CN101704827A - Novel route for cefathiamidine compounds - Google Patents
Novel route for cefathiamidine compounds Download PDFInfo
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- CN101704827A CN101704827A CN200910018011A CN200910018011A CN101704827A CN 101704827 A CN101704827 A CN 101704827A CN 200910018011 A CN200910018011 A CN 200910018011A CN 200910018011 A CN200910018011 A CN 200910018011A CN 101704827 A CN101704827 A CN 101704827A
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Abstract
The invention provides a novel route for cefathiamidine compounds. The new route comprises the following steps of: reacting N,N'-diisopropyl thiourea and sodium bicarbonate, adding 2-bromacetic acid in the mixture for reaction, adding triphosgene and triphenylphosphine oxide serving as catalysts, reacting the product of the previous reaction with N,N'-diisopropyl amidine sulfur radical acetic acid to obtain solution(A), and adding the solution(A) to aqueous solution of 7-ACA dropwise for reaction to obtain the target product. The cefathiamidine compounds prepared by the method have the advantages of higher purity and yield, low-priced raw materials, simple synthesis process, simple equipment and easy separation and purification of products.
Description
Technical field
The present invention relates to a kind of cephalosporin compound, be specifically related to a kind of synthetic method of cefathiamidine compound, belong to chemosynthesis technical field.
Background technology
Cefathiamidine, its chemical name is: (6R, 7R)-3[(acetyl oxygen) methyl]-7-[α-(N, N '-diisopropylamidinateand sulfenyl)-kharophen] 8-oxo-5-thia-1-azabicyclo [4,2,0] oct-2-ene-2-formic acid betaine, molecular formula C
19H
28N
4O
6S
2, molecular weight 472.59, structural formula is:
Be a kind of β-Nei Xiananleikangshengsu, first generation cephalosporin, antimicrobial spectrum is similar to cefoxitin, and the G+ bacterium is had stronger anti-microbial effect, particularly the G+ faecalis is had unique curative effect, is the enterococcal exclusive cynnematin of a kind of anti-G+.Be mainly used in infection such as respiratory tract infection due to the sensitive organism, biliary tract, urinary tract, gynecopathy, septicemia, pneumonia, meningitis, clinical use aseptic crystallization powder.
Cefathiamidine has the unique molecular structure of zwitter-ion inner salt, case of thermal instability, and product is easy to change in depositing process, causes color burn.In cefathiamidine synthetic, Chinese patent CN1640878A uses bromoacetyl bromide, easy residual bromide anion in product, and in addition as in the condensation reaction, the selection of solvent systems is bad, and not high to the clearance of impurity, content in crude product is lower.U.S. Pat P3646025 and " Chinese pharmaceutical chemistry impurity " 2001,10, o. 11th has all been introduced the synthetic method of cefathiamidine, but all very complicated, is not easy to realize that cost is higher difficult operation, difficult quality guarantee.
Summary of the invention
The object of the present invention is to provide a kind of synthetic method of cefathiamidine compound, solved the problem that above-mentioned prior art exists, be more suitable in large-scale industrial production, cost is low, and quality is higher.
The present invention adopts N, N '-di-isopropyl thiourea and reaction of sodium bicarbonate, add the reaction of 2-bromoacetic acid, with triphosgene and triphenylphosphinc oxide as catalyzer, and N, N '-diisopropylamidinateand ethyl thioglycollic acid reaction obtains solution (A), is added drop-wise to then that reaction obtains target product in the aqueous solution of 7-ACA (7-amino-cephalosporanic acid).We find that pleasantly surprisedly the cefathiamidine compound purity and the yield that prepare by method of the present invention all improve a lot, and the raw material that uses is cheap, synthesis technique is simple, equipment is simple, the final product separate easily is purified.
Technical scheme provided by the invention is as follows:
A kind of synthetic method of cefathiamidine compound, it comprises the steps:
(1) add N in mixed solvent, N '-di-isopropyl thiourea and sodium bicarbonate stir, and add the 2-bromoacetic acid then, stirring reaction, and regulating the pH value is 3-4, generates N, N '-diisopropylamidinateand ethyl thioglycollic acid;
(2) triphenylphosphinc oxide and triphosgene are dissolved in respectively in the solvent, drip and finish until reaction, reaction solution is added drop-wise to contains N, in the solvent of N '-diisopropylamidinateand ethyl thioglycollic acid, stirring reaction gets solution (A);
(3) solution (A) is added drop-wise in the aqueous solution of 7-ACA, regulating the pH value with sodium hydroxide is 11-12, after the reaction, is 3-4 with the salt acid for adjusting pH value, layering, and drying, concentrating under reduced pressure adds Virahol and stirs, and separates out solid, filters, and drying gets cefathiamidine.
Above-mentioned described synthetic method, mixed solvent is acetone and water in the step (1), the volume ratio of the two is 4: 1.
Above-mentioned described synthetic method is characterized in that solvent is selected from toluene, dimethylbenzene, chlorobenzene, dichlorobenzene, methylene dichloride, 1, one or more in 2-ethylene dichloride, the trichloromethane in the step (2).
Above-mentioned described synthetic method is characterized in that control reaction temperature is 2 ℃ to 8 ℃ in the step (2), and preferable reaction temperature is 5 ℃.
As the present invention's one concrete preferred version, the synthetic method of cefathiamidine compound provided by the invention comprises the steps:
(1) in being 4: 1 mixed solvent, acetone and water volume ratio add N, N '-di-isopropyl thiourea and sodium bicarbonate stir, and add the acetone soln of 2-bromoacetic acid then, the stirring at room reaction, regulate the pH value with the 1-5mol/L hydrochloric acid soln again, solid is separated out in cooling, filter, drying gets N, N '-diisopropylamidinateand ethyl thioglycollic acid;
(2) triphenylphosphinc oxide and triphosgene are dissolved in 1 respectively, in the 2-ethylene dichloride, triphenylphosphinc oxide is added drop-wise in the triphosgene and reacts, control reaction temperature is 2 ℃ to 8 ℃, after the reaction, reaction solution is added drop-wise to contains N, 1 of N '-diisopropylamidinateand ethyl thioglycollic acid, in the 2-ethylene dichloride, stirring reaction gets solution (A);
(3) solution (A) is added drop-wise in the aqueous solution of 7-ACA, regulates the pH value with sodium hydroxide, after the reaction, use the salt acid for adjusting pH value, the solid drier drying is used in layering, and concentrating under reduced pressure adds Virahol and stirs, and separates out solid, filters, and vacuum-drying gets cefathiamidine.
Above-mentioned described synthetic method, step (1) and step (3) are middle to be 3-4 with the salt acid for adjusting pH value, preferably regulating the pH value is 3; Regulating the pH value with sodium hydroxide in the step (3) is 10-12, is preferably 11.
Solid drier is selected from anhydrous magnesium sulfate, Calcium Chloride Powder Anhydrous, anhydrous sodium sulphate, anhydrous calciumsulphate or activated alumina in the above-mentioned described synthetic method, step (3), is preferably anhydrous sodium sulphate.
Synthetic route is:
1、
2、
After 7-ACA and bromoacetyl bromide react in the building-up process of cefathiamidine, with N, much lower the reaction yield of the butt joint of N '-di-isopropyl thiourea is, and the purity of product is also lower, in order to improve this reaction, we regulate butt joint and study, pass through N, N '-di-isopropyl thiourea reacts with the 2-bromoacetic acid earlier, by activated acids, dock with 7-ACA, making of temperature of reaction, reaction solvent and catalyzer has been used as research, the quality of yield and product is all improved a lot, and the purity of product meets the requirement of injection.
Embodiment
Further explain and describe content of the present invention by the following examples.But the embodiment that is provided should not be understood that protection domain of the present invention is construed as limiting.
Embodiment 1
1, N, N '-diisopropylamidinateand ethyl thioglycollic acid synthetic
The N that in the mixed solvent of the water of 2 liters acetone and 500ml, add 320 grams, N '-di-isopropyl thiourea and 200 gram sodium bicarbonates stir 10min, add the acetone soln of the 500ml of the 278 2-bromoacetic acids that restrain then, stirring at room reaction 2 hours, pH with the hydrochloric acid conditioned reaction of 2mol/L is 3 then, is cooled to 0 ℃ then, stirs and separates out solid, filter, drying gets product 410 grams, yield 94%.
2, cefathiamidine is synthetic
510 gram triphenylphosphinc oxides are dissolved in 1 liter 1, in the 2-ethylene dichloride, be added drop-wise in 1 liter of 2-ethylene dichloride of the triphosgene that contains 550 grams, keep temperature of reaction during dropping and maintain 5 ℃, after dripping, reaction is 2 hours under this temperature, then this mixed solution is added drop-wise to the N of 200 grams, 1 of the 800ml of N '-diisopropylamidinateand ethyl thioglycollic acid is in the 2-ethylene dichloride, reacted 1.5 hours down at 5 ℃, get solution (A);
Solution (A) is added drop-wise in the 2 premium on currency solution of 249 7-ACA that restrain, temperature is controlled at 0 ℃, and regulating the pH value with sodium hydroxide is 11, after dripping, reacting 1 hour, is 3 with the salt acid for adjusting pH value, anhydrous sodium sulfate drying is used in layering, concentrating under reduced pressure, spissated product is added 1 liter of Virahol to be stirred, separate out solid, filter, 20 ℃ of following vacuum-dryings, get target product 398 grams, yield: 92%.
3, ultimate analysis (C
19H
28N
4O
6S
2): C:46.62%; H:6.40%; N:11.61%.IR(cm
-1)：3427.58，3225.36，2979.52，2938.87，1773.96，1737.52。m/z：473，413，354，275，242，201。
1HNMR(D
2O)：5.60-5.59(1H)，5.11-5.10(1H)，4.86-4.84(1H)，4.69-4.65(1H)，4.22(1H)，3.97-3.93(2H)，3.92(1H)，3.64-3.59(1H)，3.37-3.33(1H)，2.05(3H)，1.25(12H).
Embodiment 2
1, N, N '-diisopropylamidinateand ethyl thioglycollic acid synthetic
The N that in the mixed solvent of the water of 4 liters acetone and 1000ml, add 640 grams, N '-di-isopropyl thiourea and 400 gram sodium bicarbonates stir 10min, add the acetone soln of the 1000ml of the 556 2-bromoacetic acids that restrain then, stirring at room reaction 2 hours, pH with the hydrochloric acid conditioned reaction of 5mol/L is 3.5 then, is cooled to 0 ℃ then, stirs and separates out solid, filter, drying gets product 813.9 grams, yield 93.3%.
2, cefathiamidine is synthetic
1020 gram triphenylphosphinc oxides are dissolved in 2 liter 1, in the 2-ethylene dichloride, be added drop-wise in 2 liters of 2-ethylene dichloride of the triphosgene that contains 1100 grams, keep temperature of reaction during dropping and maintain 4 ℃, after dripping, reaction is 2 hours under this temperature, then this mixed solution is added drop-wise to the N of 400 grams, 1 of the 1600ml of N '-diisopropylamidinateand ethyl thioglycollic acid is in the 2-ethylene dichloride, reacted 2 hours down at 4 ℃, get solution (A);
Solution (A) is added drop-wise in the 4 premium on currency solution of 498 7-ACA that restrain, temperature is controlled at 0 ℃, and regulating the pH value with sodium hydroxide is 11.5, after dripping, reacting 1 hour, is 3.5 with the salt acid for adjusting pH value, anhydrous sodium sulfate drying is used in layering, concentrating under reduced pressure, spissated product is added 2 liters of Virahols to be stirred, separate out solid, filter, 20 ℃ of following vacuum-dryings, get target product 805.5 grams, yield: 93.1%.
3, ultimate analysis (C
19H
28N
4O
6S
2): C:46.60%; H:6.41%; N:11.60%.IR(cm
-1)：3427.58，3225.36，2979.52，2938.87，1773.96，1737.52。m/z：473，413，354，275，242，201。
1HNMR(D
2O)：5.60-5.59(1H)，5.11-5.10(1H)，4.86-4.84(1H)，4.69-4.65(1H)，4.22(1H)，3.97-3.93(2H)，3.92(1H)，3.64-3.59(1H)，3.37-3.33(1H)，2.05(3H)，1.25(12H)。
Claims (10)
1. cefathiamidine compound, its synthetic method comprises the steps:
(1) with N, N '-di-isopropyl thiourea and sodium bicarbonate join in the mixed solvent, stir, and add the 2-bromoacetic acid then, stirring reaction, and regulating the pH value is 3-4, generates N, N '-diisopropylamidinateand ethyl thioglycollic acid;
(2) triphenylphosphinc oxide and triphosgene are dissolved in respectively in the solvent, drip and finish until reaction, reaction solution is added drop-wise to contains N, in the solvent of N '-diisopropylamidinateand ethyl thioglycollic acid, stirring reaction gets solution (A);
(3) solution (A) is added drop-wise in the aqueous solution of 7-ACA, regulating the pH value with sodium hydroxide is 10-12, after the reaction, is 3-4 with the salt acid for adjusting pH value, layering, and drying, concentrating under reduced pressure adds Virahol and stirs, and separates out solid, filters, and drying gets cefathiamidine.
2. synthetic method according to claim 1 is characterized in that mixed solvent is acetone and water in the step (1), and the volume ratio of the two is 4: 1.
3. synthetic method according to claim 1 is characterized in that solvent is selected from toluene, dimethylbenzene, chlorobenzene, dichlorobenzene, methylene dichloride, 1, one or more in 2-ethylene dichloride, the trichloromethane in the step (2).
4. synthetic method according to claim 1 is characterized in that control reaction temperature is 2 ℃ to 8 ℃ in the step (2).
5. synthetic method according to claim 4 is characterized in that control reaction temperature is 5 ℃ in the step (2).
6. the synthetic method of a cefathiamidine compound, it further comprises the steps:
(1) in being 4: 1 mixed solvent, acetone and water volume ratio add N, N '-di-isopropyl thiourea and sodium bicarbonate stir, and add the acetone soln of 2-bromoacetic acid then, the stirring at room reaction, regulate the pH value with the 1-5mol/L hydrochloric acid soln again, solid is separated out in cooling, filter, drying gets N, N '-diisopropylamidinateand ethyl thioglycollic acid;
(2) triphenylphosphinc oxide and triphosgene are dissolved in 1 respectively, in the 2-ethylene dichloride, triphenylphosphinc oxide is added drop-wise in the triphosgene and reacts, control reaction temperature is 2 ℃ to 8 ℃, after the reaction, reaction solution is added drop-wise to contains N, 1 of N '-diisopropylamidinateand ethyl thioglycollic acid, in the 2-ethylene dichloride, stirring reaction gets solution (A);
(3) solution (A) is added drop-wise in the aqueous solution of 7-ACA, regulates the pH value with sodium hydroxide, after the reaction, use the salt acid for adjusting pH value, the solid drier drying is used in layering, and concentrating under reduced pressure adds Virahol and stirs, and separates out solid, filters, and vacuum-drying gets cefathiamidine.
7. synthetic method according to claim 6 is characterized in that in step (1) and the step (3) with the salt acid for adjusting pH value being 3-4; Regulating the pH value with sodium hydroxide in the step (3) is 10-12.
8. synthetic method according to claim 6 is characterized in that in step (1) and the step (3) with the salt acid for adjusting pH value being 3; Regulating the pH value with sodium hydroxide in the step (3) is 11.
9. synthetic method according to claim 6 is characterized in that solid drier is selected from anhydrous magnesium sulfate, Calcium Chloride Powder Anhydrous, anhydrous sodium sulphate, anhydrous calciumsulphate or activated alumina in the step (3).
10. synthetic method according to claim 9 is characterized in that solid drier is selected from anhydrous sodium sulphate in the step (3).
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102532165A (en) * | 2010-12-20 | 2012-07-04 | 广州白云山制药股份有限公司广州白云山制药总厂 | Preparation method for cefathiamidine crystals |
| CN102838621A (en) * | 2011-06-22 | 2012-12-26 | 广州白云山制药股份有限公司广州白云山化学制药厂 | (6R,7R)-3-methyl-7-[alpha-(N,N'-diisopropyl amidine thio)-acetylamino]-8-oxo-5-thia-1-azabicyclo[4,2,0]-oct-2-alkene-2-formic betaine crystals |
| CN105646534A (en) * | 2016-02-18 | 2016-06-08 | 海南灵康制药有限公司 | Novel-crystal-form cefathiamidine compound adopting crystal product molecular assembly and form optimization technology in particle process and preparation |
| CN111018889A (en) * | 2019-12-30 | 2020-04-17 | 山东罗欣药业集团恒欣药业有限公司 | Synthesis method of cefathiamidine |
| CN111100144A (en) * | 2019-12-30 | 2020-05-05 | 山东罗欣药业集团恒欣药业有限公司 | Synthesis process of cefathiamidine |
| CN112083084A (en) * | 2019-06-14 | 2020-12-15 | 四川科伦药物研究院有限公司 | Method for detecting bromoacetic acid impurity in cefathiamidine |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE758219A (en) * | 1969-10-30 | 1971-04-29 | Bristol Myers Co | ANTIBACTERIAL AGENTS AND METHOD FOR PREPARING THEM |
| CN1640878A (en) * | 2004-12-27 | 2005-07-20 | 托新权 | Method for preparing cefathiamidide |
| CN101486718B (en) * | 2008-01-16 | 2010-12-08 | 广州白云山制药股份有限公司广州白云山化学制药厂 | Process for preparing cefathiamidine |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102532165A (en) * | 2010-12-20 | 2012-07-04 | 广州白云山制药股份有限公司广州白云山制药总厂 | Preparation method for cefathiamidine crystals |
| CN102838621A (en) * | 2011-06-22 | 2012-12-26 | 广州白云山制药股份有限公司广州白云山化学制药厂 | (6R,7R)-3-methyl-7-[alpha-(N,N'-diisopropyl amidine thio)-acetylamino]-8-oxo-5-thia-1-azabicyclo[4,2,0]-oct-2-alkene-2-formic betaine crystals |
| CN102838621B (en) * | 2011-06-22 | 2014-09-10 | 广州白云山制药股份有限公司广州白云山化学制药厂 | (6R,7R)-3-methyl-7-[alpha-(N,N'-diisopropyl amidine thio)-acetylamino]-8-oxo-5-thia-1-azabicyclo[4,2,0]-oct-2-alkene-2-formic betaine crystals |
| CN105646534A (en) * | 2016-02-18 | 2016-06-08 | 海南灵康制药有限公司 | Novel-crystal-form cefathiamidine compound adopting crystal product molecular assembly and form optimization technology in particle process and preparation |
| CN112083084A (en) * | 2019-06-14 | 2020-12-15 | 四川科伦药物研究院有限公司 | Method for detecting bromoacetic acid impurity in cefathiamidine |
| CN111018889A (en) * | 2019-12-30 | 2020-04-17 | 山东罗欣药业集团恒欣药业有限公司 | Synthesis method of cefathiamidine |
| CN111100144A (en) * | 2019-12-30 | 2020-05-05 | 山东罗欣药业集团恒欣药业有限公司 | Synthesis process of cefathiamidine |
| CN111018889B (en) * | 2019-12-30 | 2022-06-17 | 山东罗欣药业集团恒欣药业有限公司 | Synthesis method of cefathiamidine |
| CN111100144B (en) * | 2019-12-30 | 2022-12-06 | 山东罗欣药业集团恒欣药业有限公司 | Synthesis process of cefathiamidine |
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