CN109956958B - Synthesis method of 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid - Google Patents
Synthesis method of 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid Download PDFInfo
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- CN109956958B CN109956958B CN201910263131.1A CN201910263131A CN109956958B CN 109956958 B CN109956958 B CN 109956958B CN 201910263131 A CN201910263131 A CN 201910263131A CN 109956958 B CN109956958 B CN 109956958B
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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
Abstract
The invention discloses a method for synthesizing 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid, which comprises the steps of catalyzing 7-amino-3-hydroxymethyl-3-cephem-4-carboxylic acid D-7-ACA to react with an alkylating reagent by strong protonic acid in an organic solvent environment to generate 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid 7-AMCA, immediately adding a by-product separated solution into a reaction solution after the weight content of the 7-amino-3-hydroxymethyl-3-cephem-4-carboxylic acid is lower than a critical value, and filtering and recycling the separated by-product salt.
Description
Technical Field
The invention relates to the field of medical synthesis of cephalosporin antibiotic intermediates, in particular to a synthetic method of 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid.
Background
The chemical name of 7-AMCA is 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid.7-AMCA is a key intermediate for synthesizing cefpodoxime proxetil, cefpodoxime proxetil is a third-generation cephalosporin product, has effects on a plurality of gram-positive bacteria and gram-negative bacteria, rarely has drug resistance, and is stable to β lactamase, and is mainly used for treating upper and lower respiratory tract infection, urinary system infection, otitis media, skin soft tissue infection, scarlet fever and the like.
The 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid (7-AMCA) has two main synthetic routes, and 7-aminocephalosporanic acid (7-ACA) and 7-amino-3-hydroxymethyl-3-cephem-4-carboxylic acid (D-7 ACA) are respectively used as starting materials.
Wherein, 7-ACA is used as a starting material, the prepared 7-AMCA generally has the defect of low product purity, and the synthetic route also has the problems of complex reaction steps, low yield, high production cost, difficult processing of used solvent and the like.
The technical route for preparing 7-AMCA by using D-7ACA as a starting material adopts a large amount of strong acid catalysts, hydrolysis is directly carried out after the reaction is finished, β lactam ring is degraded due to too low pH value, the yield of the product is reduced, and the prepared product has low purity and poor stability.
In addition, the inventor searches the following patent technical data related to the preparation of 7-AMCA, but the technical problems are not solved:
1) patent CN102746322B discloses a preparation method of 7-AMCA, which is to react 7-aminocephalosporanic acid with BF3Methanol as catalyst, dimethyl carbonate or sulfolane as organic solvent, and alkali metal methoxyl as methoxylation reagent, crystallizing, filtering, washing, and drying. The yield can reach 84%. However, the purity of the product obtained in the patent is 97.9 percent, dangerous and expensive methoxyl alkali metal is used in the production process, and the production cost is high.
2) Patent CN105669701A discloses a preparation method of 7-AMCA, which takes 7-ACA as a starting material, methoxylsulfonic acid as a catalyst, trimethyl borate as a methylating agent and methanol as a solvent to prepare 7-AMCA. The method uses the methoxysulfonic acid which is expensive, and the chlorosulfonic acid which is used belongs to a highly toxic reagent is not easy to purchase and store. The yield of the product obtained by the method is 66.88 percent, and the liquid phase purity is about 95-96 percent.
3) Patent WO2001027117A discloses a process for the preparation of 7-AMCA by reacting 7-ACA with an azeotropic mixture of methanesulfonic acid and trimethyl borate-methanol to produce 7-AMCA, but the purity of the product obtained is low (97.5%).
4) Patent WO2013041999A discloses a preparation method of 7-AMCA, which comprises the steps of mixing 7-ACA with methanesulfonic acid and methanol or a mixture of methanesulfonic acid, methanol, trimethylboron or sulfolane, and BF 3/methanol at the temperature of 5-50 ℃, then adding methanol, and carrying out crystallization and filtration to obtain 7-AMCA. The method has low yield and purity, and the product is difficult to pump and filter and is viscous.
5) Japanese patent No. 82,192,392 and U.S. Pat. No.4,482,710 disclose the preparation of 7-amino-3-methoxymethyl-3-cephem carboxylic acid by the step of protecting 7-amino group of 7-ACA with phenylacetyl group; the 3-acetoxy group is converted to methoxy by the action of methanol-sodium bicarbonate or methanol-calcium chloride and the protected group is removed. However, this method has problems in that the yield obtained is very low (about less than 20%), and the method requires a plurality of steps.
6) EP patent No.485,204 discloses a process for the preparation of 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid by treating 7-ACA in a solution containing alkoxysulfonic acid and trialkyl borate and alkyl acetal. However, this method uses 98% trimethyl borate, which is difficult to handle, and also has a problem of poor process controllability.
7) Patent CN106046024A discloses a preparation method of 7-AMCA, which takes D-7-ACA as a raw material, trimethyl orthoformate as a methylating agent, boron trifluoride/diethyl ether as a catalyst and acetonitrile as a solvent to prepare 7-AMCA. The process needs to be carried out at a low temperature of-30 ℃, equipment requirements are strict, the ether acetonitrile mixed solvent is not easy to recycle and has potential safety hazards, and meanwhile, the problem of low product yield exists, although yield data are not disclosed in the patent, the yield is not more than 60% according to the total yield of downstream products.
8) Patent WO2017153824A discloses a preparation method of 7-AMCA, which takes D-7-ACA as raw material, trimethyl orthoformate as methylating agent and alkyl sulfonic acid as catalyst to react, and after the reaction is finished, brine is added for layering, and alkaline reagent is added for crystallization. The 7-AMCA product prepared by the method has low purity, less relative content and poor stability.
In conclusion, the 7-AMCA product produced by the existing patented technology taking 7-ACA as a raw material has low purity, complex process and low yield, the used catalyst is extremely toxic and is not easy to purchase or expensive, the mixed solvent is difficult to recover in the reaction, and the like, and the production cost is high due to the problems.
Disclosure of Invention
The invention aims to solve the technical problem of providing a method for synthesizing 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows.
A synthesis method of 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid is characterized in that in an organic solvent environment, strong protonic acid is used for catalyzing 7-amino-3-hydroxymethyl-3-cephem-4-carboxylic acid D-7-ACA to react with an alkylating agent to generate 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid 7-AMCA; the method also comprises the following post-treatment process:
A. monitoring the progress of the synthesis reaction, immediately adding a byproduct precipitation solution into the reaction solution after the weight content of the 7-amino-3-hydroxymethyl-3-cephem-4-carboxylic acid is lower than a critical value, and filtering the precipitated byproduct salt for recycling;
B. and adding water into the filtrate for hydrolysis, then cooling to a temperature not higher than 10 ℃, dropwise adding an alkaline solution at a low temperature, heating to grow crystals after the crystals are separated out, continuously dropwise adding the alkaline solution until the PH value is 3.0-4.0, washing the separated product, and drying to obtain the final product 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid.
In a preferred embodiment of the present invention, in step a, the critical value of the weight content of the 7-amino-3-hydroxymethyl-3-cephem-4-carboxylic acid is set to be less than or equal to 1% w/w of the original addition amount; the addition mode of the by-product precipitated solution is dropwise addition or one-time addition.
In a preferred embodiment of the present invention, in step a, the critical value of the weight content of the 7-amino-3-hydroxymethyl-3-cephem-4-carboxylic acid is set to be less than or equal to 10% w/w of the original addition amount; the addition mode of the by-product precipitated solution is dropwise adding, and the dropwise adding is completed when the content of the 7-amino-3-hydroxymethyl-3-cephem-4-carboxylic acid is less than or equal to 1% w/w of the original addition amount.
In a preferred embodiment of the present invention, in step a, the critical value of the weight content of the 7-amino-3-hydroxymethyl-3-cephem-4-carboxylic acid is set to be less than or equal to 30% w/w of the original addition amount; the addition mode of the by-product precipitated solution is dropwise adding, and the dropwise adding is completed when the content of the 7-amino-3-hydroxymethyl-3-cephem-4-carboxylic acid is less than or equal to 1% w/w of the original addition amount.
As a preferred technical scheme of the invention, in the step A, the by-product precipitated solution is a sodium acetate ethanol solution or a sodium acetate methanol solution; the volume ratio concentration of the sodium acetate ethanol solution or the sodium acetate methanol solution is 2-10%, and the weight consumption is 0.5-10 times of the D-7-ACA feeding amount.
In a preferred technical scheme of the present invention, in the step a, the by-product precipitated solution is a sodium acetate alcoholic solution.
As a preferred technical scheme of the invention, in the step A, the organic solvent is one or more of dimethyl carbonate, methyl formate, ethyl acetate, methanol, acetonitrile or dichloromethane, and the dosage proportion of the organic solvent is 2-10 times of the weight of D-7-ACA; the alkylating reagent is one or more of methanol, trimethyl orthoformate, sodium methoxide and dimethyl sulfate, and the dosage of the alkylating reagent is 1-2 times of the weight of D-7-ACA fed material; the strong protonic acid is one or more of concentrated sulfuric acid, nitric acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid or ethylsulfonic acid, and the dosage of the strong protonic acid is 1-4 times of the weight of the D-7-ACA feed.
As a preferred technical scheme of the invention, in the step B, after adding water into the filtrate for hydrolysis, cooling to 5-6 ℃, and then dropwise adding an alkaline solution at a low temperature.
As a preferred technical scheme, in the step B, the amount of water used for hydrolysis is 1-5 times of the weight of D-7-ACA fed material; the hydrolysis temperature is 0-30 ℃; the hydrolysis time is 10-60 minutes.
In a preferred embodiment of the present invention, in step B, the washing liquid for washing the crystal is a mixed solution of an organic solvent and water; the organic solvent is methanol, ethanol, isopropanol, n-propanol, acetone, acetonitrile or a combination thereof, the volume ratio of the organic solvent to water is 1 (1-5), and the weight consumption of the mixed solution is 5-20 times of the weight of the D-7-ACA.
The technical scheme has the beneficial effects that although the technical route still adopts D-7ACA as the raw material to prepare the 7-AMCA, the strong acid catalyst is separated out in the form of salt in the later stage of the reaction, and the byproduct salt is filtered out and then is subjected to hydrolysis crystallization, filtration and drying, so that the content of the product is improved, and the recovery difficulty of the later-stage wastewater is reduced.
In addition, the invention needs to control low temperature when alkaline solution is dripped for crystallization for the first time, so that the precipitated 7-AMCA product has good appearance. The washing product adopts a washing mode of mixed solution of solvent and water, water and organic solvent, and the prepared product has good appearance, high purity and slow degradation under high-temperature conditions.
Drawings
FIG. 1a is a photograph of 7-AMCA obtained in the control experiment of example 4 after baking at 160 ℃ for 2 hours, and 1b is a photograph of 7-AMCA obtained in the standard process (i.e., the process of example 1) after baking at 160 ℃ for 2 hours.
FIG. 2a is the automatically scaled chromatogram of the product obtained from the control experiment in example 4, and FIG. 2b is the automatically scaled chromatogram of the product obtained from the standard process (i.e., the process of example 1), showing that the new process is significantly improved.
Detailed Description
The following examples illustrate the invention in detail. The raw materials and various devices used in the invention are conventional commercially available products, and can be directly obtained by market purchase.
Example 1
(1) 100ml of dimethyl carbonate, 20g of D-7ACA and 25ml of trimethyl orthoformate were added to a 250ml four-necked flask and stirred for 10 minutes at a temperature of about 10 ℃. Then 30g of p-toluenesulfonic acid was added, the temperature was raised and controlled at 20 ℃. The reaction end point was detected by HPLC until the residual amount of D-7-ACA was less than 1%.
(2) 200ml of 5% v/v sodium acetate ethanol solution is added into a four-mouth bottle, stirred at a constant speed for 20 minutes and filtered. 40ml of water was added to the filtrate to conduct hydrolysis.
(3) And after the pH value of the hydrolysate is stable, slowly dropwise adding a sodium carbonate aqueous solution at the temperature of 5 ℃ until crystals are separated out, stopping dropwise adding the sodium carbonate solution after the crystals are separated out, and heating to 25-30 ℃ for crystal growing for half an hour. Then, sodium carbonate solution is continuously and slowly dripped, the PH is adjusted to 3.00, the mixture is filtered, crystals are respectively washed by ethanol water solution, water and ethanol, and the crystals are dried in vacuum at 50 ℃, so that the target product 7-AMCA is obtained, the white-like crystalline powder is 17.01g, the yield is 85.05 percent, and the purity is 99.02 percent.
Referring to FIG. 1b, a photograph of 7-AMCA baked at 160 ℃ for 2h is obtained. FIG. 2b is an automatically scaled chromatogram of a product, with the corresponding peak results:
example 2
(1) 40ml of methylene chloride, 20g of D-7ACA and 20ml of dimethyl sulfate were added to a 250ml four-necked flask and stirred for 10 minutes while controlling the temperature at about 10 ℃. Then 25ml of concentrated sulfuric acid was added, the temperature was raised and controlled at 35 ℃. The reaction end point was checked by HPLC until the residual amount of D-7ACA was less than 1%.
(2) 100ml of 4% v/v sodium acetate ethanol solution is added into a four-mouth bottle, stirred at a constant speed for 20 minutes and filtered. To the filtrate was added 20ml of water for hydrolysis to stabilize the pH.
(3) Controlling the temperature to be 5 ℃, slowly dripping sodium acetate solution until crystals are separated out, stopping dripping the sodium acetate solution after the crystals are separated out, and raising the temperature to 30 ℃ for growing the crystals for half an hour. And then continuously and slowly dripping sodium acetate solution, regulating the pH value to be 3.2, carrying out suction filtration, respectively washing the crystal with ethanol water solution, water and ethanol, and carrying out vacuum drying at 50 ℃ to obtain the target product 7-AMCA, wherein the yield is 86.6 percent and the purity is 99.12 percent, and the white crystalline powder is 17.32 g.
Example 3
(1) 100ml of methanol, 20g of D-7ACA and 22.5ml of trimethyl orthoformate were put into a 250ml four-necked flask and stirred for 10 minutes at a temperature of about 10 ℃. Then 20ml of methanesulfonic acid was added, the temperature was raised, and the temperature was controlled at 40 ℃. The reaction end point was detected by HPLC until the residual amount of D-7-ACA was less than 1%.
(2) 100ml of 4% v/v sodium acetate methanol solution was added to a four-necked flask, stirred at a constant speed for 20 minutes, and then filtered under suction. 20ml of water was added to the filtrate to hydrolyze until the pH stabilized.
(3) Slowly dripping ammonia water solution at the temperature of 6 ℃ until crystals are separated out, stopping dripping the ammonia water solution after the crystals are separated out, and raising the temperature to 30 ℃ for half an hour for growing the crystals. Then ammonia water solution is continuously and slowly dripped, the PH value is adjusted to be 3.2, the filtration is carried out, methanol water solution, water and methanol are respectively used for washing crystals, and the crystals are dried in vacuum at 50 ℃, so that 17.15g of the target product 7-AMCA white crystalline powder is obtained, the yield is 85.75 percent, and the purity is 99.06 percent.
Example 4 comparative experiment
The comparison test is synthesized according to the prior art method, and the process steps are as follows: 100g of 7-amino-3-hydroxymethyl-3-cephem-4-carboxylic acid was added to a mixture of 300ml of dimethyl carbonate and 96.8g of trimethyl orthoformate at a temperature ranging from 5 to 10 ℃ followed by 329.0 g of benzenesulfonic acid. The reaction mixture was stirred at about 30-40 ℃ for 20-35 minutes and the reaction checked by HPLC. The percentage of lactone relative to 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid (7-AMCA) was about 6-15%, the reaction was quenched by adding the reaction to 300ml of chilled brine and the layers were separated. Slowly adding ammonia water solution within 60-120min, maintaining the temperature at 10-30 deg.C, and adjusting pH to 3.3-3.5. The precipitated 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid (7-AMCA) was separated. Wet yield-146 g, LOD-46%, yield 78.84%, purity 97.73%.
Referring to FIG. 1a, a photograph of 7-AMCA baked at 160 ℃ for 2h is obtained. FIG. 2a is an automatically scaled chromatogram of a product, with the corresponding peak results:
the synthesis procedure of example 1 was used as a standard new procedure.
The comparative data for the two processes are as follows:
| item | Yield of | Purity of | Purity after baking for 2h at 160 DEG C |
| Comparative examples | 78.84% | 97.73% | 95.20% |
| Example 1 | 85.05% | 99.02% | 98.32% |
See also figures 1, 2. FIG. 1a is a photograph of 7-AMCA obtained in the control experiment of example 4 after baking at 160 ℃ for 2 hours, and 1b is a photograph of 7-AMCA obtained in the standard process (i.e., the process of example 1) after baking at 160 ℃ for 2 hours; FIG. 2a is the automatically scaled chromatogram of the product obtained from the control experiment in example 4, and FIG. 2b is the automatically scaled chromatogram of the product obtained from the standard process (i.e., the process of example 1), showing that the new process is significantly improved.
Example 5
The invention can also set the critical value of the weight content of the 7-amino-3-hydroxymethyl-3-cephem-4-carboxylic acid as 10-50% w/w of the original addition amount; generally, 10-30% of sodium acetate methanol solution is taken, the adding mode of the sodium acetate methanol solution is dropwise adding, and the dropwise adding is completed when the content of the 7-amino-3-hydroxymethyl-3-cephem-4-carboxylic acid is less than or equal to 1% w/w of the original adding amount. Small scale experiments showed that higher yields (91.37%) could be achieved with high purity indicators.
In conclusion, the technical route of the invention enables the strong acid catalyst to be separated out in the form of salt, and the salt as a byproduct is filtered out and then is subjected to hydrolysis crystallization, filtration and drying, so that the content of the product is improved, and the difficulty in recovering the wastewater in the later period is reduced.
The above description is only presented as an enabling solution for the present invention and should not be taken as a sole limitation on the solution itself.
Claims (8)
1. A synthesis method of 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid is characterized in that in an organic solvent environment, strong protonic acid is used for catalyzing 7-amino-3-hydroxymethyl-3-cephem-4-carboxylic acid D-7-ACA to react with an alkylating agent to generate 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid 7-AMCA; the method is characterized in that: the method also comprises the following post-treatment process:
A. monitoring the progress of the synthesis reaction, immediately adding a byproduct precipitation solution into the reaction solution after the weight content of the 7-amino-3-hydroxymethyl-3-cephem-4-carboxylic acid is lower than a critical value, and filtering the precipitated byproduct salt for recycling;
B. adding water into the filtrate for hydrolysis, then cooling to a temperature not higher than 10 ℃, dropwise adding an alkaline solution at the low temperature, heating to grow crystals after the crystals are separated out, continuously dropwise adding the alkaline solution until the PH is 3.0-4.0, washing and drying the separated product to obtain a final product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid;
in the step A, the by-product precipitated solution is a sodium acetate ethanol solution or a sodium acetate methanol solution; the volume ratio concentration of the sodium acetate ethanol solution or the sodium acetate methanol solution is 2-10%, and the weight consumption is 0.5-10 times of the D-7-ACA feeding amount.
2. The method for synthesizing 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid according to claim 1, wherein: in the step A, the critical value of the weight content of the 7-amino-3-hydroxymethyl-3-cephem-4-carboxylic acid is set to be less than or equal to 1% w/w of the original addition amount; the addition mode of the by-product precipitated solution is dropwise addition or one-time addition.
3. The method for synthesizing 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid according to claim 1, wherein: in the step A, the critical value of the weight content of the 7-amino-3-hydroxymethyl-3-cephem-4-carboxylic acid is set to be less than or equal to 10% w/w of the original addition amount; the addition mode of the by-product precipitated solution is dropwise adding, and the dropwise adding is completed when the content of the 7-amino-3-hydroxymethyl-3-cephem-4-carboxylic acid is less than or equal to 1% w/w of the original addition amount.
4. The method for synthesizing 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid according to claim 1, wherein: in the step A, the critical value of the weight content of the 7-amino-3-hydroxymethyl-3-cephem-4-carboxylic acid is set to be less than or equal to 30% w/w of the original addition amount; the addition mode of the by-product precipitated solution is dropwise adding, and the dropwise adding is completed when the content of the 7-amino-3-hydroxymethyl-3-cephem-4-carboxylic acid is less than or equal to 1% w/w of the original addition amount.
5. The method for synthesizing 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid according to claim 1, wherein: in the step A, the organic solvent is one or more of dimethyl carbonate, methyl formate, ethyl acetate, methanol, acetonitrile or dichloromethane, and the dosage proportion of the organic solvent is 2-10 times of the weight of the D-7-ACA; the alkylating reagent is one or more of methanol, trimethyl orthoformate, sodium methoxide and dimethyl sulfate, and the dosage of the alkylating reagent is 1-2 times of the weight of D-7-ACA fed material; the strong protonic acid is one or more of concentrated sulfuric acid, nitric acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid or ethylsulfonic acid, and the dosage of the strong protonic acid is 1-4 times of the weight of the D-7-ACA feed.
6. The method for synthesizing 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid according to claim 1, wherein: and in the step B, adding water into the filtrate for hydrolysis, cooling to 5-6 ℃, and then dropwise adding an alkaline solution at the low temperature.
7. The method for synthesizing 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid according to claim 1, wherein: in the step B, the amount of water used for hydrolysis is 1-5 times of the weight of D-7-ACA feed; the hydrolysis temperature is 0-30 ℃; the hydrolysis time is 10-60 minutes.
8. The method for synthesizing 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid according to claim 1, wherein: in the step B, the washing liquid for washing the crystal is a mixed liquid of an organic solvent and water; the organic solvent is methanol, ethanol, isopropanol, n-propanol, acetone, acetonitrile or a combination thereof, the volume ratio of the organic solvent to water is 1 (1-5), and the weight consumption of the mixed solution is 5-20 times of the weight of the D-7-ACA.
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