CN1084750C - Process for producing cefazolin - Google Patents
Process for producing cefazolin Download PDFInfo
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- CN1084750C CN1084750C CN96117398A CN96117398A CN1084750C CN 1084750 C CN1084750 C CN 1084750C CN 96117398 A CN96117398 A CN 96117398A CN 96117398 A CN96117398 A CN 96117398A CN 1084750 C CN1084750 C CN 1084750C
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
To simply obtian the subject compound useful for antibiotics, etc., by reacting a 7-protected amino-3-halogenomethyl-cephem carboxylic acid ester with a 5-mercaptothiazole compound and subsequently reacting the reaction product with a tetrazole acetic acid. This method for producing the highly pure cefazolin of formula V comprises reacting a 7-phenylacetic amino-2-halongenomethyl-3cephem-4- carboxylic acid ester of formula I (X is a halogen; R<1> is a carboxylic acid- protecting group) with 2-methyl-5-mercapto-1,3,4-thiadiazole of formula II in the presence of a base in at least one of water, organic solvents, etc., deesterifying the reaction product in the presence of a phenol compound, subjecting the reaction product to a phenyl acetic acid-removing reaction using immobilized penicillin G acylase, and further reaction the obtained compound of formula III with a 1H-tetrazole-1-acetic acid of formula IV in the presence of an acid halide in an organic solvent.
Description
The present invention relates to prepare the novel method of Kefzol, the called after 7-of described Kefzol (1H-tetrazolium-1-yl)-acetylaminohydroxyphenylarsonic acid 3-(2-methyl isophthalic acid, 3,4-thiadiazoles-5-yl) thiomethyl-3-cephem-4-carboxylic acid, this compound is widely used as microbiotic.
Kefzol promptly descends the formula V compound:
Normally those adopt the method for 7-amino-3-acetoxy-methyl-3-cephem-4-carboxylic acid (7-ACA) as starting raw material to the ordinary method of preparation Kefzol.
But, production method according to routine, partly introduce (2-methyl isophthalic acid by the acetoxyl group that replaces 3-position 3-acetoxy-methyl among the 7-ACA, 3,4-thiadiazoles-5-yl) reaction yield of thio group is low, and a large amount of by products of selectivity and formation in this reaction influence required degree of purity of production.
And, production method according to routine, being used for synthetic Kefzol (is 7-(1H-tetrazolium-1-yl)-acetylaminohydroxyphenylarsonic acid 3-(2-methyl isophthalic acid, 3, the productive rate and/or the purity of intermediate thiomethyl-3-cephem-4-carboxylic acid 4-thiadiazoles-5-yl)) are too low, so in order to prepare the required product Kefzol of high yield, midbody compound must pass through purifying.
Purpose of the present invention is exactly in order to overcome above-mentioned deficiency, i.e. low selectivity and the low-yield pointed out of prior art, thus the novel method for preparing the high purity Kefzol in mode easily is provided.
The invention provides the method for preparation formula V 7-(1H-tetrazolium-1-yl)-acetylaminohydroxyphenylarsonic acid 3-(2-methyl isophthalic acid, 3,4-thiadiazoles-5-yl) thiomethyl-3-cephem-4-carboxylic acid:
The method comprising the steps of:
(i) in the presence of alkali at least a solvent that is selected from organic solvent and water, make formula (I) compound
Wherein X represents halogen atom and R
1The expression carboxyl-protecting group, with formula (VIII) 2-methyl-5-sulfydryl-1,3, the reaction of 4-thiadiazoles
Perhaps in the presence of the alkali at least a solvent that is selected from organic solvent and water, make the basic salt reaction of formula (I) compound and formula (VIII) compound, obtain formula (II) compound:
R wherein
1The expression carboxyl-protecting group,
(ii) in the presence of oxybenzene compound, make formula (II) compound carry out de-esterification, obtain formula (III) 7-phenyl acetylaminohydroxyphenylarsonic acid 3-(2-methyl isophthalic acid, 3,4-thiadiazoles-5-yl) thiomethyl-3-cephem-4-carboxylic acid:
(iii) adopt immobilized penicillin G-Ntn hydrolase to make formula (III) compound carry out de-esterification and slough phenylacetyl, obtain formula (IV) 7-amino-3-(2-methyl isophthalic acid, 3,4-thiadiazoles-5-yl) thiomethyl-3-cephem-4-carboxylic acid:
(iv) in the presence of alkali in organic solvent, make formula (IV) compound and mixed anhydride reaction, wherein mixed acid anhydride be in the presence of alkali in organic solvent, through type (VI) 1H-tetrazolium-1-acetate
With the prepared in reaction of formula (VII) carboxylic acid halides or halo alkyl carbonate,
Wherein Y represents halogen atom and R
2Low alkyl group that expression can be replaced by one or more halogen atom or the lower alkoxy with 1-7 carbon atom that can be replaced by one or more halogen atom with 1-7 carbon atom.
The reaction process of front has been described method of the present invention, and the X in the formula (I) preferably represents the R in chlorine atom, bromine atoms or iodine atom and formula (I) and the formula (II)
1Preferably represent methoxy-benzyl, diphenyl methyl or the tertiary butyl.
Method of the present invention be employing formula (I) 7-phenyl acetylaminohydroxyphenylarsonic acid 3-halogenated methyl-3-cephem-4-carboxylates derivatives (hereinafter being referred to as compound (I)) as initial original, obtain the Kefzol of high yield and highly selective.
The inventive method is by reaction process 1 expression.
Reaction process 1
The first step
As described in above-mentioned reaction process 1, the first step of aforesaid method comprises: at least a organic solvent that is being selected from organic solvent and water in the presence of the alkali, make formula (I) compound and 2-methyl-5-sulfydryl-1,3,4-thiadiazoles (VIII) reaction, perhaps make the basic salt prepared in reaction of formula (I) compound and formula (VIII) compound, obtain formula (II) compound.
Compound (I) as starting raw material among the present invention is known and compound that be easy to get.
X in the formula (I) represents halogen atom.The example of halogen atom comprises chlorine atom, bromine atoms or iodine atom etc.
R in the formula (I)
1The expression carboxyl-protecting group.As carboxyl-protecting group R
1, below a large amount of protecting groups of document description all can adopt " Protective Groups inOrganic Synthesis ", the 5th chapter, Theodora W.Greene, 1981, John Wiley ﹠amp; Sons, Inc..
Therefore, any protecting group of not removing and removing in second step as described below in the first step of reaction all is available.This class protecting group that therefore, can propose comprises benzyl, to methoxy-benzyl, to nitrobenzyl, diphenyl methyl, trimethoxy benzyl, the tertiary butyl, methoxy ethoxy methyl, piperonyl, xylyl, trimethoxy dichloro benzyl, trichloromethyl, two (p-methoxyphenyl) methyl etc.
Compound (I) is converted into 7-phenyl acetylaminohydroxyphenylarsonic acid 3-(the 2-methyl isophthalic acid of formula (II), 3,4-thiadiazoles-5-yl) method of thiomethyl-3-cephem-4-carboxylates derivatives (hereinafter being referred to as " compound (II) "), be included under the alkali existence and make compound (I) and formula (VIII) 2-methyl-5-sulfydryl-1,3,4-thiadiazoles (hereinafter being referred to as " compound (VIII) ") mixes, or compound (I) is mixed with the basic salt of the compound for preparing previously (VIII).
Compound (VIII) also is known, is easy to get.And the preparation of compound (VIII) basic salt also is easy to carry out in the usual way, and for example alkali such as the sodium hydroxide with necessary amount neutralizes.
The amount of compound (VIII) or its basic salt can be selected in very wide scope, but for every mole compound (I), and normally at about 1-about 100 moles of compounds (VIII) are preferably in about 10 molar range of about 1-.
Comprise alkali metal hydrocarbonate, carbonate and oxyhydroxide such as sodium bicarbonate, saleratus, yellow soda ash, salt of wormwood, sodium hydroxide, potassium hydroxide etc. at this reaction the first step adoptable alkali, ammoniacal liquor, the secondary amine or the tertiary amine (low alkyl group such as methyl, ethyl, propyl group, sec.-propyl, the tertiary butyl) that replace by low alkyl group, particularly two-or three-(C
1-4Alkyl) amine, and corresponding quaternary ammonium salt.Used alkali also can be selected from above-mentioned alkali in preparation compound (VIII) basic salt process.
For every mole compound (I), normally at about 1-about 100 moles of the consumptions of alkali are preferably in about 10 molar range of about 1-.Above-mentioned alkali can be suitable the mixture of at least two kinds of alkali use.
In the first step of the inventive method, can adopt the basic ion exchange resin as described alkali.Select in the basic ion exchange resin that such basic ion exchange resin can suitably be used always from this class reaction, and can be any basic ion exchange resin that compound (I) and compound (VIII) are reacted.Strong basicity or weakly alkaline ion exchange resin all can adopt, and are preferred but adopt weak-base ion-exchange resin.
The representative instance of above-mentioned basic ion exchange resin comprises by at first having the macromole matrix resin chloromethylation of three dimensional network chain structure, the resin of the product of amination gained preparation then, the macromole matrix example with three dimensional network chain structure comprises the multipolymer or the acrylate copolymer of main ingredient monomer such as vinylbenzene and cross-linking monomer such as Vinylstyrene.
Such basic ion exchange resin is known, as mentioned below especially: SaishinKobunshi Zairyo Gijutsu Soran (Manual of Up-to-Date PolymerMaterials and Technology), December9,1988, Tekku Shuppan DabushikiKaisha, pp. 301-304.
And these basic ion exchange resins can be buied from many companies.The typical basic ion exchange resin that can use in the present invention is: Diaion
WA-10, WA-11, WA-20, WA-21, WA-30 (Mitsubishi ChemicalCorp.), Amberlite
IRA-35, IRA-93ZU, IRA-94S (ORGANO CORP.), and Lewatit
MP-62, MP-64, AP-49, CA-9222 (MitsuiToatsu Chemicals, Inc.).Except these, many other basic ion exchange resins also can adopt, as long as they are basic ion exchange resins.
The amount of basic ion exchange resin does not need strict control.Generally speaking, for every mole compound (I), it is about 100 moles corresponding to the consumption of the basic ion exchange resin of its exchange capacity, preferably in about 10 molar range of about 1-at about 1-.
The used reaction solvent of this reaction the first step is can be with a certain amount of compound (I), compound (VIII) and alkali dissolution, and don't any solvent or any solvent mixture of influence reaction.Be to be understood that ion exchange resin needn't dissolve.Therefore the available reaction solvent comprises ketone such as acetone in other organic solvent and water, methyl ethyl ketone, metacetone, methyl iso-butyl ketone (MIBK) etc., ester such as methyl-formiate, ethyl formate, propyl formate, methyl acetate, ethyl acetate, propyl acetate, methyl propionate, ethyl propionate etc., fatty alcohol such as methyl alcohol, ethanol, propyl alcohol etc., ether such as diethyl ether, Di Iso Propyl Ether, dibutyl ether, tetrahydrofuran (THF) diox etc., halohydrocarbon such as methylene dichloride, chloroform, bromofom, tetracol phenixin etc., nitro-paraffin such as Nitromethane 99Min., nitroethane, nitropropane etc., nitrile such as acetonitrile, propionitrile, butyronitrile, valeronitrile etc.Particularly preferably be water or water-soluble organic solvent, they are selected from multiple above-mentioned solvent.For every part of compound (I), the amount of solvent is normally about 1 part-Yue 100 parts of weight, preferably about 5 parts-Yue 20 parts of weight.
The reaction the first step is normally under atmospheric pressure carried out, but also can carry out adding to depress if desired.Temperature of reaction is normally-20 ℃ to 110 ℃, preferred 0 ℃ to 80 ℃.The mole number of the compound (VIII) that the reaction times depends on temperature of reaction, concentration of reactants, adopted etc., but normally at 0.1-20 hour, preferred 0.5-8 hour.
For advancing on the one hand of above-mentioned reaction, the hybrid mode of compound (I), compound (VIII) and alkali is not particularly limited.Typically, compound (I) is scattered in the above-mentioned reaction solvent with the preparation dispersion liquid, in this dispersion liquid, adds the solution that contains compound (III) and alkali simultaneously.But compound (I), compound (VIII) and alkali do not need to dissolve fully.Reaction system can be homogeneous phase or heterogeneous system.Be reflected in the airtight or open container and carry out.After reaction is finished, if desired, reaction mixture is cooled to about 0 ℃-Yue 10 ℃, and by filtering the crystal of collecting gained.By this method, can obtain the required compound (II) of high yield.Second step
Compound (II) is converted into 7-phenyl acetylaminohydroxyphenylarsonic acid 3-(the 2-methyl isophthalic acid of formula (III), 3,4-thiadiazoles-5-yl) thiomethyl-3-cephem-4-carboxylic acid (hereinafter being referred to as " compound (III) ") can adopt disclosed method in open (kokoku) number H6-4638 (4638/1994) of Japan's special permission.
Therefore, this de-esterification carries out in the presence of oxybenzene compound, optional acid.
Adoptable in the present invention oxybenzene compound comprises phenol, m-cresol, Ortho Cresol, p-cresol etc.Also can adopt other compound that contains one or more phenolic hydroxyl group.
Every relatively mole compound (II), the consumption of oxybenzene compound in reaction are about 1000 moles of about 1-, about 100 moles of preferably about 5-.
In this reaction, if desired, usable acid comes accelerated reaction.The acid that is used for this purpose comprises mineral acid example hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid etc. and organic acid such as formic acid, acetate, propionic acid, trifluoroacetic acid etc.Also can adopt other acidic substance.Acid is to work as the catalyzer that reaction is carried out easily, and therefore, acid can add in any suitable manner.And the adding of acid is not certain necessary.When adopting acid, every part of weight compound (II) relatively, the consumption of acid is no more than about 10 parts of weight, preferably about 0.001-1 part weight usually.
In this reaction, oxybenzene compound is also as solvent.Therefore reaction can be carried out under the solvent not having.But can adopt solvent if desired.Described solvent comprises ketone such as acetone, methyl ethyl ketone, metacetone, methyl iso-butyl ketone (MIBK) etc., ester such as methyl-formiate, ethyl formate, propyl formate, methyl acetate, ethyl acetate, propyl acetate, methyl propionate, ethyl propionate etc., fatty alcohol such as methyl alcohol, ethanol, propyl alcohol etc., ether such as diethyl ether, Di Iso Propyl Ether, dibutyl ether, tetrahydrofuran (THF), diox etc., halohydrocarbon such as methylene dichloride, chloroform, bromofom, tetracol phenixin etc., nitro-paraffin such as Nitromethane 99Min., nitroethane, nitropropane etc., nitrile such as acetonitrile, propionitrile, butyronitrile, valeronitrile etc.These solvents can be used alone or as a mixture.
Reaction is normally under atmospheric pressure carried out, but also can carry out adding to depress if desired.Temperature of reaction is normally-20 ℃ to 110 ℃, preferred 0 ℃ to 80 ℃.Mole number of the compound (VIII) that reaction times depends on temperature of reaction, concentration of reactants, adopted etc., but normally 0.1-20 hour, 0.5-8 hour.
In the above-mentioned reaction, be not particularly limited for the hybrid mode of used compound (II) and oxybenzene compound and acid catalyst.For example can be added in the oxybenzene compound or be added to oxybenzene compound in the mixture of described solvent, wherein can choose wantonly and contain described acid catalyst compound (II).But be to be understood that compound (II) and acid do not need to dissolve fully.Reaction system can be homogeneous phase or heterogeneous system.Be reflected in the airtight or open container and carry out.
After reaction is finished, extract product compound (III) with alkali aqueous solution.Alkali aqueous solution can be the aqueous solution of any following alkali: alkali metal hydrocarbonate, carbonate and oxyhydroxide such as sodium bicarbonate, saleratus, yellow soda ash, salt of wormwood, sodium hydroxide, potassium hydroxide etc., ammoniacal liquor, the secondary amine or the tertiary amine (low alkyl group such as methyl, ethyl, propyl group, sec.-propyl, the tertiary butyl) that replace by low alkyl group, particularly two-or three-(C
1-4Alkyl) amine, and corresponding quaternary ammonium salt.The concentration of solution preferably about 1% is to about 10% weight, but is not limited thereto scope.
Then, acid is added to reaches a certain crystal that makes up to pH in the aqueous extract and begin sedimentary numerical value.Above-mentioned acid can be from a large amount of acidic substance be suitably selected, for example, and organic acid such as mineral acid example hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid such as formic acid, acetate, propionic acid etc.Collect sedimentary crystal by filtering, obtain required compound (III) with high yield and high purity.
But, behind the aqueous extract process synthetic adsorbent and ion-exchange resin purification of above-claimed cpd (III), can directly carry out next step.
The synthetic adsorbent or the ion exchange resin that are used for above-mentioned purifying comprise that can remove dereaction second goes on foot used oxybenzene compound and solvent, and trace is present in a large amount of synthetic adsorbents or ion exchange resin in the aqueous extract.
The representative instance of said synthetic adsorbent is a porous crosslinked polymeric, and they are to prepare by the solution polymerization with cross-linking monomer such as Vinylstyrene such as vinylbenzene, methacrylic ester, vinyl pyridine.
Available ion exchange resin includes but not limited to the basic ion exchange resin that the front the first step is described, and also comprises the acid ion exchange resin.Typical acid ion exchange resin makes by sulfonic acid, carboxylic acid or phosphate group being incorporated into three dimensional network chain polymerization thing matrix.The example of said three dimensional network chain polymerization thing matrix comprises the multipolymer of vinylbenzene and cross-linking monomer such as Vinylstyrene, or acrylate copolymer or methacrylate polymer.
Above-mentioned synthetic adsorbent and exchange resin are known, literary composition specific as follows is described: SaishinKobunshi Zairyo-Gijutsu Soran (Manual of Up-to-Date PolymerMaterials and Technology), December9,1988, Tekku Shuppan KabushikiKaisha, pp. 301-306.
And these synthetic adsorbents and exchange resin can be buied from number companies.In the present invention's practice, the product Diaion as described below that preferred employing can obtain on market
HP series, SP series, WK series (WK-10, WK-11, WK-20), WA series (WA-10, WA-11, WA-20, WA-21 WA-30) (obtains) Amberlite by Mitsubishi ChemicalCorp.
RAXT series (e.g.AXT-33, ORGANO CORP.), IRA series (IRA-35, IRA-93ZU, IRA-94S) (ORGANOCORP.), and Lewatit
MP-62, MP-64, AP-49 and CA-9222 (Mitsui ToatsuChemicals, Inc.).Also can adopt normally used other synthetic adsorbent and ion exchange resin.
When adopting such synthetic adsorbent and exchange resin, preferably fill in it in post and make said aqueous extract by this post.The 3rd step
Then; compound (III) is converted into formula (IV) 7-amino-3-(2-methyl isophthalic acid; 3,4-thiadiazoles-5-yl) reaction of thiomethyl-3-cephem-4-carboxylic acid (hereinafter being referred to as " compound (IV) ") is adopted immobilized penicillin G-Ntn hydrolase to remove phenylacetyl by the deacylation reaction to carry out.
Used immobilization penicillin G-Ntn hydrolase can be derived from any microorganism and obtained in this enzymic catalytic reaction.Therefore available for example is the enzyme that the microorganism from following Pseudomonas derives and obtains: Escherichia such as intestinal bacteria (ATCC-9367, ATCC-11105 and NCIB-6743), Bacillus bacteria such as Bacillus gaterium (ATCC-14945), Alcaligenes such as Alcaligenes faecalis (MB-10), genus arthrobacter such as Arthrobactor Viscosus (ATCC-12594), nocardia such as Nocardia SP. (ATCC-13655), streptomyces is as giving birth to dyadic streptomycete (SPSL-15) and Kluyvera such as KluyveraCitrophila (KY-7844).Except above-mentioned enzyme, also can adopt other to have the enzyme of penicillin G-lactamase activity.These enzymes are known and are described in especially among day disclosure special permission (kokai) H2-138188 (138188/1990).
The immobilized penicillin G-Ntn hydrolase that the present invention adopts is to adopt conventional currently known methods, and by described penicillin G-Ntn hydrolase being fixed in any known insoluble carrier as preparing on the resin, this is that this area is commonly used.
The immobilized penicillin G-Ntn hydrolase that the present invention adopts is the product that can obtain from the market.These can be carrier-immobilized penicillin G-Ntn hydrolase by the product example that obtains on the market, and its commercial goods is called " PGA-450 " and " PGA-150 ", produce by Boehringer-Mannhelm, and they all easily obtain.
Strict control can suitably be selected and not need to the consumption of described immobilized penicillin G-Ntn hydrolase in very wide scope, but, relatively whenever, digest compound (III), this consumption is normally at the about 100kU of about 1U-, in the about 1kU scope of preferably about 100U-.
The reaction pH value scope is 6-10, preferred 7-8.The alkali that is used for controlling pH comprises the basic ion exchange resin, alkali metal hydrogen carbonate, carbonate and oxyhydroxide such as sodium bicarbonate, saleratus, yellow soda ash, yellow soda ash, sodium hydroxide, potassium hydroxide etc., ammoniacal liquor, the secondary amine or the tertiary amine (low alkyl group such as methyl, ethyl, propyl group, sec.-propyl, the tertiary butyl etc.) that replace by low alkyl group, particularly two-or three-(C
1-4Alkyl) amine, and corresponding quaternary ammonium salt etc.These alkali can be used in combination separately or suitably.
The basic ion exchange resin can be the described basic ion exchange resin relevant with the first step.
Only otherwise the influence reaction, without limits to the concentration of the alkali of control pH.
Temperature of reaction should be not high to making enzyme deactivation, normally at about 10 ℃-Yue 40 °, preferably in about 20 ℃-Yue 35 ℃ of scopes.
Common reaction solvent is water preferably, but if desired, as long as enzyme, compound (III) and product compound (IV) are not had detrimentally affect, can add following organic solvent such as low-grade fatty acid ester, for example ethyl acetate, butylacetate etc. and rudimentary aliphatic alcohol such as methyl alcohol, ethanol, Virahol etc.The consumption of the mixture of water or water and organic solvent does not need strict control, and can suitably select in very wide scope.Like this, for every part of weight compound (III), the consumption of solvent is about 10, the 000 parts of weight of about 1-, preferred about 10 parts-Yue 100 parts of weight.
Unless the carrying out of influence reaction, the hybrid mode of initial compounds (III), enzyme and solvent is unimportant.In general, be that compound (III) and enzyme are added in solvent such as the water, and in above-mentioned temperature and pH scope, stir the mixture of gained.Reaction is under atmospheric pressure carried out usually, but also can carry out adding to depress if desired, and reaction vessel can be airtight or open.
In other factors, the reaction times is depended on temperature of reaction, reactant concn and the enzyme dosage for compound (III), but at about 0.1-about 24 hours usually, preferably in about 8 hours scopes of about 0.1-.
After reaction was finished, filtration catalizer also transferred to iso-electric point (pH3.8) with acid with filtrate, made compound (IV) precipitate.Collect crystal by filtering, quantitatively obtain high-purity compound (IV).
As mentioned above, (this method comprises the methyl isophthalic acid with 2-to the traditional method of preparation compound (IV), 3,4-thiadiazoles-5-sulfydryl is incorporated on the 3-position methyl of the amino cephalosporins derivatives of 7-) reaction efficiency, compound (IV) purity and cost all unsatisfactory.
In contrast, the inventive method according to comprising the above-mentioned the first step, second step and the 3rd step can obtain high yield and highly purified midbody compound (IV).The 4th step
In order to obtain required formula V compound, make compound (IV) and mixed anhydride reaction by compound (IV) (being referred to as mixed acid anhydride).(a) preparation mixed acid anhydride
Can prepare the used mixed acid anhydride of the present invention by for example following method.Therefore, in the presence of alkali, in organic solvent, make the 1H-tetrazolium-1-acetate of formula (VI)
Carboxylic acid halides or the reaction of halo alkyl carbonate with formula (VII):
Wherein Y represents halogen atom such as chlorine, bromine or iodine atom, and R
2Expression can be had 1-7 by what one or more halogen atom replaced, and preferred 2-5, the low alkyl group of carbon atom, perhaps R
2Expression can be had a 1-7 by what one or more halogen atom replaced, and preferred 2-5, the lower alkoxy of carbon atom.
For formula (VII) compound, R
2The group of expression is C
1-7, preferred C
1-5Alkyl or alkoxyl group or haloalkyl or halogenated alkoxy, corresponding described alkyl or alkoxyl group can be by 1-14, preferred 1-5, more preferably 1-2 halogen atom replaces.Halogen atom can be for example chlorine, bromine or iodine atom.
Formula (VII) compound (hereinafter being referred to as " compound (VII) ") that can prepare described mixed acid anhydride with formula (VI) 1H-tetrazolium-1-acetate can be the described 2-8 of containing, the lower fatty acid carboxylic acid halides of preferred 3-6 carbon atom.Specifically, can be the carboxylic acid halides (chlorine, bromine, iodine) of acetate, propionic acid, PIVALIC ACID CRUDE (25), valeric acid, isovaleric acid etc., bromoacetyl chloride, 2-chlorpromazine chloride, 3-chlorpromazine chloride, 4-chlorobutanoylchloride etc.
Also can comprise wherein by R by the halo alkyl carbonate of formula (VII) expression
2The alkoxyl group of expression is C
1-7, preferred C
1-4Alkoxyl group, be the compound of chlorine, bromine or iodine atom as methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy or tert.-butoxy and by the halogen atom that Y represents.
In order to prepare above-mentioned mixed acid anhydride, normally about 50 moles of every mole of formula (VI) 1H-tetrazolium-1-acetate relatively, the consumption of compound (VII), about 10 moles of preferably about 1-at about 1-.
The alkali that adopts in this reaction can be the basic ion exchange resin, alkali metal hydrocarbonate, carbonate and oxyhydroxide such as sodium bicarbonate, saleratus, yellow soda ash, salt of wormwood, sodium hydroxide, potassium hydroxide etc., ammoniacal liquor, the secondary amine or the tertiary amine (low alkyl group such as methyl, ethyl, propyl group, sec.-propyl, the tertiary butyl etc.) that replace by low alkyl group, particularly two-or three-(C
1-4Alkyl) amine, and corresponding quaternary ammonium salt.These alkali can be used in combination separately or suitably.
The basic ion exchange resin can be the described basic ion exchange resin relevant with the first step.
For every mole compound (VI), normally about 50 moles of the consumptions of alkali, about 10 moles of preferably about 0.5-at about 0.1-.(if the basic ion exchange resin then is for every mole compound (VI), about 50 moles of the about 0.1-of consumption of the resin of corresponding its exchange capacity, preferably about 0.5-10 mole.)
In order to prepare mixed acid anhydride, most preferably be used mol ratio or first-class substantially mol ratios such as compound (VI), compound (VII) and alkali.
Used organic solvent comprises various ketone such as acetone when the described mixed acid anhydride of preparation, methyl ethyl ketone, metacetone, methyl iso-butyl ketone (MIBK) etc., ester such as methyl-formiate, ethyl formate, propyl formate, methyl acetate, ethyl acetate, propyl acetate, methyl propionate, ethyl propionate etc., fatty alcohol such as methyl alcohol, ethanol, propyl alcohol etc., ether such as diethyl ether, Di Iso Propyl Ether, dibutyl ether, tetrahydrofuran (THF) diox etc., halohydrocarbon such as methylene dichloride, chloroform, bromofom, tetracol phenixin etc., nitro-paraffin such as Nitromethane 99Min., nitroethane, nitropropane etc., nitrile such as acetonitrile, propionitrile, butyronitrile, valeronitrile etc., and these solvents can be used alone or as a mixture.In above-mentioned solvent, preferred especially halohydrocarbon and ether.
For every part of compound (VI), normally about 1 part-Yue 1000 parts of weight of the amount of organic solvent, preferably about 5 parts-Yue 100 parts of weight.
Reaction conditions can used routinely condition suitably be selected.Usually, normally about-50 ℃ to about 50 ℃ of temperature of reaction, preferred-30 ℃ to about 10 ℃ approximately.About 24 hours of normally about 0.1-of reaction times, about 8 hours of preferably about 0.1-.
After reaction is finished, preferably reaction mixture is maintained at about 0 ℃ of 0-and made mixed acid anhydride aging in about 8 hours.(b) reaction of mixed acid anhydride and compound (IV)
Like this Zhi Bei corresponding mixed acid anhydride in the presence of alkali in organic solvent, with formula (IV) 7-amino-3-(2-methyl isophthalic acid, 3,4-thiadiazoles-5-yl) thiomethyl-3-cephem-4-carboxylic acid reaction, obtain formula V 7-(1H-tetrazolium-1-yl)-acetylaminohydroxyphenylarsonic acid 3-(2-methyl isophthalic acid, 3,4-thiadiazoles-5-yl) thiomethyl-3-cephem-4-carboxylic acid.
In this reaction, for every mole compound (IV), the consumption of mixed acid anhydride is about 50 moles of about 1-, about 10 moles of preferably about 1-.As mixed acid anhydride, the reaction mixture that obtains from preceding step (a) can so use.Owing to contain the mixed acid anhydride that obtains in the reaction mixture and be about 60%, this situation should be taken into account when therefore in above-mentioned scope, selecting the consumption of mixed acid anhydride and compound (IV) to about 80%.
In this reaction, used alkali is included in the alkali described in " (a) preparation mixed acid anhydride ".For every mole compound (IV), about 100 moles of the normally about 1-of the consumption of alkali, about 30 moles of preferably about 1-.(if the basic ion exchange resin then is for every mole compound (IV)), the consumption of the resin of corresponding its exchange capacity is about 100 moles of about 1-, about 30 moles of preferably about 1-.) can adopt the alkali of proper ratio not only a kind of.
Used organic solvent can be the organic solvent or the solvent mixture of any kind of in this reaction, and wherein compound (IV) and mixed acid anhydride can be partly dissolved and solvent does not influence the carrying out of reaction at least.In other organic solvent, the example of solvent comprises ketone such as acetone, methyl ethyl ketone, metacetone, methyl iso-butyl ketone (MIBK) etc., ester such as methyl-formiate, ethyl formate, propyl formate, methyl acetate, ethyl acetate, propyl acetate, methyl propionate, ethyl propionate etc., fatty alcohol such as methyl alcohol, ethanol, propyl alcohol etc., ether such as diethyl ether, Di Iso Propyl Ether, dibutyl ether, tetrahydrofuran (THF) diox etc., halohydrocarbon such as methylene dichloride, chloroform, bromofom, tetracol phenixin etc., nitro-paraffin such as Nitromethane 99Min., nitroethane, nitropropane etc., nitrile such as acetonitrile, propionitrile, butyronitrile, valeronitrile etc.Preferred especially halohydrocarbon and ether.
For every part of weight compound (IV), the consumption of solvent is 1-100 part weight, preferred 5-20 part weight.
Reaction is normally under atmospheric pressure carried out, but also can carry out adding to depress if desired.Temperature of reaction is normally-50 ℃ to 110 ℃, preferred-30 ℃ to 10 ℃.Reaction times is depended on the consumption of temperature of reaction, concentration of reactants and mixed acid anhydride, but normally 0.1-24 hour, preferred 1-8 hour.
The hybrid mode of compound in the above-mentioned steps (IV), mixed acid anhydride and alkali is not crucial.Therefore, for example with the homogeneous phase solution of compound (IV) in said organic solvent.Progressively be added in the mixed acid anhydride solution for preparing previously.The joining day of alkali is not crucial, as long as described compound (IV) solution that is added in of alkali mixes with mixed acid anhydride before.
The required compound that obtains like this (V) is a Kefzol, can separate and purifying by ordinary method.Preferred purification process comprises water is added in the reaction mixture so that Kefzol is extracted in the water layer, and regulates pH and be acid, then recrystallization.If desired, according to a conventional method, the water layer that above-mentioned steps is obtained carries out activated carbon treatment or with synthetic adsorbent or ion exchange resin treatment, these methods illustrated in the 3rd step.
Therefore, according to the present invention, be starting raw material with compound (I), carry out the first, second, third and the 4th above-mentioned step, can obtain highly purified Kefzol.
And, by carrying out described first, second and third step, can high yield and high purity, do not need any purifying to prepare the intermediate that is used to prepare Kefzol, it is formula (IV) 7-amino-3-(2-methyl isophthalic acid, 3,4-thiadiazoles-5-yl) thiomethyl-3-cephem-4-carboxylic acid, its result's final product Kefzol also can high yield and high purity obtain.
Embodiment
Following embodiment further describes the present invention to limit the scope of the invention by any way.
Be to be understood that it all is known compounds that the intermediate and the 4th that obtains in first, second and each step of third step goes on foot the Kefzol that obtains.Intermediate and Kefzol are carried out Spectrum Analysis, i.e. IR, NMR and mass spectrum and high pressure liquid chromatography (HPLC), the data of gained and the real corresponding data consistent of sample, thus confirmed structure.
Embodiment 1
(1) the first step prepares 7-phenyl acetylaminohydroxyphenylarsonic acid 3-(2-methyl isophthalic acid, 3,4-thiadiazoles-5-yl) thiomethyl-3-cephem-4-carboxylic acid to the methoxy-benzyl ester
Add 7-phenyl acetylaminohydroxyphenylarsonic acid 3-chloromethyl-3-cephem-4-carboxylic acid to methoxy-benzyl ester (abbreviating " GCLE " here as) and 100ml acetone to the four-hole boiling flask of volume 200ml, and under agitation with mixture heating up to 35 ℃.In this method, most of GCLE does not dissolve fully and has just formed soup compound.
On the other hand, with 3.3g 5-methyl-2-sulfydryl-1,3, the 4-thiadiazoles is dissolved in the 22.6ml 1N aqueous sodium hydroxide solution.In 20-30 minute, this drips of solution is added in the above-mentioned soup compound.When dripping, soup compound becomes homogeneous phase solution, and crystallization occurs in several minutes.
Dripped back 10 minutes, and added 4.2m 10.5 N-hydrochloric acid and also stirred the mixture 10 minutes, be added dropwise to 89ml water then, will react to mix and be cooled to 5 ℃ or lowlyer make crystallization and wore out 1 hour.
After aging, collect 7-phenyl acetylaminohydroxyphenylarsonic acid 3-(2-methyl isophthalic acid, 3,4-thiadiazoles-5-yl) thiomethyl-3-cephem-4-carboxylic acid by suction strainer and wash to methoxy-benzyl ester (hereinafter referred is GTDE) crystal and with the 10ml cold acetone.After being higher than the crystal that 40 ℃ of following vacuum-dryings obtain like this, obtain the dry GTDE (productive rate 97%) of 11.64g.(2) second steps preparation 7-phenyl acetylaminohydroxyphenylarsonic acid 3-(2-methyl isophthalic acid, 3,4-thiadiazoles-5-yl) thiomethyl-3-cephem-4-carboxylic acid
Add 60ml m-cresol and the 0.24ml vitriol oil and they are heated to 35 ℃ to the four-hole boiling flask of volume 220ml.To wherein adding anhydrous GTDE of 10g and reaction, temperature of reaction is controlled in the 30-40 ℃ of scope, is reflected under the monitoring to carry out 2-3 hour then.
After reaction is finished, add the 200ml butylacetate and mixture is cooled to 5 ℃ or lower.In this refrigerative reaction mixture, add 65ml 4% sodium bicarbonate aqueous solution to extract 7-phenyl acetylaminohydroxyphenylarsonic acid 3-(2-methyl isophthalic acid, 3,4-thiadiazoles-5-yl) thiomethyl-3-cephem-4-carboxylic acid (hereinafter referred is GTDA) in water layer, separate then.And then in butylacetate/m-cresol layer, add 10ml water, and remaining GTDA is further extracted in the water layer.Mix twice moisture GDTA extract and wash, and abandon the butylacetate layer with the 300ml butylacetate.
The GTDA-sodium solution that makes gained is by high (energy) porous resin bead post (25ml, AXT-33 resin, ORGANO CORP.) product.Use this post of 75ml water washing then.(3) the 3rd steps preparation 7-amino-3-(2-methyl isophthalic acid, 3,4-thiadiazoles-5-yl) thiomethyl-3-cephem-4-carboxylic acid
Washing lotion precipitation with the above-mentioned second moisture GTDA extract (with the sodium bicarbonate aqueous solution form) that goes on foot and mistake post; be added to then and contain the penicillin G-Ntn hydrolase (trade(brand)name " PEG-450 " of 4g carrier-fixedly; the Boehringer-Mannhem product) in the enzymic catalytic reaction device; and under agitation keep temperature of reaction and pH respectively under 28 ℃ and 7.7-8.1 situation, carry out enzymatic deacylation reaction.
With 1N-ammoniacal liquor control pH value.The consumption of ammoniacal liquor stops, and has confirmed reaction end then.When reaction is finished, filter enzyme and use distilled water wash.
The solution of 7-amino-3-(2-methyl isophthalic acid, 3,4-thiadiazoles-5-yl) thiomethyl-3-cephem-4-carboxylic acid (hereinafter referred is " ATDA ") of almost quantitatively making is cooled to 5 ℃ or lower, and pH is transferred to 3.8 with 3N hydrochloric acid.After adjusting pH, at 5 ℃ or more make solution aging under the low temperature.By the ATDA crystal of filtration collecting precipitation, and use 20ml cold water, use the 20ml washing with acetone then.Be no more than the ATDA crystal that 40 ℃ of following vacuum-dryings obtain like this, obtaining the dry ATDA of 5.5g (based on GTDE, second step and the 3rd step common overall yield are 94%).
Synthetic Kefzol (i) preparation of (4) the 4th steps mixed acid anhydride
3.72g 1H-tetrazolium-1-acetate and 40ml methylene dichloride are housed in the four-hole boiling flask of volume 100ml, then add the 2.94g triethylamine, and mixture is cooled to-10 ℃.At-10 ℃ or more add the 3.32g pivalyl chloride under the low temperature.Then temperature is transferred to 0 ℃ and under this temperature, make mixture ageing 1 hour.The dichloromethane solution that (ii) prepares ATDA
4.3g diisopropylamine and 30ml methylene dichloride are housed in the four-hole boiling flask of volume 100ml, are dissolved in 2.94g ATDA in this dichloromethane solution and are cooled to-20 ℃ or lower.The (iii) reaction of synthetic Kefzol
In 20-30 minute,, in the mixed acid anhydride solution of front (i) preparation, be added dropwise to the above-mentioned (ii) dichloromethane solution of the ATDA of preparation in temperature-20 ℃ or more under the low temperature.
After dripping, stop cooling and in stirring at room mixture 30 minutes.After determining reaction end, in the back mixing compound, add 60ml water with the extraction Kefzol, and separate water layer.In dichloromethane layer, add 40ml water then with further extraction Kefzol.Merge twice Kefzol extract and adjust pH to 4.5.
In the aqueous extract of this Kefzol, add the 30ml methylene dichloride then.Stir the mixture, separate each phase and abandon the methylene dichloride phase.Add the 1.5g gac and stirred the mixture 15 minutes to aqueous phase.Filtering gac then, and regulate filtrate pH to 2 with 3N hydrochloric acid and make it 5 ℃ or more crystallization and aging under the low temperature.After aging, collect the Kefzol crystal and use the 20ml cold water washing by filtering.At 40 ℃ or vacuum-drying crystal under the low temperature more, obtain the Kefzol crystal of 6.07g (productive rate 92%).
Claims (9)
1. the method for preparing formula V 7-(1H-tetrazolium-1-yl)-acetylaminohydroxyphenylarsonic acid 3-(2-methyl isophthalic acid, 3,4-thiadiazoles-5-yl) thiomethyl-3-cephem-4-carboxylic acid:
The method comprising the steps of:
(i) in the presence of alkali at least a solvent that is selected from organic solvent and water, make formula (I) compound
Wherein X represents halogen atom and R
1The expression carboxyl-protecting group, with formula (VIII) 2-methyl-5-sulfydryl-1,3, the reaction of 4-thiadiazoles
Perhaps at least a solvent that is selected from organic solvent and water, make the basic salt reaction of formula (I) compound and formula (VIII) compound, obtain formula (II) compound:
R wherein
1The expression carboxyl-protecting group,
(ii) in the presence of oxybenzene compound, make formula (II) compound carry out de-esterification, obtain formula (III) 7-phenyl acetylaminohydroxyphenylarsonic acid 3-(2-methyl isophthalic acid, 3,4-thiadiazoles-5-yl) thiomethyl-3-cephem-4-carboxylic acid:
(iii) adopt immobilized penicillin G-Ntn hydrolase to make formula (III) compound carry out the deacylation reaction and slough phenylacetyl, obtain formula (IV) 7-amino-3-(2-methyl isophthalic acid, 3,4-thiadiazoles-5-yl) thiomethyl-3-cephem-4-carboxylic acid
(iv) in the presence of alkali in organic solvent, make formula (IV) compound and mixed anhydride reaction, wherein mixed acid anhydride be in the presence of alkali in organic solvent, through type (VI) 1H-tetrazolium-1-acetate
With the prepared in reaction of formula (VII) carboxylic acid halides or halo alkyl carbonate,
Wherein Y represents halogen atom and R
2Low alkyl group with 1-7 carbon atom or R that expression can be replaced by one or more halogen atom
2The lower alkoxy that expression can be replaced by one or more halogen atom with 1-7 carbon atom.
2. represent the chlorine atom according to the X in the formula of the process of claim 1 wherein (I), and the R in formula (I) and the formula (II)
1Expression is to methoxy-benzyl.
3. according to the process of claim 1 wherein that used alkali is selected from alkali metal hydrocarbonate, alkaline carbonate and alkali metal hydroxide in step (i), ammoniacal liquor, two-or three-(C
1-4Alkyl) amine, and corresponding quaternary ammonium salt and deacidite.
According to the process of claim 1 wherein step (ii) in used oxybenzene compound be m-cresol.
5. according to the process of claim 1 wherein that in step the de-esterification of formula (II) compound carries out (ii) in the oxybenzene compound in the presence of acid.
6. according to the method for claim 1; this method comprises that further with alkali aqueous solution step (ii) being obtained reaction mixture behind the de-esterification extracts; with synthetic adsorbent or ion-exchange resin purification, and the purified product deacylation is sloughed phenylacetyl in (iii) in step.
According to the process of claim 1 wherein step (iii) in used immobilization penicillin G-Ntn hydrolase be enzyme with penicillin G-lactamase activity.
8. according to the process of claim 1 wherein R in (VII)
2Expression C
1-5Alkyl or alkoxyl group or the C that is replaced by 1-5 halogen atom
1-5Alkyl or alkoxyl group.
9. be to be selected from following at least a alkali according to the process of claim 1 wherein at the (iv) used alkali of step: deacidite, alkali metal hydroxide, alkali metal hydrocarbonate, alkaline carbonate, two-or three-(C
1-4Alkyl) amine, and corresponding quaternary ammonium salt.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8261976A JPH10101679A (en) | 1996-10-02 | 1996-10-02 | Production of cefazolin |
| JP261976/96 | 1996-10-02 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1178220A CN1178220A (en) | 1998-04-08 |
| CN1084750C true CN1084750C (en) | 2002-05-15 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN96117398A Expired - Fee Related CN1084750C (en) | 1996-10-02 | 1996-12-20 | Process for producing cefazolin |
Country Status (6)
| Country | Link |
|---|---|
| JP (1) | JPH10101679A (en) |
| CN (1) | CN1084750C (en) |
| ES (1) | ES2129006B1 (en) |
| IN (1) | IN187033B (en) |
| IT (1) | IT1289763B1 (en) |
| TW (1) | TW434317B (en) |
Families Citing this family (10)
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| CN100344635C (en) * | 2003-07-22 | 2007-10-24 | 广州白云山制药股份有限公司 | 7-phenylacetylamino-3-pyridinylmethyl-3-cephalosporin-4-carboxyl acid p-methoxybenzyl ester crystal and its preparation method |
| CN100418972C (en) * | 2004-01-19 | 2008-09-17 | 广州白云山制药股份有限公司 | Cephe alkene onium salt compound and its preparation and use in preparation of cefepime |
| JP4046708B2 (en) * | 2004-06-04 | 2008-02-13 | 明治製菓株式会社 | Method for producing 3-alkenylcephem compound |
| CN101735248A (en) * | 2008-11-07 | 2010-06-16 | 日本化学工业株式会社 | Process for producing 3-alkenylcephem compounds |
| CN102321101B (en) * | 2011-07-28 | 2015-07-15 | 哈药集团制药总厂 | Preparation method of cefazolin sodium |
| CN103965215B (en) * | 2014-04-30 | 2016-04-27 | 悦康药业集团有限公司 | A kind of Cephazolin sodium compound and aseptic powder injection thereof |
| CN104910188B (en) * | 2015-05-26 | 2017-07-04 | 齐鲁安替制药有限公司 | A kind of synthetic method of Cefazolin acid |
| CN105017286B (en) * | 2015-07-09 | 2017-11-28 | 山东罗欣药业集团股份有限公司 | A kind of preparation method of cephalo-type anti-infectives |
| CN105153198B (en) * | 2015-09-17 | 2017-06-27 | 浙江华方药业股份有限公司 | A kind of preparation method of Ceftibuten |
| CN111979287A (en) * | 2020-09-21 | 2020-11-24 | 湖北凌晟药业有限公司 | Preparation method of 7-phenylacetylamino-3-nor-3-cephem-4-carboxylic acid |
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| JP6326112B2 (en) * | 2016-10-21 | 2018-05-16 | 株式会社三共 | Game machine |
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| BE824028A (en) * | 1974-01-23 | 1975-06-30 | PROCESS FOR THE PURIFICATION OF CEPHALOSPORINS CONTAINING A FREE CARBOXYLIC ACID GROUP | |
| US3954745A (en) * | 1974-09-12 | 1976-05-04 | Eli Lilly And Company | Process for preparing cefazolin |
| GB9115287D0 (en) * | 1991-07-15 | 1991-08-28 | Antibioticos Spa | Process for the preparation of cephalosporins intermediates |
-
1996
- 1996-10-02 JP JP8261976A patent/JPH10101679A/en active Pending
- 1996-12-10 TW TW085115282A patent/TW434317B/en not_active IP Right Cessation
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| Publication number | Publication date |
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| IT1289763B1 (en) | 1998-10-16 |
| JPH10101679A (en) | 1998-04-21 |
| ITTO961040A1 (en) | 1998-06-18 |
| ES2129006A1 (en) | 1999-05-16 |
| CN1178220A (en) | 1998-04-08 |
| IN187033B (en) | 2001-12-29 |
| TW434317B (en) | 2001-05-16 |
| ES2129006B1 (en) | 2000-01-16 |
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