CN103694256A - Method for synthesizing cefpirome - Google Patents
Method for synthesizing cefpirome Download PDFInfo
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- CN103694256A CN103694256A CN201310729604.5A CN201310729604A CN103694256A CN 103694256 A CN103694256 A CN 103694256A CN 201310729604 A CN201310729604 A CN 201310729604A CN 103694256 A CN103694256 A CN 103694256A
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- cefpirome
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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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
- C07D501/06—Acylation of 7-aminocephalosporanic acid
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention relates to a method for synthesizing cefpirome. The method comprises the following steps: (1) taking 7-aminocephalosporanic acid as a raw material, dropwise adding methanol and hydrochloric acid into a product obtained through a silanization reaction, an iodination reaction and a pyridine reaction to adjust the pH value, standing for layering, adding acetone and ethylamine to adjust the pH value, performing suction filtration, washing, and drying to obtain an intermediate 7-CPCA; (2) reacting the obtained intermediate with AE active ester, washing, filtering, adjusting the pH value of filter liquor by 20% sulfuric acid, performing suction filtration by ethanol, washing, and drying to obtain the cefpirome as a target product. The cefpirome synthesized by the method is high in yield and low in production cost; the method is easy to operate and suitable for industrialization production.
Description
Technical field
The present invention relates to a kind of synthetic method of cefpirome, belong to the synthetic field of medicine.
Background technology
Cefpirome as the 4th generation its feature of cynnematin be: 1, antimicrobial spectrum is wider: cefpirome is better than ceftazime and cefotaxime to the anti-microbial activity of enterobacteriaceae lactobacteriaceae, and the anti-microbial activity of pseudomonas aeruginosa is better than to cefotaxime but a little less than ceftazime.But it should be noted that the 4th generation cynnematin to gram positive coccus as Staphylococcus, streptococcus particularly the fungicidal activity of penicillin resistance pneumococcus wherein compared with third generation cephalosporin, obviously strengthen.From current existing data, the strongest to the bacteriostatic action of gram positive coccus with cefpirome in the 4th generation cynnematin.2, β-lactamase is had to better stability: compare with third generation cephalosporin, the 4th generation cynnematin Richmond-Sykes classification I type is had to good stability (6～8) by the β-lactamase of Chromosome-encoded.It should be noted that they are to wherein also having good stability by the β-lactamase of AmpC gene mediated.Due to the 4th generation cynnematin the β-lactamase of AmpC gene mediated is had to stability, so at gram negative bacilli, can try out during to third generation cephalosporin resistance the 4th generation cynnematin.3, the feature in pharmacokinetics: although the 4th cynnematin transformation period in generation is shorter, serum drug peak concentration is high.2 grams of cefpiromes of an intravenous injection after 4 hours to pseudomonas aeruginosa, 8 hours Hou Duijin Portugal bacterium, enterobacteriaceae lactobacteriaceae, suis still has germicidal action.There is report cefpirome etc. can effectively see through hemato encephalic barrier, at the drug level of tunica mucosa tracheae, lung tissue, be respectively 56%, 36% of its Plasma Concentration.
Potential applicability in clinical practice: the cefpirome having gone on the market has successfully been applied to respiratory tract infection, urinary tract infections, skin soft-tissue infection.But the 4th generation cynnematin be more suitable for serious hospital and hospital infection.Current the 4th generation cynnematin indication and non-adaptive disease mainly contain that pneumonia, anaerobic infection, Nosocomial, serious social acquired methicillin resistance gold Portugal/form staph (MRSA/MRSE) infect, granulocyte lacks the super wide spectrum enzyme of concurrent infection producing bacterial strain (ESBLs) infection, hospital infection septicemia, bacterial meningitis.
In sum, the 4th generation have any different some feature of first, second and third cynnematin of cynnematin in generation, as antimicrobial spectrum is wider, more stable to β-lactamase, Plasma Concentration is high, can see through hemato encephalic barrier etc.Preliminary clinical application result has also proved some superiority of this type of medicine.Estimate that there is very large demand in the very fast market at home of such medicine.
The 4th generation cynnematin gram positive organism, negative bacterium, anerobe are shown to broad spectrum antibiotic activity, compare with third generation kind in the past, strengthened anti-gram positive organism active, especially suis, streptococcus pneumoniae etc. is had to very strong activity, cefpirome and Cefozopran also have and pretend use the insensitive streptococcus faecium of general cynnematin.These kinds have strong active to citrobacter freundii, enterobacter cloacae, resisting pseudomonas aeruginosa effect all can be equal to ceftazime.
The form of the final iodide ion of iodine of using in the method for the synthetic cefpirome of traditional method disperses to be present in respectively to walk in waste liquid; waste liquid in production is difficult to process recovery; not only cause waste; improved production cost; also, to environment, reactant is loaded down with trivial details in post-processing operation such as deprotection, dissolving, extractive crystallizations in addition, and strong acid treatment causes yield losses; crystallization is to need a large amount of dissolving, and cost increases.
Summary of the invention
The object of the invention is to for deficiency of the prior art, provide a kind of suitable purity high, yield is high, the synthetic method of the cefpirome that waste liquid is few.
For solving the problems of the technologies described above, the present invention adopts following technical scheme to realize:
A synthetic method for cefpirome, its synthetic route is as follows:
1, the silicon of amino and carboxyl protection
2,7-CPCA's is synthetic
3, cefpirome is synthetic
Its synthetic method comprises the steps:
(1) preparation of formula I compound:
A. take 7-amino-cephalosporanic acid as raw material, be dissolved in methylene dichloride, drip hexamethyldisilazane, back flow reaction;
B. cooling, drips Iodotrimethylsilane, temperature reaction;
C. cooling, drips pyridine cyclopentene, temperature reaction;
D. cooling, drips methyl alcohol, stirs, and drips hydrochloric acid and regulates PH to 0.4～0.6, stir, and stratification, water intaking layer, adds acetone, with triethylamine, adjusts PH to 4.0-4.1, suction filtration, washing, the dry formula I compound that obtains;
(Ⅰ)
(2) preparation of formula II compound:
A. formula I compound, MEAM, methylene dichloride and methanol mixed are stirred, cooling, drips triethylamine reaction;
B. add pure water agitation and filtration, filtrate stratification, water layer adds butylacetate, stirs, stratification, water layer adds activated carbon decolorizing, and filtrate is adjusted pH=1.5 with 20% sulfuric acid, adds dehydrated alcohol, suction filtration, washing, the dry formula II compound that obtains;
(Ⅱ)
A synthetic method for cefpirome, specifically comprises the steps:
(1) preparation of formula I compound:
A. take 7-amino-cephalosporanic acid as raw material, be dissolved in methylene dichloride, be warming up to 38-42 ℃, temperature control 38-44 ℃, 50-70min, drips hexamethyldisilazane, and drip and finish, temperature control 38-44 ℃ back flow reaction, the reaction times is 6-8h;
B. be cooled to-3～-1 ℃, drip Iodotrimethylsilane, drip and finish, be warming up to 5-10 ℃, in this temperature range, react 10-12h;
C. react complete being cooled to-7～-3 ℃, drip pyridine cyclopentene, drip and finish, be warming up to 15-20 ℃, and react 7～9h in this temperature range;
D. reaction finishes, and is cooled to 0～1 ℃, 0～5 ℃ of dropping methyl alcohol of temperature control, drip off, 0～5 ℃ is stirred 1-2h, 0～5 ℃ of temperature control, drip 16% hydrochloric acid to system pH=0.4～0.6, continue to stir 10～20min, standing 25～35min, layering, water intaking layer, adds acetone, 0～5 ℃ of temperature control, adjusts pH=4.0～4.1 with triethylamine, 0～5 ℃ of growing the grain 1～2h, suction filtration, proper amount of acetone washing, 35～38 ℃ of vacuum-dryings obtain formula I compound;
(2) preparation of formula II compound:
A. formula I compound, MEAM, methylene dichloride and methanol mixed are stirred, be cooled to-7～-5 ℃ ,-5 ℃ of following triethylamines that drip, 0～5 ℃ of reaction 3～5h of temperature control;
B. reaction finishes, 5～10 ℃ of temperature controls add purified water, stir 20～40min, filter, with purified water washing leaching cake and filtrate, merge again, by the standing 20～40min of filtrate, layering, water intaking layer, add butylacetate, 5～10 ℃ of temperature controls, rapid stirring 10～20min, standing 20～40min, layering, water intaking layer adds import gac, 5～10 ℃ of decolouring 20～40min, filter, with purified water detergent active charcoal, merge with filtrate, 15～20 ℃ of temperature controls are adjusted pH=1.5 with 20% sulfuric acid, add dehydrated alcohol, crystal seed, standing 20～40min, open and stir, slowly drip dehydrated alcohol, drip and finish, continue to stir 1～2h, be cooled to 1-3 ℃, temperature control 0-2 ℃, slowly stir 1.5-2.5h, suction filtration, appropriate absolute ethanol washing, drain, 35～38 ℃ of vacuum-dryings obtain formula II compound.
Described in described step (1), the mass ratio of raw material 7-amino-cephalosporanic acid and hexamethyldisilazane is 1:0.8～0.9.
Described in described step (1), the mass ratio of raw material 7-amino-cephalosporanic acid and Iodotrimethylsilane is 1:1.1～1.3.
Described in described step (1), the mass ratio of raw material 7-amino-cephalosporanic acid and pyridine cyclopentene is 1:1.25～1.36.
Described in described step (1) a, the mass ratio of raw material 7-amino-cephalosporanic acid and methylene dichloride is 1:7.5～9.
In described step (1) d, after stratification, the volume ratio of water layer and acetone is 1:8～9.
In described step (2) a, the mass ratio of 7-CPCA, MEAM, methylene dichloride and methyl alcohol is 1:1.22～1.45:9～13:1.65～1.71.
In described step (2) a, the mass ratio of 7-CPCA and triethylamine is 1:0.25.
In described step (2) b, the mass ratio of 7-CPCA and gac is 1:0.41～0.45.
In described step (2) b, after stratification, the volume ratio of water layer and dehydrated alcohol is 1:2～2.2.
Beneficial effect of the present invention: the method that the present invention prepares cefpirome does not need refiningly just can obtain the cefpirome that purity is high, has simplified technical process, reduced three waste discharge, and the product purity making is high, yield is high.
Embodiment
Below in conjunction with specific embodiment, technical scheme of the present invention is elaborated.
Embodiment
In 500 mL four-hole boiling flasks, add successively 7-ACA 30 g, methylene dichloride 180ml, be warming up to 40 ℃, temperature control 40-42 ℃ of about 60min drips hexamethyldisilazane 24.89g, drip and finish, temperature control 40-42 ℃ back flow reaction 7 h, cool to-2 ℃, temperature control-2-2 ℃ drips Iodotrimethylsilane 33.1g, drip and finish, be warming up to 5-10 ℃, and react 11h in this temperature range, react complete cooling to-5 ℃, temperature control-5-2 ℃ drips pyridine cyclopentene 38g, drip and finish, be warming up to 15-20 ℃, and react 8h in this temperature range, reaction finishes, be cooled to 0 ℃, temperature control 0-5 ℃ drips methyl alcohol 30ml, drip off, 0-5 ℃ is stirred 1h, temperature control 0-5 ℃ drips 16% hydrochloric acid to system pH=0.5 left and right, continue to stir 15min, standing 30min, layering, water intaking layer, add acetone 300ml, temperature control 0-5 ℃ adjusts pH=4.0-4.1 with triethylamine, 0-5 ℃ of growing the grain 1h, suction filtration, proper amount of acetone washing, 35 ℃ of vacuum-dryings obtain yellow solid 34.2g, yield 93.44%.
In 500ml four-hole boiling flask, add successively 7-CPCA 12g, MEAM 14.67g, methylene dichloride 90ml, methyl alcohol 25ml, stir borehole cooling to-5 ℃,-5 ℃ of following triethylamine 3g that drip, temperature control 0-5 ℃ of reaction 4h, reaction finishes, temperature control 5-10 ℃ adds purified water 87ml, stir 30min, filter, with 8ml purified water washing leaching cake and filtrate, merge.By the standing 30min of filtrate, layering, water intaking layer, adds butylacetate 90ml, temperature control 5-10 ℃, rapid stirring 15min, standing 30min, layering, water intaking layer adds 5g import gac, 5-10 ℃ of decolouring 30min, filters, and with 15ml purified water detergent active charcoal, merges with filtrate.With 20% sulfuric acid, adjust pH=1.5 for temperature control 15-20 ℃, add dehydrated alcohol 220ml, add crystal seed 0.2g, standing 30min, opens and stirs, and slowly drips dehydrated alcohol 80ml, drip and finish, continue to stir 1h, be cooled to 2 ℃, temperature control 0-2 ℃, slowly stirs 2h, suction filtration, appropriate absolute ethanol washing, drain, 35 ℃ of vacuum-dryings obtain cefpirome 18.6g, yield 84.12%.
Above-described embodiment is only in order to illustrate technical scheme of the present invention; but not design of the present invention and protection domain are limited; those of ordinary skill of the present invention is modified or is equal to replacement technical scheme of the present invention; and not departing from aim and the scope of technical scheme, it all should be encompassed in claim scope of the present invention.
Claims (11)
1. a synthetic method for cefpirome, is characterized in that: the synthetic method of described cefpirome comprises the steps:
(1) preparation of formula I compound:
A. take 7-amino-cephalosporanic acid as raw material, be dissolved in methylene dichloride, drip hexamethyldisilazane, back flow reaction;
B. cooling, drips Iodotrimethylsilane, temperature reaction;
C. cooling, drips pyridine cyclopentene, temperature reaction;
D. cooling, drips methyl alcohol, stirs, and drips hydrochloric acid and regulates PH to 0.4～0.6, stir, and stratification, water intaking layer, adds acetone, with triethylamine, adjusts PH to 4.0-4.1, suction filtration, washing, the dry formula I compound 7-CPCA that obtains;
(Ⅰ)
(2) preparation of formula II compound:
A. 7-CPCA, MEAM, methylene dichloride and methanol mixed are stirred, cooling, drips triethylamine reaction;
B. add pure water agitation and filtration, filtrate stratification, water layer adds butylacetate, stirs, stratification, water layer adds activated carbon decolorizing, and filtrate is adjusted pH=1.5 with 20% sulfuric acid, adds dehydrated alcohol, suction filtration, washing, the dry formula II compound that obtains;
?(Ⅱ)。
2. the synthetic method of a kind of cefpirome according to claim 1, is characterized in that: the synthetic method of described cefpirome specifically comprises the steps:
(1) preparation of formula I compound:
A. take 7-amino-cephalosporanic acid as raw material, be dissolved in methylene dichloride, be warming up to 38-42 ℃, temperature control 38-44 ℃, 50-70min, drips hexamethyldisilazane, and drip and finish, temperature control 38-44 ℃ back flow reaction, the reaction times is 6-8h;
B. be cooled to-3～-1 ℃, drip Iodotrimethylsilane, drip and finish, be warming up to 5-10 ℃, in this temperature range, react 10-12h;
C. react complete being cooled to-7～-3 ℃, drip pyridine cyclopentene, drip and finish, be warming up to 15-20 ℃, and react 7～9h in this temperature range;
D. reaction finishes, and is cooled to 0～1 ℃, 0～5 ℃ of dropping methyl alcohol of temperature control, drip off, 0～5 ℃ is stirred 1-2h, 0～5 ℃ of temperature control, drip 16% hydrochloric acid to system pH=0.4～0.6, continue to stir 10～20min, standing 25～35min, layering, water intaking layer, adds acetone, 0～5 ℃ of temperature control, adjusts pH=4.0～4.1 with triethylamine, 0～5 ℃ of growing the grain 1～2h, suction filtration, proper amount of acetone washing, 35～38 ℃ of vacuum-dryings obtain formula I compound 7-CPCA;
(2) preparation of formula II compound:
A. 7-CPCA, MEAM, methylene dichloride and methanol mixed are stirred, be cooled to-7～-5 ℃ ,-5 ℃ of following triethylamines that drip, 0～5 ℃ of reaction 3～5h of temperature control;
B. reaction finishes, 5～10 ℃ of temperature controls add purified water, stir 20～40min, filter, with purified water washing leaching cake and filtrate, merge again, by the standing 20～40min of filtrate, layering, water intaking layer, add butylacetate, 5～10 ℃ of temperature controls, rapid stirring 10～20min, standing 20～40min, layering, water intaking layer adds import gac, 5～10 ℃ of decolouring 20～40min, filter, with purified water detergent active charcoal, merge with filtrate, 15～20 ℃ of temperature controls are adjusted pH=1.5 with 20% sulfuric acid, add dehydrated alcohol, crystal seed, standing 20～40min, open and stir, slowly drip dehydrated alcohol, drip and finish, continue to stir 1～2h, be cooled to 1-3 ℃, temperature control 0-2 ℃, slowly stir 1.5-2.5h, suction filtration, appropriate absolute ethanol washing, drain, 35～38 ℃ of vacuum-dryings obtain formula II compound.
3. the synthetic method of a kind of cefpirome according to claim 1, is characterized in that: described in described step (1), the mass ratio of raw material 7-amino-cephalosporanic acid and hexamethyldisilazane is 1:0.8～0.9.
4. the synthetic method of a kind of cefpirome according to claim 1, is characterized in that: described in described step (1), the mass ratio of raw material 7-amino-cephalosporanic acid and Iodotrimethylsilane is 1:1.1～1.3.
5. the synthetic method of a kind of cefpirome according to claim 1, is characterized in that: described in described step (1), the mass ratio of raw material 7-amino-cephalosporanic acid and pyridine cyclopentene is 1:1.25～1.36.
6. the synthetic method of a kind of cefpirome according to claim 1, is characterized in that: described in described step (1) a, the mass ratio of raw material 7-amino-cephalosporanic acid and methylene dichloride is 1:7.5～9.
7. the synthetic method of a kind of cefpirome according to claim 1, is characterized in that: in described step (1) d, after stratification, the volume ratio of water layer and acetone is 1:8～9.
8. the synthetic method of a kind of cefpirome according to claim 1, is characterized in that: in described step (2) a, the mass ratio of 7-CPCA, MEAM, methylene dichloride and methyl alcohol is 1:1.22～1.45:9～13:1.65～1.71.
9. the synthetic method of a kind of cefpirome according to claim 1, is characterized in that: in described step (2) a, the mass ratio of 7-CPCA and triethylamine is 1:0.25.
10. the synthetic method of a kind of cefpirome according to claim 1, is characterized in that: in described step (2) b, the mass ratio of 7-CPCA and gac is 1:0.41～0.45.
The synthetic method of 11. a kind of cefpiromes according to claim 1, is characterized in that: in described step (2) b, after stratification, the volume ratio of water layer and dehydrated alcohol is 1:2～2.2.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109651400A (en) * | 2018-12-06 | 2019-04-19 | 淄博鑫泉医药技术服务有限公司 | The synthetic method of Cefpirome Sulfate |
| CN113620975A (en) * | 2021-07-23 | 2021-11-09 | 无锡鸣鹭医药科技有限公司 | Synthesis method of cefpirome sulfate |
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| CN113620975A (en) * | 2021-07-23 | 2021-11-09 | 无锡鸣鹭医药科技有限公司 | Synthesis method of cefpirome sulfate |
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Application publication date: 20140402 |