CN103059047A - Method for preparing ceftizoxime alapivoxil hydrochloride - Google Patents

Method for preparing ceftizoxime alapivoxil hydrochloride Download PDF

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CN103059047A
CN103059047A CN2013100265741A CN201310026574A CN103059047A CN 103059047 A CN103059047 A CN 103059047A CN 2013100265741 A CN2013100265741 A CN 2013100265741A CN 201310026574 A CN201310026574 A CN 201310026574A CN 103059047 A CN103059047 A CN 103059047A
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boc
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anca
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CN103059047B (en
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施秀芳
李硕旭
周建华
邱启平
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Jiangsu Cixing Pharmaceutical Co Ltd
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Zhengzhou University
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Abstract

The invention discloses a new method for preparing ceftizoxime alapivoxil hydrochloride and belongs to the technical field of medicine synthesis. The method comprises the following steps: step (1), performing Boc protection on 7-amino of raw material 7-amino-3-cephem-4-carboxylic acid (7-ANCA) and then making the raw material have reaction with iodomethyl pivalate, then removing Boc protection group to obtain a midbody 7-amino-3-cephem-4-carboxylic pivaloyl oxymethyl ester (7-ANCA-POM); step (2), making N-t-butyloxycarboryl-L-alanine (Boc-L-Ala) and methoxyiminoacetic acid (ATMA) have condensation reaction to obtain a midbody 2-(2-N-t-butyloxycarboryl-amino-(S)-triacylamino-thiazole-4-yl)-2-(Z)-methoxyimino-acetic acid (Boc-L-Ala-ATMA); step (3), activating the midbody Boc-L-Ala-ATMA and making the midbody Boc-L-Ala-ATMA have condensation reaction with the midbody 7-ANCA-POM, and then removing the Boc protection group to prepare a target compound ceftizoxime alapivoxil hydrochloride (CZX-AP-HC1,I). The method adopts a collection type synthesis route, is simple and convenient to operate and mild in technical conditions, has high product quality and low cost, and avoids the problem about benzothiazole residue caused by the use of AE active ester in the present technique, so the collection type synthesis route is a good synthesis route suitable for industrial production.

Description

A kind of method for preparing the Ceftizoxime alapivoxil hydrochloride
Technical field
The present invention relates to the novel preparation method of a kind of oral cephalosporin Ceftizoxime alapivoxil hydrochloride (Ceftizoxime Alapivoxil Hydrochloride), belong to technical field of medicine synthesis.
Background technology
Ceftizoxime alapivoxil is the difunctionality prodrug of third generation cephalosporin for injections ceftizoxime, its has a broad antifungal spectrum and strong, and stable to various bacteriogenic β-lactamases, substantially without renal toxicity.(Chem.Pharm.Bull. 1999 for document, 47 (8): 1081-1088) studies show that Ceftizoxime alapivoxil not only has balanced water-soluble and fat-soluble (lipid is 1.15), be conducive to intestinal absorption, greatly improved Plasma Concentration, reduced dosage, and can be oral, its sugariness is 300 times of sucrose, without the distinctive peculiar smell of other cephalosporins, be particularly suitable for children taking.
At present, synthetic method according to the raw material sources Ceftizoxime alapivoxil mainly is divided into two large classes: a class is take cephalosporin nucleus 7-amino-3-cephem-4-carboxylic acid (7-ANCA) and ainothiazoly loximate as raw material, and iodometyl pivalate and N-tert-butoxycarbonyl-l-alanine (Boc-L-Ala) reaction and make.Sequencing according to reaction, be divided into again following several synthetic method: the method for synthetic Ceftizoxime alapivoxil take 7-ANCA and pivaloyl oxygen methyl esters (7-ANCA-POM) thereof as raw material, total recovery is respectively 23.3%(in 7-ANCA, route 1) and 11.7%(in 7-ANCA-POM, route 2) (US Patent No. 5389625).The method must be first carried out the silylation protection to the amino of 7-ANCA and carboxyl; used phosphorus oxychloride in the condensation reaction; need low-temperature anhydrous operation; product needs the chromatographic column separation and purification; and use relatively more expensive reagent trifluoroacetic acid when taking off the Boc protecting group; cost is higher, and severe reaction conditions is difficult for suitability for industrialized production.
Figure 2013100265741100002DEST_PATH_IMAGE001
Route 1
Figure 833457DEST_PATH_IMAGE002
Route 2
Chinese patent CN1958591B and document (Chinese Journal of Pharmaceuticals. 2007,38 (10): 683-685) reported with ( Z)-2-[[[( S)-2-(tertbutyloxycarbonyl) amino-1-oxopropyl] amino]-the 4-thiazolyl]-2-methoxyimino acetic acid (2-mercaptobenzothiazole) ester (Boc-L-Ala-AE active ester) and 7-ANCA reaction prepares the method (route 3) of Ceftizoxime alapivoxil.Similarly, Chinese patent CN101613357B has reported with 7-ANCA and 2-methoxyimino-2-(2-amino-4-thiazolyl)-(Z)-thioacetic acid benzothiazole ester (MEAM) reaction and has prepared ceftizoxime acid (CZX), then 4 with iodometyl pivalate (IMP) reaction, 7 prepare Ceftizoxime alapivoxil hydrochloride (route 4) with the Boc-L-Ala condensation.These two kinds of methods all are optimized reaction conditions, have adopted solvent crystal to replace column chromatography to separate, and yield is higher, but by product is more, and cost is higher.Simultaneously also cause easily 2-mercaptobenzothiazole (captax) residual, residual in medicine of captax has certain impact to human body, U.S. FDA to the content of captax in the rocephin that American market is sold carried out strict regulation (meticulous and specialty chemicals. 2004,12 (13): 11-12).
Figure 2013100265741100002DEST_PATH_IMAGE003
Route 3
Figure 718237DEST_PATH_IMAGE004
Route 4
Another kind of synthetic method is as raw material take ceftizoxime acid or its sodium salt, through 4 bit esterified, 7 condensations and obtain, sequencing according to 4 and 7 reactions, also be divided into following two kinds of methods: take ceftizoxime acid (CZX) as raw material, first carry out esterification through 4 and iodometyl pivalate, allow again 7 side chain NH 2Carry out condensation with Boc-L-Ala, remove at last the formation of Boc protecting group and obtain Ceftizoxime alapivoxil hydrochloride (with route 4) (document J. Antibiotics. 1999,52 (5): 491-500).The method by product is many, needs column chromatography to carry out purifying products, aftertreatment difficulty, and the yield of product lower (total recovery 33.6% is in ceftizoxime acid) is unfavorable for suitability for industrialized production.Chinese patent (CN100366625C) replaces the reaction of Boc-L-Ala and ceftizoxime pivoxil take Fmoc-L-Ala as raw material; although overcome the trifluoroacetic acid of using when removing the Boc protecting group; but raising has little significance for total yield of products; and Fmoc protecting group price is also more expensive; purification of intermediate needs column chromatography simultaneously, and total recovery 31.9%(is in ceftizoxime acid).And document (Chinese microbiotic, 2007,32 (8): 470-471) then take ceftizoxime acid as raw material, first through 7 side chain NH 2Acidylate through 4 bit esterified, then remove the Boc protecting group and makes Ceftizoxime alapivoxil (route 5) again.This route does not need through column chromatography separating purification, and total recovery increases 41.5%(in ceftizoxime acid).
Route 5
According to above-mentioned five kinds of synthesis routes are carried out assay, be not difficult to find that one of reason that its yield is low is exactly to have adopted " orthoscopic " synthetic route.We have designed more rational " convergence type " new synthesis process for this reason, and up to the present, this route there is not yet bibliographical information.
Summary of the invention
The purpose of this invention is to provide the method for preparing the Ceftizoxime alapivoxil hydrochloride that a kind of yield is high, be fit to suitability for industrialized production.
The objective of the invention is to implement by following technical solution.
The present invention at first carries out the rear and iodometyl pivalate reaction of Boc protection with the 7-bit amino of formula II compound 7-amino-3-cephem-4-carboxylic acid (7-ANCA), remove the Boc protecting group and obtain formula V midbody compound 7-amino-3-cephem-4-carboxylic acid pivaloyl oxygen methyl esters, be called for short 7-ANCA-POM;
Then, formula VI compound N-tert-butoxycarbonyl-l-alanine (Boc-L-Ala) and formula VII compound ainothiazoly loximate (ATMA) are carried out condensation reaction, obtain formula VIII midbody compound 2-(2-N-tertbutyloxycarbonyl-amino-(S)-propionamido-thiazole-4-yl)-2-(Z)-methoxyimino acetic acid, be called for short Boc-L-Ala-ATMA;
Figure 2013100265741100002DEST_PATH_IMAGE007
At last; with after the formula VIII midbody compound Boc-L-Ala-ATMA that the synthesized activation and formula V midbody compound 7-ANCA-POM carry out condensation reaction; remove the Boc protecting group and prepare formula I purpose compound Ceftizoxime alapivoxil hydrochloride, be called for short CZX-AP-HCl.
Figure 869656DEST_PATH_IMAGE008
Concrete synthesis step is as follows:
(1) formula II compound 7-amino-3-cephem-4-carboxylic acid (7-ANCA) is dissolved in the solvent, under base catalysis, with tert-Butyl dicarbonate (Boc 2O) under-10 ℃～25 ℃ conditions, react, obtain formula III compound 7-N-tertbutyloxycarbonyl-amino-3-cephem-4-carboxylic acid (7-Boc-ANCA);
Figure 2013100265741100002DEST_PATH_IMAGE009
Figure 600852DEST_PATH_IMAGE010
(2) formula III compound 7-Boc-ANCA is dissolved in the organic solvent, under base catalysis, with iodometyl pivalate lucifuge reaction under-20 ℃～10 ℃ conditions, obtain formula IV compound 7-N-t-butoxycarbonyl amino-3-cephem-4-carboxylic acid pivaloyl oxygen methyl esters (7-Boc-ANCA-POM);
Figure 2013100265741100002DEST_PATH_IMAGE011
(3) formula IV compound 7-Boc-ANCA-POM is dissolved in the organic solvent, reacts under-10 ℃～10 ℃ conditions with acid, slough the Boc protecting group, prepare formula V compound 7-amino-3-cephem-4-carboxylic acid pivaloyl oxygen methyl esters (7-ANCA-POM);
Figure 656532DEST_PATH_IMAGE012
(4) formula VI compound N-tert-butoxycarbonyl-l-alanine (Boc-L-Ala) is dissolved in the organic solvent, add the coupling condenser agent that carbodiimide class condensing agent or imidazoles condensing agent and active catalyst form, react under-10 ℃～20 ℃ conditions with formula VII compound ainothiazoly loximate (ATMA), obtain formula VIII compound 2-(2-N-tertbutyloxycarbonyl-amino-(S)-propionamido-thiazole-4-yl)-2-(Z)-methoxyimino acetic acid (Boc-L-Ala-ATMA);
Figure 2013100265741100002DEST_PATH_IMAGE013
(5) formula V compound 7-ANCA-POM and formula VIII compd B oc-L-Ala-ATMA are dissolved in the organic solvent, add the coupling condenser agent that carbodiimide class condensing agent or imidazoles condensing agent and active catalyst form, under-5 ℃～20 ℃ conditions, react, obtain formula IX compound 7 β-[(Z)-2-[2 – N-tertbutyloxycarbonyl-amino-(S)-alanyl amino-thiazolyl--4-yl]-2-methoxyimino-kharophen]-3-cephem-4-carboxylic acid pivaloyl oxygen methyl esters (Boc-CZX-AP);
(6) with formula IX compd B oc-CZX-AP organic solvent dissolution, add the organic solution that contains hydrochloric acid, under-5 ℃～10 ℃ conditions, react, prepare formula I compound Ceftizoxime alapivoxil hydrochloride.
Carbodiimide class condensing agent used in described step (4), (5) is N, N '-dicyclohexylcarbodiimide (DCC), N, N '-DIC (DIC), N-ethyl-N '-dimethylamine propyl carbodiimide hydrochloride (EDCHCl), 2-[[4-(2,2-dimethyl-1,3-dioxy base)]-methyl] carbon imide (BDDC) one of them; The imidazoles condensing agent is N, N'-carbonyl dimidazoles (CDI) or N ' N-thiocarbonyldiimidazole (TCDI); Active catalyst is N-hydroxy benzo triazole (HOBt), N-hydroxy-succinamide (HOSu), N-hydroxyl-5-norbornylene-2,3-dicarboximide (HONb), N-hydroxyl-7-azo benzotriazole (HOAt) or 3-hydroxyl-1, in 2,3-phentriazine-4 (3H)-ketone (HOOBt), DMAP (DMAP), triethylamine (TEA), the dicyclohexyl amine (DCHA) one or more.The two or three coupling condenser agent that forms among preferred DCC, EDCHCl, HOBt, HOSu, DMAP, the TEA.
Solvent can be water, acetone, methyl alcohol, ethanol, tetrahydrofuran (THF) (THF), acetonitrile, dioxane, N in the described step (1), N '-dimethyl formamide (DMF), N, among the N '-N,N-DIMETHYLACETAMIDE (DMAC) etc. one or both, particular methanol, ethanol, dioxane and water;
Described step (1) neutral and alkali material is diethylamine, triethylamine, hexahydroaniline, dicyclohexyl amine, trolamine, pyridine, quinoline or diazabicylo organic bases; Or NaOH, KOH, NaHCO 3, Na 2CO 3, KHCO 3, K 2CO 3Mineral alkali one of them; Preferred Na 2CO 3, K 2CO 3, NaOH, triethylamine, dicyclohexyl amine;
Reaction raw materials mol ratio 7-ANCA: Boc in the described step (1) 2O: alkaline matter is 1: 1.1～1.6: 1～5, preferred 1: 1.1～1.4: 1～3;
After reaction finished in the described step (1), reaction solution was first with the frozen water dilution, and then with ethyl acetate or dichloromethane extraction.Regulate extracting phase (water) pH=2 ~ 3, again with ethyl acetate or dichloromethane extraction.Then use successively 5% ~ 10% aqueous citric acid solution, distilled water or saturated NaCl solution washing, the concentrating under reduced pressure solvent is with methylene dichloride and sherwood oil mixed solvent recrystallization;
Organic solvent is one or both in methyl alcohol, ethanol, acetone, methylene dichloride, dioxane, dimethyl formamide (DMF), N,N-DIMETHYLACETAMIDE (DMAC), dimethyl sulfoxide (DMSO) (DMSO), the acetonitrile in the described step (2), preferred acetone, dioxane, DMF, DMAC;
Described step (2) neutral and alkali material is diethylamine, triethylamine, hexahydroaniline, dicyclohexyl amine, trolamine, pyridine, quinoline or diazabicylo organic bases; Or NaOH, KOH, NaHCO 3, Na 2CO 3, KHCO 3, K 2CO 3Mineral alkali one of them; Preferred Na 2CO 3, K 2CO 3, NaOH, triethylamine, dicyclohexyl amine;
The mol ratio of described step (2) Chinese style III compound and alkali and iodometyl pivalate is 1: 1～3: 1～5, preferred 1: 1～2: 1～3;
After reaction finishes in the described step (2), with the frozen water dilution, again with ethyl acetate or dichloromethane extraction, then use successively 5% ~ 10% aqueous citric acid solution, 5% ~ 10%NaHCO first 3The aqueous solution, distilled water water or saturated NaCl solution washing, the solvent concentrating under reduced pressure is with methylene dichloride and sherwood oil recrystallization;
Organic solvent can be one or both in formic acid, methyl alcohol, ethanol, Virahol, ethyl acetate, methylene dichloride, ether, isopropyl ether, tetrahydrofuran (THF), dioxane, the methyl-phenoxide, preferable formic acid, methylene dichloride, ethyl acetate, Virahol in the described step (3);
Used acid can be a kind of in hydrochloric acid, phosphoric acid, formic acid, the acetic acid in the described step (3), preferred hydrochloric acid, phosphoric acid;
Described step (3) Chinese style IV compound is 1: 1 ~ 25 with the mol ratio of acid, preferred 1: 2 ~ 18;
Add frozen water after reaction finishes in the described step (3), regulate pH=8 ~ 9 with the 10%NaOH aqueous solution, again with methylene dichloride or ethyl acetate extraction, then with distilled water or saturated NaCl solution washing organic phase, anhydrous sodium sulfate drying, condensing crystal;
Organic solvent can be one or both among methyl alcohol, ethanol, ethyl acetate, methylene dichloride, DMF, the DMAC in the described step (4), preferred methylene dichloride, DMF, DMAC;
The used preferred N of coupling condenser agent in the described step (4), one or both condensing agents that form in N '-dicyclohexylcarbodiimide or N-ethyl-N '-dimethylamine propyl carbodiimide hydrochloride and N-hydroxy benzo triazole, N-hydroxy-succinamide, DMAP, the triethylamine;
The consumption mol ratio of compound VI and compound VII is 1: 0.8～1.5 in the described step (4);
After the condensation reaction of compound VI and compound VII finishes in the described step (4), can use first 20%NaHCO 3Strip, then regulate water pH=2, again with ethyl acetate or dichloromethane extraction, distilled water and saturated NaCl solution washing.Anhydrous sodium sulfate drying, sherwood oil, methylene dichloride recrystallization;
Organic solvent can be one or both among methyl alcohol, ethanol, ethyl acetate, methylene dichloride, DMF, the DMAC in the described step (5), preferred methylene dichloride, DMF, DMAC;
The used preferred N of coupling condenser agent in the described step (5), one or both condensing agents that form in N '-dicyclohexylcarbodiimide or N-ethyl-N '-dimethylamine propyl carbodiimide hydrochloride and N-hydroxy benzo triazole, N-hydroxy-succinamide, DMAP, the triethylamine;
The consumption mol ratio of compound V and compound VIII is 1: 0.8～1.5 in the described step (5);
Available 10% aqueous citric acid solution, 10% ~ 20% NaHCO after the condensation reaction of compound V and compound VIII finishes in the described step (5) 3, distilled water or saturated NaCl solution washing, anhydrous sodium sulfate drying, sherwood oil, methylene dichloride recrystallization.
Organic solvent can be formic acid, acetic acid, methyl alcohol, ethanol, Virahol, ethyl acetate, methylene dichloride, ether, isopropyl ether, tetrahydrofuran (THF), 1 in the described step (6), among 4-dioxane, the DMF one or both, preferable formic acid, ethyl acetate, methylene dichloride, Virahol;
The organic solution of HCl can be that in HCl and methyl alcohol, ethanol, Virahol, ether, isopropyl ether, ethyl acetate, methylene dichloride, the Isosorbide-5-Nitrae-dioxane one or both form preferable formic acid, Virahol, ethyl acetate in the described step (6);
Formula IX compound described in the described step (6) is 1: 2 ~ 15 with the mol ratio of acid, preferred 1: 3 ~ 10;
After reacting completely in the described step (6), with ether or isopropyl ether precipitation, with methyl alcohol and isopropyl ether recrystallization;
In described step (1) ~ step (6), intermediate or the finished product can be selected one or more in spraying drying, lyophilize, vacuum-drying or the seasoning, and drying temperature is no more than 50 ℃.
The present invention has following advantage:
(1) synthetic route disclosed by the invention belongs to " convergence type " synthetic route, namely synthesizes first two segments, carries out condensation again.Compare with " orthoscopic " synthetic route, " convergence type " route has reduced reactions steps (calculating with ainothiazoly loximate), and it is more reasonable that segment higher price or synthetic difficulty is placed on the later stage introducing, reduced cost, and total recovery improves, and total recovery reaches more than 64%.
(2) respectively going on foot intermediate only needs simple solvent extraction, recrystallization just can obtain, and the product loss of having avoided column chromatography to cause has reduced labour intensity, reduces cost.
(3) avoided the use of the more expensive silylating reagent of price, trifluoroacetic acid and phosphorus oxychloride, the operational path reaction conditions is gentle, need not strict waterless operation.
(4) avoided residual in medicine of the use of altax and benzothiazole.
(5) this synthetic route sufficient raw is easy and simple to handle, and reaction conditions is gentle, and atom utilization is higher, reliable product quality, and cost is lower, is the synthetic route of a suitable suitability for industrialized production.
Embodiment
Mode below by embodiment further specifies the present invention, but therefore the present invention is not confined among the described scope of embodiments.
Embodiment 1
(1) preparation of formula III compound 7-N-tertbutyloxycarbonyl-amino-3-cephem-4-carboxylic acid (7-Boc-ANCA)
7-ANCA (4 g, 20 mmol) is dissolved in 50 ml dioxane and water (1: the 1) mixed solvent, under 10 ℃ of conditions, adds NaOH (1.2 g, 30 mmol), continue to stir 10 min, add (Boc) 2O (6.1 g, 28 mmol) is 10 ℃ of lower reactions.TLC detects, and after reaction finishes, adds the dilution of 50 ml cold water, uses 4 molL -1After HCl transfers to pH=2 ~ 3, use again cold ethyl acetate extraction, then use successively 5% aqueous citric acid solution, saturated NaCl solution washing, add at last anhydrous Na 2SO 4Dried overnight.Concentrating under reduced pressure is with methylene dichloride and sherwood oil recrystallization.Obtain white crystals 5.5 g, productive rate 91.6%.107 ~ 108 ℃ of fusing points; IR (KBr) ν (cm -1): 3315.97,2979.81,1790.33,1750.12,1638.93.
(2) preparation of formula IV compound 7-N-t-butoxycarbonyl amino-3-cephem-4-carboxylic acid pivaloyl oxygen methyl esters (7-Boc-ANCA-POM)
With 7-Boc-ANCA(3 g, 10 mmol) be dissolved in-10 ℃ of solvents of 30 ml N,N-DIMETHYLACETAMIDEs (DMAC), then add K 2CO 3(1.38 g, 10 mmol) splash into prefabricated iodometyl pivalate (3.4 g after stirring 15 min, 14 mmol), after lucifuge was reacted 3 h, TLC detected, add the frozen water dilution after reaction finishes, use ethyl acetate extraction, then use successively 5% aqueous citric acid solution, 5%NaHCO 3The aqueous solution, saturated NaCl solution washing add Na 2SO 4Dried overnight.The elimination siccative removes solvent under reduced pressure, with methylene dichloride and sherwood oil recrystallization, gets white block crystallization 3.89 g, productive rate 94.3%.IR(KBr)ν(cm -1): 3319.36, 2979.85, 1793.06, 1695.42, 1596.45; 1H-NMR(400Hz, CDCl 3, TMS) δ1.23(9H, s, -CO-(CH 3) 3), 1.46(9H, s, -O-C(CH 3) 3), 3.39~3.67(2H, m, 4-H), 4.95(1H, d, J=4.8Hz, 6-H), 5.22(1H, d, J=9.6Hz, -CONH-), 5.66~5.70(1H, m, 7-H), 5.84~5.96(2H, dd, J=5.6Hz, -O-CH 2-O-), 6.61~6.63(1H, dd, J=2.4Hz, 3-H).
(3) preparation of formula V compound 7-amino-3-cephem-4-carboxylic acid pivaloyl oxygen methyl esters (7-ANCA-POM)
7-Boc-ANCA-POM (2.06 g, 5 mmol) is dissolved in the 5 ml ethyl acetate solvents, places ice bath to drip 4 molL -1Hydrochloric acid aqueous isopropanol 6 ml, TLC detects, and after reaction finishes, adds cold water 30 ml, ethyl acetate 30 ml, 10%NaOH aqueous solution water transfer phase pH to 8 separates two-phase, then the ethyl acetate extraction water twice, uses distilled water, saturated NaCl solution washing three times, adds an amount of anhydrous Na 2SO 4Drying, concentrating under reduced pressure gets product 1.42 g, productive rate 90.7%.IR(KBr)ν(cm -1): 3325.32, 2964.75, 1784.31, 1624.42, 1588.21; 1H-NMR (400MHz, CDCl 3, TMS) δ1.23(9H, s, -CO-C(CH 3) 3), 3.35~3.71(2H, m, 4-H), 4.81~5.00(2H, m，6-H, 7-H), 5.81~5.97(2H, m, -O-CH 2-O-), 6.61~6.63(1H, m, 3-H).
(4) preparation of formula VIII compound 2-(2-N-tertbutyloxycarbonyl-amino-(S)-propionamido-thiazole-4-yl)-2-(Z)-methoxyimino acetic acid (Boc-L-Ala-ATMA)
With Boc-L-Ala(1.89 g, 10 mmol) join in the 20 ml dichloromethane solutions, cryosel is bathed (5 ℃) lower stirring, splash into DCC (2.48 g, 12 mmol) and HOBt(1.76 g dichloromethane solution, 13 mmol), stir 1 h after, the THF solution that adds ainothiazoly loximate (2.8g, 14mmol).TLC detects, after reaction finishes, and the NaHCO with 20% 3Aqueous solution extraction three times at ice-water bath downward modulation water pH=2, is used dichloromethane extraction three times again, then washes three times with distilled water, the saturated NaCl aqueous solution, adds an amount of anhydrous Na 2SO 4Drying is filtered, and has been evaporated to solid and has separated out, and gets white crystals 3.16 g, productive rate 85.0% with the methylene dichloride recrystallization. 1H-NMR (400MHz, CDCl 3, TMS) δ1.37(9H, s, -O-C(CH 3) 3), 1.46(3H, s, -CH 3), 3.94(3H, s, -OCH 3), 4.70(1H, q, J=4.8Hz, -CO-CH-N), 7.64(1H, s, thiazole), 9.11(1H, s, -CONH-), 10.96(1H, s, -CONH-).
(5) formula IX compound 7 β-[(Z)-2-[2 – N-tertbutyloxycarbonyl-amino-(S)-alanyl amino-thiazolyl--4-yl]-2-methoxyimino-kharophen]-preparation of 3-cephem-4-carboxylic acid pivaloyl oxygen methyl esters (Boc-CZX-AP)
With compd B oc-L-Ala-ATMA (1.49g, 4 mmol) be dissolved in the 30 ml dichloromethane solutions, splash into DCC (0.99 g under-5 ℃ of lower stirrings, 4.8 mmol) with HOBt(0.70 g, 5.2 dichloromethane solution mmol), after continuing to stir 1 h, be added dropwise to 7-ANCA-POM(1.26 g, 4 mmol) dichloromethane solution 10 ml, 0 ℃ ~ 10 ℃ lower reactions, TLC detects, after reaction finishes, add the dilution of 40 ml methylene dichloride, use successively 10% aqueous citric acid solution, 10% NaHCO 3The aqueous solution, distilled water or the saturated NaCl aqueous solution are respectively washed three times, and is last, adds an amount of anhydrous Na 2SO 4Drying is filtered, and vacuum rotary steam has been concentrated into a small amount of solid and has separated out, and puts into the vacuum drying oven Air drying, gets product 2.18 g, productive rate 81.5%.IR(KBr)ν(cm -1) :3416.8, 2976.5, 1787.7, 1753.4, 1687.3； 1H-NMR (400MHz, CDCl 3, TMS) δ1.22(9H, s, -CO-(CH 3) 3), 1.44(9H, s, -O-C(CH 3) 3), 1.63(3H, s, -CH 3), 3.42~3.68(2H, m, 4-H), 4.04(3H, s, -O-CH 3), 4.52(1H, br, -CH-), 5.09(1H, d, J=4.8Hz, 6-H), 5.46(1H, br, -CONH), 5.91(2H, dd, J=5.2Hz, -O-CH 2-O-), 6.02(1H, dd, J=4.8Hz, 7-H), 6.65(1H, dd, J=2.4Hz, 3-H), 7.30(1H, s, thiazole), 7.81(1H, d, J=6.8Hz, -NH-), 10.66(1H, br, -CONH).
(6) preparation of formula I target compound Ceftizoxime alapivoxil hydrochloride (CZX-AP-HCl)
With Boc-CZX-AP(2.0 g, 3 mmol) be dissolved in 10 ml dichloromethane solutions, under ice-water bath, be added dropwise to 4 molL -1Hydrochloric acid aqueous isopropanol 5 ml, keep continuing under the ice-water bath to stir 1 h, add excessive ether to a large amount of Precipitations are arranged, leave standstill half hour, filter.With ethanol-isopropyl ether recrystallization, vacuum Air drying, obtain faint yellow solid 1.72 g, productive rate 94.2%.IR(KBr)ν(cm -1): 3411.70, 2976.65, 1791.45, 1751.43, 1675.97； 1H-NMR (400MHz, DMSO-d) δ1.16(9H, s, -CO(CH 3) 3), 1.49(3H, d, J=4.0Hz, -CH 3), 3.64(2H, m, 4-H), 3.90(3H, s, -O-CH 3), 4.08(1H, d, J=4.0Hz, -COCH-N), 5.17(1H, d, J=8.0Hz, 6-H), 5.80(1H, d, J=8.0Hz, 7-H), 5.91 (2H, m, OCH 2O), 6.63(1H, m, 3-H), 7.48(1H, s, thiazole), 8.59(3H, br, NH 3 +), 9.74(1H, d, J=8.0Hz, -CONH), 13.07(1H, s, -CONH)； 13C-NMR (101 MHz, DMSO) δ 176.52(O- C(C(CH 3))=O), 169.37(N- C(CH)=O), 164.06(O- C(C=C)=O), 163.04(C-8), 160.44(N- C(C=N)=O), 158.08(N-C(S)=N), 148.91(=C- C(C=O)=N), 142.16(N- C(C=N)=C), 126.68(C-2), 123.54(C-3), 115.26(S- CH=C-), 80.18(O-CH 2-O), 62.66(OCH 3), 59.52(C-6), 57.49(C-7), 48.92(N- CH-C=O), 38.69(- C(CH 3) 3), 26.95(-C( CH 3) 3), 24.28(C-4), 17.14( CH 3-CH(N)(C=O))。
Embodiment 2
(1) preparation of formula III compound 7-N-tertbutyloxycarbonyl-amino-3-cephem-4-carboxylic acid (7-Boc-ANCA)
7-ANCA (4 g, 20 mmol) stirred be dissolved in about 0 ℃ in the 50 ml ethanol, add Na 2CO 3(2.6 g, 24 mmol) continue to stir 10 min.Then add (Boc) 2O (5.7 g, 26 mmol) reacts under ice-water bath, and TLC detects.Concentrating under reduced pressure reclaimed solvent after reaction finished, and added the dilution of 50 ml cold water, with cold dichloromethane extraction 2 times; In ice-water bath, regulate again water pH=2 ~ 3, then use cold dichloromethane extraction 3 times; Merge organic phase, wash three times with 5% aqueous citric acid solution, distilled water or the saturated NaCl aqueous solution successively, add anhydrous Na 2SO 4Dried overnight.With the solvent condensing crystal, use again methylene dichloride and sherwood oil recrystallization.Obtain white crystals 5.73 g, productive rate 95.5%.
(2) preparation of formula IV compound 7-N-t-butoxycarbonyl amino-3-cephem-4-carboxylic acid pivaloyl oxygen methyl esters (7-Boc-ANCA-POM)
With 7-Boc-ANCA(3 g, 10 mmol) be dissolved in the mixed solution of 30 ml DMF and dioxane (3: 1), add dicyclohexyl amine in-5 ℃ (2.79 ml, 14 mmol) stir and drip prefabricated iodometyl pivalate (2.85 g, 20 mmol) behind 15 min, and lucifuge is reacted 3 h, and TLC detects, and adds the frozen water dilution after reaction finishes, and with ethyl acetate extraction three times, then use successively 5%NaHCO 3The aqueous solution, distilled water, the saturated NaCl aqueous solution are washed three times, add anhydrous Na 2SO 4Dried overnight.Remove solvent under reduced pressure, with methylene dichloride and sherwood oil recrystallization, get white block crystallization 3.75 g, productive rate 90.8%.
(3) preparation of formula V compound 7-amino-3-cephem-4-carboxylic acid pivaloyl oxygen methyl esters (7-ANCA-POM)
With 7-Boc-ANCA-POM (2.06 g, 5 mmol) be dissolved in the 5 ml dichloromethane solvents, place cryosel to bathe (5 ℃) and drip 85% phosphoric acid solution 5 ml, add cold water 30 ml behind 30 min, with 10%NaOH aqueous solution water transfer phase pH to 8 ~ 9, then use twice of ethyl acetate extraction water, combined ethyl acetate, distillation washing twice, the saturated NaCl aqueous solution is washed three times, adds an amount of anhydrous Na 2SO 4Drying boils off solvent, gets product 1.5 g, productive rate 95.7%.
(4) preparation of formula VIII compound 2-(2-N-tertbutyloxycarbonyl-amino-(S)-propionamido-thiazole-4-yl)-2-(Z)-methoxyimino acetic acid (Boc-L-Ala-ATMA)
With Boc-L-Ala(1.89 g, 10 mmol) join in the 20 ml methylene dichloride, stir under the ice-water bath, splash into EDCHCl (2.41g, 12 mmol) and HOSu(1.5 g dichloromethane solution, 13 mmol), stir 1 h after, the DMF solution that adds ainothiazoly loximate (1.8 g, 9 mmol).TLC detects, after reaction finishes, and the NaHCO with 20% 3Aqueous solution extraction three times transfers to 2 with water pH under ice-water bath, use ethyl acetate extraction three times again, then uses successively 5% aqueous citric acid solution, distilled water, and the saturated NaCl aqueous solution is respectively washed three times, adds an amount of anhydrous Na 2SO 4Dried overnight is filtered, and has been evaporated to solid and has separated out, and gets white crystals 2.75 g, productive rate 82.0% with ethyl acetate-sherwood oil recrystallization.
(5) formula IX compound 7 β-[(Z)-2-[2 – N-tertbutyloxycarbonyl-amino-(S)-alanyl amino-thiazolyl--4-yl]-2-methoxyimino-kharophen]-preparation of 3-cephem-4-carboxylic acid pivaloyl oxygen methyl esters (Boc-CZX-AP)
With compd B oc-L-Ala-ATMA (1.86g, 5 mmol) be dissolved in the 30 ml DMF solution, splash into EDCHCl (1.21 g under-5 ℃ of lower stirrings, 6 mmol), HOBt(0.81 g, 6 mmol) and DMAP(0.12 mg, 1 mmol) DMF solution, after continuing to stir 1 h, be added dropwise to 7-ANCA-POM(1.26g, 4 mmol) DMF solution 10 ml, maintain-5 ℃ ~ 0 ℃ lower reaction.TLC detects, and after reaction finishes, adds the dilution of 40 ml methylene dichloride, uses successively 10% aqueous citric acid solution, 10% NaHCO 3The aqueous solution, distilled water or the saturated NaCl aqueous solution are respectively washed three times, and is last, adds an amount of anhydrous Na 2SO 4Drying is filtered, and vacuum rotary steam has been concentrated into a small amount of solid and has separated out, and puts into the vacuum drying oven Air drying, gets product 2.78 g, productive rate 85.3%.
(6) preparation of formula I target compound Ceftizoxime alapivoxil hydrochloride (CZX-AP-HCl)
With Boc-CZX-AP(2.0 g, 3 mmol) be dissolved in 10 ml formic acid solutions, (5 ℃) are added dropwise to 4 molL under cryosel is bathed -1Hydrochloric acid aqueous isopropanol 3 ml, keep cryosel to bathe lower the continuation and stir 1 h, add excessive ether to a large amount of Precipitations are arranged, leave standstill half hour, filter.With ethanol-isopropyl ether recrystallization, vacuum drying oven Air drying, obtain faint yellow solid 1.68 g, productive rate 92.6%.
Embodiment 3
(1) preparation of formula III compound 7-N-tertbutyloxycarbonyl-amino-3-cephem-4-carboxylic acid (7-Boc-ANCA)
7-ANCA (4 g, 20 mmol) is joined in the 50 ml methyl alcohol, in about 5 ℃, stir 10 min, then drip triethylamine (4.2 ml, 30 mmol) and continue to stir 10 min, add (Boc) 2O (5.2 g, 24 mmol), system is warming up to room temperature naturally, stirs 12 h.The reaction solution concentrating under reduced pressure reclaims solvent, add the dilution of 50 ml cold distilled waters, cold ethyl acetate extraction 2 times, after again water being transferred to pH=2-3 in ice bath, cold ethyl acetate extraction 3 times, merge organic phase, wash three times with 5% aqueous citric acid solution, distilled water or the saturated NaCl aqueous solution successively, add anhydrous Na 2SO 4Dried overnight.The elimination siccative will remove solvent under reduced pressure, directly use methylene dichloride and sherwood oil recrystallization.Obtain white crystals 5.95 g, productive rate 99.2%.
(2) preparation of formula IV compound 7-N-t-butoxycarbonyl amino-3-cephem-4-carboxylic acid pivaloyl oxygen methyl esters (7-Boc-ANCA-POM)
With 7-Boc-ANCA(3 g, 10 mmol) be dissolved in the 30 ml dichloromethane solutions, at 0 ℃ of lower K that adds 2CO 3(2.07 g, 15 mmol) stir 10 min, then drip prefabricated iodometyl pivalate (2.9 g, 12 mmol), lucifuge is reacted 3 h under ice bath, add the methylene dichloride dilution, then respectively wash three times with 5% aqueous citric acid solution, the saturated NaCl aqueous solution successively, add anhydrous Na 2SO 4Dried overnight.Concentrating under reduced pressure gets crystallization, uses at last methylene dichloride and sherwood oil recrystallization again, gets white block crystallization 3.68 g, productive rate 89.1%.
(3) preparation of formula V compound 7-amino-3-cephem-4-carboxylic acid pivaloyl oxygen methyl esters (7-ANCA-POM)
Get compounds Ⅳ (2.06 g, 5 mmol), after the adding formic acid 10 ml dissolving, under 5 ℃ of conditions, stir 10 min, drip 4 molL -1Ethanol solution hydrochloride 10 ml, add cold water 30 ml behind 60 min, methylene dichloride 30 ml, 10%NaOH aqueous solution water transfer phase pH to 9, separate two-phase, then use dichloromethane extraction water twice, merge organic phase, distillation washing twice, the saturated NaCl aqueous solution is washed three times, adds an amount of Na 2SO 4Drying boils off solvent, gets product 1.48 g, productive rate 94.5%.
(4) preparation of formula VIII compound 2-(2-N-tertbutyloxycarbonyl-amino-(S)-propionamido-thiazole-4-yl)-2-(Z)-methoxyimino acetic acid (Boc-L-Ala-ATMA)
With Boc-L-Ala(1.89 g, 10 mmol) join in the 20ml DMF solution stirring and dissolving under the ice-water bath, splash into EDCHCl (2.41 g, 12 mmol) and DMAP(0.24 mg, 2 mmol), after continuing to stir 1 h, add the DMF solution of ainothiazoly loximate (2.0 g, 10 mmol).TLC detects, after reaction finishes, and the NaHCO with 20% 3Aqueous solution extraction three times is used 4 molL under ice-water bath -1HCl transfers to 2 with water pH, uses dichloromethane extraction three times again, and then the distillation washing twice, and the saturated NaCl aqueous solution is washed three times, adds an amount of anhydrous Na 2SO 4Drying is filtered, and has been evaporated to solid and has separated out, and gets white crystals 3.28 g, productive rate 88.0% with ethyl acetate-sherwood oil recrystallization.
(5) formula IX compound 7 β-[(Z)-2-[2 – N-tertbutyloxycarbonyl-amino-(S)-alanyl amino-thiazolyl--4-yl]-2-methoxyimino-kharophen]-preparation of 3-cephem-4-carboxylic acid pivaloyl oxygen methyl esters (Boc-CZX-AP)
With compd B oc-L-Ala-ATMA (1.49g, 5 mmol) be dissolved in the 30 ml dichloromethane solutions, splash into EDCHCl (1.21 g under under ice-water bath, stirring, 6 mmol) and HOSu(0.81 g, 7mmol) and the dichloromethane solution of triethylamine (0.56 ml, 4mmol), after continuing to stir 1 h, be added dropwise to 7-ANCA-POM(1.26g, 4 mmol) dichloromethane solution 10 ml, 10 ℃ of lower reactions.TLC detects, and adds the dilution of 40 ml methylene dichloride after reaction finishes, and uses successively 10% aqueous citric acid solution, 10% NaHCO 3The aqueous solution, distilled water or the saturated NaCl aqueous solution are respectively washed three times, and is last, adds an amount of anhydrous Na 2SO 4Drying is filtered, and has been evaporated to a small amount of solid and has separated out, and puts into the vacuum drying oven Air drying, gets product 2.38 g, productive rate 89.2%.
(6) preparation of formula I target compound Ceftizoxime alapivoxil hydrochloride (CZX-AP-HCl)
With Boc-CZX-AP(2.0 g, 3 mmol) be dissolved in 10 ml formic acid solutions, under ice-water bath, be added dropwise to 4 molL -1Hydrochloric ethyl acetate solution 4 ml, keep continuing under the ice-water bath to stir 1 ~ 2 h, adding distil water dilution, ethyl acetate extraction 3 times, the distillation washing once, saturated common salt washing 2 times, anhydrous sodium sulfate drying filters, concentrate to get product, with ethanol-isopropyl ether recrystallization, obtain faint yellow solid 1.73 g, productive rate 95.3%.

Claims (2)

1. the method for a preparation formula I Ceftizoxime alapivoxil hydrochloride
It is characterized in that the method may further comprise the steps:
(1) formula II compound 7-amino-3-cephem-4-carboxylic acid is dissolved in the solvent, under base catalysis, react under-10 ℃～25 ℃ conditions with tert-Butyl dicarbonate, obtain formula III compound 7-N-tertbutyloxycarbonyl-amino-3-cephem-4-carboxylic acid, be called for short 7-Boc-ANCA;
(2) formula III compound 7-Boc-ANCA is dissolved in the organic solvent, under base catalysis, with iodometyl pivalate lucifuge reaction under-20 ℃～10 ℃ conditions, obtain formula IV compound 7-N-t-butoxycarbonyl amino-3-cephem-4-carboxylic acid pivaloyl oxygen methyl esters, be called for short 7-Boc-ANCA-POM;
(3) formula IV compound 7-Boc-ANCA-POM is dissolved in the organic solvent, reacts under-10 ℃～10 ℃ conditions with acid, slough the Boc protecting group, prepare formula V compound 7-amino-3-cephem-4-carboxylic acid pivaloyl oxygen methyl esters, be called for short 7-ANCA-POM;
(4) formula VI compound N-tert-butoxycarbonyl-l-alanine is dissolved in the organic solvent, add the coupling condenser agent that carbodiimide class condensing agent or imidazoles condensing agent and active catalyst form, react under-10 ℃～20 ℃ conditions with formula VII compound ainothiazoly loximate, obtain formula VIII compound 2-(2-N-tertbutyloxycarbonyl-amino-(S)-propionamido-thiazole-4-yl)-2-(Z)-methoxyimino acetic acid, be called for short Boc-L-Ala-ATMA;
Figure 67186DEST_PATH_IMAGE006
(5) formula V compound 7-ANCA-POM and formula VIII compd B oc-L-Ala-ATMA are dissolved in the organic solvent, add the coupling condenser agent that carbodiimide class condensing agent or imidazoles condensing agent and active catalyst form, under-5 ℃～20 ℃ conditions, react, obtain formula IX compound 7 β-[(Z)-2-[2 – N-tertbutyloxycarbonyl-amino-(S)-alanyl amino-thiazolyl--4-yl]-2-methoxyimino-kharophen]-3-cephem-4-carboxylic acid pivaloyl oxygen methyl esters, be called for short Boc-CZX-AP;
Figure 838570DEST_PATH_IMAGE007
(6) with formula IX compd B oc-CZX-AP organic solvent dissolution, add the organic solution that contains hydrochloric acid, under-5 ℃～10 ℃ conditions, react, prepare formula I compound Ceftizoxime alapivoxil hydrochloride;
Step (4), (5) described carbodiimide class condensing agent are N, N '-dicyclohexylcarbodiimide, N, N '-DIC, N-ethyl-N '-dimethylamine propyl carbodiimide hydrochloride, 2-[[4-(2,2-dimethyl-1,3-dioxy base)]-methyl] the carbon imide one of them; The imidazoles condensing agent is N, N'-carbonyl dimidazoles, N ' N-thiocarbonyldiimidazole one of them; Active catalyst is N-hydroxy benzo triazole, N-hydroxy-succinamide, N-hydroxyl-5-norbornylene-2,3-dicarboximide, N-hydroxyl-7-azo benzotriazole or 3-hydroxyl-1, in 2,3-phentriazine-4 (3H)-ketone, DMAP, triethylamine, the dicyclohexyl amine one or more.
2. the preparation method of Ceftizoxime alapivoxil hydrochloride according to claim 1 is characterized in that, in the step (1):
(a) described solvent is water, acetone, methyl alcohol, ethanol, tetrahydrofuran (THF), acetonitrile, dioxane, N, N '-dimethyl formamide, N, one or both in N '-N,N-DIMETHYLACETAMIDE;
(b) described alkaline matter is diethylamine, triethylamine, hexahydroaniline, dicyclohexyl amine, trolamine, pyridine, quinoline or diazabicylo organic bases; Or NaOH, KOH, NaHCO 3, Na 2CO 3, KHCO 3, K 2CO 3Mineral alkali one of them;
(c) reaction raw materials mol ratio 7-ANCA:Boc 2O: alkaline matter is 1: 1.1～1.6: 1～5;
In the step (2):
(a) described organic solvent is one or both in methyl alcohol, ethanol, acetone, methylene dichloride, dioxane, dimethyl formamide, N,N-DIMETHYLACETAMIDE, dimethyl sulfoxide (DMSO), the acetonitrile;
(b) described alkaline matter diethylamine, triethylamine, hexahydroaniline, dicyclohexyl amine, trolamine, pyridine, quinoline, diazabicylo organic bases one of them; Or NaOH, KOH, NaHCO 3, Na 2CO 3, KHCO 3, K 2CO 3Mineral alkali one of them;
(c) mol ratio of described formula III compound and alkaline matter and iodometyl pivalate is 1: 1～3: 1～5;
In the step (3):
(a) described organic solvent is one or both in formic acid, methyl alcohol, ethanol, Virahol, ethyl acetate, methylene dichloride, ether, isopropyl ether, tetrahydrofuran (THF), dioxane, the methyl-phenoxide;
(b) used acid is a kind of in hydrochloric acid, phosphoric acid, formic acid, the acetic acid;
(c) described formula IV compound is 1: 1 ~ 25 with the mol ratio of acid;
In the step (4):
(a) used organic solvent is methyl alcohol, ethanol, ethyl acetate, methylene dichloride, N, N '-dimethyl formamide, N, one or both in N '-N,N-DIMETHYLACETAMIDE;
(b) the used preferred N of coupling condenser agent, one or both condensing agents that form in N '-dicyclohexylcarbodiimide or N-ethyl-N '-dimethylamine propyl carbodiimide hydrochloride and N-hydroxy benzo triazole, N-hydroxy-succinamide, DMAP, the triethylamine;
(c) the consumption mol ratio of compound VI and compound VII is 1: 0.8～1.5;
In the step (5):
(a) used organic solvent is methyl alcohol, ethanol, ethyl acetate, methylene dichloride, N, N '-dimethyl formamide, N, one or both in N '-N,N-DIMETHYLACETAMIDE;
(b) the used preferred N of coupling condenser agent, one or both condensing agents that form in N '-dicyclohexylcarbodiimide or N-ethyl-N '-dimethylamine propyl carbodiimide hydrochloride and N-hydroxy benzo triazole, N-hydroxy-succinamide, DMAP, the triethylamine;
(c) the consumption mol ratio of compound V and compound VIII is 1: 0.8～1.5;
In the step (6):
(a) used organic solvent is formic acid, acetic acid, methyl alcohol, ethanol, Virahol, ethyl acetate, methylene dichloride, ether, isopropyl ether, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, N, one or both in N '-dimethyl formamide;
(b) organic solution of HCl is selected one or both in HCl and methyl alcohol, ethanol, Virahol, ether, isopropyl ether, ethyl acetate, methylene dichloride, the Isosorbide-5-Nitrae-dioxane;
(c) described formula IX compound is 1: 2 ~ 15 with the mol ratio of acid.
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