JPH07121951B2 - Purification method of cephalosporin antibiotics - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for purifying a cephalosporin compound, and more particularly to a method for desolvating a solid cephalosporin compound containing a solvent.

Problems to be Solved by the Prior Art and Invention Various organic solvents (eg, tetrahydrofuran, acetonitrile, acetone, etc.) are often used in the manufacturing process of cephalosporin compounds, but due to the characteristics of pharmaceuticals, it is necessary to prepare them as products. The remaining organic solvent should be removed almost completely.

As the industrial desolvation method for pharmaceuticals, the vacuum desolvation method at a relatively low temperature (usually 20 to 50 ° C) and the stream desolvation method using a dry gas are generally used because the pharmaceuticals are usually thermally unstable. Has been.

However, since cephalosporin compounds generally have strong affinity with organic solvents, these methods have drawbacks such as insufficient desolvation or decomposition of the cephalosporin compound.

In addition, a method of contacting with a steam flow under reduced pressure (JP-A-55-10258)
There are known methods for desolvation by substituting water for the organic solvent (hereinafter referred to as humidification desolvation method), such as 5) and a method of contacting with a humidified body adjusted to an appropriate temperature and humidity under normal pressure.

However, when the humidification desolvation method is applied to the cephalosporin compound, it may be absorbed into moisture to form a candy because it is left in a high-humidity atmosphere for a long time, or partially decomposed even at a relatively low temperature. That is, in the humidification desolvation method, in order to efficiently proceed with desolvation, it is necessary to maintain the water content of the cephalosporin compound considerably high during desolvation operation, and also the operation time is often required drying after desolvation. If you include the above, it will take a considerably long time (generally, the water content of the cephalosporin compound is allowed to reach 5 to 15%, the temperature is 20 to 40 ° C, and the operation time is 10 to 30 hours. Desolvation and drying are carried out continuously under the conditions), and under such conditions, the cephalosporin compound becomes a candy-like substance, and its quality is remarkably deteriorated by decomposition exceeding an allowable limit. In particular, when carrying out humidification desolvation on an industrial scale, variations in water content and temperature in the powder layer are likely to occur, and alteration such as candy formation tends to occur partially where the water content or temperature rises. Is. Therefore, it is difficult to apply the humidification desolvation method to a substance that is unstable in a wet state.

Means for Solving the Problems The inventors of the present invention have made various investigations on a method for purifying a cephalosporin compound, particularly a desolvation method, in order to overcome such a problem. It was found that the organic solvent can be efficiently extracted and removed in a dry state by passing the carbon dioxide present in 1) through a solid (for example, crystalline or powdery) cephalosporin compound, and completed the present invention.

That is, the present invention relates to a method for purifying a cephalosporin compound, which comprises desolvating a solid cephalosporin compound containing an organic solvent with supercritical carbon dioxide.

According to the method of the present invention, a cephalosporin compound having a strong affinity with an organic solvent can be desolvated without being humidified, and is easily decomposed by water, or easily absorbs moisture to form a candy form. The method can be applied to such a cephalosporin compound without any problem.

Since the method of the present invention does not perform the drying step after desolvation which is required in the humidification desolvation method, it is possible to prevent quality deterioration during the drying period and improve productivity. As described above, the method of the present invention is most effectively applied when it is difficult to apply the humidification desolvation method.

In the method of the present invention, a solid cephalosporin compound is packed in an extractor and supercritical carbon dioxide is continuously or intermittently passed through the extractor, and the solvent contained in the solid cephalosporin compound is supercritical carbon dioxide. Is extracted. The extractor used in the present invention is a pressure resistant container and usually has a temperature control mechanism. For pressure resistance, it is necessary to withstand pressures above the critical pressure of carbon dioxide of 75.3 kg / cm ² (absolute pressure), but it is usually about 100 to 500 kg / cm ² . The shape of the extractor is not particularly limited, but a vertical cylindrical tank having a gas inlet / outlet nozzle, a nozzle for filling and discharging a solid cephalosporin compound, or a lid is preferable. In addition, a mechanism for holding solid cephalosporin compounds is required in the extractor, but various types of solid cephalosporin compounds are required from the viewpoints of particle size, corrosivity, operability for charging and discharging, and facility economics. You can select the type of For example, a method of installing a perforated plate on the bottom of the tank and stretching and holding a filter cloth or a metal net (eg, stainless steel), a method of installing a porous sintered metal (eg, stainless steel) or a ceramic filter, a metal net on the bottom The optimum method can be selected according to the purpose, for example, by filling a solid cephalosporin compound in a cylindrical container covered with a filter cloth (for example, made of stainless steel) and mounting it in the extractor.

An example of the simplest device used in the method of the present invention is shown in FIGS.

FIG. 1 shows an example in which gaseous carbon dioxide is supplied from the upper part of the carbon dioxide cylinder, and FIG. 2 shows an example in which liquefied carbon dioxide is directly supplied from the bottom part of the carbon dioxide cylinder.

In FIG. 1 and FIG. 2, the supercritical carbon dioxide extractor 1
It flows from the upper part to the lower part, but the reverse is also possible. In this case, it is preferable to install a filter in the upper part of the container or in the vicinity of the container outlet in order to prevent loss of the powdery cephalosporin compound and prevent clogging of the exhaust system piping and valves.

The supercritical carbon dioxide used in the method of the present invention means carbon dioxide in a state of a critical temperature of 31.1 ° C. and a critical pressure of 75.3 kg / cm ² (absolute pressure) or more.

The supercritical carbon dioxide used in the method of the present invention may have a critical temperature of carbon dioxide of 31.1 ° C. or higher, but from the viewpoint of temperature controllability, thermal stability of the cephalosporin compound, etc.
It is preferably about 50 ° C. The supercritical carbon dioxide pressure may be at least 75.3 kg / cm ² (absolute pressure) of carbon dioxide, but 80 to 300 kg / cm ² (absolute pressure) from the viewpoint of pressure controllability and economy. A degree is preferable. The flow rate of supercritical carbon dioxide is not particularly limited, but is usually 0.5 to 50 kg / hour per 1 kg of solid cephalosporin compound.

It is also possible to use the same conditions as in the conventional humidification desolvation method, such as using humidified supercritical carbon dioxide, or performing desolvation after adjusting the moisture content of the solid cephalosporin compound in advance. For example, about 0.1 to 5% (W / W%) of water vapor is added to supercritical carbon dioxide, or solid cephalosporin compound is dried at 5 to 50% (W / W%) of water may be included for desolvation with supercritical carbon dioxide.

The solid cephalosporin compound used in the method of the present invention means a solid (crystalline or powdery) cephalosporin compound containing a solvent. Here, the solvent contained in the solid cephalosporin compound is an organic solvent generally used in the production of cephalosporin compounds, for example, a lower alcohol such as methyl alcohol, ethyl alcohol, n-propyl alcohol or isopropyl alcohol. Ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran, fatty acid esters having 1 to 3 carbon atoms such as methyl acetate and ethyl acetate, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, dichloromethane,
Halogenated hydrocarbons such as dichloroethane, chloroform and carbon tetrachloride, petroleum benzines, petroleum ethers, aliphatic hydrocarbons such as n-hexane and cyclohexane, aromatic hydrocarbons such as benzene, toluene and xylene, acetonitrile and propylene. Examples include nitriles such as pionitrile.

According to the method of the present invention, the solvent can be easily and efficiently desolvated from a solid cephalosporin compound, and when the solid cephalosporin compound contains a plurality of solvents, these The solvent can be desolvated at the same time. The solid cephalosporin compound is preferably used after being pulverized into a powder form in advance.

The solid cephalosporin compound used in the present method may be any of the first to fourth generation cephalosporin compounds. Specific examples of preferred cephalosporin compounds include those represented by the general formula: [Wherein R ₁ is an acyl group, R ₂ is a hydrogen atom, an alkoxymethyl group, an alkylthiomethyl group, an acyloxymethyl group,
A carbamoyloxymethyl group, an alkenyl group, a heterocyclic methyl group or a heterocyclic thiomethyl group, R ₃ is a hydrogen atom or an ester residue, R ₄ is a hydrogen atom or a methyl group, and Z is an oxygen atom or a sulfur atom] The compound or a salt thereof.

In the above, the acyl group represented by R ₁ is an acyl group derived from an organic carboxylic acid, for example, an acyl group constituting an acylamino group generally substituted at the 6-position of a penicillin derivative and the 7-position of a cephalosporin derivative. Is used.

Examples of the above-mentioned organic carboxylic acid include, for example, linear, branched or cyclic, saturated or unsaturated carbon chains in which an oxygen atom or a sulfur atom is present or not, and these aliphatic carboxylic acids. An aromatic aliphatic carboxylic acid, an aromatic oxyaliphatic carboxylic acid, an aromatic thioaliphatic carboxylic acid in which an acid is bonded to an aromatic carbon hydrogen residue or a heterocyclic group through an oxygen atom or a sulfur atom or not Heterocyclic-substituted aliphatic carboxylic acids, heterocyclic oxyaliphatic carboxylic acids, heterocyclic thioaliphatic carboxylic acids; and aromatic carboxylic acids; organic carboxylic acids such as heterocyclic carboxylic acids are used.

Here, as the aliphatic carboxylic acid, formic acid, acetic acid, propionic acid, butanoic acid, isobutanoic acid, pentanoic acid, isopentanoic acid, pivalic acid, hexanoic acid, cyclohexanoic acid, acrylic acid, crotonic acid, cyclopentane acetic acid, cyclohexane acetic acid , Cycloheptane acetic acid, cyclohexane propionic acid, cyclohexene acetic acid, cyclohexadiene acetic acid, methoxyacetic acid, cyclohexyloxyacetic acid,
Methylthioacetic acid or the like is used.

Further, phenyl, naphthyl, tolyl, xylyl, mesityl, cumenyl and the like are used as the aromatic hydrocarbon residue and aromatic group in the above organic carboxylic acid, and the heterocyclic group in the above organic carboxylic acid is, for example, furan. , Thiophene, pyrrole, pyrazole, imidazole, triazole, thiazole, isothiazole, 2-iminothiazoline, 2-oxothiazoline, methylene-1,3
-Dithietane, 2,3-dihydro-1,4-oxathiiin, 1,
4-dithiannaphthalene, dihydro-1,3-dithiin, oxazole, isoxazole, thiadiazole, oxadiazole, thiatriazole, oxatriazole, tetrazole, pyridine, pyrazine, pyrimidine,
Pyridazine, benzothiophene, benzofuran, indole, imidazole, benzimidazole, benzothiadiazole, benzoxazole, purine, quinoline,
Used as a residue of a saturated or unsaturated monocyclic or polycyclic heterocyclic compound containing one or more heteroatoms such as isoquinoline, phthalazine, naphthyridine, quinoxaline, cinazoline, pyrrolidine, imidazolidine, piperidine and piperazine in the ring. To be

Examples of the aliphatic group, aromatic hydrocarbon residue and heterocyclic group constituting these organic carboxylic acids include halogen, hydroxyl group, sulfo group, mercapto group, carboxyl group, alkyl group, alkoxy group, alkylthio group, amino group, Alkylamino group, dialkylamino group, cyano group, alkanoyl group, aryl-substituted alkanoyl group, arylcarbonyl group, alkylsulfonylamino group, alkanoyloxy group, aryl group-substituted alkanoyloxy group, arylcarbonyloxy group, hydroxyimino group, alkoxyimino Group, alkanoyloxyimino group, oxo group, thioxo group, ureido group, carbamoyl group, amidino group, formyl group and the like may have one or more suitable substituents at any position, Of which, carboxyl groups and amino Normal cephalosporins, which will be described later is,
Each may be protected with an appropriate protecting group used in the field of penicillin and peptide chemistry.

In the above, the alkyl group, the alkyl group in the alkylthio group, the alkyl group in the alkylamino group, the alkyl group in the dialkylamino group, and the alkyl group in the alkylsulfonylamino group include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl. , Isobutyl, sec-butyl, t-butyl, 1-ethylpropyl, 2
A linear or branched alkyl group having 1 to 6 carbon atoms such as -ethylpropyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl is used, and an alkoxy group is used. And alkoxy groups in the alkoxyimino group include, for example, methoxy, ethoxy, n-
Propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy and other straight-chain or branched alkoxy groups having 1 to 6 carbon atoms Used alkanoyl group, alkanoyl group in aryl group-substituted alkanoyl group, alkanoyl group in alkanoyloxy group, alkanoyl group in aryl group-substituted alkanoyloxy group, alkanoyl group in alkanoyloxyimino group, for example, acetyl,
An alkanoyl group having 2 to 7 carbon atoms such as propionyl, butyryl, n-pentanoyl, n-hexanoyl, n-heptanoyl is used. The aryl group in the aryl group-substituted alkanoyl group, the aryl group in the arylcarbonyl group, and the aryl group-substituted alkanoyloxy group are used. Examples of the aryl group in the group and the aryl group in the arylcarbonyloxy group include phenyl, naphthyl, tolyl, xylyl, mesityl and the like.

Further, the acyl group represented by R ₁ is a protecting group for an amino group which is easily removed in peptide chemistry, for example,
alkoxycarbonyl groups such as tert-butoxycarbonyl, iso-bornyloxycarbonyl, etc., such as benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-
In addition to the use of aralkyloxycarbonyl groups such as methoxybenzyloxycarbonyl, etc., a publication published by JFW McOmie ["Protective Groups in Organic Chemistry"] ;
Plenum Press, New York (N.
Y.), 1973], Chapter 2 of J. W. Burton (JW Barton), the protecting group for the easily leaving amino group can also be used as the acyl group.

Of the above acyl groups, preferably R ₁ is of the formula R ₅ —R ₆ —CO—
[In the formula, R ₅ is a heterocyclic group which may have a substituent, R ₆ is an alkylene group or a formula (In the formula, R ₆ ′ represents a hydrogen atom or an alkyl group which may have a substituent), or a group represented by the formula: [In the formula, R ₇ represents an alkanoyloxy group which may have a substituent].

The heterocyclic group in the optionally substituted heterocyclic group represented by R ₅ is a 5-membered heterocyclic group containing one nitrogen atom, a sulfur atom or an oxygen atom and further one nitrogen atom. Those that include or do not include are used. Specific examples of this heterocyclic group include, for example, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-thienyl, 3-thienyl, 2-
Furyl, 3-furyl and the like are used. As the substituent in this heterocyclic group, the same substituents as the aliphatic group, the aromatic hydrocarbon residue and the heterocyclic group constituting the organic carboxylic acid in the above definition of the acyl group are used. Of these, an amino group is particularly preferable.

As the alkylene group represented by R ₆ , for example, an alkylene group having 1 to 3 carbon atoms such as methylene, dimethylmethylene, ethylmethylene, ethylene and methylethylene is used.

Examples of the alkyl group in the alkyl group which may have a substituent represented by R ₆ ′ include, for example, methyl, ethyl, n-
Propyl, isopropyl, n-butyl, isobutyl, sec-
Butyl, t-butyl, 1-ethylpropyl, 2-ethylpropyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl and the like having 1 to 6 carbon atoms
The straight chain or branched alkyl group of is used, and these are, for example, methoxycarbonyl, ethoxycarbonyl, n-
It may be substituted with 1 or 2 alkoxycarbonyl groups having 1 to 6 carbon atoms such as propoxycarbonyl, t-butoxycarbonyl and n-hexyloxycarbonyl.

formula The group represented by can have any steric configuration of syn- or anti-configuration, but the syn-configuration is particularly preferred.

Examples of the alkanoyloxy group in the optionally substituted alkanoyloxy group represented by R ₇ include acetoxy, propionyloxy, n-butyryloxy, n-pentanoyloxy, isopentanoyloxy, n
-Alkanoyloxy groups having 2 to 7 carbon atoms such as -hexanoyloxy, isohexanoyloxy, n-heptanoyloxy, etc. are used, and these are aliphatic groups and aromatic groups constituting the organic carboxylic acid in the above definition of the acyl group. It may have a substituent similar to the substituent on the group hydrocarbon residue and the heterocyclic group. Of these substituents, the amino group is particularly preferable.

Particularly preferably R ₁ is of the formula [In the formula, Q ₁ is an alkyl group, a group represented by the formula —CH ₂ COOQ ₂ , or a formula Represents a group represented by the formula (wherein —COOQ ₂ represents a carboxyl group which may be esterified).

The alkyl group represented by Q ₁ is, for example, methyl, ethyl, n-
Propyl, isopropyl, n-butyl, isobutyl, sec-
A linear or branched alkyl group having 1 to 4 carbon atoms such as butyl and t-butyl is used.

A group represented by the formula-COOQ ₂ , or a formula -COOQ _{2 in the} group represented by represents an optionally esterified carboxyl group, and examples of the ester residue represented by Q ₂ include methyl, ethyl, n-propyl, isopropyl, n-butyl,
A linear or branched alkyl group having 1 to 4 carbon atoms such as isobutyl, sec-butyl and t-butyl, and an aralkyl group having 7 to 19 carbon atoms such as benzyl, phenethyl and trityl are used.

The acyl group of the acyloxymethyl group represented by R ₂ is the same as the acyl group represented by R ₁ .

Examples of the heterocyclic group in the heterocyclic methyl group or the heterocyclic thiomethyl group represented by R ₂ include a 5- to 6-membered heterocyclic group containing one sulfur atom, a nitrogen atom or an oxygen atom, and 2 to 4 nitrogen atoms. A 5- to 6-membered heterocyclic group containing 1 to 2
A 5- to 6-membered heterocyclic group containing one nitrogen atom and one sulfur atom or oxygen atom and the like are used.

More specifically showing the heterocyclic group, for example, 1,3,4-
Thiadiazolyl 1,2,4-thiadiazolyl Etc. Thiadiazolyl, 1 H -tetrazol-5-yl 2 H -tetrazol-5-yl Such as tetrazolyl, 1 H -1,2,3-triazolyl 2 H -1,2,3-triazolyl 1 H -1,3,5-triazolyl 1 H -1,2,4-triazolyl Triazolyl such as 1,3,4-oxadiazolyl Oxazolyl Thiazolyl Thiazolinyl Pyridyl Pyridazinyl Tetrazolopyridazinyl Etc. are used.

These heterocyclic groups may be condensed with a 6-membered ring group containing 2 or less nitrogen atoms, a benzene ring or a 5-membered ring group containing 1 sulfur atom, and are optionally substituted with 1 to 3 groups. It may be replaced individually. Specific examples of the optional substituent include, for example, methyl, ethyl, n-propyl and the like having 1 to 6 carbon atoms.
Alkyl groups such as esterified carboxy groups such as methoxycarbonyl and ethoxycarbonyl, hydroxy and carboxy such as dimethylamino (having 1 to 6 carbon atoms) alkylamino groups such as pivaloyloxymethoxycarbonyl and the like having 2 carbon atoms To 7 alkanoyloxy substituted alkoxycarbonyl having 1 to 6 carbon atoms, alkyl group having 1 to 6 carbon atoms substituted with sulfo, etc., for example, halogen such as chlorine and bromine, mercapto group, hydroxy group,
Substituents such as amino groups, eg, alkylthio groups having 1 to 6 carbon atoms such as methylthio and ethylthio, and alkoxy groups having 1 to 6 carbon atoms such as methoxy and ethoxy are used. Further, the nitrogen atom of the pyridazinyl group and the pyridyl group may be oxidized. The alkoxymethyl group represented by R ₂ is, for example, an alkoxymethyl group having 1 to 6 carbon atoms such as methoxymethyl, ethoxymethyl and propoxymethyl, and the alkylthiomethyl group is, for example, methylthiomethyl, ethylthiomethyl, propyl. An alkylthiomethyl group having 1 to 6 carbon atoms such as thiomethyl is used, and an alkenyl group having 2 to 4 carbon atoms such as vinyl, allyl and 1-butenyl is used as the alkenyl group.

Examples of the ester residue represented by R ₃ include those represented by the general formula [Wherein X represents a hydrogen atom or an alkyl group, Y represents a hydrogen atom, an alkyl group, an alkoxy group, an alkenyloxy group or a phenyl group], and further, for example, methoxymethyl, ethoxymethyl, isopropoxymethyl and the like. Alkoxymethyl group such as 1-alkoxyethyl group such as 1-methoxyethyl, 1-ethoxyethyl, alkylthiomethyl group such as methylthiomethyl, ethylthiomethyl, iso-propylthiomethyl, tert-butyl, 2,2,2 -Trichloroethyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, trityl, benzhydryl, bis (p-methoxyphenyl) methyl, phenacyl, 2-methylthioethyl, trimethylsilyl, dimethylsilyl, phthalidyl, (2-oxo-5- Methyl-1,3
-Dioxolen-4-yl) methyl and the like are used,
JF W McOmie (JFWMcOmie)
Publications ["Protective Groups in Org Chemistry
anic Chemistry) "Plenum Pres
s), New York (NY) (1973)], chapter 5 of E. Haslam describes other easily removable protecting groups for carboxyl groups as ester residues. . As the alkyl group represented by X,
For example, methyl, ethyl, n-propyl, isopropyl, n-
A straight chain having 1 to 6 carbon atoms such as butyl, isobutyl, sec-butyl, t-butyl, 1-ethylpropyl, 2-ethylpropyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl or A branched alkyl group and a cycloalkyl group having 5 to 7 carbon atoms such as cyclopentyl, cyclohexyl, and cycloheptyl are used.

Examples of the alkyl group represented by Y include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, 1-ethylpropyl, 2
-Ethylpropyl, pentyl, 1,1-dimethylpropyl,
1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-butylpropyl, 2-butylpropyl, 3-methylbutyl, 1,
1,2-trimethylpropyl, 1,2,2-trimethylpropyl,
2-methylbutyl, 1,1,2,2-tetramethylpropyl, 1,1
-Diethylpropyl, hexyl, heptyl, 1-propylbutyl, octyl, 1,1-diethyl-2-methylpropyl, nonyl, 1-butylpentyl, 1,1-diethyl-2,2-
A linear or branched alkyl group having 1 to 13 carbon atoms such as dimethylpropyl, decyl, 1-hexylheptyl, etc., such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl. , Saturated cycloaliphatic alkyl groups having 3 to 12 carbon atoms such as cyclododecyl, for example, carbons such as bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl, bicyclo [3.3.1] nonyl, adamantre An alicyclic alkyl group having a crosslinked structure represented by the formulas 4 to 12 is used.

Further, a linear or branched alkyl group having 1 to 13 carbon atoms represented by Y is the above-mentioned cycloalkyl group or alkoxycarbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, etc.). It may be substituted with 1 to 3 linear or branched alkoxycarbonyl groups (1 to 3) or phenyl groups.

Examples of the alkoxy group represented by Y include methoxy,
Ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy, 2,2-dimethylpropoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1-ethylpropoxy, n-hexyloxy, 1-methylpentyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 4-methylpentyloxy, 1-ethylbutoxy, 2-ethylbutoxy, 3-ethylbutoxy, n -Heptyloxy, 1
-Methylhexyloxy, 2-methylhexyloxy, 3-
From carbon number 1 such as methylhexyloxy, 4-methylhexyloxy, 5-methylhexyloxy, 1-ethylpentyloxy, 2-ethylpentyloxy, 3-ethylpentyloxy, 4-ethylpentyloxy, 1-propylbutoxy 7 straight or branched alkoxy groups such as cyclopropoxy, cyclobutoxy, cyclopentyloxy,
A saturated monocyclic alicyclic alkoxy group having 3 to 12 carbon atoms such as cyclohexyloxy, cycloheptyloxy, cyclooctyloxy, cyclononyloxy, cyclodecyloxy, cycloundecyloxy, and cyclododecyloxy,
For example, an alicyclic alkoxy group having a cross-linking structure having 4 to 12 carbon atoms such as bicyclo [2.2.1] heptyloxy, bicyclo [3.2.1] octyloxy, bicyclo [3.3.1] nonyloxy, adamantyloxy and the like is used.

The cyclic (cyclo) alkoxy group represented by Y may be substituted with the above linear or branched alkyl group,
The linear or branched alkoxy group represented by Y may be substituted with the alicyclic alkyl group described above.

Examples of the alkenyloxy group represented by Y include vinyloxy, allyloxy, 1-propenyloxy, 1-methyl-1-propenyloxy, 2-methyl-1-propenyloxy, 1-butenyloxy, 2-butenyloxy, 3-butenyloxy, 1-methyl-1-butenyloxy, 2-methyl-1-butenyloxy, 3-methyl-1-butenyloxy, 1-methyl-2-butenyloxy, 2-methyl-2-butenyloxy, 3-methyl-2-butenyloxy, 1- Methyl-3-butenyloxy, 2-methyl-3-butenyloxy, 3-methyl-3-butenyloxy, 1-pentenyloxy, 2-pentenyloxy, 3-pentenyloxy, 4-pentenyloxy, 1-methyl-1-pentenyloxy , 2-Methyl-4-hexenyloxy, 3-methyl-4-hexenyloxy, 4-methyl-4-hexenyl Oxy, 5-methyl-4-hexenyloxy, 1,3-butanedienyloxy,
A straight chain or branched alkenyloxy group having 2 to 7 carbon atoms which may have 1 to 3 unsaturated bonds such as 1,6-heptanedienyloxy is used.

Of the above general formula [I], most preferably, R ₁ is 2-
(2-aminothiazol-4-yl) acetyl, R ₂ is 1
-(2-Dimethylaminoethyl) -1H-tetrazole-
5-ylthiomethyl group, R ₃ is a formula A group represented by [the symbols in the formula have the same meaning as defined above],
R ₄ is a hydrogen atom and Z is a sulfur atom. Especially the formula Among the groups represented by, X is preferably a methyl group and Y is preferably a cyclohexyloxy group. The compound represented by the general formula [I] will be described in more detail below.

When the molecule of the cephalosporin compound used in the present invention contains an acidic group such as a sulfo group or a carboxyl group, it may be used in the form of a pharmaceutically acceptable salt by a method known per se, for example, Alkali metals such as sodium and potassium, non-toxic cations such as alkaline earth metals such as magnesium and calcium, basic amino acids such as arginine, ornithine, lysine and histidine, such as N-methylglucamine, diethanolamine and triethanolamine. It may be used by forming a basic salt with a polyhydroxyalkylamine such as trishydroxymethylaminomethane. When an amino group is contained in the molecule of the cephalosporin compound, for example, an inorganic acid such as hydrochloric acid, sulfuric acid or phosphoric acid, such as maleic acid, acetic acid, citric acid, succinic acid, tartaric acid, malic acid or malon. Acids, fumaric acid, benzoic acid, mandelic acid, ascorbic acid, organic acids such as methanesulfonic acid, etc. Acids with acids known to form pharmaceutically acceptable salts in the field of penicillin or cephalosporins You may use it as an addition salt.

Desolvation of solid cephalosporin compounds, supercritical carbon dioxide containing the solvent, a method known per se, for example, the solvent is separated from the supercritical carbon dioxide by a method of adsorbing and separating the solvent with an adsorbent such as activated carbon. After that, it can be used again as carbon dioxide as a raw material in the method of the present invention.

The cephalosporin compound desolvated and purified by the method of the present invention is used as an antibacterial agent by a method known per se for treating and preventing infectious diseases of humans or mammals.

The solid cephalosporin compound as a raw material is produced by a method known per se.

For example, the method described in JP-A-55-79393 and JP-A-53-21192,
JP 57-77690, JP 58-189186, JP 59-89691, JP
59-190995, JP-A-59-225191, JP-A-59-225192, JP-A-59
-225193, JP60-38387, JP59-190995, JP60-67
482, JP 60-64987, JP 60-218394, JP 60-22469
3. After obtaining the cephalosporin compound by the method described in JP-A-60-239490, etc., pass an inert gas containing an organic solvent gas (eg, air, nitrogen) or wash with an organic solvent. Manufactured by.

Effects of the Invention The method of the present invention decomposes a solid cephalosporin compound,
It is possible to desolvate stably and efficiently without polymerizing. The solvent content of the desolvated solid cephalosporin compound is extremely low (usually it can be 0.05 W / W% or less), and the cephalosporin compound obtained has a high titer without any decrease in potency. It has high purity and high quality and is extremely useful as an industrial desolvation method.

Hereinafter, the method of the present invention will be described in detail with reference to Reference Examples, Examples and Comparative Examples. % Used in Reference Examples, Examples and Comparative Examples
Indicates% by weight unless otherwise specified.

Reference Example 1 (a) Production of 1-chloroethyl cyclohexyl carbonate Cyclohexanol 18.3 g, pyridine 14.5 g, methylene chloride
The 300 ml solution was cooled to −78 ° C., and 20 ml of 1-chloroethyl chloroformate was added dropwise thereto over 10 minutes while stirring. After dropping, the cold bath was removed, and the mixture was stirred at room temperature for 16 hours, then saturated saline
It was washed 3 times with 300 ml. Then, after drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 33.1 g (yield 88%) of the title compound as a colorless oily substance. bp100-113 ℃ / 5
~ 6mmHg (B) Preparation of 1-iodoethyl cyclohexyl carbonate 16.5 g of 1-chloroethyl cyclohexyl carbonate obtained in (a) above and 50 g of sodium iodide in 500 ml of acetonitrile were stirred at 70 ° C for 45 minutes and then concentrated under reduced pressure to obtain The residue was extracted with ether. The extracts were combined and the solvent was evaporated under reduced pressure to give the title compound as a pale-yellow oil.

NMR (CD₃CN, TMS (external standard)) δ: 0.7 to 2.3 (10H, m),
2.18 (3H, d, J = 6Hz), 4.1 to 4.9 (1H, m), 6.67 (1H, q, J
= 6Hz) (c) 1- (Cyclohexyloxycarbonyloxy)
Ethyl 7β- [2- (2-aminothiazol-4-i
Le) acetamide] -3-[[[1- (2-dimethyla
Minoethyl) -1H-tetrazol-5-yl] thio] meth
Chill] cef-3-em-4-carboxylate dihydrochloride
Preparation of salt 7β- [2- (2-aminothiazol-4-yl) acetate
Toamido] -3-[[[1- (2-dimethylaminoethyl
Ru) -1H-tetrazol-5-yl] thio] methyl] ce
36 g of potassium f-3-em-4-carboxylate in dimethyl
Dissolve in 300 ml of formamide and add to this solution while stirring with ice cooling.
1-iodoethyl cyclohexyl obtained in the above (b)
50 ml of dimethylformamide solution of carbonate
And stirred for 5 minutes. 20% food with the reaction mixture cooled with ice
It was poured into a mixed solution of 1.5 l of brine and 1.5 l of ethyl acetate. Organic layer
Separated, washed twice with 1.5 l of saturated saline solution, and with 400 ml of 1N hydrochloric acid.
Extracted. This extract is called Diaion MCI Gel CHP20P
(75-150μ, Mitsubishi Kasei Kogyo) column chroma
Topographies, 0.01N hydrochloric acid, then 20V / V% acetoni
Eluted with trill / 0.01N hydrochloric acid. Elution fraction containing the target compound
Collected, concentrated under reduced pressure, and lyophilized to give a colorless powder.
1- (cyclohexyloxycarbonyloxy) ethyl
 7β- [2- (2-aminothiazol-4-yl) a
Cetamide] -3-[[[1- (2-dimethylaminoe
Tyl) -1H-tetrazol-5-yl] thio] methyl]
Cef-3-M-4-carboxylate dihydrochloride 9.6g
was gotten.

4 g of the obtained compound was placed in a glass container having a filter plate at the bottom, 30 ml of acetone was added, and the mixture was sufficiently suspended by stirring and then vacuum filtered to give 1- (cyclohexyloxycarbonyloxy) ethyl 7β- [2- (2-Aminothiazol-4-yl) acetamide] -3-[[[1-
(2-Dimethylaminoethyl) -1H-tetrazole-5
-Yl] thio] methyl] cef-3-em-4-carboxylate dihydrochloride was isolated. Subsequently, dry air (temperature 25 ° C., relative humidity 5.1%) was aerated for 7 hours while stirring every 30 minutes (air flow rate 100 ml / min) to perform desolvation. Acetone content: 3.2% (determined by gas chromatography), 1- (cyclohexyloxycarbonyloxy) ethyl 7β- [2- (2-aminothiazole-4
-Yl) acetamido] -3-[[[1- (2-dimethylaminoethyl) -1H-tetrazol-5-yl] thio] methyl] cef-3-em-4-carboxylate.
Dihydrochloride content 99.3% (measured by high performance liquid chromatography), 1- (cyclohexyloxycarbonyloxy) ethyl 7β- [2- (2-aminothiazole-4)
-Yl) acetamido] -3-[[[1- (2-dimethylaminoethyl) -1H-tetrazol-5-yl] thio] methyl] cef-3-em-4-carboxylate.
Dihydrochloride hydrolyzate 7β- [2- (2-aminothiazol-4-yl) acetamide] -3-[[[1-
(2-Dimethylaminoethyl) -1H-tetrazole-5
-Yl] thio] methyl] cef-3-em-4-carboxylic acid dihydrochloride (hereinafter sometimes referred to as hydrolysis product) content: 0.2% (dehydration, desolvated substance conversion, high performance liquid chromatography) Was measured by).

Reference Example 2 1 containing 3.2% of acetone obtained in Reference Example 1
-(Cyclohexyloxycarbonyloxy) ethyl
7β- [2- (2-Aminothiazol-4-yl) acetamide] -3-[[[1- (2-dimethylaminoethyl) -1H-tetrazol-5-yl] thio] methyl] cef-3-em 5 g of -4-carboxylate dihydrochloride was placed in a glass filter, and bubbling air was bubbled through a 1: 1 mixture of isopropyl alcohol and n-hexane at room temperature for 2 hours to adsorb isopropyl alcohol and n-hexane. .

As a result of quantitative analysis, acetone content: 3.2%, isopropyl alcohol content: 0.6%, n-hexane content: 0.05% (dehydration,
It was a solvent-removed substance standard and measured by gas chromatography).

Reference Example 3 7β- [2- (2-aminothiazol-4-yl) acetamide] -3-[[[1- (2-dimethylaminoethyl) -1H-tetrazol-5-yl] thio] methyl] cef- 5 g of 3-M-4-carboxylic acid dihydrochloride was placed in a glass filter, and air bubbled in ethyl acetate was aerated for 1 hour at room temperature to adsorb ethyl acetate. As a result of the quantitative analysis, the content of ethyl acetate was 0.12% (dehydration, desolvated product standard, measured by gas chromatography).

Reference Example 4 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-Methoxyiminoacetamide] -3- [1,
2,3-Thiadiazol-5-yl-thiomethyl] cef-
Ethanol 20 with 5 g of sodium 3-M-4-carboxylate
After suspending in ml, the mixture was vacuum filtered with a glass filter, and then the crystals were washed with 20 ml of methanol. Immediately after washing, the crystals were aerated with dry air for 30 minutes and analyzed to find that the methanol content was 1.7% and the ethanol content was 1.4% (dehydration, desolvation standard, measured by gas chromatography).

Examples Example 1 Powdered 1- (cyclohexyloxycarbonyloxy) ethyl 7β- [2- (2
-Aminothiazol-4-yl) acetamide] -3-
[[[1- (2-Dimethylaminoethyl) -1H-tetrazol-5-yl] thio] methyl] cef-3-em-4
-Fill 20 g of carboxylate dihydrochloride (hereinafter referred to as compound-1) into a vertical cylindrical container having a diameter of 14 mm and a height of 300 mm and a filter plate at the bottom, and the outside temperature of the container and the fluid inlet temperature are 35 ° C.
In addition, while adjusting the pressure inside the container to 150 kg / cm ² , carbon dioxide is made to flow through the powder layer from the upper part of the container to the lower part (flow rate: 0.8
Acetone was extracted and removed.
After 5 hours, the flow of carbon dioxide was stopped, the pressure of the apparatus was returned to normal pressure, and the contents were taken out and quantitatively analyzed. The residual acetone content was 0.05% or less (measured by gas chromatography, in the following Examples and Comparative Examples. The same). No increase in hydrolysis products was observed, and the content of compound-1 was 99.2% (measured by high performance liquid chromatography). Further, no formation of a candy-like melt was observed (visual observation).

Example 2 15 g of a powdered compound-15 containing 4.1% of acetone, 0.6% of isopropyl alcohol, and 0.05% of n-hexane was charged into the vertical cylindrical container of Example 1 and the temperature was 35 ° C., the pressure was 150 kg / cm ² , and the dioxide was dioxide. 5 under the condition of carbon flow rate 0.7l / min (converted value in standard condition)
After the solvent had been extracted and removed for a period of time, the contents were taken out and quantitatively analyzed. As a result, acetone was reduced to 0.005% or less, isopropyl alcohol to 0.005% or less, and n-hexane to 0.0005% or less.

Example 3 Powdered 7β- [2- (2 containing 0.12% of ethyl acetate
-Aminothiazol-4-yl) acetamide] -3-
[[[1- (2-Dimethylaminoethyl) -1H-tetrazol-5-yl] thio] methyl] cef-3-em-4
-5 g of carboxylic acid dihydrochloride was filled in the vertical cylindrical container of Example 1 and the solvent was extracted and removed for 5 hours under the same conditions as in Example 2, and as a result, the content of ethyl acetate was 0.0005% or less. It was decreasing.

Example 4 Powdered 7β- [2- (2-aminothiazol-4-yl) -containing 1.7% methanol and 1.4% ethanol.
(Z) -2-Methoxyiminoacetamide] -3- [1,
2,3-Thiadiazol-5-yl-thiomethyl] cef-
The vertical cylindrical container of Example 1 was filled with 5 g of sodium 3-em-4-carboxylate, and the solvent was extracted and removed under the same conditions as in Example 2 for 5 hours. As a result, the content of both methanol and ethanol was 0.05. It has decreased to less than%. Acetone 3.
The powdery compound-1 containing 2% was desolvated by the conventional method and the following results were obtained.

Comparative Example 1 Vacuum Desolvation Method Compound-1 was placed in a petri dish so that the pressure was about 5 mm,
Place the petri dish in a laboratory heating vacuum dryer at 60 ℃, 2-3T
As a result of vacuum desolvation under the conditions of orr, the acetone content decreased to 1.2% after 2 hours, but desolvation did not proceed thereafter and remained at 1.2% after 6 hours.

Comparative Example 2 Airflow Desolvation Method Compound-1 50 g was placed in a container with a lower filter plate having a diameter of 70 mm (powder height of about 3 cm), and dry air (relative humidity 5.1%) was passed through the lower filter plate to pass the desolvent. Performed (flow rate
1.5l / min). Desolvation was carried out for 4 hours while adjusting the air temperature to 25 ° C, but the acetone content was 2.9%, and when the air temperature was further raised to 60 ° C and desolvation was carried out for 2 hours, the acetone content dropped to 1.2%. However, after that the air temperature is 60
The acetone content remained 1.2% after 6 hours at ℃.

Comparative Example 3 Humidification Desolvation Method Compound-1 (35 g) was charged into a cylindrical container having a diameter of 4 cm and a filter plate at the bottom, and the temperature was 25 ° C. while stirring every 30 minutes.
Humidified air having a relative humidity of 80 ° C. was passed through the lower filter plate to the powder layer for desolvation (flow rate 1 / min). The acetone content was 0.8% after 6 hours and decreased to 0.05% or less after 10 hours. However, the initial moisture content was 0.9% and 8.5 after 10 hours.
%, And formation of a partially candy-like melt was observed. Directly enter the drying process, dry air flow rate 1 / min,
Air-drying was carried out at a temperature of 25 ° C for 5 hours, then the temperature was raised to 40 ° C for another 5 hours, for a total of 10 hours. After drying, the contents were taken out, and the small lumps changed from the candy-shaped portion by the humidifying desolvent were separated by sieving and the weight was measured. As a result, the small lump production rate was 6.2%. The acetone content of this small blob is
Although it was less than 0.05%, the hydrolysis product, which was 0.2% before the solvent removal operation, increased to 1.7%, and the quality deterioration was remarkable. Also, the acetone content of other parts is
Although it was less than 0.05%, the hydrolysis product increased to 0.7%, and the quality deterioration was obvious.

[Brief description of drawings]

1 and 2 show the simplest apparatus for purifying the solid cephalosporin compound of the present invention. 1 ... Extractor, 5 ... Heater 2 ... Carbon dioxide cylinder, 6 ... Pressure control valve 3 ... Condenser 4 ... High-pressure metering pump Fig. 1 Carbon dioxide supplied from carbon dioxide cylinder 2 is condensed It is liquefied in the vessel 3 and sent under pressure by the high-pressure metering pump 4. Further, after being heated to a predetermined temperature by the heater 5 to be converted into supercritical carbon dioxide, it enters the extractor 1 in which the solid cephalosporin compound is pre-filled. The supercritical carbon dioxide is contacted with the solid cephalosporin compound to extract the residual solvent, and then discarded through the pressure control valve 6. FIG. 2 Liquefied carbon dioxide is directly supplied from the carbon dioxide cylinder 2, and after the pressurized liquid is sent by the high-pressure metering pump 4, it is turned into supercritical carbon dioxide by the heater 5. Hereinafter, the same as FIG.

Claims (1)

[Claims] 1. A method for purifying a cephalosporin compound, which comprises desolvating a solid cephalosporin compound containing an organic solvent with supercritical carbon dioxide.