CN105175432A - Preparation method of cefditore - Google Patents
Preparation method of cefditore Download PDFInfo
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- CN105175432A CN105175432A CN201510567751.6A CN201510567751A CN105175432A CN 105175432 A CN105175432 A CN 105175432A CN 201510567751 A CN201510567751 A CN 201510567751A CN 105175432 A CN105175432 A CN 105175432A
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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
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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
Abstract
The invention belongs to the field of medicine synthesis, and particularly relates to a preparation method of cefditore. The method comprises the following steps that (1) under the photophobic condition, 7-ATCA and AE-active ester are added into methylene dichloride; catalysts are added; the temperature is lowered to 0 to 5 DEG C; triethylamine is added to obtain cefdiporen acid; a water solution of organic amine is added into organic solvents containing dissolved cefdiporen acid; crystal separation is carried out to obtain organic amine salts of the cefdiporen acid; (2) the organic amine salts of the cefdiporen acid take a reaction with iodomethyl pivalate under the existence of tetrabutylammonium bromide and sodium carbonate in N,N-dimethyl formamide to obtain the cefditore. The preparation method has the advantages that the organic amine salts of the cefdiporen acid are used; the defects of difficult storage and poor stability of the sodium salts of the cefdiporen acid are effectively avoided; E-shaped isomers are effectively removed; meanwhile, the esterification condition is optimized, so that the purity of final products is higher.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, be specifically related to a kind of preparation method of Cefditoren pivoxil Cephalosporins.
Background technology
Cefditoren pivoxil Cephalosporins, chemistry is by name: 2,2-dimethyl propylene acyloxymethyl (6R, 7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-methoxyl group imido kharophen]-3-[(Z)-2-(4-methyl isophthalic acid, 3-thiazole-5-base) vinyl]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-manthanoate, trade(brand)name: Meiact (Meiact).Developed by Japanese Meiji Seika Kaisba company, in 1994 in Japan's listing, be used for the treatment of gram positive organism and the microbial infection of Grain-negative.
Show after deliberation, cefditoren to streptococcus pneumoniae, hemophilus influenzae, micrococcus scarlatinae, streptococcus aureus, the microbial Community Acquired Respiratory Tract Infection treatment of the large principal causative of moraxelle catarrhalis 5 significantly.Compared with the β-lactam antibitics of third-generation cephalosporin and quinlone, Macrolide, enzyme-containing inhibitor, cefditoren is to these five large pathogenic bacterium, particularly all show remarkable anti-microbial activity to penicillin resistance pneumococcus, streptococcus aureus and some zymogenic bacterias, concrete molecular formula is as follows.
The synthetic route of Cefditoren pivoxil Cephalosporins is numerous, as: EP101666, EP175610, WO2005016936 etc.But the main route adopting US2006/0173175 report at present, as follows:
Be obtained by reacting cefditoren acid with cefditoren parent nucleus 7ATCA and 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester, add Sodium isooctanoate salify and obtain cefditoren sodium; React under cefditoren sodium and iodometyl pivalate, obtain Cefditoren pivoxil Cephalosporins, but this product purity be obtained by reacting is unstable.As: adding Sodium isooctanoate solid reaction, to obtain the impurity of cefditoren sodium more and large, and its quality and purity directly have influence on the yield and quality of preparing S-1108.
Document reacts completely for making cefditoren sodium, select-20 DEG C as temperature of reaction and increased the consumption (cefditoren sodium: iodometyl pivalate mol ratio=1:2.1) of iodometyl pivalate, the cefditoren sodium participating in reaction under this condition does not remain substantially, but the consumption of, iodometyl pivalate too high due to temperature of reaction used is too large, cause the impurity that produces as methylol Cefditoren pivoxil Cephalosporins, Δ-
3the impurity such as isomer, E isomer and α-pivaloyl group Cefditoren pivoxil Cephalosporins, dimer, open loop dimer are too large, and directly reduce drug effect and the quality of product, the Cefditoren pivoxil Cephalosporins product obtained is difficult to meet the regulation of pharmacopeia.
Summary of the invention
In view of above-mentioned complex process and impurity is more; contriver finds through a series of research; methylol Cefditoren pivoxil Cephalosporins or α-pivaloyl group Cefditoren pivoxil Cephalosporins, dimer may be cefditoren acid with the process of pivaloyl iodine methyl esters generation esterification in generate, primary amine group and iodometyl pivalate there occurs acylation reaction and alkylated reaction and generate respectively.And E isomer may be relevant with the factor such as temperature, solvent, UV-irradiation, metal ion, these impurity can increase further in storage process, and the content of above-mentioned impurity has a crucial factor for the validity period of Cefditoren pivoxil Cephalosporins preparation.
For considering above-mentioned factor, come from the theory of design based on quality, through a large amount of tests, explore a kind of preparation method of more efficient Cefditoren pivoxil Cephalosporins, the method is simple to operate, and product yield is high, quality is good, method process stabilizing, is applicable to suitability for industrialized production.
The technical solution used in the present invention is as follows:
A preparation method for Cefditoren pivoxil Cephalosporins, is characterized in that comprising the following steps:
1) under lucifuge condition, 7-ATCA (7-amino-3-[(Z)-2-(4-methyl-5-thiazole base) vinyl]-3-cephem-4-carboxylic acid) and 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester (2-methoxyimino-2-(2-amino-4-thiazolyl)-(z)-thioacetic acid benzothiazole ester) are joined in methylene dichloride, add catalyzer, cool to 0 DEG C ~ 5 DEG C, add triethylamine, obtain cefditoren acid; In the organic solvent being dissolved with cefditoren acid, add the aqueous solution of organic amine, crystallization obtains the organic amine salt of cefditoren acid;
2) organic ammonium salt of cefditoren acid is in DMF, and Tetrabutyl amonium bromide and sodium carbonate exist down and iodometyl pivalate reacts, and obtain Cefditoren pivoxil Cephalosporins.
Further, a kind of detailed preparation method of Cefditoren pivoxil Cephalosporins, is characterized in that comprising the following steps:
1) under lucifuge condition, 7-ATCA (7-amino-3-[(Z)-2-(4-methyl-5-thiazole base) vinyl]-3-cephem-4-carboxylic acid) and 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester (2-methoxyimino-2-(2-amino-4-thiazolyl)-(z)-thioacetic acid benzothiazole ester) are joined in methylene dichloride, add catalyzer, cool to 0 DEG C ~ 5 DEG C, add triethylamine, react complete, pure water is added in reaction solution, separatory, collect aqueous phase dilute hydrochloric acid and regulate pH to 3.5-4.4, with organic solvent extraction, the aqueous solution adding organic amine in organic solvent extraction liquid separates out solid, obtain the organic amine salt of cefditoren acid,
2) organic ammonium salt of cefditoren acid is at N, in dinethylformamide, Tetrabutyl amonium bromide and sodium carbonate exist down and iodometyl pivalate reacts, after completion of the reaction, sodium thiosulfate solution and ethyl acetate is dripped in reaction solution, dilute hydrochloric acid regulates pH, separate organic layer, aqueous layer with ethyl acetate extracts, merge organic layer, wash with sodium carbonate solution with after sodium thiosulfate solution washing, activated carbon decolorizing, add dehydrated alcohol after filtrate 20 DEG C of evaporated under reduced pressure, crystallization obtains Cefditoren pivoxil Cephalosporins.
Catalyzer wherein: step 1 described above) is DMAP, and its consumption is the 5%-10% of 7-ATCA molar weight.
Step 1 described above) described in 7-ATCA, 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester active ester, triethylamine molar ratio example be 1:1.05 ~ 1.10:1.4 ~ 1.5.
Step 1 described above) described in organic solvent be preferably ethyl acetate, its consumption is as the criterion can dissolve cefditoren acid under agitation condition, also can be excessive a little, certainly greatly excessive is also allow, just to need to add the water yield more for Crystallization Process, the preferred organic amine aqueous solution add volume be the 3.5-4.5 of ethyl acetate volume doubly.
Step 1 described above) described in organic amine be preferably in diisopropyl ethyl amine, Diisopropylamine, tert-butylamine, dibenzyl amine, dicyclohexylamine, tert-Octylamine one or more.More preferably Diisopropylamine.Surprisingly, adding of organic amine, be not only after becoming organic amine salt, the stability of cefditoren acid organic amine salt increases, in subsequent reactions, impurity is less, more makes us unexpected, and the cefditoren acid organic amine salt obtained is almost pure Z configuration, the amount of E isomer is negligible degree, and this is very useful to the purity of finished product.
Step 2 described above) described in cefditoren acid ammonium salt, iodometyl pivalate molar ratio be: 1:1.10 ~ 1.30; The consumption of Tetrabutyl amonium bromide is the 8%-12% of cefditoren acid ammonium salt quality; Temperature of reaction is-15 ~-20 DEG C.Preferably, step 2 described above) described in cefditoren acid ammonium salt, iodometyl pivalate molar ratio be: 1:1.15 ~ 1.20, the consumption of Tetrabutyl amonium bromide is 10% of cefditoren acid ammonium salt quality.
Step 2 described above) described in pH be that 5.8-6.5, pH are less than 5.8 or be greater than 6.5, the Cefditoren pivoxil Cephalosporins of salify increases, and causes and extracts difficulty.
Beneficial effect of the present invention: highway route design of the present invention is ingenious, the especially preparation of cefditoren acid ammonium salt, the sodium salt etc. that effectively prevent cefditoren acid should not store, the shortcoming of poor stability, effectively removes the isomer of E; Make for temperature in follow-up esterification is also accessible-15 ~-20 DEG C of industrialization simultaneously; adding of Tetrabutyl amonium bromide; the material input ratio optimized; make the selectivity of reaction better; effectively decrease cefditoren acid primary amine group and iodometyl pivalate there occurs the possibility of acylation reaction and alkylated reaction, make the purity of product higher.
Embodiment
Below in conjunction with test example and embodiment, the present invention is described in further detail.But this should be interpreted as that the scope of the above-mentioned theme of the present invention is only limitted to following embodiment, all technology realized based on content of the present invention all belong to scope of the present invention.
Embodiment 1
Under room temperature lucifuge condition, 32.4g (0.10mol) 7-ATCA and 37.6g (0.1075mol) 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester is joined in 200ml methylene dichloride, add DMAP 1.0g, stirring cools to 0 DEG C ~ 5 DEG C, slow dropping 14.6g (0.145mol) triethylamine, add rear 10 DEG C ~ 15 DEG C insulation reaction, HPLC monitors 7-ATCA < 0.5% for reacting completely, after completion of the reaction, 400ml pure water is added in reaction solution, stir 15min, separatory, collect aqueous phase, aqueous phase dichloromethane extraction once regulates pH to 3.5-4.4 with dilute hydrochloric acid afterwards, three extractions are divided by 1000ml ethyl acetate, washing once, the aqueous solution 4000mL containing 40g Diisopropylamine is added in acetic acid ethyl acetate extract, stirring reaction, solid is separated out in 5-10 DEG C, suction filtration vacuum-drying obtains micro-yellow powder shape solid 56.4g, yield 92.8%, it is 99.46% that HPLC detects purity, and E isomer does not detect, high resolution mass spectrum theoretical value: 607.1705, measured value: 607.1739,
1hNMR (500MHz, D
2o): 8.90 (1H, S), 6.75 (1H, S), 6.77 (1H, d, J=11.8Hz), 6.32 (1H, d, J=11.6Hz), 5.85 (dd, J
1=4.8Hz, J
2=8.0Hz, 1H), 5.26 (d, J=4.8Hz, 1H), 3.83 (3H, s), 3.57 (1H, d, J=18.6Hz), 3.40 (1H, d, J=18.6Hz), 2.34 (3H, s), 2.26 – 2.18 (m, 2H), 1.19 (d, J=6.4Hz, 12H, CH3).
Under room temperature lucifuge condition, 60.8g (0.1mol) cefditoren acid Diisopropylamine is joined 300mlN, in dinethylformamide, add 6.1g (10%) Tetrabutyl amonium bromide and sodium carbonate 5.3g (0.05mol) again, cool to-15 ~-20 DEG C, add 28.4g (0.1175) iodometyl pivalate,-15 DEG C ~-20 DEG C insulation reaction, HPLC monitors cefditoren sodium < 3% and is considered as reacting completely, stopped reaction, to drip in reaction solution and 2% sodium thiosulfate solution 140ml and 500ml ethyl acetate stir, drip dilute hydrochloric acid and regulate pH to 6.2, separate organic layer, aqueous layer with ethyl acetate extracts, merge organic layer, with the sodium carbonate solution washing with 2% after the sodium thiosulfate solution washing of 1%, washing, activated carbon decolorizing, filtrate 20 DEG C of evaporated under reduced pressure, add dehydrated alcohol, about-20 DEG C freezing crystallization 4h, filter, filter cake less than 40 DEG C decompression dryings, obtain light yellow solid 58.2g, yield 93.8%, HPLC content 99.20%, wherein cefditoren sodium does not detect, methylol Cefditoren pivoxil Cephalosporins content is 0.04%, Δ-
3content of isomer is 0.200%, and E isomer content is the content of 0.009%, α-pivaloyl group Cefditoren pivoxil Cephalosporins is 0.033%, and dimeric content is 0.23%.
Embodiment 2
Under room temperature lucifuge condition, 32.4g (0.10mol) 7-ATCA and 38.0g (0.1085mol) 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester is joined in 200ml methylene dichloride, add DMAP 1.0g, stirring cools to 0 DEG C ~ 5 DEG C, slow dropping 14.6g (0.145mol) triethylamine, add rear 10 DEG C ~ 15 DEG C insulation reaction, HPLC monitors 7-ATCA < 0.5% for reacting completely, after completion of the reaction, 400ml pure water is added in reaction solution, stir 15min, separatory, collect aqueous phase, aqueous phase dichloromethane extraction once regulates pH to 3.5-4.4 with dilute hydrochloric acid afterwards, three extractions are divided by 1000ml ethyl acetate, washing once, the aqueous solution 3800mL containing Diisopropylamine 40g is added in acetic acid ethyl acetate extract, stirring reaction, solid is separated out in 5-10 DEG C, suction filtration vacuum-drying obtains micro-yellow powder shape solid 55.3g, yield 91.0%, it is 99.06% that HPLC detects purity, and E isomer does not detect.
Under room temperature lucifuge condition, 60.8g (0.1mol) cefditoren acid Diisopropylamine is joined 300mlN, in dinethylformamide, add 6.1g (10%) Tetrabutyl amonium bromide and sodium carbonate 5.3g (0.05mol) again, cool to-15 ~-20 DEG C, add 29.0g (0.12mol) iodometyl pivalate,-15 DEG C ~-20 DEG C insulation reaction, HPLC monitors cefditoren sodium < 3% and is considered as reacting completely, stopped reaction, to drip in reaction solution and 2% sodium thiosulfate solution 150ml and 500ml ethyl acetate stir, drip dilute hydrochloric acid and regulate pH to 6.0, separate organic layer, aqueous layer with ethyl acetate extracts, merge organic layer, with the sodium carbonate solution washing with 2% after the sodium thiosulfate solution washing of 1%, washing, activated carbon decolorizing, filtrate 20 DEG C of evaporated under reduced pressure, add dehydrated alcohol, about-10 DEG C freezing crystallization 4h, filter, filter cake less than 40 DEG C decompression dryings, obtain light yellow solid 59.5g, yield 95.8%, HPLC content 99.40%, wherein cefditoren sodium does not detect, methylol Cefditoren pivoxil Cephalosporins content is 0.08%, Δ-
3content of isomer is 0.200%, and E isomer content is the content of 0.008%, α-pivaloyl group Cefditoren pivoxil Cephalosporins is 0.043%, and dimeric content is 0.38%.
Embodiment 3
Under room temperature lucifuge condition, 324g (1mol) 7-ATCA and 383g (1.095mol) 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester is joined in 2000ml methylene dichloride, add DMAP 11g, stirring cools to 0 DEG C ~ 5 DEG C, slow dropping 148g triethylamine, add rear 10 DEG C ~ 15 DEG C insulation reaction, HPLC monitors 7-ATCA < 1.0% for reacting completely, after completion of the reaction, 4000ml pure water is added in reaction solution, stir 30min, separatory, collect aqueous phase, aqueous phase dichloromethane extraction once regulates pH to 3.5-4.4 with dilute hydrochloric acid afterwards, three extractions are divided by 5L ethyl acetate, washing once, the aqueous solution 21L containing 350g Diisopropylamine is added in acetic acid ethyl acetate extract, stirring reaction, solid is separated out in 5-10 DEG C, suction filtration vacuum-drying obtains micro-yellow powder shape solid 560g, yield 92.1, it is 99.24% that HPLC detects purity, and E isomer does not detect.
Under room temperature lucifuge condition, 60.8g (0.1mol) cefditoren acid Diisopropylamine is joined 300mlN, in dinethylformamide, add 6.1g (10%) Tetrabutyl amonium bromide and sodium carbonate 5.3g (0.05mol) again, cool to-15 ~-20 DEG C, add 28.1g (0.117mol) iodometyl pivalate,-15 DEG C ~-20 DEG C insulation reaction, HPLC monitors cefditoren sodium < 3% and is considered as reacting completely, stopped reaction, to drip in reaction solution and 2% sodium thiosulfate solution 145ml and 500ml ethyl acetate stir, drip dilute hydrochloric acid and regulate pH to 6.3, separate organic layer, aqueous layer with ethyl acetate extracts, merge organic layer, with the sodium carbonate solution washing with 2% after the sodium thiosulfate solution washing of 1%, washing, activated carbon decolorizing, filtrate 20 DEG C of evaporated under reduced pressure, add dehydrated alcohol, about-15 DEG C freezing crystallization 4h, filter, filter cake less than 40 DEG C decompression dryings, obtain light yellow solid 59.2g, yield 95.6%, HPLC content 99.24%, wherein cefditoren sodium does not detect, methylol Cefditoren pivoxil Cephalosporins content is 0.10%, Δ-
3content of isomer is 0.208%, and E isomer content is the content of 0.005%, α-pivaloyl group Cefditoren pivoxil Cephalosporins is 0.037%, and dimeric content is 0.30%.
Simultaneous test embodiment 1
Under room temperature lucifuge condition, 32.4g (0.10mol) 7-ATCA and 37.6g (0.1075mol) 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester is joined in 200ml methylene dichloride, add DMAP 1.0g, stirring cools to 0 DEG C ~ 5 DEG C, slow dropping 14.6g (0.145mol) triethylamine, add rear 10 DEG C ~ 15 DEG C insulation reaction, HPLC monitors 7-ATCA < 0.5% for reacting completely, after completion of the reaction, 400ml pure water is added in reaction solution, stir 15min, separatory, collect aqueous phase, aqueous phase dichloromethane extraction once regulates pH to 3.5-4.4 with dilute hydrochloric acid afterwards, three extractions are divided by 1000ml ethyl acetate, washing once, concentrate and obtain solid.Solid 500ml acetone solution, adds the 100ml aqueous solution containing 30g Sodium isooctanoate, in 15 DEG C ~ 20 DEG C insulated and stirred 2h, filter, filter cake less than 40 DEG C decompression dryings, obtain light yellow solid 43.2g, it is 94.4% that HPLC detects purity, and E isomer content is 0.852%, and yield is 82.0%.
The synthesis of cefditoren pivoxil is with reference to US2006/0173175 preparation:
Result: molar yield 73.8%, HPLC content 95.8%, wherein cefditoren sodium does not detect, methylol Cefditoren pivoxil Cephalosporins content is 0.34%, Δ-
3content of isomer is 0.52%, and E isomer content is the content of 1.29%, α-pivaloyl group Cefditoren pivoxil Cephalosporins is 0.53%, and dimeric content is 0.80%.
Visible by comparative example: diisopropyl amine salt cefditoren acid intermediate prepared by the present invention has more excellent effect for the preparation of cefditoren pivoxil, and impurity is less, and product purity is higher, and the preparation for preparation provides more excellent raw material sources.
Claims (9)
1. a preparation method for Cefditoren pivoxil Cephalosporins, is characterized in that it comprises the following steps:
1) under lucifuge condition, 7-ATCA (7-amino-3-[(Z)-2-(4-methyl-5-thiazole base) vinyl]-3-cephem-4-carboxylic acid) and 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester (2-methoxyimino-2-(2-amino-4-thiazolyl)-(z)-thioacetic acid benzothiazole ester) are joined in methylene dichloride, add catalyzer, cool to 0 ~ 5 DEG C, add triethylamine, obtain cefditoren acid; In the organic solvent being dissolved with cefditoren acid, add the aqueous solution of organic amine, crystallization obtains the organic amine salt of cefditoren acid;
2) organic ammonium salt of cefditoren acid is in DMF, and Tetrabutyl amonium bromide and sodium carbonate exist down and iodometyl pivalate reacts, and obtain Cefditoren pivoxil Cephalosporins.
2. preparation method as claimed in claim 1, is characterized in that it comprises following optimization step further:
1) under lucifuge condition, 7-ATCA (7-amino-3-[(Z)-2-(4-methyl-5-thiazole base) vinyl]-3-cephem-4-carboxylic acid) and 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester (2-methoxyimino-2-(2-amino-4-thiazolyl)-(z)-thioacetic acid benzothiazole ester) are joined in methylene dichloride, add catalyzer, cool to 0 ~ 5 DEG C, add triethylamine, react complete, pure water is added in reaction solution, separatory, collect aqueous phase dilute hydrochloric acid and regulate pH to 3.5-4.4, with organic solvent extraction, the aqueous solution adding organic amine in organic solvent extraction liquid separates out solid, obtain the organic amine salt of cefditoren acid.
2) organic ammonium salt of cefditoren acid is at N, in dinethylformamide, Tetrabutyl amonium bromide and sodium carbonate exist down and iodometyl pivalate reacts, after completion of the reaction, sodium thiosulfate solution and ethyl acetate is dripped in reaction solution, dilute hydrochloric acid regulates pH, separate organic layer, aqueous layer with ethyl acetate extracts, merge organic layer, wash with sodium carbonate solution with after sodium thiosulfate solution washing, activated carbon decolorizing, add dehydrated alcohol after filtrate 20 DEG C of evaporated under reduced pressure, crystallization obtains Cefditoren pivoxil Cephalosporins.
3. preparation method as claimed in claim 1 or 2, is characterized in that step 1) described in catalyzer be DMAP, its consumption is the 5%-10% of 7-ATCA molar weight.
4. preparation method as claimed in claim 1 or 2, step 1) described in organic amine be preferably in diisopropyl ethyl amine, Diisopropylamine, tert-butylamine, dibenzyl amine, dicyclohexylamine, tert-Octylamine one or more.
5. preparation method as claimed in claim 4, step 1) described in organic amine be preferably Diisopropylamine.
6. preparation method as claimed in claim 1 or 2, is characterized in that step 1) described in organic solvent be preferably ethyl acetate, the described organic amine aqueous solution add volume be the 3.5-4.5 of ethyl acetate volume doubly.
7. preparation method as claimed in claim 1 or 2, is characterized in that step 2) described in cefditoren acid ammonium salt, iodometyl pivalate molar ratio be: 1:1.10 ~ 1.30; The consumption of Tetrabutyl amonium bromide is the 8%-12% of cefditoren acid ammonium salt quality; Temperature of reaction is-15 ~-20 DEG C.
8. preparation method as claimed in claim 1 or 2, is characterized in that step 2) described in cefditoren acid ammonium salt, iodometyl pivalate molar ratio be: 1:1.15 ~ 1.20; The consumption of Tetrabutyl amonium bromide is 10% of cefditoren acid ammonium salt quality.
9. preparation method as claimed in claim 1 or 2, is characterized in that step 2) described in pH be 5.8-6.5.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105732664A (en) * | 2016-02-05 | 2016-07-06 | 青岛麦瑞特医药技术有限公司 | Method for preparing cefditoren pivoxil cephalosporins |
| CN108129492A (en) * | 2018-02-02 | 2018-06-08 | 王成宇 | A kind of preparation method of high-purity Cefditoren pivoxil Cephalosporins |
| CN109336904A (en) * | 2018-11-21 | 2019-02-15 | 山东罗欣药业集团股份有限公司 | A kind of preparation method of Cefditoren pivoxil Cephalosporins |
| CN110183468A (en) * | 2019-06-20 | 2019-08-30 | 重庆医药高等专科学校 | The preparation method of Cefditoren pivoxil Cephalosporins dimer |
| CN111233894A (en) * | 2020-01-13 | 2020-06-05 | 浙江东邦药业有限公司 | Cefditoren pivoxil delta3Process for the preparation of isomers |
| CN113234059A (en) * | 2021-05-26 | 2021-08-10 | 四川智强医药科技开发有限公司 | Preparation method of lipoic acid impurity A |
| CN113788844A (en) * | 2021-09-08 | 2021-12-14 | 湖北凌晟药业有限公司 | Preparation method of E-type cefditoren sodium |
| CN115448931A (en) * | 2022-10-20 | 2022-12-09 | 齐鲁安替制药有限公司 | Preparation method for reducing content of methylene dimer in cefteram pivoxil |
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| WO2005016936A2 (en) * | 2003-08-14 | 2005-02-24 | Ranbaxy Laboratories Limited | Process for selective preparation of z-isomer of cefditoren and pharmaceutically acceptable salts and esters thereof |
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| CN105732664A (en) * | 2016-02-05 | 2016-07-06 | 青岛麦瑞特医药技术有限公司 | Method for preparing cefditoren pivoxil cephalosporins |
| CN108129492A (en) * | 2018-02-02 | 2018-06-08 | 王成宇 | A kind of preparation method of high-purity Cefditoren pivoxil Cephalosporins |
| CN109336904B (en) * | 2018-11-21 | 2020-06-09 | 山东罗欣药业集团股份有限公司 | Preparation method of cefditoren pivoxil |
| CN109336904A (en) * | 2018-11-21 | 2019-02-15 | 山东罗欣药业集团股份有限公司 | A kind of preparation method of Cefditoren pivoxil Cephalosporins |
| CN110183468A (en) * | 2019-06-20 | 2019-08-30 | 重庆医药高等专科学校 | The preparation method of Cefditoren pivoxil Cephalosporins dimer |
| CN110183468B (en) * | 2019-06-20 | 2020-05-01 | 重庆医药高等专科学校 | Preparation method of cefditoren pivoxil dimer |
| CN111233894A (en) * | 2020-01-13 | 2020-06-05 | 浙江东邦药业有限公司 | Cefditoren pivoxil delta3Process for the preparation of isomers |
| CN111233894B (en) * | 2020-01-13 | 2021-07-09 | 浙江东邦药业有限公司 | Cefditoren pivoxil delta3Process for the preparation of isomers |
| CN113234059A (en) * | 2021-05-26 | 2021-08-10 | 四川智强医药科技开发有限公司 | Preparation method of lipoic acid impurity A |
| CN113234059B (en) * | 2021-05-26 | 2023-08-15 | 四川智强医药科技开发有限公司 | Preparation method of lipoic acid impurity A |
| CN113788844A (en) * | 2021-09-08 | 2021-12-14 | 湖北凌晟药业有限公司 | Preparation method of E-type cefditoren sodium |
| CN115448931A (en) * | 2022-10-20 | 2022-12-09 | 齐鲁安替制药有限公司 | Preparation method for reducing content of methylene dimer in cefteram pivoxil |
| CN115448931B (en) * | 2022-10-20 | 2023-11-03 | 齐鲁安替制药有限公司 | Preparation method for reducing content of methylene dimer in cefditoren pivoxil |
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