CN107445978A - A kind of synthesis of cefalonium and purification process - Google Patents
A kind of synthesis of cefalonium and purification process Download PDFInfo
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- CN107445978A CN107445978A CN201710733178.0A CN201710733178A CN107445978A CN 107445978 A CN107445978 A CN 107445978A CN 201710733178 A CN201710733178 A CN 201710733178A CN 107445978 A CN107445978 A CN 107445978A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
- C07D501/06—Acylation of 7-aminocephalosporanic acid
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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
- C07D501/48—Methylene radicals, substituted by hetero rings
- C07D501/56—Methylene radicals, substituted by hetero rings with the 7-amino radical acylated by carboxylic acids containing hetero rings
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- Cephalosporin Compounds (AREA)
Abstract
The invention discloses a kind of synthesis of cefalonium and purification process, belong to medical production technical field, including synthesis procedure and purification procedures, the synthesis procedure includes the synthesis procedure of cefalonium intermediate and the synthesis procedure of cefalonium crude product, it is characterized in that it is raw material using D 7ACA, by the synthesis procedure of cefalonium intermediate and the synthesis procedure of cefalonium crude product, and then cefalonium fine work is obtained using purification procedures, the beneficial effects of the invention are as follows:This technological reaction is gentle, and security is higher；Catalyst is introduced, highly shortened the reaction time, improves production efficiency；7 ACA successfully are instead of using D 7ACA, production cost is greatly reduced.
Description
Technical field
The invention belongs to medical production technical field, relate more specifically to synthesis and the purification process of a kind of cefalonium.
Background technology
Cefalonium, Chinese nickname (6R, 7R) -3- [(4- formamido -1- pyridines) methyl] -8- oxos -7- [(2- thiophenes
Fen -2- bases acetyl) amino] -5- thia -1- azabicyclos [4.2.0] oct-2-ene -2- carboxylic acid inner salts.It is mainly used in the withered milk of milk cow
Phase mastitis is prevented and treated.The medicine belongs to long-acting, broad-spectrum antibiotic, can effectively treat and prevent the withered milk phase each bacterial infection of milk cow.
The national inventing patent of Patent No. 201310747582.5 discloses《One kind is by 7-amino-cephalosporanic acid one-step method
Prepare the preparation method of cefalonium》, make use of 7-amino-cephalosporanic acid in water environment with organic solvent, 2- thiophen acetyl chlorides
Reacted with ethyl acetate under alkaline environment, cefalonium is obtained using one-step method, the method course of reaction is without to centre
Body carries out separation proposition, and easy to operate, reactions steps are simple, high income；It is simple and easy to get using 7-amino-cephalosporanic acid as raw material,
The market price is low, greatly reduces manufacturing cost.However, the technique uses 7-amino-cephalosporanic acid as raw material and in water environment
In reacted with thiophen acetyl chloride, but 2- thiophen acetyl chlorides are the dangerous material medicines of national regulation, and class of risk code is R14：Meet
Water can fiercely react, R29：Meet water and discharge toxic gas, R34：It can cause to burn, therefore, 2- thiophen acetyl chlorides exist in water
Under conditions of be absolutely unsafe, or even serious human safety issues occur, can not ensure reaction for original at all certainly
Expect the demand of quality；The special technique is reacted 60-150 hours at 15-50 DEG C, reaction time length, energy consumption high efficiency
It is extremely low.
It is worth noting that production cefalonium uses 7-amino-cephalosporanic acid as raw material more at present, with 7- amino cephalo alkane
Acid is starting material, and inevitably generation lactone impurity brings burden to follow-up purification process in technical process, country
Periodical《The new intermediate D-7-ACA of cephalosporin analog antibiotic》Disclose D-7-ACA and carry out cephalo instead of 7-amino-cephalosporanic acid
Class pharmaceutical synthesis, absolutely prove that D-7-ACA can substitute 7-amino-cephalosporanic acid and produce a variety of cephalosporin analog antibiotics, and D-7-
ACA has lower-cost advantage relative to 7-amino-cephalosporanic acid, but the D-7-ACA enumerated in this article is in synthesis cephalo bacterium
Application in element, its reaction principle are differed with preparing the principle of cefalonium in the prior art, and 7- is replaced using D-7-ACA
Amino-cephalo-alkanoic acid carries out synthesis cefalonium with prior art and lacks theoretical foundation, exists with D-7-ACA production cefaloniums
Technical bottleneck.
Therefore, seek a kind of safe, timesaving and the efficient technique using D-7-ACA production cefaloniums is compeled in eyebrow
Eyelash.
The content of the invention
To solve the above problems, overcome the deficiencies in the prior art, the invention provides a kind of safe, timesaving and efficiently
Cefalonium synthesis and purification process, can effectively solve that prior art production cefalonium security is poor, production is all
The problem of phase length and cost high-quality difference.
The present invention solve above-mentioned technical problem concrete technical scheme be：The synthesis of cefalonium and purification process, including
Synthesis procedure and purification procedures, the synthesis procedure include the conjunction of the synthesis procedure and cefalonium crude product of cefalonium intermediate
Into process, it is characterised in that the synthesis procedure of the cefalonium intermediate comprises the following steps：
（1）D-7ACA is hanged and is dissolved in dichloromethane solution, the organic base of predetermined number is added under preset temperature, at 0-5 DEG C
After lower stirring 60min, 2- thiophen acetyl chlorides are added dropwise, control 30min is added dropwise, and reacts 30min at 0-5 DEG C, then heat up
1h is reacted to 20-25 DEG C, deionized water is added, stratification, obtains aqueous phase and organic phase, the aqueous phase is adjusted with 6N hydrochloric acid
PH=3.0-3.2 is saved, solid, and the growing the grain 2h at 20-25 DEG C is separated out, finally carries out suction filtration operation, obtain among cefalonium
Body；
The synthesis procedure of the cefalonium crude product comprises the following steps：
（2）The cefalonium intermediate is hanged and is dissolved in deionized water, inorganic base and catalyst are added at 20-25 DEG C, is stirred
Pyrazinamide is added after mixing to dissolving, 55-65 DEG C of reaction 1-2h is warming up to, 20-25 DEG C is cooled to, with second acid for adjusting pH=3.0-
4.0, acetone is then added, growing the grain 2h at 0-5 DEG C is cooled to, finally carries out suction filtration operation, obtain cefalonium crude product；
The purification procedures comprise the following steps：
（3）It is dissolved in the cefalonium crude product is outstanding in deionized water, and is warming up to 40-45 DEG C, acetone is added dropwise to complete
Dissolving, activated carbon decolorizing 30min is added, filtering, 0-5 DEG C is cooled the filtrate to, acetone is slowly added dropwise, the growing the grain 5h at 0-5 DEG C
Filter afterwards and obtain cefalonium fine work.
Further, in the synthesis procedure of the described cefalonium intermediate：
Described D-7ACA quality and the volume ratio of dichloromethane are 1g：30ml；
The amount ratio of described D-7ACA and the material of 2- thiophen acetyl chlorides is 1:1-1.1；
Described D-7ACA quality and the volume ratio of deionized water are 1g：15ml.
Further, in the synthesis procedure of the described cefalonium crude product：
The quality of described spore Luoning intermediate and the volume ratio of deionized water are 1g：25ml-30ml；
Described spore Luoning intermediate and the amount ratio of the material of inorganic base are 1:1.2-1.3；
Described spore Luoning intermediate and the amount ratio of the material of catalyst are 1:2-3；
Described spore Luoning intermediate and the amount ratio of the material of Pyrazinamide are 1:1.5；
The quality of described spore Luoning intermediate and the volume ratio of acetone are 1g:20ml.
Further, the catalyst is sodium iodide, and reaction mechanism is：Iodide ion substitutes, and then iodide ion is left away
Nitrogen-atoms obtains cefalonium on attack pyridine ring after formation carbonium ion afterwards, and iodide ion is good substituent and leaving group.
Further, in the purification procedures：
The quality of described spore Luoning crude product and the volume ratio of deionized water are 1g：20ml；
The quality of described spore Luoning crude product and the volume ratio of acetone are 1g：8ml；
The mass ratio of described spore Luoning crude product and model CPL activated carbon is 10:1；
The quality of described spore Luoning crude product is 1g with the volume ratio that acetone is added dropwise：20ml.
Further, the organic base is any one in triethylamine or diisopropylethylamine or DBU, addition it is described
The amount of the material of organic base is 3-6 times of the amount of D-7ACA materials.
Further, the amount of the material of the organic base of addition is 4-5 times of amount of D-7ACA material.
Further, the temperature control of the organic base is at 0 ~ 10 DEG C.
Further, the temperature control of the organic base is at 0 ~ 5 DEG C.
Further, the inorganic base is sodium carbonate or sodium acid carbonate.
The beneficial effects of the invention are as follows：This technological reaction is gentle, and security is higher；Catalyst is introduced, is greatly shortened
In the reaction time, improve production efficiency；7-ACA successfully is instead of using D-7ACA, production cost is greatly reduced.
Brief description of the drawings：
Accompanying drawing 1 is reaction equation schematic diagram of the present invention；
Embodiment：
Detail is just for the sake of that can fully understand embodiments of the invention in the description of the invention, but is used as ability
The technical staff in domain will be appreciated that the implementation of the present invention is not limited to these details.In addition, known 26S Proteasome Structure and Function not by
Detailed description or displaying, to avoid having obscured the main points of the embodiment of the present invention.For one of ordinary skill in the art
Speech, the concrete meaning of above-mentioned term in the present invention can be understood with concrete condition.
The embodiment of the present invention：
Embodiment one：
20gD-7ACA is hanged and is dissolved in 600mlDCM, 35.2g triethylamines are added at 0-5 DEG C, maintains and is stirred at 0-5 DEG C
60min, is slowly added dropwise 13.96g 2- thiophen acetyl chlorides, and control 30min is added dropwise, gone to after reacting 30min at 0-5 DEG C
1h is reacted at 20-25 DEG C, 300ml deionized waters is added, stratification, aqueous phase 6N salt acid for adjusting pH=3.0-3.2, separates out solid
Body, dried at 20-25 DEG C after growing the grain 2h, after suction filtration and obtain cefalonium intermediate 26.0g, yield 84.47%, purity
98.33%。
20g cefaloniums intermediate is hanged and is dissolved in 500ml water, 5.7g sodium acid carbonates and 21.2g are added at 20-25 DEG C
Sodium iodide, stirring 30min add 10.3g Pyrazinamides, are warming up at 60-65 DEG C and react 1-2h, be cooled to 20-25 to dissolving
DEG C, with second acid for adjusting pH=3.0-4.0,400ml acetone control 30min is then added dropwise and is added dropwise, is cooled to growing the grain at 0-5 DEG C
2h, filter, drying obtains cefalonium crude product 14.7g, yield 52.5%, purity 87.22%.
It is dissolved in 10g cefaloniums crude product is outstanding in 200ml deionized waters, is warming up to 40-45 DEG C, 80ml acetone is added dropwise to molten
Solution, 1.0g model CPL activated carbon decolorizing 30min are added, filtered, filtrate is cooled to 0-5 DEG C, 200ml acetone is slowly added dropwise, and controls
1.0h processed is added dropwise, the growing the grain 5h at 0-5 DEG C, filters drying and obtains cefalonium fine work 6.9g, yield 69.0%, purity
98.15%。
Embodiment two：
20gD-7ACA is hanged and is dissolved in 600mlDCM, 44.9g diisopropylethylamine is added at 0-5 DEG C, is maintained at 0-5 DEG C
60min is stirred, 13.96g2- thiophen acetyl chlorides are slowly added dropwise, control 30min is added dropwise, and turns after 30min is reacted at 0-5 DEG C
1h is reacted to 20-25 DEG C, 300ml deionized waters is added, stratification, aqueous phase 6N salt acid for adjusting pH=3.0-3.2, separates out
Solid, dried after being filtered at 20-25 DEG C after growing the grain 2h and obtain cefalonium intermediate 25.2g, yield 81.87%, purity
98.19%。
20g cefaloniums intermediate is hanged and is dissolved in 500ml water, 7.17g sodium carbonate and 21.2g are added at 20-25 DEG C
Sodium iodide, stirring 30min add 10.3g Pyrazinamides, are warming up at 60-65 DEG C and react 1-2h, be cooled to 20-25 to dissolving
DEG C, with second acid for adjusting pH=3.0-4.0,400ml acetone control 30min is then added dropwise and is added dropwise, is cooled to growing the grain at 0-5 DEG C
2h, filter, drying obtains cefalonium crude product 15.1g, yield 53.93%, purity 85.86%.
It is dissolved in 10g cefaloniums crude product is outstanding in 200ml deionized waters, is warming up to 40-45 DEG C, 80ml acetone is added dropwise to molten
Solution, 1.0g model CPL activated carbon decolorizing 30min are added, filtered, filtrate is cooled to 0-5 DEG C, 200ml acetone is slowly added dropwise, and controls
1.0h processed is added dropwise, the growing the grain 5h at 0-5 DEG C, filters drying and obtains cefalonium fine work 7.3g, yield 73.0%, purity
98.41%。
In order to more intuitively show the product advantage of the present invention, spy is with scheme one：With the synthesis of cefalonium of the present invention
With purification process and scheme two：Catalyst-sodium iodide is not used to carry out pair with the synthesis of cefalonium of the present invention and purification process
Than, fully reaction 2 hours, and being detected in real time using thin-layer chromatography, yield is determined, and with scheme three（According to national inventing patent
201310747582.5《A kind of preparation method that cefalonium is prepared by 7- amino-cephalo-alkanoic acid one-step method》Described in work
Skill, introduced in a manner of quoting）；Scheme four（According to national inventing patent 201310747582.5《One kind is by 7- amino cephalo alkane
Sour one-step method prepares the preparation method of cefalonium》Described in technique introduced in a manner of quoting, and with the addition of catalyst-iodate
Sodium is reacted）Contrasted, result of the test is as follows：
Table 1：Catalyst is for reaction time and the data comparison of product yield
| Sample | Reaction raw materials | Cost | Catalyst | Total reaction time | Yield |
| Scheme one | D-7ACA | It is low | Have | 16.5h | 53.93% |
| Scheme two | D-7ACA | It is low | Nothing | 16.5h | 4.6% |
| Scheme three | 7-ACA | It is high | Nothing | 62h | 60% |
| Scheme four | 7-ACA | It is high | Have | 62h | 60% |
Data above analysis is understood：
（1）For scheme one compared with scheme two, scheme one employs catalyst-sodium iodide, using D-7ACA as raw material, overall reaction 16.5
Hour, yield reaches 53.93%, and scheme two does not employ catalyst-sodium iodide, and using D-7ACA as raw material, overall reaction 16.5 is small
When, yield only has 4.6%；
（2）For scheme one compared with scheme three, scheme one employs catalyst-sodium iodide, using D-7ACA as raw material, overall reaction 16.5
Hour, yield reaches 53.93%, and scheme three, not using catalyst-sodium iodide, overall reaction 62 hours, is received using 7-ACA as raw material
Rate is 60%, and the reaction time compared with scheme three of scheme one has notable sexual clorminance；Scheme one is 53.93% less than side on yield
The 60% of case three.
（3）Scheme three is compared with scheme four, and scheme three is using 7-ACA as raw material, not using catalyst-sodium iodide, overall reaction
62 hours, yield 60%；Scheme four is using 7-ACA as raw material, using catalyst-sodium iodide, overall reaction 62 hours, yield
60%, catalyst-sodium iodide does not act on for 7-ACA one-step synthesis.
Therefore, this programme uses sodium iodide to react the catalyst of generation cefalonium as D-7ACA, is greatly improved
The yield of product, and relative to prior art the reaction time is substantially reduced, and higher yield is maintained, improve production
Efficiency, reduce production cost.
In summary：This programme is reaction raw materials using D-7ACA, dexterously devises reaction process, optimizes reaction bar
Part, the safety coefficient of reaction is greatly improved, reduces the probability of happening of accident；Catalyst has correctly been used simultaneously,
Reaction time is highly shortened, and maintains higher yield, production efficiency is improved, reduces production cost.The present invention
Relative to substantive distinguishing features of the prior art with protrusion and the progress with conspicuousness.
Claims (10)
1. synthesis and the purification process of a kind of cefalonium, including synthesis procedure and purification procedures, the synthesis procedure includes head
The synthesis procedure of spore Luoning intermediate and the synthesis procedure of cefalonium crude product, it is characterised in that the cefalonium intermediate
Synthesis procedure comprises the following steps：
（1）D-7ACA is hanged and is dissolved in dichloromethane solution, the organic base of predetermined number is added under preset temperature, at 0-5 DEG C
After lower stirring 60min, 2- thiophen acetyl chlorides are added dropwise, control 30min is added dropwise, and reacts 30min at 0-5 DEG C, then heat up
1h is reacted to 20-25 DEG C, deionized water is added, stratification, obtains aqueous phase and organic phase, the aqueous phase is adjusted with 6N hydrochloric acid
PH=3.0-3.2 is saved, solid, and the growing the grain 2h at 20-25 DEG C is separated out, finally carries out suction filtration operation, obtain among cefalonium
Body；
The synthesis procedure of the cefalonium crude product comprises the following steps：
（2）The cefalonium intermediate is hanged and is dissolved in deionized water, inorganic base and catalyst are added at 20-25 DEG C, is stirred
Pyrazinamide is added after mixing to dissolving, 55-65 DEG C of reaction 1-2h is warming up to, 20-25 DEG C is cooled to, with second acid for adjusting pH=3.0-
4.0, acetone is then added, growing the grain 2h at 0-5 DEG C is cooled to, finally carries out suction filtration operation, obtain cefalonium crude product；
The purification procedures comprise the following steps：
（3）It is dissolved in the cefalonium crude product is outstanding in deionized water, and is warming up to 40-45 DEG C, acetone is added dropwise to complete
Dissolving, activated carbon decolorizing 30min is added, filtering, 0-5 DEG C is cooled the filtrate to, acetone is slowly added dropwise, the growing the grain 5h at 0-5 DEG C
Filter afterwards and obtain cefalonium fine work.
2. synthesis and the purification process of cefalonium according to claim 1, it is characterised in that the described cephalo Lip river
In the synthesis procedure of peaceful intermediate：
Described D-7ACA quality and the volume ratio of dichloromethane are 1g：30ml；
The amount ratio of described D-7ACA and the material of 2- thiophen acetyl chlorides is 1:1-1.1；
Described D-7ACA quality and the volume ratio of deionized water are 1g：15ml.
3. synthesis and the purification process of cefalonium according to claim 1, it is characterised in that the described cephalo Lip river
In the synthesis procedure of peaceful crude product：
The quality of described spore Luoning intermediate and the volume ratio of deionized water are 1g：25ml-30ml；
Described spore Luoning intermediate and the amount ratio of the material of inorganic base are 1:1.2-1.3；
Described spore Luoning intermediate and the amount ratio of the material of catalyst are 1:2-3；
Described spore Luoning intermediate and the amount ratio of the material of Pyrazinamide are 1:1.5；
The quality of described spore Luoning intermediate and the volume ratio of acetone are 1g:20ml.
4. synthesis and the purification process of the cefalonium according to claim 1 or 3, it is characterised in that the catalyst is iodine
Change sodium.
5. synthesis and the purification process of cefalonium according to claim 1, it is characterised in that in the purification procedures：
The quality of described spore Luoning crude product and the volume ratio of deionized water are 1g：20ml；
The quality of described spore Luoning crude product and the volume ratio of acetone are 1g：8ml；
The mass ratio of described spore Luoning crude product and model CPL activated carbon is 10:1；
The quality of described spore Luoning crude product is 1g with the volume ratio that acetone is added dropwise：20ml.
6. synthesis and the purification process of cefalonium according to claim 1, it is characterised in that the organic base is three second
Any one in amine or diisopropylethylamine or DBU, the amount of the material of the organic base of addition are the amount of D-7ACA materials
3-6 times.
7. synthesis and the purification process of cefalonium according to claim 6, it is characterised in that the organic base of addition
Material amount be D-7ACA 4-5 times of amount of material.
8. synthesis and the purification process of cefalonium according to claim 1, it is characterised in that the temperature of the organic base
Control is at 0 ~ 10 DEG C.
9. synthesis and the purification process of cefalonium according to claim 8, it is characterised in that the temperature of the organic base
Control is at 0 ~ 5 DEG C.
10. synthesis and the purification process of cefalonium according to claim 1, it is characterised in that the inorganic base is carbonic acid
Sodium or sodium acid carbonate.
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| CN110330510A (en) * | 2019-08-19 | 2019-10-15 | 齐鲁动物保健品有限公司 | A kind of preparation method of cefalonium dihydrate crystal form |
| CN113372362A (en) * | 2021-06-09 | 2021-09-10 | 艾美科健（中国）生物医药有限公司 | Synthesis method of cefalonium impurity B |
| CN116514840A (en) * | 2023-06-30 | 2023-08-01 | 齐鲁晟华制药有限公司 | Preparation method of delta-3 cefalotin isomer compound |
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| CN102258521A (en) * | 2011-06-03 | 2011-11-30 | 山东鲁抗立科药物化学有限公司 | Cefodizime sodium composition and preparation method thereof |
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| CN116514840A (en) * | 2023-06-30 | 2023-08-01 | 齐鲁晟华制药有限公司 | Preparation method of delta-3 cefalotin isomer compound |
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