CN101941982B - Novel preparation method of pharmaceutical ceforanide - Google Patents

Abstract

The invention aims to provide a novel preparation method of a known antibiotic-ceforanide, which is characterized by subjecting 7-amino-cephalosporanic acid (7-ACA) and 1-hydroxymethyl-5-thiol-tetrazole (MTAA) to react with an organic solvent of boron trifluoride in an organic solvent to prepare an important intermediate (6R, 7R)-3-(((1-carboxymethyl-1-H-tetrazole-5-group)sulfur)methyl)-7-amino-8-oxo-5-thia/azabicyclic (4,2,0)oct-2-ene-2-formic acid (3-MTAA-7-ACA) through after treatment, then protecting primary amine in 2-aminomethyl-phenylacetic acid (2-AMPA) by an ester reagent in an organic solvent, salifying the 2-AMPA with inorganic alkali to form alkali metal salt in ethanol, namely forming the alkali metal salt of derivatives with unsaturated ethylenic bonds and condensing the important intermediate and the alkali metal salt to form the ceforanide through certain treatment, thus changing the situation that the drug is produced by the foreign companies in a monopolistic manner at present.

Description

The novel preparation method of medicinal ceforanide

Technical field

Ceforanide is known microbiotic, the invention belongs to the preparation field of ceforanide, and the preparation method that security is higher and yield is high of a kind of difference and synthetic ceforanide in the past is provided.

Background technology

Since cephalo thiophene (Cephalothion) in 1964 appearance; Cephalosporins medicine obtains flourish; Even to this day existing nearly 60 kinds of worldwide production and sales of medicine; Directly treating most of bacterial infection patients, as s-generation injection cephalosporin microbiotic class medicine------ceforanide (Ceforanide: molecular formula C ₂₀H ₂₁N ₇O ₆S ₂Molecular weight 519.56; CAS registration number [60925-61-3]) and with ceforanide is main, and medicinal be that the ceforanide for inj (Ceforanide for Injection different name Radacef trade(brand)name Precef, code name BL-S786) of solubility promoter is that U.S. Bristol-Myers Squibb Co. (Bristol-Myers Squibb is called for short BMS) researches and develops with L-Methionin (L-Lysine); In 1984 in U.S.'s list marketing, afterwards in the list marketing in succession of the multinational family of American-European state.

Use the semi-synthetic cephalosporins Broad spectrum antibiotics as the non-enteron aisle of the s-generation; Its fungicidal activity is to the biosynthetic restraining effect of bacterial cell wall by it; The stability that some β-Nei Xiananmeis are had and producing; By antibiotic and even germicidal action, and this veriety is treatment by one of effective kind of the caused infection of these article sensitive strain of Gram-negative and positive bacteria to Gram-negative bacteria and gram-positive microorganism.

What particularly point out is: ceforanide is to by the responsive G of these article ^-And G ⁺The caused bone of bacterial strain, sacroiliitis, infection such as intimitis are the drug of first choice usefulness in the cephalosporins medicine, are lower respiratory infection, urinary system infection, septicemia, skin and soft tissue infection to the respiratory tract infection special envoy in addition, and good therapeutic action is arranged.

As before the operation, during, afterwards preventive measures, using these article also is the effective ways of the danger of minimizing postoperative infection.

Ceforanide is mainly used in the infection of Gram-negative bacteria as microbiotic commonly used of a kind of modern times.The product patent of this medical compounds exists for many years abroad, occupies unshakable patent status always.

Summary of the invention

Problems such as ceforanide is known microbiotic, and its product and preparation method all have patent documentation open abroad, and still disclosed preparation method exists the cost height in the above-mentioned document, and security is not enough, and yield is unsatisfactory.

The object of the invention aims to provide the preparation method of a kind of difference and synthetic ceforanide in the past; Higher and the yield increase of its security, this method has been avoided the hidden danger in the process of industrialization scale operation ceforanide in the prior art, and the yield of this product is significantly improved; And preparing method's of the present invention mild condition; Adopt the mixing acid alkaline process, it is few that the three wastes are produced, also less for environmental pollution.

The present invention relates to ceforanide (6R, 7R)-3-[[[1-(ethyloic)-1H-tetrazolium-5-yl] sulphur] methyl-7-[[[2-(aminomethyl-phenyl] ethanoyl] amino]-8-oxo-5-sulfo--1-azabicyclo [4.2.0] oct-2-ene-formic acid preparation new improve one's methods and with the preparation of L-Methionin aseptic mixture.Reaction among the preparation method of the present invention be two the step condensations, reaction temperature with, need not to be easy to the danger of blast, be easy to realize suitability for industrialized production.

Ceforanide (is called for short: CRD-H)

The method for preparing ceforanide of the present invention comprises the steps:

1. ceforanide is rough

A) by 7-amino-Cephalosporanic acid (7-ACA) and 1-ethyloic 5-sulfydryl-tetrazole (MTAA) in organic solvent; Organic solvent reaction with boron trifluoride; Through aftertreatment make important intermediate (6R, 7R)-3-[[[1-(ethyloic)-1H-tetrazolium-5-yl] sulphur] methyl]-7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid (3-MTAA-7ACA)

Annotate: 7-amino-cephalosporanic acid promptly; 7-amino-3-acetyl-o-methyl-8-oxo 5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid

Above-mentioned a) middle indication organic solvent is ether, acetonitrile, acetone etc.;

Above-mentioned a) described in aftertreatment for adding water, at 0-30 degree centigrade, transfer isoelectric point crystallizing with ammoniacal liquor.

B) 2-aminomethyl-toluylic acid (being called for short 2-AMPA [5]) is in organic solvent (ethanol, acetone, Virahol etc.), with mineral alkali (NaOH, NaHCO ₃, Na ₂CO ₃And KOH, KHCO ₃, K ₂CO ₃Deng) form an alkali metal salt through acetate, form with ester class reagent (like methyl acetoacetate, methyl aceto acetate, propyl acetoacetate etc.) protection primary amine groups again;

C) with b) in generate with an alkali metal salt of the verivate of unsaturated ethylene linkage at organic solvent (DMF, CH ₂Cl ₂, CHCl ₃Deng) in the reaction of rudimentary chloro thing, exist down at organic bases (triethylamine, Trimethylamine 99, DBU etc.), process the solution (being called for short active ester-A liquid) of its ester class reactive derivative, be cooled to-20 ℃ to-25 ℃ subsequent use;

Rudimentary here muriate specially refers to: methyl chlorocarbonate, chloro ethyl formate, pivaloyl chloride etc.

D) with 3-MTAA-7-ACA at organic solvent (CH ₂Cl ₂, DMF, acetonitrile etc.) in suspend, under reflux state, make its silylanization obtain the silicone grease solution (silicone greaseization-[B] liquid) of 3-MTAA-7-ACA with silica reagent (HMDS, TMSI-CL, BSA, BSU etc.), be cooled to 0 ℃ to-5 ℃ subsequent use;

E) [A] liquid and [B] liquid are cooled to respectively under-10 degrees centigrade to-25 degrees centigrade,,, obtain the bullion of CRD-H through aftertreatment with reaction in [B] liquid impouring [A] liquid 6-8 hour.

2. the process for purification of ceforanide:

A) bullion with compound [1] suspends in water; With organic bases N.N-dimethyl benzylamine (being called for short DMBA); Crystallization in organic solvent Virahol or acetone etc. obtains the N.N-dimethylamino benzylidene amine salt (be called for short CRD-H.DMBA) of compound [1], and product purity is brought up to more than 95% from 80%.

B) compound [8] is soluble in water, and through the decarburization source of reducing phlegm and internal heat, after the aseptically process, with mineral acid-Hydrogen chloride, dilute sulphuric acid is transferred isoelectric point crystallizing in clean area, and cooling is filtered, washing, drying, the aseptic crystallization product of Compound C RD-H.

3, the preparation of ceforanide for inj:

A) the L-Methionin that aseptically process is carried out at the end is dissolved in the water for injection of cooling, after activated carbon treatment, and again through aseptically process, lyophilize (H ₂O＜1.0%) gets aseptic L-Methionin.

B) respectively aseptic CRD-H and aseptic L-Methionin are sieved through the 30-40 eye mesh screen, press the 0.95-1.15 mixed in molar ratio, promptly get ceforanide for inj (including L-Methionin solubility promoter) raw material.

C) above-mentioned raw materials is sub-packed in the cillin bottle, and loading amount is 0.5g, 1.0g (in ceforanide).

Description of drawings

Fig. 1,3-MTAA-7-ACA [compound 4] HPLC figure

Fig. 2, obtain 3-MTAA-7-ACA [compound 4] HPLC figure by crude product refining

Fig. 3, bullion CRD-H [compound 1] HPLC figure

Fig. 4, CRD-H.DMBA [compound 8] HPLC figure

Fig. 5, the pure article of CRD-H. [compound 1] HPLC figure

Wherein above-mentioned HPLC collection of illustrative plates test condition is following:

C ₁₈Post (Didmosil) 5 μ 250 * 4.6mm

λ (detection wavelength) 254nm

Flow velocity 1ml/min

Fig. 1, Fig. 2 0.1M KH ₂PO ₄: methyl alcohol=95: 5

Fig. 3-Fig. 5 0.1M KH ₂PO ₄: methyl alcohol=85: 15

Embodiment:

Below pass through some particular compound synthetic embodiments; Again foregoing of the present invention is done further invention in detail; But should this be interpreted as the above-mentioned subject area of the present invention only for following instance, allly all belong to the scope of the invention based on the attainable technology of foregoing of the present invention.Part of compounds is listed in the last of embodiment part with the numbering form of compound [n] with its molecular formula and substruction formula, helps to understand the present invention.Yield is the mol molar yield, and the condensation yield reaches: 94.55%.

Embodiment 1:

3-[[[1-(ethyloic)-1H-tetrazolium-5-yl] sulphur] methyl]-7-amino-cephalosporanic acid, preparation:

Get 7-ACA, 40.8g, compound [3]-MTAA 25.2g places respectively in the 1 liter three-necked bottle, adds acetonitrile 200ml, stirs.Room temperature drips BF ₃/ CH ₃CN (BF ₃Content 16-25%) 300ml after question response is accomplished, when being the transparent and homogeneous reaction solution, adds ice-water 200ml with it in above-mentioned suspension-s, uses 5%NH ₃/ H ₂O transfers the PH=2.5 crystallization. and after crystallization finished, cooling was filtered, and acetone is washed vacuum-drying, treats compound [4] 48.0g, and HPLC purity 98.69% is seen Fig. 1, yield 95.0%.

Thus it is clear that, HPLC purity >=98.5% in the method for the present invention.

Embodiment 2:

The preparation of compound [4]:

In above-mentioned routine 1, BF ₃/ CH ₃CN uses BF instead ₃/ diethyl ether solution replaces, and like the method preparation, also can obtain the product of equal in quality.

Embodiment 3:

The purifying of compound [4]:

With compound [4] bullion (HPLC purity 95.27%) 45g, be suspended in 150ml H ₂Among the O, add Hydrogen chloride to dissolving, activated carbon decolorizing obtains clear liquor. use 5%NH ₃/ H ₂O transfers the PH=2.5 crystallization, filters, and washing, vacuum-drying obtains the pure article of compound [4], 34.0g, HPLC purity 98.55%. sees Fig. 2, yield 85%.

Embodiment 4:

The preparation of 2-aminomethyl (containing the ethylene linkage verivate) sodium phenylacetate:

In 1 liter three-necked bottle, add 2-aminomethyl phenyl acetate 50.0g, ethanol 500ml, sodium hydroxide 13.0g, temperature rising reflux; All clear, stream add methyl aceto acetate (be called for short EAA) 40.0ml. target compound and separate out gradually. reacted 2-4 hour, to be crystallized separate out completion after, cool to room temperature; Vacuum concentration, remove about 1/3rd volume ethanol after, ice-water cooling is filtered; Washing with alcohol, vacuum-drying gets compound [6] 75.0g, and yield is more than 83%.

Embodiment 5:

The preparation of compound [6]:

In above-mentioned routine 4, use methyl acetoacetate (being called for short EAM) or propyl acetoacetate (being called for short EAP) replacement EAA instead, can get analog result.

Embodiment 6:

The preparation of compound [6] potassium:

The foregoing description 4 is among the embodiment 5. and NaOH is substituted with KOH can get identical result.

Embodiment 7:

Synthesizing of ceforanide-compound [1]:

The preparation of compound [7] ester derivative-solution [A]

With compound [6] 50.0g, DMF350ml joins in the 1 liter three-necked bottle; Stirring suspension adds pyridine 8.0ml in the time of 20 degrees centigrade to 35 degrees centigrade, arrive below-25 degrees centigrade in-20 degrees centigrade; Drip pivalyl chloride 28ml, reaction 2-4 hour is subsequent use under this temperature.

The preparation of the silylanization solution [B] of compound [4]:

Compound [4] 38.5g places in the 1 liter three-necked bottle, stirs to add CH down ₂Cl ₂350ml, BSA 70g adds a small amount of agent trimethylchlorosilane that starts, and is heated to backflow, stirring reaction. and question response liquid was kept 2 hours after changeing clearly, was cooled to 0-5 degree centigrade of subsequent use condensation:

With the solution [B] that is cooled to below 5 degrees centigrade, join in the solution [A] of precooling under stirring ,-20 degrees centigrade to-25 degrees centigrade were reacted ten hours. and move into room temperature, add water 200ml, stir phase-splitting. water is through CH ₂Cl ₂After the washing, activated carbon decolorizing filters, and gets crystal solution. with 2N hydrochloric acid PH=2.5 crystallization, filter, and washing, acetone is washed, and vacuum-drying gets compound [1] bullion 34.5g.HPLC purity 81.75%.See Fig. 3, yield 83.89%.

Embodiment 8:

The preparation of compound [7] ester derivative solution [A]:

In example 7, during preparation solution [A], use Vinyl chloroformate. methyl-chloroformate substitutes pivalyl chloride, and it is subsequent use also can to make activity [A].

The preparation of compound [4] silylanization solution [B].

When solution [B] among the embodiment 7 was prepared, BSA replaced with hmds (HMDS), trimethylchlorosilane silica reagents such as (TMSI-CL), also can.

Condensation: press same procedure operation among the embodiment 7, also can obtain the ceforanide bullion of homogeneity.

Embodiment 9:

The preparation of ceforanide N.N-dimethyl benzylamine-compound:

Bullion ceforanide 50.0g water 250ml is suspended, add about N.N-dimethyl benzylamine (DMBA) 55ml and dissolve clearly, cross and filter crystal solution through it; Add the acetone cooling and stirring crystallization of 2.5 times of volumes, treat that mass crystallization is separated out after, after adding 2.5 times of crystallizations of acetone and accomplishing; Filter, acetone is washed, vacuum-drying; Get 55.0g, white crystals .HPLC purity 97.23%.See Fig. 4.

Embodiment 10:

The preparation of aseptic ceforanide-compound [1]

50.0g is dissolved in 500ml H with ceforanide-dimethylbenzyl amine salt (being called for short CRD-HDMBA) ₂Among the O, and use NaHCO ₃A little transfers to the solution all clear. and adjust back again to PH=6.5, add activated carbon decolorizing, filter; Must clarify crystal solution. sterile filtration, it is filtrated in clean zone, transfers PH=2.5 with Hydrogen chloride; Crystallization is filtered, washing; Acetone is washed, vacuum-drying. and get aseptic ceforanide crystallization 35.0g purity HPLC and see Fig. 5, crystal habit (X-powdery diffractometry).

Embodiment 11:

The preparation of aseptic L-Methionin

With the L-Methionin 50g of food grade without aseptically process, be dissolved in the 100ml water, (concentration is between 5-20%) adds activated carbon decolorizing, and sterile filtration is advanced in the source of reducing phlegm and internal heat again, the target compound of gained filtrating freeze-drying system.

Ceforanide (is called for short: CRD-H)

Compound [1]

7-amino-cephalosporanic acid (is called for short: 7-ACA)

Compound [2]

1-ethyloic-5-sulfydryl-tetrazole (is called for short: MTAA)

Compound [3]

3-[[[1-(ethyloic)-1H-tetrazolium-5 base] sulphur] methyl-7-amino-Cephalosporanic acid (being called for short 3-MTAA-7-ACA)

Compound [4]

2-aminomethyl phenyl acetate (is called for short: 2-AMPA)

Compound [5]

Wherein: R ₁Alkalimetal ion such as=Na, K

R ₂＝-OC ₂H ₅，-OCH ₃

2-aminomethyl (containing ethylene linkage verivate protection base)-toluylic acid an alkali metal salt

Compound [6]

Wherein:

R ₂=same compound [6]

2-aminomethyl (containing ethylene linkage verivate protection base)-phenylacetic acid ester

Compound [7]

Ceforanide-dimethylamino salt (being called for short CRD-HDMBA)

Compound [8]

2-azido-methyl-toluylic acid

Compound [9]

7-[[2-(azido-methyl)-phenylacetyl] amido]-Cephalosporanic acid

Compound [10]

1-ethyloic-5-sulfydryl-tetrazole disodium

Compound [11]

7-(2-azido-methyl-phenylacetyl amido)-3-[[[1-(ethyloic)-1H-tetrazolium-5-yl] sulphur] methyl]-Cephalosporanic acid

Compound [12]

Compare with existing patented technology simultaneously, for example in the WO2008/010043 patent, though also use similar route synthesising target compound [1], the present invention compares with it, is improved by many places, to form new preparation method.

A) preparation of compound [4], the BSA of the used silica reagent of the present invention in the WO2008/010043 patent, while available HMDS (hmds) TMSI-CL (trimethylchlorosilane) etc., and use the single solvent methylene dichloride (to use CH among the WO2008/010043 ₂CL ₂-DMF mixed solvent) do not add any basifier and under reflux state, make (adding tetramethyl guanidine among the WO2008/010043) dichloromethane solution of silylanization of compound [4] subsequent use (making the solution for standby of mixed solvent of the silylanization of compound [4] among the WO2008/010043-10 degrees centigrade to-25 degrees centigrade reactions).

B) contain in ethylene linkage derivative compound [7] formulations prepared from solutions what made for starting raw material by compound [5], it is that single DMF suspension (is used CH among the WO2008/010043 that the present invention uses solvent ₂Cl ₂Suspend) with pyridine, tetramethyl guanidine, the CH of organic basess such as triethylamine ₂Cl ₂Following and the pivalyl chloride CH of catalysis ₂Cl ₂Liquid reaction and make (use the neutral catalyst Hydrogen bromide among the WO2008/0100423, add the DMF starting after pivalyl chloride mixes and react and make).

C) simultaneously at above-mentioned b) in during compound [7] formulations prepared from solutions, the ethylene linkage amino protecting agent that contains that present method is prepared is lower alkoxy compound (being the low alkyl group reactive derivative among the WO2008/010043).

D) in the preparation of compound [1] bullion, the present invention is adjusted into condensation temp between-20 degrees centigrade to-25 degrees centigrade, but not-45 to-55 among the WO2008/010043; After reaction finishes, with in the reaction solution impouring ice-aqueous systems but not in hydrochloric acid-aqueous solution of 1: 1 in the patent, tell the water isoelectric point crystallizing; Use Hydrogen chloride to transfer PH from alkali to acid, finally to be the crystallization of PH=2.5 among the present invention, and be to use ammoniacal liquor from acid to alkali, finally to be the crystallization of PH=2.5 in the patent, both are diametrically opposite two notions; And mild condition; The three wastes are few, reduce environmental pollution, and the feature of environmental protection is good.

2. though in the isozygotying of compound bullion, all adopt organic bases salify purifying, the organic bases and the crystalline method that adopt separately are all inequality:

The organic bases that the present invention adopts is a N.N-dimethyl benzylamine (DMBA) and adopt N.N-two ring ethylethylenediamines (DCEDA) among the WO2008/010043; The salify crystallization method: the present invention is that compound [1] bullion adds the acetone crystallization behind aqueous phase and DMBA salify, uses the acetone crystallization again and add the DCEDA salify with acetone-water in mutually among the WO2008/010043.

3. the preparation of compound [1] aseptic powder, the present invention add an amount of mineral alkali (NaHCO during compound [8] is soluble in the aqueous phase ₃, Na ₂CO ₃) transfer PH to complete dissolving, through activated carbon decolorizing, solution in clean area, is transferred PH crystallization with diluted acid through sterile filtration, but not directly dissolving among the WO2008/010043, diluted acid is transferred the PH crystallization.

4. compound [1] also can be without organic bases salify purifying, and direct purification gets final product, and during purifying, compound [1] bullion is suspended in water, and uses NaHCO ₃Transfer PH to neutral dissolving, activated carbon decolorizing is transferred isoelectric point crystallizing with the clear liquor that obtains with diluted acid, filters and gets, and is not directly compound [1] bullion to be joined among the WO2008/010043 to add water in the formic acid after the stirring and dissolving and get throw out.

5, the preparation of relevant aseptic L-Methionin; After the present invention adopts non-sterile L-Methionin water-soluble; Through activated carbon treatment, sterile filtration, it is that direct freeze-drying forms between the 5%-20% that its solution is controlled at concentration; Be different among the WO2008/010043 and get, thereby avoided Virahol to be difficult to the defective of drying with isopropanol precipitating.

Claims (3)

1. the preparation method of a ceforanide, its process step is following:

(I) begin to synthesize:

(a) with 7-amino-Cephalosporanic acid (7-ACA) and 1-ethyloic-5-sulfydryl-tetrazole (MTAA) in organic solvent; Organic solvent reaction with boron trifluoride; Through aftertreatment make important intermediate (6R, 7R)-3-(((1-ethyloic-1-H-tetrazolium-5-yl) sulphur) methyl)-7-amino-8-oxo-5-thia azabicyclo (4,2; 0) oct-2-ene-2-formic acid (3-MTAA-7-ACA), above-mentioned organic solvent is selected from acetonitrile, acetone in the above-mentioned steps (a); The organic solvent of boron trifluoride is to be selected from BF ₃/ CH ₃CN; Aftertreatment wherein refers to and adds water, at 0-30 degree centigrade, transfers isoelectric point crystallizing with ammoniacal liquor;

(b) 2-aminomethyl-toluylic acid (2-AMPA) with ester class reagent protection primary amine groups, forms an alkali metal salt with mineral alkali in ethanol in organic solvent, forms an alkali metal salt with the verivate of unsaturated ethylene linkage, as follows:

Wherein: R ₁=Na, the K alkalimetal ion

R ₂＝-OC ₂H ₅，-OCH ₃

2-aminomethyl (containing ethylene linkage verivate protection base)-toluylic acid an alkali metal salt

Ester class reagent is selected from methyl acetoacetate, methyl aceto acetate, propyl acetoacetate in the above-mentioned steps (b); Mineral alkali is selected from NaOH, NaHCO ₃, Na2CO ₃And KOH, KHCO ₃, K ₂CO ₃

(c) with generate in the step (b) with an alkali metal salt of the verivate of unsaturated ethylene linkage in organic solvent with rudimentary muriate reaction; Under the situation that organic bases exists; Form the solution of ester class reactive derivative of an alkali metal salt of above-mentioned verivate with unsaturated ethylene linkage; Be called for short active ester A liquid, be cooled to-20 ℃ to-25 ℃, subsequent use;

In the above-mentioned steps (C), organic solvent is selected from DMF, CH ₂Cl ₂, CHCl ₃, organic bases is selected from triethylamine, Trimethylamine 99, DBU, and rudimentary muriate is selected from methyl chlorocarbonate, chloro ethyl formate, pivaloyl chloride;

(d) 3-MTAA-7-ACA is suspended in organic solvent, under reflux state, makes it obtain the silicone grease solution of 3-MTAA-7-ACA, be called for short silicone grease B liquid at silylanization with silica reagent, be cooled to 0 ℃ to-5 ℃ subsequent use;

Wherein silica reagent is selected from BSU in the above-mentioned steps (d), and organic solvent is selected from CH ₂Cl ₂, DMF, acetonitrile;

(e) with above-mentioned two kinds of solution, promptly active ester A liquid and silicone grease B liquid are cooled to-10 ℃ to-25 ℃, and silicone grease B liquid is poured in the active ester A liquid while stirring, react 6-8 hour, move into room temperature, add water 200ml, stir phase-splitting. and water is through CH ₂Cl ₂After the washing, activated carbon decolorizing filters, and gets crystal solution. with 2N hydrochloric acid PH=2.5 crystallization, filter, and washing, acetone is washed, and vacuum-drying gets the bullion 44.0g of ceforanide, HPLC purity 81.75%;

(II) then, further make with extra care as follows:

(f) the ceforanide bullion is suspended in water, add organic bases N, N-dimethyl benzylamine (DMBA), behind its salify, crystallization in organic solvent Virahol or acetone again obtains the N of ceforanide, and N-dimethylamino benzylidene amine salt (CRD-HDMBA) is as follows:

Ceforanide-dimethylbenzyl amine salt (CRD-HDMBA)

(g) above-mentioned ceforanide dimethylbenzyl amine salt (CRD-HDMBA) is soluble in water, adds activated carbon decolorizing, filters, and must clarify crystal solution; Aseptically process is transferred isoelectric point crystallizing with mineral acid in clean area, cooling is filtered; Washing, drying obtains ceforanide aseptic crystallization product.

2. a basis the process of claim 1 wherein that the middle organic solvent of step (b) is selected from ethanol, acetone, Virahol.

3. a basis the process of claim 1 wherein that the middle mineral acid of step (g) is Hydrogen chloride or dilute sulphuric acid.

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