CN102725297A - Process for preparation of cephalosporin derivative - Google Patents

Process for preparation of cephalosporin derivative Download PDF

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Publication number
CN102725297A
CN102725297A CN2011800074870A CN201180007487A CN102725297A CN 102725297 A CN102725297 A CN 102725297A CN 2011800074870 A CN2011800074870 A CN 2011800074870A CN 201180007487 A CN201180007487 A CN 201180007487A CN 102725297 A CN102725297 A CN 102725297A
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formula
salt
carboxylic acid
cephem
methylthiazol
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和久井淳
大原宣彦
田久保洋介
松本信夫
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Nippon Chemical Industrial Co Ltd
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Nippon Chemical Industrial Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • 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
    • A61K31/542—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—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, cefaclor, or cephalexine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • 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
    • C07D501/02—Preparation
    • C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
    • C07D501/06—Acylation of 7-aminocephalosporanic acid
    • 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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Cephalosporin Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

Provided is a process by which an objective cephalosporin derivative having a high Z-isomer content or an alkali metal salt thereof can be prepared via simple steps with industrial advantages. A process for the preparation of a cephalosporin derivative (4a) or an alkali metal salt thereof, characterized by comprising the first step of bringing an aqueous solution of 7-amino-3-[(E/Z)-2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid (1) or an alkali salt thereof into contact with an active carbon that has an iodine adsorptivity of 1200mg/g or more as determined by JIS K-1474 and a methylene blue adsorptivity of 250ml/g or more as determined thereby to prepare the carboxylic acid (1) having an enhanced content of Z-isomer (2) or an alkali metal salt thereof, and the second step of subjecting the carboxylic acid (1); which has been prepared in the first step and has an enhanced content of Z-isomer (2) to reaction with a compound (3).

Description

The method of manufacture of cephalosporins derivatives
Technical field
The present invention relates to the method for manufacture of a kind of containing ratio of the Z of making body than the cephalosporins derivatives and an alkali metal salt thereof of E height.
Background technology
7-shown in the known formula (7) [2-methoxyimino-2-(thiazolamine-4-yl) acetamido]-3-[2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid (cis-isomeride (syn-isomer), cis-isomeride (cis-isomer)) is the cephalosporin antibiotics that is called as the excellence of ME1207 (Cefditoren).
Figure BDA00001940361100011
At present; The compound method motion of this ME1207 has following method: shown in following reaction process (1); (for example, with reference to patent documentation 1) made in reaction through the 7-amino-3-shown in compound shown in the formula (A) and the following formula (2) [(Z)-2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid or its an alkali metal salt.
Reaction process (1)
But, in the method for said reaction process (1), in order to obtain cephalosporin antibiotics, the R in the formula as target 1Need to use shielded amino, therefore, must need the operation of removing of amino protecting group, it is complicated that operation becomes, unfavorable in industry.
7-amino-3-[2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid or its an alkali metal salt (compound (2)) are the material as the manufacturing midbody of cephalosporins.As far as this compound, the three-dimensional arrangement that has 3 thiazolinyl is Z configuration and these 2 kinds of isomer of E configuration.Known in these 2 kinds of isomer, be to comprise above-mentioned ME1207 with it as the cephalosporins of the raw material isomer that agent shows excellent anti-microbial effect as medicinal antibiosis at interior Z body.
By the synthetic cephalosporins of 7-amino-3-[2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid or its an alkali metal salt the time, in reaction system, only there is the Z body and do not exist the E body very important as far as possible.
Consider from this viewpoint; Motion has 7-amino-3-[2-(4-methylthiazol-5-yl) the vinyl]-3-cephem-4-carboxylic acid that high porous polymer or gac mixed with Z body and E body exist or the aqueous solution effect of its an alkali metal salt, the containing ratio of raising Z body in patent documentation 2.As the high porous polymer that uses in this method, but illustration acrylic resin, phenolic resin, styrene resin.On the other hand, as gac, can use the so common gac of zinc chloride carbon or water vapour carbon.
Method according to record in the said patent documentation 2; 7-amino-3-[2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid or its an alkali metal salt of containing ratio of Z body can be improved; In addition, through this compound is used as intermediate raw material, can obtain the high cephalosporins derivatives of Z body containing ratio; But for the cephalosporins derivatives of final purpose thing, the higher compound of containing ratio of expectation Z body.
The prior art document
Patent documentation
Patent documentation 1: the special fair 3-64503 communique of Japan
Patent documentation 2: TOHKEMY 2005-343854 communique
Summary of the invention
Invent problem to be solved
Therefore, the object of the present invention is to provide and a kind ofly can overcome the cephalosporins derivatives of the various shortcomings that above-mentioned prior art has or the method for manufacture of its an alkali metal salt.
Be used to solve the method for problem
The present invention has realized above-mentioned purpose through the cephalosporins derivatives shown in a kind of formula (4a) or the method for manufacture of its an alkali metal salt are provided, and the invention is characterized in, comprising:
First operation; The aqueous solution that makes the 7-amino-3-shown in the following formula (1) [(E/Z)-2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid or its an alkali metal salt is more than the 1200mg/g with the iodine absorption property that records according to JIS K-1474 and the methylene blue absorption property is that gac more than the 250ml/g contacts, the 7-amino-3-containing ratio of the 7-amino-3-shown in the following formula that has been improved (2) [(Z)-2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid or its an alkali metal salt, shown in the formula (1) [(E/Z)-2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid or its an alkali metal salt; With
Figure BDA00001940361100031
Figure BDA00001940361100041
Second operation; Then; Compound shown in 7-amino-3-shown in the formula (1) of the containing ratio of the 7-amino-3-shown in the general formula (2) that made the raising that obtains in said first operation [(Z)-2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid or its an alkali metal salt [(E/Z)-2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid or its an alkali metal salt and the formula (3) reacts
Figure BDA00001940361100042
(in the formula, R 1The expression alkyl.X representes active ester groups.）
The effect of invention
According to the present invention; Can use 7-amino-3-[(E/Z)-2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid or its an alkali metal salt, high cephalosporins derivatives or its an alkali metal salt as target of containing ratio of Z body is provided with advantageous method in the industry through easy operation.
Embodiment
< first operation >
In first operation of the present invention, has following characteristic: make specific gac and contain compound or its alkali salt effect shown in the above-mentioned formula (1) of Z body and E body, make this gac optionally adsorb the E body and be removed, improve the containing ratio of Z body thus.At this so-called alkali salt, be meant acceptable alkali salt on the pharmacology.In addition, in following explanation, the compound shown in the formula (1) and its an alkali metal salt are generically and collectively referred to as " alkenylcephem compounds ".
The alkenylcephem compounds that uses among the present invention is made up of the mixture of Z body and E body.Z body and E body are known compound.The ratio that exists of Z body in the alkenylcephem compounds and E body does not limit especially, and this exists ratio to exist with ... creating conditions of alkenylcephem compounds etc.For purposes of the present invention, the ratio that exists of expectation Z body is higher than the ratio that exists of E body fully, and the method for the application of the invention can obtain the Z body easy and with high yield.Existing under the state of ratio before the processing that utilizes gac of E body in the alkenylcephem compounds is generally 0.3～20%; Be in particular 2～12%, this exist ratio by based on after the calculating formula of the E body containing ratio that uses among the embodiment that the states containing ratio of calculating represent.
In the present invention, alkenylcephem compounds is contacted with gac with the state of the aqueous solution.For alkenylcephem compounds is processed the aqueous solution, for example get final product with alkaline purification alkenylcephem compounds and the form of processing corresponding salt (for example an alkali metal salt).As alkali, can use alkali metal hydroxides such as sodium hydroxide, Pottasium Hydroxide, Lithium Hydroxide MonoHydrate; Alkali metal hydrocarbonates such as sodium hydrogencarbonate; Alkaline carbonates such as yellow soda ash, salt of wormwood, Quilonum Retard etc.The aqueous solution through containing these alkali mixes with alkenylcephem compounds, can alkenylcephem compounds be made into the aqueous solution.
The degree that the pH of the above-mentioned aqueous solution does not have crystalization to separate out with the salt of alkenylcephem compounds is that high pH zone get final product, preferably is made as 7.1～9.0 usually, and it is regional especially preferably to be made as 7.5～8.5 weak base.In addition, the concentration of the salt of contained alkenylcephem compounds is not to be criticality in the present invention in the above-mentioned aqueous solution, and the lower concentration of the degree of not separating out for the crystal of this salt gets final product.
As other method that is used for alkenylcephem compounds is made into the aqueous solution, can enumerate with this alkenylcephem compounds of mineral acid treatment and process the method for corresponding inorganic acid salt form.As mineral acid, for example can enumerate: hydrochloric acid, sulfuric acid, nitric acid etc.Through these mineral acids are mixed with alkenylcephem compounds, can access the aqueous solution that this compound is the state of inorganic acid salt.
The above-mentioned pH that contains the aqueous solution of inorganic acid salt gets final product for low pH is regional with the non-setting degree of this inorganic acid salt, preferably is made as 0.5～1.7 usually, especially preferably is made as 0.8～1.4.In addition, the concentration of contained inorganic acid salt is not to be criticality in the present invention in the above-mentioned aqueous solution, for the non-setting degree of the crystal of this inorganic acid salt gets final product.
If more above-mentioned an alkali metal salt and inorganic acid salt then preferably use inorganic acid salt.Its reason is that by product toluylic acid or derivatives thereof (being described in detail in the back about this) absorption that produces in the time of can when the E body is removed in absorption, will synthesizing alkenylcephem compounds is removed.In the inorganic acid salt, when particularly using hydrochloride, can further improve the purity of Z body, so preferred.
In addition; When activated carbon treatment, when in system, existing the toluylic acid or derivatives thereof to exist, owing to compare with the E body; Gac adsorbs the toluylic acid or derivatives thereof more easily; So from reducing the usage quantity of expensive gac, also have the viewpoint of the purity that further improves the Z body to consider, particularly preferably in carry out the treatment process of following (A) in advance or/and treatment process (B) is come the interior toluylic acid or derivatives thereof of the system of removing as much as possible before gac contact.
Optionally adsorb the gac of removing the E body for being used for from alkenylcephem compounds, inventors of the present invention concentrate on studies, and the result is clear and definite, and to use the gac at the peak of peak with big fine pore and little fine pore be effective.And then; Inventors of the present invention further study, the result is clear and definite have iodine absorption property that gac that such fine pore distributes records according to JIS K-1474 and the methylene blue absorption property that likewise records according to JIS K-1474 in specific scope.Among the present invention,, can from alkenylcephem compounds, optionally adsorb and remove the E body through using this have specific iodine absorption property and the gac of methylene blue absorption property.
About above-mentioned specific iodine absorption property, use this value to be the gac more than the 1200mg/g.In addition, obtain the iodine absorption property in the industry and surpass 1700mg/g and have the gac of methylene blue absorption property of the following stated concurrently extremely difficult, therefore, the upper limit of the iodine absorption property of the gac that uses among the present invention is made as 1700mg/g.Therefore, the scope of iodine absorption property is preferably 1200～1700mg/g, more preferably 1400～1700mg/g.Certainly, because the value of iodine absorption property is high more preferred more, so use the gac that has above the iodine absorption property of 1700mg/g not have any influence.
For the methylene blue absorption property, use this value to be the gac more than the 250ml/g.In addition, obtain the methylene blue absorption property in the industry and surpass 500ml/g and have the gac of above-mentioned iodine absorption property concurrently extremely difficult, therefore, the upper limit of the methylene blue absorption property of the gac that uses among the present invention is made as 500ml/g.Therefore, the scope of methylene blue absorption property is preferably 250～500ml/g, more preferably 260～500ml/g.Certainly, because the value of methylene blue absorption property is high more good more, so use the gac that has above the methylene blue absorption property of 500ml/g not have any influence.
Usually, in each item rerum natura of employed gac, the iodine absorption property is below the 1200mg/g in the water treatment etc.; The methylene blue absorption property is that (with reference to " Application of Brand Active Carbon technology ", chief editor Li Benying sets, the husband of nation of peace portion, press: TechnoSystems below the 200ml/g; Inc.; Publish day: on July 25th, 2000, the 409th page, the 555th page), therefore, these physics values of the gac that uses among the present invention are high more a lot of than the value of common gac.This is owing to be distributed with big pore and little pore.Generally speaking, the iodine absorption property is the distribution index (that is, the adsorptivity index of the compound that molecular weight is little) of little pore, and the methylene blue absorption property is the distribution index (that is the adsorptivity index of the compound that, molecular weight is big) of big pore.
As the gac that satisfies above-mentioned iodine absorption property and methylene blue absorption property, can enumerate for example with the steam activation gac as raw material such as coconut husk, coal, wooden material.At this moment, suitably control the condition of granulation through suitable control activatory conditioned disjunction, to satisfy above-mentioned physics value.In addition, the shape of gac can be powder, granular or fibrous, perhaps also can be molding.As the gac that satisfies above-mentioned physics value, also can use commercially available article.As so commercially available article, can enumerate for example can be that Unitika NACF AdallA-20 (trade(brand)name) maybe can be that liquid phase is with gac CL-KP (trade(brand)name), CL-K (trade(brand)name) etc. from the gac that the aginomoto fine chemistry is bought from the gac that Unitika Co., Ltd. buys.
The not special restriction of the method that above-mentioned gac is contacted with alkenylcephem compounds.For example can be employed in and add above-mentioned active carbon method in the aqueous solution of alkenylcephem compounds, or opposite method of in above-mentioned gac, adding the aqueous solution of alkenylcephem compounds.Perhaps can also adopt above-mentioned gac is filled in the post; With pump etc. the aqueous solution of alkenylcephem compounds is delivered in the post; It is passed through in post; And then make its round-robin method repeatedly in post, and the method that the device that contains gac in the moldinies such as strainer is contacted with the aqueous solution of alkenylcephem compounds.The not special restriction of the ratio of the amount of gac and the amount of alkenylcephem compounds.For example consider from rate of loss that can reduce the Z body and the viewpoint that can effectively remove E body and toluylic acid; Preferably with respect to alkenylcephem compounds contained in the aqueous solution 100 weight parts; Make 10～300 weight parts, particularly the gac of 10～200 weight parts is in contact with it.
The also not special restriction of the method that above-mentioned gac is contacted with alkenylcephem compounds.Temperature when for example contacting can be made as 0～20 ℃.Temperature through will contact the time is located in this scope, can reduce the wastage rate of Z body, and can effectively remove E body and toluylic acid, so preferred.Temperature during with contact as condition, is preferably 0.5～3 hour in above-mentioned scope duration of contact, is preferably 1～2 hour especially.During making that both contact, can make reaction system is whipped state, perhaps also can be static condition.
Above method can only be carried out 1 time, perhaps also can repeat with the purpose of the purity that improves the Z body more than 2 times repeatedly.
Through above operation, from the alkenylcephem compounds that contains Z body and E body, the E body is optionally adsorbed by gac to be removed, and the containing ratio of Z body improves.Then; Gac is separated with treatment solution; The acid (processing water miscible situation) that in treatment solution, adds hydrochloric acid, nitric acid, sulfuric acid etc. with alkali; Or add the slightly acidic zone of alkali (processing water miscible situation) such as sodium hydroxide with pH regulator to 3.8～4.8 of solution with mineral acid, make the crystal settling of the compound shown in the formula (2).Through filtering or centrifugal the separation, utilize organic solvents such as water and methyl alcohol to clean in the crystal that obtains.With the pH regulator of treatment solution to above-mentioned scope, the compound shown in the formula (2) is separated out, can reclaim as the raising of object the compound shown in the formula (1) of containing ratio of Z body with high purity and high yield.
In the present invention, the alkenylcephem compounds that uses as starting substance can obtain through general's protective reaction that for example the 7-substituted acyl amino-3-shown in the following formula (6) [(E/Z)-2-(4-methylthiazol-5-yl) vinyl]-salt of 3-cephem-4-carboxylic acid supplies to carry out 7 amido linkages in enzyme reaction.As long as this salt is for water-soluble, and then its kind is not special limits.As water miscible salt, can enumerate for example alkali metal salts or ammonium salt.
Figure BDA00001940361100081
(in the formula, R 3Expression benzyl, phenoxymethyl.M representes the positively charged ion of 1 valency.）
As the solvent of above-mentioned enzyme reaction, consider from the viewpoint of bringing into play enzymic activity to greatest extent, preferably make water.The pH of enzyme reaction becomes the major cause that the activity to enzyme impacts.Consider that from this viewpoint although also depend on the kind of enzyme, preferred pH maintains 7.5～8.5.Can use various alkali aqueous solutions to keep pH, for example can use alkali metal hydroxides such as sodium hydroxide or Pottasium Hydroxide; Alkali metal hydrocarbonates such as sodium hydrogencarbonate; The aqueous solution of the alkaline carbonate of yellow soda ash or salt of wormwood etc. etc.The temperature of enzyme reaction also becomes the major cause that enzymic activity is impacted.Consider from this viewpoint, although also depend on the kind of enzyme, preferably with the temperature maintenance of reaction system at 25～35 ℃.Reaction times is not criticality in the present invention.Normally reacting disappears from reaction system until the compound shown in the formula (6) gets final product.As condition, the reaction times can be made as 1～3 hour usually with the scope of above-mentioned pH and temperature.
As the enzyme that uses, can especially restrictedly not use present known penicillin G acylase.Can use for example penicillin G Ntn hydrolase PGA-150, PGA-300, the PGA-450 of Boehringer Mannheim corporate system; The penicillin G acylase of Dalas Biotech Limited system; The penicillin G acylase of Roche Molecular Biochemicals corporate system; The IPA-750 of Hu'nan Fulaige Biological Technology Co. Ltd.; The Syntha CLEC-PA of Atlus Biologics corporate system etc.
The usage quantity of enzyme also depends on its kind, but is 30～150 weight parts with respect to compound 100 weight parts shown in the formula (6) preferably, is preferably 50～100 weight parts especially.
Through above enzyme reaction, can obtain the salt of alkenylcephem compounds.In this enzyme reaction, 7 acid amides of the compound shown in the through type (6) is protected the going to protect of base and is generated the toluylic acid or derivatives thereof (following these are generically and collectively referred to as " toluylic acid class ") as by product.This toluylic acid etc.;, the object of this method of manufacture is impurity for being high 7-amino-3-[2-(4-methylthiazol-5-yl) the vinyl]-3-cephem-4-carboxylic acid of the containing ratio of Z body; Therefore, in the present invention, need supply before second operation, to get rid of its existence as far as possible.
As in the method that supplies before second operation, to remove toluylic acid, can implement through following arbitrary operation before alkenylcephem compounds contacts with gac or after the contact.
(A) at alkenylcephem compounds shown in the formula (1) with before gac contacts, with an organic solvent the aqueous solution of the alkenylcephem compounds shown in the formula (1) is carried out the operation of the extraction treatment of above-mentioned toluylic acid class.
(B) at alkenylcephem compounds shown in the formula (1) with before gac contacts, the partial crystallization treatment procedures that this alkenylcephem compounds is separated out from the aqueous solution of the alkenylcephem compounds shown in the formula (1).
(C) at the alkenylcephem compounds shown in the formula (1) with after gac contacts, through above-mentioned separate out the compound shown in the operation recovery type (2) before, with an organic solvent carry out the operation of the extraction treatment of above-mentioned toluylic acid class.
Below, the treatment process of above-mentioned (A) is described.
Consider from the viewpoint that the extraction of carrying out the toluylic acid class is reliably removed; Preferably before extraction treatment; The pH regulator of the aqueous solution of salt that utilizes the compound shown in the formula (1) that mineral acid will obtain through above-mentioned enzyme reaction is to acidic region; Particularly be adjusted to below 2, be adjusted to below 1 especially, and the salt of compound shown in the formula in the aqueous solution (1) is processed the form of corresponding inorganic acid salt.As this mineral acid, can enumerate hydrochloric acid, nitric acid, sulfuric acid etc.
Organic solvent as using in the extraction treatment has (1) low-grade carboxylic acid's lower alkyl esters class, (2) ketone, (3) ethers, (4) to replace or non-substituted aromatic hydrocarbon based, (5) halogenated hydrocarbons, (6) aliphatic hydrocarbon, (7) cycloalkane.These organic solvents can use separately or make up more than 2 kinds and use.As the low-grade carboxylic acid's of (1) lower alkyl esters class, can enumerate: methyl-formiate, ethyl formate, propyl formate, butyl formate, methyl acetate, ETHYLE ACETATE, propyl acetate, butylacetate, methyl propionate, ethyl propionate etc.As the ketone of (2), can enumerate: methylacetone, espeleton, mibk, diethyl ketone etc.As the ethers of (3), can enumerate: diethyl ether, ethyl propyl ether, ethyl-butyl ether, dipropyl ether, DIPE, dibutyl ether, methylcyclohexane, glycol dimethyl ether etc.As the replacement of (4) or non-substituted aromatic hydrocarbon based, can enumerate: benzene,toluene,xylene, chlorobenzene, phenylmethylether etc.As the halogenated hydrocarbons of (5), can enumerate: methylene dichloride, chloroform, ethylene dichloride, trichloroethane, ethylene dibromide, propylene dichloride, tetracol phenixin etc.As the aliphatic hydrocarbon of (6), can enumerate pentane, hexane, heptane, octane etc.As the cycloalkane of (7), can enumerate: pentamethylene, hexanaphthene, suberane, cyclooctane etc.
Among these organic solvents, preferably the solubleness in 20 ℃ of water is the solvent below the 1 weight %, particularly, and preferred toluene, chloroform, chlorobenzene etc., preferred especially toluene.
When using the organic solvent that polarity is high and the solubleness in water is high, organic solvent just is dissolved in the aqueous solution of the alkenylcephem compounds that carries out extraction treatment.The aqueous solution of the alkenylcephem compounds that is dissolved with organic solvent is supplied in above-mentioned when utilizing the processing of gac, and gac can adsorb organic solvent, and therefore, the absorption of E body is removed efficient and reduced, and is difficult to improve the purity of Z body.Therefore, under the situation of using the high organic solvent of solubleness in water, before the processing that utilizes gac, need concentrate the aqueous solution after the extraction treatment and from this aqueous solution, remove the enrichment process of organic solvent.The solubleness of use in water does not need enrichment process when being the low organic solvent of solubleness below the 1 weight % for 20 ℃, therefore, favourable in industry.
To the every 1kg of the alkenylcephem compounds in the above-mentioned aqueous solution, these organic solvents preferably use 5～50 liters, more preferably use 10～30 liters.In addition, extraction treatment is preferably carried out at 0～20 ℃.As long as be this preferred ratio, then in extraction treatment, just can reduce the containing ratio of toluylic acid class effectively.
In method of manufacture of the present invention, after extraction treatment, with based on after the calculating formula of the toluylic acid containing ratio that uses among the embodiment that the states containing ratio of calculating represent the toluylic acid class, it is reduced to below 8%.Through repeating repeatedly extraction treatment, the containing ratio of toluylic acid class descends gradually, therefore, can't reach under the situation below 8% through 1 extraction treatment at the containing ratio of toluylic acid class, preferably carries out repeatedly SX.
After the treatment process of above-mentioned (A), the aqueous solution that the extraction treatment of utilizing organic solvent is finished directly contacts with gac.
Below, the treatment process of above-mentioned (B) is described.
Consider from making the viewpoint that the compound shown in the formula (1) is separated out and yield reclaims well; The pH regulator of the aqueous solution of salt that utilizes the compound shown in the formula (1) that mineral acid will obtain through above-mentioned enzyme reaction is to the slightly acidic territory; Particularly; Be adjusted to 3.5～4.8, be adjusted to 3.5～4.5 especially, the salt of compound shown in the formula in the aqueous solution (1) is made as the state of separating out easily with the free form.In addition, can carry out pH regulator through in this aqueous solution, adding mineral acids such as hydrochloric acid, nitric acid, sulfuric acid.
Then,, more preferably remain on 1～10 ℃, the compound shown in the formula (1) in the aqueous solution is separated out through this aqueous solution is preferably remained on below 20 ℃.In addition, partial crystallization is handled and can under agitation be carried out, and also can under leaving standstill, carry out.Compound as shown in the formula (1) of precipitate carries out solid-liquid separation through domestic method, is reclaimed by the treatment solution that contains the toluylic acid class.
In method of manufacture of the present invention, after partial crystallization is handled, with based on after the calculating formula of the toluylic acid containing ratio that uses among the embodiment that the states containing ratio of calculating represent the toluylic acid class, it is reduced to below 8%.Partial crystallization is handled and is compared with the extraction treatment of above-mentioned (A), and the efficient height is removed in the separation of toluylic acid class, therefore, as long as under the condition below the above-mentioned pH4.8, below 20 ℃, can handle that then the containing ratio of toluylic acid class is reduced to below 2% through 1 partial crystallization.In addition, handle through 1 partial crystallization at the containing ratio of toluylic acid class can't reach 8% below, preferably under the situation that can't reach below 2%, preferably carry out repeatedly the partial crystallization processing.
After the treatment process of above-mentioned (B), will be dissolved in the water and process the aqueous solution, this aqueous solution is contacted with gac through the precipitate (compound shown in the formula (1)) that this treatment process obtains.
Below, the treatment process of above-mentioned (C) is described.
Making before the compound shown in the formula (2) separates out and reclaim the compound of formula (1) as the containing ratio that has improved the Z body, utilize organic solvent that toluylic acid class contained in the treatment solution of activated carbon treatment is extracted through the separating out operation after the above-mentioned activated carbon treatment.Particularly; Gac is separated with treatment solution; In treatment solution, add acid (processing water miscible situation) or alkali (processing the situation of the aqueous solution with mineral acid) with alkali; The pH of solution preferably is made as below 2, more preferably is made as below 1, with an organic solvent from this aqueous solution, the toluylic acid class is carried out SX.Through carrying out repeatedly SX repeatedly, the concentration of the toluylic acid class in the treatment solution reduces gradually.
As employed organic solvent in the SX, can use and the identical solvent of above-mentioned (A) operation.Particularly, there are (1) low-grade carboxylic acid's lower alkyl esters class, (2) ketone, (3) ethers, (4) to replace or non-substituted aromatic hydrocarbon based, (5) halogenated hydrocarbons, (6) aliphatic hydrocarbon, (7) cycloalkane.These organic solvents can use separately or make up more than 2 kinds and use.As the low-grade carboxylic acid's of (1) lower alkyl esters class, can enumerate: methyl-formiate, ethyl formate, propyl formate, butyl formate, methyl acetate, ETHYLE ACETATE, propyl acetate, butylacetate, methyl propionate, ethyl propionate etc.As the ketone of (2), can enumerate: methylacetone, espeleton, mibk, diethyl ketone etc.As the ethers of (3), can enumerate: diethyl ether, ethyl propyl ether, ethyl-butyl ether, dipropyl ether, DIPE, dibutyl ether, methylcyclohexane, glycol dimethyl ether etc.As the replacement of (4) or non-substituted aromatic hydrocarbon based, can enumerate: benzene,toluene,xylene, chlorobenzene, phenylmethylether etc.As the halogenated hydrocarbons of (5), can enumerate: methylene dichloride, chloroform, ethylene dichloride, trichloroethane, ethylene dibromide, propylene dichloride, tetracol phenixin etc.As the aliphatic hydrocarbon of (6), can enumerate: pentane, hexane, heptane, octane etc.As the cycloalkane of (7), can enumerate: pentamethylene, hexanaphthene, suberane, cyclooctane etc.
Through carrying out repeatedly above SX, the concentration of toluylic acid class preferably is reduced to below 8%, the concentration of said toluylic acid class by based on after the calculating formula of the toluylic acid containing ratio that uses among the embodiment that the states containing ratio of calculating represent.After the SX, the alkali that in treatment solution, adds sodium hydrogencarbonate etc. carries out isoelectric precipitation, and crystal is separated out and with its recovery.
The treatment process of the treatment process of above-mentioned (A), (B) and treatment process (C) can appropriate combination be carried out; In addition; Under the situation that the treatment process of (A) and treatment process combination (B) are carried out, carry out the not special restriction of which kind of treatment process earlier.
In addition; Through above-mentioned gac is contacted with alkenylcephem compounds in the strongly-acid zone; The toluylic acid class also is adsorbed when utilizing this charcoal absorption to remove the E body, therefore, and before activated carbon treatment; Through carrying out above-mentioned (A) operation and/above-mentioned (B) operation, has the such advantage of usage quantity of the gac that can reduce use.At this moment, the usage quantity of gac for example with respect to alkenylcephem compounds contained in the aqueous solution 100 weight parts, preferably is made as 10～200 weight parts with gac, especially preferably is made as 20～100 weight parts.
In addition; It is painted that the compound shown in the formula (1) of containing ratio of Z body that used raising that existing method obtains appears, and through before activated carbon treatment, carrying out the treatment process of above-mentioned (A) and (B) treatment process, also can remove coloring components; Therefore; Improved the compound shown in the formula (1) of containing ratio of Z body can reduce painted, its result, also have the formula (4a) of final purpose thing or (4b) shown in painted also few advantage of cephalosporins derivatives.
As stated; In the present invention; The alkenylcephem compounds that preferably will contain the toluylic acid or derivatives thereof uses as raw material, and said alkenylcephem compounds is that the salt with the compound shown in the formula (6) supplies to carry out the protective reaction of 7 carboxamido-group and the by product of this protective reaction of generating in enzyme reaction.
Compound shown in the formula (6) can be synthetic through known method.For example through making the 7-substituted acyl amino-3-shown in the following formula (8) [(E/Z)-2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid cpd carry out 4 carboxylic acid protecting groups' protective reaction, can access the compound shown in the formula (6).As protective reaction, can adopt as the known the whole bag of tricks of the carboxylic acid protecting group's in the 'beta '-lactam compounds protective reaction.For example can adopt the protective reaction in the phenols of putting down in writing in the japanese kokai publication hei 61-263984 communique.
Figure BDA00001940361100131
(in the formula, R 3The same.R 4The expression carboxylic acid protecting group.）
In the formula (8), as R 4Shown carboxylic acid protecting group for example can enumerate: can be powered subbase and roll into a ball substituted benzyl and maybe can be powered subbase and roll into a ball substituted diphenyl methyl etc.As electron-donating group, for example can enumerate: the alkoxyl group of the alkyl of carbonatoms 1～6, hydroxyl, carbonatoms 1～6 etc.
< second operation >
After first operation finishes; Compound reaction shown in the 7-amino-3-shown in the formula (1) of containing ratio of Z body that made the raising that obtains in above-mentioned first operation [(E/Z)-2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid or its an alkali metal salt and the above-mentioned general formula (3) obtains as cephalosporins derivatives or its an alkali metal salt shown in (4a) of target.Below, the 7-amino-3-shown in the formula (1) of the containing ratio that has improved the Z body [(E/Z)-2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid or its an alkali metal salt are generically and collectively referred to as " refining alkenylcephem compounds ".
In the formula of the compound shown in the formula of second operation (3), R 1The expression alkyl.As abovementioned alkyl, for example can enumerate: the low alkyl group of carbonatomss 1～6 such as methyl, ethyl, propyl group, butyl.
Wherein, to the R in the formula 1, methyl can directly be derivatized to ME1207, so preferred especially.
In the formula of compound, X representes active ester groups shown in the formula (3).As far as being equivalent to the active ester groups of the X in this formula, for example can enumerate: the importing that the reaction through the compound shown in the formula (9) and the compound that in the compound of formula (9), imports active ester groups generates has the reaction residue of the compound of active ester groups.
(the R in the formula 1The same.）
As the compound that in the compound of above-mentioned formula (9), imports active ester groups, for example can enumerate: THIONYL CHLORIDE 97, oxalyl chloride, dicyclohexyl carbodiimide, curing two [benzothiazolyl-(2)], 2-hydroxyl-benzothiazoles, 2-halo-N-picoline salt or thiophosphoric acid (for example diethylammonium thiophosphoric acid) etc.From excellent with the reactivity of refining alkenylcephem compounds; In addition; Consider that from the viewpoint that can high yield obtains object the X in the special preferred formula is that the reaction residue of curing two [benzothiazolyl-(2)] is the benzothiazolyl shown in the following formula (5)-2-sulfenyl.
Figure BDA00001940361100142
In addition, the compound shown in the above-mentioned general formula (9) is that known reaction is (for example with reference to japanese kokai publication sho 58-152488 communique and Japan special table 2006-507290 communique with the reaction that in the compound of formula (9), imports the compound of active ester groups.）
Among the present invention, as far as the R in the compound, particularly formula shown in the formula (3) 1For methyl, X are that the compound of the benzothiazolyl shown in the formula (5)-2-sulfenyl can obtain object with high yield, in addition, itself also can obtain this compound in industry, so preferred especially.
From obtaining the viewpoint consideration of object with high purity and high yield, the addition of compound in reaction system shown in the preferred formula (3) is 1.0～1.5 with respect to refining alkenylcephem compounds with molar ratio computing, is preferably 1.1～1.3 and carries out.
Being reflected in the solvent of second operation carried out in the presence of alkali.
Alkali as using for example can preferably use triethylamine, tri-n-butyl amine, TERTIARY BUTYL AMINE, dicyclohexyl amine, N-methylmorpholine, 2, organic basess such as 3-Dimethylamino pyridine, N-Methyl pyrrolidone.
From obtaining the viewpoint consideration of object with high purity and high yield, the addition of alkali is 0.9～1.5 with respect to refining alkenylcephem compounds with molar ratio computing, is preferably 1.0～1.2 and carries out.
As the solvent that can use; Alcohol, water, acetone, acetonitrile, THF, methylene dichloride, ethylene dichloride, chloroform, N, DMSO 99.8MIN., THF, ETHYLE ACETATE, propyl acetate, n-butyl acetate equal solvents such as particular methanol, ethanol, 1-propyl alcohol, 2-propyl alcohol, butanols; In addition, these solvents can use a kind or use as the mixed solvent more than 2 kinds.
Temperature of reaction is-10～40 ℃, is preferably 0～20 ℃.Reaction times is more than 2 hours, is preferably 4～10 hours.
After reaction finishes; After not cleaning with methylene dichloride or chloroform etc. as required with water blended organic solvent; Use inorganic acid for adjusting pH to slightly acidic side, and then under reduced pressure remove and desolvate, obtain cephalosporins derivatives or its an alkali metal salt shown in the formula (4a) as target thus.In addition, an alkali metal salt of wherein so-called formula (4a) is meant acceptable alkali salt on the pharmacology.
< the 3rd operation >
In addition; Cephalosporins derivatives shown in the formula that obtains among known the present invention (4a) or its an alkali metal salt; Through the 3rd operation of reacting with chloromethyl pivalate under the existence that is arranged on Soiodin; Can make the R in the cephalosporins derivatives, particularly formula shown in the high formula (4b) of the containing ratio of Z body 1For 7-[2-methoxyimino-2-(thiazolamine-4-yl) acetamido]-3-[2-(4-methylthiazol-5-yl) the vinyl]-3-cephem-4-carboxylic acid pivalyl oxygen methyl esters (Cefditoren pivoxil Cephalosporins) of methyl for can be used as the material of cephalosporin antibiotics.
(in the formula, R 1The expression alkyl.）
More than, the present invention will be described based on the preferred embodiment of the present invention, but the present invention is not restricted to above-mentioned embodiment, 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, the present invention will be described in more detail through embodiment.But scope of the present invention is not restricted to said embodiment.
Before illustrative embodiment and comparative example, the analytical procedure of using is described.High performance liquid chromatograph (HPLC) is used in the analysis of alkenylcephem compounds and refining alkenylcephem compounds.Its detailed content is described below.
Post: Unison UK-C18,3 μ m, 250mm * 4.6mm
Column temperature: 30 ℃
Moving phase (volume ratio): acetonitrile 13%, 10mM heptanesulfonic acid sodium water solution 87%
Flow: 0.8ml/min
Detect wavelength: 254nm
Sample size: 10 μ l
Z body RT: 29.0～30.0 minutes
E stops RT: 31.0～32.0 minutes
E body containing ratio (calculating formula): [E bulk area value/(Z bulk area value+E bulk area value)] * 100 (%)
The analytical procedure of the containing ratio of toluylic acid is described below.
Post: SUPELCO ODS HYPERSIL 5 μ m250 * 4.6mm
Column temperature: 25 ℃
Moving phase (volume ratio): acetonitrile 20%, 50mM potassium dihydrogen phosphate aqueous solution 80%
Flow: 1.0ml/min
Detect wavelength: 225nm
Sample size: 10 μ l
Z body+E body RT: 2.5～3.5 minutes
Toluylic acid RT: 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]
The protective reaction operation of (1) 7 amido linkage
In four-hole boiling flask, take by weighing the compound shown in the following formula of 10.0g (10) (containing ratio 3.5% of E body), add the sodium bicarbonate aqueous solution 240g of 6 weight %, process sodium-salt aqueous solution.In this aqueous solution, add 7.0g penicillium mould-G acyltransferase (PGA-450, Dalas Biotech Limited system).The 5 weight % aqueous sodium carbonates that the annex solution temperature is 25～35 ℃ are controlled at 7.5～8.5 and carry out 7 protective reactions of the sodium salt of the compound shown in the 2 little up-to-date styles (10) with pH.After reaction finishes, in the aqueous solution, contain the sodium salt 7.0g that contains compound shown in the following formula (11) of 3.5%E body in E body containing ratio.In addition, contain toluylic acid 16.6% in the toluylic acid containing ratio.
Figure BDA00001940361100171
Figure BDA00001940361100181
(2) the toluylic acid class is removed operation (A operation)
Filter out enzyme (PGA-450) in the aqueous solution that from first operation, obtains; The liquid temperature is remained on 0～10 ℃ and interpolation concentrated hydrochloric acid; With the pH regulator to 0.9 of the aqueous solution, the sodium salt of the compound shown in the formula contained in the aqueous solution (11) is processed the hydrochloride of the compound shown in the formula (11).The aqueous solution after pH regulator finished moves in the separating funnel, the liquid temperature is remained on 20 ℃ and the toluene that adds 150ml therein extract and remove by product and impurity.Toluylic acid containing ratio after the extraction treatment is 6.1%.In addition, the concentration of the alkenylcephem compounds in the aqueous solution after the extraction treatment is 2.2 weight %.
(3) first operations
(aginomoto fine chemistry corporate system, the trade(brand)name CL-K) 3.2g of disposable interpolation gac in the aqueous solution after SX also stirred 1 hour at 3 ℃.The iodine absorption property that this gac records according to JIS K-1474 is 1550mg/g, and the methylene blue absorption property is 310ml/g.Then, filter out gac, the aqueous sodium hydroxide solution that in the aqueous solution, adds 1N is adjusted to pH4.3, slaking 1 hour.The crystal of compound is separated out through this slaking shown in the formula (2).Filter and collect the crystal of being separated out, water and washed with methanol crystal are also dry.The crystalline analytical results that obtains is described below.In addition, the value of the Z body yield among the following analysis result for calculating through following calculating formula, in addition, each item rerum natura of the compound of the formula (11) that obtains after first operation finished is shown in table 1.
Z body yield (%)=A * B/C
A: the thick yield of the crystalline that obtains after first operation (%)
B; Purity (%) as the Z body of compound shown in the formula (2)
C; The toluylic acid class is removed the theoretical yield (%) of the inorganic acid salt of the compound shown in the formula (11) of operation as the Z body of the compound shown in the formula (1) of benchmark
(analytical results)
Z body yield: 92.0%
E body containing ratio: 0.29%
Toluylic acid containing ratio: 0.1%
Tone (range estimation): white
· 1H-NMR（D 2O/DCI）ppm
2.52(s、3H)、3.56～3.60(d、1H、18.3Hz)、3.75～3.78(d、1H、18.6Hz)、5.25～5.26(d、1H、5.2Hz)、5.44～5.45(d、1H、5.2Hz)、6.78(s、2H)、9.78(s、1H)
(4) second operations
Figure BDA00001940361100191
X is formula (5) and R in compound 4.0g shown in the formula (11) that in four-hole boiling flask, obtains in above-mentioned first operation of adding, the formula (3) 1Be CH 3Compound (3a) 5.3g, water 25g, THF 25g, the triethylamine 1.4g of base, and 5～10 ℃ of stirrings 5 hours.Then, in reaction solution, add 2.5% sodium bicarbonate aqueous solution 40g, clean 2 times with methylene dichloride 80g.And then adding 1N hydrochloric acid is adjusted to pH2.0, slaking 30 minutes in water layer.Compound is separated out through this slaking shown in the formula (7).Filter and collect the crystal of being separated out, water and washed with methanol crystal are also dry.The crystalline analytical results that obtains is described below.In addition, each item rerum natura with the cephalosporins derivatives that obtains after the end of second operation is shown in table 2.
Z body yield: 74.0%
E body containing ratio: 0.23%
· 1H-NMR（D 2O）ppm
2.27(s、3H)、3.23～3.26(d、1H、18.3Hz)、3.49～3.53(d、1H、18.3Hz)、3.88(s、3H)、5.26～5.27(d、1H、4.6Hz)、5.73～5.74(d、1H、4.6Hz)、6.19～6.21(d、1H、11.9Hz)、6.55～6.57(d、1H、11.5Hz)、6.92(s、1H)、8.67(s、1H)
[embodiment 2]
In first operation of embodiment 1, use CL-KP (trade(brand)name) 2.8g of aginomoto fine chemistry corporate system as gac, in addition, likewise obtain the crystal of the compound shown in the formula (11) with embodiment 1.The iodine absorption property of this gac is 1620mg/g, and the methylene blue absorption property is 280ml/g.
Then, after likewise reacting with second operation of embodiment 1, add 2.5% sodium bicarbonate aqueous solution 40g and clean 2 times with methylene dichloride 80g, water layer is concentrated.The sodium salt of the compound shown in the formula (7) is separated out through concentrating.And then add acetone 50g and 0～5 ℃ of slaking 30 minutes, filter the crystal that collection is separated out, water and acetone crystal are also dry.In addition, each item rerum natura of the compound of the formula (11) that obtains after first operation finished is shown in table 1, and each item rerum natura of the cephalosporins derivatives that obtains after second operation is finished is shown in table 2.
Z body yield: 67.0%
E body containing ratio: 0.10%
[embodiment 3]
The protective reaction operation of (1) 7 amido linkage
With same operation of embodiment 1 and condition under carry out enzyme reaction.After reaction finishes, in the aqueous solution, contain the sodium salt 7.0g that contains the compound shown in the formula (11) of 3.5%E body in E body containing ratio.In addition, contain toluylic acid 16.6% in the toluylic acid containing ratio.
(2) toluylic acid is removed operation (B operation)
Filter out enzyme (PGA-450) in the aqueous solution that from first operation, obtains, the liquid temperature is remained on 10 ℃ and be adjusted to pH4.2 with concentrated hydrochloric acid, directly slaking is 1 hour.Compound shown in the formula (1) is separated out through this slaking, then filters, and reclaims precipitate.The toluylic acid containing ratio of the precipitate that obtains in addition, is 0.5%.
(3) first operations
The precipitate 7.0g (containing Z body 6.5g) that obtains in second operation is dispersed in the water of 340g, remains on 20 ℃ and be adjusted to pH1.0, this precipitate dissolving with the vitriol oil.Disposable interpolation was stirred 1 hour as CL-KP (trade(brand)name, iodine absorption property 1620mg/g, the methylene blue absorption property 280ml/g) 1.5g of the aginomoto fine chemistry corporate system of gac and at 3 ℃ in this aqueous solution.Then, filter out gac, the aqueous sodium hydroxide solution that in the aqueous solution, adds 1N is adjusted to pH4.2, slaking 1 hour, and the crystal of compound is separated out through this slaking shown in the formula (11).Filter and collect the crystal of being separated out, water and washed with methanol crystal are also dry.Each item rerum natura of the compound of the formula (11) that obtains after first operation is finished in addition, is shown in table 1.
(4) second operations
Implement the operation same, obtain the sodium salt of the compound shown in the formula (7) with embodiment 2.In addition, each item rerum natura with the cephalosporins derivatives that obtains after the end of second operation is shown in table 2.
[comparative example 1]
Likewise carry out enzyme reaction with the protective reaction operation of 7 amido linkages of embodiment 1, from the aqueous solution of the sodium salt that contains the compound shown in the resulting formula (11), filter out enzyme.To all filtrate and remain on 20 ℃ of liquid temperature and be adjusted to pH0.9 with concentrated hydrochloric acid.Obtain the aqueous solution of the hydrochloride of the compound shown in the formula (11) thus.Then; The iodine absorption property that disposable interpolation records according to J1SK-1474 in this aqueous solution is that 1080mg/g and methylene blue absorption property are gac (the aginomoto fine chemistry corporate system of 180ml/g; Trade(brand)name SD-2) 5.6g replaces the gac that uses in first operation of embodiment 1, and stirs 1 hour at 3 ℃.Toluylic acid containing ratio after the activated carbon treatment is 1.1%.Then, filter out gac, likewise the whole filtratings that obtain are carried out SX with second operation of embodiment 1.The aqueous sodium hydroxide solution that adds 1N in the aqueous solution after SX is adjusted to pH4.3, slaking 1 hour.The crystal of the compound shown in the formula (11) is separated out through this slaking.Filter and collect the crystal of being separated out, water and washed with methanol crystal are also dry.Each item rerum natura of the compound of the formula (11) that obtains after first operation is finished in addition, is shown in table 1.
(second operation)
Implement the operation same, obtain the sodium salt of the compound shown in the formula (7) with embodiment 2.In addition, each item rerum natura with the cephalosporins derivatives that obtains after the end of second operation is shown in table 2.
[comparative example 2]
Gac (SD-2) 3.2g that the gac that uses in first operation of disposable interpolation and comparative example 1 is identical also stirred 1 hour at 3 ℃; In addition; Implement protective reaction operation, (2) toluylic acid of (1) 7 amido linkage and remove operation, obtain the crystal of the compound shown in the formula (11).In addition, each item rerum natura with the cephalosporins derivatives that obtains after the end of first operation is shown in table 1.
(second operation)
Implement the operation same, obtain the sodium salt of the compound shown in the formula (7) with embodiment 2.In addition, each item rerum natura with the cephalosporins derivatives that obtains after the end of second operation is shown in table 2.
[table 1]
Figure BDA00001940361100221
* carrying out extraction treatment after the activated carbon treatment: the toluylic acid containing ratio after the activated carbon treatment is 1.1%.
[table 2]
Result by table 2 can know, compares with the cephalosporins derivatives of comparative example 1～2 through the cephalosporins derivatives that embodiments of the invention 1～3 obtain, and the containing ratio of Z body is high, and then does not also have painted.
[embodiment 4]
(1) the 3rd operation
The sodium salt 4.5g of the compound shown in the formula that obtains among the embodiment 2 (7) is dissolved in N (DMF) 25g, add uses the DMF solution 25m1 of the chloromethyl pivalate (1.39g) and the trimethylacetic acid iodine methyl esters of Soiodin (1.39g) preparation and this temperature stirring 1 hour at 0～5 ℃.Then, in reaction solution, add ETHYLE ACETATE 200g, with the water cleaning of 100g 3 times.Next, concentrate up to crystal and begin to separate out, add normal hexane 100g and 0～5 ℃ of slaking 1 hour.After slaking finishes; Filter and collect crystal; Clean and drying with normal hexane, obtain the yellowish white crystal of 7-[2-methoxyimino-2-(thiazolamine-4-yl) acetamido]-3-[2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid trimethyl acetoxyl methyl esters (Cefditoren pivoxil Cephalosporins).
(analytical procedure is put down on September 28th, 19, No. 316, MHLW's bulletin, Cefditoren pivoxil Cephalosporins item with reference to " Japanese Pharmacopoeia (officina side) 15 editions (first [) " to HPLC purity 97.8%.）
Utilizability in the industry
According to the present invention; Can use 7-amino-3-[(E/Z)-2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid or its an alkali metal salt; And through easy operation with advantageous method in the industry, high cephalosporins derivatives or its an alkali metal salt as target of containing ratio of Z body is provided.

Claims (7)

1. the cephalosporins derivatives shown in the formula (4a) or the method for manufacture of its an alkali metal salt is characterized in that, comprising:
First operation; Make the aqueous solution of the 7-amino-3-shown in the following formula (1) [(E/Z)-2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid or its an alkali metal salt; Be more than the 1200mg/g with the iodine absorption property that records according to JIS K-1474 and the methylene blue absorption property is that gac more than the 250ml/g contacts, the 7-amino-3-containing ratio of the 7-amino-3-shown in the following formula that has been improved (2) [(Z)-2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid or its an alkali metal salt, shown in the formula (1) [(E/Z)-2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid or its an alkali metal salt; With
Figure FDA00001940361000011
Second operation; Then; 7-amino-3-the containing ratio of the 7-amino-3-shown in the general formula (2) that made the raising that obtains in said first operation [(Z)-2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid or its an alkali metal salt, shown in the formula (1) [(E/Z)-2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid or its an alkali metal salt; React with the compound shown in the formula (3)
Figure FDA00001940361000021
In the formula, R 1The expression alkyl, X representes active ester groups.
2. method of manufacture as claimed in claim 1 is characterized in that:
Said active ester groups is the benzothiazolyl shown in the formula (5)-2-sulfenyl.
Figure FDA00001940361000022
3. according to claim 1 or claim 2 method of manufacture is characterized in that:
Compound shown in the said formula (1) is handled and formed inorganic acid salt with mineral acid, the said aqueous solution in the low pH zone of containing this inorganic acid salt is contacted with said gac.
4. method of manufacture as claimed in claim 3 is characterized in that:
Said inorganic acid salt is a hydrochloric acid.
5. like each described method of manufacture in the claim 1～4, it is characterized in that:
To use pH regulator to 3.8～4.8 of the treatment solution after the said activated carbon treatment, make the crystal settling of the compound shown in the formula (2).
6. like each described method of manufacture in the claim 1～5, it is characterized in that:
Said formula; The aqueous solution of the 7-amino-3-(1) [(E/Z)-2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid or its an alkali metal salt obtains through following operation: with formula; (6) the 7-substituted acyl amino-3-shown in [(E/Z)-2-(4-methylthiazol-5-yl) vinyl]-3-cephem-salt of 4-carboxylic acid supplies to carry out in enzyme reaction the protective reaction of 7 amido linkages; Obtain containing said general formula as the toluylic acid or derivatives thereof of the by product of this protective reaction; The aqueous solution of the 7-amino-3-(1) [(E/Z)-2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid or its salt; Carry out following then; (A) or; (B) the arbitrary treatment process in
(A) operation of extraction treatment; With an organic solvent the aqueous solution of the 7-amino-3-shown in the said formula (1) that obtains [(E/Z)-2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid or its salt is carried out the extraction treatment of said toluylic acid or derivatives thereof
(B) partial crystallization treatment procedures; This 7-amino-3-[(E/Z)-2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid or its salt are separated out from the aqueous solution of the 7-amino-3-shown in the said formula (1) that obtains [(E/Z)-2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid or its salt
Figure FDA00001940361000031
In the formula, R 3Expression benzyl, phenoxymethyl, M representes the univalent positively charged ion.
7. the cephalosporins derivatives shown in the formula (4b) or the method for manufacture of its an alkali metal salt is characterized in that:
Also have the 3rd operation, in the presence of Soiodin, the cephalosporins derivatives shown in the said general formula (4a) that obtains through each described method in the claim 1～6 or its an alkali metal salt and chloromethyl pivalate reacted,
In the formula, R 1The same.
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