CN102453042B - Preparation method of high-purity cefathiamidine - Google Patents
Preparation method of high-purity cefathiamidine Download PDFInfo
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Abstract
The invention relates to a preparation method of cefathiamidine, in particular to a preparation method of high-purity cefathiamidine with low content of impurity acetyl bromide-7-ACA (acetic acid). The preparation method comprises the following steps: adding acetyl bromide-7-ACA, a reaction solvent and less auxiliary solvent into a reactor, and adding alkali to completely dissolve the acetyl bromide-7-ACA; adding N,N'-di-isopropyl thiourea, reacting for 0.5 to 8.0 hours at the temperature between 0 and 40 DEG C; regulating the system temperature to be between 0 and 35 DEG C, dripping a crystallization solvent, then continuing to stir, filtering, cleaning, and drying to obtain the cefathiamidine. According to the preparation method in the invention, residues of the reactant acetyl bromide-7-ACA in cefathiamidine can be effectively reduced, the content of the acetyl bromide-7-ACA in the cefathiamidine is reduced to 0.2 percent or lower, and the content of the acetyl bromide-7-ACA can be reduced to lower than 0.1 percent or completely removed by virtue of further refining, so that the safety of the cefathiamidine is further improved.
Description
Technical field
The present invention relates to the preparation method of cefathiamidine, particularly relate to the preparation method of the high-purity cefathiamidine that impurity acetobrom-7-ACA content is low.
Background technology
Cefathiamidine, chemical name is (6R, 7R)-3-[(ethanoyl oxygen base) 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 is C
19h
28n
4o
6s
2, its structural formula is as follows:
Cefathiamidine structural formula
Cefathiamidine is first-generation b-lactam antibiotics, and antimicrobial spectrum is similar to cefoxitin.Gram positive organism and part negative bacterium are had to anti-microbial activity, especially strong to the effect of gram positive coccus.Streptococcus viridans, Hemolytic streptococcus, anhemolytic streptococcus, diphtheria corynebacterium, Clostridium perfringens, tetanus bacillus and anthrax bacillus are all had to good anti-microbial effect.
Version " Chinese Pharmacopoeia " regulation in 2005: the high-content of single impurity is no more than 1.0%, and total impurities content is no more than 2.5%; 2010 version " Chinese Pharmacopoeia " stipulate that the high-content of single impurity is no more than 0.5%, total impurities content is no more than 1.5%.Thereby the specification of quality of cefathiamidine has been improved greatly, require the highly purified cefathiamidine product of preparation.In addition, cefathiamidine has inner salt structure, and case of thermal instability is easily degraded in the process of producing storage.And the raising of cefathiamidine purity is also conducive to the raising of cefathiamidine stability.
At present, producing the conventional 7-ACA of cefathiamidine is its raw material, react with bromoacetyl bromide, generate acetobrom-7-ACA, acetobrom-7-ACA again with N, N '-di-isopropyl thiourea reaction generates cefathiamidine crude product, crude product is further refining obtains meeting the cefathiamidine that pharmacopeia requires, as shown in Figure 1, reaction formula is as follows for its production process schematic diagram:
Generally speaking, the major impurity of cefathiamidine has: remove acetyl cefathiamidine, remove acetyl oxygen cefathiamidine, reaction raw materials residue acetobrom-7-ACA, N, N '-di-isopropyl thiourea.Wherein, impurity acetobrom-7-ACA is reaction intermediate, and it is to cefathiamidine safety effects maximum.The neural system that has been found that people is very sensitive to the compound of bromine, in human body, inject or absorb after the compound of a small amount of bromine, nerve just can be benumbed gradually, is mainly that bromine-containing compound has toxic side effect in various degree to human body because bromide anion has the effect that suppresses zona rolandica.Press current methods (US 3,646,025) the cefathiamidine crude product of preparing, the residual quantity of acetobrom-7-ACA is about 1.7%～2.0%, and acetobrom-7-ACA is approximately 80%～85% by the clearance of purification step, acetobrom-7-ACA is at the content approximately 0.5%～0.8% of cefathiamidine finished product.If can just control the residual quantity of acetobrom-7-ACA in the reaction process of preparing cefathiamidine, can effectively reduce or remove completely its residual at cefathiamidine finished product, be of great importance to promoting cefathiamidine security.
Summary of the invention
Therefore, the object of this invention is to provide the preparation method of the residual better cefathiamidine of security of a kind of effective reduction acetobrom-7-ACA.
At present, acetobrom-7-ACA and N, N '-di-isopropyl thiourea is generally in organic solvent (as methylene dichloride), under organic bases (as triethylamine) condition, reacts, and generates cefathiamidine.Inventor's discovery, the polarity of reaction solvent has material impact to reaction, take polar solvent as reaction solvent, can cause multiple side reaction, increase by product, and yield is low; Take nonpolar or low polar solvent as reaction solvent, side reaction is few, but the residual height of acetobrom-7-ACA, and be difficult to effectively remove acetobrom-7-ACA impurity by methods such as immersion, washings, also generally can only remove 80～85% by recrystallization, this has just affected cefathiamidine purity.
The present invention is at acetobrom-7-ACA and N, in the reaction of N '-di-isopropyl thiourea, using non-polar solvent or low polar solvent as reaction solvent, add a small amount of if the polar solvent of lower alcohol or acid amides etc. is as secondary solvent simultaneously, the strict ratio of controlling reaction solvent and secondary solvent, can effectively control cefathiamidine Crystallization Process, finally add non-polar solvent or low polar solvent as crystallization solvent.Both avoided the generation of side reaction, significantly reduce again acetobrom-7-ACA residual, and reaction yield had been high.When key of the present invention is reaction beginning, strictly control the ratio of reaction solvent and secondary solvent, in an appropriate scope, both avoid side reaction to occur, reduce the residual quantity of acetobrom-7-ACA, and change cefathiamidine crystal size and crystal outward appearance.
By the enforcement of the inventive method, can in the process of preparing cefathiamidine crude product, just effectively control the residual quantity of acetobrom-7-ACA, make its residual quantity at cefathiamidine crude product be reduced to 0.2% or lower (for example sometimes can accomplish 0.1% left and right) by 1.7%～2.0% original left and right, further in the refining cefathiamidine crystal obtaining, the content of acetobrom-7-ACA can be reduced to 0.1% or lower (sometimes can reach NF degree), greatly reduces its residual at cefathiamidine finished product.
According to the present invention, the technology of the present invention solution is as follows:
In reactor, add acetobrom-7-ACA, reaction solvent and secondary solvent, add alkali that acetobrom-7-ACA is dissolved completely, then add N, N '-di-isopropyl thiourea, in 0.5 ~ 8.0 hour (preferably 1 ~ 4 hour) of 0 ~ 40 ℃ (preferably 15 ~ 40 ℃) reaction; Then regulation system temperature is at 0 ~ 35 ℃ (preferably 0 ~ 25 ℃), then drips crystallization solvent, continues to stir, and then filters, and washing, dries, and obtains cefathiamidine, and its reaction formula is as follows:
Wherein, acetobrom-7-ACA and N, the consumption of N '-di-isopropyl thiourea is 1:1～1.5 in molar ratio, preferably 1:1～1.2;
Described reaction solvent is non-polar solvent or low polar solvent, can be the one in methylene dichloride, chloroform, ethylene dichloride, normal hexane and hexanaphthene, and preferred methylene dichloride; Reaction solvent consumption and acetobrom-7-ACA consumption by volume/weight is 1～15 mL/1 g, preferably 3～12 mL/1 g, most preferably 7～11 mL/1 g;
Described alkali is triethylamine, diethylamine or ammoniacal liquor, and preferred triethylamine; The consumption of described alkali is for dissolving acetobrom-7-ACA completely;
Described secondary solvent is selected among lower alcohol, DMF and N,N-dimethylacetamide isopolarity solvent, and wherein lower alcohol is methyl alcohol, ethanol or Virahol etc., and described secondary solvent particular methanol or ethanol, particularly preferably methyl alcohol; Secondary solvent consumption and acetobrom-7-ACA consumption by volume/weight is 0.01～2 mL/1 g, preferably 0.01～1 mL/1 g, more preferably 0.08～0.25 mL/1 g;
And reaction solvent is 100～10:1, preferably 80～20:1 with the ratio of the volume of secondary solvent;
Described crystallization solvent be in the nonpolar or low polar solvent such as methylene dichloride, acetone, ether, sherwood oil, normal hexane and hexanaphthene one or both, preferably acetone; Crystallization solvent load and acetobrom-7-ACA consumption by volume/weight is 1～15 mL/1 g, preferably 3～12 mL/1 g.
As required, the cefathiamidine of preparing according to the inventive method is further refining by the method described in CN 1212324C or CN 100338072C, can obtain high-purity cefathiamidine crystal, wherein the content of acetobrom-7-ACA, below 0.1%, is removed even completely.
The present invention does not have increase equipment or processing step is removed acetobrom-7-ACA impurity, by at acetobrom-7-ACA and N, N '-di-isopropyl thiourea reaction system adds a small amount of secondary solvent, the Crystallization Process of regulation and control cefathiamidine crystallization, change the size-grade distribution of crystal, its granularity is attenuated, make crystal outward appearance generation noticeable change, reduce the impurity wrapping up in product.Can effectively reduce residual in cefathiamidine crude product of reactant acetobrom-7-ACA by the enforcement of this programme.Make its content in cefathiamidine crude product be down to 0.2% or lower (for example sometimes can accomplish 0.1% left and right), further refining its content that can make is reduced to 0.1% below or removing completely.The present invention operates simple and easy controlled, produces yield high, and yield reaches 85%～100%, and acetobrom-7-ACA is residual low cefathiamidine crude product, is conducive to further refine and obtain highly purified cefathiamidine, is suitable for suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 is cefathiamidine production process schematic diagram;
Fig. 2 A and 2B are respectively the HPLC color atlas of the cefathiamidine that comparing embodiment 1 and embodiment 1 make;
Fig. 3 A and 3B are respectively the particle size distribution figure of the cefathiamidine that comparing embodiment 1 and embodiment 1 make;
Fig. 4 A and 4B are respectively the electron-microscope scanning figure of the cefathiamidine that comparing embodiment 1 and embodiment 1 make.
Embodiment
Further set forth technical scheme of the present invention by following embodiment, but following examples should not be construed as limiting the scope of the invention.
Comparing embodiment 1
At 40 ℃, in 250ml there-necked flask, add 10g acetobrom-7-ACA, 80ml methylene dichloride, drip triethylamine and just dissolve to acetobrom-7-ACA; Add N, N '-di-isopropyl thiourea 4.5g, reacts 3 hours.Be cooled to 6～8 ℃, drip acetone 100ml.Finish, continue to stir 30 minutes, suction filtration, uses acetone foam washing, drains, and obtains off-white color solid 9.3g, yield 93% in room temperature vacuum-drying.
Adopt high performance liquid chromatograph device, according to the chromatographic condition of relative substance item method in version " Chinese Pharmacopoeia " cefathiamidine in 2010, the cefathiamidine making is carried out to HPLC analysis, collection of illustrative plates as shown in Figure 2 A, wherein, is located peak in 5.1 minutes and is represented cefathiamidine, within 4.1 minutes, locate peak and represent acetobrom-7-ACA, calculate according to area percentage, acetobrom-7-ACA accounts for 1.98%, and cefathiamidine purity is 96.14%.
Adopt laser fineness gage Mastersizer 2000, detection method is dry method, and cefathiamidine Granularity Distribution figure is shown in Fig. 3 A.
Adopt electron-microscope scanning instrument (FEI Quanta 400F) to observe its outward appearance, see Fig. 4 A.
Embodiment 1
At 40 ℃, in 250ml there-necked flask, add 10g acetobrom-7-ACA, 80ml methylene dichloride and 8mL methyl alcohol, drip triethylamine and just dissolve to acetobrom-7-ACA; Add N, N '-di-isopropyl thiourea 4.5g, reacts 3 hours.Be cooled to 6～8 ℃, drip acetone 100ml.Finish, continue to stir 30 minutes, suction filtration, uses acetone foam washing, drains, and obtains off-white color solid 9.2g, yield 92% in room temperature vacuum-drying.
Adopt high performance liquid chromatograph device, according to the chromatographic condition of relative substance item method in version " Chinese Pharmacopoeia " cefathiamidine in 2010, the cefathiamidine making is carried out to HPLC analysis, collection of illustrative plates as shown in Figure 2 B, wherein, is located peak in 5.5 minutes and is represented cefathiamidine, within 4.1 minutes, locate peak and represent acetobrom-7-ACA, calculate according to area percentage, acetobrom-7-ACA accounts for 0.10%, and cefathiamidine purity is 98.54%.
Adopt laser fineness gage Mastersizer 2000, detection method is dry method, and cefathiamidine Granularity Distribution figure is shown in Fig. 3 B.
Adopt electron-microscope scanning instrument (FEI Quanta 400F) to observe its outward appearance, see Fig. 4 B.
H-NMR：（MeOH-d
4）δ1.32(12H),?δ2.00（3H）,?δ3.30(1H),?δ3.35(1H),?δ3.60(1H),?δ4.04(2H),?δ4.2(1H),?δ4.83(1H),?δ4.99(1H),?δ5.03(1H),?δ5.65(1H)。
Result shows: in the cefathiamidine making in (1) embodiment 1, acetobrom-7-ACA residual quantity is 0.1%, in the cefathiamidine making in comparing embodiment 1, acetobrom-7-ACA residual quantity is 1.98%, by method of the present invention, acetobrom-7-ACA residual quantity obviously reduces, and cefathiamidine purity improves.
(2) from Fig. 3 and Fig. 4, can see, the cefathiamidine crude product volume average particle size that embodiment 1 makes is 5.660 mm, than the volume average particle size of comparing embodiment 1,13.579 mm are little, and the cefathiamidine outward appearance that embodiment 1 makes is tabular crystal, and the cefathiamidine crystal that comparing embodiment 1 makes becomes particulate state.This has reduced the possibility of parcel impurity, thereby reduces the residual quantity of acetobrom-7-ACA in cefathiamidine crude product.
Embodiment 2
At 25 ℃, in 250ml there-necked flask, add 10g acetobrom-7-ACA, 80ml methylene dichloride and 5mL methyl alcohol, drip triethylamine and just dissolve to acetobrom-7-ACA; Add N, N '-di-isopropyl thiourea 4.2g, reacts 4 hours.Be cooled to 0～3 ℃, drip methylene dichloride 80ml.Finish, continue to stir 30 minutes, suction filtration, uses acetone foam washing, drains, and obtains white solid 8.5g in room temperature vacuum-drying, yield 85%.
Adopt high performance liquid chromatograph device, according to the chromatographic condition of relative substance item method in version " Chinese Pharmacopoeia " cefathiamidine in 2010, the cefathiamidine making is carried out to HPLC analysis (collection of illustrative plates omission), calculate according to area percentage, acetobrom-7-ACA accounts for 0.20%, cefathiamidine purity 98.31%.
Embodiment 3
At 30 ℃, in 250ml there-necked flask, add 10g acetobrom-7-ACA, 110ml methylene dichloride and 10mL ethanol, drip triethylamine and just dissolve to acetobrom-7-ACA; Add N, N '-di-isopropyl thiourea 4.3g, reacts 4 hours.Be cooled to 3～6 ℃, drip acetone 80ml.Finish, continue to stir 30 minutes, suction filtration, uses acetone foam washing, drains, and obtains white solid 9.0g in room temperature vacuum-drying, yield 90%.
Adopt high performance liquid chromatograph device, according to the chromatographic condition of relative substance item method in version " Chinese Pharmacopoeia " cefathiamidine in 2010, the cefathiamidine making is carried out to HPLC analysis (collection of illustrative plates omission), calculate according to area percentage, acetobrom-7-ACA accounts for 0.18%, cefathiamidine purity 98.20%.
Embodiment 4
At 35 ℃, in 250ml there-necked flask, add 10g acetobrom-7-ACA, 110ml methylene dichloride and 8mL DMF, drip triethylamine and just dissolve to acetobrom-7-ACA; Add N, N '-di-isopropyl thiourea 4.5g, reacts 2.5 hours; Be cooled to 10～15 ℃, continue reaction 1 hour.Drip normal hexane 100ml, finish, continue to stir 30 minutes, suction filtration, uses acetone foam washing, drains, and obtains micro-off-white color solid 8.8g, yield 88% in room temperature vacuum-drying.
Adopt high performance liquid chromatograph device, according to the chromatographic condition of relative substance item method in version " Chinese Pharmacopoeia " cefathiamidine in 2010, the cefathiamidine making is carried out to HPLC analysis (collection of illustrative plates omission), calculate according to area percentage, acetobrom-7-ACA accounts for 0.15%, cefathiamidine purity 98.63%.
Embodiment 5
At 33 ℃, in 250ml there-necked flask, add 10g acetobrom-7-ACA, 110ml methylene dichloride and 10mL N,N-dimethylacetamide, drip diethylamine and just dissolve to acetobrom-7-ACA; Add N, N '-di-isopropyl thiourea 4.5g, reacts 3 hours, is cooled to 20～25 ℃, continues reaction 1 hour.Drip hexanaphthene 120ml.Finish, continue to stir 30 minutes, suction filtration, uses acetone foam washing, drains, and obtains white solid 8.5g in room temperature vacuum-drying, yield 85%.
Adopt high performance liquid chromatograph device, according to the chromatographic condition of relative substance item method in version " Chinese Pharmacopoeia " cefathiamidine in 2010, the cefathiamidine making is carried out to HPLC analysis (collection of illustrative plates omission), calculate according to area percentage, acetobrom-7-ACA accounts for 0.15%, cefathiamidine purity 98.15%.
Embodiment 6
At 20 ℃, in 250ml there-necked flask, add 10g acetobrom-7-ACA, 110ml methylene dichloride and 2mL ethanol, drip triethylamine and just dissolve to acetobrom-7-ACA; Add N, N '-di-isopropyl thiourea 4.3g, reacts 5 hours.Be cooled to 10～15 ℃, drip acetone 90ml.Finish, continue to stir 30 minutes, suction filtration, obtains white solid 9.1 g, yield 91% in room temperature vacuum-drying.
Adopt high performance liquid chromatograph device, according to the chromatographic condition of relative substance item method in version Chinese Pharmacopoeia cefathiamidine in 2010, the cefathiamidine making is carried out to HPLC analysis (collection of illustrative plates omission), calculate according to area percentage, acetobrom-7-ACA accounts for 0.2%, cefathiamidine purity 98.18%.
Comparing embodiment 2
At 40 ℃, in 250ml there-necked flask, add 10g acetobrom-7-ACA, 50ml methyl alcohol, drip triethylamine and just dissolve to acetobrom-7-ACA; Add N, N '-di-isopropyl thiourea 4.5g, reacts 90 minutes.Be cooled to 6～8 ℃, drip acetone 720ml, start to have crystal to separate out, continue to stir, growing the grain 120 minutes at 6～8 ℃, suction filtration, uses acetone foam washing, drains, and obtains glassy yellow solid 0.5g in room temperature vacuum-drying, and yield is low, and only 5%.
Adopt high performance liquid chromatograph device, according to the chromatographic condition of relative substance item method in version " Chinese Pharmacopoeia " cefathiamidine in 2010, the cefathiamidine making is carried out to HPLC analysis (collection of illustrative plates omission).Wherein, acetobrom-7-ACA does not have residual; But impurity goes acetyl oxygen cefathiamidine extremely to increase (1.42%, be generally 0.5% left and right or lower); In retention time
t=2.9 min, 7.1 min, 7.9 min tri-place's impurity peaks (it is concrete what compound that prior art not yet analyzes), calculate and be respectively 1.04%, 0.72%, 0.86% according to area percentage, under normal circumstances, all content is very low for these three impurity, all, below 0.1%, even can't detect.Cefathiamidine purity is 94.18%.
Comparing embodiment 3
At 40 ℃, in 250ml there-necked flask, add 10g acetobrom-7-ACA, 50ml DMF, drip triethylamine and just dissolve to acetobrom-7-ACA; Add N, N '-di-isopropyl thiourea 4.5g, reacts 40 minutes slowly crystallize outs, continues reaction to 90 minutes.Be cooled to 6～8 ℃, drip acetone 400ml, continue to stir, growing the grain 120 minutes at 6～8 ℃, suction filtration, uses acetone foam washing, drains, and obtains class brown solid 9.0g, yield 90% in room temperature vacuum-drying.
Adopt high performance liquid chromatograph device, according to the chromatographic condition of relative substance item method in version " Chinese Pharmacopoeia " cefathiamidine in 2010, the cefathiamidine making is carried out to HPLC analysis (collection of illustrative plates omission).Wherein, acetobrom-7-ACA does not have residual; But remove acetyl oxygen cefathiamidine, N, N '-di-isopropyl thiourea impurity increases (0.66%, 4.68%, two impurity generally are 0.3% left and right) extremely; In retention time
t=there is another new impurity peaks in 2.9 min, is calculated as 1.24% according to area percentage, and under normal circumstances, this foreign matter content is very low, below 0.1%, even can't detect.Cefathiamidine purity is 92.40%.
Claims (5)
1. a preparation method for cefathiamidine, the method comprises: in reactor, add acetobrom-7-ACA, reaction solvent and a small amount of secondary solvent, add alkali that acetobrom-7-ACA is dissolved completely, then add N, N '-di-isopropyl thiourea, 20～40 ℃ of reactions 0.5～8.0 hour; Regulation system temperature is at 0～25 ℃, then drips crystallization solvent, continues to stir, and then filters, and washing, dries, and obtains cefathiamidine;
Wherein, acetobrom-7-ACA and N, the consumption of N '-di-isopropyl thiourea is 1:1～1.2 in molar ratio;
Described reaction solvent is methylene dichloride, reaction solvent consumption and acetobrom-7-ACA consumption by volume/weight is 7～11mL/1g;
Described alkali is triethylamine, diethylamine or ammoniacal liquor, and the consumption of described alkali is for dissolving acetobrom-7-ACA completely;
Described secondary solvent is selected among methyl alcohol, ethanol, DMF and N,N-dimethylacetamide, secondary solvent consumption and acetobrom-7-ACA consumption by volume/weight is 0.2～1mL/1g;
And reaction solvent is 55～10:1 with the ratio of the volume of secondary solvent;
Described crystallization solvent be in methylene dichloride, acetone, normal hexane and hexanaphthene one or both, crystallization solvent load and acetobrom-7-ACA consumption by volume/weight is 8～12mL/1g.
2. the preparation method of cefathiamidine according to claim 1, is characterized in that, described reaction is carried out 1～4 hour.
3. the preparation method of cefathiamidine according to claim 1 and 2, is characterized in that, described alkali is triethylamine.
4. the preparation method of cefathiamidine according to claim 1 and 2, is characterized in that, described secondary solvent is methyl alcohol or ethanol.
5. the preparation method of cefathiamidine according to claim 1 and 2, is characterized in that, described crystallization solvent is acetone.
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| CN103556226B (en) * | 2013-10-23 | 2016-08-24 | 广州白云山医药集团股份有限公司白云山化学制药厂 | Cefathiamidine monocrystal |
| CN103833773B (en) * | 2013-12-20 | 2016-01-27 | 悦康药业集团有限公司 | A kind of cefathiamidine compound |
| CN105440054B (en) * | 2015-09-17 | 2018-08-14 | 山西振东泰盛制药有限公司 | A kind of technique preparing cefathiamidine |
| 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 |
| CN110407857B (en) * | 2019-07-22 | 2020-11-03 | 山东罗欣药业集团股份有限公司 | Preparation process of cefathiamidine |
| CN113219082A (en) * | 2021-03-26 | 2021-08-06 | 天圣制药集团股份有限公司 | HPLC detection method for impurities of 7-ACA and analogues in cefathiamidine and preparation thereof |
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