CN101805357B - Cefaclor compound and novel preparation method thereof - Google Patents
Cefaclor compound and novel preparation method thereof Download PDFInfo
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- CN101805357B CN101805357B CN2010101572300A CN201010157230A CN101805357B CN 101805357 B CN101805357 B CN 101805357B CN 2010101572300 A CN2010101572300 A CN 2010101572300A CN 201010157230 A CN201010157230 A CN 201010157230A CN 101805357 B CN101805357 B CN 101805357B
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Abstract
The invention relates to a cephem compound for industrial production and a novel preparation method thereof, in particular to a cefaclor compound and a novel preparation method thereof. Since the p-nitrophenol is used as the activating agent, the invention has the advantages of good reaction stability, mild reaction conditions, high product yield, high purity, low cost and suitability for industrial production. Therefore, the invention can be widely applied in the synthesis of the currently known cephem compound.
Description
Technical field
The present invention relates to a kind of novel method, particularly cefaclor compound and new preparation method thereof of outstanding industrial production cephem (cephem) compound, said cephem belongs to medical technical field as medicine, particularly microbiotic.
Background technology
At present; Cephem compounds is to produce like this: in organic solvent; Amino cephem carboxylic (cephalosporanic acid) verivate etc. of 7-amino-3-cephem-4-carboxylate derivatives or 7-is reacted in organic solvent with acyl chlorides or carboxylic acid, accomplished amidate action thus.
For example, Japanese Unexamined Patent Publication No 125,190/1997,68; 795/1978 and 68,796/1978 (back two corresponding to GB1576625 and GB1576626), yet; The reactive derivative of acyl chlorides or carboxylic acid form is under violent reaction conditions, to prepare, and unstable, and is reactive low; Long reaction time, byproduct of reaction is many, and the yield of preparation cephem compounds is low.
Cefaclor, chemical name is: (6R, 7R)-7-[(R)-2-amino-2-phenylacetylamino]-3-chloro-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid monohydrate, molecular formula: C
15H
14ClN
3O
4SH
2O, molecular weight: 385.82, structural formula is:
Cefaclor is a second generation cephalosporin; Belong to oral semi-synthetic microbiotic; Effect with broad-spectrum antimicrobial; Its mechanism of action is identical with other cynnematin, mainly syntheticly reaches germicidal action through what suppress cell walls, mainly is applicable to respiratory system, urinary system, Otorhinolaryngologic Department and skin due to the sensitive organism, soft tissue infection etc.
In U.S. Pat 3925372, introduced a kind of compound method of cefaclor, 7-ACCA is through N, and the silica-based ethanamide of O-pair-front three is protected, and the mixed anhydride reactant that forms with phenylglycine sodium salt (methyl sodium salt) and methyl-chloroformate makes, and yield is merely 43%.In U.S. Pat 5608055; The synthesis technique of cefaclor is to be raw material with 7-ACCA, and the condensation of process acidylate, hydrolysis obtain the hydrochloride aqueous solution of cefaclor, add DMF then and make cefaclor DMF mixture; Obtain cefaclor bulk drug, yield 60% through transforming again.
7-amino-3-chloro-3-cephem-4-acid (being called for short 7-ACCA) is a key intermediate of the synthesis of cefaclor; Successfully realized suitability for industrialized production at present; Selecting 7-ACCA and D-phenylglycine for use is that midbody is the simplest at present through the enzymic catalytic reaction the synthesis of cefaclor, the most frequently used, one of the most industrialized method; But, influence the yield and the purity of product because the active temperature influence of blue or green toxin acylase enzymatic is bigger.
Summary of the invention
The purpose of this invention is to provide the method for a kind of production suc as formula the cephem compounds shown in (IV), the novel method of particularly producing cefaclor, inventive point of the present invention is to adopt p-NP as acvator; Reaction stability is good; Reaction conditions is gentle, and product yield is high, purity is high, and cost is low; Be suitable for suitability for industrialized production, and therefore can be widely used for synthetic at present known at cephem compounds.
Technical scheme of the present invention is following:
The present invention provides the method for a kind of production by the cephem compounds of following general formula (IV) expression:
Wherein, R is low alkyl group, halogen atom, low-grade acyloxy, the low-grade acyloxy alkyl.R is that the specific examples of halogen atom can comprise chlorine, bromine, iodine and fluorine atom, preferred chlorine atom; Low alkyl group is meant the straight or branched alkyl that contains 1-6 carbon atom, and its specific examples comprises methyl, ethyl, propyl group, butyl, amyl group and hexyl, preferable methyl and ethyl; Low-grade acyloxy is meant the straight or branched aliphatic series acyloxy that contains 1-6 carbon atom, and its specific examples comprises acetoxyl group, propionyloxy and butyryl acyloxy, preferred acetoxyl group; The low-grade acyloxy alkyl is meant that its specific examples comprises acetoxy-methyl, acetoxyl group ethyl, propionyloxy methyl and propionyloxy ethyl by the substituted above-mentioned low alkyl group of above-mentioned any low-grade acyloxy, preferred acetoxy-methyl.
This method comprises: (1) in the presence of solvent and alkali, by the D-phenylglycine p-nitrophenyl phenolic ester of D-phenylglycine and p-NP prepared in reaction general formula (II) expression,
Add the 3-cephem-4-acid of general formula (III) expression again, stirring reaction is regulated pH value 3-6.5 with acid, makes the cephem compounds of general formula (IV) expression.
Wherein, the R definition is the same;
The reaction mol ratio of the 3-cephem-4-carboxylic acid of D-phenylglycine, p-NP and general formula (III) expression is 1: 1-1.5: 1, be preferably 1: 1.2: 1.
Used alkali in the reaction of the present invention, both also organic basess of mineral alkali is like sodium hydrogencarbonate, yellow soda ash, saleratus, salt of wormwood, sodium hydroxide, Pottasium Hydroxide, ammoniacal liquor; Triethylamine, tri-n-butylamine, diisopropyl ethyl amine, pyridine N, accelerine, one or more of sodium acetate, potassium acetate etc., wherein, preferred sodium hydrogencarbonate, triethylamine, tri-n-butyl amine etc.
About the present invention's used solvent in reaction, can adopt following polarity arbitrarily or non-polar solvent respectively, methylene dichloride for example, ethylene dichloride, chloroform, tetracol phenixin; Toluene, YLENE, acetonitrile, ETHYLE ACETATE, butylacetate, dioxan, THF; Acetone, N, dinethylformamide, DMAC N,N; Pure like methyl alcohol, ethanol, Virahol, water etc., particularly water and methylene dichloride; Also can adopt the mixed solvent of two or multiple solvent composition in the above-mentioned solvent effectively, for example, mixed solvents such as water-dichloromethane, alcohol-water, THF-water, DMAC N,N base-methylene dichloride.
In the present invention, should not limit, influence reaction of the present invention only if selected temperature is unfavorable significantly temperature of reaction.Yet reaction is normally accomplished after carrying out 2-6 hour under 0-30 ℃, particularly in 20-25 ℃ room temperature range, can more easily prepare required compound.
The present invention further provides the novel method of preparation cefaclor, and its technical scheme is following:
Through with D-phenylglycine and p-NP reaction, add 7-amino-3-chloro-3-cephem-4-acid again, stirring reaction is used acid for adjusting pH value 3-6.5, stirs and separates out solid, filters, washs, and vacuum-drying obtains the product cefaclor.
Synthetic route is:
In the aforesaid method, the reaction mol ratio of D-phenylglycine, p-NP and 7-amino-3-chloro-3-cephem-4-acid is 1: 1-1.5: 1, be preferably 1: 1.2: 1.Be to contain in the solvent of triethylamine to react in entire reaction course preferably, preferable reaction temperature is 15-25 ℃, preferably uses the hydrochloric acid soln of 5%-15% to regulate the pH value and is 4.5-6.5; Fractionation, water is used solvent wash, again fractionation; Water uses the hydrochloric acid soln of 5%-15% to regulate pH value to be 3.5-5 again, more preferably uses 10% hydrochloric acid soln adjusting pH value to be 5-6, fractionation; Water is used washed with dichloromethane, fractionation again, and water uses 10% hydrochloric acid soln to regulate the pH value to be 4-4.5 again.
Above-mentioned method behind the salt acid for adjusting pH value, stirs and separates out solid, filters, and washing with acetone, 40-50 ℃ of vacuum-drying obtains cefaclor.
Prepare the preferred embodiment of cefaclor as the present invention, its compound method is following:
D-phenylglycine and triethylamine are joined in the solvent, in the time of 15-25 ℃, stir, add p-NP; Insulation reaction 1 hour, and then add the solution that 7-amino-3-chloro-3-cephem-4-acid, triethylamine and solvent form, 15-25 ℃ of reaction 2 hours, stir; Add entry, use 10% hydrochloric acid soln to regulate the pH value and be 5-6, fractionation, water is used washed with dichloromethane; Fractionation again, water are used 10% hydrochloric acid soln to regulate pH value to be 4-4.5 again, and solid is separated out in stirring; Filter, use washing with acetone,, get the product cefaclor 40-50 ℃ of following vacuum-drying.
Embodiment
Below come further to explain or explanation content of the present invention that but the embodiment that is provided should not be understood that protection domain of the present invention is constituted restriction through embodiment.
Midbody D-phenylglycine used in the present embodiment is available from Guangzhou big uncle chemical industry ltd, and midbody 7-amino-3-chloro-3-cephem-4-acid is available from Wuhan milky way chemical industry ltd, and p-NP is available from grand source, Huaiyang County chemical industry ltd.
The HPLC analysis condition:
Stationary phase: Inertsil ODS-2 (4.6 * 150mm)
Moving phase: 6% CH
3The KH of CN/50mM
2PO
4The aqueous solution (pH:3.4), flow velocity: 1.0ml/min
Detector: UV 254nm.
Interior mark reagent: of benzene aminolevulinic.
Embodiment 1
Prepare 7 β-(D-α-phenyl glycyl is amino)-3-chloro-3-cephem-4-carboxylic acid (cefaclor)
151gD-phenylglycine and 100ml triethylamine are joined in the 400ml methylene dichloride, add 167g (1.2mol) p-NP, be 20 ℃ in temperature and reacted 1 hour down, add the solution of 7-amino-3-chloro-3-cephem-4-acid, 200ml triethylamine and the formation of 400ml methylene dichloride of 234g then; Under this temperature, reacted 2 hours, stir, add 6L water, using 15% hydrochloric acid soln adjusting pH is 6; Fractionation, water are used the 500ml washed with dichloromethane 1 time again, fractionation; The pH of the hydrochloric acid soln regulation system of water use 15% is 4.5, stirs, and separates out solid; Filter, use the 100ml washing with acetone, 50 ℃ of following vacuum-dryings; Get product cefaclor 359g, yield 93%, HPLC purity: 98.5%.
Embodiment 2
Prepare 7 β-(D-α-phenyl glycyl is amino)-3-chloro-3-cephem-4-carboxylic acid (cefaclor)
151gD-phenylglycine and 100ml triethylamine are joined in the 400ml acetonitrile, stir, add 167g (1.2mol) p-NP, be 20 ℃ in temperature and reacted 1 hour down; Add the solution of 7-amino-3-chloro-3-cephem-4-acid, 200ml triethylamine and the formation of 400ml acetonitrile of 234g then, under this temperature, reacted 2 hours again, stir, add 3L water; Using 5% hydrochloric acid soln adjusting pH is 5, fractionation, and water is again with 500ml acetonitrile washing 1 time, fractionation; The pH of the hydrochloric acid soln regulation system of water use 5% is 4, stirs, and separates out solid; Filter, use the 100ml washing with acetone, 40 ℃ of following vacuum-dryings; Get product cefaclor 355.3g, yield 92.1%, HPLC purity: 97.5%.
Embodiment 3
Prepare 7 β-(D-α-phenyl glycyl is amino)-3-chloro-3-cephem-4-carboxylic acid (cefaclor)
151gD-phenylglycine and 100ml triethylamine are joined in the 400ml ETHYLE ACETATE, stir, add 167g (1.2mol) p-NP, be 25 ℃ in temperature and reacted 1 hour down; Add the solution of 7-amino-3-chloro-3-cephem-4-acid, 200ml triethylamine and the formation of 400ml ETHYLE ACETATE of 234g then, under this temperature, reacted 4 hours again, stir, add 8L water; Using 10% hydrochloric acid soln adjusting pH is 5.5 fractionation, and water is again with 500ml ETHYLE ACETATE washing 1 time, fractionation; The pH of the hydrochloric acid soln regulation system of water use 10% is 4.2, stirs, and separates out solid; Filter, use the 100ml washing with acetone, 45 ℃ of following vacuum-dryings; Get product cefaclor 360g, yield 93.3%, HPLC purity: 98.6%.
Embodiment 4
Prepare 7 β-(D-α-phenyl glycyl is amino)-3-chloro-3-cephem-4-carboxylic acid (cefaclor)
151gD-phenylglycine and 100ml triethylamine are joined in the 400ml methylene dichloride, stir, add 167g (1.2mol) p-NP, be 25 ℃ in temperature and reacted 1 hour down; Add the solution of 7-amino-3-chloro-3-cephem-4-acid, 200ml triethylamine and the formation of 400ml methylene dichloride of 234g then, under this temperature, reacted 2 hours again, stir, add 3L water; Using 10% hydrochloric acid soln adjusting pH is 5.3, fractionation, and water is used the 500ml washed with dichloromethane 1 time again, fractionation; The pH of the hydrochloric acid soln regulation system of water use 10% is 4.3, stirs, and separates out solid; Filter, use the 100ml washing with acetone, 40 ℃ of following vacuum-dryings; Get product cefaclor 354.2g, yield 91.8%, HPLC purity: 98.6%.
Claims (9)
1. the preparation method of a compound as follows,
Comprise: in the presence of solvent and alkali, by D-phenylglycine and p-NP prepared in reaction suc as formula the D-phenylglycine p-nitrophenyl phenolic ester shown in (II),
Add 7-amino-3-chloro-3-cephem-4-acid again, stirring reaction is used acid for adjusting pH value, obtains product cefaclor monohydrate.
2. preparation method according to claim 1 is characterized in that described alkali is to be selected from sodium hydroxide, Pottasium Hydroxide, ammoniacal liquor, triethylamine, sodium acetate, potassium acetate, yellow soda ash, salt of wormwood, sodium hydrogencarbonate, saleratus, Sodium phosphate, dibasic, volatile salt and the ammonium carbamate one or more.
3. preparation method according to claim 1 is characterized in that described alkali is triethylamine.
4. preparation method according to claim 1; It is characterized in that described solvent is selected from water, methylene dichloride, ethylene dichloride, acetonitrile, THF, N; Dinethylformamide, DMAC N,N, toluene, ETHYLE ACETATE, butylacetate, isopropyl acetate.
5. preparation method according to claim 1 is characterized in that using acid for adjusting pH value to be 4.5-6.5, and water is washed in fractionation again, fractionation again, and the gained water uses acid for adjusting pH value to be 3.5-5 again.
6. preparation method according to claim 1 is characterized in that using acid for adjusting pH value to be 5-6, and water is washed in fractionation again, fractionation again, and water uses acid for adjusting pH value to be 4-4.5 again.
7. according to each described preparation method among the claim 1-6, it is characterized in that using the salt acid for adjusting pH value.
8. preparation method according to claim 7, it is characterized in that D-phenylglycine, p-NP and
The reaction mol ratio of 7-amino-3-chloro-3-cephem-4-acid is 1: 1-1.5: 1.
9. preparation method according to claim 8 is characterized in that the reaction mol ratio of D-phenylglycine, p-NP and 7-amino-3-chloro-3-cephem-4-acid is 1: 1.2: 1.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1461323A (en) * | 1973-02-23 | 1977-01-13 | Lilly Co Eli | Alpha-aminoacyl-3-halo-cephalosporins |
| EP0429895A1 (en) * | 1989-12-01 | 1991-06-05 | Irca S.P.A. - Industrie Ricerche Chimiche D' Albano | Process for preparing monohydrate 7-(D-2-amino-2-phenylacetamido)-3-cefem-4-carboxylic acid and intermediate formed in the process |
| EP0547646A2 (en) * | 1991-11-11 | 1993-06-23 | Biochimica Opos Spa | Crystalline form of a cephalosporin antibiotic |
| CN1184814A (en) * | 1996-09-25 | 1998-06-17 | 卫材化学株式会社 | Production process of cephem compound |
| CN1273587A (en) * | 1998-07-01 | 2000-11-15 | 大塚化学株式会社 | Process for preparation of 3-cephem compounds |
-
2010
- 2010-04-28 CN CN2010101572300A patent/CN101805357B/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1461323A (en) * | 1973-02-23 | 1977-01-13 | Lilly Co Eli | Alpha-aminoacyl-3-halo-cephalosporins |
| EP0429895A1 (en) * | 1989-12-01 | 1991-06-05 | Irca S.P.A. - Industrie Ricerche Chimiche D' Albano | Process for preparing monohydrate 7-(D-2-amino-2-phenylacetamido)-3-cefem-4-carboxylic acid and intermediate formed in the process |
| EP0547646A2 (en) * | 1991-11-11 | 1993-06-23 | Biochimica Opos Spa | Crystalline form of a cephalosporin antibiotic |
| CN1184814A (en) * | 1996-09-25 | 1998-06-17 | 卫材化学株式会社 | Production process of cephem compound |
| CN1273587A (en) * | 1998-07-01 | 2000-11-15 | 大塚化学株式会社 | Process for preparation of 3-cephem compounds |
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