CN101704827B

CN101704827B - Synthesis method of cefathiamidine compound

Info

Publication number: CN101704827B
Application number: CN2009100180111A
Authority: CN
Inventors: 邱民
Original assignee: Hainan Meida Pharmaceutical Co Ltd
Current assignee: Hainan Lingkang Pharmaceutical Co Ltd
Priority date: 2009-08-18
Filing date: 2009-08-18
Publication date: 2012-01-11
Anticipated expiration: 2029-08-18
Also published as: CN101704827A

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

A kind of compound method of cefathiamidine compound

Technical field

The present invention relates to a kind of cephalosporin compound, be specifically related to a kind of compound 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 with 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 property powder.

Cefathiamidine has the unique molecular structure of zwitter-ion inner salt, meets thermally labile, and product is easy to change in depositing process, causes color burn.In cefathiamidine synthetic, Chinese patent CN1640878A uses bromoacetyl bromide, easy bromine ion 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 compound 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 compound 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 99.5 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 title 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 through 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 following:

A kind of compound method of cefathiamidine compound, it comprises the steps:

(1) in mixed solvent, add N, N '-di-isopropyl thiourea and sodium hydrogencarbonate 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 99.5 are dissolved in respectively in the solvent, drip until reaction and accomplish, 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, uses sodium hydroxide to regulate the pH value and be 11-12, after the reaction, use the salt acid for adjusting pH value to be 3-4, layering, drying, concentrating under reduced pressure adds Virahol and stirs, and separates out solid, filters, and drying gets cefathiamidine.

Above-mentioned described compound method, mixed solvent is acetone and water in the step (1), the volume ratio of the two is 4: 1.

Above-mentioned described compound method is characterized in that solvent is selected from toluene, YLENE, chlorobenzene, dichlorobenzene, methylene dichloride, 1, one or more in 2-ethylene dichloride, the trichloromethane in the step (2).

Above-mentioned described compound 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 compound method of cefathiamidine compound provided by the invention comprises the steps:

(1) in acetone and water volume ratio are 4: 1 mixed solvent, add N, N '-di-isopropyl thiourea and sodium hydrogencarbonate stir; The acetone soln that adds the 2-bromoacetic acid then, the stirring at room reaction is regulated the pH value with the 1-5mol/L hydrochloric acid soln again; Solid is separated out in cooling, filters; Drying gets N, N '-diisopropylamidinateand ethyl thioglycollic acid;

(2) triphenylphosphinc oxide and TRIPHOSGENE 99.5 are dissolved in 1 respectively, in the 2-ethylene dichloride, triphenylphosphinc oxide is added drop-wise in the TRIPHOSGENE 99.5 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,, after the reaction, uses the salt acid for adjusting pH value with sodium hydroxide adjusting pH value, layering, dry with solid drier, concentrating under reduced pressure adds Virahol and stirs, and separates out solid, filters, and vacuum-drying gets cefathiamidine.

Use the salt acid for adjusting pH value to be 3-4 in the above-mentioned described compound method, step (1) and step (3), preferably regulating the pH value is 3; Use sodium hydroxide to regulate the pH value in the step (3) and be 10-12, be preferably 11.

Solid drier is selected from anhydrous magnesium sulfate, Calcium Chloride Powder Anhydrous, SODIUM SULPHATE ANHYDROUS 99PCT, anhydrous calciumsulphate or activated alumina in the above-mentioned described compound method, step (3), is preferably SODIUM SULPHATE ANHYDROUS 99PCT.

Synthetic route is:

After the reaction of 7-ACA and bromoacetyl bromide, with N, much lower the reaction yield of the butt joint of N '-di-isopropyl thiourea is in the building-up process of cefathiamidine; And product gas purity is also lower, and in order to improve this reaction, we regulate butt joint and study; Through N, N '-di-isopropyl thiourea reacts with the 2-bromoacetic acid earlier, through 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, product gas purity meets the requirement of injection.

Embodiment

Below come further to explain or explanation content of the present invention through embodiment.But the embodiment that is provided should not be understood that protection domain of the present invention is constituted restriction.

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, adds 320 grams, N '-di-isopropyl thiourea and 200 gram sodium hydrogencarbonates stir 10min; The acetone soln of 500ml that adds the 2-bromoacetic acid of 278 grams then, stirring at room reaction 2 hours, the pH that uses the hydrochloric acid conditioned reaction of 2mol/L then was 3; Be cooled to 0 ℃ then, stir and separate 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, are added drop-wise in 1 liter of 2-ethylene dichloride of the TRIPHOSGENE 99.5 that contains 550 grams; Keep maintain during dropping at 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 7-ACA of 249 grams, temperature is controlled at 0 ℃, and using sodium hydroxide to regulate the pH value is 11, after dripping; Reacted 1 hour, using the salt acid for adjusting pH value is 3, and anhydrous sodium sulfate drying is used in layering; Concentrating under reduced pressure adds 1 liter of Virahol with spissated product and stirs, and separates out solid, filters; 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, adds 640 grams, N '-di-isopropyl thiourea and 400 gram sodium hydrogencarbonates stir 10min; The acetone soln of 1000ml that adds the 2-bromoacetic acid of 556 grams then, stirring at room reaction 2 hours, the pH that uses the hydrochloric acid conditioned reaction of 5mol/L then was 3.5; Be cooled to 0 ℃ then, stir and separate 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, are added drop-wise in 2 liters of 2-ethylene dichloride of the TRIPHOSGENE 99.5 that contains 1100 grams; Keep maintain during dropping at 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 7-ACA of 498 grams, temperature is controlled at 0 ℃, and using sodium hydroxide to regulate the pH value is 11.5, after dripping; Reacted 1 hour, using the salt acid for adjusting pH value is 3.5, and anhydrous sodium sulfate drying is used in layering; Concentrating under reduced pressure adds 2 liters of Virahols with spissated product and stirs, and separates out solid, filters; 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。

Claims

1. the compound method of a cefathiamidine compound, it comprises the steps:

(1) with N, it is in 4: 1 the mixed solvent, to stir that N '-di-isopropyl thiourea and sodium hydrogencarbonate join acetone and water volume ratio, adds the 2-bromoacetic acid then, stirring reaction, and regulating pH value is 3-4, generation N, N '-diisopropylamidinateand ethyl thioglycollic acid;

(2) be dissolved in triphenylphosphinc oxide and TRIPHOSGENE 99.5 in the solvent respectively; And triphenylphosphinc oxide is added drop-wise in the TRIPHOSGENE 99.5 until reaction accomplishes, reaction solution is added drop-wise to contains N, in the solvent of N '-diisopropylamidinateand ethyl thioglycollic acid; Stirring reaction; Get solution (A), wherein said solvent is selected from toluene, YLENE, chlorobenzene, dichlorobenzene, methylene dichloride, 1, one or more in 2-ethylene dichloride, the trichloromethane;

(3) solution (A) is added drop-wise in the aqueous solution of 7-ACA, uses sodium hydroxide to regulate the pH value and be 10-12, after the reaction, use the salt acid for adjusting pH value to be 3-4, layering, drying, concentrating under reduced pressure adds Virahol and stirs, and separates out solid, filters, and drying gets cefathiamidine.

2. compound method according to claim 1 is characterized in that control reaction temperature is 2 ℃ to 8 ℃ in the step (2).

3. compound method according to claim 2 is characterized in that control reaction temperature is 5 ℃ in the step (2).

4. compound method according to claim 1, it further comprises the steps:

5. compound method according to claim 4 is characterized in that using the salt acid for adjusting pH value in step (1) and the step (3) is 3; Using sodium hydroxide to regulate the pH value in the step (3) is 11.

6. compound method according to claim 4 is characterized in that solid drier is selected from anhydrous magnesium sulfate, Calcium Chloride Powder Anhydrous, SODIUM SULPHATE ANHYDROUS 99PCT, anhydrous calciumsulphate or activated alumina in the step (3).

7. compound method according to claim 6 is characterized in that solid drier is selected from SODIUM SULPHATE ANHYDROUS 99PCT in the step (3).