CN106831639B - The preparation method of Cefcapene side-chain acid - Google Patents
The preparation method of Cefcapene side-chain acid Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/44—Acylated amino or imino radicals
- C07D277/48—Acylated amino or imino radicals by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof, e.g. carbonylguanidines
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Abstract
The present invention relates to a kind of preparation methods of Cefcapene side-chain acid, belong to medicine intermediate technical field.The preparation method is that ketene dimer is added into alcohol organic solvent under nitrogen protection, then bromine is added dropwise to be reacted, the mixed liquor quenching reaction of methylene chloride and water is added, separate organic phase, acetic acid is added into organic phase, propionic aldehyde is added dropwise simultaneously after cooling and organic alkali catalyst A is reacted, then thiocarbamide is added to be reacted, it is concentrated through vacuum distillation, methylene chloride is added into concentrate, di-tert-butyl dicarbonate and organic alkali catalyst B are reacted, then liquid alkaline is added to be reacted, hydrochloric acid is added dropwise after cooling and carries out crystallization, through filtering, isopropanol water solution elution, (Z) -2- (2- t-butoxycarbonyl amino thiazole-4-yl) -2- penetenoic acid is obtained after drying, that is Cefcapene side-chain acid.The present invention is using ketene dimer as starting material, and side reaction is few, high income, and obtained product purity is high, and reaction condition is mild, is more easy to realize industrial production.
Description
Technical field
The present invention relates to a kind of preparation methods of Cefcapene side-chain acid, belong to medicine intermediate technical field.
Background technique
The pivaloyl oxygen methyl esters of Cefcapene (S-1006) is researched and developed by Yan Yeyi company of Japan, in 1997 with Flomox
Trade name Initial Public Offering.Method of cefcapene pivoxil is the orally available cephalosporin analog antibiotic of the third generation, and pharmacological research shows to aerobic G+ bacterium
MSSA MIC80 be 3.13 μ g/mL, the μ of MIC80≤0.1 g/ identical as Cefotiam, Cefaclor, to streptococcus pneumonia
ML is better than Cefaclor, suitable with Cefditoren, very to the activity of the streptococcus pneumonia of penicillin resistant (contain moderate drug resistance)
By force, MIC80 is 0.78 μ g/mL；To citrobacter freundii, enterobacter cloacae, providencia rettgeri, the mucous membrane in G- bacterium
Scorching Branhamella catarrhalis, the activity of serratia marcescens are stronger than Cefditoren, Cefotiam；It is bloodthirsty to Proteus, influenza
Bacillus, morganella morganii strain, the activity of gonococcus are stronger than Cefaclor, Cefotiam, suitable with Cefteram；To resistant to ammonia benzyl west
The haemophilus influenzae of woods has very strong activity, and MIC80 is 0.05 μ g/mL；Activity to anaerobic bacteria be comparison medicine in it is strongest,
Dosage is small.
Entitled (Z) -2- (2- t-butoxycarbonyl amino the thiazole-4-yl) -2- penta of chemistry of Cefcapene side-chain acid (BTPA)
Olefin(e) acid, molecular formula C13H18N2O4S, molecular weight 298.36, BTPA are the important intermediate for synthesizing Cefcapene, synthesis side
Method be usually using ethyl acetoacetate as starting material, etherified, bromination, cyclization, hydrolysis and etc. synthesize, can also first bromine
Change, it is rear to be etherified, but all there is a problem of that side reaction is more, yield is low.Its reaction equation is as follows:
Summary of the invention
The object of the present invention is to provide a kind of preparation methods of Cefcapene side-chain acid, solve traditional synthesis presence
Side reaction is more, problem that product yield is low, have the characteristics that side reaction occur less, product yield it is high.
The preparation method of Cefcapene side-chain acid of the present invention, comprising the following steps:
(1) 4- acetyl bromide acetic acid esters is prepared:
Under nitrogen protection, ketene dimer is added into alcohol organic solvent, bromine is then added dropwise and is reacted, is added two
The mixed liquor quenching reaction of chloromethanes and water separates organic phase to get 4- acetyl bromide acetic acid esters is arrived；
(2) (Z) -2- (thiazolamine -4- base) -2- pentenoate is prepared:
Acetic acid is added into organic phase, propionic aldehyde is added dropwise simultaneously after cooling and organic alkali catalyst A is reacted, is then added
Thiocarbamide is reacted, and is concentrated through vacuum distillation, obtains (Z) -2- (thiazolamine -4- base) -2- pentenoate；
(3) Cefcapene side-chain acid is prepared:
Methylene chloride, di-tert-butyl dicarbonate and organic alkali catalyst B are added into concentrate to be reacted, is then added
Liquid alkaline is reacted, and hydrochloric acid is added dropwise after cooling and carries out crystallization, obtains (Z) -2- after filtering, isopropanol water solution elution, drying
(2- t-butoxycarbonyl amino thiazole-4-yl) -2- penetenoic acid, i.e. Cefcapene side-chain acid.
Wherein it is preferred to which technical solution is as follows:
Alcohol organic solvent is the fatty alcohol of C1~C6, preferably methanol or ethyl alcohol in step (1).
Ketene dimer in step (1), bromine, alcohol organic solvent molar ratio be 1:1~1.1:6~12.
The mass ratio of alcohol organic solvent, methylene chloride, water in step (1) is 1:1:1.5~2.
Alcohol organic solvent is cooled to after -30~-20 DEG C in step (1), ketene dimer is added, bromine is added dropwise and carries out instead
0~10 DEG C of seasonable reaction temperature, reaction time 1h.
Cooling temperature is -20~-10 DEG C in step (2)；It is 20~30 DEG C that reaction temperature when thiocarbamide is reacted, which is added,
Reaction time is 1h；Vapo(u)rizing temperature≤10 DEG C when vacuum distillation.
Organic alkali catalyst A is the mixture of piperidines and pyridine in step (2), and the molar ratio of piperidines and pyridine is 1:0.5
~1.
Organic alkali catalyst B in step (3) is pyridine or 4-N, N- dimethyl aminopyridine.
Reaction temperature when methylene chloride, di-tert-butyl dicarbonate and organic alkali catalyst B are reacted is added in step (3)
Degree is 30~40 DEG C, reaction time 8h；It is 60~80 DEG C that reaction temperature of liquid alkaline when being reacted, which is added, and the reaction time is
4h。
The concentration of isopropanol water solution is 30~40wt% in step (3).
The following are the typical chemical equations of the present invention:
Beneficial effects of the present invention are as follows:
Preparation method of the invention is using ketene dimer as starting material, and side reaction is few, high income, at low cost, obtains
Product purity it is high, reaction condition is mild, easy to operate, it is easier to realize industrialized production.
Specific embodiment
The present invention is described further with reference to embodiments.
Embodiment 1
The preparation of 4- acetyl bromide acetic acid esters:
64mL (1.6mol) methanol is added in the three-necked flask that the capacity equipped with blender and thermometer is 500mL ,-
Ketene dimer 16.8g (0.2mol) is added at 20 DEG C, is added dropwise bromine 33.6g (0.21mol), temperature is maintained at -30~-25 DEG C,
It is added dropwise in 2h, is warming up to 0~5 DEG C, insulation reaction 1h, 39mL methylene chloride and 100mL water, stirring 5 is added in end of reaction
Organic phase is separated after minute to get 4- acetyl bromide acetic acid esters is arrived, through liquid-phase chromatographic analysis, purity 97.5%；
(Z) preparation of -2- (thiazolamine -4- base) -2- pentenoate:
1.2g (0.02mol) acetic acid is added into organic phase, 15.9g is added dropwise simultaneously at a temperature of -20~-15 DEG C
The organic alkali catalyst A (0.22mol) positive propionic aldehyde and be made of 0.8g (0.01mol) pyridine and 0.86g (0.01mol) piperidines,
2h or more is dripped off, and 16.7g (0.22mol) thiocarbamide is added, is rapidly heated to 25~30 DEG C, and addition 60mL aqueous solution is washed after keeping the temperature 1h
It washs twice, is down to 10 DEG C or less reduced pressures, obtain 36.2g (Z) -2- (thiazolamine -4- base) -2- pentenoate, yield
85.3%, through liquid-phase chromatographic analysis, purity 98.5%；
(Z) preparation of -2- (2- t-butoxycarbonyl amino thiazole-4-yl) -2- penetenoic acid:
17g methylene chloride, bis- dimethyl dicarbonate of 40.8g are added into (Z) -2- (thiazolamine -4- base) -2- pentenoate
Butyl ester, 0.7g pyridine react 8 hours at 30~35 DEG C, and addition 22.6g concentration is 30wt% liquid alkaline, 60mL water, it is warming up to 65~
Hydrochloric acid crystallization is added dropwise at 30~35 DEG C in 70 DEG C of reaction 4h, then filtering is drenched with the isopropanol water solution that 40mL concentration is 30wt%
It washes, it is dry, obtain 47.8g Cefcapene side-chain acid, yield 80.2%, through liquid-phase chromatographic analysis, purity 99.3%.
Embodiment 2
The preparation of 4- acetyl bromide acetic acid esters:
93mL (1.6mol) ethyl alcohol is added in the three-necked flask that the capacity equipped with blender and thermometer is 500mL ,-
20 DEG C or less addition ketene dimer 16.8g (0.2mol) are added dropwise bromine 35.2g (0.22mol), -30~-25 DEG C of temperature holding, and 2
It is added dropwise in hour, is warming up to 0~5 DEG C, insulation reaction 1h, end of reaction is added 39mL methylene chloride and 100mL water, stirs
It mixes and separates within 5 minutes organic phase to get 4- acetyl bromide acetic acid esters is arrived, through liquid-phase chromatographic analysis, purity 98.0%；
(Z) preparation of -2- (thiazolamine -4- base) -2- pentenoate:
1.2g (0.02mol) acetic acid is added into organic phase, 17.3g is added dropwise simultaneously at a temperature of -20~-15 DEG C
The organic alkali catalyst A (0.24mol) positive propionic aldehyde and be made of 0.8g (0.01mol) pyridine and 0.86g (0.01mol) piperidines,
2h or more is dripped off, and 18.2g (0.24mol) thiocarbamide is added, is rapidly heated to 25~30 DEG C, and the washing of 60mL aqueous solution is added in heat preservation 1h
Twice, 10 DEG C or less reduced pressures are down to, 37.0g (Z) -2- (thiazolamine -4- base) -2- pentenoate, yield are obtained
87.2%, through liquid-phase chromatographic analysis, purity 98.9%；
(Z) preparation of -2- (2- t-butoxycarbonyl amino thiazole-4-yl) -2- penetenoic acid:
17g methylene chloride, bis- dimethyl dicarbonate of 44.5g are added into (Z) -2- (thiazolamine -4- base) -2- pentenoate
Butyl ester, 0.7g pyridine react 8 hours at 30~35 DEG C, and liquid alkaline, 60mL water that 22.6g concentration is 30wt% is added, is warming up to 65
~70 DEG C of reaction 4h, 30~35 DEG C of dropwise addition hydrochloric acid crystallizations, filtering, the isopropanol water solution that then 40mL concentration is 30wt% drench
It washes, it is dry, obtain 48.6g Cefcapene side-chain acid, yield 81.4%, through liquid-phase chromatographic analysis, purity 99.5%.
Claims (9)
1. a kind of preparation method of Cefcapene side-chain acid, it is characterised in that: the following steps are included:
(1) under nitrogen protection, ketene dimer is added into alcohol organic solvent, bromine is then added dropwise and is reacted, is added two
The mixed liquor quenching reaction of chloromethanes and water, separates organic phase；
(2) acetic acid is added into organic phase, propionic aldehyde is added dropwise simultaneously after cooling and organic alkali catalyst A is reacted, is then added
Thiocarbamide is reacted, and is concentrated through vacuum distillation；
(3) methylene chloride, di-tert-butyl dicarbonate and organic alkali catalyst B are added into concentrate to be reacted, are then added
Liquid alkaline is reacted, and hydrochloric acid is added dropwise after cooling and carries out crystallization, obtains cephalo card after filtering, isopropanol water solution elution, drying
Product side-chain acid；
Organic alkali catalyst A is the mixture of piperidines and pyridine in step (2), and the molar ratio of piperidines and pyridine is 1:0.5~1.
2. the preparation method of Cefcapene side-chain acid according to claim 1, it is characterised in that: there is alcohols in step (1)
Solvent is the fatty alcohol of C1~C6.
3. the preparation method of Cefcapene side-chain acid according to claim 1, it is characterised in that: double ethylene in step (1)
Ketone, bromine, alcohol organic solvent molar ratio be 1:1~1.1:6~12.
4. the preparation method of Cefcapene side-chain acid according to claim 1, it is characterised in that: the alcohols in step (1)
Organic solvent, methylene chloride, water mass ratio be 1:1:1.5~2.
5. the preparation method of Cefcapene side-chain acid according to claim 1, it is characterised in that: by alcohols in step (1)
Ketene dimer is added in organic solvent after being cooled to -30~-20 DEG C, be added dropwise 0~10 DEG C of reaction temperature when bromine is reacted, instead
It is 1h between seasonable.
6. the preparation method of Cefcapene side-chain acid according to claim 1, it is characterised in that: cooling temperature in step (2)
Degree is -20~-10 DEG C；It is 20~30 DEG C that reaction temperature when thiocarbamide is reacted, which is added, reaction time 1h；When vacuum distillation
Vapo(u)rizing temperature≤10 DEG C.
7. the preparation method of Cefcapene side-chain acid according to claim 1, it is characterised in that: organic in step (3)
Base catalyst B is pyridine or 4-N, N- dimethyl aminopyridine.
8. the preparation method of Cefcapene side-chain acid according to claim 1, it is characterised in that: two are added in step (3)
Reaction temperature when chloromethanes, di-tert-butyl dicarbonate and organic alkali catalyst B are reacted is 30~40 DEG C, and the reaction time is
8h；It is 60~80 DEG C that reaction temperature when liquid alkaline is reacted, which is added, reaction time 4h.
9. the preparation method of Cefcapene side-chain acid according to claim 1, it is characterised in that: isopropanol in step (3)
The concentration of aqueous solution is 30~40wt%.
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| CN110143873A (en) * | 2019-06-20 | 2019-08-20 | 济南大学 | A kind of method of the intermediate 4- acetyl bromide methyl acetate of micro- reaction synthesis Method of cefcapene pivoxil side-chain acid |
| CN112321444A (en) * | 2020-09-17 | 2021-02-05 | 江西邦浦医药化工有限公司 | Synthesis method of 4-bromo-3-oxo-N-phenylbutanamide |
| CN113025679B (en) * | 2021-03-17 | 2023-04-28 | 石药集团内蒙古中诺药业有限公司 | Enzymatic preparation process of cefcapene precursor acid of t-butyloxycarbonyl |
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Patent Citations (4)
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| CN1058595A (en) * | 1990-07-19 | 1992-02-12 | 盐野义制药株式会社 | Thioalkylthio cephalosporin derivatives |
| CN101007793A (en) * | 2007-01-22 | 2007-08-01 | 山东汇海医药化工有限公司 | Method for preparation of EHATA |
| CN101182314A (en) * | 2007-11-30 | 2008-05-21 | 山东金城医药化工有限公司 | Method for preparing 2-(2-butoxy carbonyl amino thiazole-4-group)-2-pentenoic acid ester |
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