CN101935325B - Preparation method of cefepime hydrochloride - Google Patents
Preparation method of cefepime hydrochloride Download PDFInfo
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- CN101935325B CN101935325B CN2010102864062A CN201010286406A CN101935325B CN 101935325 B CN101935325 B CN 101935325B CN 2010102864062 A CN2010102864062 A CN 2010102864062A CN 201010286406 A CN201010286406 A CN 201010286406A CN 101935325 B CN101935325 B CN 101935325B
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- 0 CC(OCC(CS[C@]1C2*)=C(*)N1C2=O)=* Chemical compound CC(OCC(CS[C@]1C2*)=C(*)N1C2=O)=* 0.000 description 1
- APQDILOFUHDFDO-FPWNXMDDSA-N CCC([C@@H]1N)N(/C(/C(O)=O)=C(/COC(C)=O)\CS)C1=O Chemical compound CCC([C@@H]1N)N(/C(/C(O)=O)=C(/COC(C)=O)\CS)C1=O APQDILOFUHDFDO-FPWNXMDDSA-N 0.000 description 1
- AVFZOVWCLRSYKC-UHFFFAOYSA-N CN1CCCC1 Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention discloses a preparation method of cefepime hydrochloride, comprising the following steps of: reacting oxalyl chloride with 2-methoxyimino-2-(2-aminothiazole-4-yl) acetic acid hydrochloride to obtain a midbody I, i.e. 2-methoxyimino-2-(2-aminothiazole-4-yl) acetyl chloride hydrochloride; mixing silanized 7-aminoce-phalosporanic acid and silanized N-methylpyrrolidine, and reacting to obtain a midbody II, i.e. hydriodic acidification (6R, 7R)-7-amino-3-[(1-methyl-1-tetrahydro pyrrolidine) methyl]-3-cephem-4-formic betaine, in the presence of trimethyl idodine silicon hydride, isopropanol and an aqueous solution of hydrogen iodide; dissolving the midbody II into dichloromethane, sequentially adding trimethylchlorosilane and hexamethyldisilazane for reaction, and then adding the midbody I and triethylamine to react to prepare the cefepime hydrochloride. The cefepime hydrochloride prepared by the method has the advantages of uniform crystal form, good flowability and simple process and is suitable for industrialized production.
Description
Technical field
The present invention relates to the pharmaceutical chemistry technical field, be specifically related to a kind of preparation method of cefepime Hydrochloride.
Background technology
Cefepime Hydrochloride, commodity are called Maxipime, are developed by Bu Mai-Shi your company, go on the market in Switzerland in 1993; 1998, Shi Guibao company in Shanghai sold with its introduction and in China.The chemistry of cefepime Hydrochloride is by name: 1-[[(6R; 7R)-and 7-[2-(2-amino-4-thiazolyl)-glyoxylyl is amino]-2-carboxyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-3-yl] methyl]-1-methylpyrrole salt, 72-(Z)-(O-methyloxime) dihydrochloride monohydrate; Structural formula is:
Cefepime Hydrochloride be the 4th generation cephalosporin for injections, it is on third generation cephalosporin molecular structure basis, introduces the substituent compound of c-3 ' season ammonia in 7-amino-cephalosporanic acid (7-ACA) parent nucleus c-3 position.Have following characteristics with third generation cephalosporin comparison cefepime Hydrochloride: (1) wider antimicrobial spectrum promptly has stronger activity to gram-positive microorganism; (2) bacteriogenic β-Nei Xiananmei there are higher stability and lower inducibility, especially AmpC enzyme and the part that can decompose third-generation cephalosporin and produce high lethality rate are produced extended spectrum definite effect is arranged; (3) can penetrate the adventitia of gram negative bacillus and higher avidity is arranged quickly with multiple penicillin-binding protein.
In view of cefepime Hydrochloride antimicrobial spectrum and sterilizing power widely, preparation and the corresponding preparation method of studying its safety and stability have great importance.But; Adopt the synthetic cefepime Hydrochloride ubiquity crystal formation heterogeneity that obtains of prior art, mobile difference and the high defective of its related substances, severe reaction conditions, raw material are not easy to obtain in the existing simultaneously synthesizing cefepime hydrochloride, and complex process, yield is low, product purity is low; And solvent for use toxicity is big in the reaction; Can not recycle, environment is had pollution, cost is high.
A kind of compound method of antibiotic cefepime hydrochloride is disclosed among the one Chinese patent application CN200810022542.3; This method has been used strong acid and highly basic; Corrosive equipment; Thereby shorten the work-ing life of production unit, also can make and be mixed with particulate matter in the product, indexs such as the clarity that causes the cefepime Hydrochloride preparation and heavy metal do not meet Chinese Pharmacopoeia and stipulate.
Disclose the cefepime hydrochloride compound prepared of a kind of novel synthesis among the one Chinese patent application CN200910017763.6, with ainothiazoly loximate and formic acid reaction, generated 2-(2-formamido-thiazole-4-yl)-2-methoxy iminodiacetic acid earlier; Add 7-MPYCA and triethylamine again, with N, N-diisopropylethylamine and N; Dinethylformamide is a solvent; With the Tosyl chloride is catalyzer, and stirring reaction makes cefepime Hydrochloride.In this method with Tosyl chloride as catalyzer, influence the finished product yield and quality, the by product isomer that produces in the reaction process is not in addition removed, and causes related substance and the cephalo polymer content of the finished product high.
Therefore, be necessary to study the novel synthesis of the cefepime Hydrochloride of the simple and product crystal formation homogeneous of a kind of technology, good fluidity.
Summary of the invention
It is simple, quality controllable and be suitable for the preparation method of the cefepime Hydrochloride of suitability for industrialized production to the invention provides a kind of operation; Fundamentally avoided existing preparing method's reaction conditions temperature harsh; Complicated process of preparation; The cefepime Hydrochloride crystal formation heterogeneity of preparation, the phenomenon of mobile difference has improved the qualification rate of product greatly.
A kind of preparation method of cefepime Hydrochloride may further comprise the steps:
(1) oxalyl chloride is added dropwise in the organic solvent, gradation adds 2-methoxyimino-2-(thiazolamine-4-yl) acetic acid hydrochloride, obtains intermediate compound I through replacement(metathesis)reaction: 2-methoxyimino-2-(thiazolamine-4-yl) acetyl chloride hydrochloride;
(2) under nitrogen protection, the silylanization 7-amino-cephalosporanic acid is mixed with silylanization N-crassitude, stir, add Iodotrimethylsilane; Be warming up to 30 ℃～40 ℃, reacted 38～42 hours, obtain thick shape slurries, cool to 3 ℃～10 ℃; Add Virahol, continue that temperature is reduced by 1 ℃～2 ℃ and stirred 12 minutes～18 minutes, add aqueous solution of hydrogen iodide; Stir, crystallization cools to 0～5 ℃ of insulation 1～3 hour; Filter the gained solid through vacuum-drying, obtain intermediate II: hydroiodic acid HIization (6R, 7R)-7-amino-3-[(1-methyl isophthalic acid-tetrahydro pyrrolidine) methyl]-3-cephem-4-formic acid betaine;
(3) intermediate II is dissolved in methylene dichloride, adds the reaction of trimethylchlorosilane and hexamethyldisilazane successively, get reaction solution, add the reaction of intermediate compound I and triethylamine again and make cefepime Hydrochloride.
In order to reach effect better, preferably:
In the step (1), described organic solvent is N, one or both in dinethylformamide (DMF), the methylene dichloride.
The process control temp that oxalyl chloride is added dropwise in the organic solvent is 5 ℃～6 ℃, can prevent that oxalyl chloride from decomposing, and guarantees that oxalyl chloride can fully react with 2-(thiazolamine-4-yl)-2-methoxyimino acetic acid hydrochloride.
Described conditions of replacement reaction is: stirred 10 minutes～20 minutes, and be cooled to-20 ℃～-30 ℃ reactions 2 hours～4 hours; Further be preferably and stirred 10 minutes, be cooled to-25 ℃ of reactions 2.5 hours.Replacement(metathesis)reaction can be carried out in the environment of a gentleness like this, and reaction is complete more and by product reaction is less, obtains the higher ultimate aim product of purity.
In order further to improve the purity of title product cefepime Hydrochloride; In the step (1); Described replacement(metathesis)reaction finishes after product and uses washed with dichloromethane ,-30 ℃～-20 ℃ vacuum-dryings, obtains intermediate compound I: 2-methoxyimino-2-(thiazolamine-4-yl) acetyl chloride hydrochloride.
In the step (2), the mass percentage concentration of described aqueous solution of hydrogen iodide is 50%～60%.
Described silylanization 7-amino-cephalosporanic acid prepares according to the preparation method of existing silylanization 7-amino-cephalosporanic acid; Be generally: 7-amino-cephalosporanic acid (being called for short 7-ACA) and anhydrous cyclohexane are added in the reaction flask; Controlled temperature is at 20 ℃～25 ℃; Add hexamethyldisilazane and trimethylammonium iodo solution of silane and be controlled at 55 ℃ of backflows 12 hours, obtain the silylanization 7-ACA of pulpous state, it is subsequent use to lower the temperature.
Described silylanization N-crassitude prepares according to the preparation method of existing silylanization N-crassitude; Be generally: N-methyltetrahydro pyrroles (being the N-crassitude) and hexanaphthene are added in the reaction flask; Controlled temperature adds trimethylammonium iodo silane for 15 ℃～20 ℃; Stirred 10 minutes, and made silylanization N-crassitude.
Step specifically comprises in (3): intermediate II is dissolved in methylene dichloride, adds the reaction of trimethylchlorosilane and hexamethyldisilazane successively, get reaction solution, this reaction solution is warming up to 25 ℃～30 ℃; Insulation reaction 70 minutes～100 minutes is cooled to-40 ℃～-20 ℃ again, adds the reaction of intermediate compound I and triethylamine successively; Obtain slurries, the slurries of gained were stirred 40 minutes～50 minutes at-20 ℃～25 ℃, solid is dissolved in water; Refilter and remove insolubles, the layering of will filtrating is incorporated water layer into washing lotion behind the washing organic layer; Through activated carbon decolorizing, filtration, add hydrochloric acid and acetone in the gained filtrating, stirred 45 minutes～75 minutes down in 18 ℃～28 ℃; Cool to 0 ℃ afterwards, filter, with obtaining cefepime Hydrochloride in 35 ℃～45 ℃ dryings behind the washing with acetone; Further to remove by product and the Δ-isomer in the dereaction, guarantee that the purity of final product is up to specification.
In the step (3), described stirring velocity is 200 rev/mins～2000 rev/mins, further is preferably 230 rev/mins～260 rev/mins, can further make the products obtained therefrom crystal formation even, and good fluidity is beneficial to the preparation of follow-up cefepime Hydrochloride preparation.
The operation of step (1) and step (3) is preferably under the protection of nitrogen gas to be carried out.
The reaction equation of compound method of the present invention is following:
1, the replacement(metathesis)reaction in the step (1):
2, the reaction in the step (2):
The preparation of silylanization 7-ACA:
The preparation of silylanization N-crassitude:
The intermediate II hydroiodic acid HIization (6R, 7R)-preparation of 7-amino-3-[(1-methyl isophthalic acid-tetrahydro pyrrolidine) methyl]-3-cephem-4-formic acid betaine:
3, the reaction in the step (3):
The not strict qualification of the consumption of reaction raw materials is generally measured than reacting according to chemical reaction among the present invention, also can excessively react.
The not strict qualification of reaction solvent, catalyst consumption among the present invention can be adjusted according to the consumption of reaction raw materials: more increase reaction solvent of reaction raw materials and catalyst consumption, less minimizing reaction solvent of reaction raw materials and catalyst consumption.
The usage and dosage of cefepime Hydrochloride of the present invention:
These article can be used for intravenous drip or deep part muscle (like musculus lateralis externi or stern muscle group) injection, are generally the course of treatment 7～10 days, and severe infections can prolong the course of treatment.
Intravenous drip:, be dissolved in 50～100ml sterilized water for injection with these article 1～2g; Or mass percentage concentration is 0.9% sodium chloride injection; Or mass percentage concentration is 5% glucose injection; Or mass percentage concentration is that 5% glucose and mass percentage concentration are 0.9% sodium chloride injection; Or in the Lactated Ringer'S Solution (Lactated Ringer ' s solution), finish being no less than in 30 minutes to instil.
Intramuscular injection: every 0.5g cefepime Hydrochloride is with the dissolving of 1.5ml sterilized water for injection, and use at once after preparation.Cefepime Hydrochloride can use with other microbiotic or other drug simultaneously, but can not mix in same syringe or infusion bottle.
The same with other cephalosporins medicines, the color of cefepime Hydrochloride solution can change along with the shelf time to some extent, and this characteristic does not influence the effect or the tolerance of medicine.
Grownup and child patient more than 12 years old: when intravenous infusion or intramuscular injection, recommended dose is per 12 hours 1g.Dosage can increase to per 12 hours instillation 2g, can per 8 hours instillation 2g when being in a bad way or life-threatening infection is arranged.For urinary tract infections, recommended dose is intravenous drip in per 12 hours or intramuscular injection 500mg.
Child patient that renal function is normal 1 month to 12 years old and bacterial meningitis patient: more than 2 months, body weight is less than 40 kilograms patient, and recommended dose is: per 8 hours 50mg/kg, be 7～10 days the course of treatment.
Use the experience of cefepime Hydrochloride limited for the children below 2 months, can use the dosage of 50mg/kg.Yet, use the pharmacokinetic data of this medicine to show patient more than 2 months, per 8 hours or the dosage that gave 30mg/kg in 12 hours are considered to for the pediatric patients in 1 to February of birth back enough.Should be careful when using these article for these patients.
For the pediatric patients of body weight, can use adult's dosage greater than 40 kilograms.For more than 12 years old but body weight is less than 40 kilograms patient, the consumption that is less than 40 kilograms according to 12 years old following body weight uses.
Children use the intramuscular injection experience limited.
Compared with prior art, the present invention has following advantage:
The crystal formation homogeneous of cefepime Hydrochloride of the present invention, good fluidity, purity height and its related substances are low; In addition, residual organic solvent content is low in the cefepime Hydrochloride of the present invention, is lower than significantly all that " two ones of Chinese pharmacopoeia versions in 2005 are to the limited amount in the regulation of residual solvent.
Each step reaction starting material is easy to get among the preparation method of the present invention, and reaction conditions is gentle, and yield height and product purity are high, and operating procedure is simple, and cost is low, and production need not any specific installation, is fit to suitability for industrialized production.
Embodiment
Embodiment 1
Intermediate compound I: the preparation of 2-methoxyimino-2-(thiazolamine-4-yl) acetyl chloride hydrochloride: in reaction flask, add DMF (8.76L, 113mol) and methylene dichloride (375L), controlled temperature is 5 ℃; (9.64L 111mol), stirred 10 minutes to drip oxalyl chloride; Cool to-25 ℃, under the nitrogen protection in 11 minutes, gradation adds 2-methoxyimino-2-(thiazolamine-4-yl) acetic acid hydrochloride (25kg; 104mol); Stirring reaction is 2.5 hours under this temperature, under nitrogen atmosphere, filter, the gained solid with the 80L washed with dichloromethane after-25 ℃ of vacuum-dryings (through P
2O
5), obtain light yellow solid 23.48kg (90mol), in the quality of 2-methoxyimino-2-(thiazolamine-4-yl) acetic acid hydrochloride, the yield of light yellow solid is 93.92%.
Embodiment 2
Intermediate II: hydroiodic acid HIization (6R, 7R)-preparation of 7-amino-3-[(1-methyl isophthalic acid-tetrahydro pyrrolidine) methyl]-3-cephem-4-formic acid betaine:
(1) preparation of silylanization 7-ACA slurries: in reaction flask, add 7-ACA (20.0kg, 73.5mol) with anhydrous cyclohexane 140L, controlled temperature adds hexamethyldisilazane (18.6L at 25 ℃; 88.0mol) and trimethylammonium iodo silane (0.4L; 2.8mol) solution, refluxed 12 hours at 55 ℃, obtain (19.92kg; 73.21mol) the silylanization 7-ACA of pulpous state, it is subsequent use to lower the temperature.
(2) preparation of silylanization N-methyl tetrahydro pyrrolidine slurries: in reaction flask, add N-methyltetrahydro pyrroles (10.68L; 102.7mol) and hexanaphthene 40L; (14.6L 102.7mol), stirred 10 minutes 20 ℃ of addings of controlled temperature trimethylammonium iodo silane; Make (10.12L, silylanization N-methyl tetrahydro pyrrolidine 97.31mol).
(3) preparation of intermediate II: under nitrogen protection, above-mentioned silylanization 7-ACA slurries and silylanization N-methyl tetrahydro pyrrolidine slurries are mixed, stirred adding Iodotrimethylsilane (4.2L 30 minutes in 20 ℃; 29.5mol), be warmed up to 37 ℃, reacted 40 hours, obtain thick shape slurries; Cool to 5 ℃, add the Virahol of 10L, continue to be cooled to 4 ℃ and stirred 15 minutes; Adding 20L mass percentage concentration is 57% aqueous solution of hydrogen iodide, and temperature is controlled at 20 ℃, stirs 15 minutes.Tell organic phase, with 10L water washing organic phase, washing water add zeyssatite 3kg after incorporating water into; 20 ℃ are stirred 5 minutes adding 4kg gacs and decoloured filtration, gained filtrating 25 ℃ of stirrings in 30 minutes; Use the 40L water washing, add 500L isopropanol precipitation and crystallization, cool to 0 ℃; Be incubated 1 hour, filter, with 80L isopropanol water solution (volume ratio of Virahol and water is 4: 1) and 80L washed with isopropyl alcohol; Vacuum-drying (45 ℃) gets solid 18.82kg, and in the quality of 7-ACA, product yield is 94.10%.
Embodiment 3
The preparation of cefepime Hydrochloride: under the atmosphere of 20 ℃ of nitrogen; In stirring down; With intermediate II hydroiodic acid HIization (6R; 7R)-(18.82kg 42.38mol) is dissolved in the 300L methylene dichloride 7-amino-3-[(1-methyl isophthalic acid-tetrahydro pyrrolidine) methyl]-3-cephem-4-formic acid betaine, adds trimethylchlorosilane 5.8L successively and hexamethyldisilazane 5.8L obtains reaction solution.This reaction solution is warmed up to 25 ℃ and be incubated 1.5 hours gradually, cools to-40 ℃ then, in-40～-20 ℃; In 40 minutes; Adding intermediate compound I 2-methoxyimino-2-(thiazolamine-4-yl) acetyl chloride hydrochloride 23.48kg and triethylamine 22.9L successively, is 10 ℃ with the gained slurries in temperature, stirs 45 minutes under the stirring velocity of 246r/min; Within 10 minutes, add entry 70L afterwards; Under the stirring velocity of room temperature 246.5r/min, stirred 1 hour, dissolved solids removes by filter insolubles.The filtrating layering is with incorporating water layer into behind the 15L water washing organic layer, through twice activated carbon decolorizing; Filter, in filtrating, add aqueous hydrochloric acid and the acetone 480L of 31L, 10mol/L, under the stirring velocity of room temperature 246.5r/min, stirred 1 hour; Cool to 0 ℃ afterwards, filter, with the washing with acetone of 100L; In 40 ℃ of dryings, obtain product 18.32kg, fusing point is 187～191 ℃.In the quality of intermediate II, product yield is 97.34%.
Said product is carried out ultimate analysis, by percentage to the quality:
Theoretical value: C:39.9%, H:4.9%, O:16.8%, Cl:12.5%, N:14.7%, S:11.2%;
Measured value: C:39.6%, H:4.8%, O:17.3%, Cl:12.3%, N:14.6%, S:11.4%;
Confirm that through ultimate analysis and DTA said product is a cefepime Hydrochloride, and contain 2 molecule hydrochloric acid and 1 molecular crystal water in a part cefepime Hydrochloride.
Embodiment 4
Making with extra care of cefepime Hydrochloride
Embodiment 3 gained cefepime Hydrochloride 21.81kg are dropped in the reaction kettle, add 31.6L water stirring and dissolving and cooling, drop to 10 ℃ after the dissolving; Insulation also drips 252.8L acetone in solution; Dripped off the continued insulated and stirred 3 hours, and separated out a large amount of solids, suction filtration is also with 50L washing with acetone filter cake.The gained filter cake is got the cefepime Hydrochloride elaboration in 25 ℃ of following dryings of vacuum after 24 hours, be weighed as 19.96kg, yield 91.52%, 188～190 ℃ of fusing points.
Embodiment 5
Intermediate compound I: the preparation of 2-methoxyimino-2-(thiazolamine-4-yl) acetyl chloride hydrochloride: in reaction flask, add DMF (8.76L, 113mol) and methylene dichloride (375L), controlled temperature is 5.5 ℃; (9.64L 111mol), stirred 15 minutes to drip oxalyl chloride; Cool to-20 ℃, under the nitrogen protection in 11 minutes, gradation adds 2-methoxyimino-2-(thiazolamine-4-yl) acetic acid hydrochloride (25kg; 104mol); Stirring reaction is 2 hours under this temperature, under nitrogen atmosphere, filter, the gained solid with the 80L washed with dichloromethane after-20 ℃ of vacuum-dryings (through P
2O
5), obtain light yellow solid 23.24kg, in the quality of 2-methoxyimino-2-(thiazolamine-4-yl) acetic acid hydrochloride, the yield of light yellow solid is 92.96%.
The preparation of silylanization 7-ACA slurries and silylanization N-methyl tetrahydro pyrrolidine slurries is with embodiment 2.
Intermediate II: hydroiodic acid HIization (6R; 7R)-and the preparation of 7-amino-3-[(1-methyl isophthalic acid-tetrahydro pyrrolidine) methyl]-3-cephem-4-formic acid betaine: except adopting mass percentage concentration is 50% aqueous solution of hydrogen iodide; All the other are with embodiment 2 steps (3); Obtain intermediate II solid 18.76kg, in the quality of 7-ACA, product yield is 93.80%.
The preparation of cefepime Hydrochloride: under the atmosphere of 20 ℃ of nitrogen; In stirring down; With intermediate II hydroiodic acid HIization (6R; 7R)-and 7-amino-3-[(1-methyl isophthalic acid-tetrahydro pyrrolidine) methyl]-3-cephem-4-formic acid betaine 18.76kg, be dissolved in the 300L methylene dichloride, add trimethylchlorosilane 5.8L successively and hexamethyldisilazane 5.8L obtains reaction solution.This reaction solution is warmed up to 30 ℃ and be incubated 70 minutes gradually, cools to-30 ℃ then, in-30～-20 ℃; In 40 minutes; Adding intermediate compound I 2-methoxyimino-2-(thiazolamine-4-yl) acetyl chloride hydrochloride 23.24kg and triethylamine 22.9L successively, is 10 ℃ with the gained slurries in temperature, stirs 45 minutes under the stirring velocity of 246r/min; Within 10 minutes, add entry 70L afterwards; Under the stirring velocity of room temperature 250r/min, stirred 1 hour, dissolved solids removes by filter insolubles.The filtrating layering is with incorporating water layer into behind the 15L water washing organic layer, through twice activated carbon decolorizing; Filter, in filtrating, add aqueous hydrochloric acid and the acetone 480L of 31L, 10mol/L, under the stirring velocity of room temperature 246r/min, stirred 1 hour; Cool to 0 ℃ afterwards, filter, with the washing with acetone of 100L; In 40 ℃ of dryings, obtain product 18.02kg, fusing point is 188～189 ℃.In the quality of intermediate II, product yield is 96.05%.
Said product is carried out ultimate analysis, by percentage to the quality:
Theoretical value: C:39.9%, H:4.9%, O:16.8%, Cl:12.5%, N:14.7%, S:11.2%;
Measured value: C:39.8%, H:4.8%, O:17.3%, Cl:12.3%, N:14.5%, S:11.3%;
Confirm that through ultimate analysis and DTA said product is a cefepime Hydrochloride, and contain 2 molecule hydrochloric acid and 1 molecular crystal water in a part cefepime Hydrochloride.
Making with extra care of cefepime Hydrochloride: above-mentioned cefepime Hydrochloride 18.02kg is refining according to the process for purification among the embodiment 4, make cefepime Hydrochloride highly finished product 17.06g, yield 94.69%, 188.5～189 ℃ of fusing points.
Embodiment 6
Intermediate compound I: the preparation of 2-methoxyimino-2-(thiazolamine-4-yl) acetyl chloride hydrochloride: in reaction flask, add DMF (8.76L, 113mol) and methylene dichloride (375L), controlled temperature is 6 ℃; (9.64L 111mol), stirred 20 minutes to drip oxalyl chloride; Cool to-30 ℃, under the nitrogen protection in 11 minutes, gradation adds 2-methoxyimino-2-(thiazolamine-4-yl) acetic acid hydrochloride (25kg; 104mol); Stirring reaction is 4 hours under this temperature, under nitrogen atmosphere, filter, the gained solid with the 80L washed with dichloromethane after-20 ℃ of vacuum-dryings (through P
2O
5), obtain light yellow solid 23.10kg, in the quality of 2-methoxyimino-2-(thiazolamine-4-yl) acetic acid hydrochloride, the yield of light yellow solid is 92.40%.
The preparation of silylanization 7-ACA slurries and silylanization N-methyl tetrahydro pyrrolidine slurries is with embodiment 2.
Intermediate II: hydroiodic acid HIization (6R; 7R)-and the preparation of 7-amino-3-[(1-methyl isophthalic acid-tetrahydro pyrrolidine) methyl]-3-cephem-4-formic acid betaine: except adopting mass percentage concentration is 60% aqueous solution of hydrogen iodide; All the other are with embodiment 2 steps (3); Obtain intermediate II solid 18.70kg, in the quality of 7-ACA, product yield is 93.50%.
The preparation of cefepime Hydrochloride: under the atmosphere of 20 ℃ of nitrogen; In stirring down; With intermediate II hydroiodic acid HIization (6R; 7R)-and 7-amino-3-[(1-methyl isophthalic acid-tetrahydro pyrrolidine) methyl]-3-cephem-4-formic acid betaine 18.70kg, be dissolved in the 360L methylene dichloride, add trimethylchlorosilane 5.8L successively and hexamethyldisilazane 5.8L obtains reaction solution.This reaction solution is warmed up to 30 ℃ and be incubated 100 minutes gradually, cools to-20 ℃ then, in-20 ℃; In 40 minutes, add intermediate compound I 2-methoxyimino-2-(thiazolamine-4-yl) acetyl chloride hydrochloride 23.10kg and triethylamine 22.9L successively, be 10 ℃ with the gained slurries in temperature; Stirred 45 minutes under the stirring velocity of 280r/min, within 10 minutes, add entry 70L afterwards, under the stirring velocity of room temperature 280r/min, stirred 1 hour; Dissolved solids removes by filter insolubles.The filtrating layering is with incorporating water layer into behind the 15L water washing organic layer, through twice activated carbon decolorizing; Filter, in filtrating, add aqueous hydrochloric acid and the acetone 480L of 31L, 10mol/L, under the stirring velocity of room temperature 280r/min, stirred 1 hour; Cool to 0 ℃ afterwards, filter, with the washing with acetone of 100L; In 40 ℃ of dryings, obtain product 17.96kg, fusing point is 189～189.5 ℃.In the quality of intermediate II, product yield is 96.04%.
Said product is carried out ultimate analysis, by percentage to the quality:
Theoretical value: C:39.9%, H:4.9%, O:16.8%, Cl:12.5%, N:14.7%, S:11.2%;
Measured value: C:39.7%, H:4.7%, O:17.4%, Cl:12.4%, N:14.8%, S:11.0%;
Confirm that through ultimate analysis and DTA said product is a cefepime Hydrochloride, and a part cefepime Hydrochloride contains 2 molecule hydrochloric acid and 1 molecular crystal water.
Making with extra care of cefepime Hydrochloride: above-mentioned cefepime Hydrochloride 17.96kg is refining according to the process for purification among the embodiment 4, make cefepime Hydrochloride highly finished product 17.02g, yield 94.80%, 188～189 ℃ of fusing points.
The cefepime Hydrochloride highly finished product of embodiment 4,5 and 6 preparations, through detecting, nuclear magnetic data is following:
LC-MS?m/z：481[MH
+]；
1H-NMR(DMSO)：2.09(m，4H)，2.97(s，3H)，3.46～3.64(m，4H)，3.94(s，3H)，4.108，3.71(dd，2H)，4.61，4.41(dd，2H)，5.38(d，1H)，5.88(dd，1H)，6.93(s，1H)，9.20(brs，4H)，9.89(d，1H).
13C-NMR(DMSO)：21.13，28.60，47.23，58.37，59.03，62.89，63.04，64.18，63.65，110.40，113.43，132.50，132.79，144.74，160.86，162.93，163.24，170.00。
Show that the inventive method successfully synthesizes cefepime Hydrochloride.
Comparative Examples 1
7-MPCA's is synthetic:
In flask, add 40g (0.14mol) 7-amino-cephalosporanic acid (7-ACA), 27.4g (0.17mol) hexamethyldisilane, methylene dichloride 240ml, 35 ℃ were stirred 6 hours down.Be cooled to-10 ℃ then, add N, N-Diethyl Aniline 27ml drips Iodotrimethylsilane 61.2g (0.3mol) then, stirring reaction 1.5 hours.Then, drip 20.4g (0.24mol) N-crassitude, after dropwising, insulation reaction 1 hour rises to room temperature reaction then naturally and spends the night.After reaction finishes, drip the mixed solution of Virahol 50ml, concentrated hydrochloric acid 160ml and deionized water 300ml, the control feed temperature is no more than 15 ℃ in the dropping process, under this temperature, fully stirs to dissolve fully to solid in 10 minutes.Separatory then, organic phase merges water with the extraction of 300ml deionized water.Stir down, add 650ml acetone fast, produce a large amount of crystal, stir after 5 hours, filter.Filter cake is used washing with acetone again with acetone/deionized water (volume ratio is 10/1) 150ml washing, obtains 7-MPCA39g after the drying, yield 73%.
The product ultimate analysis (mass percent, %): theoretical value %:C42.22; H6.54; N11.36; Measured value %:C42.23; H6.51; N1.38.
The preparation of cefepime Hydrochloride:
In flask, add deionized water 550ml, DMF250ml, add 7-MPCA39g and AE active ester 80g, be chilled to-5 ℃ then, drip triethylamine 37ml, in the dropping process, temperature is no more than 0 ℃.After dropwising, continue to stir 1 hour.Heat up then 20 ℃ and reacted 6 hours, reaction solution is with 600ml dichloromethane extraction three times.Organic phase is used the back extraction of 300ml deionized water again, merges water, and water is used activated carbon decolorizing.
Water adds the hydrochloric acid 40.6ml of 6mol/l then with the quick post filter of aluminium sesquioxide post, at room temperature stirs 1 hour, adds acetone 2.5L then, stirs after 4 hours, filters, and filter cake is used washing with acetone, and oven dry obtains cefepime Hydrochloride 52.6g, yield 84%.The product ultimate analysis (mass percent, %): theoretical value %:C38.71; H5.13; N14.26; Measured value %:C38.73; H5.14; N14.24.
(application number: the cefepime Hydrochloride that 200810022542.3) makes carries out stability test for cefepime Hydrochloride that the present invention is made and Comparative Examples 1; Adopt the method for accelerated test that it is carried out study on the stability; 25 ℃ of temperature; Relative humidity 60% condition is quickened to place 6 months, and the result sees table 1.
Table 1
| Sample | Content after January | Content after February | Content after March | Content after June |
| Embodiment 4 | 95.9％ | 95.16％ | 95.02％ | 94.80％ |
| Embodiment 5 | 94.86％ | 94.66％ | 94.48％ | 94.36％ |
| Embodiment 6 | 94.02％ | 93.88％ | 93.72％ | 93.56％ |
| Comparative Examples 1 | 92.60％ | 91.86％ | 91.68％ | 90.46％ |
It is thus clear that the stability of the cefepime Hydrochloride of the inventive method preparation is superior to prior art (application number: the 200810022542.3) cefepime Hydrochloride of preparation.
The cefepime Hydrochloride prepared to the present invention carries out quality examination; Concrete detection method is all according to second one of Pharmacopoeia of the People's Republic of China version in 2005; The wherein detection method of granularity reference " second appendix IN of Chinese pharmacopoeia version in 2005, the result sees table 2:
Table 2
Can know that by above result cefepime Hydrochloride of the present invention obviously is superior to prior art (application number: 200810022542.3).
Mobile investigate (mensuration at slope of repose)
Foundation: measure the slope of repose to investigate the flowability of product with the fixed funnel method.
Method: funnel is fixed on the plotting paper of horizontal positioned, carefully with the foregoing description 4, embodiment 5, and embodiment 6 makes product and pours in the funnel, measure three times, and the result sees table 3, table 4, table 5.The cone height that forms with product is H, and the radius of cone bottom is r, then tan α=H/r (α is the slope of repose); The slope of repose is more little, and then the product flowability is good more.
The result is measured at the cefepime Hydrochloride slope of repose of table 3 embodiment 4 preparations
The result is measured at the cefepime Hydrochloride slope of repose of table 4 embodiment 5 preparations
The result is measured at the cefepime Hydrochloride slope of repose of table 5 embodiment 6 preparations
Conclusion; Cefepime Hydrochloride of the present invention slope of repose is less; Be significantly less than Comparative Examples 1 (application number: slope of repose (38.63 °) 200810022542.3), explain the present invention control product after stirring velocity and the churning time mobile better, be easy to the operation of follow-up work.
Claims (10)
1. the preparation method of a cefepime Hydrochloride may further comprise the steps:
(1) oxalyl chloride is added dropwise in the organic solvent, gradation adds 2-methoxyimino-2-(thiazolamine-4-yl) acetic acid hydrochloride, obtains intermediate compound I through replacement(metathesis)reaction: 2-methoxyimino-2-(thiazolamine-4-yl) acetyl chloride hydrochloride;
(2) under nitrogen protection, the silylanization 7-amino-cephalosporanic acid is mixed with silylanization N-crassitude, stir, add Iodotrimethylsilane; Be warming up to 30 ℃～40 ℃, reacted 38～42 hours, obtain thick shape slurries, cool to 3 ℃～10 ℃; Add Virahol, continue that temperature is reduced by 1 ℃～2 ℃ and stirred 12 minutes～18 minutes, add aqueous solution of hydrogen iodide; Stir, crystallization cools to 0～5 ℃ of insulation 1～3 hour; Filter the gained solid through vacuum-drying, obtain intermediate II: hydroiodic acid HIization (6R, 7R)-7-amino-3-[(1-methyl isophthalic acid-tetrahydro pyrrolidine) methyl]-3-cephem-4-formic acid betaine;
(3) intermediate II is dissolved in methylene dichloride, adds the reaction of trimethylchlorosilane and hexamethyldisilazane successively, get reaction solution, add the reaction of intermediate compound I and triethylamine again and make cefepime Hydrochloride;
The structural formula of described silylanization 7-amino-cephalosporanic acid is:
The structural formula of described silylanization N-crassitude is:
2. the preparation method of cefepime Hydrochloride as claimed in claim 1 is characterized in that, in the step (1), described organic solvent is N, one or both in dinethylformamide, the methylene dichloride.
3. the preparation method of cefepime Hydrochloride as claimed in claim 1 is characterized in that, in the step (1), the process control temp that oxalyl chloride is added dropwise in the organic solvent is 5 ℃～6 ℃.
4. the preparation method of cefepime Hydrochloride as claimed in claim 1 is characterized in that, in the step (1), described conditions of replacement reaction is: stirred 10 minutes～20 minutes, and be cooled to-20 ℃～-30 ℃ reactions 2 hours～4 hours.
5. the preparation method of cefepime Hydrochloride as claimed in claim 4 is characterized in that, described conditions of replacement reaction is: stirred 10 minutes, and be cooled to-25 ℃ of reactions 2.5 hours.
6. the preparation method of cefepime Hydrochloride as claimed in claim 1; It is characterized in that; In the step (1); Described replacement(metathesis)reaction finishes after product and uses washed with dichloromethane ,-30 ℃～-20 ℃ vacuum-dryings, obtains intermediate compound I: 2-methoxyimino-2-(thiazolamine-4-yl) acetyl chloride hydrochloride.
7. the preparation method of cefepime Hydrochloride as claimed in claim 1 is characterized in that, in the step (2), the mass percentage concentration of described aqueous solution of hydrogen iodide is 50%～60%.
8. the preparation method of cefepime Hydrochloride as claimed in claim 1 is characterized in that, step specifically comprises in (3): intermediate II is dissolved in methylene dichloride; Add the reaction of trimethylchlorosilane and hexamethyldisilazane successively, get reaction solution, this reaction solution is warming up to 25 ℃～30 ℃; Insulation reaction 70 minutes～100 minutes is cooled to-40 ℃～-20 ℃ again, adds the reaction of intermediate compound I and triethylamine successively; Obtain slurries, the slurries of gained were stirred 40 minutes～50 minutes at-20 ℃～25 ℃, solid is dissolved in water; Refilter and remove insolubles, the layering of will filtrating is incorporated water layer into washing lotion behind the washing organic layer; Through activated carbon decolorizing, filtration, add hydrochloric acid and acetone in the gained filtrating, stirred 45 minutes～75 minutes down in 18 ℃～28 ℃; Cool to 0 ℃ afterwards, filter, with obtaining cefepime Hydrochloride in 35 ℃～45 ℃ dryings behind the washing with acetone.
9. the preparation method of cefepime Hydrochloride as claimed in claim 8 is characterized in that, in the step (3), described stirring velocity is 200 rev/mins～2000 rev/mins.
10. the preparation method of cefepime Hydrochloride as claimed in claim 9 is characterized in that, described stirring velocity is 230 rev/mins～260 rev/mins.
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| CN102675345A (en) * | 2012-06-01 | 2012-09-19 | 苏州中联化学制药有限公司 | Method for preparing cefepime hydrochloride |
| CN103665003A (en) * | 2013-11-28 | 2014-03-26 | 山东鑫泉医药有限公司 | Refining method of high-purity cefepime dihydrochloride monohydrate |
| CN103804396B (en) * | 2013-12-20 | 2016-01-27 | 悦康药业集团有限公司 | A kind of cefepime hydrochloride compound prepared |
| CN104327098B (en) * | 2014-10-21 | 2016-01-20 | 鲁南制药集团股份有限公司 | A kind of cefetamet diisopropylamine |
| CN105061470A (en) * | 2015-08-18 | 2015-11-18 | 齐鲁安替（临邑）制药有限公司 | One-pot synthesis method of cefotaxime acid |
| CN107201391B (en) * | 2017-07-04 | 2020-07-07 | 吉林省爱诺德生物工程有限公司 | Synthesis method of cefepime hydrochloride |
| CN108285436B (en) * | 2018-03-16 | 2020-10-16 | 河北合佳医药科技集团股份有限公司 | Preparation process of AE-active ester |
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| WO2004092183A2 (en) * | 2003-04-16 | 2004-10-28 | Sandoz Ag | Processes for the preparations of cefepime |
| CN101337971A (en) * | 2008-08-15 | 2009-01-07 | 苏州万庆药业有限公司 | Method for synthesizing antibiotic cefepime hydrochloride |
| CN101638412A (en) * | 2009-08-28 | 2010-02-03 | 海南永田药物研究院有限公司 | Cefepime hydrochloride compound prepared by new synthetic method |
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| WO2004092183A2 (en) * | 2003-04-16 | 2004-10-28 | Sandoz Ag | Processes for the preparations of cefepime |
| CN101337971A (en) * | 2008-08-15 | 2009-01-07 | 苏州万庆药业有限公司 | Method for synthesizing antibiotic cefepime hydrochloride |
| CN101638412A (en) * | 2009-08-28 | 2010-02-03 | 海南永田药物研究院有限公司 | Cefepime hydrochloride compound prepared by new synthetic method |
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