CN110256464B - Method for preparing cefditoren pivoxil ring-opening dimer - Google Patents
Method for preparing cefditoren pivoxil ring-opening dimer Download PDFInfo
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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
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
Abstract
The invention discloses a preparation method of a cefditoren pivoxil ring-opening dimer, which is characterized by comprising the following steps: firstly, amino on cefditoren pivoxil is protected by Cbz (benzyloxycarbonyl), then, the ring opening is carried out to obtain a Cbz protected cefditoren pivoxil ring-opening product, then, the Cbz protected cefditoren pivoxil ring-opening product reacts with the cefditoren pivoxil to obtain a Cbz protected cefditoren pivoxil ring-opening dimer, and finally, the Cbz protection is removed to obtain a product. The preparation method provided by the invention is simple in steps, low in cost and suitable for large-scale preparation. The content of the open-loop dimer of cefditoren pivoxil prepared by the preparation method provided by the invention can reach more than 95.0%, the yield can reach 58%, a theoretical basis is provided for safe use of medicines, effective data support is provided for the quality standard of cefditoren pivoxil, and effective guarantee is provided for clinical safe use of medicines.
Description
Technical Field
The invention relates to a preparation method of a cefditoren pivoxil ring-opening dimer, belonging to the field of impurity analysis in drug synthesis.
Background
Cefditoren Pivoxil (Cefditoren Pivoxil) with the chemical name (6R, 7R) -2, 2-dimethylpropanoyloxymethyl-7- [ (Z) -2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido ] -3- [ (Z) -2- (4-methyl-1, 3-thiazol-5-yl) ethenyl ] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate.
Cefditoren pivoxil is an ester type oral third-generation cephalosporin antibiotic developed by Mingmingzhiguo corporation, first marketed in Japan in 1994, marketed in China in 4 months in 2001 under the trade name of Meiaic (Meiact), and is mainly used for clinically treating infections caused by gram-positive bacteria and gram-negative bacteria. The product has wide antibacterial effect, and especially has antibacterial effect against gram-positive bacteria such as Staphylococcus and Streptococcus (including Streptococcus pneumoniae), gram-negative bacteria such as Escherichia coli, Carbambust sweat coccus, Klebsiella, Proteus, Haemophilus influenzae, and anaerobic bacteria such as Peptostreptococcus and Bacteroides. The medicine has the action mechanism of inhibiting the synthesis of bacterial cell walls, and has the characteristics of wide antibacterial spectrum, obvious curative effect, safety, stability, good oral absorption, high blood concentration, wide in-vivo distribution and the like.
More methods for synthesizing cefditoren pivoxil are reported at present, such as WO2005016936 and EP 0175610. However, most processes mainly use the synthesis method reported in US2006/0173175, and the route is shown as follows:
the method comprises the steps of reacting cefditoren mother nucleus 7-ATCA with AE active ester to obtain cefditoren acid, salifying under the alkaline condition of sodium isooctanoate to obtain cefditoren sodium, and finally reacting the cefditoren sodium with iodomethyl pivalate to obtain the target product cefditoren pivoxil.
In the process of research and development of new drugs, the quality of the drugs is an important standard for measuring the quality of the drugs, and the quality of the drugs is determined by the curative effect and the toxic and side effects of the drugs, namely the effectiveness and the safety of the drugs. The content of the effective components of the medicine is an important mark for reflecting the purity of the medicine, and impurities in the medicine directly influence the curative effect of the medicine and can cause toxic and side effects. The impurities of the medicine are other chemical substances except the introduced or generated medicine in the processes of production, storage and transportation, and the existence of the impurities not only affects the purity of the medicine, but also brings non-therapeutic active toxic and side effects and must be controlled. For safe and effective use of drugs, the quality standards of drugs have strict requirements on the purity of active ingredients of drugs and the limits of impurities, and generally, more than 0.1% of drug impurities should be identified and quantified by a selective method.
For drug developers, the main work is not only how to obtain high-quality drug Substances (APIs) and develop efficient synthesis processes, but also how to study the types and sources of impurities in the drug substances and how to control the generation of process impurities. Usually, researchers can firstly orient impurities generated in a synthesis process, and secondly develop an efficient impurity synthesis route so as to obtain a large amount of impurity reference substances and ensure the development of quality detection work (such as impurity HPLC positioning, impurity content measurement and the like) of each batch of raw material medicines.
The main impurities present in cefditoren pivoxil are:
the cefditoren pivoxil ring-opening dimer is used as an important impurity to be researched in quality control of cefditoren pivoxil, and the impurity reference substance is mainly obtained by separating and extracting from a cefditoren pivoxil crude product at present, but the method has the defects of complicated steps, low yield and low purity, and impurities with similar structures are difficult to completely separate, so that the detection accuracy is influenced. With the advancement of the national research work on drug consistency, the preparation method of the impurity compound cefditoren pivoxil ring-opening dimer is determined, a qualified reference substance is provided, and the quality control of cefditoren pivoxil can be performed positively.
Disclosure of Invention
In view of the above technical problems, a first object of the present invention is to provide a method for preparing cefditoren pivoxil ring-opened dimer.
In order to achieve the purpose, the technical scheme of the invention is as follows: the preparation method of the cefditoren pivoxil ring-opening dimer is characterized by comprising the following steps: firstly, amino on cefditoren pivoxil is protected by Cbz (benzyloxycarbonyl), then, the ring opening is carried out to obtain a Cbz protected cefditoren pivoxil ring-opening product, then, the Cbz protected cefditoren pivoxil ring-opening product reacts with the cefditoren pivoxil to obtain a Cbz protected cefditoren pivoxil ring-opening dimer, and finally, the Cbz protection is removed to obtain a product.
The Cbz (benzyloxycarbonyl) protection of the amino group on cefditoren pivoxil comprises the following steps: adding cefditoren pivoxil and a first organic solvent into a reaction container, cooling to 0-5 ℃ under stirring, dropwise adding excessive benzyl chloroformate, dropwise adding organic base at the same time, controlling the pH value of the system to be 6.5-7.5, reacting at 5-15 ℃ after the addition is finished, adding water after the reaction is finished, stirring, standing for layering, washing an organic layer with water, and concentrating under reduced pressure to obtain an oily substance which is directly used for the next reaction.
The corresponding equation is:
in the scheme, the method comprises the following steps: the molar ratio of the cefditoren pivoxil to the benzyl chloroformate is 1: 1.01-1.2. Is beneficial to the reaction.
In the scheme, the method comprises the following steps: the first organic solvent is dichloromethane or trichloromethane, and the organic base is one of triethylamine, tributylamine, diethylamine, diisopropylethylamine and pyridine.
The step of obtaining Cbz protected cefditoren pivoxil ring-opening product by ring opening is as follows: dissolving the oily matter in the first step in a second solvent, cooling to-20 to-5 ℃ under stirring, slowly adding an alkaline substance, heating to 10-20 ℃ after the addition for reaction, adding ethyl acetate and water after the reaction, stirring and extracting, adjusting the pH value to 3-4 with acid liquor, standing for layering, washing an organic layer with saturated saline water, drying, filtering, and concentrating under reduced pressure until the oily matter is dried to obtain the oily matter which directly enters the next step for reaction.
The corresponding equation is:
in the scheme, the method comprises the following steps: the second organic solvent is one of dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and 2-methyltetrahydrofuran; the alkaline substance is one of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate and sodium carbonate.
Preferably: the molar amount of the basic substance is 1 to 1.2 times of the molar amount of cefditoren pivoxil calculated on the basis of cefditoren pivoxil.
The step of reacting the Cbz protected cefditoren pivoxil ring-opened product with cefditoren pivoxil to obtain the Cbz protected cefditoren pivoxil ring-opened dimer comprises the following steps: dissolving the oily matter in the previous step in the first organic solvent, cooling to below-30 ℃ under the protection of nitrogen, dropwise adding excessive methanesulfonyl chloride or pivaloyl chloride or ethyl chloroformate, stirring for 2-10 minutes, dropwise adding excessive organic base, continuing stirring for 20-50 minutes after the addition is finished, then adding a solution of the first organic solvent of cefditoren pivoxil pre-cooled to below-20 ℃, stirring to complete reaction at below-20 ℃ to-10 ℃, adding water, stirring, standing for layering, washing the organic layer with water and saturated saline water in sequence, drying, filtering, concentrating under reduced pressure to obtain a light yellow solid, and directly carrying out the next reaction.
The corresponding equation is:
in the scheme, the method comprises the following steps: the molar amount of the methanesulfonyl chloride or pivaloyl chloride or ethyl chloroformate is 1.1 to 1.3 times the molar amount of cefditoren pivoxil and the molar amount of the organic base is 1.5 to 1.6 times the molar amount of cefditoren pivoxil, calculated as cefditoren pivoxil in the first step.
The procedure for removing the Cbz protection is as follows: and dissolving the light yellow solid obtained in the previous step in the second organic solvent, adding palladium-carbon, replacing with nitrogen, hydrogenating at room temperature until the reaction is complete, filtering, concentrating under reduced pressure to obtain a crude product, and purifying by silica gel column chromatography to obtain the product.
The reaction equation is:
in the scheme, the method comprises the following steps: silica gel column chromatography is carried out by adopting ethyl acetate-petroleum ether with the volume ratio of 1:1 for elution.
Has the advantages that: the preparation method provided by the invention is simple in steps, low in cost and suitable for large-scale preparation. The content of the open-loop dimer of cefditoren pivoxil prepared by the preparation method provided by the invention can reach more than 95.0%, the yield can reach 58%, a theoretical basis is provided for safe use of medicines, effective data support is provided for the quality standard of cefditoren pivoxil, and effective guarantee is provided for clinical safe use of medicines.
Detailed Description
The invention is further illustrated by the following examples:
example 1
A. Preparation of Cbz protected cefditoren pivoxil
Adding 6.2g (0.01mol) of cefditoren pivoxil and 100ml of dichloromethane into a reaction bottle, cooling to 0 ℃ under stirring, dropwise adding 0.0101mol of benzyl chloroformate, dropwise adding triethylamine, controlling the pH value of the system to be between 6.5, reacting at about 5 ℃ after the addition is finished, adding 100ml of water after the reaction is finished, stirring for 15 minutes, standing for layering, washing an organic layer with water, concentrating under reduced pressure to obtain an oily substance, and directly carrying out the next reaction without purification.
B. Preparation of Cbz protected cefditoren pivoxil ring-openers
Dissolving the oily substance in the previous step in 50ml of dimethyl sulfoxide, cooling to-20 ℃ under stirring, slowly adding 0.01mol of sodium hydroxide, heating to 10 ℃ for reaction, after checking the reaction by HPLC, adding 50ml of water and 50ml of ethyl acetate, adjusting the pH value to 3.5 by using 5% hydrochloric acid under stirring, standing for layering, extracting a water layer by using 20ml of ethyl acetate, combining ethyl acetate layers, washing by using saturated saline water, drying by anhydrous magnesium sulfate, filtering, concentrating under reduced pressure to obtain the oily substance, and directly carrying out the next reaction without separation.
C. Preparation of Cbz protected cefditoren pivoxil ring-opened dimer
Dissolving the oily matter in the previous step in 60ml of dichloromethane, cooling to the temperature below minus 30 ℃ under the protection of nitrogen, dropwise adding 0.011mol of methanesulfonyl chloride, stirring for 2 minutes, dropwise adding 0.015mol of triethylamine, continuing to stir for 20 minutes after the addition is finished, adding a solution of 6.2g of cefditoren pivoxil and 50ml of dichloromethane which are pre-cooled to the temperature below minus 20 ℃, stirring for 3 hours at the temperature below minus 20 ℃, completely reacting, adding 100ml of water, stirring for 5 minutes, standing for layering, washing an organic layer with 50ml of water and 50ml of saturated saline in sequence, drying with anhydrous magnesium sulfate, filtering, concentrating under reduced pressure to obtain a light yellow solid, and directly carrying out the next reaction without purification.
D. Preparation of cefditoren pivoxil ring-opening dimer
The solid obtained above was dissolved in 100ml of tetrahydrofuran, 2g of 10% palladium on charcoal was added, the reaction was completed by replacement with nitrogen and hydrogenation at room temperature, and the mixture was filtered and concentrated under reduced pressure to obtain about 9.5g of crude product. Purification by silica gel column chromatography eluting with ethyl acetate-petroleum ether (1:1) gave 7.28g of product. The purity of the product is 97.8 percent by HPLC detection, RRT2.71 and the relative retention time of the product is consistent with that of a cefditoren pivoxil ring-opening dimer control product.
MS mass spectrometry analysis of the product
The molecular ion peak of the product is M/z1242.23(M + 1). Formula C of this product50H56N12O14S6Is consistent with molecular weight 1241.46.
Obtaining the product1H-NMR and13CNMR structure was confirmed to be consistent with the control profile.
The HPLC detection conditions are as follows:
a chromatographic column: daisogel C18, 10. mu.100A, 30X 250mm
Octadecylsilane bonded silica was used as a packing material (Chemco Pak CHEMCOSOB 5-ODS-H4.6 mm. times.250 mm 5 μm column).
The ammonium formate solution (1.58 g ammonium formate, 900ml water, pH adjusted to 4.5 with formic acid solution, water diluted to 1000ml) was taken and acetonitrile-methanol was taken to 450: 250: 250 is mobile phase A; the ammonium formate solution (1.58 g ammonium formate, 900ml water, pH adjusted to 4.5 with formic acid solution, water diluted to 1000ml) was taken and acetonitrile-methanol was taken to 450: 550: 550 is mobile phase B; adjusting the flow rate to about 1ml/min to maintain the cefditoren pivoxil main peak for about 14 minutes, and eluting according to the following gradient procedure (see table one); the column temperature is 40 ℃; the detection wavelength was 254 nm.
Under these conditions, the relevant parameter for the substance concerned is
Example 2
A. Preparation of Cbz protected cefditoren pivoxil
Adding 6.2g (0.01mol) of cefditoren pivoxil and 100ml of trichloromethane into a reaction bottle, cooling to 5 ℃ under stirring, dropwise adding 0.012mol of benzyl chloroformate, simultaneously dropwise adding diethylamine, controlling the pH value of the system to be 7.5, reacting at about 15 ℃ after the addition is finished, adding 100ml of water after the reaction is finished, stirring for 15 minutes, standing for layering, washing an organic layer with water, concentrating under reduced pressure to obtain an oily substance, and directly carrying out the next reaction without purification.
B. Preparation of Cbz protected cefditoren pivoxil ring-openers
Dissolving the oily matter in 50ml of N, N-dimethylformamide, cooling to-15 ℃ under stirring, slowly adding 0.012mol of potassium hydroxide, heating to 20 ℃ for reaction, after checking the reaction by HPLC, adding 50ml of water and 50ml of ethyl acetate, adjusting the pH value to 3 with 5% hydrochloric acid under stirring, standing for layering, extracting the water layer with 20ml of ethyl acetate, combining ethyl acetate layers, washing with saturated saline, drying with anhydrous magnesium sulfate, filtering, concentrating under reduced pressure to obtain the oily matter, and directly carrying out the next reaction without separation.
C. Preparation of Cbz protected cefditoren pivoxil ring-opened dimer
Dissolving the oily matter in the previous step in 60ml of trichloromethane, cooling to below-30 ℃ under the protection of nitrogen, dropwise adding 0.012mol of pivaloyl chloride, stirring for 8 minutes, dropwise adding 0.016mol of pyridine, continuing to stir for 40 minutes after the addition is finished, adding a solution of 6.2g of cefditoren pivoxil and 50ml of dichloromethane which are pre-cooled to below-20 ℃, stirring and reacting for 3 hours at-10 ℃, completely reacting, adding 100ml of water, stirring for 5 minutes, standing and layering, washing an organic layer with 50ml of water and 50ml of saturated saline in sequence, drying with anhydrous magnesium sulfate, filtering, concentrating under reduced pressure to obtain a light yellow solid, and directly carrying out the next reaction without purification.
D. Preparation of cefditoren pivoxil ring-opening dimer
The solid obtained above was dissolved in 100ml of 2-methyltetrahydrofuran, 2g of 10% palladium on charcoal was added, the reaction was completed by replacement with nitrogen and hydrogenation at room temperature, and the mixture was filtered and concentrated under reduced pressure to obtain about 9.42g of crude product. Purification by silica gel column chromatography eluting with ethyl acetate-petroleum ether (1:1) gave 7.32g of product.
The purity of the product is 95.9 percent by HPLC detection, RRT2.71 is consistent with the relative retention time of a cefditoren pivoxil ring-opening dimer control product. MS, MS,1H-NMR and13the C-NMR structure was confirmed to be consistent with the spectrum of the control.
Example 3
A. Preparation of Cbz protected cefditoren pivoxil
Adding 6.2g (0.01mol) of cefditoren pivoxil and 100ml of dichloromethane into a reaction bottle, cooling to 2 ℃ under stirring, dropwise adding 0.0105mol of benzyl chloroformate, simultaneously dropwise adding diisopropylethylamine, controlling the pH value of the system to be 7.0, reacting at about 10 ℃ after the addition is finished, adding 100ml of water after the reaction is finished, stirring for 15 minutes, standing for layering, washing an organic layer with water, concentrating under reduced pressure to obtain an oily substance, and directly carrying out the next reaction without purification.
B. Preparation of Cbz protected cefditoren pivoxil ring-openers
Dissolving the oily substance in the previous step in 50ml of N-methyl pyrrolidone, cooling to-10 ℃ under stirring, slowly adding 0.0105mol of potassium carbonate, heating to 15 ℃ for reaction, after checking the reaction by HPLC, adding 50ml of water and 50ml of ethyl acetate, adjusting the pH value to 4 by using 5% hydrochloric acid under stirring, standing for layering, extracting a water layer by using 20ml of ethyl acetate, combining ethyl acetate layers, washing by using saturated saline water, drying by anhydrous magnesium sulfate, filtering, concentrating under reduced pressure to obtain the oily substance, and directly carrying out the next reaction without separation.
C. Preparation of Cbz protected cefditoren pivoxil ring-opened dimer
Dissolving the oily matter in the previous step in 60ml of dichloromethane, cooling to below minus 30 ℃ under the protection of nitrogen, dropwise adding 0.013mol of ethyl chloroformate, stirring for 6 minutes, dropwise adding 0.016mol of diethylamine, continuously stirring for 20-50 minutes after the addition is finished, adding a solution of 6.2g of cefditoren pivoxil and 50ml of dichloromethane which are pre-cooled to below minus 20 ℃, stirring for 3 hours at the temperature of minus 15 ℃, completely reacting, adding 100ml of water, stirring for 5 minutes, standing for layering, washing an organic layer with 50ml of water and 50ml of saturated saline in sequence, drying anhydrous magnesium sulfate, filtering, concentrating under reduced pressure to obtain a light yellow solid, and directly carrying out the next reaction without purification.
D. Preparation of cefditoren pivoxil ring-opening dimer
The solid obtained above was dissolved in 100ml of N, N-dimethylformamide, 2g of 10% palladium on charcoal was added, the reaction was completed by replacement with nitrogen and hydrogenation at room temperature, and the reaction mixture was filtered and concentrated under reduced pressure to obtain about 9.15g of a crude product. Purification by silica gel column chromatography eluting with ethyl acetate-petroleum ether (1:1) gave 7.01g of product.
The purity of the product is 96.8 percent by HPLC detection, RRT2.71 and the relative retention time of the product is consistent with that of a cefditoren pivoxil ring-opening dimer control product. MS, MS,1H-NMR and13the C-NMR structure was confirmed to be consistent with the spectrum of the control.
Example 4
A. Preparation of Cbz protected cefditoren pivoxil
Adding 6.2g (0.01mol) of cefditoren pivoxil and 100ml of dichloromethane into a reaction bottle, cooling to 3 ℃ under stirring, dropwise adding 0.011mol of benzyl chloroformate, dropwise adding pyridine at the same time, controlling the pH value of the system to be 6.8, reacting at about 10 ℃ after the addition is finished, adding 100ml of water after the reaction is finished, stirring for 15 minutes, standing for layering, washing an organic layer with water, concentrating under reduced pressure to obtain an oily substance, and directly carrying out the next reaction without purification.
B. Preparation of Cbz protected cefditoren pivoxil ring-openers
Dissolving the oily substance in the previous step in 50ml tetrahydrofuran, cooling to-5 ℃ under stirring, slowly adding 0.011mol of sodium carbonate, heating to 15 ℃ for reaction, checking by HPLC to complete the reaction, adding 50ml of water and 50ml of ethyl acetate, adjusting the pH value to 3.2 with 5% hydrochloric acid under stirring, standing for layering, extracting the water layer with 20ml of ethyl acetate, combining the ethyl acetate layers, washing with saturated saline water, drying with anhydrous magnesium sulfate, filtering, concentrating under reduced pressure to obtain the oily substance, and directly carrying out the next reaction without separation.
C. Preparation of Cbz protected cefditoren pivoxil ring-opened dimer
Dissolving the oily matter in the previous step in 60ml dichloromethane, cooling to below-30 ℃ under the protection of nitrogen, dropwise adding 0.012mol of methanesulfonyl chloride, stirring for 5 minutes, dropwise adding 0.016mol of diisopropylethylamine, continuing stirring for 30 minutes after the addition is finished, adding a solution of 6.2g of cefditoren pivoxil and 50ml dichloromethane which are pre-cooled to below-20 ℃, stirring and reacting for 3 hours at-15 ℃, completely reacting, adding 100ml of water, stirring for 5 minutes, standing and layering, washing an organic layer with 50ml of water and 50ml of saturated saline in sequence, drying with anhydrous magnesium sulfate, filtering, concentrating under reduced pressure to obtain a light yellow solid, and directly carrying out the next reaction without purification.
D. Preparation of cefditoren pivoxil ring-opening dimer
The solid obtained above was dissolved in 100ml of N, N-dimethylacetamide, 2g of 10% palladium on charcoal was added, the mixture was replaced with nitrogen and then hydrogenated at room temperature until the reaction was completed, and the mixture was filtered and concentrated under reduced pressure to obtain about 8.9g of crude product. Purification by silica gel column chromatography eluting with ethyl acetate-petroleum ether (1:1) gave 6.72g of product.
The purity of the product is 95.9 percent by HPLC detection, RRT2.71 is consistent with the relative retention time of a cefditoren pivoxil ring-opening dimer control product. MS, MS,1H-NMR and13the C-NMR structure was confirmed to be consistent with the spectrum of the control.
Example 5
A. Preparation of Cbz protected cefditoren pivoxil
Adding 6.2g (0.01mol) of cefditoren pivoxil and 100ml of dichloromethane into a reaction bottle, cooling to 2 ℃ under stirring, dropwise adding 0.011mol of benzyl chloroformate, dropwise adding tributylamine simultaneously, controlling the pH value of the system to be 6.5, reacting at about 10 ℃ after the addition is finished, adding 100ml of water after the reaction is finished, stirring for 15 minutes, standing for layering, washing an organic layer with water, concentrating under reduced pressure to obtain an oily substance, and directly carrying out the next reaction without purification.
B. Preparation of Cbz protected cefditoren pivoxil ring-openers
Dissolving the oily matter in 50ml of 2-methyltetrahydrofuran, cooling to-10 ℃ under stirring, slowly adding 0.011mol of lithium hydroxide, heating to 15 ℃ for reaction, after checking the reaction by HPLC, adding 50ml of water and 50ml of ethyl acetate, adjusting the pH value to 3.3 by using 5% hydrochloric acid under stirring, standing for layering, extracting a water layer by using 20ml of ethyl acetate, combining ethyl acetate layers, washing by using saturated saline water, drying by using anhydrous magnesium sulfate, filtering, concentrating under reduced pressure to obtain the oily matter, and directly carrying out the next reaction without separation.
C. Preparation of Cbz protected cefditoren pivoxil ring-opened dimer
Dissolving the oily matter in the previous step in 60ml of dichloromethane, cooling to below minus 30 ℃ under the protection of nitrogen, dropwise adding 0.012mol of methanesulfonyl chloride, stirring for 2-10 minutes, dropwise adding 0.016mol of tributylamine, continuously stirring for 40 minutes after the addition is finished, adding a solution of 6.2g of cefditoren pivoxil and 50ml of dichloromethane which are pre-cooled to below minus 20 ℃, stirring and reacting for 3 hours at the temperature of minus 15 ℃, completely reacting, adding 100ml of water, stirring for 5 minutes, standing and layering, washing an organic layer with 50ml of water and 50ml of saturated saline in sequence, drying anhydrous magnesium sulfate, filtering, concentrating under reduced pressure to obtain a light yellow solid, and directly carrying out the next reaction without purification.
D. Preparation of cefditoren pivoxil ring-opening dimer
The solid obtained above was dissolved in 100ml of tetrahydrofuran, 2g of 10% palladium on charcoal was added, the reaction was completed by replacement with nitrogen and hydrogenation at room temperature, and the mixture was filtered and concentrated under reduced pressure to obtain about 8.99g of crude product. Purification by silica gel column chromatography eluting with ethyl acetate-petroleum ether (1:1) gave 6.90g of product.
The purity of the product is 96.5 percent by HPLC detection, RRT2.71 and the relative retention time of the product is consistent with that of a cefditoren pivoxil ring-opening dimer control product. MS, MS,1H-NMR and13the C-NMR structure was confirmed to be consistent with the spectrum of the control.
The present invention is not limited to the above-described embodiments, and those skilled in the art will understand that: various changes, modifications, substitutions and alterations can be made to the embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the claims and their equivalents.
Claims (11)
1. The preparation method of the cefditoren pivoxil ring-opening dimer is characterized by comprising the following steps: firstly, carrying out Cbz protection on an amino group on cefditoren pivoxil, then carrying out ring opening to obtain a Cbz protected cefditoren pivoxil ring-opening product, then reacting the Cbz protected cefditoren pivoxil ring-opening product with cefditoren pivoxil to obtain a Cbz protected cefditoren pivoxil ring-opening dimer, and finally removing the Cbz protection to obtain a cefditoren pivoxil ring-opening dimer; the reaction formula of each step is as follows:
2. the process for preparing cefditoren pivoxil ring-opened dimer according to claim 1, wherein the step of protecting the amino group of cefditoren pivoxil with Cbz comprises: adding cefditoren pivoxil and a first organic solvent into a reaction container, cooling to 0-5 ℃ under stirring, dropwise adding excessive benzyl chloroformate, dropwise adding organic base at the same time, controlling the pH value of the system to be 6.5-7.5, reacting at 5-15 ℃ after the addition is finished, adding water after the reaction is finished, stirring, standing for layering, washing an organic layer with water, and concentrating under reduced pressure to obtain an oily substance which is directly used for the next reaction.
3. The process for preparing cefditoren pivoxil ring-opened dimer according to claim 2, wherein: the molar ratio of the cefditoren pivoxil to the benzyl chloroformate is 1: 1.01-1.2.
4. The process for preparing cefditoren pivoxil ring-opened dimer according to claim 3, wherein: the first organic solvent is dichloromethane or trichloromethane, and the organic base is one of triethylamine, tributylamine, diethylamine, diisopropylethylamine and pyridine.
5. The process for the preparation of cefditoren pivoxil ring-opened dimer according to any one of claims 1 to 4, wherein: the step of obtaining Cbz protected cefditoren pivoxil ring-opening product by ring opening is as follows: dissolving the oily matter in the previous step in a second organic solvent, cooling to-20 to-5 ℃ under stirring, slowly adding an alkaline substance, heating to 10 to 20 ℃ after the addition for reaction, adding ethyl acetate and water after the reaction is finished, stirring and extracting, adjusting the pH value to 3-4 with acid liquor, standing for layering, washing an organic layer with saturated saline water, drying, filtering, and concentrating under reduced pressure until the oily matter is dried to obtain the oily matter which directly enters the next step for reaction.
6. The process for preparing cefditoren pivoxil ring-opened dimer according to claim 5, wherein: the second organic solvent is one of dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and 2-methyltetrahydrofuran; the alkaline substance is one of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate and sodium carbonate.
7. The process for preparing cefditoren pivoxil ring-opened dimer according to claim 6, wherein: the molar amount of the basic substance is 1 to 1.2 times of the molar amount of cefditoren pivoxil calculated on the basis of cefditoren pivoxil.
8. The process according to claim 5, wherein the step of reacting the Cbz-protected cefditoren pivoxil ring-opened product with cefditoren pivoxil to obtain the Cbz-protected cefditoren pivoxil ring-opened dimer comprises: dissolving the oily matter in the previous step in the first organic solvent, cooling to below-30 ℃ under the protection of nitrogen, dropwise adding excessive methanesulfonyl chloride or pivaloyl chloride or ethyl chloroformate, stirring for 2-10 minutes, dropwise adding excessive organic base, continuing stirring for 20-50 minutes after the addition is finished, then adding a solution of the first organic solvent of cefditoren pivoxil pre-cooled to below-20 ℃, stirring to complete reaction at below-20 ℃ to-10 ℃, adding water, stirring, standing for layering, washing the organic layer with water and saturated saline water in sequence, drying, filtering, concentrating under reduced pressure to obtain a light yellow solid, and directly carrying out the next reaction.
9. The process according to claim 8, wherein the reaction mixture comprises: the molar amount of said methanesulfonyl chloride or pivaloyl chloride or ethyl chloroformate is 1.1 to 1.3 times the molar amount of cefditoren pivoxil and the molar amount of said organic base is 1.5 to 1.6 times the molar amount of cefditoren pivoxil, calculated as cefditoren pivoxil in the first step.
10. The process according to claim 8, wherein the Cbz deprotection step comprises: and dissolving the light yellow solid obtained in the previous step in the second organic solvent, adding palladium-carbon, replacing with nitrogen, hydrogenating at room temperature until the reaction is complete, filtering, concentrating under reduced pressure to obtain a crude product, and purifying by silica gel column chromatography to obtain the product.
11. The process for preparing cefditoren pivoxil ring-opened dimer according to claim 10, wherein: silica gel column chromatography is carried out by adopting ethyl acetate-petroleum ether with the volume ratio of 1:1 for elution.
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