -3- cephem -4- carboxylic acid 7-AMCA, and solution is precipitated lower than the addition by-product into reaction solution is immediately begun to after critical value in the weight content of 7- amino -3- methylol -3- cephem -4- carboxylic acid, the by-product salt of precipitation recycles after filtering.Strongly acidic catalyst is precipitated in a salt form in the phase to this technology route after the reaction, reduces the recovery difficult of later period waste water, while avoiding the degradation of beta-lactam ring under strongly acidic conditions, improves the purity and yield of product.
Description
Technical field
The present invention relates to the medical synthesis fields of cephalosporin analog antibiotic intermediate, and in particular to a kind of 7- amino -3- methoxy
The synthetic method of ylmethyl -3- cephem -4- carboxylic acid.
Background technique
The chemical name of 7-AMCA are as follows: 7- amino -3- methoxy -3- cephem -4- carboxylic acid.7-AMCA is synthesis head
The key intermediate of spore pool oxime ester.Cefpodoxime Proxetil is third generation cephalo product, equal to the blue scholar's positive bacteria of many leather and negative bacterium
There are effect, rare drug resistance, and beta lactamase is stablized.Lower respiratory tract infection, urinary system infection contamination, middle ear on primary treatment
Inflammation, skin soft-tissue infection, scarlet fever etc..
There are mainly two types of 7- amino -3- methoxy -3- cephem -4- carboxylic acid, that is, 7-AMCA synthetic routes, respectively
With 7-amino-cephalosporanic acid (7-ACA) and 7- amino -3- methylol -3- cephem -4- carboxylic acid (D-7ACA) for starting material.
Wherein, using 7-ACA as starting material, the 7-AMCA being prepared generally existing the shortcomings that product purity is low, separately
That there is also reaction steps is complicated for outer synthetic route, yield is low, high production cost, it is difficult using solvent the problems such as.
Wherein, the technology path of 7-AMCA is prepared using D-7ACA as starting material, uses a large amount of strongly acidic catalyst,
Direct hydrolysis after reaction, too low pH value lead to the degradation of beta-lactam ring, reduce the yield of product, prepare simultaneously
Product deposit that purity is low, and stability is poor.
In addition, inventor retrieves to obtain, to prepare relevant patented technology data to 7-AMCA as follows, but does not solve
Above-mentioned technical problem:
1) patent CN102746322B discloses the preparation method of 7-AMCA a kind of, by reactant 7-amino-cephalosporanic acid in BF3-
Methanol makees catalyst, and dimethyl carbonate or sulfolane do organic solvent, and methoxyl group alkali metal makees methoxylation reagent and reacted, and leads to
Crystallization is crossed, is filtered, washing is dried to obtain.Its yield can reach 84%.But the patent products obtained therefrom purity is 97.9%, is produced
Journey uses dangerous and more expensive price methoxyl group alkali metal, high production cost.
2) patent CN105669701A discloses the preparation method of 7-AMCA a kind of, using 7-ACA as starting material, methoxyl group
Sulfonic acid is catalyst, and trimethylborate is methylating reagent, and methanol is that solvent prepares 7-AMCA.The methoxyl group sulphur that this method uses
Acid is expensive, and has used chlorosulfonic acid and belonged to poisonous reagent, is not easy to purchase and stores.The product yield obtained with the method
66.88%, liquid phase purity 95~96% or so.
3) patent WO2001027117A discloses the preparation method of 7-AMCA a kind of, with 7-ACA and methanesulfonic acid and boric acid three
Methyl esters-methanol azeotropic mixture reaction generates 7-AMCA, but this method products obtained therefrom purity is lower (97.5%).
4) patent WO2013041999A discloses the preparation method of 7-AMCA a kind of, with 7-ACA and methanesulfonic acid and methanol
Or methanesulfonic acid, methanol, the mixture of trimethyl borine or sulfolane, BF3/ methanol 5 DEG C -50 DEG C at a temperature of, first is then added
Through crystallization, 7-AMCA is obtained by filtration in alcohol.This method yield and purity are lower, and product filters difficulty, sticky.
5) Japanese Patent No. 82,192,392 and United States Patent (USP) No.4,482,710 are disclosed by being protected with phenylacetyl group
The step of protecting the 7- amino of 7-ACA prepares 7- amino -3- methoxy -3- cephem carboxylic；By methanol-sodium bicarbonate or
3- acetoxyl group is converted methoxyl group by the effect of methanol-calcium chloride, and removes protection group.But this method there are the problem of
It is that the yield that obtains is very low (approximately less than 20%), and this method needs multiple steps.
6) EP patent No.485,204 is disclosed by containing alkoxy sulfonic acid and trialkyl borate and alkyl acetal
Solution in processing 7-ACA come the method for preparing 7- amino -3- methoxy -3- cephem -4- carboxylic acid.However, this side
Method uses reluctant 98% trimethylborate, and there is also the problems of process controllability difference.
7) patent CN106046024A discloses the preparation method of 7-AMCA a kind of, using D-7-ACA as raw material, orthoformic acid front three
Ester is methylating reagent, and boron trifluoride/ether is catalyst, and acetonitrile is that solvent prepares 7-AMCA.The technique need to be low at -30 DEG C
It is carried out in warm situation, equipment requirement is stringent, and ether acetonitrile mixed solvent is difficult to recycle and there are security risks, exists simultaneously
The low problem of product yield, though undisclosed yield data in patent, speculates, yield is no more than according to downstream product total recovery
60%。
8) patent WO2017153824A discloses the preparation method of 7-AMCA a kind of, using D-7-ACA as raw material, orthoformic acid
Trimethyl is methylating reagent, and alkyl sulfonic acid is that catalyst is reacted, and salt water stratification is added after reaction, alkalinity examination is added
Agent crystallization.Product purity is low by the 7-AMCA prepared using this method, and relative amount is less, exists simultaneously the problem of stability difference.
In conclusion product purity is low by the existing 7-AMCA produced using 7-ACA as the patented technology of raw material, work
Skill process is complicated, yield is low, and the catalyst severe toxicity used is not easy to purchase or expensive, mixed solvent do react there is also
The problems such as being not easily recycled, it is high that problem above also results in its production cost.It is existing to prepare 7-AMCA by raw material of D-7-ACA
Technology path, used a large amount of strongly acidic catalyst, after reaction direct hydrolysis, too low pH value leads to beta-lactam
The problem of degradation of ring, it is low that there are yields, high production cost, in addition obtained product purity is low, stability is poor, results in the skill
The industrialization of art route is restricted, and the market development of product is restricted.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of conjunctions of 7- amino -3- methoxy -3- cephem -4- carboxylic acid
At method.
In order to solve the above technical problems, the technical solution used in the present invention is as follows.
A kind of 7- amino -3- methoxy -3- cephem -4- carboxylic acid synthetic method passes through under organic solvent environment
Strong protonic acid catalysis 7- amino -3- methylol -3- cephem -4- carboxylic acid D-7-ACA is reacted with alkylating reagent, generates 7-
Amino -3- methoxy -3- cephem -4- carboxylic acid 7-AMCA；This method further includes following aftertreatment technology:
A, the progress of above-mentioned synthetic reaction is monitored, and low in the weight content of 7- amino -3- methylol -3- cephem -4- carboxylic acid
It immediately begins to add by-product precipitation solution into reaction solution after critical value, the by-product salt of precipitation recycles benefit after filtering
With；
B, filtrate adds water to be hydrolyzed, and is then cooled to not higher than 10 DEG C, alkaline solution is added dropwise at low temperature, rises after precipitating crystal
Warm growing the grain, continue to be added dropwise alkaline solution to PH be 3.0~4.0 when, the product of precipitation is washed, it is dry to get final product
7- amino -3- methoxy -3- cephem -4- carboxylic acid.
As a preferred technical solution of the present invention, in step A, the 7- amino -3- methylol -3- cephem -4-
The weight content critical value setting of carboxylic acid be less than/be equal to its original additive amount 1% w/w；Solution is precipitated in the by-product
Addition manner is to be added dropwise or be added at one time.
As a preferred technical solution of the present invention, in step A, the 7- amino -3- methylol -3- cephem -4-
The weight content critical value setting of carboxylic acid be less than/be equal to its original additive amount 10% w/w；Solution is precipitated in the by-product
Addition manner be added dropwise, and the content of 7- amino -3- methylol -3- cephem -4- carboxylic acid be less than/be equal to its original addition
It completes to be added dropwise when 1% w/w of amount.
As a preferred technical solution of the present invention, in step A, the 7- amino -3- methylol -3- cephem -4-
The weight content critical value setting of carboxylic acid be less than/be equal to its original additive amount 30% w/w；Solution is precipitated in the by-product
Addition manner be added dropwise, and the content of 7- amino -3- methylol -3- cephem -4- carboxylic acid be less than/be equal to its original addition
It completes to be added dropwise when 1% w/w of amount.
As a preferred technical solution of the present invention, in step A, it is that sodium acetate ethyl alcohol is molten that solution, which is precipitated, in the by-product
Liquid or sodium acetate methanol solution；The volume by volume concentration of acetic acid sodium ethoxide solution or sodium acetate methanol solution is 2~10%, and weight is used
Amount is 0.5~10 times of D-7-ACA inventory.
As a preferred technical solution of the present invention, in step A, it is that sodium acetate alcohol is molten that solution, which is precipitated, in the by-product
Liquid.
As a preferred technical solution of the present invention, in step A, the organic solvent is dimethyl carbonate, formic acid first
Ester, ethyl acetate, methanol, acetonitrile or methylene chloride it is one or more, usage ratio be D-7-ACA charged material weight 2~
10 times；The alkylating reagent is one of methanol, trimethyl orthoformate, sodium methoxide, dimethyl suflfate or a variety of, dosage
It is 1~2 times of D-7-ACA charged material weight；The strong protonic acid is the concentrated sulfuric acid, nitric acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, methyl sulphur
One of acid or ethylsulfonic acid are a variety of, and dosage is 1~4 times of D-7-ACA charged material weight.
As a preferred technical solution of the present invention, in step B, after filtrate adds water to be hydrolyzed, it is cooled to 5~6 DEG C
Then alkaline solution is added dropwise at low temperature.
As a preferred technical solution of the present invention, in step B, the amount for hydrolyzing water used is D-7-ACA charged material weight
1~5 times；Hydrolysis temperature is 0~30 DEG C；Hydrolysis time is 10~60 minutes.
As a preferred technical solution of the present invention, in step B, the cleaning solution of washing crystal is organic solvent and water
Mixed liquor；The organic solvent is methanol, ethyl alcohol, isopropanol, normal propyl alcohol, acetone, acetonitrile or combinations thereof, organic solvent and water
Volume ratio be 1:(1~5), the weight consumption of mixed liquor is 5~20 times of D-7-ACA charged material weight.
The beneficial effects of adopting the technical scheme are that although this technology route still uses D-7ACA for raw material
7-AMCA is prepared, the reaction later period is precipitated strongly acidic catalyst in a salt form, knot is hydrolyzed again after filtering out by-product salt
Brilliant, filtering, drying, improve the content of product, reduce the recovery difficult of later period waste water.The technology path avoids β simultaneously
The degradation of lactam nucleus under strongly acidic conditions improves yield, and product purity obtained is high, stability is good.In addition the technology road
Line can directly recycle reaction dissolvent, and directly extract byproduct of reaction, greatly saved production cost, substantially dropped
Low waste discharge.
In addition, the present invention need to control low temperature when first time alkaline solution crystallization being added dropwise, the 7-AMCA product being precipitated in this way
Appearance is good.Cleaning product using the mixed liquor of solvent and water, water, organic solvent mode of washing, the product appearance prepared is good,
Purity is high is degraded under hot conditions slow.
Detailed description of the invention
Attached drawing 1a is photo of the 7-AMCA obtained by check experiment after 160 DEG C of baking 2h in embodiment 4, and 1b is standard work
Photo of the 7-AMCA obtained by skill (i.e. 1 technique of embodiment) after 160 DEG C of baking 2h.
Attached drawing 2a is the auto zoom chromatogram of check experiment products obtained therefrom in embodiment 4, and 2b is that standard technology (is implemented
1 technique of example) products obtained therefrom auto zoom chromatogram, it is seen that new process have apparent progressive.
Specific embodiment
The present invention is described in detail in following embodiment.Various raw materials used in the present invention and items of equipment are conventional city
Product is sold, can be bought and be directly obtained by market.
Embodiment 1
(1) into 250ml four-hole bottle, 100ml dimethyl carbonate, 20gD-7ACA is added, 25ml trimethyl orthoformate stirs 10 points
Clock, temperature are controlled at 10 DEG C or so.Then addition 30g p-methyl benzenesulfonic acid, raising temperature, 20 DEG C of temperature control.It is anti-with HPLC detection
Terminal is answered, until the residual quantity of D-7-ACA is less than 1%.
(2) the acetic acid sodium ethoxide solution 200ml of 5% v/v is added into four-hole bottle, at the uniform velocity stirs 20 minutes, filters.To
40ml water is added in filtrate to be hydrolyzed.
(3) after hydrolyzate pH stablizes, 5 DEG C of temperature control are slowly added dropwise aqueous sodium carbonate, until precipitating crystal, crystalline substance to be precipitated
Stop that sodium carbonate liquor is added dropwise after body, is warming up to 25~30 DEG C of growing the grain half an hour.It then proceedes to that sodium carbonate liquor is slowly added dropwise, adjusts
PH to 3.00 is saved, ethanol water, water, ethanol washing crystal are used in filtering respectively, and 50 DEG C of vacuum drying both obtain target product 7-
AMCA, off-white color crystalline powder 17.01g, yield 85.05%, purity 99.02%.
Referring to attached drawing 1b, for the photo that 160 DEG C of baking 2h of 7-AMCA are made.Attached drawing 2b is the auto zoom chromatography of product
Figure, corresponding peak result are as follows:
。
Embodiment 2
(1) into 250ml four-hole bottle, 40ml methylene chloride, 20gD-7ACA is added, 20ml dimethyl suflfate stirs 10 minutes, temperature
Degree control is at 10 DEG C or so.Then the addition 25ml concentrated sulfuric acid, raising temperature, 35 DEG C of temperature control.Reaction end is detected with HPLC, until
The residual quantity of D-7ACA is less than 1%.
(2) the acetic acid sodium ethoxide solution 100ml of 4% v/v is added into four-hole bottle, at the uniform velocity stirs 20 minutes, filters.To
20ml water is added in filtrate and is hydrolyzed and stablizes to PH.
(3) 5 DEG C of temperature control, are slowly added dropwise sodium acetate solution, until precipitating crystal, stop that sodium acetate is added dropwise after precipitating crystal
Solution is warming up to 30 DEG C of growing the grain half an hour.It then proceedes to that sodium acetate solution is slowly added dropwise, adjusting PH is 3.2, filters, uses second respectively
Alcohol solution, water, ethanol washing crystal, 50 DEG C of vacuum drying, both obtain target product 7-AMCA, off-white color crystalline powder
17.32g, yield 86.6%, purity 99.12%.
Embodiment 3
(1) into 250ml four-hole bottle, 100ml methanol, 20gD-7ACA is added, 22.5ml trimethyl orthoformate stirs 10 minutes,
Temperature is controlled at 10 DEG C or so.Then 20ml Loprazolam is added, increases temperature, controls 40 DEG C of temperature.It is detected and is reacted with HPLC
Terminal, until the residual quantity of D-7-ACA is less than 1%.
(2) the sodium acetate methanol solution 100ml of 4% v/v is added into four-hole bottle, at the uniform velocity stirs 20 minutes, it is carried out
It filters.20ml water is added into filtrate to be hydrolyzed, stablizes to PH.
(3) ammonia spirit is slowly added dropwise for 6 DEG C of temperature control, until precipitating crystal, stops that ammonia spirit is added dropwise after precipitating crystal,
It is warming up to 30 DEG C of growing the grain half an hour.It then proceedes to that ammonia spirit is slowly added dropwise, adjusting PH is 3.2, is filtered, water-soluble with methanol respectively
Liquid, water, methanol wash crystal, and 50 DEG C of vacuum drying both obtain target product 7-AMCA off-white color crystalline powder 17.15g, yield
85.75%, purity 99.06%.
Embodiment 4, comparative test
Check experiment is synthesized according to prior art method, and processing step is as follows: by 7- amino -3- methylol -3- cephem -
4- carboxylic acid 100g, is added in the mixture of dimethyl carbonate 300ml and trimethyl orthoformate 96.8g, range 5-10 DEG C it
Between, then it is added 329.0 grams of benzene sulfonic acid.Reaction mixture 30-40 DEG C or so stirring 20-35 minutes, checked by HPLC anti-
It answers.Relative to 7- amino -3- methoxy -3- cephem -4- carboxylic acid (7-AMCA), lactone percentage is about 6-15%, will
Quenching reaction object and separating layer in the cooling salt water of 300ml is added in reactant.Ammonium hydroxide is slowly added within the time of 60-120min
Solution maintains the temperature within the scope of 10-30 DEG C, adjusts pH value and reaches 3.3-3.5.Isolate the 7- amino -3- methoxyl group of precipitating
Methyl -3- cephem -4- carboxylic acid (7-AMCA).- 146 grams, LOD-46% of wet yield, yield 78.84%, purity 97.73%.
Referring to attached drawing 1a, for the photo that 160 DEG C of baking 2h of 7-AMCA are made.Attached drawing 2a is the auto zoom chromatography of product
Figure, corresponding peak result are as follows:
。
Using the synthesis technology of embodiment 1 as standard new process.
The correlation data of process is as follows in two:
| Project | Yield | Purity | Purity after 160 DEG C of baking 2h |
| Comparative example | 78.84% | 97.73% | 95.20% |
| Embodiment 1 | 85.05% | 99.02% | 98.32% |
Referring also to attached drawing 1,2.Attached drawing 1a is photograph of the 7-AMCA obtained by check experiment after 160 DEG C of baking 2h in embodiment 4
Piece, 1b are the photo after 7-AMCA obtained by standard technology (i.e. 1 technique of embodiment) toasts 2h at 160 DEG C；Attached drawing 2a is embodiment 4
The auto zoom chromatogram of middle check experiment products obtained therefrom, 2b are the automatic of standard technology (i.e. 1 technique of embodiment) products obtained therefrom
Scale chromatogram, it is seen that new process has apparent progressive.
Embodiment 5
The weight content critical value setting of 7- amino -3- methylol -3- cephem -4- carboxylic acid can also be that its is original by the present invention
The 10-50% w/w of additive amount；The range of 10-30% is generally taken, the addition manner of sodium acetate methanol solution is dropwise addition, and in 7-
The content of amino -3- methylol -3- cephem -4- carboxylic acid is completed to be added dropwise when being less than/be equal to 1% w/w of its original additive amount.
Small-scale test display, can also obtain higher yield (91.37%) under the premise of high-purity index.
To sum up embodiment filters out pair as it can be seen that strongly acidic catalyst is precipitated in a salt form in technology path of the invention
Crystallization, filtering, drying is hydrolyzed after product salt again, improves the content of product, reduces the recovery difficult of later period waste water.It should
Technology path avoids the degradation of beta-lactam ring under strongly acidic conditions simultaneously, improves yield, and product purity obtained is high, steady
It is qualitative good.In addition the technology path can directly recycle reaction dissolvent, and directly extract byproduct of reaction, greatly save
About production cost, significantly reduces waste discharge.
Foregoing description is only proposed as the enforceable technical solution of the present invention, not as to the single of its technical solution itself
Restrictive condition.
Claims (10)
1. a kind of 7- amino -3- methoxy -3- cephem -4- carboxylic acid synthetic method, under organic solvent environment, by strong
Protic Acid Catalyzed 7- amino -3- methylol -3- cephem -4- carboxylic acid D-7-ACA is reacted with alkylating reagent, generates 7- ammonia
Base -3- methoxy -3- cephem -4- carboxylic acid 7-AMCA；It is characterized by: this method further includes following post-processing work
Skill:
A, the progress of above-mentioned synthetic reaction is monitored, and low in the weight content of 7- amino -3- methylol -3- cephem -4- carboxylic acid
It immediately begins to add by-product precipitation solution into reaction solution after critical value, the by-product salt of precipitation recycles benefit after filtering
With；
B, filtrate adds water to be hydrolyzed, and is then cooled to not higher than 10 DEG C, alkaline solution is added dropwise at low temperature, rises after precipitating crystal
Warm growing the grain, continue to be added dropwise alkaline solution to PH be 3.0~4.0 when, the product of precipitation is washed, it is dry to get final product
7- amino -3- methoxy -3- cephem -4- carboxylic acid.
2. a kind of 7- amino -3- methoxy -3- cephem -4- carboxylic acid synthetic method according to claim 1, special
Sign is: in step A, the weight content critical value setting of the 7- amino -3- methylol -3- cephem -4- carboxylic acid be less than/
Equal to 1% w/w of its original additive amount；The addition manner that solution is precipitated in the by-product is to be added dropwise or be added at one time.
3. a kind of 7- amino -3- methoxy -3- cephem -4- carboxylic acid synthetic method according to claim 1, special
Sign is: in step A, the weight content critical value setting of the 7- amino -3- methylol -3- cephem -4- carboxylic acid be less than/
Equal to 10% w/w of its original additive amount；The addition manner that solution is precipitated in the by-product is dropwise addition, and in 7- amino -3- hydroxyl
The content of methyl -3- cephem -4- carboxylic acid is completed to be added dropwise when being less than/be equal to 1% w/w of its original additive amount.
4. a kind of 7- amino -3- methoxy -3- cephem -4- carboxylic acid synthetic method according to claim 1, special
Sign is: in step A, the weight content critical value setting of the 7- amino -3- methylol -3- cephem -4- carboxylic acid be less than/
Equal to 30% w/w of its original additive amount；The addition manner that solution is precipitated in the by-product is dropwise addition, and in 7- amino -3- hydroxyl
The content of methyl -3- cephem -4- carboxylic acid is completed to be added dropwise when being less than/be equal to 1% w/w of its original additive amount.
5. a kind of 7- amino -3- methoxy -3- cephem -4- carboxylic acid synthetic method according to claim 1, special
Sign is: in step A, it is acetic acid sodium ethoxide solution or sodium acetate methanol solution that solution, which is precipitated, in the by-product；Sodium acetate ethyl alcohol
The volume by volume concentration of solution or sodium acetate methanol solution is 2~10%, and weight consumption is 0.5~10 times of D-7-ACA inventory.
6. a kind of 7- amino -3- methoxy -3- cephem -4- carboxylic acid synthetic method according to claim 1, special
Sign is: in step A, it is sodium acetate alcoholic solution that solution, which is precipitated, in the by-product.
7. a kind of 7- amino -3- methoxy -3- cephem -4- carboxylic acid synthetic method according to claim 1, special
Sign is: in step A, the organic solvent is dimethyl carbonate, methyl formate, ethyl acetate, methanol, acetonitrile or methylene chloride
It is one or more, usage ratio is 2~10 times of D-7-ACA charged material weight；The alkylating reagent is methanol, orthoformic acid
One of trimethyl, sodium methoxide, dimethyl suflfate are a variety of, and dosage is 1~2 times of D-7-ACA charged material weight；It is described strong
Bronsted acid is one of the concentrated sulfuric acid, nitric acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, methane sulfonic acid or ethylsulfonic acid or a variety of, dosage
It is 1~4 times of D-7-ACA charged material weight.
8. a kind of 7- amino -3- methoxy -3- cephem -4- carboxylic acid synthetic method according to claim 1, special
Sign is: in step B, after filtrate adds water to be hydrolyzed, being cooled to 5~6 DEG C and then alkaline solution is added dropwise at low temperature.
9. a kind of 7- amino -3- methoxy -3- cephem -4- carboxylic acid synthetic method according to claim 1, special
Sign is: in step B, the amount for hydrolyzing water used is 1~5 times of D-7-ACA charged material weight；Hydrolysis temperature is 0~30 DEG C；Hydrolysis
Time is 10~60 minutes.
10. a kind of 7- amino -3- methoxy -3- cephem -4- carboxylic acid synthetic method according to claim 1,
Be characterized in that: in step B, the cleaning solution of washing crystal is the mixed liquor of organic solvent and water；The organic solvent be methanol,
The volume ratio of ethyl alcohol, isopropanol, normal propyl alcohol, acetone, acetonitrile or combinations thereof, organic solvent and water is 1:(1~5), mixed liquor
Weight consumption is 5~20 times of D-7-ACA charged material weight.
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