JPS637551B2 - - Google Patents

Description

[Detailed description of the invention]

This invention provides a general formula useful as an antibacterial substance. (In the formula, R ¹ means an amino group or a protected amino group, R ² means a thiadiazolylthio group which may have an alkyl group, and R ³ means a carboxy group or a protected carboxy group.) 3,7-disubstituted-3-cephem-4-
This invention relates to carboxylic acid compounds and their salts. The object compound () of this invention is a new compound, and can be produced, for example, by methods 1 to 4 shown below. Method 1 Method 2 Method 3 Method 4 [In the formula, R ¹ , R ² and R ³ have the same meanings as before, R ¹
is a protected amino group, R ¹ ″ is an amino group, R ² ′ is a thiadiazolylthio group which may have an alkyl group, and Y is the formula −R ² ′ (wherein R ² ′ is (same meaning) respectively]. The raw material compound of this invention can be produced, for example, by the production method shown below. Production method (1) Manufacturing method (2) Manufacturing method (3) Manufacturing method (4) Manufacturing method (5) Manufacturing method(6) (In the formula, R ¹ , R ¹ ′, R ¹ ″, R ² , R ² ′, R ³ and Y
have the same meanings as before, Z means a protected carboxy group, respectively) Compounds () and (a) ~
(c) and raw material compounds (), (a), (),
(), (a) ~ (c), (), (a), (
)
and () to (XII) include tautomers.
That is, the formulas in these target compounds and starting compounds

The group represented by [Formula] (in which R ¹ has the same meaning as before) is a tautomer of the formula

It can also be represented by the following formula: (wherein R ^1a means an imino group or a protected imino group). That is, these groups are in a balanced relationship and can be represented by the balanced formula below. (In the formula, R ¹ and R ^1a have the same meanings as before.) The tautomers of the above-mentioned amino compounds and the corresponding imino compounds are well known, and both can be mutually converted to form substantially the same compound. It is also well known to those skilled in the art that it can be treated as In the description and claims of this specification, these target compounds and starting compounds will be conveniently expressed by the formula

[Formula] (in which R ¹ has the same meaning as before) is not limited thereto, and the other tautomer is also included within the scope of the present invention. Salts of the object compound () of this invention include:
For example, alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, salts with inorganic bases such as ammonium salts, trimethylamine salts, triethylamine salts, pyridine salts, picoline salts, and dicyclohexylamine. salts, salts with organic bases such as N,N'-dibenzylethylenediamine salts, salts with organic acids such as acetates, maleates, tartrates, methanesulfonates, benzenesulfonates, toluenesulfonates, etc. , salts with inorganic acids such as hydrochloride, hydrobromide, sulfate, and phosphate, and salts with amino acids such as arginine salt, aspartate, and glutamate. Next, the definition of the above general formula will be explained. As a protecting group for a protected amino group,
Examples include commonly used amino protecting groups such as acyl groups, benzyl groups, etc. as described below. As the acyl moiety in the above acyl group,
Examples include carbamoyl group, thiocarbamoyl group, aliphatic acyl group, acyl group containing an aromatic ring or a heterocycle, and more specifically, formyl, acetyl, propionyl, butyryl, isobutyryl,
Alkanoyl groups such as valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tertiary butoxycarbonyl, pentyloxycarbonyl, tertiary Alkoxycarbonyl groups such as pentyloxycarbonyl and hexyloxycarbonyl, alkanesulfonyl groups such as mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, arenesulfonyl groups such as benzenesulfonyl and toluenesulfonyl, benzoyl, toluoyl, naphthoyl, Examples include aroyl groups such as phthaloyl and indancarbonyl, aralkanoyl groups such as phenylacetyl and phenylpropionyl, and aralkoxycarbonyl groups such as benzyloxycarbonyl and phenethyloxycarbonyl. , iodine, halogens including fluorine, cyano, methyl, ethyl, propyl, isopropyl,
It may have one or more suitable substituents such as alkyl groups such as butyl, alkenyl groups such as vinyl and allyl. Preferred examples of the above-mentioned acyl groups include lower alkylcarbamoyl groups such as carbamoyl, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, and isopropylcarbamoyl, and lower alkylthiocarbamoyl groups such as methylthiocarbamoyl, ethylthiocarbamoyl, propylthiocarbamoyl, and isopropylthiocarbamoyl. group, formyl, acetyl, propionyl,
Lower alkanoyl groups such as butyryl, isobutyryl, valeryl, pivaloyl, trichloroacetyl,
Trihalo lower alkanoyl groups such as trifluoroacetyl, lower groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, tertiary pentyloxycarbonyl, hexyloxycarbonyl, etc. Examples include alkoxycarbonyl groups, lower alkanesulfonyl groups such as mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, and butanesulfonyl, and arenesulfonyl groups such as benzenesulfonyl and toluenesulfonyl. The thiadiazolyl group in the thiadiazolylthio group which may have an alkyl group includes 1,
Examples include 2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, and the like. Examples of the alkyl group in the thiadiazolylthio group which may have an alkyl group include methyl, ethyl, propyl, isopropyl, butyl,
Examples include isobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, etc., but lower alkyl groups such as methyl and ethyl are preferred. Examples of the protected carboxy group include esters, such as methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tertiary butyl ester, pentyl ester, hexyl ester, 1- Alkyl esters such as cyclopropylethyl ester, 2-iodoethyl ester, mono (or di or tri) haloalkyl esters such as 2,2,2-trichloroethyl ester, acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester , valeryloxymethyl ester, pivaloyloxymethyl ester, 2
- alkyl esters with one or more suitable substituents, vinyl esters, such as alkanoyloxyalkyl esters such as acetoxyethyl ester and 2-propionyloxyethyl ester, alkanesulfonylalkyl esters such as mesylmethyl ester and ethanesulfonyl ethyl ester; Alkenyl esters such as allyl esters, alkynyl esters such as ethynyl esters and propynyl esters, benzyl esters, 4-methoxybenzyl esters, 4-nitrobenzyl esters, phenethyl esters, trityl esters, diphenylmethyl esters, bis(methoxyphenyl) aralkyl esters optionally having one or more suitable substituents, such as methyl esters, 3,4-dimethoxybenzyl esters, 4-hydroxy-3,5-ditertiary butylbenzyl esters, phenyl esters, Examples include aryl esters which may have one or more suitable substituents, such as tolyl ester, tertiary butyl phenyl ester, xylyl ester, mesityl ester, cumenyl ester, and the like. Groups that can be converted into the group represented by the formula -R ² ' are:
For example, halogens such as chlorine and bromine, azide groups, formyloxy, acetoxy, propionyloxy,
Examples include acid residues such as alkanoyloxy groups such as butyryloxy, acyloxy groups such as aroyloxy groups such as benzoyloxy and toluoyloxy, and preferably halogen and lower alkanoyloxy groups. Next, a method for producing the object compound of the present invention will be explained. Regarding method 1, the object compound of this invention () or a salt thereof is obtained by reacting the compound () or a reactive derivative thereof at the amino group, or a salt thereof with the compound () or a reactive derivative thereof at the carboxy group, or a salt thereof. Manufactured by Examples of reactive derivatives at the amino group of compound () include Schiff's base (imino type) produced by the reaction of compound () and a carbonyl compound or its enamine type isomer, compound () and bis(trimethylsilyl)acetamide. All those commonly used in amidation reactions are included, such as silyl derivatives produced by reaction with silyl compounds such as, or derivatives produced by reaction of compound () with phosphorus trichloride, phosgene, etc. Further, examples of compound () and salts of compound () include salts at its amino group or carboxy group, and examples of salts at the amino group include acetate, maleate, tartrate,
Examples include salts with organic acids such as benzenesulfonate and toluenesulfonate; salts with inorganic acids such as hydrochloride, hydrobromide, sulfate, and phosphate; Salts include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, salts with inorganic bases such as ammonium salts, and salts with organic bases such as triethylamine salts and dicyclohexylamine salts. Salt is an example. Examples of reactive derivatives at the carboxyl group of compound () include acid halides, acid anhydrides, active amides, and active esters, but particularly frequently used ones include acid chlorides, acid azides, dialkyl phosphoric acid mixtures, etc. Anhydride, phenyl phosphoric acid mixed anhydride, diphenyl phosphoric acid mixed anhydride, dibenzyl phosphoric acid mixed anhydride, halogenated phosphoric acid mixed anhydride, dialkyl phosphorous acid mixed anhydride, sulfurous acid mixed anhydride, thiosulfuric acid mixed anhydride, sulfuric acid mixed anhydride , alkyl carbonic acid mixed anhydrides, aliphatic carboxylic acids (e.g. pivalic acid, pentanoic acid, isopentanoic acid,
Acid anhydrides such as 2-ethylbutanoic acid, trichloroacetic acid) mixed anhydrides, aromatic carboxylic acid (e.g. benzoic acid) mixed anhydrides, symmetrical acid anhydrides, imidazole, 4-substituted imidazole, dimethylpyrazole, triazole, tetrazole, etc. acid amide, cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH ₃ ) ₂ N+=CH
-]Ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-
Dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesyl phenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, Pyridyl ester, piperidyl ester, 8
-quinolylthioester, or N,N-dimethylhydroxylamine, 1-hydroxy-2-
Examples include esters with 1-hydroxybenzotriazoles such as (1H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxybenzotriazole, and 1-hydroxy-6-chlorobenzotriazole. These are appropriately selected depending on the type of compound () used. This reaction usually involves water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate,
The reaction is carried out in a solvent such as dimethylformamide, pyridine, or other general organic solvents that do not adversely affect the reaction. Among these, hydrophilic solvents can also be used in combination with water. When using the compound () in the form of a free acid or its salt in this reaction, for example, N,
N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide, N,
N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide, N-ethyl-N'-(3
-dimethylaminopropyl)carbodiimide,
N,N'-carbonylbis(2-methylimidazole)pentamethyleneketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine, alkoxyacetylene, 1-alkoxy-1-chloroethylene 1-(4-chlorobenzenesulfonyloxy)- Sulfonic acid ester type condensing agents such as 6-chlorobenzotriazole, phosphorous acid trialkyl ester, polyphosphoric acid ethyl ester, polyphosphoric acid isopropyl ester, phosphorous oxychloride, phosphorous trichloride, thionyl chloride, oxalyl chloride, triphenylphosphine, N-Ethylbenzisoxazolium salt, N-ethyl-5-phenylisoxazolium-3'-sulfonate, and other (chloromethylene) dimethylammonium chloride Magazine "Chemistry Domain" Vol. 19 No. 12 No. 12
Advantageously, it is carried out in the presence of a condensing agent such as Vilsmeier's reagent as described on page 26 (1965). In addition, this reaction can be applied to alkali metal hydroxides, alkali metal hydrogen carbonates, alkali metal carbonates, trialkylamines, N,N-dialkylanilines, N,N
The reaction may be carried out in the presence of an organic or inorganic base such as -dialkylbenzylamine, alkali metal alkoxide, or pyridine, and a liquid base or the above-mentioned condensing agent can also be used as a solvent. Although the reaction temperature is not particularly limited, it is usually carried out under cooling or at room temperature. Regarding method 2, the object compound (a) of this invention or its salts is a combination of compound () or its salts and compound ().
Alternatively, it is produced by reacting the mercapto group with a reactive derivative thereof. Examples of the reactive derivative at the mercapto group of the compound () include metal salts such as alkali metal salts such as sodium salts and potassium salts, and alkaline earth metal salts such as magnesium salts. The reaction of compound () with compound () or its reactive derivative at the mercapto group can be carried out using solvents that do not adversely affect this reaction, such as water, acetone, chloroform, nitrobenzene, dimethylformamide, methanol, ethanol, dimethyl sulfoxide, etc. Good results are often obtained when the reaction is carried out in a mixed solvent or a mixed solvent thereof, and good results are often obtained when the reaction is carried out under near-neutral reaction conditions. When compound () and/or compound () are used in the free state, this reaction can be carried out using organic or inorganic compounds such as, for example, alkali metal hydroxides, alkali metal carbonates, alkali metal hydrogen carbonates, trialkylamines, pyridine, etc. It often proceeds advantageously in the presence of a base. The temperature of this reaction is not particularly limited, but it is usually carried out at room temperature to elevated temperature. In this reaction and subsequent treatment, compounds may be obtained in which a protected amino group and/or a protected carboxy group are converted into the corresponding free amino group and/or carboxy group, respectively. These cases are also included within the scope of this invention. Regarding Method 3 The object compound (b) of this invention or its salts is produced by subjecting compound (c) or its salts to an amino-protecting group elimination reaction. Examples of the salts of compound (c) include those exemplified as salts of the carboxy group of compound () in Method 1 above. The amino-protecting group elimination reaction includes all methods commonly used for removing amino-protecting groups, such as hydrolysis and reduction. For example, hydrolysis involves the use of acids,
Methods using bases, hydrazine, etc. are included.
Among these methods, hydrolysis using acids is one of the most common methods, for example, alkoxycarbonyl groups such as tertiary pentyloxycarbonyl groups, substituted alkoxycarbonyl groups, cycloalkoxycarbonyl groups, substituted Alternatively, it can be applied to the removal of groups such as unsubstituted aralkoxycarbonyl groups, aralkyl groups such as trityl, substituted phenylthio groups, substituted alkylidene groups, substituted cycloalkylidene groups, and substituted aralkylidene groups. Examples of acids include organic and inorganic acids such as formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, and hydrochloric acid. Those that can be easily removed by commonly used methods are preferred. These acids are appropriately selected depending on the type of amino protecting group to be removed. When an acid is used in this elimination reaction, the reaction can be carried out either in the absence of a solvent or in the presence of a solvent such as water, an organic solvent, or a mixed solvent thereof. Hydrolysis using hydrazine is applied for example to eliminate groups such as succinyl, phthaloyl, etc. The reductive elimination method is applied, for example, to elimination of groups such as haloalkoxycarbonyl groups such as trichloroethoxycarbonyl, substituted or unsubstituted aralkoxycarbonyl groups such as benzyloxycarbonyl, and pyridylmethoxycarbonyl. Reductive desorption methods include, for example, reduction methods using alkali metal borohydrides such as sodium borohydride, metals such as tin, zinc, and iron, or combinations of these metals with chromium salt compounds such as chromium chloride and chromium acetate. , a reduction method using an organic or inorganic acid such as acetic acid, propionic acid, or hydrochloric acid, and a catalytic reduction method using a commonly used catalyst such as Raney nickel, platinum oxide, or palladium-carbon. When the amino protecting group is an acyl group, these are generally removed by hydrolysis. For example, when the acyl group is a trifluoroacetyl group, it is easily eliminated by simply contacting with water, and when the acyl group is a haloalkoxycarbonyl group, 8-quinolyloxycarbonyl group, etc., copper, zinc It is desorbed by treatment with heavy metals such as In addition, when the amino protecting group is an acyl group,
After acting with an iminohalogenating agent and then an iminoetherifying agent, it is removed by hydrolysis as necessary. Examples of iminohalogenating agents include thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, etc. Examples of iminoetherifying agents include alcohols such as alkanols such as methanol, ethanol, and propanol, or metal alkoxides. Examples include: The reaction temperature in the amino-protecting group elimination reaction is not particularly limited, and is appropriately selected depending on the type of amino-protecting group, the type of elimination method, etc., but it is carried out under mild conditions such as cooling or room temperature. There are many things. In this reaction and subsequent treatments, compounds in which a protected carboxy group is converted into a corresponding free carboxy group may be obtained, and these cases are, of course, included within the scope of the present invention. Regarding method 4, the object compound () or a salt thereof of the present invention is produced by reducing the compound () or a salt thereof. Examples of the salts of the compound () include those exemplified as the salts of the compound () in Method 1 above. The reduction methods used in this reaction include all conventional methods for converting carbonyl groups into hydroxyl groups, such as methods using alkali metal borohydrides such as sodium borohydride, potassium borohydride, etc. Applicable. This reaction is often carried out in, for example, water, methanol, ethanol, tetrahydrofuran, dioxane or other common organic solvents that do not adversely affect the reaction. This reaction can also be carried out using, for example, alkali metals such as sodium and potassium, alkaline earth metals such as magnesium and calcium, inorganic bases such as their hydroxides, carbonates and bicarbonates, trialkylamines such as trimethylamine and triethylamine, Picoline, N-methylpyrrolidine, N-methylphorphorine, 1,5-diazabicyclo[4,3,0]non-5-ene, 1,
4-diazabicyclo[2,2,2]octane,
It can also be carried out in the presence of a base such as an organic base such as 1,8-diazabicyclo[5,4,0]undecene-7. The temperature of this reaction is not particularly limited, but it is often carried out under mild conditions such as cooling or heating. Next, a method for producing the raw material compound will be explained. Manufacturing method (1) The compound () or its salts are the compound ()
or a reactive derivative thereof at the amino group or a salt thereof is produced by reacting the compound () or a reactive derivative at the carboxyl group thereof or a salt thereof. Reactive derivatives at the carboxy group of the compound () and their salts include the compound ()
Examples of the reactive derivatives at the carboxy group of and salts thereof include the same as those mentioned above. The reaction conditions described in Method 1 above can be applied. Production method (2) Compound (a) or a salt thereof is produced by reacting compound () or a salt thereof with compound () or a reactive derivative thereof in a mercapto group. The reaction conditions described in Method 2 above can be applied. Manufacturing method (3) Compound (b) or a salt thereof is a compound (b) or a salt thereof.
c) or a salt thereof to an amino-protecting group elimination reaction. Examples of the salts of compound (c) include those exemplified as salts of the carboxy group of compound () in Method 1 above. The reaction conditions described in Method 3 above can be applied. Manufacturing method (4) The compound () or its salts are the compound ()
or a reactive derivative thereof at the amino group or a salt thereof, and a compound () or a reactive derivative thereof at the carboxy group or a salt thereof. The reaction conditions for producing this compound () are substantially the same as those for producing the compound () described in Method 1 above. That is, the reactive derivatives and salts at the amino group of compound () are the same as those exemplified as the reactive derivatives and salts at the amino group of compound (), and the reaction conditions are also the same as those used in Method 1. It should be the same as the one. Manufacturing method (5) The compound () or a salt thereof of the present invention is produced by combining the compound () or a reactive derivative at its amino group or a salt thereof, and the compound () or a reactive derivative at its carboxyl group or a salt thereof. Manufactured by reaction. The reaction conditions for producing this compound () are substantially the same as those for producing the compound () described in Method 1 above. Production method (6) (a)→Production method of (a) Compound (a) is produced by reducing compound (a). The reaction conditions described in Method 4 above can be applied. Method for producing ()→(XI) Compound (XI) is produced by reacting the corresponding compound () or its reactive derivative at the amino group, or a salt thereof with an amino protecting agent. Examples of the reactive derivatives at the amino group of the compound () and their salts include the same ones as mentioned above as the reactive derivatives at the amino group of the compound () and their salts. Amino protecting agents include, for example, aliphatic, aromatic or heterocyclic carboxylic acids (or sulfonic acids or carbonic esters or carbamic acids) and their corresponding thio acids and reactive derivatives of these acids and aliphatic, aromatic Examples include acylating agents including group or heterocyclic isocyanates (or thioisocyanates),
Examples of the reactive derivative of the acid mentioned above include those similar to those exemplified as the reactive derivative at the carboxy group of compound (). In addition, the above amino protecting agent allows the compound ()
The amino protecting group introduced into the amino group of
As the protecting group for the protected amino group, the same ones as exemplified above can be mentioned. The reaction of this invention is carried out under similar reaction conditions to those described in Method 1 above. Method for producing (XI)→(XII) Compound (XII) can be produced by oxidizing compound (XI). Oxidation methods include methods that use selenium dioxide, such as trivalent manganese acetate [Mn(OAc) ₃ ], manganese dioxide, and manganese compounds such as potassium permanganate, as well as methods that use so-called active methylene groups with carboxylic acid. All methods commonly used for converting into groups are included. This reaction is often carried out in water, dioxane, tetrahydrofuran or other common organic solvents that do not adversely affect the reaction. Although this reaction temperature is not particularly limited, it is often carried out with or under heating. Method for producing (XII)→(a) Compound (a) is produced by subjecting compound (XII) to an elimination reaction of the carboxy protecting group. For this elimination reaction, all methods commonly used for eliminating carboxy protecting groups, such as hydrolysis and reduction, can be applied. The hydrolysis reaction is carried out using, for example, alkali metals such as sodium and potassium, alkaline earth metals such as magnesium and calcium, or their hydroxides, carbonates, bicarbonates, trialkylamines such as trimethylamine and triethylamine, picoline, 1, Organic or inorganic such as 5-diazabicyclo[4,3,0]non-5-ene, 1,4-diazabicyclo[2,2,2]octane, 1,8-diazabicyclo[5,4,0]undecene-7, etc. The reaction often proceeds advantageously in the presence of a base or an organic or inorganic acid such as formic acid, acetic acid, propionic acid, hydrochloric acid, hydrobromic acid, or sulfuric acid. Reduction methods include, for example, reduction using a metal such as zinc or zinc amalgam, or a chromium salt compound such as chromium chloride or chromium acetate, and an organic or inorganic acid such as acetic acid, propionic acid, or hydrochloric acid, platinum wire, or platinum sponge. , platinum catalyst such as platinum black, colloidal platinum, palladium sponge, palladium black, palladium oxide, palladium-barium sulfate, palladium-barium carbonate, palladium-carbon, palladium-silica gel, palladium catalyst such as colloidal palladium, reduced nickel, nickel oxide Examples include reduction methods using commonly used catalysts such as nickel catalysts such as nickel, Raney nickel, and urushibara nickel. The temperature for this elimination reaction is not particularly limited, and is appropriately selected depending on the type of carboxy protecting group, the type of elimination method, etc. The above-mentioned tautomers in this invention may mutually change into different isomers during the reaction of each step and/or during post-treatment of those reactions, but of course, these cases also fall within the scope of this invention. included in. In this invention, the target compound () is obtained in a free state, such as when it has a free carboxy group at the 4-position or (and) a free amino group in the substituent at the 7-position. In such cases, salts such as those described above may be obtained by conventional methods, if necessary. The object compound of this invention () and its salts are all new compounds and are useful as antibacterial substances. When the object compound () of this invention is used as a medicine, it may be used in the form of a pharmaceutically acceptable salt. The object compounds of this invention () and pharmaceutically acceptable salts are administered in the form of compositions containing effective and non-toxic amounts thereof. The composition is used in a dosage form suitable for oral or parenteral administration, together with inorganic or organic, solid or liquid pharmaceutical carriers commonly used in pharmaceutical formulations. In this case, oral preparations include solid preparations such as tablets, capsules, troches, and powders, and liquid preparations such as syrups, and non-performing preparations include injections,
Examples include suppositories. These various formulations can be manufactured by methods well known in the art. Next, the present invention will be explained with reference to examples. Production of raw material compounds (1) (a) 2-(2-amino-1,3-thiazol-4-yl)acetic acid ethyl ester (14 g) was mixed with pyridine (40 g) and methylene chloride (300 g).
ml) of chromic acid tertiary
A diethyl ether solution (70 ml) containing a pentyl ester (0.35 mol) was added to the mixture over 10 minutes while cooling to -20°C with stirring, and after stirring at the same temperature for 2 hours, the mixture was further stirred at 0°C for 30 minutes. After the reaction, the reaction mixture was poured into water (200ml),
Separate the organic layer. The organic layer was treated with 2N hydrochloric acid, water,
After washing with a 5% aqueous sodium bicarbonate solution and then water, and drying over magnesium sulfate, the solvent was distilled off to give a dark and colored oily 2-(2-3).
pentyloxycarbonylamino-1,3
-thiazol-4-yl)acetic acid ethyl ester (12 g) is obtained. IR (liquid film): 1667, 1660 (CO) cm ^-1 NMR δCDCl ₃ ppm: 3.75 (2H, s), 6.75 (1H,
s) (b) In a solution of selenium dioxide (0.11 g) in dioxane (2.5 ml) and water (0.1 ml),
2-(2-tertiary pentyloxycarbonylamino-1,3-thiazol-4-yl)acetic acid ethyl ester (0.3 g) and dioxane (2.5 ml) were added to 110°C with stirring,
Stir at the same temperature for 30 minutes. Furthermore, selenium dioxide (0.055g) was added to the reaction solution, and at the same temperature
Stir for 1.5 hours. After the reaction, the reaction solution is separated by decantation, the residue is washed with a small amount of dioxane, the two solutions are combined, and the solvent is distilled off. The residue was dissolved in ethyl acetate, washed with water, and the solvent was distilled off to give a colored oily 2-(2-tertiary pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylic acid ethyl ester (0.22 g) is obtained. IR (liquid film): 1720, 1690 (CO) cm ^-1 NMR δCDCl ₃ ppm: 8.3 (1H, s) (c) 2-(2-tertiary pentyloxycarbonylamino-1,3-thiazole-4- )
A mixture of glyoxylic acid ethyl ester (2.8 g) and ethanol (10 ml) is mixed with a solution of sodium hydroxide (0.54 g) in water (20 ml) and stirred at room temperature for 1 hour. A small amount of ethanol is distilled off from the reaction solution, the residue is washed with diethyl ether, and the aqueous layer is separated. Add ethyl acetate to the aqueous layer and PH with 10% hydrochloric acid.
After adjusting to 1 to 2, the ethyl acetate layer was separated. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, treated with activated carbon, and the solvent was distilled off to give 2-(2-tertiary pentyloxycarbonylamino-1, 3-thiazol-4-yl)
Obtain glyoxylic acid (1.75 g). IR (Nudiyol): 1730, 1680 (CO) cm ^-1 NMR δd ₆ -dimethylsulfoxide ppm: 8.4
(1H,s) (2) 2-(2-tertiary pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylic acid (1.7 g), sodium hydrogen carbonate (0.5 g), ethanol (10 ml), and Water (10ml)
Sodium borohydride (0.23
g) was added while stirring on ice, and the mixture was stirred at the same temperature for 1 hour. After the reaction, the reaction solution is slightly concentrated and the residue is
After adding 1N aqueous sodium hydroxide solution (6 ml) and diethyl ether (20 ml), the aqueous layer is separated. Add ethyl acetate to the aqueous layer and add 10% hydrochloric acid.
After adjusting the pH to 1-2, separate the ethyl acetate layer.
The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, treated with activated carbon, and then the solvent was distilled off to give 2-hydroxy-2-(2-tertiary pentyloxycarbonylamino-1 , 3-thiazol-4-yl)acetic acid (1.5 g) is obtained. IR (Nujiol): 1690−1740 (CO) cm ^-1 NMR δd ₆ -dimethylsulfoxide ppm: 5.0
(1H, s), 7.05 (1H, s) (3) (a) Acetic anhydride (384ml), sulfuric acid (169.2ml)
was added dropwise over 15 to 20 minutes while cooling to below 35°C, and then stirred at 55 to 60°C for 1 hour. Next, to this was added 2-(2-amino-1,3-thiazol-4-yl)acetic acid ethyl ester (506 g).
was added over 15 to 20 minutes while stirring on ice, and then stirred at the same temperature for 1 hour. After the reaction, the solvent was distilled off, diisopropyl ether (2500 ml) was added to the residue, and the mixture was stirred at room temperature for 1 hour. The precipitate was collected, washed with diisopropyl ether, and dried at mp125-126°C.
-(2-formylamino-1,3-thiazol-4-yl)acetic acid ethyl ester (451.6
g) is obtained. On the other hand, the remaining liquid was concentrated, and the residue was washed with diisopropyl ether (500 ml) and dried to further obtain the same objective compound (78.5 g). IR (nujiol): 1737, 1700cm ^-1 NMR δCDCl ₃ ppm: 1.25 (3H, t, J = 8Hz),
3.7 (2H, s), 4.18 (2H, q, J=8Hz),
6.9 (1H, s), 8.7 (1H, s) (b)-(i) A solution obtained by heating a mixture of selenium dioxide (186.5 g), dioxane (3.75) and water (75 ml) to reflux. ,2
-(2-formylamino-1,3-thiazol-4-yl)acetic acid ethyl ester (250 g) was added, and the mixture was heated to reflux with stirring for 5 hours. After the reaction, the reaction solution was filtered, the solution was left at room temperature overnight, and after cooling, the precipitate was collected and washed with dioxane and methanol to give 2-(2-formylamino-1,3
-thiazol-4-yl)glyoxylic acid ethyl ester (84.5 g) is obtained. Further, the solvent was distilled off from the mother liquor, the residue was washed with methanol, and the same target compound (56.0
g) is obtained. IR (Nujiol): 1738, 1653 cm ^-1 NMR δd ₆ -dimethylsulfoxide ppm: 1.34
(3H, t, J = 8Hz), 4.38 (2H, q, J
=8Hz), 8.52 (1H, s), 8.57 (1H, s) (b)-(ii) Manganese acetate. A mixture of tetrahydrate (120 g), acetic acid (1000 ml) and acetic anhydride (100 ml) was stirred in an oil bath at 130-135°C for 20 minutes, and then potassium permanganate (20 g) was added to this at 105-110°C. The mixture was added to the solution over a period of 5 minutes under heating and stirring, and then stirred at 130 to 135°C for 30 minutes. Then cool it to room temperature,
After adding 2-(2-formylamino-1,3-thiazol-4-yl)acetic acid ethyl ester (53.5 g), stir at 38-40°C for 15 hours while introducing air at a rate of 6000 ml/min. . After the reaction, the precipitate was collected, washed with acetic acid and then with water, and dried.
2-(2-formylamino-1,3-thiazol-4-yl)glyoxylic acid ethyl ester (41.5 g) is obtained at 233°C (decomposed). (c) Add 1N aqueous sodium hydroxide solution (2.23) to a solution of 2-(2-formylamino-1,3-thiazol-4-yl)glyoxylic acid ethyl ester (281 g) in water (1.1).
Add to the mixture under ice-cooling and stirring at 10-15°C for 5 minutes. After the reaction, filter the reaction solution and adjust the pH of the solution to 1 with concentrated hydrochloric acid. When the precipitate is removed, washed with water and dried, it has a temperature of mp133-136℃ (decomposition).
-(2-formylamino-1,3-thiazol-4-yl)glyoxylic acid (234 g) is obtained. NMR δNaDCO ₃ ppm: 8.27 (1H, s), 8.6 (1H,
s) (4) To a suspension of 2-(2-formylamino-1,3-thiazol-4-yl)glyoxylic acid (20 g) in water (400 ml), add sodium hydrogen carbonate (8.4 g) on ice. After stirring for 10 minutes at the same temperature, diethyl ether (10 ml) is added.
Next, add sodium borohydride (1.52
g) was added over 10 minutes while stirring at the same temperature, and then stirred at the same temperature for 1 hour and 50 minutes. After the reaction,
Filter the reaction solution, adjust the pH to 4.0 with 10% hydrochloric acid, and concentrate under reduced pressure until the volume reaches 100 ml. Adjust the pH of the concentrated liquid to 1 with 10% hydrochloric acid and strain to precipitate crystals. This was then stirred at room temperature for 1 hour and then left in an ice chamber overnight. Remove the precipitate, wash it twice with ice water, and dry it by suction.
2-Hydroxy-2 at mp188-189℃ (decomposition)
-(2-formylamino-1,3-thiazol-4-yl)acetic acid (14.8 g) is obtained. IR (nujiol): 1730, 1635 cm ^-1 NMR δNaDCO ₃ ppm: 5.07 (1H, s), 7.15 (1H,
s), 8.5(1H,s) (5) (a) 2-(2-amino-1,3-thiazol-4-yl)acetic acid methyl ester (100g)
When processed in the same manner as in (3)(a) above, mp154~
2-(2-formylamino-1,3-
Thiazol-4-yl)acetic acid methyl ester (109.9 g) is obtained. IR (Nudiyol): 1733, 1680cm ^-1 NMR δd ₆ -dimethylsulfoxide ppm: 3.72
(3H, s), 3・89 (2H, s), 7.01 (1H,
s), 8.45 (1H, s) (b) 2-(2-formylamino-1,3-thiazol-4-yl)acetic acid methyl ester (60
When g) is processed in the same manner as (3)(b)-(ii) above,
2-(2-formylamino-1,3-thiazol-4-yl)glyoxylic acid methyl ester (27.1 g) is obtained, mp223-225°C (decomposition). NMR _δd6 -dimethylsulfoxide ppm: 3.95
(3H, s), 8.2 (1H, s), 8.3 (1H, s) (c) 2-(2-formylamino-1,3-thiazol-4-yl)glyoxylic acid methyl ester in the above (3)( When processed in the same way as c),
2-(2-formylamino-1,3-thiazol-4-yl)glyoxylic acid of mp 133-136°C (decomposition) is obtained. (6) Phosphorous oxychloride (2.36 g) was added dropwise to dimethylformamide (2.25 g) under ice-cooling and stirring, and the mixture was heated to 40°C.
After stirring for 30 minutes, ethyl acetate (50 ml) was added thereto and the mixture was cooled to -20°C. Next, add 2-(2
-Tertiary pentyloxycarbonylamino-
1,3-thiazol-4-yl)glyoxylic acid (4 g) was gradually added over 5 minutes while stirring and cooling at -20 to -10°C, followed by stirring at the same temperature for 40 minutes. The mixture thus obtained was mixed with 3-(5-
Methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-amino-3-cephem-
4-carboxylic acid (5.3 g), bis(trimethylsilyl)acetamide (15.4 ml) and ethyl acetate (100 ml) were stirred at room temperature for 30 minutes and then cooled to -40°C. After stirring for a minute, the mixture is further stirred at -5 to 0°C for 30 minutes. The reaction mixture was poured into a 5% aqueous sodium hydrogen carbonate solution, the aqueous layer was separated, and the remaining ethyl acetate layer was diluted with a 5% aqueous sodium hydrogen carbonate solution.
Extract times. The aqueous layers thus obtained were combined, washed with ethyl acetate, ethyl acetate (100 ml) was added, and the pH value of the aqueous layer was adjusted to 2 with 10% hydrochloric acid while stirring under ice cooling. After filtering, separate the ethyl acetate layer, extract the remaining aqueous layer twice with ethyl acetate, and then combine the ethyl acetate layers. The ethyl acetate layer is washed with a saturated aqueous sodium chloride solution and then with water, dried over magnesium sulfate, and then the solvent is distilled off. The residue was triturated in diethyl ether, taken up, washed with diethyl ether and dried to give 3-
(5-methyl-1,3,4-thiadiazole-
2-yl)thiomethyl-7-[2-(2-tertiary pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylamide]-
3-cephem-4-carboxylic acid (3.79 g) is obtained. IR (Nudiyol): 1782 (β-lactam) cm ^-1 NMR δd ₆ -dimethylsulfoxide ppm: 2.7
(3H, s), 3.57−3.85 (2H, broad s),
4.2, 4.57 (2H, ABq, J=14Hz), 5.2
(1H, d, J = 5Hz), 5.77 (1H, d, J
= 5 Hz), 8.4 (1 H, s) (7) Phosphorous oxychloride (2.36 g) was added dropwise to dimethylformamide (2.24 g) under ice-cooling and stirring, and the mixture was heated at 40°C.
After stirring for 30 minutes, ethyl acetate (40 ml) was added thereto, and the mixture was cooled to -20 to -15°C while stirring. Next, 2-(2-tertiary pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylic acid (4 g) was added to the mixture at the same temperature, and the mixture was stirred at the same temperature for 30 minutes. The mixture thus obtained was mixed with bis(trimethylsilyl)acetamide (15 ml), 3-(1,3,4-thiadiazol-2-yl)thiomethyl-7-amino-3-
Cefem-4-carboxylic acid (6.35 g) and ethyl acetate (50 ml) were stirred at room temperature for 10 minutes, dimethylformamide (6 ml) was added and the mixture was stirred.
Add to the solution obtained by cooling to 40°C, stir at the same temperature for 30 minutes, and then add to the solution at -20°C for 30 minutes.
Stir for a minute. The reaction mixture was poured into a 5% aqueous sodium hydrogen carbonate solution, the aqueous layer was separated, and the precipitate was collected after washing with ethyl acetate. The sample is washed with a mixture of acetone and water, the washings are extracted with ethyl acetate, and the extract is washed with an aqueous sodium chloride solution and then with water. On the other hand, after removing the precipitate, ethyl acetate is added to the solution to adjust the pH to 1 to 2, and then the ethyl acetate layer is separated. The ethyl acetate layer thus obtained is combined with the ethyl acetate extract obtained previously, washed with water, dried over magnesium sulfate, treated with activated carbon, and then the solvent is distilled off. The residue was triturated in diethyl ether, taken up and dried to give a yellow colored powder of 3-(1,3,4-thiadiazol-2-yl)thiomethyl-7-
[2-(2-tertiary pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylamide]-3-cephem-4-carboxylic acid (3.2 g) is obtained. NMR δd ₆ -dimethylsulfoxide ppm: 3.57,
3.87 (2H, ABq, J=15Hz), 3.67, 4.27
(2H, ABq, J=16Hz), 5.17 (1H, d,
J = 5Hz), 5.77 (1H, d, J = 5Hz),
8.33 (1H, s), 9.53 (1H, s) (8) Phosphorous oxychloride (10.3 g) was added dropwise to dimethylformamide (9 g) over 20 minutes while stirring on ice, and the mixture was stirred at 40°C for 30 minutes. After that, ethyl acetate (140 ml) was added thereto, and the mixture was cooled to -20°C while stirring.
Then, to this, 2-(2-tertiary pentyloxycarbonylamino-1,3-thiazole-4
-yl) glyoxylic acid (16 g) was added;
Stir for 30 minutes at -20 to -15°C. The mixture thus obtained was stirred with 7-aminocephalosporanic acid (18.2 g), bis(trimethylsilyl)acetamide (56 ml) and ethyl acetate (220 ml) at room temperature for 30 minutes and then cooled to -40°C. Add to the solution in one portion and stir for 1 hour at -50 to -40°C and 1 hour at -25 to -20°C, respectively. After the reaction, the reaction mixture was poured into a 5% aqueous sodium hydrogen carbonate solution (800 ml) and the aqueous layer was separated. The aqueous layer was adjusted to pH 2 with 10% hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulfate, treated with activated carbon, and the solvent is distilled off. The residue was powdered in a mixture of diethyl ether (100 ml) and diisopropyl ether (200 ml), taken and dried to give powdered 7-
[2-(2-tertiary pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylamide]cephalosporanic acid (23.1g)
get. IR (Nudiyol): 1783 (β-lactam) cm ^-1 NMR δd ₆ -dimethylsulfoxide ppm: 2.17
(3H, s), 3.4-3.9 (2H, m), 4.8, 5.17
(2H, ABq, J=13Hz), 5.25 (1H, d,
J=5Hz), 5.9 (1H, d, J=5Hz), 8.45
(1H, s) The following compound is obtained in the same manner. 7-[2-(2-formylamino-1,3-
Thiazol-4-yl)glyoxylamide]cephalosporanic acid, mp 145°C. IR (Nudiyol): 1780 (β-lactam) cm ^-1 3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-
(2-formylamino-1,3-thiazol-4-yl)glyoxylamide]-3-cephem-4-carboxylic acid. IR (Nudiyol): 1780 (β-lactam) cm ^-1 3-(1,3,4-thiazol-2-yl)
Thiomethyl-7-[2-(2-formylamino-1,3-thiazol-4-yl)glyoxylamide]-3-cephem-4-carboxylic acid. IR (Nudiyol): 1775 (β-lactam) cm ^-1 3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-
(2-amino-1,3-thiazol-4-yl)glyoxylamide]-3-cephem-
4-carboxylic acid, mp 156-160°C (decomposed). 3-(1,3,4-thiadiazole-2-
yl)thiomethyl-7-[2-(2-amino-
1,3-thiazol-4-yl)glyoxylamide]-3-cephem-4-carboxylic acid hydrochloride, powder. IR (Nudiyol): 1778 (β-lactam) cm ^-1 (9) 7-[2-(2-tertiary pentyloxycarbonylamino-1,3-thiazol-4-yl)
Glyoxylamide] To a solution of cephalosporanic acid (5.4 g) in methanol (54 ml), add 1N aqueous sodium hydroxide solution (54 ml) for 10 minutes.
After cooling to ~15°C, a solution of sodium borohydride (142.2 mg) in water (3.5 ml) was added dropwise at the same temperature over 30 minutes.
Stir for 15 minutes at the same temperature. After the reaction, the reaction mixture was concentrated under reduced pressure at 30-35°C, and the residue was worked up in the same manner as in Example 3 below to obtain powdered 7-
[2-hydroxy-2-(2-tertiary pentyloxycarbonylamino-1,3-thiazole-
4-yl)acetamido]cephalosporanic acid (4.2 g) is obtained. IR (Nudiyol): 1783 (β-lactam) cm ^-1 NMR δd ₆ -dimethylsulfoxide ppm: 2.07
(3H, s), 4.7, 5.07 (2H, ABq, J=14
Hz), 5.08 (1H, s), 5.13 (1H, d, J=
5Hz), 5.53-5.95 (1H, m), 7.03 (1H,
s) (10) 3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-(2-
tertiary pentyloxycarbonylamino-1,
3-thiazol-4-yl)glyoxylamide]-3-cephem-4-carboxylic acid (8.56 g)
A solution of sulfuric acid (180 ml) was stirred at room temperature for 5.5 hours. After the reaction, the reaction solution was transferred to Example 4 below.
After treatment in the same manner as -5, 3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-(2-amino-1,3-thiazol-4-yl) glyoxylamide]-
3-cephem-4-carboxylic acid (2.6 g) is obtained. mp156−160℃ (decomposition). The following compound is obtained in the same manner. 3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-
(2-amino-1,3-thiazol-4-yl)glyoxylamide]-3-cephem-
4-Carboxylic hydrochloride, powder. IR (Nudiyol): 1760-1780 (broad, β-lactam) cm ^-1 3-(1,3,4-thiadiazole-2-
yl)thiomethyl-7-[2-(2-amino-
1,3-thiazol-4-yl)glyoxylamide]-3-cephem-4-carboxylic hydrochloride, powder. IR (Nudiyol): 1778 (β-lactam) cm ^-1 Example 1 Phosphorous oxychloride (0.794 g) was added dropwise to dimethylformamide (5 ml) under ice-cooling and stirring, and after stirring at 40°C for 30 minutes, the temperature was reduced to -20°C. Cooling. This was then added to 2-hydroxy-2-(2-formylamino-1,3-
-20 thiazol-4-yl)acetic acid (0.505g)
-20 to -10℃ after gradual addition under cooling to 45℃
Stir for a minute. The mixture thus obtained was mixed with 3-
(1,3,4-thiadiazol-2-yl)thiomethyl-7-amino-3-cephem-4-carboxylic acid (0.937g), bis(trimethylsilyl)acetamide (2.5ml) and methylene chloride (15ml)
was stirred at room temperature for 2 hours, then at 35-40°C for 2 hours, and then cooled to -30°C. to remove. The residue was purified by conventional methods to yield 3-(1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-formylamino-1,3-thiazol-4-yl). ) Acetamide]-3-cephem-4-carboxylic acid (0.491 g) is obtained. IR (Nudiyol): 1778 (β-lactam) cm ⁻¹ The following compound is obtained in the same manner. (1) 3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-amino-1,3-thiazol-4-yl)acetamide] -3-Cefem-4-carboxylic acid, pale yellow powder. (2) 3-(1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-
(2-amino-1,3-thiazol-4-yl)
Acetamide]-3-cephem-4-carboxylic acid, pale and colored powder, mp 151-180°C (decomposition). Example 2 3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-(2-tertiary
-3
-To a solution of cefem-4-carboxylic acid (3.36 g) in methanol (35 ml), 1N aqueous sodium hydroxide solution (5.5 ml) was added under ice cooling, and then to this was added sodium borohydride (91 mg). A solution of 2.5ml in water was added dropwise at 10-15°C over 2 minutes. After stirring the mixture at the same temperature for 10 minutes,
Methanol is distilled off at a temperature below 40°C under reduced pressure. The remaining aqueous layer is washed with a small amount of ethyl acetate, adjusted to pH 5-6 with 10% hydrochloric acid, and further washed with a small amount of ethyl acetate. Then, after adjusting the pH to 2 with 10% hydrochloric acid,
Extract with ethyl acetate. The extract is washed with water and then with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, treated with activated carbon, and the solvent is distilled off to a small amount. The precipitate was collected by filtration, washed with a small amount of ethyl acetate, and dried to give 3-(5-methyl-1,
3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-tertiarypentyloxycarbonylamino-1,3-thiazol-4-yl)acetamide]-3-cephem-4
-Carboxylic acid (1.69 g) is obtained. On the other hand, the mother liquor and the ethyl acetate washings were combined, concentrated under reduced pressure, and the precipitate was treated in the same manner as above to further obtain the same objective compound (0.80 g). IR (Nudiyol): 1785 (β-lactam) cm ^-1 NMR δd ₆ -dimethylsulfoxide ppm: 2.67
(3H, s), 3.55−3.83 (2H, broad s),
4.25, 4.53 (2H, ABq, J=14Hz), 5.1
(1H, s), 5.13 (1H, d), 5.7 (1H, d),
7.05 (1H, s) Example 3 3-(1,3,4-thiadiazol-2-yl)
Thiomethyl-7-[2-(2-tertiary pentyloxycarbonylamino-1,3-thiazole-4-
glyoxylamide]-3-cephem-4
-To a solution of carboxylic acid (3.1 g) in methanol (30 ml), add 1N aqueous sodium hydroxide solution (5.2
ml) was added under ice-cooling and stirring, and then a solution of sodium borohydride (0.074 g) in water (2 ml) was added dropwise over 10 minutes, and then stirred at the same temperature for 30 minutes.
Stir for a minute. After the reaction, the reaction mixture is concentrated under reduced pressure, water and ethyl acetate are added to the residue, and the aqueous layer is separated. The aqueous layer is adjusted to pH 5-6 with 10% hydrochloric acid and washed with ethyl acetate. Add ethyl acetate to the aqueous layer, adjust the pH to 1-2 with 10% hydrochloric acid, and separate the ethyl acetate layer. The ethyl acetate layer is washed with water, dried over magnesium sulfate, treated with activated carbon, and then the solvent is distilled off. The residue was triturated in diethyl ether, filtered, and dried to give 3-(1,3,
4-thiadiazol-2-yl)thiomethyl-7
-[2-Hydroxy-2-(2-tertiarypentyloxycarbonylamino-1,3-thiazole-4
-yl)acetamido]-3-cephem-4-carboxylic acid (2.2 g) is obtained. NMR δd ₆ -dimethylsulfoxide ppm: 3.53,
3.8 (2H, ABq, J=17Hz), 4.33, 4.7
(2H, ABq, J=13Hz), 5.0 (1H, s),
5.15 (1H, d, J = 4Hz), 5.6 (1H, d,
J=4Hz), 7.0 (1H, s), 9.43 (1H, s) The following compound is obtained in the same manner. (1) 3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-amino-1,3-thiazol-4-yl)acetamide] -3-Cefem-4-carboxylic acid, pale yellow powder. (2) 3-(1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-
(2-amino-1,3-thiazol-4-yl)
Acetamide]-3-cephem-4-carboxylic acid, pale and colored powder, mp 151-180°C (decomposition). (3) 3-(1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-
(2-formylamino-1,3-thiazole-
4-yl)acetamido]-3-cephem-4
-Carboxylic acid. IR (Nudiyol): 1778 (β-lactam) cm ⁻¹ Example 4 3-(5-Methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2- tertiarypentyloxycarbonylamino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (2.30
g) in 98% sulfuric acid (25 ml) at room temperature.
Stir for 2.5 hours. After the reaction, the acidic acid is distilled off under reduced pressure. The residue was powdered with acetonitrile (25 ml), collected by filtration, washed with a small amount of acetonitrile, and then dissolved in a 5% aqueous sodium bicarbonate solution (14 ml). This solution was brought to pH 6 with acetic acid, then the pH
Subject to alumina column chromatography using 5.0 acetate buffer as the elution solvent. The eluate (300 ml) containing the target compound is adjusted to pH 3 with 10% hydrochloric acid and washed twice with ethyl acetate (50 ml). The aqueous layer was subjected to column chromatography using Amberlite XAD-4 (manufactured by Rohm and Haas), and after washing the column with water, 20% methanol aqueous solution (100 ml), 50% methanol aqueous solution (100 ml), 70% methanol Elute in order of aqueous solution (400ml). The eluate (500 ml) containing the target compound was collected and diluted with methanol under reduced pressure for 30-30 min.
Distill at 35°C. When the remaining aqueous solution is freeze-dried, a pale yellow powder of 3-(5-methyl-1,3,4
-thiadiazol-2-yl)thiomethyl-7-
[2-Hydroxy-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (0.60 g) is obtained. IR (Nujiol): 1770 (β-lactam) cm ^-1 NMR δNaDCO ₃ ppm: 2.75 (3H, s), 3.4, 3.75
(2H, ABq, J=14Hz), 4.0, 4.52 (2H,
ABq, J = 14Hz), 5.15 (1H, d, J = 5
Hz), 5.2 (1H, s), 5.7 (1H, m), 6.76
(1/2H, s), 6.9 (1/2H, s) Example 5 3-(1,3,4-thiadiazol-2-yl)
Thiomethyl-7-[2-hydroxy-2-(2-tertiary pentyloxycarbonylamino-1,3-
thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (2.1 g) and 98-100
% acidic acid (40 ml) is stirred at room temperature for 2.5 hours. After the reaction, the reaction solution is concentrated under reduced pressure. The residue was triturated with acetonitrile, and the powder was collected by filtration and washed with ether to obtain a brown powder (1.3 g).
Dissolve this in a 5% aqueous sodium hydrogen carbonate solution (20 ml) and adjust the pH to 6 with acetic acid. This mixture is subjected to neutral alumina column chromatography using PH5.0 acetate buffer as an elution solvent. The eluate (230 ml) containing the target compound is collected, adjusted to pH 2.8-3.0 with 10% hydrochloric acid, and washed with ethyl acetate. Ethyl acetate in the aqueous layer is distilled off under reduced pressure. The remaining aqueous layer was subjected to column chromatography using Amberlite XAD-4 (manufactured by Rohm and Haas). After washing the column with water, 20% methanol aqueous solution (80 ml), 50% methanol aqueous solution (80 ml), 70% methanol aqueous solution (80 ml), % methanol aqueous solution (300ml). The eluate containing the target compound is collected, and methanol is distilled off under reduced pressure. When the remaining aqueous solution is freeze-dried, a light brown powder of 3-
(1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-amino-1,3-thiazol-4-yl)acetamide]-3-cephem-4-carboxylic acid (0.40g)
get. mp151−180℃ (decomposition). IR (nujiyor): 1770, 1680, 1620, 1520cm
^-1 NMR δd ₆ -dimethylsulfoxide ppm: 3.68
(2H, m), 4.43, (2H, dd, J=12.8,
22.6Hz), 4.87 (1H, broad s), 5.11 (1H,
d, J=5.0Hz), 5.2-6.1 (3H, m), 6.43
(1H, s), 9.57 (1H, s)

Claims (1)

[Claims] 1. General formula (In the formula, R ¹ means an amino group or a protected amino group, R ² means a thiadiazolylthio group which may have an alkyl group, and R ³ means a carboxy group or a protected carboxy group.) 3,7-disubstituted-3-cephem-4-
Carboxylic acid compounds and their salts.