CN105859747A - Cefepime dihydrochloride preparation method suitable for industrial production - Google Patents
Cefepime dihydrochloride preparation method suitable for industrial production Download PDFInfo
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- CN105859747A CN105859747A CN201610314754.3A CN201610314754A CN105859747A CN 105859747 A CN105859747 A CN 105859747A CN 201610314754 A CN201610314754 A CN 201610314754A CN 105859747 A CN105859747 A CN 105859747A
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- preparation
- cefepime hydrochloride
- industrialized production
- cefepime
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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
- C07D501/38—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof
- C07D501/46—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof with the 7-amino radical acylated by carboxylic acids containing hetero rings
Abstract
The invention relates to the technical field of chemical medicine synthesizing, in particular to a cefepime dihydrochloride preparation method suitable for industrial production. The preparation method is characterized in that crude cefepime dihydrochloride is obtained by the acylation reaction of a compound I (7-MPCA) and a compound II (MAEM) and acidizing crystallization, and refining is performed to obtain the high-purify cefepime dihydrochloride. The preparation method has the advantages that a single solvent is used, and recycling and reusing are facilitated; the refining process is performed in an anhydrous system, product degradation under the strong acid condition during the refining process is reduced, and corrosion to production equipment is avoided; the acylation reaction and the refining are simple to operate, extremely high product conversion rate is achieved, production cost is low, and the method is suitable for industrial production of high-quality cefepime dihydrochloride.
Description
(1) technical field
The present invention relates to chemicals synthesis technical field, particularly to a kind of cefepime Hydrochloride being suitable to industrialized production
Preparation method.
(2) background technology
Cefepime (cefepime, BMY-28142, CFPM) is to be opened by Mei-Shi Guibao (Bristol-Myerssquibb) when hundred
Send out forth generation injection cephalosporin analog antibiotic, in 1993 in Sweden's Initial Public Offering, the most successively France, Italy,
The multinational listing such as Japanese, Canadian, lists for 1996 in the U.S., within 1998, enters Chinese market.
Compared with third generation cephalosporin analog antibiotic, the antimicrobial spectrum of Cefepime is wider, and antibacterial activity is higher, produces bacterium
Beta-lactamase more stable.Cefepime has good activity to gram-negative bacteria particularly enterobacteria Pseudomonas aeruginosa, right
Gram positive bacteria also has good antibacterial activity, and clinic cures mainly by sensitive microbial lower respiratory tract, the urinary tract, skin and skin
Soft tissue and abdominal cavity infection, and septicemia and Neutrophilic granulocytopenia companion fever patient empirical treatment etc..Due to hydrochloric acid
The advantages such as Cefepime is efficient, low toxicity, wide spectrum, are used, determined curative effect the most in a large number.
Cefepime Hydrochloride (cefepime hydrochloride 1) chemical entitled 1-[[(6R, 7R)-7-[(2Z)-
(2-amino-4-thiazolyl) (methoxyimino) acetamido]-2-carboxyl-8-oxo-5-thia-1-azabicyclic
[4.2.0] oct-2-ene-3-base] methyl]-1-crassitude hydrochloride, its molecular formula is C19H24N6O5S2·2HCl·
H2O, molecular weight is 571.50, structural formula is as follows:
The main preparation methods of cefepime Hydrochloride has at present:
(1) patent CN201010568846.7 discloses the preparation method of a kind of highly purified cefepime Hydrochloride, passes through electric osmose
Cefepime Hydrochloride is carried out isolated and purified by analysis, acid-base reaction, charcoal absorption and preparative chromatography post, and its purity can reach
99.9%.This patented method step is numerous and diverse, and cost is high, and yield is low, is not suitable for large-scale industrial production；
(2) patent application 201410072841.0 discloses the preparation method of a kind of high-purity hydrochloric acid Cefepime, first prepares
The cefepime Hydrochloride crude product aqueous solution containing 0.5-0.6kg/L, then under the sound field of certain frequency and power output, is initially charged
Oxolane adds the mixed solution crystallization of isopropanol and hexamethylene, and the cefepime Hydrochloride purity obtained is more than 99.9%.
The method is firstly because crystallization process needs certain sound field reflecting, and to producing, equipment requirement is higher, and next employs three kinds has
The mixed liquor crystallization of machine solvent, solvent pressure recovery is relatively big, and the method still suffers from needing for large-scale industrial production in a word
The place to improve further；
(3) patent CN103665003A discloses the process for purification of a kind of high-purity cefepime dihydrochloride monohydrate, but
Its initiation material is Cefepime inner salt, because it is difficult to obtain solid, so being also not carried out business-like production and selling,
Therefore this patented method also cannot realize industrialized production.
(3) summary of the invention
The present invention is in order to make up the deficiencies in the prior art, it is provided that what a kind of conversion rate of products height, production cost were low is suitable to industry
The preparation method of the cefepime Hydrochloride that metaplasia is produced.
The present invention is achieved through the following technical solutions:
The preparation method of a kind of cefepime Hydrochloride being suitable to industrialized production, with chemical compounds I (6R, 7R)-7-amino-3-[(1-
Methyl isophthalic acid-pyrrolidines) methyl] cephalo-3-alkene-4-carboxylic acid inner salt and compound ii (Z)-2-(thiazolamine-4-base)-2-first
Oxyimino group thioacetic acid-2'-MEAM is raw material, comprises the steps:
(1) with dichloromethane as solvent, in the presence of the sulfurous acid that mass fraction is 6%, organic base catalytic chemical compounds I and chemical combination
Thing II condensation reaction, after reaction terminates, after add water extraction, desolventing technology, adds recrystallisation solvent crystallization, obtains cefepime Hydrochloride
Crude product；
(2) by cefepime Hydrochloride dissolving crude product to organic solvent, after activated-carbon filter core system filters, recrystallisation solvent is added
Crystallization, obtains highly purified cefepime Hydrochloride product.
The present invention is generated by chemical compounds I (7-MPCA) and compound ii (MAEM) acylation reaction, acidizing crystal obtains salt
Acid Cefepime crude product, then by being refining to obtain highly purified cefepime Hydrochloride.The inventive method synthesis uses single solvent,
It is easy to recovery；Subtractive process is carried out in anhydrous system, has both reduced and has degraded under product strong acid condition in subtractive process,
Turn avoid the corrosion to the equipment of production.And acylation reaction and purification step are easy and simple to handle, and conversion rate of products is high, therefore
Production cost is low, is suitable to the high-quality cefepime Hydrochloride of industrialized production.
It is a discovery of the invention that under given conditions, during cefepime Hydrochloride dissolving crude product, add appropriate in dissolution solvent
Recrystallisation solvent, be possible not only to play the effect of hydrotropy, it is also possible to be effectively improved the dissolution filter of product except chromatic effect, obtain
Product look level substantially improves.
The more excellent technical scheme of the present invention is:
In step (1), organic base is diisopropylamine, triethylamine or diethylamine；Sulfurous acid is 0.5-with the volume ratio of dichloromethane
1:100；Chemical compounds I is 1:1.0-1.2 with the mol ratio of compound ii；Organic base is 1-1.4:1 with the mol ratio of chemical compounds I；
Setting-up point is 0-5 DEG C；Recrystallisation solvent is one or more in acetone, isopropanol and ethanol.
In step (2), organic solvent is the one of methyl alcohol, DMF and DMA or many
Kind；Recrystallisation solvent is one or more in acetone, ethanol, isopropanol, isopropyl ether, n-hexane and hexamethylene；Recrystallisation solvent with
The organic solvent volume of dissolved product is than for 6-10:1.
Term illustrates:
If no special instructions, the present invention is previously mentioned 7-MPCA and MAEM and all refers in particular to compound corresponding in term explanation.
(6R, 7R)-7-amino-3-[(1-methyl isophthalic acid-pyrrolidines) methyl] cephalo-3-alkene-4-carboxylic acid inner salt inner salt (7-
MPCA) chemical structural formula is as follows:
(Z)-2-(thiazolamine-4-base)-2-methoxyimino thioacetic acid-2'-MEAM (MAEM) chemistry
Structural formula is as follows:
The synthesis route of the method for the invention is as follows:
Beneficial effect:
(1) present invention is simple to operate, and reactions steps is few, and is suitable to industrialized production；
(2) synthetic reaction of the present invention uses low toxicity dichloromethane easy to recovery of applied, beneficially environmental protection, reduce production cost and
Environmental protection is paid；
(3) present invention loses the most very from 7-MPCA to cefepime Hydrochloride crude product reaction conversion ratio more than 98%, purification step product
Little；
(4) cosolvent when present invention refines and recrystallisation solvent are same solvent, and recrystallisation solvent is compared with dissolution solvent, at low ratio
Hydrotropy during example, ratio increases to a certain degree, then makes product crystallization；
(5) the cefepime Hydrochloride purity that the present invention is refining to obtain is more than 99.9%, and solution colour has reached colourless unexpectedly
Rank.
(4) detailed description of the invention
Below by embodiment, technical scheme is described further, but the embodiment provided not it should be understood that
For scope is construed as limiting.
Embodiment 1: the preparation of cefepime Hydrochloride crude product
In reaction bulb, put into dichloromethane 150L, be cooled to 0-5 DEG C, add 7-MPCA 20kg(67mol), MAEM 25kg
(71mol), add 6% sulfurous acid solution 1.5L, keep temperature to be not higher than 5 DEG C, be slowly added to triethylamine 11.2L(80mol), add
Insulation 0-5 DEG C after complete, reacts to 7-MPCA residual less than 0.5%(HPLC)；
Purified water 90L, layering is put in reaction bulb；Again with 15L water back extraction dichloromethane, combining water layer, add activated carbon 1kg,
Decolouring 1 hour, filter, filter cake 10L washes, and filtrate merges, and keeps temperature 15-25 DEG C, adds acetone 300L, crystal seed
0.05kg, after growing the grain 2 hours to a large amount of precipitation, then used time 90-120min, add acetone 390L, 0-5 DEG C of stirring 1 hour of lower the temperature.
Filtering, acetone washs, and vacuum drying obtains cefepime Hydrochloride crude product 37.5kg(66mol), product quality result is listed in table 1
In.
Embodiment 2: prepared by cefepime Hydrochloride crude product
In reaction bulb, put into dichloromethane 150L, be cooled to 0-5 DEG C, add 7-MPCA 20kg(67mol), MAEM 27kg
(77mol), add 6% sulfurous acid solution 0.75L, keep temperature to be not higher than 5 DEG C, be slowly added to triethylamine 10.3L(74mol), add
Insulation 0-5 DEG C after complete, reacts to 7-MPCA residual less than 0.5%(HPLC)；
Purified water 90L, layering is put in reaction bulb；Again with 15L water back extraction dichloromethane, combining water layer, add activated carbon 1kg,
Decolouring 1 hour, filter, filter cake 10L washes, and filtrate merges, and keeps temperature 15-25 DEG C, adds isopropanol 320L, crystal seed
0.05kg, after growing the grain 2 hours to a large amount of precipitation, then used time 90-120min, adding isopropanol 400L, lower the temperature 0-5 DEG C, it is little to stir 1
Time.Filtering, isopropanol washs, and vacuum drying obtains cefepime Hydrochloride crude product 37.6kg(66mol), product quality result is listed in
In table 1.
Embodiment 3: prepared by cefepime Hydrochloride crude product
In reaction bulb, put into dichloromethane 150L, be cooled to 0-5 DEG C, add 7-MPCA 20kg(67mol), MAEM 26kg
(74mol), add 6% sulfurous acid solution 1L, keep temperature to be not higher than 5 DEG C, be slowly added to diisopropylamine 11.3L(80mol), add
Insulation 0-5 DEG C after complete, reacts to 7-MPCA residual less than 0.5%(HPLC)；
Purified water 90L, layering is put in reaction bulb；Again with 15L water back extraction dichloromethane, combining water layer, add activated carbon 1kg,
Decolouring 1 hour, filter, filter cake 10L washes, and filtrate merges, and keeps temperature 15-25 DEG C, adds ethanol 360L, crystal seed
0.05kg, after growing the grain 2 hours to a large amount of precipitation, then used time 90-120min, add ethanol 420L, 0-5 DEG C of stirring 1 hour of lower the temperature.
Filtering, ethanol washs, and vacuum drying obtains cefepime Hydrochloride crude product 37.5kg(66mol), product quality result is listed in table 1
In.
Embodiment 4: the preparation of high-purity hydrochloric acid Cefepime
In reaction bulb, put into methyl alcohol 60L and acetone 30L, keep temperature 15-20 DEG C, put into the hydrochloric acid head that previous embodiment obtains
Spore pyrrole oxime crude product 30kg, after stirring and dissolving, is filtered by the activated-carbon filter core system of 0.2 μm, 6L methyl alcohol and 3L acetone mixture
Washing, filtrate merges.In filtrate, add acetone 30L, crystal seed 0.01kg, growing the grain 1-2 hour, continuously add acetone 300L, use
Time 2-3 hour, after adding, cool to 0-5 DEG C, after stirring 1 hour, centrifugal, be dried and to obtain cefepime Hydrochloride 29.5kg, mole receive
Rate is 98.3%.The results are shown in Table 2 for product quality.
Embodiment 5: the preparation of high-purity hydrochloric acid Cefepime
In reaction bulb, put into methyl alcohol 60L and isopropanol 30L, keep temperature 15-20 DEG C, put into the hydrochloric acid that previous embodiment obtains
Cefepime crude product 30kg, after stirring and dissolving, is filtered by the activated-carbon filter core system of 0.2 μm, and 6L methyl alcohol and 3L isopropanol mix
Conjunction liquid washs, and filtrate merges.In filtrate, add isopropanol 30L, crystal seed 0.01kg, growing the grain 1-2 hour, continuously add isopropanol
360L, 2-3 hour used time, after adding, cools to 0-5 DEG C, after stirring 1 hour, centrifugal, is dried to obtain cefepime Hydrochloride
29.4kg, molar yield is 98.0%.The results are shown in Table 2 for product quality.
Embodiment 6: the preparation of high-purity hydrochloric acid Cefepime
In reaction bulb, put into DMF 60L and ethanol 30L, keep temperature 15-20 DEG C, put into previous embodiment
The cefepime Hydrochloride crude product 30kg obtained, after stirring and dissolving, is filtered by the activated-carbon filter core system of 0.2 μm, N, N-diformazan
Base formamide 6L and the washing of ethanol 3L mixed liquor, filtrate merges.Ethanol 60L, crystal seed 0.01kg, growing the grain 1-2 is added in filtrate
Hour, continuously add ethanol 390L, 2-3 hour used time, after adding, cool to 0-5 DEG C, after stirring 1 hour, centrifugal, it is dried
Cefepime Hydrochloride 29.2kg, molar yield is 97.3%.The results are shown in Table 2 for product quality.
Table 1: cefepime Hydrochloride crude product quality results
Table 2: refined cefepime Hydrochloride quality results
Claims (10)
1. the preparation method of the cefepime Hydrochloride being suitable to industrialized production, it is characterised in that: with chemical compounds I (6R, 7R)-
7-amino-3-[(1-methyl isophthalic acid-pyrrolidines) methyl] cephalo-3-alkene-4-carboxylic acid inner salt and compound ii (Z)-2-(2-amino thiophene
Azoles-4-base)-2-methoxyimino thioacetic acid-2'-MEAM is raw material, comprises the steps: that (1) is with dichloro
Methane is solvent, in the presence of the sulfurous acid that mass fraction is 6%, and organic base catalytic chemical compounds I and compound ii condensation reaction,
After reaction terminates, after add water extraction, desolventing technology, add recrystallisation solvent crystallization, obtain cefepime Hydrochloride crude product；(2) by salt
Acid Cefepime dissolving crude product is in organic solvent, after activated-carbon filter core system filters, adds recrystallisation solvent crystallization, obtains height
The cefepime Hydrochloride product of purity.
The preparation method of the cefepime Hydrochloride being suitable to industrialized production the most according to claim 1, it is characterised in that: step
Suddenly, in (1), organic base is diisopropylamine, triethylamine or diethylamine.
The preparation method of the cefepime Hydrochloride being suitable to industrialized production the most according to claim 1, it is characterised in that: step
Suddenly, in (1), sulfurous acid is 0.5-1:100 with the volume ratio of dichloromethane.
The preparation method of the cefepime Hydrochloride being suitable to industrialized production the most according to claim 1, it is characterised in that: step
Suddenly, in (1), chemical compounds I is 1:1.0-1.2 with the mol ratio of compound ii.
The preparation method of the cefepime Hydrochloride being suitable to industrialized production the most according to claim 1, it is characterised in that: step
Suddenly, in (1), organic base is 1-1.4:1 with the mol ratio of chemical compounds I.
The preparation method of the cefepime Hydrochloride being suitable to industrialized production the most according to claim 1, it is characterised in that: step
Suddenly, in (1), setting-up point is 0-5 DEG C.
The preparation method of the cefepime Hydrochloride being suitable to industrialized production the most according to claim 1, it is characterised in that: step
Suddenly, in (1), recrystallisation solvent is one or more in acetone, isopropanol and ethanol.
The preparation method of the cefepime Hydrochloride being suitable to industrialized production the most according to claim 1, it is characterised in that: step
Suddenly, in (2), organic solvent is one or more of methyl alcohol, DMF and DMA.
The preparation method of the cefepime Hydrochloride being suitable to industrialized production the most according to claim 1, it is characterised in that: step
Suddenly, in (2), recrystallisation solvent is one or more in acetone, ethanol, isopropanol, isopropyl ether, n-hexane and hexamethylene.
The preparation method of the cefepime Hydrochloride being suitable to industrialized production the most according to claim 1, it is characterised in that:
In step (2), the organic solvent volume of recrystallisation solvent and dissolved product is than for 6-10:1.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107201391A (en) * | 2017-07-04 | 2017-09-26 | 吉林省爱诺德生物工程有限公司 | A kind of synthetic method of cefepime Hydrochloride |
| CN109776572A (en) * | 2019-01-23 | 2019-05-21 | 华北制药河北华民药业有限责任公司 | A kind of purification process of cefepime Hydrochloride |
| CN111057076A (en) * | 2019-12-31 | 2020-04-24 | 北京鑫开元医药科技有限公司 | Preparation method and application of cefepime impurity |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5594129A (en) * | 1991-09-10 | 1997-01-14 | Bristol-Myers Squibb Company | Process for the preparation of a cephalosporin antibiotic |
| WO2004092183A2 (en) * | 2003-04-16 | 2004-10-28 | Sandoz Ag | Processes for the preparations of cefepime |
| WO2006008749A1 (en) * | 2004-07-16 | 2006-01-26 | Hetero Drugs Limited | Process for preparing pure cephalosporine intermediates |
-
2016
- 2016-05-13 CN CN201610314754.3A patent/CN105859747B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5594129A (en) * | 1991-09-10 | 1997-01-14 | Bristol-Myers Squibb Company | Process for the preparation of a cephalosporin antibiotic |
| WO2004092183A2 (en) * | 2003-04-16 | 2004-10-28 | Sandoz Ag | Processes for the preparations of cefepime |
| WO2006008749A1 (en) * | 2004-07-16 | 2006-01-26 | Hetero Drugs Limited | Process for preparing pure cephalosporine intermediates |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107201391A (en) * | 2017-07-04 | 2017-09-26 | 吉林省爱诺德生物工程有限公司 | A kind of synthetic method of cefepime Hydrochloride |
| CN107201391B (en) * | 2017-07-04 | 2020-07-07 | 吉林省爱诺德生物工程有限公司 | Synthesis method of cefepime hydrochloride |
| CN109776572A (en) * | 2019-01-23 | 2019-05-21 | 华北制药河北华民药业有限责任公司 | A kind of purification process of cefepime Hydrochloride |
| CN111057076A (en) * | 2019-12-31 | 2020-04-24 | 北京鑫开元医药科技有限公司 | Preparation method and application of cefepime impurity |
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