CN101613357A - Synthesis process of ceftizoxime hydrochloride propisochlor - Google Patents
Synthesis process of ceftizoxime hydrochloride propisochlor Download PDFInfo
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- CN101613357A CN101613357A CN200910101436A CN200910101436A CN101613357A CN 101613357 A CN101613357 A CN 101613357A CN 200910101436 A CN200910101436 A CN 200910101436A CN 200910101436 A CN200910101436 A CN 200910101436A CN 101613357 A CN101613357 A CN 101613357A
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- ceftizoxime
- hcl
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- alapivoxil
- organic solvent
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- 229960001991 ceftizoxime Drugs 0.000 title claims abstract description 64
- NNULBSISHYWZJU-LLKWHZGFSA-N ceftizoxime Chemical compound N([C@@H]1C(N2C(=CCS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 NNULBSISHYWZJU-LLKWHZGFSA-N 0.000 title claims abstract description 33
- 238000000034 method Methods 0.000 title claims abstract description 24
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 21
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 title abstract description 3
- KZNDFYDURHAESM-UHFFFAOYSA-N 2-chloro-n-(2-ethyl-6-methylphenyl)-n-(propan-2-yloxymethyl)acetamide Chemical compound CCC1=CC=CC(C)=C1N(COC(C)C)C(=O)CCl KZNDFYDURHAESM-UHFFFAOYSA-N 0.000 title abstract 2
- -1 iodomethyl ester Chemical class 0.000 claims abstract description 64
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 51
- 238000006243 chemical reaction Methods 0.000 claims abstract description 38
- 229950009966 ceftizoxime alapivoxil Drugs 0.000 claims abstract description 31
- 238000003756 stirring Methods 0.000 claims abstract description 31
- 150000002148 esters Chemical class 0.000 claims abstract description 21
- 239000002904 solvent Substances 0.000 claims abstract description 20
- 239000003960 organic solvent Substances 0.000 claims abstract description 17
- 239000002994 raw material Substances 0.000 claims abstract description 11
- 239000002253 acid Substances 0.000 claims abstract description 10
- 239000012467 final product Substances 0.000 claims abstract description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 39
- VOPANQNVVCPHQR-IVVGYLHBSA-N 2,2-dimethylpropanoyloxymethyl (6r,7r)-7-[[(2z)-2-[2-[[(2s)-2-aminopropanoyl]amino]-1,3-thiazol-4-yl]-2-methoxyiminoacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound N([C@@H]1C(N2C(=CCS[C@@H]21)C(=O)OCOC(=O)C(C)(C)C)=O)C(=O)\C(=N/OC)C1=CSC(NC(=O)[C@H](C)N)=N1 VOPANQNVVCPHQR-IVVGYLHBSA-N 0.000 claims description 30
- 239000007787 solid Substances 0.000 claims description 28
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- 238000001035 drying Methods 0.000 claims description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 17
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 16
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 16
- 239000000178 monomer Substances 0.000 claims description 16
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 16
- 229920002554 vinyl polymer Polymers 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 230000035484 reaction time Effects 0.000 claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 14
- 229910052740 iodine Inorganic materials 0.000 claims description 14
- 239000011630 iodine Substances 0.000 claims description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 12
- 239000000047 product Substances 0.000 claims description 9
- YGBFLZPYDUKSPT-MRVPVSSYSA-N cephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)C[C@H]21 YGBFLZPYDUKSPT-MRVPVSSYSA-N 0.000 claims description 8
- 238000004090 dissolution Methods 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 239000006210 lotion Substances 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 239000012141 concentrate Substances 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 6
- 230000008025 crystallization Effects 0.000 claims description 6
- 239000010410 layer Substances 0.000 claims description 6
- 239000012044 organic layer Substances 0.000 claims description 6
- 235000010265 sodium sulphite Nutrition 0.000 claims description 6
- 238000000967 suction filtration Methods 0.000 claims description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 3
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 230000006837 decompression Effects 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 230000001105 regulatory effect Effects 0.000 claims description 2
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 2
- 238000001291 vacuum drying Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 229950009297 pivoxil Drugs 0.000 abstract 2
- QVHJQCGUWFKTSE-YFKPBYRVSA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound OC(=O)[C@H](C)NC(=O)OC(C)(C)C QVHJQCGUWFKTSE-YFKPBYRVSA-N 0.000 abstract 1
- AIRXGBDVYJWRGO-VBSBDVEKSA-N 2,2-dimethylpropanoyloxymethyl (6r,7r)-7-[[(2z)-2-[2-[[(2s)-2-aminopropanoyl]amino]-1,3-thiazol-4-yl]-2-methoxyiminoacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate;hydrochloride Chemical compound Cl.N([C@@H]1C(N2C(=CCS[C@@H]21)C(=O)OCOC(=O)C(C)(C)C)=O)C(=O)\C(=N/OC)C1=CSC(NC(=O)[C@H](C)N)=N1 AIRXGBDVYJWRGO-VBSBDVEKSA-N 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 238000005303 weighing Methods 0.000 description 16
- 206010013786 Dry skin Diseases 0.000 description 12
- 239000000843 powder Substances 0.000 description 4
- 238000010025 steaming Methods 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical group [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
Landscapes
- Cephalosporin Compounds (AREA)
Abstract
The invention discloses a synthesis process of ceftizoxime hydrochloride propisochlor, which comprises the following four steps: (1) 7-amino-hydrocephalosporanic acid and AE active ester are taken as raw materials, and the 7-amino-hydrocephalosporanic acid is dissolved by an organic solvent and then reacts with the AE active ester; stirring and reacting at room temperature; (2) dissolving ceftizoxime prepared in the step (1) by using an organic solvent, and then stirring and reacting with iodomethyl ester; (3) dissolving the ceftizoxime pivoxil prepared in the step (2) by using an organic solvent, and reacting the dissolved ceftizoxime pivoxil with tert-butyloxycarbonyl-alanine; (4) and (3) reacting the N-tert-butoxycarbonylalanyl ceftizoxime alapivoxil prepared in the step (3) with a HCL/methanol solution by using methanol as a solvent to obtain a final product, namely ceftizoxime alapivoxil hydrochloride. The method has the characteristics of cheap and easily obtained raw materials, mild reaction conditions, reliable purity, higher yield, reduction of the cost required by production and suitability for industrial production.
Description
Technical field
The present invention relates to a kind of synthesis technique of HCL ceftizoxime alapivoxil.
Background technology
Ceftizoxime alapivoxil is the prodrug of ceftizoxime for inj, is the difunctional ester type of ceftizoxime derivative, but pro ore, and oral back is by esterase hydrolyzed, discharges ceftizoxime and brings into play its drug effect.This product has not only improved the oral absorption rate, and has improved the sugariness of this product, is more suitable in children.
At present synthetic Ceftizoxime alapivoxil mainly contains three kinds of approach, and one is raw material with ceftizoxime acid or its sodium salt, bit esterified through 4-, the condensation of 7-position, and deprotection becomes hydrochloride to prepare Ceftizoxime alapivoxil.This method by product is more, is difficult for purifying, needs to adopt column chromatography to come the separation and purification product, and yield is low, is not suitable for amplifying producing.(Dong Chuanming, Zhang Fengxia, Luo Faxin etc., the study on the synthesis of microbiotic Ceftizoxime alapivoxil [J]. Chinese microbiotic magazine, 2007,8 (32), 8)
The second route be U.S. Pat 5389625 report with 7-amino-3-do not have-3-cephem-4-carboxylic acid (7-ANCA) is the method that starting raw material prepares Ceftizoxime alapivoxil.With 7-ANCA is raw material, need carry out silica reagent protection amino and carboxyl earlier, uses phosphorus oxychloride, needs cold operation, exists cost higher, shortcomings such as severe reaction conditions.
Article three, route is with (Z)-2[[[(S)-2-(tertbutyloxycarbonyl)-1-oxopropyl] amino]-the 4-thiazolyl]-2-methoxyimino acetate is starting raw material, and is synthetic through following route:
This route exists by product more, the shortcoming that cost is higher.
Summary of the invention
In order to address the above problem, the object of the present invention is to provide the synthesis technique of HCL ceftizoxime alapivoxil, it is cheap and easy to get that this method has raw material, the reaction conditions gentleness, purity is reliable, and yield is higher, reduced and produced required cost, be fit to the characteristics of suitability for industrialized production.
For reaching above-mentioned purpose, the present invention adopts following technical scheme,
A kind of synthesis technique of HCL ceftizoxime alapivoxil, processing step comprise following four steps:
(1) be raw material with 7-amino-hydrogen Cephalosporanic acid and AE active ester, 7-amino-hydrogen Cephalosporanic acid reacts with the AE active ester by behind the organic solvent dissolution; At room temperature carrying out stirring reaction, is that washing lotion is taken out and washed by water and vinyl acetic monomer then, and water layer is regulated pH value behind 5-6, filtration, and drying obtains the solid ceftizoxime;
Reaction equation is:
(2) ceftizoxime of step (1) preparation is carried out stirring reaction with the iodine methyl esters after by organic solvent dissolution; Extract by vinyl acetic monomer then, organic layer is that washing lotion is lost and is washed with sodium bicarbonate and sodium bisulfite, and by dry, decompression obtains a solid ceftizoxime pentyl ester afterwards;
Reaction equation is:
(3) the ceftizoxime pentyl ester with step (2) preparation passes through to react with tertbutyloxycarbonyl-L-Ala behind the organic solvent dissolution; Be solvent with dicyclohexylcarbodiimide and ether again, concentrate after the reaction that the solidifying agent that adds diethyl ether is then separated out solid final vacuum drying, make solid N-tert-butoxy carbonyl alanyl ceftizoxime third pentyl ester;
Reaction equation is:
(4) N-tert-butoxy carbonyl alanyl ceftizoxime third pentyl ester that step (3) is prepared adds the reaction of HCl-low-alcohol solution with the organic solvent dissolution of ester class or alcohols, uses the ether suction filtration, solidify, the decorating film dissolve with methanol adds a certain amount of isopropyl ether crystallization, stir light yellow product.Filter, drying gets the final product HCL ceftizoxime alapivoxil.
Reaction equation is:
The mol ratio of 7-amino in the described step (1)-hydrogen Cephalosporanic acid and AE active ester add-on is 1: 1.0-1: 4.0; Organic solvent in the step (1) adopts a kind of in acetone, acetonitrile, the methyl alcohol; The volume ratio of the add-on of water and vinyl acetic monomer is 1: 1-3; And adopt the salt acid for adjusting pH value of 6N-12N in the step (1); The stirring reaction time is 5-10 hour.
The mol ratio of 7-amino in the described step (1)-hydrogen Cephalosporanic acid and AE active ester add-on is 1: 1.2; The volume ratio of the add-on of water and vinyl acetic monomer is 1: 1.
The mol ratio of ceftizoxime and iodine methyl esters add-on is 1 in the described step (2): 0.8-2; Organic solvent adopts dimethyl formamide, tetrahydrofuran (THF), methyl-sulphoxide, acetonitrile, CH in the step (2)
2Cl
2In a kind of; And the middle ceftizoxime of step (2) will be cooled to 0 ℃ and react with the iodine methyl esters; The stirring reaction time is 3-6 hour; Describedly be lost to wash to be meant successively with mass percent concentration to be that 1% sodium bicarbonate and mass percent concentration are that 1% sodium sulfite solution is washed, repeat respectively to give a baby a bath on the third day after its birth time.
The mol ratio of ceftizoxime and iodine methyl esters add-on is 1: 1.2 in the described step (2); And the middle ceftizoxime of step (2) will be cooled to 0 ℃ and react with the iodine methyl esters; The stirring reaction time is 3 hours.
The mol ratio of a ceftizoxime pentyl ester and tertbutyloxycarbonyl-L-Ala add-on is in the described step (3): 1: 1.0-6.8; Organic solvent adopts tetrahydrofuran (THF), dimethyl formamide, methyl-sulphoxide, acetonitrile, CH in the step (3)
2Cl
2In a kind of; And the reaction times is 4-10 hour in the step (3).
The mol ratio of a ceftizoxime pentyl ester and tertbutyloxycarbonyl-L-Ala add-on is in the described step (3): 1: 2.25; And the reaction times is 6 hours in the step (3).
N-tert-butoxy carbonyl alanyl ceftizoxime third pentyl ester is with adding 0.5-10ml HCL/ methyl alcohol among every 1g in the described step (4), HCL/ Virahol, HCL/ ether, a kind of in the HCL/ ethyl acetate solution; And temperature of reaction-5 ℃ in the step (4), the reaction times is 2 hours, churning time is 1 hour.
Add 1ml HCL/ methanol solution in the described step (4) in every 1g N-tert-butoxy carbonyl alanyl ceftizoxime third pentyl ester; And temperature of reaction-5 ℃ in the step (4), the reaction times is 2 hours, churning time is 1 hour.
Drying temperature is 60 ℃ in described each step.
The invention has the beneficial effects as follows: the deficiency that the present invention is directed to above-mentioned route, with 7-ANCA is starting raw material, preferred reaction conditions and reagent, synthetic Ceftizoxime alapivoxil, raw material is cheap and easy to get, the reaction conditions gentleness, purity is reliable, yield is higher, has reduced and has produced required cost, is fit to suitability for industrialized production.
Embodiment
Embodiment 1
A kind of synthesis technique of HCL ceftizoxime alapivoxil, (1) at first prepares the solid ceftizoxime: the AE active ester 12.21g that takes by weighing 0.04mol 7-ANCA 8g and 0.04mol, 7-ANCA is joined in the 40ml acetone solvent, at room temperature carried out stirring reaction 6 hours with the AE active ester, concentrate and remove acetone, be that washing lotion is taken out and washed by 25ml water and 25ml vinyl acetic monomer then, the water layer subacidity of the salt acid for adjusting pH value of 6N at 5-6, stir, filter, 60 ℃ of dryings obtain pale yellow powder shape solid 13g ceftizoxime; Yield is 162.5%.
(2) take by weighing the ceftizoxime 3.83g (0.01mol) that step (1) makes, add DMF solvent 20ml, be cooled to 0 ℃, carry out stirring reaction with 3g iodine methyl esters (0.012mol) and become clear after 3 hours; Add the 150ml vinyl acetic monomer then and extract, organic layer is that 1% sodium bicarbonate and mass percent concentration are that 1% sodium sulfite solution is washed with mass percent concentration successively, repeats respectively to give a baby a bath on the third day after its birth time.By 60 ℃ of dryings, the pressure reducing and steaming solvent obtains a yellow solid ceftizoxime pentyl ester 4.2g afterwards; Yield 109.7%.
(3) take by weighing the ceftizoxime pentyl ester (0.008mol) that 4.2g step (2) prepares, dissolve with 20mlTHF, add DCC 6g under the room temperature, after the muddiness, add 3.5g tertbutyloxycarbonyl-L-Ala (0.018mol) reaction 6 hours, be concentrated to 5ml behind the reaction solution, add the 40ml ether solvent, separate out solid, 60 ℃ of dryings of vacuum make 4.83g faint yellow solid N-tert-butoxy carbonyl alanyl ceftizoxime third pentyl ester; Yield 115%.
(4) the N-tert-butoxy carbonyl alanyl ceftizoxime third pentyl ester 2.4g (0.004mol) that takes by weighing step (3) preparation is dissolved in the 15ml methanol solvate, add 2.4mlHCL/ methanol solution (1: 5) reaction under the room temperature, temperature of reaction-5 ℃, reaction is more than 2 hours, use the ether suction filtration, solidify the decorating film dissolve with methanol, add a certain amount of isopropyl ether crystallization, stir and got light yellow product in 1 hour.Filter, drying gets final product HCL ceftizoxime alapivoxil 2.04g, yield 85.0%.
Embodiment 2
A kind of synthesis technique of HCL ceftizoxime alapivoxil, (1) at first prepares the solid ceftizoxime: take by weighing 0.04mol 7-ANCA 8g and 0.04mol AE active ester 12.72g, 7-ANCA is joined in the 40ml acetonitrile solvent, at room temperature carried out stirring reaction 5 hours with the AE active ester, concentrate and remove acetone, be that washing lotion is taken out and washed by 25ml water and 25ml vinyl acetic monomer then, the water layer subacidity of the salt acid for adjusting pH value of 6N at 5-6, stir, filter, 60 ℃ of dryings obtain pale yellow powder shape solid 11.81g ceftizoxime; Yield is 147.6%.
(2) take by weighing the ceftizoxime 3.83g (0.01mol) that step (1) makes, add tetrahydrofuran solvent 20ml, be cooled to 0 ℃, carry out stirring reaction with iodine methyl esters 1.94g (0.008mol) and become clear after 3 hours; Add the 150ml vinyl acetic monomer then and extract, organic layer is that 1% sodium bicarbonate and mass percent concentration are that 1% sodium sulfite solution is washed with mass percent concentration successively, repeats respectively to give a baby a bath on the third day after its birth time.By 60 ℃ of dryings, the pressure reducing and steaming solvent obtains a yellow solid ceftizoxime pentyl ester 3.45g afterwards; Yield 90.0%.
(3) take by weighing the ceftizoxime pentyl ester that 3.45g (0.007mol) step (2) prepares, dissolve with the 20ml acetonitrile, add DCC6g under the room temperature, after the muddiness, add tertbutyloxycarbonyl-L-Ala 1.32g (0.007mol) and reacted 6 hours, be concentrated to 5ml behind the reaction solution, add the 40ml ether solvent, separate out solid, 60 ℃ of dryings of vacuum make 3.71g faint yellow solid N-tert-butoxy carbonyl alanyl ceftizoxime third pentyl ester; Yield 107.5%.
(4) the N-tert-butoxy carbonyl alanyl ceftizoxime third pentyl ester 2.4g (0.004mol) that takes by weighing step (3) preparation is dissolved in the 15ml isopropanol solvent, add 1.2mlHCL/ aqueous isopropanol (1: 5) reaction under the room temperature, temperature of reaction-5 ℃, reaction is more than 2 hours, use the ether suction filtration, solidify the decorating film dissolve with methanol, add a certain amount of isopropyl ether crystallization, stir and got light yellow product in 1 hour.Filter, drying gets final product HCL ceftizoxime alapivoxil 1.81g, yield 75.3%.
Embodiment 3
A kind of synthesis technique of HCL ceftizoxime alapivoxil, (1) at first prepares the solid ceftizoxime: take by weighing 0.04mol 7-ANCA 8g and 0.1mol AE active ester 30.52g, 7-ANCA is joined in the 40ml methanol solvate, at room temperature carried out stirring reaction 7.5 hours with the AE active ester, concentrate and remove acetone, be that washing lotion is taken out and washed by 25ml water and 50ml vinyl acetic monomer then, the water layer subacidity of the salt acid for adjusting pH value of 9N at 5-6, stir, filter, 60 ℃ of dryings obtain pale yellow powder shape solid 12.64g ceftizoxime; Yield is 157.9%.
(2) take by weighing the ceftizoxime 3.83g (0.01mol) that step (1) makes, add dimethylsulfoxide solvent 20ml, be cooled to 0 ℃, carry out stirring reaction with iodine methyl esters 3.39g (0.014mol) and become clear after 4.5 hours; Add the 150ml vinyl acetic monomer then and extract, organic layer is that 1% sodium bicarbonate and mass percent concentration are that 1% sodium sulfite solution is washed with mass percent concentration successively, repeats respectively to give a baby a bath on the third day after its birth time.By 60 ℃ of dryings, the pressure reducing and steaming solvent obtains a yellow solid ceftizoxime pentyl ester 3.92g afterwards; Yield 102.4%.
(3) take by weighing the ceftizoxime pentyl ester that 3.92g (0.008mol) step (2) prepares, use 20mlCH
2Cl
2Dissolving, add 6gDCC under the room temperature, after the muddiness, adding tertbutyloxycarbonyl-L-Ala 5.15g (0.027mol) reacted 6 hours, be concentrated to 5ml behind the reaction solution, add the 40ml ether solvent, separate out solid, 60 ℃ of dryings of vacuum make 4.08g faint yellow solid N-tert-butoxy carbonyl alanyl ceftizoxime third pentyl ester; Yield 104.2%.
(4) the N-tert-butoxy carbonyl alanyl ceftizoxime third pentyl ester 2.4g (0.004mol) that takes by weighing step (3) preparation is dissolved in the 15ml ether solvent, add 1.2mlHCL/ diethyl ether solution (1: 5) reaction under the room temperature, temperature of reaction-5 ℃, reaction is more than 2 hours, use the ether suction filtration, solidify the decorating film dissolve with methanol, add a certain amount of isopropyl ether crystallization, stir and got light yellow product in 1 hour.Filter, drying gets final product HCL ceftizoxime alapivoxil 1.79g, yield 74.6%.
Embodiment 4
A kind of synthesis technique of HCL ceftizoxime alapivoxil, (1) at first prepares the solid ceftizoxime: take by weighing 0.04mol 7-ANCA 8g and 0.16mol AE active ester 50.88g, 7-ANCA is joined in the 40ml acetone solvent, at room temperature carried out stirring reaction 10 hours with the AE active ester, concentrate and remove acetone, be that washing lotion is taken out and washed by 25ml water and 75ml vinyl acetic monomer then, the water layer subacidity of the salt acid for adjusting pH value of 12N at 5-6, stir, filter, 60 ℃ of dryings obtain pale yellow powder shape solid 12.26g ceftizoxime; Yield is 153.3%.
(2) take by weighing the ceftizoxime 3.83g (0.01mol) that step (1) makes, add acetonitrile solvent 20ml, be cooled to 0 ℃, carry out stirring reaction with iodine methyl esters 4.84g (0.02mol) and become clear after 6 hours; Add the 150ml vinyl acetic monomer then and extract, organic layer is that 1% sodium bicarbonate and mass percent concentration are that 1% sodium sulfite solution is washed with mass percent concentration successively, repeats respectively to give a baby a bath on the third day after its birth time.By 60 ℃ of dryings, the pressure reducing and steaming solvent obtains a yellow solid ceftizoxime pentyl ester 3.73g afterwards; Yield 97.3%.
(3) take by weighing the ceftizoxime pentyl ester that 3.73g (0.008mol) step (2) prepares, dissolve with the 20ml methyl-sulphoxide, add 6gDCC under the room temperature, after the muddiness, add tertbutyloxycarbonyl-L-Ala 10.18g (0.054mol) and reacted 6 hours, be concentrated to 5ml behind the reaction solution, add the 40ml ether solvent, separate out solid, 60 ℃ of dryings of vacuum make 4.01g faint yellow solid N-tert-butoxy carbonyl alanyl ceftizoxime third pentyl ester; Yield 107.5%
(4) the N-tert-butoxy carbonyl alanyl ceftizoxime third pentyl ester 2.4g (0.004mol) that takes by weighing step (3) preparation is dissolved in the 15ml ethyl acetate solvent, add 1.2mlHCL/ ethyl acetate solution (1: 5) reaction under the room temperature, temperature of reaction-5 ℃, more than the reaction 2hr, use the ether suction filtration, solidify the decorating film dissolve with methanol, add a certain amount of isopropyl ether crystallization, stir 1hr and get light yellow product.Filter, drying gets final product HCL ceftizoxime alapivoxil 1.70g, yield 70.9%.
Claims (10)
1, a kind of synthesis technique of HCL ceftizoxime alapivoxil is characterized in that processing step comprises following four steps:
(1) be raw material with 7-amino-hydrogen Cephalosporanic acid and AE active ester, 7-amino-hydrogen Cephalosporanic acid reacts with the AE active ester by behind the organic solvent dissolution; At room temperature carrying out stirring reaction, is that washing lotion is taken out and washed by water and vinyl acetic monomer then, and water layer is regulated pH value behind 5-6, filtration, and drying obtains the solid ceftizoxime;
(2) ceftizoxime of step (1) preparation is carried out stirring reaction with the iodine methyl esters after by organic solvent dissolution; Extract by vinyl acetic monomer then, organic layer is that washing lotion is lost and is washed with sodium bicarbonate and sodium bisulfite, and by dry, decompression obtains a solid ceftizoxime pentyl ester afterwards;
(3) the ceftizoxime pentyl ester with step (2) preparation passes through to react with tertbutyloxycarbonyl-L-Ala behind the organic solvent dissolution; Be solvent with dicyclohexylcarbodiimide and ether again, concentrate after the reaction that the solidifying agent that adds diethyl ether is then separated out solid final vacuum drying, make solid N-tert-butoxy carbonyl alanyl ceftizoxime third pentyl ester;
(4) N-tert-butoxy carbonyl alanyl ceftizoxime third pentyl ester that step (3) is prepared adds the reaction of HCl-low-alcohol solution with the organic solvent dissolution of ester class or alcohols, uses the ether suction filtration, solidify, the decorating film dissolve with methanol adds a certain amount of isopropyl ether crystallization, stir light yellow product.Filter, drying gets the final product HCL ceftizoxime alapivoxil.
2, the synthesis technique of HCL ceftizoxime alapivoxil as claimed in claim 1 is characterized in that: the mol ratio of 7-amino in the described step (1)-hydrogen Cephalosporanic acid and AE active ester add-on is 1: 1.0-1: 4.0; Organic solvent in the step (1) adopts a kind of in acetone, acetonitrile, the methyl alcohol; The volume ratio of the add-on of water and vinyl acetic monomer is 1: 1-3; And adopt the salt acid for adjusting pH value of 6N-12N in the step (1); The stirring reaction time is 5-8 hour.
3, the synthesis technique of HCL ceftizoxime alapivoxil as claimed in claim 2 is characterized in that: the mol ratio of 7-amino in the described step (1)-hydrogen Cephalosporanic acid and AE active ester add-on is 1: 1.2; The volume ratio of the add-on of water and vinyl acetic monomer is 1: 1; And adopt the salt acid for adjusting pH value of 6N in the step (1); The stirring reaction time is 6 hours.
4, the synthesis technique of HCL ceftizoxime alapivoxil as claimed in claim 1 is characterized in that: the mol ratio of ceftizoxime and iodine methyl esters add-on is 1 in the described step (2): 0.8-2; Organic solvent adopts dimethyl formamide, tetrahydrofuran (THF), methyl-sulphoxide, acetonitrile, CH in the step (2)
2C1
2In a kind of; And the middle ceftizoxime of step (2) will be cooled to 0 ℃ and react with the iodine methyl esters; The stirring reaction time is 3-6 hour; Describedly be lost to wash just be meant successively with mass percent concentration to be that 1% sodium bicarbonate and mass percent concentration are that 1% sodium sulfite solution is washed, repeat respectively to give a baby a bath on the third day after its birth time.
5, the synthesis technique of HCL ceftizoxime alapivoxil as claimed in claim 4 is characterized in that: the mol ratio of ceftizoxime and iodine methyl esters add-on is 1: 1.2 in the described step (2); And the middle ceftizoxime of step (2) will be cooled to 0 ℃ and react with the iodine methyl esters; The stirring reaction time is 3 hours.
6, the synthesis technique of HCL ceftizoxime alapivoxil as claimed in claim 1 is characterized in that: the mol ratio of a ceftizoxime pentyl ester and tertbutyloxycarbonyl-L-Ala add-on is in the described step (3): 1: 1.0-6.8; Organic solvent adopts tetrahydrofuran (THF), dimethyl formamide, methyl-sulphoxide, acetonitrile, CH in the step (3)
2Cl
2In a kind of; And the reaction times is 4-10 hour in the step (3).
7, the synthesis technique of HCL ceftizoxime alapivoxil as claimed in claim 6 is characterized in that: the mol ratio of a ceftizoxime pentyl ester and tertbutyloxycarbonyl-L-Ala add-on is in the described step (3): 1: 2.25; And the reaction times is 6 hours in the step (3).
8, the synthesis technique of HCL ceftizoxime alapivoxil as claimed in claim 1, it is characterized in that: add 0.5-10ml HCL/ methyl alcohol in the described step (4) in every 1g N-tert-butoxy carbonyl alanyl ceftizoxime third pentyl ester, the HCL/ Virahol, the HCL/ ether, a kind of in the HCL/ ethyl acetate solution; And temperature of reaction-5 ℃ in the step (4), the reaction times is 2 hours, churning time is 1 hour.
9, the synthesis technique of HCL ceftizoxime alapivoxil as claimed in claim 8 is characterized in that: add 1ml HCL/ methanol solution in the described step (4) in every 1g N-tert-butoxy carbonyl alanyl ceftizoxime third pentyl ester; And temperature of reaction-5 ℃ in the step (4), the reaction times is 2 hours, churning time is 1 hour.
10, the synthesis technique of HCL ceftizoxime alapivoxil as claimed in claim 1 is characterized in that: drying temperature is 60 ℃ in described each step.
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