CN104962600A - Process for production of 3-alkenylcephem compound - Google Patents
Process for production of 3-alkenylcephem compound Download PDFInfo
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- CN104962600A CN104962600A CN201510382381.9A CN201510382381A CN104962600A CN 104962600 A CN104962600 A CN 104962600A CN 201510382381 A CN201510382381 A CN 201510382381A CN 104962600 A CN104962600 A CN 104962600A
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Abstract
The present invention provides a process for production of 3-alkenylcephem compound. Enzymatic reaction of a salt of 7-amino-3-[(E/Z)-2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid is performed to obtain an aqueous solution containing phenylacetic acid or its derivative as a byproduct of the deprotection reaction, the phenylacetic acid or its derivative is extracted from the aqueous solution with an organic solvent or precipitated from the aqueous solution by crystallization, and the aqueous solution is brought into contact with activated carbon to increase the content of 7-amino-3-[2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid or its salt, wherein R1 represents benzyl or 4-phenylene ether methyl and M represents univalent positive ion.
Description
The divisional application that the application is the applying date is on November 3rd, 2009, application number is 200910207425.9, denomination of invention is the application of " manufacture method of 3-alkenyl cephem compounds ".
Technical field
The present invention relates to a kind of 7-amino-3-[(E/Z)-2-(4-methylthiazol-5-base) vinyl]-3-cephem-4-carboxylic acid or its salt (following, these are generically and collectively referred to as " alkenyl cephem compounds ") manufacture in, make the containing ratio of Z body improve than E body and reduce the method for impurity.
Background technology
7-amino-3-[2-(4-methylthiazol-5-base) vinyl]-3-cephem-4-carboxylic acid or its salt are as the useful material of the manufacture intermediate of cephalosporins.It is 2 kinds of isomer that Z configuration and E configure that this compound exists in the three-dimensional arrangement of the alkenyl of 3.Known to these 2 kinds of isomer are manufactured cephalosporins as raw material, what show the anti-microbial effect of excellence as medicinal antibiosis agent is using the cephalosporins of Z body as raw material.Therefore, when synthesizing cephalosporins by 7-amino-3-[2-(4-methylthiazol-5-base) vinyl]-3-cephem-4-carboxylic acid or its salt, it is very important for only there is Z body in reaction system and there is not E body as far as possible.
From this viewpoint, propose in patent documentation 1: 7-amino-3-[2-(4-methylthiazol-5-base) vinyl]-3-cephem-4-carboxylic acid Z body being mixed with E body exist or the aqueous solution of its an alkali metal salt and high porous polymer, gac effect, improve the containing ratio of Z body.As the high porous polymer used in the method, exemplify acrylic resin, phenolic aldehyde system resin, phenylethylene resin series.On the other hand, as gac, use the common gac that zinc chloride charcoal, water vapour charcoal are such.
According to the method recorded in aforementioned documents, the high 7-amino-3-of the containing ratio of Z body [2-(4-methylthiazol-5-base) vinyl]-3-cephem-4-carboxylic acid or its an alkali metal salt can be obtained.But, in order to be used by the manufacture intermediate of this compound as cephalosporins, expect the containing ratio improving Z body further.
In addition, the salt of known 7-amino-3-[2-(4-methylthiazol-5-base) vinyl]-3-cephem-4-carboxylic acid is by obtaining the salt of 7-substituted acyl amino-3-[2-(4-methylthiazol-5-base) vinyl]-3-cephem-4-carboxylic acid to carry out the deprotection reaction of 7 amido linkages for enzyme reaction.Contain by product, i.e. the toluylic acid or derivatives thereof of deprotection reaction as impurity in the compound obtained by this deprotection reaction.When the compound these being contained impurity is used for the manufacture intermediate of cephalosporins, produces the problem hindering antibiotic building-up reactions such, therefore, be necessary to reduce these impurity.
From this viewpoint, propose in patent documentation 2: use the organic solvents such as methyl iso-butyl ketone (MIBK) to remove the toluylic acid or derivatives thereof as impurity from the aqueous solution extraction after aforementioned deprotection reaction, make these content be below 100ppm.
Patent documentation 1: Japanese Unexamined Patent Publication 2005-343854 publication
Patent documentation 2: Japanese Unexamined Patent Publication 2002-316991 publication
Summary of the invention
the problem that invention will solve
Therefore, the object of the invention is to, provide the containing ratio of Z body high and as the poor 7-amino of toluylic acid or derivatives thereof-3-[2-(4-methylthiazol-5-base) the vinyl]-3-cephem-4-carboxylic acid of impurity or the manufacture method of its salt.
the method of dealing with problems
The present invention is by providing the manufacture method of 7-amino-3-[(E/Z)-2-(4-methylthiazol-5-base) the vinyl]-3-cephem-4-carboxylic acid shown in a kind of formula (3) or its salt, this manufacture method improves the containing ratio of 7-amino-3-[(Z)-2-(4-methylthiazol-5-base) the vinyl]-3-cephem-4-carboxylic acid shown in following formula (2) or its salt, it is characterized in that, by the salt of 7-substituted acyl amino-3-[(E/Z)-2-(4-methylthiazol-5-base) the vinyl]-3-cephem-4-carboxylic acid shown in following formula (1) for enzyme reaction to carry out the deprotection reaction of 7 amido linkages, obtain the by product comprising this deprotection reaction, i.e. 7-amino-3-[(E/Z)-2-(4-methylthiazol-5-base) the vinyl]-3-cephem-4-carboxylic acid shown in following formula (3) of toluylic acid or derivatives thereof or the aqueous solution of its salt, then, carry out the treatment process of following (A) or (B), then, the aqueous solution of [(E/Z)-2-(4-methylthiazol-5-base) the vinyl]-3-cephem-4-carboxylic acid of the 7-amino-3-shown in the following formula after this treatment process (3) or its salt is contacted with gac process, thus achieve aforementioned object.
(A) with an organic solvent, to comprise aforementioned deprotection reaction by product, i.e. toluylic acid or derivatives thereof following formula (3) shown in 7-amino-3-[(E/Z)-2-(4-methylthiazol-5-base) vinyl]-3-cephem-4-carboxylic acid or the aqueous solution of its salt carry out the operation of the extraction treatment of aforementioned toluylic acid or derivatives thereof.
(B) carry out making this 7-amino-3-[(E/Z)-2-(4-methylthiazol-5-base) vinyl]-3-cephem-4-carboxylic acid or its salt from comprise aforementioned deprotection reaction by product, i.e. toluylic acid or derivatives thereof following formula (3) shown in 7-amino-3-[(E/Z)-2-(4-methylthiazol-5-base) vinyl]-3-cephem-4-carboxylic acid or its salt the aqueous solution the operation of crystallization process separated out.
In formula, R
lrepresent benzyl or Phenoxymethyl.M represents the positively charged ion of monovalence.
Embodiment
In the present invention; first; by by the salt of 7-substituted acyl amino-3-[(E/Z)-2-(4-methylthiazol-5-base) the vinyl]-3-cephem-4-carboxylic acid shown in previously described formula (1) for enzyme reaction with the deprotection reaction of amide protecting group carrying out 7, thus obtain the aqueous solution of the salt of 7-amino-3-[(E/Z)-2-(4-methylthiazol-5-base) the vinyl]-3-cephem-4-carboxylic acid shown in previously described formula (3).As long as this salt is for water-soluble, its kind is not particularly limited.Such as an alkali metal salt, ammonium salt can be enumerated as water miscible salt.Therefore, as the positively charged ion of the monovalence shown in the M in previously described formula (1), the alkalimetal ions such as sodium ion, ammonium ion can be enumerated.
As the solvent of aforesaid enzyme reaction, from the view point of playing enzymic activity to greatest extent, preferably use water.The pH of enzyme reaction is the principal element had an impact to the activity of enzyme.Also depend on the kind of enzyme, from this viewpoint, preferred pH maintains 7.0 ~ 9.0, is in particular 7.2 ~ 8.8.Various alkali aqueous solution, the such as alkali metal hydroxide such as sodium hydroxide, potassium hydroxide can be used; The alkali metal hydrocarbonates such as sodium bicarbonate; The aqueous solution of the alkaline carbonate such as sodium carbonate, salt of wormwood, ammoniacal liquor etc. maintains pH.The temperature of enzyme reaction is also the principal element had an impact to the activity of enzyme.From this viewpoint, also depend on the kind of enzyme, preferably the temperature of reaction system is maintained 20 ~ 40 DEG C, be in particular 22 ~ 38 DEG C.Reaction times is not criticality in the present invention.Generally carry out reacting until the compound shown in formula (1) disappears from reaction system.Using the scope of aforesaid pH and temperature as condition, the reaction times can be generally 1 ~ 3 hour.
The concentration adding the compound shown in previously described formula (1) contained by the solution in enzyme solution is not criticality in the present invention, as long as the lower concentration of the degree do not separated out for crystal.Generally can be the scope of 1 ~ 10 % by weight.
As used enzyme, existing known penicillin G acylase can be used with no particular limitation.Penicillin-G-amidases PGA-150, PGA-300, PGA-450 that such as Boehringer Mannheim manufactures can be used; The penicillin G acylase that Dalas BiotechLimited manufactures; The Penicillin-G-amidases that Roche MolecularBiochemicals manufactures; The IPA-750 of Hu'nan Fulaige Biological Technology Co. Ltd.; The Syntha CLEC-PA etc. that Atlus Biologics Inc. manufactures.
The consumption of enzyme also depends on its kind, and relative to the compound shown in 100 weight part formulas (1), the consumption of enzyme is preferably 30 ~ 150 weight parts, is particularly preferably 50 ~ 100 weight parts.
Compound shown in formula (1) synthesizes by known method.Such as; by carrying out the deprotection reaction of 4 carboxylic acid protecting groups to 7-substituted acyl amino-3-[(E/Z)-2-(4-methylthiazol-5-base) the vinyl]-3-cephem-4-carboxylic acid cpd shown in following formula (4), thus the compound shown in formula (1) can be obtained.As deprotection reaction, can adopt as the known various methods of the deprotection reaction of the carboxylic acid protecting group in 'beta '-lactam compounds.Such as, that record in Japanese Unexamined Patent Publication 61-263984 publication, in phenol deprotection reaction can be adopted.
In formula, R
lidentical with aforementioned definitions, R
2represent carboxylic acid protecting group.
In formula (4), as R
2represented carboxylic acid protecting group, can enumerate such as can by the benzyl of electron donating group-substituted, can by the diphenyl-methyl etc. of electron donating group-substituted.As electron-donating group, the alkyl of such as carbon number 1 ~ 6 can be enumerated; The alkoxyl group etc. of hydroxyl, carbon number 1 ~ 6.
In the compound shown in previously described formula (1) contained by solution before enzyme reaction and the compound shown in previously described formula (3) contained by solution after enzyme reaction, the ratio that exists of Z body and E body is not particularly limited.There is the manufacturing condition etc. that ratio depends on compound in this.Represent with the containing ratio calculated based on the calculating formula of the E body containing ratio used in embodiment described later, E body containing ratio is generally 0.3 ~ 20%, is in particular 2 ~ 12%.For purposes of the present invention, expect that the ratio that exists of Z body exists ratio, the manufacture method of the application of the invention fully higher than E body, can be easy and obtain Z body with high yield.
By above enzyme reaction, obtain the aqueous solution of the salt of the compound shown in formula (3).In this enzyme reaction, the deprotection of the amide protecting group of 7 in the compound shown in through type (1) and the toluylic acid or derivatives thereof (following, these are generically and collectively referred to as " toluylic acid class ") that generates as by product.Containing the toluylic acid class of about 16 ~ 17% in the aqueous solution of the salt of the compound shown in formula (3) obtained by enzyme reaction.This containing ratio is the value calculated based on the calculating formula of the toluylic acid containing ratio used in embodiment described later.This toluylic acid class is impurity for the high alkenyl cephem compounds of the target compound of this manufacture method, the i.e. containing ratio of Z body, is therefore necessary that get rid of it exists as far as possible.
Therefore, in the present invention, in order to reduce the content of toluylic acid or derivatives thereof, next the aqueous solution of the salt of the compound shown in the aforementioned formula (3) obtained by enzyme reaction is carried out to the treatment process of following (A) or (B).
(A) with an organic solvent, to comprise aforementioned deprotection reaction by product, i.e. toluylic acid or derivatives thereof following formula (3) shown in 7-amino-3-[(E/Z)-2-(4-methylthiazol-5-base) vinyl]-3-cephem-4-carboxylic acid or the aqueous solution of its salt carry out the operation of the extraction treatment of aforementioned toluylic acid or derivatives thereof.
(B) carry out making this 7-amino-3-[(E/Z)-2-(4-methylthiazol-5-base) vinyl]-3-cephem-4-carboxylic acid or its salt from comprise aforementioned deprotection reaction by product, i.e. toluylic acid or derivatives thereof following formula (3) shown in 7-amino-3-[(E/Z)-2-(4-methylthiazol-5-base) vinyl]-3-cephem-4-carboxylic acid or its salt the aqueous solution the operation of crystallization process separated out.
Below, the treatment process of aforementioned (A) is described.
From the view point of the extraction removing reliably carrying out toluylic acid class, preferably before extraction treatment, the PH of the aqueous solution of the salt of the compound shown in the formula obtained by aforementioned enzyme reaction (3) is adjusted to acidic region, specifically less than 2, particularly less than 1 by mineral acid, the salt of the compound shown in the formula (3) in the aqueous solution made the form of corresponding inorganic acid salt.As mineral acid, hydrochloric acid, nitric acid, sulfuric acid etc. can be enumerated.
As the organic solvent for extraction treatment, the lower alkyl esters class of (1) low-grade carboxylic acid, (2) ketone, (3) ethers, (4) substituted or unsubstituted aromatic hydrocarbon based, (5) halogenated hydrocarbon, (6) aliphatic hydrocarbon, (7) cycloalkane can be enumerated.These organic solvents can be used alone or in combination of two kinds or more.As the lower alkyl esters class of (1) low-grade carboxylic acid, methyl-formiate, ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, butylacetate, methyl propionate, ethyl propionate etc. can be enumerated.As (2) ketone, methyl propyl ketone, methyl butyl ketone, methyl iso-butyl ketone (MIBK), metacetone etc. can be enumerated.As (3) ethers, diethyl ether, ethyl propyl ether, ethyl-butyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, methylcyclohexane, glycol dimethyl ether etc. can be enumerated.Substituted or unsubstituted aromatic hydrocarbon based as (4), benzene,toluene,xylene, chlorobenzene, phenylmethylether etc. can be enumerated.As (5) halogenated hydrocarbon, methylene dichloride, chloroform, ethylene dichloride, trichloroethane, ethylene dibromide, propylene dichloride, tetracol phenixin etc. can be enumerated.As (6) aliphatic hydrocarbon, pentane, hexane, heptane, octane etc. can be enumerated.As (7) cycloalkane, pentamethylene, hexanaphthene, suberane, cyclooctane etc. can be enumerated.
In the middle of these organic solvents, preferably 20 DEG C time to the solubleness of water be less than 1 % by weight material.Specifically, preferred toluene, chloroform, chlorobenzene etc., particularly preferably toluene.
Use polarity high, to the organic solvent that the solubleness of water is high time, organic solvent dissolves in the aqueous solution of the alkenyl cephem compounds of extraction treatment.When the aqueous solution being dissolved with the alkenyl cephem compounds of organic solvent being supplied the process by gac described in detail later, charcoal absorption organic solvent, therefore, the absorption removing efficiency of E body reduces, and is difficult to the purity improving Z body.Therefore, when using the organic solvent to the solubleness of water is high, before carrying out the process by gac, the aqueous solution after extraction treatment to be concentrated thus the enrichment process removing organic solvent from this aqueous solution is necessary.When to use the solubleness of water be the low organic solvent of less than 1 % by weight such solubleness 20 DEG C time, do not need enrichment process, thus industrially favourable.
Relative to the alkenyl cephem compounds 1kg in aqueous solution, these organic solvents preferably use 5 ~ 50 liters, more preferably use 10 ~ 30 liters.In addition, preferably at 0 ~ 20 DEG C, extraction treatment is carried out.As long as be this preferred ratio, then in extraction treatment, effectively can reduce the containing ratio of toluylic acid class.
In manufacture method of the present invention, preferably after extraction treatment, the containing ratio of toluylic acid class is reduced to less than 8%.This containing ratio is the value calculated based on the calculating formula of the toluylic acid containing ratio used in embodiment described later.By repeated multiple times extraction treatment, the containing ratio of toluylic acid class reduces gradually.When the containing ratio of toluylic acid class can not be made to become below 8% by 1 extraction treatment, preferably carry out repeatedly solvent extraction.
Below, the treatment process of aforementioned (B) is described.
Separate out and efficient recovery from the view point of the compound made shown in formula (3), by mineral acid, the pH of the aqueous solution of the salt of the compound shown in the formula obtained by aforementioned enzyme reaction (3) is adjusted to slightly acidic region (specifically pH3.5 ~ 4.8, particularly pH3.5 ~ 4.5), the salt of the compound shown in the formula (3) in the aqueous solution is made easily with the state that the form of free acid is separated out.In addition, pH adjustment can be undertaken by adding the mineral acids such as hydrochloric acid, nitric acid, sulfuric acid in this aqueous solution.
Next, by this aqueous solution being remained on preferably less than 20 DEG C, more preferably at 1 ~ 10 DEG C, the compound shown in formula (3) in the aqueous solution can being made to separate out.In addition, crystallization process can under agitation be carried out, and also can carry out under leaving standstill.Precipitate and the compound shown in formula (3) carry out solid-liquid separation by ordinary method, utilize the treatment solution comprising toluylic acid class to reclaim.
In manufacture method of the present invention, after crystallization process, it is preferred that the containing ratio of toluylic acid class is reduced to less than 8%.This containing ratio is the value calculated based on the calculating formula of the toluylic acid containing ratio used in embodiment described later.Compared with the extraction treatment of aforementioned (A), the separation removing efficiency of the toluylic acid class of crystallization process is high, therefore, as long as under the condition of less than 20 DEG C, just the containing ratio of toluylic acid class can be reduced to less than 2% with 1 crystallization process in aforesaid pH3.5 ~ 4.8.In addition, when the containing ratio of toluylic acid class not being reduced to less than 8%, preferably less than 2% with 1 crystallization process, preferably repeatedly crystallization process is carried out.
In addition, as required, also the treatment process combination of the treatment process of aforementioned (A) and aforementioned (B) can be carried out.Now, first carry out any treatment process to be not particularly limited.
Then, 7-amino-3-[(E/Z)-2-(4-methylthiazol-5-base) the vinyl]-3-cephem-4-carboxylic acid shown in formula (3) after the treatment process of the treatment process of aforementioned (A) or aforementioned (B) is terminated or the aqueous solution of its salt (alkenyl cephem compounds) contact with gac, the E body of alkenyl cephem compounds contained in this aqueous solution of absorption removing, improves the containing ratio of Z body.When having carried out the treatment process of aforementioned (A), the aqueous solution utilizing organic solvent to complete extraction treatment can be made directly to contact with gac.When having carried out the treatment process of aforementioned (B), the precipitate obtained (compound shown in formula (3)) is dissolved in the water and makes the aqueous solution, this aqueous solution is contacted with gac by this treatment process.In any one situation, the concentration of the alkenyl cephem compounds in the aqueous solution contacted with gac, is preferably 0.1 ~ 5 % by weight from the viewpoint of processing efficiency, is more preferably 0.5 ~ 4 % by weight.
The pH of the aqueous solution contacted with gac is set to the weakly alkaline region of 7.1 ~ 9.0 or the acidic region of below pH2.0, especially 0.8 ~ 1.4, from activated carbon treatment, there is no the precipitate of crystal and the viewpoint effectively can carrying out activated carbon treatment is preferred.Especially below pH2.0 is set to, when being in particular the acidic region of 0.8 ~ 1.4, owing to can also be adsorbed the toluylic acid class removing and do not removed completely by the treatment process of aforementioned (A) or (B) by activated carbon treatment simultaneously, therefore from the viewpoint of the target compound that can obtain toluylic acid class and reduce further, be preferred.The adjustment of pH can use ammoniacal liquor, amine, aforesaid mineral acid etc.As amine, Trimethylamine 99, triethylamine etc. can be enumerated.
The method that gac contacts with the alkenyl cephem compounds in the aqueous solution is not particularly limited.As contact method, otherwise can adopt the method for such as adding gac in the aqueous solution of alkenyl cephem compounds in gac, add the method for the aqueous solution of alkenyl cephem compounds.Or, as contact method, can also adopt and gac is filled in post, the aqueous solution pump etc. of alkenyl cephem compounds is delivered in post, make the method that it passes through and then makes it repeatedly circulate in post in post; By the method that the device containing gac in the moldinies such as strainer contacts with the aqueous solution of alkenyl cephem compounds.The ratio of the amount of gac and the amount of alkenyl cephem compounds is not particularly limited.Such as, from the view point of the rate of loss of Z body can be made to reduce, preferably relative to alkenyl cephem compounds 100 weight part contained in the aqueous solution, 10 ~ 200 weight parts, particularly 20 ~ 100 parts by weight of activated carbon are in contact with it.In addition, as long as be this preferred ratio, then the containing ratio of toluylic acid class also residual also effectively can be reduced in the treatment process of aforementioned (A) or (B) further in contact pairs after.
When using gac, can in the aqueous solution of alkenyl cephem compounds repeatedly portion-wise addition gac.By such operation, E body burden can be made to reduce further thus improve Z body burden.In addition, during whole gac that disposable interpolation uses, also there is the worry of dust explosion and the problem of operability, if portion-wise addition, then can eliminate these problems.
The condition that gac contacts with alkenyl cephem compounds is also not particularly limited.Such as, temperature when contacting can be 0 ~ 20 DEG C.By temperature when making contact within the scope of this, the rate of loss of Z body can be made to reduce and effectively can remove E body, therefore preferably.Temperature during to contact is condition in above-mentioned scope, is preferably 0.5 ~ 3 hour duration of contact, is particularly preferably 0.5 ~ 2 hour.During making both contacts, reaction system can be whipped state or also can be static condition.
Process by gac only can carry out 1 time, or can repeat more than 2 times repeatedly to improve the purity of Z body.
As gac, can use such as using zinc chloride activation gac, the steam activation gac as raw material such as Exocarpium cocois (Cocos nucifera L), coal, wooden material.These can be used alone or in combination of two kinds or more.
For the gac for optionally adsorbing removing E body from alkenyl cephem compounds, the present inventor etc. conduct in-depth research, and have found out and have used the gac with the peak of large micropore diameter and the peak of little micropore diameter to be effective.And then the present inventor etc. makes further research, found out the iodine absorption property that the gac with such micropore diameter distribution measures according to JIS K-1474 and equally according to the methylene blue adsorption number performance of JIS K-1474 mensuration in specific scope.In the present invention, by using such gac with specific iodine absorption property and methylene blue adsorption number performance, from alkenyl cephem compounds, can optionally adsorb removing E body further.
As gac, preferably use the material that the value of above-mentioned specific iodine absorption property is more than 1200mg/g.In addition, to obtain that iodine absorption property is greater than 1700mg/g and has the following gac of methylene blue adsorption number performance described concurrently be extremely difficult due to industrial, and the upper limit of the iodine absorption property of the gac therefore used in the present invention is 1700mg/g.Therefore, the ranging preferably from 1200 ~ 1700mg/g, be more preferably 1400 ~ 1700mg/g of iodine absorption property.Especially the value of iodine absorption property is more high more preferred, therefore uses the gac with the iodine absorption property being greater than 1700mg/g without any impact.
As gac, preferably use the material that methylene blue adsorption number performance is more than 250ml/g.In addition, because the industrial methylene blue adsorption number performance that obtains is greater than 500ml/g and the gac having above-mentioned iodine absorption property concurrently is extremely difficult, the upper limit of the methylene blue adsorption number performance of the gac therefore used in the present invention is 500ml/g.Therefore, the ranging preferably from 250 ~ 500ml/g, be more preferably 260 ~ 500ml/g of methylene blue adsorption number performance.Especially the value of methylene blue adsorption number performance is more high more preferred, therefore uses the gac with the methylene blue adsorption number performance being greater than 500ml/g without any impact.
Usually, in each physical property of the gac used in water treatment etc., iodine absorption property is below 1200mg/g, methylene blue adsorption number performance is that (with reference to " utilisation technology of gac ", chief editor: Li Benying sets below 200ml/g, An Bu nation husband, sale room: TechnoSystems, Inc., issue date: on July 25th, 2000, the 409th page, the 555th page), these physics values of the gac therefore used in the present invention are higher than the value of common gac a lot.This is owing to being distributed with large micropore and little micropore.Generally, iodine absorption property be the distribution index of little micropore (namely, the index of the adsorptivity of the compound that molecular weight is little), methylene blue adsorption number performance is the distribution index (that is, the index of the adsorptivity of the compound that molecular weight is large) of large micropore.
As the gac meeting above-mentioned iodine absorption property and methylene blue adsorption number performance, can enumerate such as using the steam activation gac as raw material such as Exocarpium cocois (Cocos nucifera L), coal, wooden material.Now, by suitably controlling the condition activated, the condition suitably controlling granulation, above-mentioned physics value is met.In addition, the shape of gac can be powder, granular or fibrous, or can be molding.As the gac meeting above-mentioned physics value, also commercially available product can be used.As such commercially available product, the gac such as can bought from UnitikaLtd. can be enumerated, i.e. Unitika activated carbon fiber ADALL A-20 (trade(brand)name); Can from Ajinomoto Fine-Techno Co., the gac that Inc. has bought, i.e. liquid phase gac CL-KP (trade(brand)name) etc.
By above operation, E body optionally can be adsorbed removing by gac from the alkenyl cephem compounds comprising Z body and E body, improves the containing ratio of Z body.Thereafter gac is separated with treatment solution.The alkali such as sodium hydroxide are added in the treatment solution of isolating active charcoal, the pH of solution is adjusted to the slightly acidic region of 3.8 ~ 4.8, preferably carry out 0.5 ~ 3 hour, more preferably slaking in 0.5 ~ 1.5 hour, then can make the crystal settling of the compound shown in formula (2).Gained crystal by filtering, centrifugation and being separated, by the organic solvent washing such as water and methyl alcohol.The pH for the treatment of solution is adjusted to above-mentioned scope, in the pH of this scope, makes the compound shown in formula (2) separate out, thus can high purity and reclaim target compound with high yield.
As described in detail above, in the present invention, the aqueous solution of the alkenyl cephem compounds obtained by enzyme reaction is carried out to the treatment process of aforementioned (A) or (B), then use activated carbon treatment.When carrying out treatment process (the solvent extraction process) of aforementioned (A), compared with the situation of the treatment process by carrying out aforementioned (A) after this aqueous solution activated carbon treatment, for realizing about the amount of the gac of necessity of same Z body containing ratio is half amount, this is industrially extremely beneficial.Can think that this reason is because when using activated carbon treatment before solvent extraction process, gac not only adsorbs E body, also adsorbs toluylic acid class, the absorption removing efficiency of E body reduces.
Carry out the situation of the treatment process (crystallization process) of aforementioned (B) also in the same manner as the situation of the treatment process of above-mentioned aforementioned (A), due to removing toluylic acid class can be separated by crystallization, the amount of the gac used in the activated carbon treatment after therefore can reducing.The treatment process (crystallization process) of aforementioned (B) is compared with the treatment process (solvent extraction process) of aforementioned (A), because the separation removing efficiency of toluylic acid class is high, the consumption of gac therefore can be reduced by a larger margin.In addition, when adopting the treatment process of aforementioned (A), in the aqueous solution of activated carbon treatment, although just a small amount of but remainingly have organic solvent, therefore this organic solvent of charcoal absorption, under this state, the absorption removing efficiency of E body reduces.On the other hand, when adopting the treatment process of aforementioned (B), the absorption removing efficiency of such E body can not be caused to reduce.From this point, the reduction for activated carbon dosage when adopting the treatment process of aforementioned (B) is favourable.
And then the compound shown in formula (2) obtained by existing method presents painted, and according to the present invention, by extraction treatment or crystallization process, coloring components is also removed, and therefore, also can make the painted minimizing of the target compound finally obtained.
Above, based on the preferred embodiment of the present invention, the present invention will be described, but the present invention is not by the restriction of aforementioned embodiments, and the appropriate change in the scope of the usual creativity of those skilled in the art also belongs to scope of the present invention.
embodiment
Below, by embodiment, the present invention will be described in more detail.But scope of the present invention does not limit by this embodiment.
Before explanation embodiment and comparative example, used analytical procedure is described.High performance liquid chromatograph (HPLC) is used in analysis.It is specific as follows.
Post: Unison UK-C18,3 μm, 250mm × 4.6mm
Column temperature: 30 DEG C
Moving phase (volume ratio): acetonitrile 13%, 10mM sodium sulfonate in the heptan aqueous solution 87%
Flow: 0.8ml/min
Determined wavelength: 254nm
Injection rate: 10 μ l
Z body retention time: 29.0 ~ 30.0 minutes
E body retention time: 31.0 ~ 32.0 minutes
E body containing ratio (calculating formula): [E dignity product value/(Z dignity product value+E dignity product value)] × 100 (%)
The analytical procedure of the containing ratio of toluylic acid is as follows.
Post: SUPELCO ODS HYPERSIL 5 μm of 250 × 4.6mm
Column temperature: 25 DEG C
Moving phase (volume ratio): acetonitrile 20%, 50mM potassium dihydrogen phosphate aqueous solution 80%
Flow: 1.0ml/min
Determined wavelength: 225nm
Injection rate: 10 μ l
Z body+E body retention time: 2.5 ~ 3.5 minutes
Toluylic acid retention time: 8.5 ~ 9.5 minutes
Toluylic acid containing ratio (calculating formula)
(toluylic acid area value/((Z+E) honorable product value+toluylic acid area value)) × 100 (%)
embodiment 1
(1) the 1st operation
Taking the compound (containing ratio 3.5% of E body) shown in 10.0g following formula (5) joins in four-hole boiling flask, adds 6 % by weight sodium bicarbonate aqueous solution 240g, makes the aqueous solution of sodium salt.7.0g penicillin G acylase (PGA-450, Dalas Biotech Limited manufactures) is added in this aqueous solution.Add 5 % by weight aqueous sodium carbonates of liquid temperature 25 ~ 35 DEG C, while pH to be controlled 7 deprotection reactions of the sodium salt carrying out compound shown in 2 little up-to-date styles (5) on 7.5 ~ 8.5 limits.After reaction terminates, in the aqueous solution containing in E body containing ratio containing 3.5%E body following formula (6) shown in the sodium salt 7.0g of compound.In addition, the toluylic acid of 16.6% is comprised in toluylic acid containing ratio.
(2) the 2nd operations
The aqueous solution obtained from the 1st operation is crossed and is filtered enzyme (PGA-450), while liquid temperature is remained on 0 ~ 10 DEG C of limit to add concentrated hydrochloric acid, the pH of the aqueous solution is adjusted to 0.9, the sodium salt of the compound shown in formula (6) contained in the aqueous solution is made the hydrochloride of the compound shown in formula (6).The aqueous solution completing pH adjustment is transferred to separating funnel, while liquid temperature to be remained on the toluene that 20 DEG C of limits add 150ml wherein, extraction removing by product and impurity.Toluylic acid containing ratio after extraction treatment is 6.1%.In addition, the concentration of the alkenyl cephem compounds in the aqueous solution after extraction treatment is 2.2 % by weight.
(3) the 3rd operations
In the aqueous solution after solvent extraction, disposable interpolation 3.2g gac (Ajinomoto Fine-Techno Co., Inc. manufacture, trade(brand)name SD-2), stirs 1 hour at 3 DEG C.This gac according to the iodine absorption property that JIS K-1474 measures be 1080mg/g, methylene blue adsorption number performance is 180ml/g.Thereafter, cross and filter gac, add 1N aqueous sodium hydroxide solution in aqueous and pH is adjusted to 4.3, slaking 1 hour.By this slaking, the crystal of the compound shown in formula (3) is separated out.The crystal that collecting by filtration is separated out, with water and methanol wash crystal, drying.The analytical results of gained crystal is as follows.In addition, the Z body yield in following analysis result is the value calculated by following calculating formula.
Z body yield (%)=A × B/C
The thick yield (%) of the crystal obtained after the A: the 3 operation
B: the purity (%) of the Z body of the compound shown in formula (3)
C: the theoretical yield (%) of the Z body of the compound shown in the formula (3) being benchmark with the inorganic acid salt of the compound shown in the formula (6) of the 2nd operation
(analytical results)
Z body yield: 90.3%
E body containing ratio: 1.65%
Toluylic acid containing ratio: 0.1%
Tone (visual): white
.
1h-NMR (D
2o/DCl) ppm is from TSP
2.52(s、3H、CH
3)、
3.56～3.60(d、1H、S-CH(H)、18.3Hz)、
3.75～3.78(d、1H、S-CH(H)、18.6Hz)、
5.25～5.26(d、1H、S-CH、5.2Hz)、
5.44～5.45(d、1H、N-CH、5.2Hz)、
6.78(s、2H、CH＝CH)、9.78(s、1H、S-CH＝N)
comparative example 1
This comparative example is the reversed order by the 2nd operation in embodiment 1 and the 3rd operation.In detail, carry out enzyme reaction with same operation of the 1st operation of embodiment 1, cross from the aqueous solution of the obtained sodium salt containing compound shown in formula (6) and filter enzyme.Limit keeps liquid temperature 20 DEG C of limits to add concentrated hydrochloric acid, and the pH of whole filtrate is adjusted to 0.9.Obtain the aqueous solution of the hydrochloride of the compound shown in formula (6) thus.Then, the gac that disposable interpolation 5.6g is identical with the gac used in the 3rd operation of embodiment 1 in this aqueous solution, stirs 1 hour at 3 DEG C.Toluylic acid containing ratio after activated carbon treatment is 1.1%.Thereafter, cross and filter gac, to operate equally with the 2nd operation of embodiment 1, solvent extraction is carried out to the whole filtrate of gained.PH is adjusted to 4.3 by the aqueous sodium hydroxide solution adding 1N in the aqueous solution after solvent extraction, slaking 1 hour.By this slaking, the crystal of the compound shown in formula (3) is separated out.The crystal that collecting by filtration is separated out, with water and methanol wash crystal, drying.The analytical results of gained crystal is as follows.
(analytical results)
Z body yield: 86.5%
E body containing ratio: 1.46%
Toluylic acid containing ratio: 0.1%
Tone (visual): faint yellow
embodiment 2
In the 3rd operation of embodiment 1,2.8g AjinomotoFine-Techno Co. is used, the CL-KP (trade(brand)name) that Inc. manufactures, in addition as gac, operate similarly to Example 1, obtain the crystal of the compound shown in formula (3).The iodine absorption property of this gac is 1620mg/g, methylene blue adsorption number performance is 280ml/g.The analytical results of gained crystal is shown in table 1.
embodiment 3
In 2nd operation of embodiment 2, replace toluene and use chloroform, in addition, operating similarly to Example 2, obtain the crystal of the compound shown in formula (3).The analytical results of gained crystal is shown in table 1.
embodiment 4
(1) the 1st operation
Enzyme reaction is carried out under the operation identical with embodiment 1 and condition.After reaction terminates, in the aqueous solution in E body containing ratio containing 3.5%E body formula (6) shown in the sodium salt of compound contain 7.0g.In addition, the toluylic acid of 16.6% is comprised in toluylic acid containing ratio.
(2) the 2nd operations
Cross from the aqueous solution that the 1st operation obtains and filter enzyme, while filtrate is remained on 10 DEG C of limits to add concentrated hydrochloric acid, the pH of the aqueous solution is adjusted to 1.1, the sodium salt of the compound shown in formula (6) contained in the aqueous solution is made the hydrochloride of the compound shown in formula (6).The aqueous solution completing pH adjustment is transferred to separating funnel, while liquid temperature to be remained on the toluene that 10 DEG C of limits add 150ml wherein, extraction removing by product and impurity.Toluylic acid containing ratio after extraction treatment is 5.9%.In addition, the concentration of the alkenyl cephem compounds in the aqueous solution after extraction treatment is 2.3 % by weight.
(3) the 3rd operations
While the aqueous solution after extraction treatment is remained on 10 DEG C of limit strong aquas pH is adjusted to 8.0.The CL-KP (trade(brand)name) that disposable interpolation 1.5g manufactures as the AjinomotoFine-Techno Co. of gac, Inc. in this aqueous solution, stirs 1 hour at 5 DEG C.Thereafter, cross and filter gac, add concentrated hydrochloric acid in aqueous and pH is adjusted to 4.3, slaking 1 hour.By this slaking, the crystal of the compound shown in formula (3) is separated out.The crystal that collecting by filtration is separated out, with water and methanol wash, drying.The analytical results of gained crystal is shown in table 1.
Table 1
* the extraction treatment after activated carbon treatment: the toluylic acid containing ratio after activated carbon treatment is 1.1%
After extraction treatment, carry out activated carbon treatment in embodiment 1, on the other hand, in comparative example 1, after activated carbon treatment, carry out extraction treatment.In embodiment 1 and comparative example 1, toluylic acid containing ratio in the crystal of the alkenyl cephem compounds finally obtained all is similarly 0.1%, but embodiment 1 is compared with comparative example 1, about the amount realizing the same necessary gac of toluylic acid containing ratio is half amount, and Z body yield improves.In addition, in embodiment 1, gained alkenyl cephem compounds is also not painted.
And then, from contrast with embodiment 2 of embodiment 1, use when there is the gac of specific iodine absorption property and methylene blue adsorption number performance, can further improve Z body yield and E body containing ratio.In addition, from contrast with embodiment 3 of embodiment 2, when using toluene in extraction treatment, Z body yield and E body containing ratio can especially be improved.In addition, from contrast with embodiment 4 of embodiment 2, when the pH for the aqueous solution of activated carbon treatment is basic region, just can reach good Z body yield and E body containing ratio with little activated carbon dosage, but toluylic acid containing ratio slightly increases.
embodiment 5
(1) the 1st operation
Enzyme reaction is carried out under the operation identical with embodiment 1 and condition.After reaction terminates, in the aqueous solution in E body containing ratio containing 3.5%E body formula (6) shown in the sodium salt of compound contain 7.0g.In addition, the toluylic acid of 16.6% is comprised in toluylic acid containing ratio.
(2) the 2nd operations
Cross from the aqueous solution that the 1st operation obtains and filter enzyme (PGA-450), while liquid temperature is remained on 10 DEG C of limit concentrated hydrochloric acids pH is adjusted to 4.2, direct slaking 1 hour.By this slaking, the compound shown in formula (3) is separated out, and then filters, and reclaims precipitate.In addition, the toluylic acid containing ratio of the precipitate obtained is 0.5%.
(3) the 3rd operations
While be scattered in the water of 340g by the 7.1g precipitate obtained in the 2nd operation (the Z body containing 6.5g), and remain on 20 DEG C, while pH is adjusted to 1.0 with the vitriol oil, this precipitate is dissolved.In this aqueous solution, disposable interpolation 1.5g is as the Ajinomoto Fine-Techno Co. of gac, Inc. CL-KP (the trade(brand)name manufactured, iodine absorption property is 1620mg/g, and methylene blue adsorption number performance is 280ml/g), stir 1 hour at 3 DEG C.Thereafter, cross and filter gac, add 1N aqueous sodium hydroxide solution in aqueous and pH is adjusted to 4.2, slaking 1 hour.By this slaking, the crystal of the compound shown in formula (3) is separated out.The crystal that collecting by filtration is separated out, with water and methanol wash crystal, drying.The analytical results of gained crystal is shown in table 2.
embodiment 6
(1) the 1st operation
Enzyme reaction is carried out under the operation identical with embodiment 1 and condition.After reaction terminates, in the aqueous solution in E body containing ratio containing 3.5%E body formula (6) shown in the sodium salt of compound contain 7.0g.In addition, the toluylic acid of 16.6% is comprised in toluylic acid containing ratio.
(2) the 2nd operations
Cross from the aqueous solution that the 1st operation obtains and filter enzyme, while filtrate is remained on 10 DEG C of limits, 15 % by weight sulfuric acid pH to be adjusted to 4.3, direct slaking 1 hour.By this slaking, the compound shown in formula (3) is separated out, and then filters, and reclaims precipitate.In addition, the toluylic acid containing ratio of the precipitate obtained is 0.5%.
(3) the 3rd operations
While be scattered in the water of 340g by the 7.1g precipitate obtained in the 2nd operation (the Z body containing 6.5g), and remain on 10 DEG C, pH is adjusted to 1.2 by limit 15 % by weight sulfuric acid, is dissolved by this precipitate.The CL-KP (trade(brand)name) that disposable interpolation 1.5g manufactures as the Ajinomoto Fine-Techno Co. of gac, Inc. in this aqueous solution, stirs 1 hour at 3 DEG C.Thereafter, cross and filter gac, add 1N aqueous sodium hydroxide solution in aqueous and pH is adjusted to 4.3, slaking 1 hour.By this slaking, the crystal of the compound shown in formula (3) is separated out.The crystal that collecting by filtration is separated out, with water and methanol wash crystal, drying.The analytical results of gained crystal is shown in table 2.
embodiment 7
Except the 3rd operation is as described below, similarly to Example 5, the crystal of the compound shown in formula (3) is obtained.
While be scattered in the water of 340g by the 7.1g precipitate obtained in the 2nd operation (the Z body containing 6.5g), and remain on 10 DEG C, pH is adjusted to 8.1 by limit 5 % by weight ammoniacal liquor, is dissolved by this precipitate.The CL-KP (trade(brand)name) that disposable interpolation 1.5g manufactures as the Ajinomoto Fine-Techno Co. of gac, Inc. in this aqueous solution, stirs 1 hour at 7 DEG C.Thereafter, cross and filter gac, add concentrated hydrochloric acid in aqueous and pH is adjusted to 4.3, slaking 1 hour.By this slaking, the crystal of the compound shown in formula (3) is separated out.The crystal that collecting by filtration is separated out, with water and methanol wash crystal, drying.The analytical results of gained crystal is shown in table 2.
embodiment 8
Except the 3rd operation is as described below, similarly to Example 5, the crystal of the compound shown in formula (3) is obtained.
While be scattered in the water of 340g by the 7.1g precipitate obtained in the 2nd operation (the Z body containing 6.5g), and remain on 10 DEG C, while pH is adjusted to 1.1 with concentrated hydrochloric acid, this precipitate is dissolved.In this aqueous solution, add the ADALL A-20 (trade(brand)name, iodine absorption property is 1580mg/g, and methylene blue adsorption number performance is 310ml/g) that 1.8g manufactures as the Unitika Ltd. of gac, leave standstill 1 hour at 8 DEG C.Thereafter, cross and filter gac, add 1N aqueous sodium hydroxide solution and pH is adjusted to 4.3, slaking 1 hour.By this slaking, the crystal of the compound shown in formula (3) is separated out.The crystal that collecting by filtration is separated out, with water and methanol wash crystal, drying.The analytical results of gained crystal is shown in table 2.
embodiment 9
Except the 3rd operation is as described below, operate similarly to Example 5, obtain the crystal of the compound shown in formula (3).
While be scattered in the water of 340g by the 7.1g precipitate obtained in the 2nd operation (the Z body containing 6.5g), and remain on 10 DEG C, while pH is adjusted to 1.1 with concentrated hydrochloric acid, this precipitate is dissolved.The SD-2 (trade(brand)name) that disposable interpolation 1.6g manufactures as the Ajinomoto Fine-Techno Co. of gac, Inc. in this aqueous solution, stirs 1 hour at 4 DEG C.Thereafter, cross and filter gac, add concentrated hydrochloric acid in aqueous and pH is adjusted to 4.3, slaking 1 hour.By this slaking, the crystal of the compound shown in formula (3) is separated out.The crystal that collecting by filtration is separated out, with water and methanol wash crystal, drying.The analytical results of gained crystal is shown in table 2.
From the contrast of table 1 and table 2, compared with extraction treatment, the amplitude that the toluylic acid containing ratio of crystallization process reduces is large, consequently, when carrying out crystallization process, by little activated carbon dosage, the alkenyl cephem compounds that good Z body yield, E body containing ratio and toluylic acid containing ratio are low just can be obtained.
From the contrast of embodiment 5,6,8 and embodiment 9, the situation of crystallization process is also same with the situation of extraction treatment, uses when having the gac of specific iodine absorption property and methylene blue adsorption number performance, can improve Z body yield and E body containing ratio further.In addition, from the contrast of embodiment 5,6 and embodiment 7, when the pH for the aqueous solution of activated carbon treatment is acidic region, toluylic acid containing ratio can be reduced further, and Z body yield and E body containing ratio become better.
industrial utilizability
According to the present invention, when manufacturing 7-amino-3-[(E/Z)-2-(4-methylthiazol-5-base) vinyl]-3-cephem-4-carboxylic acid or its salt, also can improve Z body than ever relative to the containing ratio of E body and also can reduce impurity.
Claims (3)
1. 7-amino-3-[(E/Z)-2-(4-methylthiazol-5-base) the vinyl]-3-cephem-4-carboxylic acid shown in a formula (3) or the manufacture method of its salt, this manufacture method improves the containing ratio of 7-amino-3-[(Z)-2-(4-methylthiazol-5-base) the vinyl]-3-cephem-4-carboxylic acid shown in following formula (2) or its salt, it is characterized in that, by the salt of 7-substituted acyl amino-3-[(E/Z)-2-(4-methylthiazol-5-base) the vinyl]-3-cephem-4-carboxylic acid shown in following formula (1) for enzyme reaction to carry out the deprotection reaction of 7 amido linkages, obtain the by product comprising this deprotection reaction, i.e. 7-amino-3-[(E/Z)-2-(4-methylthiazol-5-base) the vinyl]-3-cephem-4-carboxylic acid shown in following formula (3) of toluylic acid or derivatives thereof or the aqueous solution of its salt, then, by adding mineral acid, pH is adjusted to acidic region, obtain the by product comprising aforementioned deprotection reaction, the i.e. aqueous solution of the inorganic acid salt of 7-amino-3-[(E/Z)-2-(4-methylthiazol-5-base) the vinyl]-3-cephem-4-carboxylic acid shown in previously described formula (3) of toluylic acid or derivatives thereof, then the treatment process of following (A) or (B) is carried out
Then, the aqueous solution of [(E/Z)-2-(4-methylthiazol-5-base) the vinyl]-3-cephem-4-carboxylic acid of the 7-amino-3-shown in the following formula after this treatment process (3) or its salt is contacted with gac process, the iodine absorption property that foregoing active charcoal measures according to JIS K-1474 is more than 1200mg/g, methylene blue adsorption number performance is more than 250ml/g, wherein
(A) with an organic solvent; to comprise described deprotection reaction by product, i.e. toluylic acid or derivatives thereof following formula (3) shown in 7-amino-3-[(E/Z)-2-(4-methylthiazol-5-base) vinyl]-3-cephem-4-carboxylic acid or the aqueous solution of its salt carry out the operation of the extraction treatment of aforementioned toluylic acid or derivatives thereof
(B) carry out making this 7-amino-3-[(E/Z)-2-(4-methylthiazol-5-base) vinyl]-3-cephem-4-carboxylic acid or its salt from comprise described deprotection reaction by product, i.e. toluylic acid or derivatives thereof following formula (3) shown in 7-amino-3-[(E/Z)-2-(4-methylthiazol-5-base) vinyl]-3-cephem-4-carboxylic acid or its salt the aqueous solution the operation of crystallization process separated out
In formula, R
lrepresent benzyl or Phenoxymethyl, M represents the positively charged ion of monovalence,
2. manufacture method according to claim 1, the organic solvent in the treatment process of aforementioned (A) is toluene.
3. manufacture method according to claim 1 and 2, is adjusted to 3.8 ~ 4.8 by with the pH of the treatment solution after the process of foregoing active charcoal, makes the crystal settling of the compound shown in previously described formula (2).
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