CN101628915B - Method for preparing 3-alkenylcephem compounds - Google Patents
Method for preparing 3-alkenylcephem compounds Download PDFInfo
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- CN101628915B CN101628915B CN200910118652.4A CN200910118652A CN101628915B CN 101628915 B CN101628915 B CN 101628915B CN 200910118652 A CN200910118652 A CN 200910118652A CN 101628915 B CN101628915 B CN 101628915B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
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Abstract
The invention provides a method for preparing 3-alkenylcephem compounds. 7-amino-3-[(E/Z)-2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4- carboxylic acid or aqueous solution of alkali metal salts thereof is contacted with activated carbon, wherein the adsorption capacities of the activated carbon to iodine and methylene blue trihydrate are above 1200mg/g and 250ml/g respectively according to JIS K-1474, thereby increasing the content of 7-amino-3-[(E/Z)-2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4- carboxylic acid or aqueous solution of alkali metal salts thereof.
Description
Technical field
The present invention relates to a kind of at 7-amino-3-[(E/Z)-2-(4-methylthiazol-5-yl) vinyl] in the manufacture of-3-cephem-4-carboxylic acid or its an alkali metal salt, the method that the containing ratio of Z body is improved than E body.
Background technology
7-amino-3-[2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid or its an alkali metal salt be as the useful material of the manufacture intermediate of cephalosporins.This compound existence is 2 kinds of isomer of Z configuration and E configuration in the three-dimensional arrangement of the alkenyl of 3.Known when manufacturing cephalosporins using these 2 kinds of isomer as raw material, what as medicinal antibiosis, agent showed excellent anti-microbial effect is the cephalosporins using Z body as raw material.Therefore, by 7-amino-3-[2-(4-methylthiazol-5-yl) vinyl] when-3-cephem-4-carboxylic acid or the synthetic cephalosporins of its an alkali metal salt, in reaction system, only there is Z body and do not exist E body very important as far as possible.
From this viewpoint, in patent documentation 1, proposed: 7-amino-3-[2-(4-methylthiazol-5-yl) vinyl that Z body is mixed with E body exist] aqueous solution of-3-cephem-4-carboxylic acid or its an alkali metal salt, with high porous polymer, gac effect, improve the containing ratio of Z body.As the high porous polymer using in the method, exemplify acrylic resin, phenolic aldehyde is resin, phenylethylene resin series.On the other hand, as gac, use zinc chloride charcoal, the so common gac of water vapour charcoal.
According to the method for recording in aforementioned documents, 7-amino-3-[2-(4-methylthiazol-5-yl) vinyl that the containing ratio that can obtain Z body has improved]-3-cephem-4-carboxylic acid or its an alkali metal salt.But for the manufacture intermediate using this compound as cephalosporins is used, expectation further improves the containing ratio of Z body.
Patent documentation 1:JP2005-343854A
Summary of the invention
the problem that invention will solve
Therefore, the object of the invention is to, provide can overcome various shortcomings that aforementioned prior art has, 7-amino-3-[2-(4-methylthiazol-5-yl) vinyl] manufacture method of-3-cephem-4-carboxylic acid or its an alkali metal salt.
for the method for dealing with problems
The present invention is by providing the 7-amino-3-[(Z shown in following formula (2))-2-(4-methylthiazol-5-yl) vinyl] the 7-amino-3-[(E/Z shown in the formula (1) that improved of the containing ratio of-3-cephem-4-carboxylic acid or its an alkali metal salt)-2-(4-methylthiazol-5-yl) vinyl] manufacture method of-3-cephem-4-carboxylic acid or its an alkali metal salt, it is characterized in that, make the 7-amino-3-[(E/Z shown in following formula (1))-2-(4-methylthiazol-5-yl) vinyl] aqueous solution of-3-cephem-4-carboxylic acid or its an alkali metal salt contacts to process with gac, the iodine absorption property that this gac is measured according to JIS K-1474 is more than 1200mg/g, methylene blue adsorption number performance is more than 250ml/g, thereby realized aforementioned object.
Embodiment
The invention is characterized in, the compound shown in the aforementioned formula (1) that makes to comprise Z body and E body or its alkali salt and specific gac effect, make this gac optionally adsorb E body and be removed, and improves the containing ratio of Z body.Here so-called alkali salt, refers to the alkali salt allowing on pharmacology.In addition, in the following description, compound and an alkali metal salt thereof shown in formula (1) is generically and collectively referred to as " alkenyl cephem compounds ".
The alkenyl cephem compounds using in the present invention is by the compositions of mixtures of Z body and E body.Z body and E body are known compound.Z body in alkenyl cephem compounds and the ratio that exists of E body are not particularly limited, and this exists ratio to depend on creating conditions of alkenyl cephem compounds etc.For purposes of the present invention, expectation Z body there is ratio E body exist ratio high fully, the method for the application of the invention, can obtain Z body easy and with high yield.The containing ratio of the E body in alkenyl cephem compounds is generally 0.3～20%, particularly 2～12% under the state by before activated carbon treatment.This containing ratio is the value that the calculating formula of the E body containing ratio based on using in aftermentioned embodiment is calculated.
In the present invention, alkenyl cephem compounds is contacted with gac with the state of the aqueous solution.For alkenyl cephem compounds is made to the aqueous solution, for example, use alkaline purification alkenyl cephem compounds, and make the form of corresponding salt (for example an alkali metal salt).As alkali, can use the alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; The alkali metal hydrocarbonates such as sodium bicarbonate; The alkaline carbonates such as sodium carbonate, salt of wormwood, Quilonum Retard etc.By the aqueous solution that comprises these alkali is mixed with alkenyl cephem compounds, alkenyl cephem compounds can be made to the aqueous solution.
The pH of aqueous solution is the high pH region of the degree separated out of non-crystallizableization of salt of alkenyl cephem compounds.Generally be preferably 7.1～9.0, particularly 7.5～8.5 weakly alkaline region.In addition, the concentration of the salt of the alkenyl cephem compounds that aqueous solution is contained is not criticality in the present invention, the lower concentration of the degree that the crystal of this salt is not separated out.
As for alkenyl cephem compounds being made to other method of the aqueous solution, can enumerate with this alkenyl cephem compounds of mineral acid treatment, and make the method for the form of corresponding inorganic acid salt.As mineral acid, can enumerate such as hydrochloric acid, sulfuric acid, nitric acid etc.By these mineral acids are mixed with alkenyl cephem compounds, can obtain the aqueous solution that this compound becomes the state of inorganic acid salt.
The pH of the aforesaid aqueous solution that comprises inorganic acid salt is the low pH region of the non-setting degree of this inorganic acid salt.Generally be preferably 0.5～1.7, particularly 0.8～1.4.In addition, the concentration of the inorganic acid salt that the aforesaid aqueous solution is contained is not criticality in the present invention, the non-setting degree of crystal of this inorganic acid salt.
Aforesaid an alkali metal salt and inorganic acid salt are compared, preferably use inorganic acid salt.This reason is, can be when E body be removed in absorption, and the by product producing during by synthetic alkenyl cephem compounds, toluylic acid or derivatives thereof (this describes in detail in the back) absorption are removed.In inorganic acid salt, while particularly using hydrochloride, can further improve the purity of Z body, therefore preferably.
For for optionally adsorbing from alkenyl cephem compounds the gac of removing E body, the inventor etc. conduct in-depth research, and have found out that it is effective using the gac with the peak of large micropore diameter and the peak of little micropore diameter.And then the inventor etc. is further studied, to have found out and there is the gac that such micropore diameter distributes, the iodine absorption property of measuring according to JIS K-1474 and the methylene blue adsorption number performance measured according to JIS K-1474 are equally in specific scope.In the present invention, by using such gac with specific iodine absorption property and methylene blue adsorption number performance, can from alkenyl cephem compounds, optionally adsorb and remove E body.
About above-mentioned specific iodine absorption property, use this value for gac more than 1200mg/g.In addition, to obtain the gac that iodine absorption property surpasses 1700mg/g and have the methylene blue adsorption number performance of the following stated concurrently be extremely difficult due to industrial, therefore, on the iodine absorption property of the gac using in the present invention, is limited to 1700mg/g.Therefore, the scope of iodine absorption property is preferably 1200～1700mg/g, and then is preferably 1400～1700mg/g.Certainly, because the value of iodine absorption property is more high more preferred, thereby use the gac have over the iodine absorption property of 1700mg/g not have any impact.
For methylene blue adsorption number performance, use this value for gac more than 250ml/g.In addition, to obtain the gac that methylene blue adsorption number performance surpasses 500ml/g and have above-mentioned iodine absorption property concurrently be extremely difficult due to industrial, therefore, in the methylene blue adsorption number performance of the gac using in the present invention, is limited to 500ml/g.Therefore, the scope of methylene blue adsorption number performance is preferably 250～500ml/g, 260～500ml/g more preferably.Certainly, because the value of methylene blue adsorption number performance is more high better, thereby use the gac have over the methylene blue adsorption number performance of 500ml/g not have any impact.
Conventionally, in each physical property of the gac using in water treatment etc., iodine absorption property is below 1200mg/g, methylene blue adsorption number performance is following (reference " utilisation technology of gac ", chief editor: Li Benying tree, the husband of An Bu nation, sale room: TechnoSystems of 200ml/g, Inc., issue date: on July 25th, 2000, the 409th page, the 555th page), thus these physics values of the gac using in the present invention high more a lot of than the value of common gac.This is owing to being distributed with large micropore and little micropore.Generally speaking, iodine absorption property is the distribution index (that is, the adsorptivity index of the compound that molecular weight is little) of little micropore, and methylene blue adsorption number performance is the distribution index (that is the adsorptivity index of the compound that, molecular weight is large) of large micropore.
As the gac that meets above-mentioned iodine absorption property and methylene blue adsorption number performance, can enumerate such as the steam activation gac using Exocarpium cocois (Cocos nucifera L), coal, wooden material etc. as raw material.Now, the condition activating by suitable control, suitably control the condition of granulation, to meet above-mentioned physics value.In addition, the shape of gac can be powder, granular or fibrous, or can be molding.As the gac that meets above-mentioned physics value, also can use commercially available product.As such commercially available product, can enumerate the gac that for example can buy from UnitikaLtd. and be Unitika activated carbon fiber ADALL A-20 (trade(brand)name), can be from Ajinomoto Fine-Techno Co., the gac that Inc. has bought is liquid phase with gac CL-KP (trade(brand)name) etc.
Above-mentioned gac is not particularly limited with the method that alkenyl cephem compounds contacts.Otherwise for example can adopt the method for adding above-mentioned gac in the aqueous solution of alkenyl cephem compounds in above-mentioned gac, to add the method for the aqueous solution of alkenyl cephem compounds.Or can also adopt above-mentioned gac is filled in post, the aqueous solution of alkenyl cephem compounds is delivered in post with pump etc., it is passed through in post, and then make its method of circulation repeatedly in post; The method that the device that contains gac in the moldinies such as strainer is contacted with the aqueous solution of alkenyl cephem compounds.The amount of gac is not particularly limited with the ratio of the amount of alkenyl cephem compounds.For example, from making the viewpoint that the rate of loss of Z body is few and can effectively remove E body and toluylic acid, preferably, with respect to alkenyl cephem compounds 100 weight parts contained in the aqueous solution, 10～300 weight parts, particularly 50～200 weight part gacs are in contact with it.
Above-mentioned gac is also not particularly limited with the condition that alkenyl cephem compounds contacts.For example, temperature while contacting can be 0～20 ℃.Temperature when making to contact is within the scope of this, can make the rate of loss of Z body few and can effectively remove E body and toluylic acid, therefore preferably.Temperature while take contact duration of contact is condition in above-mentioned scope, preferably 0.5～3 hour, particularly preferably 1～2 hour.During making that both contact, reaction system can be for whipped state or can is also static condition.
Above method can only be carried out 1 time, or also can repeat in order to improve the purity of Z body 2 times above repeatedly.
By above operation, from the alkenyl cephem compounds that comprises Z body and E body, E body is optionally adsorbed and removes by gac, and the containing ratio of Z body improves.Thereafter gac is separated with treatment solution, in treatment solution, add the alkali (making water miscible situation with mineral acid) such as the acid such as hydrochloric acid, nitric acid, sulfuric acid (making water miscible situation with alkali) or sodium hydroxide the pH of solution to be adjusted to 3.8～4.8 slightly acidic region, make the crystal settling of the compound shown in formula (2).By gained crystal by filtration or centrifugation and separation, by organic solvent washings 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, thereby can reclaim target compound with high purity and high yield.
Can also before operating the compound shown in recovery type (2) by above-mentioned separating out, carry out following operation, that is, remove with contained toluylic acid in the treatment solution of activated carbon treatment, the operation that further improves the purity of the compound shown in formula (2).Specifically, gac is separated with treatment solution, in treatment solution, add acid (making water miscible situation with alkali) or alkali (making water miscible situation with mineral acid) to make the pH of solution be preferably below 2 and then be preferably below 1, with an organic solvent solvent extraction toluylic acid from this aqueous solution.By repeated multiple times solvent extraction, the concentration of the toluylic acid in treatment solution reduces gradually.
The organic solvent using as solvent extraction, can enumerate, (1) low-grade carboxylic acid's lower alkyl esters class, (2) ketone, (3) ethers, (4) replace or unsubstituted aromatic hydrocarbon based, (5) halogenated hydrocarbon, (6) aliphatic hydrocarbon, (7) cycloalkane.Two or more use alone or in combination of these organic solvents.As (1) low-grade carboxylic acid's lower alkyl esters class, can enumerate methyl-formiate, ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, butylacetate, methyl propionate, ethyl propionate etc.As (2) ketone, can enumerate methyl propyl ketone, methyl butyl ketone, methyl iso-butyl ketone (MIBK), metacetone etc.As (3) ethers, can enumerate diethyl ether, ethyl propyl ether, ethyl-butyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, methylcyclohexane, glycol dimethyl ether etc.As (4) replacement or unsubstituted aromatic hydrocarbon based, can enumerate benzene,toluene,xylene, chlorobenzene, phenylmethylether etc.As (5) halogenated hydrocarbon, can enumerate methylene dichloride, chloroform, ethylene dichloride, trichloroethane, ethylene dibromide, propylene dichloride, tetracol phenixin etc.As (6) aliphatic hydrocarbon, can enumerate pentane, hexane, heptane, octane etc.As (7) cycloalkane, can enumerate pentamethylene, hexanaphthene, suberane, cyclooctane etc.
By repeatedly carrying out above solvent extraction, can make the containing ratio of toluylic acid be reduced to and be suitably for below 8%.This containing ratio is the value that the calculating formula of the toluylic acid containing ratio based on using in aftermentioned embodiment is calculated.After solvent extraction, in treatment solution, add the alkali such as sodium bicarbonate to carry out isoelectric precipitation, crystal is separated out, reclaim crystal.
In the present invention, the alkenyl cephem compounds using as initial substance is by obtaining as follows: for example, by the 7-substituted acyl amino-3-[(E/Z shown in following formula (3))-2-(4-methylthiazol-5-yl) vinyl] salt of-3-cephem-4-carboxylic acid obtains to carry out the deprotection reaction of 7 amido linkages for enzyme reaction.This salt is as long as be not particularly limited for water-soluble its kind.As water miscible salt, can enumerate for example an alkali metal salt, ammonium salt.
In formula, R
1represent benzyl or Phenoxymethyl.M represents the positively charged ion of monovalence.
As the solvent of aforesaid enzyme reaction, from bringing into play to greatest extent the viewpoint of enzymic activity, preferably make water.The pH of enzyme reaction is the principal element that the activity of enzyme is exerted an influence.The kind that also depends on enzyme, from this viewpoint, preferably pH maintains 7.5～8.5.Can use various alkali aqueous solutions, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide; The alkali metal hydrocarbonates such as sodium bicarbonate; The aqueous solution of the alkaline carbonate such as sodium carbonate, salt of wormwood etc. maintains pH.The temperature of enzyme reaction is also the principal element that the activity of enzyme is exerted an influence.From this viewpoint, also depend on the kind of enzyme, preferably the temperature of reaction system is maintained to 25～35 ℃.Reaction times is not criticality in the present invention.Generally to react until the compound shown in formula (3) disappears from reaction system.Using the scope of aforesaid pH and temperature as condition, the reaction times can be generally 1～3 hour.
As used enzyme, can use with no particular limitation known penicillin G acylase in the past.Can use Penicillin-G-amidases PGA-150, PGA-300, PGA-450 that for example Boehringer Mannheim manufactures; 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 that Atlus Biologics Inc. manufactures etc.
The usage quantity of enzyme also depends on its kind, and compound 100 weight parts with respect to shown in formula (3) are preferably 30～150 weight parts, are particularly preferably 50～100 weight parts.
By above enzyme reaction, obtain the salt of alkenyl cephem compounds.In this enzyme reaction, the deprotection of the acid amides protecting group of 7 in the compound shown in through type (3) and generate the toluylic acid or derivatives thereof (below these being generically and collectively referred to as to " toluylic acid class ") as by product.This toluylic acid etc. for the target compound of this manufacture method, be high 7-amino-3-[2-(4-methylthiazol-5-yl) vinyl of containing ratio of Z body]-3-cephem-4-carboxylic acid is impurity, thereby is necessary to get rid of its existence as far as possible.For this object, the inventor etc. conduct in-depth research, and are surprised to find that, by make above-mentioned gac contact with alkenyl cephem compounds in strongly-acid region, when utilizing this charcoal absorption to remove E body, toluylic acid class is also adsorbed.From this viewpoint, method of the present invention is more excellent than the method for prior art.
Like this; what in the present invention, be applicable to is that the alkenyl cephem compounds that comprises toluylic acid or derivatives thereof is used as raw material, and by the salt of the compound shown in formula (3), for enzyme reaction, to carry out, the deprotection reaction of 7 amido linkages generates this toluylic acid or derivatives thereof, the by product of this deprotection reaction.
In order effectively to remove toluylic acid class by above-mentioned gac, preferably the pH of the aqueous solution being set as to strongly-acid region is 0.5～1.7, particularly 0.8～1.4.From this viewpoint, alkenyl cephem compounds is applicable to being present in the aqueous solution with the form of its inorganic acid salt, and makes the aqueous solution in strongly-acid region.
Compound shown in formula (3) can be synthetic by known method.For example; by making the 7-substituted acyl amino-3-[(E/Z shown in following formula (4))-2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid cpd carries out 4 carboxylic acid protecting groups' deprotection reaction, can obtain the compound shown in formula (3).As deprotection reaction, can adopt as the deprotection reaction of the carboxylic acid protecting group in 'beta '-lactam compounds and known the whole bag of tricks.For example, can adopt the deprotection reaction in the phenols being documented in JP 61-263984A.
In formula, R
1identical 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 be by diphenyl-methyl of electron donating group-substituted etc.As electron-donating group, can enumerate for example alkyl of carbon number 1～6; The alkoxyl group of hydroxyl, carbon number 1～6 etc.
Above, based on the preferred embodiment of the present invention, the present invention will be described, but the present invention is not subject to the restriction of aforementioned embodiments, and the appropriate change in the scope of the common 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 is not limited by this embodiment.
Before explanation embodiment and comparative example, used analytical procedure is described.In analysis, use high performance liquid chromatograph (HPLC).It is specific as follows.
Post: Unison UK-C18,3 μ m, 250mm * 4.6mm
Column temperature: 30 ℃
Moving phase (volume ratio): acetonitrile 13%, 10mM sodium sulfonate in the heptan aqueous solution 87%
Flow: 0.8ml/min
Detect 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: E bulk area value/(Z bulk area value+E bulk area value) * 100 (%)
The analytical procedure of the content of toluylic acid is as follows.
Post: SUPELCO ODS HYPERSIL 5 μ m 250 * 4.6mm
Column temperature: 25 ℃
Moving phase (volume ratio): acetonitrile 20%, 50mM potassium primary phosphate 80%
Flow: 1.0ml/min
Detect 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) bulk area value+toluylic acid area value)) * 100 (%)
embodiment 1
(1) the 1st operation
Take the compound shown in 10.0g following formula (5) (containing ratio 3.5% of E body) and join in four-hole boiling flask, add 6 % by weight sodium bicarbonate aqueous solution 240g, make the aqueous solution of sodium salt.In this aqueous solution, add 7.0g penicillin-G acyltransferase (PGA-450, Dalas Biotech Limited manufacture).5% aqueous sodium carbonate that adds 25～30 ℃ of liquid temperatures, limit is controlled at by pH 7 deprotection reactions that the sodium salt of compound shown in 2 little up-to-date styles (5) is carried out on 7.7～8.5 limits.After reaction finishes, in solution, contain the sodium salt 7.0g containing the compound shown in the following formula (6) of 3.5%E body in E body containing ratio.In addition, in toluylic acid containing ratio, comprise toluylic acid 16.6%.
(2) the 2nd operations
Then the 1st operation, filters out enzyme, and limit remains on 20 ℃ by liquid temperature, to add below concentrated hydrochloric acid, pH is adjusted to 0.9.Obtain thus the aqueous solution of the hydrochloride of the compound shown in formula (6).Then, in this aqueous solution, add 6.2g gac (the Unitika activated carbon fiber ADALL A-20 (trade(brand)name) that Unitika Ltd. manufactures), standing 1 hour.The iodine absorption property that this gac is measured according to JIS K-1474 is 1580mg/g, and methylene blue adsorption number performance is 310ml/g., filter out gac, in the aqueous solution, add the aqueous sodium hydroxide solution of 1N that pH is adjusted to 4.3, slaking 1 hour thereafter.By this slaking, separate out the crystal of the compound shown in formula (1).Filter and collect the crystal of separating out, water and methanol wash crystal, dry.The analytical results of gained crystal is as follows.
Z body yield: 92.0%
E body containing ratio: 0.28%
Toluylic acid containing ratio (removing by filter after gac): 3.9%
1h-NMR (D
2o/DCl) ppm is from TSP2.52 (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)
embodiment 2
In the 1st operation of embodiment 1, the material that in the compound shown in use formula (5), the containing ratio of E body is 4.6%, the 1st operation is carried out in operation similarly to Example 1.After reaction finishes, in solution, contain the sodium salt 7.0g containing the compound of the formula (6) of 4.6%E body in E body containing ratio.In addition, in toluylic acid containing ratio, comprise toluylic acid 16.7%., remove by filter enzyme, carry out the 2nd operation thereafter.In the 2nd operation, limit remains on 20 ℃ by liquid temperature, to add below concentrated hydrochloric acid, pH is adjusted to 0.9.Obtain thus the aqueous solution of the hydrochloride of the compound shown in formula (6).Then, in this aqueous solution, add 5.6g gac (Ajinomoto Fine-Techno Co., lnc. (trade(brand)name)), stir 1 hour.The iodine absorption property of this gac is 1620mg/g, and methylene blue adsorption number performance is 280ml/g.Thereafter, remove by filter gac, the aqueous sodium hydroxide solution that adds lN in the aqueous solution is adjusted to 4.3 by pH, slaking 1 hour.By this slaking, the crystal of the compound shown in formula (1) is separated out.Filter and collect the crystal of separating out, water and methanol wash crystal, dry.Operation similarly to Example 1 in addition.The analytical results of gained crystal is as follows.
Z body yield: 91.9%
E body containing ratio: 0.25%
Toluylic acid containing ratio (removing by filter after gac): 3.9%
embodiment 3
In the 1st operation of embodiment 2, the material that in the compound shown in use formula (5), the containing ratio of E body is 3.5%, the 1st operation is carried out in operation similarly to Example 2.After reaction finishes, in solution, contain the sodium salt 7.0g containing the compound of the formula (6) of 3.5%E body in E body containing ratio.In addition, in toluylic acid containing ratio, comprise toluylic acid 16.7%.Then, in the 2nd operation of embodiment 2, replace concentrated hydrochloric acid and use 15 % by weight sulfuric acid.Operate similarly to Example 2 in addition the crystal that obtains the compound shown in formula (1).Operation similarly to Example 2 in addition.The analytical results of gained crystal is as follows.
Z body yield: 93.3%
E body containing ratio: 0.15%
Toluylic acid containing ratio (removing by filter after gac): 4.1%
embodiment 4
In the 1st operation of embodiment 2, the material that in the compound shown in use formula (5), the containing ratio of E body is 3.5%, the 1st operation is carried out in operation similarly to Example 2.After reaction finishes, in solution, contain the sodium salt 7.0g containing the compound of the formula (6) of 3.5%E body in E body containing ratio.In addition, in toluylic acid containing ratio, comprise toluylic acid 16.7%.The pH of this aqueous solution is between 7.7～8.5.Then, add the same material of gac using in 4.6g and embodiment 2 in this aqueous solution, limit keeps 20 ℃ of limits to stir 1 hour., remove by filter gac, in the aqueous solution, add the hydrochloric acid of 3N that pH is adjusted to 4.3, slaking 1 hour thereafter.By this slaking, the crystal of the compound shown in formula (1) is separated out.Filter and collect the crystal of separating out, water and methanol wash crystal, dry.Operation similarly to Example 2 in addition.The analytical results of gained crystal is as follows.In the present embodiment, the pH of the aqueous solution when gac is played a role is in alkaline region, thereby the amount of toluylic acid is than embodiment 2 height.
Z body yield: 92.5%
E body containing ratio: 0.20%
Toluylic acid containing ratio (removing by filter after gac): 17.0%
embodiment 5
In the 1st operation of embodiment 2, the material that in the compound shown in use formula (5), the containing ratio of E body is 3.5%, the 1st operation is carried out in operation similarly to Example 1.After reaction finishes, in solution, contain the sodium salt 7.0g containing the compound of the formula (6) of 3.5%E body in E body containing ratio.In addition, in toluylic acid containing ratio, comprise toluylic acid 16.8%.Then, carry out the operation same with the 2nd operation of embodiment 2.Wherein, the usage quantity of gac is 4.6g.Operate similarly to Example 2 in addition the crystal that obtains the compound shown in formula (1).The analytical results of gained crystal is as follows.
Z body yield: 93.7%
E body containing ratio: 0.12%
Toluylic acid containing ratio (removing by filter after gac): 4.0%
comparative example 1
Carry out the operation same with the 1st operation of embodiment 1.After reaction finishes, in solution, contain the sodium salt 6.9g containing the compound of the formula (6) of 3.5%E body in E body containing ratio.In addition, in toluylic acid containing ratio, comprise toluylic acid 16.7%.Then, carry out the operation same with the 2nd operation of embodiment 1.Wherein, as gac, use Ajinomoto Fine-Techno Co., the CL-H (trade(brand)name) that Inc. manufactures.The iodine absorption property that this gac is measured according to JIS K-1474 is 980mg/g, and methylene blue adsorption number performance is 180ml/g.The usage quantity of this gac is 4.6g.Operate similarly to Example 1 in addition the crystal that obtains the compound shown in formula (1).The analytical results of gained crystal is as follows.In addition, toluylic acid amount is 6.2%.
Z body yield: 94.2%
E body containing ratio: 3.0%
comparative example 2
Carry out the operation same with the 1st operation of embodiment 1.After reaction finishes, in solution, contain the sodium salt 7.0g containing the compound of the formula (6) of 3.5%E body in E body containing ratio.In addition, in toluylic acid containing ratio, comprise toluylic acid 16.7%.Then, carry out the operation same with the 2nd operation of embodiment 1.Wherein, as gac, use Ajinomoto Fine-Techno Co., the BA-WD (trade(brand)name) that Inc. manufactures.The iodine absorption property that this gac is measured according to JIS K-1474 is 970mg/g, and methylene blue adsorption number performance is 180ml/g.The usage quantity of this gac is 4.6g.Operate similarly to Example 1 in addition the crystal that obtains the compound shown in formula (1).The analytical results of gained crystal is as follows.In addition, toluylic acid amount is 5.8%.
Z body yield: 93.0%
E body containing ratio: 2.8%
From above result, by the gac with specific iodine absorption property and methylene blue adsorption number performance used according to the invention, optionally remove E body.In addition, also can remove toluylic acid.
industrial utilizability
As described in detail above, according to the present invention, at 7-amino-3-[(E/Z)-2-(4-methylthiazol-5-yl) vinyl] in the manufacture of-3-cephem-4-carboxylic acid or its an alkali metal salt, can be than improving Z body with respect to the containing ratio of E body with contact.
Claims (4)
1. the manufacture method of the 7-amino-3-shown in a formula (1) ［ (E/Z)-2-(4-methylthiazol-5-yl) vinyl ］-3-cephem-4-carboxylic acid or its an alkali metal salt, it has improved the containing ratio of the 7-amino-3-shown in following formula (2) ［ (Z)-2-(4-methylthiazol-5-yl) vinyl ］-3-cephem-4-carboxylic acid or its an alkali metal salt, it is characterized in that, the aqueous solution of the 7-amino-3-shown in following formula (1) ［ (E/Z)-2-(4-methylthiazol-5-yl) vinyl ］-3-cephem-4-carboxylic acid or its an alkali metal salt is contacted to process with gac, the iodine absorption property that this gac is measured according to JIS K-1474 is more than 1200mg/g, methylene blue adsorption number performance is more than 250ml/g,
Wherein, the compound shown in aforementioned formula (1) is made to inorganic acid salt by mineral acid treatment, the aqueous solution that the pH that makes to comprise this inorganic acid salt is 0.5～1.7 contacts with aforementioned gac.
2. manufacture method according to claim 1, wherein, aforementioned mineral acid is hydrochloric acid.
3. manufacture method according to claim 1; compound shown in the aforementioned formula (1) that its use comprises toluylic acid or derivatives thereof is as raw material; described toluylic acid or derivatives thereof is the by product of this deprotection reaction that the salt of the 7-substituted acyl amino-3-shown in following formula (3) ［ (E/Z)-2-(4-methylthiazol-5-yl) vinyl ］-3-cephem-4-carboxylic acid is generated to carry out the deprotection reaction of 7 amido linkages for enzyme reaction
In formula, R
lrepresent benzyl or Phenoxymethyl, M represents alkalimetal ion or ammonium ion.
4. manufacture method according to claim 1, is adjusted to 3.8～4.8 by the pH of the treatment solution with after aforementioned activated carbon treatment, makes the crystal settling of the compound shown in formula (2).
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2008184328A JP4659074B2 (en) | 2008-07-15 | 2008-07-15 | Method for producing 3-alkenylcephem compound |
| JP2008184328 | 2008-07-15 | ||
| JP2008-184328 | 2008-07-15 |
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| CN101628915A CN101628915A (en) | 2010-01-20 |
| CN101628915B true CN101628915B (en) | 2014-04-02 |
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| JP (1) | JP4659074B2 (en) |
| KR (1) | KR20100008351A (en) |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20010016581A1 (en) * | 1993-11-17 | 2001-08-23 | Johannes Ludescher | Separation of cephalosporin isomers |
| CN1964981A (en) * | 2004-06-04 | 2007-05-16 | 大塚化学株式会社 | Process for production of 3-alkenylcephem compounds |
-
2008
- 2008-07-15 JP JP2008184328A patent/JP4659074B2/en not_active Expired - Fee Related
-
2009
- 2009-02-27 CN CN200910118652.4A patent/CN101628915B/en not_active Expired - Fee Related
- 2009-07-14 KR KR1020090064164A patent/KR20100008351A/en not_active Application Discontinuation
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20010016581A1 (en) * | 1993-11-17 | 2001-08-23 | Johannes Ludescher | Separation of cephalosporin isomers |
| CN1964981A (en) * | 2004-06-04 | 2007-05-16 | 大塚化学株式会社 | Process for production of 3-alkenylcephem compounds |
Non-Patent Citations (3)
| Title |
|---|
| 应维琪 等.简易水处理活性炭的选择和应用方法.《环境污染与防治》.2005,第27卷(第6期),全文. |
| 立本英机.活性炭质量基准.《活性炭的应用技术》.2007,第26页. * |
| 简易水处理活性炭的选择和应用方法;应维琪 等;《环境污染与防治》;20050930;第27卷(第6期);全文 * |
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| KR20100008351A (en) | 2010-01-25 |
| JP4659074B2 (en) | 2011-03-30 |
| JP2010024148A (en) | 2010-02-04 |
| CN101628915A (en) | 2010-01-20 |
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