CN113336775A - Synthesis method of cefotaxime intermediate - Google Patents
Synthesis method of cefotaxime intermediate Download PDFInfo
- Publication number
- CN113336775A CN113336775A CN202110684544.4A CN202110684544A CN113336775A CN 113336775 A CN113336775 A CN 113336775A CN 202110684544 A CN202110684544 A CN 202110684544A CN 113336775 A CN113336775 A CN 113336775A
- Authority
- CN
- China
- Prior art keywords
- product
- reaction
- acid
- raw material
- synthesis method
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/18—7-Aminocephalosporanic or substituted 7-aminocephalosporanic acids
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a synthesis method of a cefotaxime intermediate, belonging to the technical field of chemical synthesis. According to the invention, the product a and the product b with higher purity and yield can be obtained in the step (1) and the step (2), so that the problems of incomplete reaction and high difficulty in post-treatment and purification are solved; during the step (3), PCl is selected for deacetylation5The method is a reaction raw material, has mild reaction conditions and few impurities, avoids the severe conditions of introducing chlorine and the like in the 7-ACCA deprotection process, avoids separating impurities by column chromatography, and has simple process operation; the raw material used in the denitration group benzyl in the step (4) is sodium hydrosulfite, the reaction conditions are mild in an acetone/water system, the p-nitrobenzyl alcohol is successfully reduced into the p-aminobenzyl alcohol, the safety risk brought by the p-nitrobenzyl alcohol in waste liquid and wastewater treatment is avoided, the raw material acetone can be recovered, and the method is suitable for industrial production. The invention has short synthesis process route, product purity more than or equal to 97.4 percent and total molar yield more than or equal to 50.5 percent.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a synthesis method of a cefotaxime intermediate.
Background
The cefacin is a third-generation semi-synthetic cephalosporin, has broad-spectrum antibacterial activity, and has the characteristics of quick absorption, long half-life period, high bioavailability, lasting drug effect, good safety, lasting curative effect and the like for dogs and cats.
The reported synthesis routes of the cefotaxime include two, the original process route takes penicillin G potassium salt as a raw material, carboxyl is protected by para-nitro bromine, and a cefotaxime mother nucleus intermediate is finally obtained through the procedures of oxidation, 1, 3-thiazoline ring formation, exocyclic olefinic bond transposition, ozone oxidation, reduction, side chain introduction, deprotection and the like in sequence, the process route is long, the yield is low, the quantity of industrial three wastes is large, and a large technical bottleneck exists in industrial production.
The other route is that 7-ANCA intermediate reported in patent CN105254648A is used as a raw material, and the cefuroxime mother nucleus intermediate is obtained through 4 steps of reaction, the process route is greatly simplified, but the reaction conditions are harsh, the post-treatment requires column chromatography to obtain the intermediate with better purity, and the method is not suitable for industrial scale-up production.
Therefore, the synthesis method of the cefotaxime intermediate, which has the advantages of short process route, high product yield and mild reaction conditions, is of great significance.
Disclosure of Invention
The invention aims to provide a synthesis method of a cefotaxime intermediate, which has the advantages of short process route, high product yield and mild reaction conditions and is suitable for industrial production.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a synthesis method of a cefotaxime intermediate, which comprises the following steps:
(1) mixing benzene sulfinic acid, a first organic solvent and 2, 3-dihydrofuran, and carrying out electrophilic addition reaction to obtain a product a;
(2) mixing the raw material 1, a second organic solvent, a product a, a catalyst, N-methyl pyrrolidone and a first acid-binding agent, and carrying out nucleophilic substitution reaction to obtain a product b;
(3) mixing the product b, a third organic solvent, a second acid-binding agent and PCl5Mixing, performing chlorination, adding a monohydric alcohol/methyl isobutyl ketone mixed solution into the obtained chlorination feed liquid, performing esterification, adding an aqueous solution of alkali into the obtained esterification feed liquid, adjusting the pH value to 7.0-7.5, and performing hydrolysis reaction to obtain a product c;
(4) mixing the product c, water, acetone and sodium hydrosulfite, and carrying out denitrification benzyl reaction on the obtained mixed feed liquid under the condition that the pH value is 6.8-7.2 to obtain a product d;
preferably, in the step (1), the temperature of the electrophilic addition reaction is 20 to 35 ℃ and the time is 3 to 6 hours.
Preferably, in step (1), the first organic solvent comprises dichloromethane, chloroform, diethyl ether, toluene, tetrahydrofuran or 2, 3-dihydrofuran; the mass ratio of the first organic solvent to the benzene sulfinic acid is preferably (5-8): 1.
Preferably, in the step (1), the molar ratio of the 2, 3-dihydrofuran to the benzene sulfinic acid is 1 (1.02-1.2).
Preferably, in the step (2),
the catalyst comprises one or more of zinc bromide, zinc chloride, lithium chloride, nickel bromide, nickel acetate, sodium bromide and sodium iodide;
the first acid-binding agent comprises one or more of pyridine, 2, 6-lutidine, morpholine, 2-methylpyridine, triethylamine and diethylamine;
the molar ratio of the raw material 1 to the product a is 1 (1.0-2.2);
the molar ratio of the raw material 1 to the first acid-binding agent is 1 (1.2-2.0);
the molar ratio of the raw material 1 to the catalyst is 1 (0.5-1.2);
the molar ratio of the raw material 1 to the N-methyl pyrrolidone is 1 (0.01-0.1).
Preferably, in the step (2), the temperature of the nucleophilic substitution reaction is 40-55 ℃ and the time is 16-24 h.
Preferably, in the step (3),
the third organic solvent comprises dichloromethane, chloroform or carbon tetrachloride;
the second acid-binding agent comprises pyridine, 2-methylpyridine or 2, 6-dimethylpyridine;
the monohydric alcohol in the monohydric alcohol/methyl isobutyl ketone mixed solution is methanol, ethanol or isopropanol;
the volume ratio of the monohydric alcohol to the methyl isobutyl ketone in the monohydric alcohol/methyl isobutyl ketone mixed solution is (8-10) to (1-2);
the mass ratio of the product b to the monohydric alcohol/methyl isobutyl ketone mixed solution is 1 (8-12);
the product b, a second acid-binding agent and PCl5The molar ratio of (1), (1.8-3.0).
Preferably, in the step (3), the temperature of the chlorination reaction is-15 to-10 ℃ and the time is 4 to 6 hours; the temperature of the esterification reaction is-10 to-5 ℃, and the time is 4 to 6 hours.
Preferably, in the step (4), the molar ratio of the product c to the sodium hydrosulfite is 1 (3.0-3.8); the mass ratio of the product c to water to acetone is 1: (5-10): (3-6).
Preferably, in the step (4), the temperature of the denitrobenzyl reaction is 35-42 ℃ and the time is 2-4 hours.
According to the invention, the product a and the product b with higher purity and yield can be obtained in the step (1) and the step (2), so that the problems of incomplete reaction and high difficulty in post-treatment and purification are solved; phosphorus pentachloride is selected as a reaction raw material during the phenylacetyl removal in the step (3), the reaction condition is mild, the impurities are few, the severe conditions of introducing chlorine gas and the like in the 7-ACCA deprotection process are avoided, the impurities are separated by column chromatography, and the process operation process is simple; the raw material used in the denitration group benzyl in the step (4) is sodium hydrosulfite, the reaction conditions are mild in an acetone/water system, the p-nitrobenzyl alcohol is successfully reduced into the p-aminobenzyl alcohol, the safety risk brought by the p-nitrobenzyl alcohol in waste liquid and wastewater treatment is avoided, and meanwhile, the raw material acetone can be recovered, so that the cost is lower, and the method is more suitable for industrial production.
In addition, the used raw material 1 is a 7-ACCA (cefaclor nucleus) intermediate, most of equipment can be produced with the 7-ACCA in a collinear way, the industrial production equipment is reduced, and the investment is saved.
The invention has short synthesis process route and high product yield, and the obtained product is convenient to purify. The results of the examples show that the overall target product purity is greater than or equal to 97.4%, and the total molar yield is greater than or equal to 50.5%.
Drawings
FIG. 1 is a high performance liquid purity spectrum of product a of example 1;
FIG. 2 is a high performance liquid purity spectrum of product b of example 1;
FIG. 3 is a high performance liquid purity spectrum of product d from example 1.
Detailed Description
The invention provides a synthesis method of a cefotaxime intermediate, which comprises the following steps:
(1) mixing benzene sulfinic acid, a first organic solvent and 2, 3-dihydrofuran, and carrying out electrophilic addition reaction to obtain a product a;
(2) mixing the raw material 1, a second organic solvent, a product a, a catalyst, N-methyl pyrrolidone and a first acid-binding agent, and carrying out nucleophilic substitution reaction to obtain a product b;
(3) mixing the product b, a third organic solvent, a second acid-binding agent and PCl5Mixing, performing chlorination, adding a monohydric alcohol/methyl isobutyl ketone mixed solution into the obtained chlorination feed liquid, performing esterification, adding an aqueous solution of alkali into the obtained esterification feed liquid, adjusting the pH value to 7.0-7.5, and performing hydrolysis reaction to obtain a product c;
(1) mixing benzene sulfinic acid, a first organic solvent and 2, 3-dihydrofuran, and carrying out electrophilic addition reaction to obtain a product a;
(2) mixing the raw material 1, a second organic solvent, a product a, a catalyst, N-methyl pyrrolidone and a first acid-binding agent, and carrying out nucleophilic substitution reaction to obtain a product b;
(3) mixing the product b, a third organic solvent, a second acid-binding agent and PCl5Mixing, performing chlorination, adding a monohydric alcohol/methyl isobutyl ketone mixed solution into the obtained chlorination feed liquid, performing esterification, adding an aqueous solution of alkali into the obtained esterification feed liquid, adjusting the pH value to 7.0-7.5, and performing hydrolysis reaction to obtain a product c;
(4) mixing the product c, water, acetone and sodium hydrosulfite, and carrying out denitrification benzyl reaction on the obtained mixed feed liquid under the condition that the pH value is 6.8-7.2 to obtain a product d;
in the present invention, the starting materials used are all commercially available products well known in the art, unless otherwise specified.
In the invention, benzene sulfinic acid, a first organic solvent and 2, 3-dihydrofuran are mixed for electrophilic addition reaction to obtain a product a.
In the present invention, the first organic solvent preferably includes dichloromethane, chloroform, diethyl ether, toluene, tetrahydrofuran or 2, 3-dihydrofuran, more preferably dichloromethane, chloroform or tetrahydrofuran, and most preferably dichloromethane.
In the present invention, it is preferable that the benzenesulfinic acid is dissolved in the first organic solvent, and then the 2, 3-dihydrofuran is added dropwise at room temperature to perform the mixing.
In the invention, the mass ratio of the first organic solvent to the benzene sulfinic acid is preferably (5-8): 1, and more preferably (6-7): 1. In the invention, the molar ratio of the 2, 3-dihydrofuran to the benzene sulfinic acid is preferably 1 (1.02-1.2), more preferably 1 (1.05-1.15), and most preferably 1 (1.08-1.10).
In the invention, the temperature of the electrophilic addition reaction is preferably 20-35 ℃, and more preferably 25-30 ℃; the time of the electrophilic addition reaction is preferably 3 to 6 hours, and more preferably 4 to 5 hours. The invention preferably employs TLC plates to control the electrophilic addition reaction.
In the present invention, the electrophilic addition reaction has the formula 1:
after the electrophilic addition reaction is completed, the obtained reaction liquid is preferably subjected to post-treatment; the post-treatment preferably comprises the steps of concentrating the reaction liquid under reduced pressure, adding dichloromethane for dissolution, and sequentially washing with alkaline water and clear water to obtain an organic layer; and drying, filtering and concentrating the organic layer under reduced pressure to dryness to obtain a product a. In the present invention, the alkali water is preferably a saturated sodium bicarbonate solution. The invention has no special requirements on the processes of the alkaline water washing and the clear water washing, and the alkaline water washing and the clear water washing which are well known in the field can be adopted. In the present invention, the drying agent is preferably anhydrous sodium sulfate, and the drying time is preferably 30 minutes. The amount of the drying agent used in the present invention is not particularly limited, and may be those known in the art. The process of the reduced pressure concentration is not particularly required in the invention, and the reduced pressure concentration process well known in the field can be adopted.
The product a is prepared by adopting the steps, the reaction is thorough, the product a with higher purity and yield can be obtained, and the problem that the post-treatment purification is difficult due to incomplete reaction is solved.
After the product a is obtained, the raw material 1, a second organic solvent, the product a, a catalyst, N-methyl pyrrolidone and a first acid-binding agent are mixed for nucleophilic substitution reaction to obtain a product b.
In the present invention, the second organic solvent preferably includes tetrahydrofuran, 2-methyltetrahydrofuran or toluene, and more preferably tetrahydrofuran or 2-methyltetrahydrofuran.
In the present invention, the catalyst preferably comprises one or more of zinc bromide, zinc chloride, lithium chloride, nickel bromide, nickel acetate, sodium bromide and sodium iodide, more preferably one or more of zinc bromide, lithium chloride and sodium bromide, and most preferably zinc bromide and/or sodium bromide. When the catalyst comprises a plurality of the substances, the proportion of each catalyst is not particularly required, and any proportion can be adopted.
In the present invention, the first acid scavenger preferably comprises one or more of pyridine, 2, 6-lutidine, morpholine, 2-methylpyridine, triethylamine and diethylamine, more preferably one or more of pyridine, 2, 6-lutidine, morpholine and 2-methylpyridine, and most preferably morpholine. When the first acid-binding agent comprises a plurality of the substances, the proportion of each acid-binding agent is not particularly required, and any proportion can be adopted.
The invention has no special requirement on the dosage of the second organic solvent, and the raw material 1 and the product a can be completely dissolved.
In the invention, the molar ratio of the raw material 1 to the product a is preferably 1 (1.0-2.2), more preferably 1 (1.2-2.0), and further preferably 1 (1.5-1.8); the mol ratio of the raw material 1 to the first acid-binding agent is preferably 1 (1.2-2.0), more preferably 1 (1.4-1.8), and further preferably 1 (1.5-1.6); the molar ratio of the raw material 1 to the catalyst is preferably 1 (0.5-1.2), more preferably 1 (0.6-1.0), and further preferably 1 (0.7-0.9); the molar ratio of the raw material 1 to the N-methylpyrrolidone is preferably 1 (0.01-0.1), more preferably 1 (0.02-0.08), and even more preferably 1 (0.04-0.06).
In the present invention, mixing the raw material 1, the second organic solvent, the product a, the catalyst, the N-methylpyrrolidone, and the first acid scavenger preferably includes: respectively dissolving a raw material 1 and a product a into a second organic solvent to obtain a dissolved solution of the raw material 1 and a dissolved solution of the product a; and (2) adding the solution of the product a and a catalyst into the solution of the raw material 1, dropwise adding N-methylpyrrolidone and a first acid-binding agent, heating to the temperature of nucleophilic substitution reaction, and carrying out nucleophilic substitution reaction.
The invention has no special requirement on the dropping rate of the N-methyl pyrrolidone and the first acid-binding agent, and the N-methyl pyrrolidone and the first acid-binding agent can be dropped drop by drop. The invention adopts a dripping mode to facilitate the nucleophilic substitution reaction to be more sufficient. In the present invention, N-methylpyrrolidone facilitates the acceleration of the rate of nucleophilic substitution reaction and promotes the reaction to proceed more thoroughly.
In the invention, the temperature of the nucleophilic substitution reaction is preferably 40-55 ℃, and more preferably 45-50 ℃; the time is preferably 16 to 24 hours, more preferably 18 to 22 hours, and further preferably 20 to 21 hours. The invention preferably uses TLC point plate to control the reaction progress.
In the present invention, the nucleophilic substitution reaction has the formula 2:
after the nucleophilic substitution reaction, the present invention preferably subjects the obtained reaction solution to a post-treatment. In the present invention, the post-treatment preferably comprises: concentrating the reaction solution under reduced pressure, and adding dichloromethane into a substrate for secondary dissolution to obtain a dissolved solution; mixing and stirring the dissolved solution and a saturated sodium bicarbonate aqueous solution to generate a precipitate, filtering, and layering filtrate to obtain an organic layer; washing the organic layer with saturated sodium bicarbonate water solution, layering, washing the lower layer with clear water, drying the obtained organic layer with anhydrous sodium sulfate, filtering, concentrating the obtained filtrate under reduced pressure to dryness, adding a crystallization solvent into the obtained substrate for pulping and crystallizing, filtering and drying to obtain a product b.
The present invention does not require any particular process for the above-mentioned concentration under reduced pressure, and can be carried out by a concentration under reduced pressure known in the art. The invention has no special requirement on the addition amount of the dichloromethane, and can completely dissolve the substrate. The amount of the saturated aqueous sodium bicarbonate solution used in the present invention is not particularly limited, and may be those known in the art. In the present invention, the mixing and stirring time is preferably 30 min. In the present invention, the crystallization solvent is preferably methanol, ethanol, isopropanol, ethyl acetate, isobutanol, preferably methanol or isopropanol, and most preferably methanol. The invention has no special requirements on the pulping and crystallization process, and the pulping and crystallization process well known in the field can be adopted. In the invention, the drying temperature is preferably 40-45 ℃, the drying time has no special requirement, and the drying is carried out until the drying is complete.
After a product b is obtained, the product b, a third organic solvent, a second acid-binding agent and PCl are mixed5Mixing, performing chlorination reaction, adding monohydric alcohol/methyl isobutyl ketone mixed solution into the chlorination reaction solution, performing esterification reaction, and esterifyingAnd adding an alkali aqueous solution into the reaction liquid to adjust the pH value to 7.0-7.5, and performing hydrolysis reaction to obtain a product c.
Firstly, the product b, a third organic solvent, a second acid-binding agent and PCl5Mixing and carrying out chlorination reaction.
In the present invention, the third organic solvent preferably includes a solvent including dichloromethane, chloroform or carbon tetrachloride; the second acid scavenger preferably comprises pyridine, 2-methylpyridine or 2, 6-dimethylpyridine.
The invention has no special requirement on the dosage of the third organic solvent, and the product b can be completely dissolved.
In the invention, the product b, the second acid scavenger and PCl5The molar ratio of (A) to (B) is preferably 1 (2.0 to 2.5) to (2.0 to 2.5), more preferably 1 (2.2 to 2.4) to (2.2 to 2.4).
In the invention, the product b, a third organic solvent, a second acid-binding agent and PCl5The mixing preferably comprises: dissolving the product b by using a third organic solvent, cooling the solution of the product b to-15 to-10 ℃, and then adding an acid-binding agent and PCl5And carrying out chlorination reaction.
In the present invention, the temperature of the chlorination reaction is preferably-15 to-10 ℃, more preferably-14 to-12 ℃; the time is preferably 4 to 6 hours, more preferably 4.5 to 5.5 hours. Phenylacetyl and PCl in the product b in the chlorination reaction process5The reaction produces imine chloride.
After the chlorination reaction is finished, the method directly adds monohydric alcohol/methyl isobutyl ketone mixed solution into the obtained chlorination reaction feed liquid to carry out esterification reaction.
In the present invention, the monohydric alcohol in the monohydric alcohol/methyl isobutyl ketone mixed solution is preferably methanol, ethanol or isopropanol, and more preferably methanol; the volume ratio of the monohydric alcohol to the methyl isobutyl ketone in the monohydric alcohol/methyl isobutyl ketone mixed solution is preferably (8-10): 1-2; in the invention, the mass ratio of the product b to the mixed solution of monohydric alcohol/methyl isobutyl ketone is preferably 1 (8-12), more preferably 1 (9-11), and still more preferably 1 (9.5-10).
In the present invention, the monohydric alcohol/methyl isobutyl ketone mixed solution is preferably added dropwise. The invention has no special requirement on the dropping speed, and the dropping can be carried out dropwise.
In the present invention, the temperature of the esterification reaction is preferably-10 to-5 ℃, more preferably-8 to-6 ℃; the time is preferably 4 to 6 hours, more preferably 4.5 to 5.5 hours.
In the esterification reaction process, monohydric alcohol/methyl isobutyl ketone mixed solution is used for quenching excessive phosphorus pentachloride, and imine chloride obtained by chlorination reaction reacts with monohydric alcohol to generate imine ester.
The invention selects phosphorus pentachloride as the reaction raw material, has mild reaction conditions and few impurities, avoids the severe conditions of introducing chlorine and the like in the 7-ACCA deprotection process, avoids the separation of impurities by column chromatography, and has simple process operation process.
After the esterification reaction is finished, adding an alkali aqueous solution into the obtained esterification reaction feed liquid to adjust the pH value to 7.0-7.5, and carrying out hydrolysis reaction to obtain a product c.
In the present invention, the mass fraction of the alkali in the aqueous solution of the alkali is preferably 5%; the invention has no special requirement on the type of the alkali in the aqueous solution of the alkali, and the alkali for adjusting the pH value, which is well known in the field, can be adopted. The method has no special requirement on the addition amount of the aqueous solution of the alkali, and can control the pH value of the esterification reaction feed liquid to be 7.0-7.5. In the present invention, the aqueous solution of the base is preferably added dropwise. The invention has no special requirement on the dropping speed, and the dropping can be carried out dropwise.
In the invention, the imine ester obtained after the esterification is hydrolyzed under the proper pH value condition and the action of water, and the phenylacetyl is removed to generate imine, namely a product c.
After adding the aqueous solution of alkali, the invention preferably adds sodium bicarbonate aqueous solution and clear water to the obtained product in turn to wash once respectively, stratify, concentrate the lower layer to dry, add solvent to the obtained dry product to crystallize, get product c. The invention has no special requirements on the washing process by adding the sodium bicarbonate water solution and the clean water, and the washing process known in the field can be adopted. The concentration process of the present invention is not particularly limited, and may be a concentration process well known in the art. In the invention, the solvent for crystallization preferably comprises one or more of ethanol, methanol, isopropanol and ethyl acetate, and when the solvent for crystallization comprises a plurality of the substances, the proportion of each solvent in the invention has no special requirement and can be any proportion. In the present invention, the mass ratio of the product b to the crystallization solvent is preferably 1: (6-10), more preferably 1: (7-8).
The phenylacetyl in the product b is removed through the whole step (3) to obtain a product c, and a specific reaction equation is shown as a formula 3:
after the product c is obtained, the product c, water, acetone and sodium hydrosulfite are mixed, and the obtained mixed feed liquid is subjected to denitration benzyl reaction under the condition that the pH value is 6.8-7.2, so that a product d is obtained.
In the invention, the molar ratio of the product c to the sodium hydrosulfite is preferably 1 (3.0-3.8), and more preferably 1 (3.2-3.6); the mass ratio of the product c, water and acetone is preferably 1: (5-10): (3-6), more preferably 1: (6-8): (4-5).
The method carries out the denitration benzyl reaction in an acetone/water system, has mild reaction conditions, successfully reduces the p-nitrobenzyl alcohol into the p-aminobenzyl alcohol, avoids the safety risk brought by the p-nitrobenzyl alcohol in the waste liquid and the waste water treatment, simultaneously recycles the raw material acetone, has lower cost and is more suitable for industrial production.
In the present invention, mixing the product c, water, acetone and sodium hydrosulfite preferably comprises: firstly, dissolving a product c into water and acetone to obtain a solution of the product c; adding sodium hydrosulfite into the solution of the product c in batches, heating to the temperature of the denitration benzyl reaction, and carrying out the denitration benzyl reaction.
In the invention, preferably, alkali liquor is dripped into the dissolved solution of the product c in the process of adding sodium hydrosulfite and the process of carrying out denitration benzyl reaction, and the pH value of the reaction system is controlled to be 6.8-7.2. In the present invention, the alkali solution is preferably a sodium hydroxide solution with a mass concentration of 5%.
In the invention, the sodium hydrosulfite is added in batches, so that the decomposition of materials caused by too fast reaction and too large pH fluctuation can be prevented. The invention has no special requirements on the specific batch of the sodium hydrosulfite added in batches, and can play the above role. In the invention, the sodium hydrosulfite plays a role in reducing nitro and removing p-nitrobenzyl.
In the invention, the temperature of the denitrified benzyl reaction is preferably 35-42 ℃, and more preferably 38-40 ℃; the time is preferably 2 to 4 hours, more preferably 2.5 to 3.5 hours, and further preferably 3 hours.
In the present invention, the formula of the denitrobenzyl reaction is shown in formula 4:
after the denitrobenzyl reaction is completed, hydrochloric acid is preferably dripped into the obtained reaction liquid to adjust the pH value to 2.8-3.5, the crystal is grown for 1 hour at the temperature of 25-35 ℃, and finally, the product d is obtained through suction filtration, leaching and drying in sequence. In the present invention, the mass fraction of the hydrochloric acid is preferably 5%. The invention preferably uses acetone and water to carry out leaching respectively; in the present invention, the drying temperature is preferably 30 to 40 ℃.
The synthesis method of the cefotaxime intermediate provided by the invention is described in detail by referring to the following examples, but the method is not to be construed as limiting the scope of the invention.
Example 1
Step (1): weighing 28g of benzenesulfinic acid, dissolving the benzenesulfinic acid in 700mL of dichloromethane, dropwise adding 10g of 2, 3-dihydrofuran at room temperature, keeping the temperature of 25 ℃ for reaction for 5 hours, performing center control on a TLC point plate, after the reaction is finished, concentrating the reaction material liquid at 45 ℃ under reduced pressure, dissolving a substrate in 300mL of dichloromethane, washing the substrate by 100mL of sodium bicarbonate saturated solution and 100mL of clear water, drying an organic layer for 30 minutes by using 5g of anhydrous sodium sulfate, performing suction filtration, concentrating the filtrate under reduced pressure until the organic layer is dried to obtain a product a12.3g, adding 30mL of tetrahydrofuran to the product a to obtain a tetrahydrofuran solution of the product a, and performing sampling detection to obtain the HPLC solution with the purity of 98.8% and the molar yield of 82.3%.
Step (2): dissolving 115g of raw material in 60mL of tetrahydrofuran, adding a tetrahydrofuran solution of a product a and 9.0g of zinc bromide as a catalyst, dropwise adding 1mL of N-methylpyrrolidone (NMP) and 3g of pyridine, heating to 45 ℃, reacting for 20 hours, controlling in a TLC point plate, concentrating under reduced pressure at 45 ℃ after the reaction is finished to constant weight, adding 300mL of dichloromethane for secondary dissolution, adding 100mL of saturated sodium bicarbonate aqueous solution, stirring for 30 minutes, generating precipitates, filtering, layering filtrate, washing an organic layer for 1 time by adding 100mL of saturated sodium bicarbonate aqueous solution, layering, washing a lower layer for 1 time by adding 100mL of clear water, adding 3g of anhydrous sodium sulfate into the obtained organic layer, drying for 30 minutes, filtering, concentrating the filtrate under reduced pressure at 35 ℃ to dryness, adding 150mL of methanol into a substrate, pulping at room temperature, crystallizing, filtering, drying at 40 ℃ to obtain a product b11.8g, and sampling and detecting the purity of 91.3% and the molar yield of 73.6%.
And (3): 10g of the product b is taken and dissolved by 300mL of dichloromethane, the temperature is reduced to-15 ℃, and 3.8g of pyridine and PCl are added510.0g of the mixture is reacted for 4 hours at the temperature of minus 15 ℃, methanol/methyl isobutyl ketone mixed solution (comprising 80mL of methanol and 30mL of methyl isobutyl ketone) is dripped to quench, the temperature is controlled at minus 8 ℃, the reaction is kept for 4 hours, a sample TLC point plate is used for controlling the reaction in a central way, the raw material point disappears, and the reaction is considered to be complete. Dropwise adding 5% sodium hydroxide aqueous solution, controlling the pH value to be 7.25, washing with 100mL of saturated sodium bicarbonate aqueous solution and 100mL of clear water respectively, layering, concentrating the lower layer to dryness, adding 80mL of ethanol, pulping at room temperature, crystallizing for 2 hours, and filtering to obtain the product c7.93g (which is not dried).
And (4): adding 60mL of water and 30mL of acetone into a product c (whole batch), controlling the temperature to be 22 ℃, adding 10.0g of sodium hydrosulfite in batches, adjusting and controlling the pH value to be 6.89 by using a sodium hydroxide solution with the mass concentration of 5% in the feeding process, keeping the temperature to react for 3 hours at 40 ℃ after feeding, adjusting the pH value to be 7.11 by using 5% liquid alkali, clarifying the reaction liquid, dropwise adding 5% hydrochloric acid to adjust the pH value to be 3.0 after the reaction is finished, separating out light yellow solid, controlling the temperature to be 30 ℃, growing crystals for 1 hour, leaching the solid respectively by using 30mL of acetone and 30mL of water for 1 time, and drying at 35 ℃ to obtain d4.3g of the product, wherein the purity is 97.1%, and the molar yield of the step 3 and the step 4 is 83.4%.
Example 2
The difference from example 1 is in step (1): weighing 28g of benzenesulfinic acid, dissolving the benzenesulfinic acid in 400mL of tetrahydrofuran, dropwise adding 10g of 2, 3-dihydrofuran at room temperature, keeping the temperature of 25 ℃ for reaction for 5 hours, performing center control on a TLC point plate, after the reaction is finished, concentrating the benzenesulfinic acid to be dry at 45 ℃ under reduced pressure, adding 300mL of dichloromethane into a substrate, washing the benzenesulfinic acid by 100mL of saturated solution of sodium bicarbonate and 100mL of clear water, drying an organic layer for 30 minutes by using 5g of anhydrous sodium sulfate, performing suction filtration, concentrating a filtrate under reduced pressure to be dry to obtain a product a10.3g, adding 30mL of tetrahydrofuran into the substrate to obtain a tetrahydrofuran solution of the product a, and performing sampling detection on the HPLC (high performance liquid chromatography) purity of 98.0% and the molar yield of 68.6%.
Example 3
The difference from the example 2 is only that tetrahydrofuran is changed into 2, 3-dihydrofuran, so that the 2, 3-dihydrofuran is used as a solvent and a raw material, the purity of the product a is 98.6%, and the molar yield is 71.3%.
From the results of examples 1 to 3, it can be seen that the reaction yield of step (1) in the dichloromethane system is the highest, and the purity is not very different.
Example 4
The only difference from embodiment 1 is step (2), which is replaced by: dissolving 115g of raw material in 60mL of tetrahydrofuran, adding a tetrahydrofuran solution of a product a and 8.4g of catalyst sodium bromide, dropwise adding NMP1mL and pyridine 3g, heating to 45 ℃, reacting for 20 hours, performing center control on a TLC point plate, concentrating at 45 ℃ under reduced pressure to constant weight after the reaction is finished, adding 300mL of dichloromethane for secondary dissolution, adding 100mL of saturated sodium bicarbonate aqueous solution, stirring for 30min, generating a precipitate, filtering, layering filtrate, adding 100mL of saturated sodium bicarbonate aqueous solution into an organic layer, washing for 1 time, layering, and washing a lower layer for 1 time with 100mL of clear water. Adding 3g of anhydrous sodium sulfate into an organic layer, drying for 30min, filtering, concentrating the filtrate at 30 ℃ under reduced pressure to constant weight, adding 150mL of methanol into a substrate, pulping and crystallizing at room temperature, filtering, and drying at 45 ℃ to obtain b9.8g of a product, wherein the purity is 96.5% by sampling detection, and the molar yield is 60.8%.
The steps (3) and (4) are the same as the example 1, and the obtained product d reaches the quality standard.
Examples 5 to 9
The difference from example 4 lies in the types of the catalyst and acid-binding agent in step (2), the specific catalysts and acid-binding agent are shown in table 1, the purity and molar yield of the product b are also shown in table 1, and the purity and molar yield of the product d are also shown in table 2.
TABLE 1 purity and yield of catalyst and acid scavenger and product b used in examples 5-9
From the results of the embodiments 4 to 9, it can be seen that morpholine is used as an acid-binding agent in the step (2) under the mixed catalysis of zinc bromide and sodium bromide, the reaction effect is the best, and the purity and the yield of the obtained product b are the best.
TABLE 2 purity and molar yield of product d obtained in examples 5-8
| d product purity (%) | Molar yield (%) | Loss due to dryness (%) | Source of product b |
| 97.4 | 85.6 | 1.2 | Example 5 |
| 98.3 | 84.1 | 0.03 | Example 6 |
| 97.9 | 83.6 | 0.11 | Example 7 |
| 98.5 | 82.9 | 0.06 | Example 8 |
When the product b is qualified, the product d can be prepared in a qualified mode, and the product quality and the yield are stable, so the purity and the yield of the product d obtained in the example 4 and the example 9 are not measured.
Examples 10 to 11 and comparative example 1
The purity and molar yield data of product b obtained with varying amounts of NMP over example 4 are shown in table 3.
TABLE 3 purity and molar yield of product b obtained in examples 4, 10 to 11 and comparative example 1
| Amount of NMP | Purity of final product (%) | Yield (%) | |
| Example 4 | 1mL | 96.5 | 60.8 |
| Example 10 | 4mL | 97.4 | 77.4 |
| Example 11 | 8mL | 98.2 | 75.2 |
| Comparative example 1 | 0 | 97.0 | 66.5 |
In table 3, the purity of the finished product of comparative example 1 is the purity after the secondary refining. This is because the product obtained in comparative example 1 has a large viscosity and is poorly crystallized due to the absence of NMP, requiring secondary refining; in the embodiment 4 and the embodiments 10 to 11 in which NMP is added, the crystal powder can be obtained at one time, and secondary refining is not needed, so that the purity of the product can be qualified at one time; it is demonstrated that the present invention can accelerate the rate of nucleophilic substitution reaction and promote the reaction to proceed more thoroughly by adding NMP.
Structural characterization:
the products a, b and d of example 1 were subjected to hydrogen nuclear magnetic resonance, and the obtained hydrogen spectra are shown in fig. 1 to 3, respectively. The corresponding data are as follows:
and (3) a product a:1HNMR(400Hz，DMSO)δ7.89(dt，J＝8.5，1.7Hz，2H)，7.83-7.73(m，1H)，7.72-7.62(m，2H)，5.17(dd，J＝8.1，4.0Hz，1H)，3.98-3.74(m，2H)，2.46-2.41(m，2H)，2.03-1.73(m，2H)。
and (3) a product b:1HNMR(400MHz，DMSO)δ9.23(t，J＝8.9Hz，1H)，8.29–8.20(m，2H)，7.69(t，J＝8.0Hz，2H)，7.32–7.25(m，4H)，6.96(d，J＝1.5Hz，1H)，5.55–5.44(m，1H)，5.39(d，J＝14.0Hz，2H)，5.29(d，J＝1.5Hz，1H)，5.22(t，J＝4.5Hz，1H)，3.65–3.43(m，2H)，3.34(s，1H)，4.43-4.41(m，1H)，3.76-3.74(m，2H)，1.88-1.85(m，2H)。
and (3) a product d:1H NMR(400MHz，DMSO)δ11.10-11.03(t，J＝8.6Hz，1H)，4.49-4.46(d，J＝1.5Hz，1H)，4.73-4.68(d，J＝4.5Hz，1H)，3.13-3.09(m，2H)，2.01-2.03(m，2H)，4.41-4.43(d，1H)，1.85-1.79(m，4H)，3.76-3.70(m，2H)。
as can be seen from FIGS. 1 to 3 and the above-mentioned hydrogen spectrum data, the structures of the product a, the product b and the product d prepared by the present invention are indeed shown in the structural formulas.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (10)
1. A synthesis method of a cefotaxime intermediate is characterized by comprising the following steps:
(1) mixing benzene sulfinic acid, a first organic solvent and 2, 3-dihydrofuran, and carrying out electrophilic addition reaction to obtain a product a;
(2) mixing the raw material 1, a second organic solvent, a product a, a catalyst, N-methyl pyrrolidone and a first acid-binding agent, and carrying out nucleophilic substitution reaction to obtain a product b;
(3) mixing the product b, a third organic solvent, a second acid-binding agent and PCl5Mixing, performing chlorination, adding a monohydric alcohol/methyl isobutyl ketone mixed solution into the obtained chlorination feed liquid, performing esterification, adding an aqueous solution of alkali into the obtained esterification feed liquid, adjusting the pH value to 7.0-7.5, and performing hydrolysis reaction to obtain a product c;
(4) mixing the product c, water, acetone and sodium hydrosulfite, and carrying out denitrification benzyl reaction on the obtained mixed feed liquid under the condition that the pH value is 6.8-7.2 to obtain a product d;
2. the synthesis method according to claim 1, wherein in the step (1), the temperature of the electrophilic addition reaction is 20 to 35 ℃ and the time is 3 to 6 hours.
3. The method of claim 1, wherein in step (1), the first organic solvent comprises dichloromethane, chloroform, diethyl ether, toluene, tetrahydrofuran, or 2, 3-dihydrofuran; the mass ratio of the first organic solvent to the benzene sulfinic acid is preferably (5-8): 1.
4. The synthesis method according to claim 1, wherein in the step (1), the molar ratio of the 2, 3-dihydrofuran to the benzene sulfinic acid is 1 (1.02-1.2).
5. The synthesis method according to claim 1, wherein, in the step (2),
the catalyst comprises one or more of zinc bromide, zinc chloride, lithium chloride, nickel bromide, nickel acetate, sodium bromide and sodium iodide;
the first acid-binding agent comprises one or more of pyridine, 2, 6-lutidine, morpholine, 2-methylpyridine, triethylamine and diethylamine;
the molar ratio of the raw material 1 to the product a is 1 (1.0-2.2);
the molar ratio of the raw material 1 to the first acid-binding agent is 1 (1.2-2.0);
the molar ratio of the raw material 1 to the catalyst is 1 (0.5-1.2);
the molar ratio of the raw material 1 to the N-methyl pyrrolidone is 1 (0.01-0.1).
6. The synthesis method according to claim 1 or 5, wherein in the step (2), the temperature of the nucleophilic substitution reaction is 40-55 ℃ and the time is 16-24 h.
7. The synthesis method according to claim 1, wherein, in the step (3),
the third organic solvent comprises dichloromethane, chloroform or carbon tetrachloride;
the second acid-binding agent comprises pyridine, 2-methylpyridine or 2, 6-dimethylpyridine;
the monohydric alcohol in the monohydric alcohol/methyl isobutyl ketone mixed solution is methanol, ethanol or isopropanol;
the volume ratio of the monohydric alcohol to the methyl isobutyl ketone in the monohydric alcohol/methyl isobutyl ketone mixed solution is (8-10) to (1-2);
the mass ratio of the product b to the monohydric alcohol/methyl isobutyl ketone mixed solution is 1 (8-12);
the product b, a second acid-binding agent and PCl5The molar ratio of (1), (1.8-3.0).
8. The synthesis method according to claim 7, wherein in the step (3), the temperature of the chlorination reaction is-15 to-10 ℃ and the time is 4 to 6 hours; the temperature of the esterification reaction is-10 to-5 ℃, and the time is 4 to 6 hours.
9. The synthesis method according to claim 1, wherein in the step (4), the molar ratio of the product c to the sodium hydrosulfite is 1 (3.0-3.8); the mass ratio of the product c to water to acetone is 1: (5-10): (3-6).
10. The synthesis method according to claim 9, wherein in the step (4), the temperature of the denitrobenzyl reaction is 35-42 ℃ and the time is 2-4 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110684544.4A CN113336775A (en) | 2021-06-21 | 2021-06-21 | Synthesis method of cefotaxime intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110684544.4A CN113336775A (en) | 2021-06-21 | 2021-06-21 | Synthesis method of cefotaxime intermediate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113336775A true CN113336775A (en) | 2021-09-03 |
Family
ID=77478260
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110684544.4A Pending CN113336775A (en) | 2021-06-21 | 2021-06-21 | Synthesis method of cefotaxime intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113336775A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117186116A (en) * | 2023-09-07 | 2023-12-08 | 浙江荣耀生物科技股份有限公司 | Preparation method of cefvicin intermediate |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1462275A (en) * | 2000-08-10 | 2003-12-17 | 武田药品工业株式会社 | Phosphonocephem compound |
| CN101210019A (en) * | 2006-12-31 | 2008-07-02 | 北京金源化学集团有限公司 | Methoxy cephalosporin intermediate |
| CN105254648A (en) * | 2015-11-13 | 2016-01-20 | 广东温氏大华农生物科技有限公司 | Convenia synthetic method and Convenia sodium salt synthetic method |
| CN112321611A (en) * | 2020-10-29 | 2021-02-05 | 湖北凌晟药业有限公司 | Preparation method of cefixadine mother nucleus |
-
2021
- 2021-06-21 CN CN202110684544.4A patent/CN113336775A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1462275A (en) * | 2000-08-10 | 2003-12-17 | 武田药品工业株式会社 | Phosphonocephem compound |
| CN101210019A (en) * | 2006-12-31 | 2008-07-02 | 北京金源化学集团有限公司 | Methoxy cephalosporin intermediate |
| CN105254648A (en) * | 2015-11-13 | 2016-01-20 | 广东温氏大华农生物科技有限公司 | Convenia synthetic method and Convenia sodium salt synthetic method |
| CN112321611A (en) * | 2020-10-29 | 2021-02-05 | 湖北凌晟药业有限公司 | Preparation method of cefixadine mother nucleus |
Non-Patent Citations (2)
| Title |
|---|
| DEARG S. BROWN ET AL.: "SUBSTITUTION REACTIONS OF 2-BENZENESULPHONYL CYCLIC ETHERS WITH CARBON NUCLEOPHILES", 《TETRAHEDRON》, vol. 45, no. 13, 31 December 1989 (1989-12-31), pages 4293 - 4308, XP001080102, DOI: 10.1016/S0040-4020(01)81323-5 * |
| EDITED BYKUMAR GADAMASETTI ET AL.: "《Process Chemistry in the Pharmaceutical Industry》", 10 December 2007, pages: 191 - 204 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117186116A (en) * | 2023-09-07 | 2023-12-08 | 浙江荣耀生物科技股份有限公司 | Preparation method of cefvicin intermediate |
| CN117186116B (en) * | 2023-09-07 | 2024-06-07 | 浙江荣耀生物科技股份有限公司 | Preparation method of cefvicin intermediate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP4114200B2 (en) | Method for producing nateglinide crystals | |
| CN108947891B (en) | Method for safely preparing pimavanserin and tartrate thereof by using triphosgene | |
| JP7267508B2 (en) | Manufacturing method of losartan | |
| CN115011661B (en) | Synthesis method of 3 beta-ursodeoxycholic acid | |
| CN113336775A (en) | Synthesis method of cefotaxime intermediate | |
| CN107523603A (en) | A kind of method that enzyme process prepares Cefaclor | |
| CN104193765A (en) | Method for synthesizing cefixime | |
| CN106222230A (en) | A kind of method of green enzymatic clarification cefaclor | |
| CN111116587A (en) | Preparation method of avibactam intermediate compound | |
| US20100256414A1 (en) | Process for the preparation of chirally pure nateglinide | |
| CN108690049A (en) | The method that Amoxicillin is detached from the reaction product that enzyme process prepares Amoxicillin | |
| CN107964558A (en) | A kind of cefotiam hydrochloride impurity takes off the preparation method of tetrazole Cefotiam | |
| CN107955021A (en) | A kind of production method of the Ceftriaxone Sodium of low impurity | |
| CN109266713A (en) | A kind of preparation method suitable for industrial Cefaclor | |
| CN108623598A (en) | A kind of preparation method of Imipenem intermediate and Imipenem | |
| CN117430526B (en) | Cefixime side chain ring opening acid impurity and preparation method thereof | |
| CN109535025B (en) | Preparation method of Evonib intermediate 3, 3-difluorocyclobutylamine hydrochloride | |
| CN113896691B (en) | Continuous preparation method of buprofezin | |
| KR20020065970A (en) | New manufacturing process of an useful intermediate for preparing tazobactam | |
| CN115197242A (en) | Preparation method of cefpodoxime proxetil impurity I | |
| CN114591234A (en) | Industrial production method of 4- (7-methoxyquinoline-4-yl) -2-methylphenol hydrochloride | |
| CN115010723A (en) | Cesporanic acid sulfoxide composition and preparation method thereof | |
| CN116253711A (en) | Texazolamide phosphate intermediate and preparation method thereof | |
| RU2276146C1 (en) | Method for preparing 5-amino-1,2,3-thiadiazole | |
| CN108752311A (en) | A kind of sulbenicillin sodium intermediate and its method for being used to prepare sulbenicillin sodium |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20210903 |